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Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update

Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update Hepatol Int (2016) 10:1–98 DOI 10.1007/s12072-015-9675-4 GU IDELINES Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update 1 1 2,27 3 4 • • • • • S. K. Sarin M. Kumar G. K. Lau Z. Abbas H. L. Y. Chan 5 6 7 8 9 • • • • • C. J. Chen D. S. Chen H. L. Chen P. J. Chen R. N. Chien 10 11 12 13 14 15 • • • • • • A. K. Dokmeci Ed Gane J. L. Hou W. Jafri J. Jia J. H. Kim 16 17 18 7 19 • • • • • C. L. Lai H. C. Lee S. G. Lim C. J. Liu S. Locarnini 20 21 22 23 24 • • • • • M. Al Mahtab R. Mohamed M. Omata J. Park T. Piratvisuth 25 26 28 29 30 • • • • • B. C. Sharma J. Sollano F. S. Wang L. Wei M. F. Yuen 31 32 S. S. Zheng J. H. Kao Received: 20 May 2015 / Accepted: 14 September 2015 / Published online: 13 November 2015 The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Worldwide, some 240 million people have update the recommendations for the optimal management chronic hepatitis B virus (HBV), with the highest rates of of chronic HBV infection. The 2015 guidelines were infection in Africa and Asia. Our understanding of the developed by a panel of Asian experts chosen by the natural history of HBV infection and the potential for APASL. The clinical practice guidelines are based on therapy of the resultant disease is continuously improving. evidence from existing publications or, if evidence was New data have become available since the previous unavailable, on the experts’ personal experience and APASL guidelines for management of HBV infection were opinion after deliberations. Manuscripts and abstracts of published in 2012. The objective of this manuscript is to important meetings published through January 2015 have & S. K. Sarin Department of Infectious Diseases and Hepatology Unit, shivsarin@gmail.com Nanfang Hospital, Guangzhou, China Department of Medicine, Aga Khan University, Karachi, Department of Hepatology, Institute of Liver and Biliary Pakistan Sciences, New Delhi, India Beijing Friendship Hospital, Capital Medical University, Division of Gastroenterology and Hepatology, Humanity and Beijing, China Health Medical Centre, Hong Kong SAR, China Seoul, Korea Department of Hepatogastroenterlogy, Sindh Institute of Urology and Transplantation, Karachi, Pakistan Department of Medicine, University of Hong Kong, Hong Kong, China Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China Internal Medicine Asan Medical Center, Seoul, Korea 5 18 Genomics Research Center, Academia Sinica, National Division of Gastroenterology and Hepatology, National Taiwan University, Taipei, Taiwan University Health System, Singapore, Singapore 6 19 Department of Internal Medicine, National Taiwan Research and Molecular Development, Victorian Infectious University College of Medicine, Taipei, Taiwan Diseases Reference Laboratory, Melbourne, Australia 7 20 Graduate Institute of Clinical Medicine, National Taiwan Bangabandhu Sheikh Mujib Medical University, Dhaka, University College of Medicine, Taipei, Taiwan Bangladesh Department of Internal Medicine, National Taiwan Department of Medicine, Faculty of Medicine, University University Hospital, Taipei, Taiwan Malaya, Kuala Lumpur, Malaysia Liver Research Unit, Chang Gung Memorial Hospital and Yamanashi Hospitals (Central and Kita) Organization, 1-1-1 University, Chilung, Taiwan Fujimi, Kofu-shi, Yamanashi 400-8506, Japan Department of Gastroenterology, Ankara University School Department of Internal Medicine, Institute of of Medicine, Ankara, Turkey Gastroenterology, Yonsei University College of Medicine, Seoul, Korea New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand 123 2 Hepatol Int (2016) 10:1–98 been evaluated. This guideline covers the full spectrum of according to the Grading of Recommendations Assessment care of patients infected with hepatitis B, including new Development and Evaluation (GRADE) system (Table 1). terminology, natural history, screening, vaccination, The strength of recommendations reflects the quality of the counseling, diagnosis, assessment of the stage of liver underlying evidence, which has been classified into one of disease, the indications, timing, choice and duration of three levels, according to the GRADE system: high (A), single or combination of antiviral drugs, screening for moderate (B) or low (C). The GRADE system offers two HCC, management in special situations like childhood, grades of recommendation: strong (1) and weak (2) [1, 2] pregnancy, coinfections, renal impairment and pre- and (Table 1). Thus, the higher the quality of evidence, the more post-liver transplant, and policy guidelines. However, areas likely a strong recommendation is warranted; the greater the of uncertainty still exist, and clinicians, patients, and public variability in values and preferences, or the greater the health authorities must therefore continue to make choices uncertainty, the more likely a weaker recommendation is on the basis of the evolving evidence. The final clinical warranted. Grades are not provided for definitions. practice guidelines and recommendations are presented here, along with the relevant background information. 1 Introduction Keywords HBV  Guidelines  Acute hepatitis An estimated 240 million persons worldwide are chroni- cally infected with hepatitis B virus (HBV) [3], placing Methodology of guideline development them at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). These APASL clinical practice guidelines represent an Although most chronically HBV-infected subjects will not update of the last APASL guidelines published in 2012. develop hepatic complications, 15–40 % will develop The 2015 guidelines were developed by a panel of Asian serious sequelae during their lifetime. experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publica- Why this update was needed? tions or, if evidence was unavailable, on the experts’ per- sonal experience and opinion after deliberations. New data have become available since the previous Manuscripts and abstracts of important meetings published APASL guidelines for management of HBV infection were through January 2015 have been evaluated. The evidence published in 2012. These new data and information relate and recommendations in these guidelines have been graded to new terminology, natural history of hepatitis B, diag- nosis, assessment of the stage of liver disease using inva- sive and noninvasive methods, and the indications, timing, NKC Institute of Gastroenterology and Hepatology, Prince of choice and duration of treatments in noncirrhotic and cir- Songkla University, Songkhla, Thailand rhotic patients and in special situations like childhood, Department of Gastroenterology, G.B. Pant Hospital, pregnancy, coinfections, renal impairment and pre- and New Delhi, India post-liver transplant. In the current guidelines, policy rec- Department of Medicine, University of Santo Tomas, Manila, ommendations for support and directions for HBV pre- Philippines vention and eradication in Asian countries have also been The Institute of Translational Hepatology, Beijing, China provided. The 2015 guidelines are an update to the 2012 APASL guidelines, and reflect new knowledge and evi- Treatment and Research Center for Infectious Diseases, Beijing 302 Hospital, Beijing, China dence regarding HBV infection. Peking University Hepatology Institute, Beijing, China Division of Gastroenterology and Hepatology, Department of 2 Context of guidelines Medicine, University of Hong Kong, Pofulam, Hong Kong Department of Hepatobiliary and Pancreatic Surgery, 2.1 Epidemiology and public health burden Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Combined Multi- of chronic HBV infection in Asia Pacific organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, HBV infection is a serious global public health problem. It Hangzhou 310003, Zhejiang Province, China is estimated that at least two billion people, or one-third of Graduate Institute of Clinical Medicine and Hepatitis the world’s population, have been infected with HBV. Research Center, National Taiwan University College of Approximately 240 million people, or about 6 % of the Medicine, National Taiwan University Hospital, Taipei, Taiwan world’s population, are chronically infected with HBV [3]. 123 Hepatol Int (2016) 10:1–98 3 Table 1 Grading of evidence and recommendations (adapted from the GRADE system) [1, 2] Notes Symbol Grading of evidence High quality Meta-analysis or randomized trials without important limitations or double-upgraded observational A studies . Further research is very unlikely to change our confidence in the estimate of effect Moderate quality Downgraded randomized trials; upgraded observational studies . Further research is likely to have an B important impact on our confidence in the estimate of effect and may change the estimate Low Double-downgraded randomized trials; observational studies C Very low quality Triple-downgraded randomized trials; downgraded observational studies; case series/case reports Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any estimate of effect is uncertain Grading of recommendation Strong recommendation Factors influencing the strength of the recommendation included the quality of the evidence, presumed 1 warranted patient-important outcomes, and cost Weaker Variability in preferences and values or greater uncertainty: more likely a weak recommendation is 2 recommendation warranted. Recommendation is made with less certainty; higher cost or resource consumption Cohort, cross sectional, and case–control studies are collectively referred to as observational studies. Limitations that reduce the quality of evidence of randomized controlled studies include study limitations (such as lack of allocation concealment, lack of blinding, large losses to follow-up, failure to adhere to an intention-to-treat analysis, stopping early for benefit, or failure to report outcomes), inconsistent results, indirectness of evidence, imprecision, and publication bias. Factors that can increase the quality of evidence of observational studies include large magnitude of effect, plausible confounding that would reduce a demonstrated effect, and dose–response gradient The prevalence of HBV infection is highly heterogeneous 0.5 % in 2004 [9]. This has also resulted in a marked throughout the world, with an intermediate to high preva- decline in the incidence of infant fulminant hepatitis, lence in the Asia-Pacific region, representing three-quarters mortality associated with chronic liver disease and HCC in of chronic HBV-positive subjects worldwide [4]. In addi- those born since advocacy of HBV vaccination began [10]. tion, the Western Pacific region (defined by the World In mainland China, a national survey of HBV seroepi- Health Organization as 37 countries including China, demiology has already shown a decrease in the general Japan, South Korea, Philippines, and Vietnam) accounts prevalence of HBsAg, from 9.75 % in 1992 to 7.18 % in for nearly 50 % of all chronic HBV infection globally, 2006, and a decrease in children \5 years of age, from although it has less than one-third of the world’s population 9.67 % in 1992 to 0.96 % in 2006 [11]. [5]. In Korea, the prevalence rates of chronic HBsAg posi- Prior to implementation of the HBV vaccination pro- tive subjects were 4.61 % in 1998 and 2.98 % in 2010; gram, the Asian-Pacific region was divided into three cat- among teenagers (10–19 years), it decreased from 2.2 % in egories in terms of HBsAg prevalence [6]. High-prevalence 1998 to 0.12 % in 2010 [12]. ([8 %) regions included mainland China, the Hong Kong A study conducted in Taiwan showed relative risk of special administrative region (SAR), Taiwan, Korea, HCC of 9.6 % for males who were positive for HBsAg Mongolia, Philippines, Thailand, Vietnam, and the South alone, but the risk increased to 60.2 % in males who were Pacific island nations. Intermediate-prevalence (2–8 %) both HBsAg- and HBeAg-positive [13]. It is estimated that regions included central Asia, the Indian subcontinent, approximately one-third liver cirrhosis cases and more than Indonesia, Malaysia, and Singapore. Low-prevalence half of the HCC cases in the Asian region are attributable to (\2 %) regions included Australia and New Zealand, HBV [14]. Indeed, chronic HBV infection is the dominant although prevalence has increased in recent years due to risk factor for HCC in most areas of Asia-Pacific. More immigrants from high-prevalence countries [7, 8]. than 700,000 new HCC cases were diagnosed in 2008, with Universal HBV vaccination in newborns has dramati- an age-adjusted incidence of 10.8 per 100,000 worldwide cally changed the epidemiology of chronic HBV infection. [15]. Most HCC cases ([80 %) occur in eastern Asia and A systematic review published by WHO experts in 2012 sub-Saharan Africa, where the incidence is [20 per showed a decrease in prevalence of chronic HBV infection 100,000 individuals [16], and is higher in males than from 1990 to 2005 in most regions of the world [3]. females. For example, in Korea, the age-standardized For example, in Taiwan, where universal vaccination of incidence rate of HCC is 47.1 per 100,000 persons for newborns was started in 1983–1985, HBsAg prevalence in males and 11.4 per 100,000 persons for females. In Thai- children younger than 15 years of age decreased from land, the annual incidence is 38.6/100,000 persons for 9.8 % in 1984 to 0.7 % in 1999, and was further reduced to males and 17.2/100,000 persons for females, and in China 123 4 Hepatol Int (2016) 10:1–98 it is 37.9/100,000 and 14.2/100,000 for males and females, a conventional ALT level of 40 IU/ml rather than respectively [16]. the lowered values of 30 and 19 IU/ml for males In India, where a large study in 1987 of approximately and females, respectively (Table 2). 8575 pregnant women had shown a 3.7 % incidence of 2. Chronic HBV infection is defined as HBsAg seropositive status at 6 months or beyond. HBV infection [17], a recent study of 20,104 pregnant women revealed a prevalence of around 1.1 %. The precise 3. Low replicative chronic HBV infection is defined as HBsAg(?) anti-HBe(?) with persistent normal reasons for the decreased incidence of HBV infection could be the introduction of the HBV vaccination [18] and the serum ALT (PNALT) and HBV DNA \2000 IU/ ml and no evidence of liver injury. This phase is also wide availability of antiviral drugs to treat the primary infection in infected subjects. A large number of past known as ‘‘inactive carrier’’ and ‘‘inactive chronic studies have shown a reduction in the prevalence of HBV HBV infection.’’ However, the use of ‘low replica- infection in the Indian subcontinent. tive chronic HBV infection’ term is preferred, as it explains the state of HBV infection. The term 2.2 Terminology in chronic HBV infection ‘‘inactive carrier’’ should be avoided, as HBV infection is a dynamic interaction between the host and the virus, and the inactive state could change at Various clinical terms relating to HBV infection have been adopted worldwide for diagnosis, staging of the disease, different time points and gives the individual an undue false sense of security. natural history, and treatment strategies. These can be classified into five categories: 4. Chronic hepatitis B is defined as chronic necroin- flammatory disease of the liver caused by persistent 1. Related to HBV infection infection with HBV. It can be subdivided into 2. Related to natural history of chronic HBV infection HBeAg-positive and HBeAg-negative chronic hep- 3. Related to response to antiviral therapy atitis B (CHB). 4. Related to resistance to nucleo(s)tide analogues (NAs) 5. Resolved hepatitis B is defined as previous HBV 5. Occult HBV infection infection with a current state of HBsAg(-) and anti- HBs(?) 6. Acute exacerbation or flare of hepatitis in chronic Terminologies related to HBV infection HBV-infected patient is defined as intermittent 1. Alanine aminotransferase (ALT) level Determina- elevations of serum aminotransferase level to more tion of serum ALT level is important for starting than five times the upper limit of normal and more antiviral treatment as well as for follow-up of than twice the baseline value [22]. patients with chronic HBV infection. Serum ALT 7. Reactivation of hepatitis B Reactivation of HBV level is termed as high normal serum ALT if it is replication should be defined as a marked increase in between 0.5 and 19 the upper limit of laboratory HBV replication (C2 log increase from baseline reference (ULN); as low normal serum ALT if the levels or a new appearance of HBV DNA to a level level is B0.59 ULN; as minimally raised serum of C100 IU/ml) in a person with previously stable or ALT if between ULN and 29 ULN of ALT level; undetectable levels, or detection of HBV DNA with a level C20,000 IU/ml in a person with no baseline and as raised ALT if[29 ULN [19]. Some authors have suggested lower values be used to define the HBV DNA [22, 23]. In one earlier study, HBV DNA ULN for an ALT level of 30 U/l for male and level of [20,000 IU/ml had a positive predictive 19 U/l for female [20]. While it would be worth- value of 98 % in diagnosing reactivation of reacti- while to have the lower ALT values for early vation of HBV [23]. identification of liver injury and treatment of 8. HBeAg clearance is defined as loss of HBeAg in a patients chronically infected with HBV, at present, person who was previously HBeAg positive. the majority of countries in Asia are using ALT of 9. HBeAg seroconversion is defined as loss of HBeAg 40 IU/ml as the upper limit of normal. Although and detection of anti-HBe in a person who was previously HBeAg positive and anti-HBe negative. there is data to suggest that patients with ALT values [0.5 times the upper limit of normal but 10. HBeAg reversion is defined as reappearance of \1.0 of ULN still have liver disease [21], there is HBeAg in a person who was previously HBeAg little data to show that patients belonging to such a negative and anti-HBe positive. sub-group, if treated, respond to antiviral therapy. 11. Hepatic decompensation is defined as significant Due to these reasons, after due deliberations, the liver dsyfunction as indicated by raised serum APASL guidelines committee suggested the use of bilirubin (more than 2.5 times the upper limit of 123 Hepatol Int (2016) 10:1–98 5 Table 2 Terminologies related to HBV infection Terminology Definition ALT level High normal Serum ALT between 0.5 and 19 upper limit of laboratory reference (ULN) Low normal Serum ALT B0.59 ULN Minimally raised Serum ALT between ULN and 29 ULN Raised Serum ALT 29 ULN Chronic HBV infection HBsAg seropositive status beyond 6 months Low replicative chronic HBV infection HBsAg(?), HBeAg(-) anti-HBe(?) status with persistent normal serum ALT, HBV DNA\2000 IU/ ml and no evidence of liver injury Incidentally detected HBsAg positive An asymptomatic individual who has been found to be HBsAg positive on routine blood screening. subject (IDAHS) Such a subject could have different levels of HBV DNA and could have no evidence of liver disease to varied stages of liver disease, and hence needs to be worked up Chronic hepatitis B Chronic necroinflammatory disease of liver caused by persistent infection with hepatitis B virus. It can be subdivided into HBeAg-positive and HBeAg-negative chronic hepatitis B Resolved hepatitis B infection Previous HBV infection, but now HBsAg(-) and anti-HBs(?) Acute exacerbation or flare of hepatitis Intermittent elevations of aminotransferase to more than 5 times the upper limit of normal and more B than twice the baseline value Reactivation of hepatitis B Reappearance of active necroinflammatory disease of liver in a patient known to have the inactive chronic HBV infection state or resolved hepatitis B infection HBeAg clearance Loss of HBeAg in a person who was previously HBeAg positive HBeAg seroconversion Loss of HBeAg and detection of anti-HBe in a person who was previously HBeAg positive and anti- HBe negative HBeAg reversion Reappearance of HBeAg in a person who was previously HBeAg negative, anti-HBe positive Hepatic decompensation Defined as significant liver dysfunction as indicated by raised serum bilirubin (more than 2.5 times the upper limit of normal) and prolonged prothrombin time (prolonged by more than 3 s), or INR[1.5 or occurrence of complications such as ascites and hepatic encepahalopathy Undetectable serum HBV DNA Serum HBV DNA below detection limit of a PCR-based assay normal) and prolonged prothrombin time (prolonged pegylated interferon alpha (IFN or PEG-IFN), and antiviral by more than 3 s), or occurrence of complications agents such as nucleoside/nucleotide analogues (Table 3). such as ascites and hepatic encephalopathy [24]. 12. Undetectable serum HBV DNA is defined as a serum Biochemical response (B) Biochemical response is HBV DNA level below the detection limit (\12 IU/ defined as normalization of ALT levels. It can be evaluated ml) of a sensitive validated quantitative PCR-based at several time points during therapy, and at the end and assay. after the end of therapy. Since ALT activity often fluctuates over time, a minimum follow-up of at least 1 year post- treatment with ALT determinations at least every 3 months Terminologies related to natural history of chronic HBV is required to confirm sustained off-treatment biochemical infection response. The rates of sustained off-treatment biochemical responses may sometimes be difficult to evaluate, as tran- Please refer to the section on natural history below. sient (usually \3 months duration) ALT elevations before long-term biochemical remission may occur in some CHB Terminologies related to response to antiviral therapy patients within the first year after treatment discontinua- tion. In such cases, additional close ALT follow-up of at Responses can be divided into biochemical, serological, least 2 years after ALT elevation seems to be reasonable in virological and histological responses. All responses can be order to confirm sustained off-therapy biochemical remis- estimated at several time points during and after therapy. sion [25]. However, biochemical responses may not cor- The definitions of virological responses vary according to relate with DNA responses. the timing (on or after therapy) and type of therapy. Two different types of drugs can be used in the treatment of Serological response for HBeAg Serological response for CHB: immune modulators such as conventional or HBeAg applies only to patients with HBeAg-positive CHB 123 6 Hepatol Int (2016) 10:1–98 Table 3 Terminologies related to response to antiviral therapy and resistance to NAs Terminology Definition Biochemical response Normalization of serum ALT level Serological response For HBeAg HBeAg loss and seroconversion to anti-HBe in patients with HBeAg-positive chronic HBV infection For HBsAg HBsAg loss and seroconversion to anti-HBs Virological response on IFN/Peg-IFN therapy Virological response HBV DNA levels below 2000 IU/ml Sustained virological response HBV DNA levels below 2000 IU/ml for at least 12 months after the end of therapy Virological response on NA therapy Primary nonresponse Reduction of serum HBV DNA \1 log IU/ml at 12 weeks of oral antiviral therapy in an adherent patient Suboptimal or partial virological Reduction of serum HBV DNA[1 log IU/ml but still detectable at 24 weeks of oral antiviral therapy in an response adherent patient Virological response Undetectable serum HBV DNA during therapy Virological breakthrough Increase of serum HBV DNA [1 log IU/ml from nadir of initial response during therapy, as confirmed 1 month later Secondary treatment failure Viral breakthrough in an adherent patient (due to drug resistance) Sustained off-treatment No clinical relapse during follow-up after stopping therapy virological response Complete response Sustained virological response with HBsAg seroclearance Viral relapse Serum HBV DNA [2000 IU/ml after stopping treatment in patients with virological response Clinical relapse Viral relapse along with ALT [29 ALT Histological response Decrease in histology activity index by at least two points and no worsening of fibrosis score compared to pre-treatment liver biopsy or fibrosis reduction by at least one point by Metavir staging Drug resistance Genotypic resistance Detection of mutations in the HBV genome that are known to confer resistance and develop during antiviral therapy Phenotypic resistance Decreased susceptibility (in vitro testing) to inhibition by antiviral drugs; associated with genotypic resistance Cross resistance Mutation selected by one antiviral agent that also confers resistance to other antiviral agents and is defined as HBeAg loss and seroconversion to anti- Virological responses on NA therapy HBe. Primary non-response is defined as \1 log 10 IU/ml decrease in HBV DNA level from baseline at 3 months of Serological response for HBsAg Serological response for HBsAg applies to all CHB patients and is defined as therapy. HBsAg loss and development of anti-HBs (any titers). Suboptimal or partial virological response is defined as a decrease in HBV DNA of more than 1 log10 IU/ml, but Virological responses on IFN/PEG-IFN therapy with HBV DNA detectable after at least 6 months of therapy in compliant patients. Responses to Peg-IFN therapy are defined differently than Virological response is defined as undetectable HBV DNA by a sensitive PCR assay. It is usually evaluated responses to NA therapy. Primary non-response has not been well established. every 3–6 months during therapy, depending on the severity of liver disease and the type of NA. Virological response is defined as an HBV DNA con- centration of \2000 IU/ml. It is usually evaluated at Virological breakthrough is defined as a confirmed 6 months and at the end of therapy, as well as at 6 and increase in HBV DNA level of more than 1 log10 IU/ml 12 months after the end of therapy. compared to the nadir (lowest value) HBV DNA level on Sustained off-treatment virological response is defined therapy (as confirmed 1 month later); it may precede a as HBV DNA levels below 2000 IU/ml for at least biochemical breakthrough, characterized by an increase in 12 months after the end of therapy. ALT levels. The main causes of virological breakthrough 123 Hepatol Int (2016) 10:1–98 7 on NA therapy are poor adherence to therapy and/or ‘‘horizontal’’ transmission) typically have a prolonged selection of drug-resistant HBV variants (resistance). immune-tolerance phase, followed by an often equally Sustained off-treatment virological response NA(s) may prolonged immune-clearance phase. These individuals be discontinued in some patients. Sustained off-treatment include nearly all Asian and African patients and some virological response may be defined as no clinical relapse from the Mediterranean countries, accounting for a during follow-up after stopping therapy. majority of the world’s HBV-infected population. About Viral relapse is defined as serum HBV DNA[2000 IU/ 70–85 % of HBeAg seroconverters remain in sustained ml after stopping treatment in patients with virological remission, but HBeAg-negative hepatitis occurs in the response. remaining HBeAg seroconverters; the latter is a critically Clinical relapse is defined as viral relapse along with important subgroup in which progression of liver disease ALT [29 ALT. often continues [26]. In fact, the majority (75 %) of cir- Complete response is defined as sustained off-treatment rhosis complications and HCC occur in this population of virological response, together with loss of HBsAg. HBeAg-negative, chronic HBV-infected people [27]. An Histological response is defined as a decrease in his- additional complexity is that HBV can cause HCC even in tology activity index by at least two points and no wors- patients who do not develop cirrhosis. ening of fibrosis score compared to pre-treatment liver By contrast, patients who acquire the virus after early biopsy, or fibrosis reduction by at least one point by childhood generally do not experience the immune-tolerant Metavir staging. phase. The disease typically becomes quiescent after the HBV resistance to NA(s) is characterized by selection of immune-clearance phase, characterized by HBeAg sero- HBV variants with amino acid substitutions that confer conversion to anti-HBe and HBV DNA that remains at a reduced susceptibility to the administered NA(s). Resis- relatively low level or becomes undetectable. tance may result in primary non-response or virological breakthrough on therapy. Phases of chronic HBV infection following vertical Genotypic resistance is defined as detection in the HBV transmission genome of mutations that are known to confer resistance and develop during antiviral therapy. Immune-tolerant phase In patients with perinatally Phenotypic resistance is defined as decreased suscepti- acquired HBV infection, the first phase (immune tolerance) bility (in vitro testing) to inhibition by antiviral drugs is characterized by the absence of biochemical symptoms associated with genotypic resistance. of liver disease (i.e., elevated transaminase levels), despite Cross resistance is defined as mutation selected for by evidence of active HBV replication denoted by the pres- one antiviral agent that also confers resistance to other ence of HBeAg and HBV DNA in serum. During this antiviral agents. phase, which may last 1–4 decades in different populations and individuals, spontaneous and treatment-induced 2.3 Natural history of chronic HBV infection HBeAg seroconversion is infrequent (\5 %/year). Liver biopsy during immune tolerance often reveals an absence A number of phases of chronic HBV infection are recog- of inflammation and scarring. nized, reflecting the dynamic interaction between the virus Diagnosis of immune-tolerant phase The differential and the human host immune system. Once HBV infection has become chronic, its subsequent course largely consists diagnosis of immune tolerance and immune clearance depends mainly on sequential determinations of serum of four phases of the underlying liver disease, of variable ALT levels. However, a slightly increased serum ALT duration and outcome. All phases have been pathogeneti- cally linked to the level of HBV replication and the level, even though it is within the normal range, has been reported to be significantly associated with risk of liver- strength and targets of the host immune reactivity against the replicating HBV. Transition from one phase of related mortality in the general population [28]. Therefore, some have proposed lowering the upper limit of normal chronicity to the next is not recognizable in all patients, either because it may not be an obligatory step in the (ULN) to 30 IU/l for male and 19 IU/l for female [29], although this still remains controversial. The immune tol- overall natural course of the infection, or because it is of very short duration. erant phase is defined as persistence of HBeAg-positive HBV infection without significant ongoing necroinflam- Importance of age of acquisition of the virus matory disease of the liver. Some authors have suggested that the immune-tolerant phase can be defined as having HBeAg positivity, persistently normal serum ALT levels, Patients who acquire HBV infection either at birth or within the first 1–2 years of life (i.e., either ‘‘vertical’’ or and serum HBV DNA [2 9 10 IU/ml, with liver biopsy 123 8 Hepatol Int (2016) 10:1–98 examination showing only minimal histological changes progression [33]. The duration of the immune tolerance [30, 31]. Two important questions are: (1) What should the phase is related to such factors as age of infection cutoff HBV DNA levels be for considering the patients to (younger [ older), mode of infection (vertical [ horizon- be in the immunotolerant phase of infection; and (2) how to tal), immune status (suppressed [ competent), ethnicity predict histology without liver biopsy, based on ALT and (Asians[ non-Asians), HBV genotype C [ B, D [ A, HBV DNA levels? In two studies on HBeAg-positive baseline biochemical and histological activity (high- patients with normal ALT and HBV DNA [2 9 10 IU/ er [ lower), and ALT flare during follow-up (pre- ml, including 57 and 40 Asian patients, liver biopsy sent [ absent) [30]. showed only mild disease in all, and no patient had a histological fibrosis score of [1[32, 33]. However, in a Immune-reactive phase During the immune-reactive Korean study, 28 % of HBeAg-positive patients with nor- phase (also known as immune active/immune clearance/ mal ALT and HBV DNA [2 9 10 IU/ml had significant HBeAg-positive CHB/HBeAg clearance phase), symp- histology [34]. Also, in an Indian study of 73 HBeAg- toms of liver disease may appear for the first time, as the positive patients with persistently normal ALT, 40 % had host immune response leads to hepatocyte lysis with a significant fibrosis. Of these patients, 23 had HBV DNA flare in aminotransferase levels. Increased immune pres- levels of C2 9 10 IU/ml and 50 had HBV DNA levels of sure on the virus during this phase is reflected by sup- \2 9 10 IU/ml. The median (range) of fibrosis scores pression of serum HBV DNA levels and accelerated among HBeAg-positive patients with persistently normal clearance of HBeAg with seroconversion to anti-HBe ALT was comparable between patients with HBV DNA positivity. This phase is characterized by the presence of levels C2 9 10 IU/ml [1.0 (0.0–3.0)] and HBV DNA HBeAg, high or fluctuating serum HBV DNA levels, levels of \2 9 10 IU/ml [1.0 (0.0–4.0); p = 0.649]. The persistent or intermittent elevation in serum aminotrans- area under ROC curve (AUROC) to determine whether ferases, and active inflammation on liver biopsy. These there is a HBV DNA level that could differentiate patients flares may precede HBeAg seroconversion, but many with fibrosis from without any fibrosis on liver biopsy was flares only result in transient decreases in serum HBV 0.424, indicating that HBV DNA is a poor surrogate for DNA levels without loss of HBeAg, and some flares may fibrosis on liver biopsy [21, 35]. Thus, liver fibrosis cannot lead to hepatic decompensation. More typically, the flare be predicted based on HBVDNA levels and ALT alone subsides after a variable period of time, although the [35]. associated liver injury may not regress and fibrosis can result [38]. The annual rate of spontaneous HBeAg More important than defining the immune-tolerant phase clearance in this phase ranges from 3 to 12 %. Factors is to identify patients with histological evidence of liver associated with higher rates of spontaneous HBeAg disease. Recent studies have found an association between seroconversion include older age, higher aminotransferase even low levels of HBV DNA and CHB complications, levels, and HBV genotypes (A, B, D, F, B [ C) [39, 40]. especially in Asian patients who acquire the virus early in Genotype C is also associated with more liver injury at life [36]. the time of seroconversion [41]. In a study from Alaska, it The duration of the immune-tolerant phase is variable. was found that after losing HBeAg, those with genotypes In vertical HBV transmission from HBeAg-positive C and F were more likely to revert to the HBeAg-positive mothers, it may last for more than three decades, while state as compared to those with other genotypes (A, B, D) under other conditions, such as in horizontal HBV spread (p\ 0.001) [40]. among children, it appears to be very short and is hardly This phase may end not only in HBeAg seroconversion, recognizable. but also in HBsAg clearance and seroconversion to anti- A study from Taiwan followed 240 patients (54 % male, HBs. However, in a number of patients, HBV replication mean age 27.6 years) who presented in this phase, and continues despite HBeAg loss and the development of anti- found that only 5 % progressed to cirrhosis and none to HBe antibodies. The duration of this phase, and the fre- HCC during a follow-up period of 10.5 years [26]. These quency and severity of the flares, correlates with the risk of findings indicate that prognosis is generally favorable for cirrhosis and HCC [42]. Recurrent flares occur more patients who are in the immune-tolerant phase. commonly in males and may explain why HBV-related Transition from immune tolerance to immune clearance cirrhosis and HCC are more common in males than in phase Spontaneous HBeAg seroconversion generally females. occurs before 40 years of age in more than 90 % of HBsAg HBsAg titer has been found to be higher during the positive patients [37]. However, loss of immune tolerance immune tolerance phase than during the immune clearance occurs at a rate of 10–15 %/year, and patients who progress phase, as well as being higher in HBeAg(?) than in to the immune-clearance phase often face disease HBeAg(-) patients [43, 44]. 123 Hepatol Int (2016) 10:1–98 9 Low replicative phase Although the previous phase of significant fibrosis (F C2). In patients with persistently immune reactivity against HBV may have unfavorable normal ALT as defined by updated criteria, HAI was 3.0 outcomes, with progression of the underlying liver (1.0–81), fibrosis score was 1.0 (0.0–2.0), and distribution necroinflammation and fibrosis to cirrhosis and even to of fibrosis stages (0/1/2/3/4) were 35/46/19/0/0 %, development of HCC and death, it largely terminates respectively. Twenty-one percent of HBeAg-negative sooner or later in HBeAg clearance and transition to a low patients with persistently normal ALT (PNALT) and HBV replicative phase. This phase is characterized by absence of DNA \2 9 10 IU/ml had histologically active liver dis- HBeAg, presence of anti-HBe, persistently normal ease [histological activity index (HAI) C3 and/or fibrosis aminotransferase levels, and low or undetectable serum stage C2]. Of the 58 patients who had baseline initial liver HBV DNA. Liver biopsy usually shows mild hepatitis and biopsy, 28 underwent repeat liver biopsy after median minimal fibrosis, but inactive cirrhosis may be observed in 50 months (range 36–68). The median change in the patients who had accrued severe liver injury during the Hepatic Activity Index (HAI) from initial biopsy was 2.0 preceding ‘‘immune clearance’’ phase. However, in (range 0–4). Six (21 %) subjects had no change in HAI, 45–65 % of cases, ALT activity can fluctuate with long eight (29 %) had a one-point change, six (21 %) had a two- periods of normal ALT levels. This phase has also been point change, six (21 %) had a three-point change, and two referred to as the ‘‘inactive HBsAg carrier’’ state, but this is (7.1 %) had a four-point change. The median change in an erroneous label for a fair proportion of patients, given fibrosis score from initial biopsy was 1 (0–1). Eight (29 %) that the potential for further disease flares exists and other subjects had no change in fibrosis score and 20 (71 %) had complications such as HCC can supervene. Indeed, for a one-point change [21, 49, 50]. Spontaneous ALT flares patients with infection acquired at an early age, the occurred at 4.3 %/year among patients who were HBeAg majority of complications occur after HBeAg negative with persistently normal ALT, so that cumulative seroconversion. probability for ALT flare was 47 % at 10 years [50]. Other studies have also found that 30–40 % of patients who HBV DNA levels in HBeAg-negative patients with normal exhibited normal serum ALT for more than 6 months had ALT It has traditionally been believed that patients who significant histological findings [51, 52]. are HBeAg negative with normal ALT have low HBV Long-term prognosis of HBeAg-negative patients with DNA levels. However, recent studies have shown that this normal ALT Many studies have shown that although the may not always be true. Among 414 HBeAg-negative rate of liver disease progression was associated with higher Taiwanese CHBV-infected patients with persistently nor- ALT levels, most cases of cirrhosis and HCC occurred in mal serum ALT levels, compared to CHBV-infected patients with ALT \45 U/l [53–55]. In another study of patients with low–normal ALT (\0.59 ULN), those with 3233 Chinese patients with chronic HBV infection who high-normal ALT (0.5–19 ULN) had a greater frequency were grouped on the basis of ALT at presentation and of serum HBV DNA levels [2000 IU/ml and a higher followed for 4 years, it was found that the group with ALT prevalence of core promoter mutations [45]. In another values that were one to two times the ULN (range of study from India, 35 % of HBeAg-negative patients with comparison 0.5–6 U/l times the ULN) was at highest risk of persistently normal ALT for at least 1 year had HBV DNA complications of cirrhosis and HCC. However, the risk of C2 9 10 IU/ml. Even when the recently updated ULN cirrhosis and HCC was greater for the group of patients values (30 IU/l for male and 19 IU/l for female) were used, with ALT [0.5–U/l9 ULN than for the group with ALT 42 % of such patients had HBV DNA C2 9 10 IU/ml \0.5 U/l9 ULN. More than two-thirds of the patients who [21]. experienced complications were already HBeAg negative Histology in HBeAg-negative patients with normal when the complications occurred [27]. In a report from ALT Elevated ALT has been considered to be associated REVEAL study group, 1932 HBsAg-seropositive and with active liver disease on histology, while normal ALT HBeAg seronegative participants with low serum levels of has been considered to be associated with inactive histol- HBV DNA (\2 9 10 IU/ml) and 18,137 HBsAg- ogy. Many initial studies showed that among patients with seronegative and anti-HCV-seronegative participants were chronic HBV infection with normal ALT, about 50–90 % compared. All of them had serum ALT levels\45 U/l and had either minimal or mild changes (chronic persistent no HCC or cirrhosis diagnosed before or within 1 year after hepatitis) on biopsy [46–48]. Recent studies have described study entry. The multivariate-adjusted hazard ratio (95 % higher prevalence of liver injury in such patients. Among confidence interval) was 4.6 (2.5–8.3) for HCC incidence 58 Indian HBeAg-negative patients with persistently nor- and 2.1 (1.1–4.1) for liver-related death for those with low mal ALT who were biopsied, median (range) HAI was 3.0 replicative chronic HBV infection compared to controls (1.0–10.0), fibrosis score was 1.0 (0.0–3.0) and 14 % had [36]. 123 10 Hepatol Int (2016) 10:1–98 Reactivation phase The previous anti-HBe-positive low course. In a study of 164 anti-HBe-positive patients who replicative phase is not always equivalent to a permanent were monitored at monthly intervals for a median period of termination of replication and of HBV-induced chronic 21 months, 64 % had fluctuating ALT levels, including liver damage. Although many patients remain in the low 44 % whose ALT levels were intermittently normal [61]. replicative phase for a long period of time and may also Several investigators have attempted to define cutoff HBV lose HBsAg (around 2 %/year), others retain or redevelop, DNA levels that would differentiate patients with HBeAg- over time, significant HBV replication and progressive negative chronic hepatitis from inactive carriers, but in liver damage [18, 19, 25]. This state of HBV-induced liver view of the fluctuating course, serial testing is more reli- damage was first referred to as the reactivation phase, or able than a single test [62]. ‘‘HBeAg-negative/anti-HBe positive chronic hepatitis B’’ A recent study found that reactivation of hepatitis B [54]. In one study of 283 Taiwanese patients followed for a following HBeAg seroconversion correlated significantly median of 8.6 years after spontaneous HBeAg serocon- with genotype C (p = 0.003), male sex (p = 0.03), ALT version, 67 % had sustained remission, 4 % had HBeAg levels[59 upper normal limit during the HBeAg-positive reversion, and 24 % had HBeAg-negative CHB. Cirrhosis phase (p = 0.02), and age at HBeAg seroconversion developed in 8 % and HCC in 2 %, the risk being higher in C40 years (p = 0.002) [63]. those who had active hepatitis after HBeAg seroconversion HBeAg-negative CHB was originally reported in [55]. Mediterranean countries, but has now been reported in all It is important to differentiate patients in the low parts of the world. Currently, HBeAg-negative CHB rep- replicative phase from patients who remain at risk of pro- resents the most common type of CHB, particularly in gressive disease. Differentiation between these two cate- European, African and Middle East countries of the gories of patients has been based on a HBV DNA cutoff of Mediterranean Basin. 2000 IU/ml [56, 57]. However, this level remains contro- Spontaneous HBsAg seroclearance has been reported to versial. In a recent study, it has been shown that HBsAg occur at a rate of 0.5–1 %/year in patients with chronic C1000 IU/ml could be used to identify patients with high HBV infection [64]. HBsAg seroclearance is generally risk of reactivation [58]. In one Asian study, it was reported accompanied by undetectable serum HBV DNA, normal- that in patients with HBV DNA \2000 IU/ml, a HBsAg ization of liver biochemistries, and improved liver histol- level below 1000 IU/ml was associated with a 2 % inci- ogy [65]. However, HCC has been reported in a small dence of HCC at 20 years, which increased to 8 % with an percent of patients, the risk being higher in those with HBsAg level above 1000 IU/ml. This association between cirrhosis, HCV coinfection, or older age at the time of HBsAg and the development of HCC is not observed if HBsAg seroclearance [66]. HBV DNA is above 2000 IU/ml [59]. It is therefore HBsAg levels are important in predicting HBsAg loss worthwhile to reconsider whether terminologies such as during follow-up. One Asian study found that in inactive HBV carrier are appropriate or should be HBeAg(-) patients with persistently normal ALT, a abandoned. decline C1 log10 IU/ml during a 2-year time period or a The reactivation phase is characterized by negative or single measurement below 200 IU/ml are the best predic- positive HBeAg, positive anti-HBe, detectable HBV DNA, tors of HBsAg loss [positive predictive value (PPV) elevated aminotransferases, and continued necroinflam- 100 %] [66]. Also, a threshold of HBsAg decline C0.3 mation. Whereas most patients reach this phase after a log10 IU/ml/year identifies patients with high probability variable duration of low replicative state, some progress of HBsAg loss with a negative predictive value (NPV) of directly from HBeAg-positive chronic hepatitis to HBeAg- 95 % and a PPV of 85 % [58]. negative chronic hepatitis. Patients in this phase are usually older and have more advanced liver disease, as this rep- Phases of chronic HBV infection following horizontal resents a later phase in the course of chronic HBV infec- transmission tion. Serum HBV DNA levels are lower than in HBeAg- positive patients, but may be high. The high levels of serum Horizontally acquired disease also evolves through a HBV DNA result from a spontaneous mutation in the core number of phases with active replication and hepatic or core promoter region of the viral genome [60]. The necroinflammatory activity in the early months and years precore mutation produces a stop codon in a region of the of chronic HBV infection. With time, replication often HBV genome that prevents the formation of HBeAg, diminishes and host immune pressure results in HBeAg/ whereas the basal core promoter (BCP) mutation affects anti-HBe seroconversion. This is followed by a quiescent HBeAg transcription. These mutations, either singly or in phase of infection with lessened liver injury and evolution combination, permit HBV replication in the absence of into an inactive HBV infection state. Certain patients HBeAg. The hallmark of this phase is its fluctuating appear to suffer little morbidity after HBeAg 123 Hepatol Int (2016) 10:1–98 11 seroconversion. For instance, studies of HBsAg-positive Saharan Africa, Northern Europe, India and Western Africa. Italian patients in the inactive infection state, who were Genotypes B and C are common in Asia. Genotype C mainly initially identified when they were rejected as blood exists in East and Southeast Asia. Genotype D is prevalent in donors, showed that these individuals experienced no Africa, Europe, the Mediterranean region and India. Geno- appreciable increase in liver-related morbidity over many type E is restricted to West Africa. Genotype F is found in years [64]. This observation reflects the benefit of HBeAg Central and South America. Genotype G has been reported in seroconversion following adult acquisition of HBV; that is, France, Germany, and the United States. Genotype H is this event typically leads to a durable decrease in viral found in Central America [75]. Geographic distribution of activity and liver damage. HBV genotype may correlate with the modes of transmis- sion. For example, genotypes B and C are prevalent in highly Predictors of disease progression in chronic HBV infection endemic areas where perinatal or vertical transmission plays an important role in the viral spreading, whereas the Chronic HBV infection and cirrhosis The annual inci- remaining genotypes are frequently found in areas where dence of cirrhosis has been estimated to be 2–6 % for horizontal transmission is the main mode of transmission. HBeAg-positive and 8–10 % for HBeAg-negative patients. In a study from Japan, the persistence of HBV infection The higher rate of cirrhosis among HBeAg-negative after acute hepatitis B was higher in patients with genotype A patients is related to older age and more advanced liver (23 %) than in those with genotype B (11 %) or C (7 %) disease at presentation. Among HBeAg-positive patients, infection [76]. The rate of chronicity after acute genotype D the rate of cirrhosis development is higher in those who infection has also been reported to be relatively high [77]. remained HBeAg positive during follow-up. Additional HBV genotype C patients may experience delayed factors have been identified to be associated with pro- HBeAg seroconversion and a lengthier period of active gression to cirrhosis: habitual alcohol intake, concurrent HBV replication than genotype B patients. With these infection with hepatitis C virus (HCV) or human immun- unfavorable features, genotype C patients are more prone odeficiency virus (HIV), high levels of HBV replication, to develop advanced fibrosis, cirrhosis, and even HCC than and patients who had HBeAg reversion, HBV genotype genotype B patients [78–80]. (C [ B) [67, 68] and a higher proportion ([45 %) of BCP Compared with genotypes C and D patients, genotype A mutataion [69]. In one study of 3774 HBsAg chronic HBV- and B patients had a higher rate of spontaneous HBsAg infected subjects aged 30–65 years, the adjusted relative seroclearance [81, 82]. risk of cirrhosis for patients with baseline serum HBV DNA Genotype C infections conferred a higher frequency of 4 6 [10 and [10 copies/ml was 2.3 (95 % CI 1.6–3.5) and BCP A1762T/G1764A mutation than genotype B, and 9.3 (95 % CI 6.5–13.1), respectively [70]. Collectively, HBV viral load was higher in genotype C than in genotype these data suggest that persistent high levels of HBV B patients [72]. Similarly, genotype D-infected patients replication (with accompanying hepatitis) increase the risk who had more progressive liver disease had a higher of cirrhosis, but the prognostic significance of a high serum prevalence of BCP A1762T/G1764A mutation than those HBV DNA level at a single time point in a young HBV- with genotype A infection [83]. Frequency of pre-S dele- infected subject (\30 years old) is unclear. tion was significantly higher in genotype C patients than in genotype B patients, and pre-S deletion is associated with Chronic HBV infection and HCC The annual incidence higher risk for HCC development [84]. of HCC has been estimated to be \1 % for noncirrhotic HBV genotype A has better responses to IFN-a treatment chronic HBV-infected patients and 2–3 % for patients with than genotype D patients, regardless of HBeAg status. Fur- cirrhosis. Additional risk factors for HCC include coin- ther, HBV genotype B has a higher response rate to IFN-a fection with HCV, a family history of HCC [71], habitual treatment than genotype C in HBeAg-positive patients [85]. alcohol intake, high levels of HBV replication HBV There is no significant association between HBV geno- genotype C [ B) [72], and core promoter mutations [73], type and response to nucleos(t)ide analogues [85]. as well as obesity, diabetes, and smoking [74]. 2.4 Clinical significance of HBV genotypes 3 Guidelines and common mutants 3.1 Screening for chronic HBV infection Based on the extent of divergence in the entire HBV genomic sequence, at least ten HBV genotypes (A–J) and several The impact of vaccination has been profound in reducing subtypes have been identified: [8 % for genotypes and the global burden of HBV, particularly in children and young adults, but millions of chronic HBV-infected 4–8 % for subtypes. Genotype A is highly prevalent in sub- 123 12 Hepatol Int (2016) 10:1–98 patients remain. Seroprevalence studies have been widely 2. There should be a simple, safe, precise and validated performed and show that chronic HBV infection continues screening test to be a major health problem; a representative case was that 3. Treatment started at an early stage should be of more of China, where the seroprevalence rate in 1992 was 9.8 % benefit than treatment initiated later 4. There should be evidence that the screening test is and was reduced to 7.2 % in 2006 after vaccination. While these optimistic trends do indicate an eventual eradication effective in reducing mortality and morbidity 5. The benefit of screening should outweigh the physical of the virus, this would appear to be many decades away. In the interim, there is good established treatment for patients and psychological harm caused by the test, diagnostic procedures and treatment chronically infected with HBV that can reduce liver-related outcomes [86], although HBsAg clearance is still not a 6. The opportunity cost of the screening program should realistic goal. With the World Health Organization (WHO) be economically balanced in relation to expenditure on resolution on viral hepatitis, the WHO has launched a medical care as a whole number of initiatives [87], which include the Global 7. There should be a plan for managing and monitoring Hepatitis Network and a Framework for Action, in order to the screening program and an agreed set of quality tackle these issues. It is recognized that one of the major assurance standards 8. Potential screening participants should receive ade- obstacles to action remains the large burden of undiagnosed cases of chronic HBV infection around the globe. However, quate information about benefits and disadvantages of participation estimates of such a hidden burden of disease are poorly documented. In a large cross sectional study screening for 9. Case finding should be a continuing process and not a hepatitis B amongst Asian Americans in San Francisco once-and-for-all project (n = 3163), 65 % of those who tested HBsAg positive were Chronic HBV infection clearly falls into this category; unaware they had had chronic HBV infection—either they consequently, screening to detect those with CHB infection had never been tested before or had not been previously is a justifiable exercise. diagnosed [88]. In a US-based insurance cohort study, the difference in the proportion of patients who tested positive Screening and linkage to care for HBsAg compared to the expected number estimated from the NHANES study was 21 % [89]. A study from Italy A large number of studies of epidemiology of chronic HBV showed that based on HBV prevalence data of 1.29 % from infection only examine those who are detected to be the Ligurian region, there should be 20,438 chronically HBsAg seropositive, but little is known of screening uptake infected patients, but only 445 (2.2 % of the estimated (% of patients who agree to take the test), and of these, how chronic HBV infection population) were actually chroni- many were referred and evaluated as requiring therapy. cally infected on follow-up [90]. European estimates indi- Consequently, screening to detect seropositive patients is cate that three-quarters of those infected with chronic HBV insufficient as a management strategy, without proper infection are unaware of their infection [91]. In Asia, a linkage to care. The Institute of Medicine recommenda- Japanese study on HBV and HCV prevalence examined tions [95], while specific to the US, can be broadly applied patients, such as first time blood donors and those having a to many other countries as well. They found that the US periodic health examination, who were unaware of their infrastructure for management of chronic viral hepatitis hepatitis status. The prevalence of HBV in this population was poor, and broadly recommended three important ini- was estimated to be 0.63 % or 68,792 persons [92]. In tiatives: increased disease surveillance, improved provider general, there are few studies that examine this issue of and community education, and integration and enhance- under-diagnosis of chronic HBV infection, and approaches ment of viral hepatitis services. In particular, the viral that can resolve the issue. It is estimated that 45 % of people hepatitis services should encompass five core elements in a living with CHB remain undiagnosed, resulting in poor coordinated and comprehensive manner—outreach and health outcomes and risk of transmission [93]. awareness; prevention of new infections; identification of infected people; social and peer support; and medical Principles of screening management of infected people, as otherwise newly diag- nosed patients will be lost and will not receive the benefit In a key article published over 40 years ago, the World of potential therapy that may be lifesaving. Health Organization established several principles for Consequently, the logistic chain of screening begins health screening [94]. In this article, the criteria were: with information and education, followed by agreement to undergo testing, testing itself, and then evaluation; it 1. Screening should be directed towards an important health problem ends with treatment in those who need it. A good 123 Hepatol Int (2016) 10:1–98 13 example of the approach to screening and linkage to care screening may potentially detect such complications, is the Hepatitis Outreach Network, which combines the whether screening followed by treatment would prevent expertise and resources of the Mount Sinai School of such complications has not yet been demonstrated. Medicine, the NYC Department of Health and Mental Treatment for chronic HBV infection has reduced out- Hygiene, and community-based organizations [96]. A comes in patients with significant liver fibrosis or similar study was undertaken in Sheffield in the UK [97]. advanced liver disease, and treatment of chronic HBV Consequently, many stakeholders need to come together infection for those without cirrhosis has shown to and coordinate efforts and resources in order for this improve surrogate markers such as LFTs, liver histology strategy to be effective. However, screening itself is a and HBeAg seroconversion [102]. While cancer screen- major exercise. ing programs can have potentially harmful consequences due to nonspecificity of tests (leading to anxiety and Evidence for screening unnecessary testing), this does not appear to be the case with screening for hepatitis B. In addition, in the While it seems sensible and rational to perform screening screening test for hepatitis B, HBsAg has a high level of for chronic HBV infection, a screening strategy needs to sensitivity and specificity [103], making false positives or have evidence of efficacy, based on evidence that negatives extremely low. However, social issues, screening reduces mortality or complications of disease. including discrimination and stigmatization of the Some screening strategies are potentially harmful, par- patients, need to be addressed adequately before ticularly in the case of cancer screening, when there are embarking on screening programs. false negative or positive results, adverse events of labeling or early diagnosis and adverse effects of treat- Types of screening ment or investigation [98]. Consequently, proof of effi- cacy relies on randomized control trials of screening There are several types of screening: mass screening or using one of two designs [98]—the first is randomized to population screening involves screening a large population, screening versus no screening, with treatment of those multiphasic health screening involves a battery of screen- screened and found to be suitable for therapy; the second ing tests on the same occasion, and opportunistic screening is where all participate in screening and those with refers to screening offered to patients who attend a health positive test results are randomized to treatment or no practitioner for some other reason. treatment. In both scenarios, a significant difference in Population-based screening is where a test is offered outcome (e.g., liver cancer, cirrhosis or mortality) then systematically to all individuals in the defined target group within a framework of agreed policy, protocols, quality favors the screening arm. Unfortunately, no such studies have been performed in chronic HBV infection, and it management, monitoring and evaluation. This involves would seem that such studies are unlikely, since the lead considerable infrastructure and protocols. Such a time to development of such complications would take scheme does not appear to have been established for many decades. Secondly, the second screening strategy chronic HBV infection in most countries. Establishment of of not treating if there is a positive result may be ethi- a screening strategy then requires deliberation on the mode cally difficult to carry out, if patients fulfill treatment in which the strategy is delivered. Such interventions have criteria. Consequently, evidence for screening is largely to be tested in randomized control trials to determine which based on observational data. In the REVEAL study [53], have the best outcomes in terms of proportion of patients 164 cases of HCC were detected during follow-up. In taking up screening, proportion of patients that test positive evaluation of cirrhosis, during the initial screening, 436 and proportion who require treatment. cases of cirrhosis were found, and a further 365 cases Opportunistic screening is less organized and generally were discovered during follow-up [99]. There was also a less effective, as it relies on the healthcare worker to significant increase in liver-related mortality [100]. Most remember to initiate the process, to provide information screening studies did not examine clinical outcomes, but and education, and to inform about the testing process rather, the number of patients screened and the number and consequences if tested positive, and options for of positive HBsAg cases found. As the largest and most therapy, all of which involve considerable time and comprehensive screening program, the BFreeNYC pro- effort. In an excellent systematic review of community gram reached 11,000, screened approximately 9000 screening strategies for chronic HBV infection, Robotin people, and diagnosed and managed six cases of HCC and George [104], reviewed strategies that specifically and 22 of end-stage liver failure [101]. These studies excluded screening conducted by state and local public show that screening does pick up significant cases of health departments. They categorized programs into four advanced liver disease and their complications. While models: 123 14 Hepatol Int (2016) 10:1–98 (A) Community clinic model with screening integrated • detect and evaluate stage of the liver disease and extent into routine primary care services. Screening is of liver damage; based on risk factors and doctors provide counseling • plan antiviral therapy which can delay or reverse the and testing referrals progression of liver disease; (B) Community outreach model, which involves screen- • permit ultrasound surveillance to detect HCC at a ing in community settings (e.g., health fairs) and potentially treatable stage; volunteers providing logistic support • counsel to avoid excessive alcohol use; (C) Partnership and contract model, where screening is • take measures to reduce risk of transmission to others; outsourced to a general health screening company • avoid unnecessary vaccination, as vaccination is not (D) Outreach and partnership model, which contains beneficial for persons already chronically infected and elements of (B) and (C), where screening occurs in is unnecessary for persons already immune (either community setting with a community organization through prior vaccination or a previous resolved acute that has direct links to the target community infection; • vaccinate unprotected individuals. The systematic review found that screening uptake was highest for programs using an outreach and partnership The prevalence of HBV varies markedly between dif- model (C), while the community outreach model (B) had ferent countries of the Asia Pacific region. The prevalence less uptake, and screenings offered by clinical experts had of chronic infection ranges from 10 % of the population in low uptakes (1–2 %). Successful linkage to care was China to\2 % in Australia [6]. So there are areas of high, offered by some programs, but many programs had high medium, and low endemicity based on a prevalence of dropout rates. No data on the proportion of patients HBsAg positivity of C8, 2–7, and \2 %, respectively requiring treatment or referral for treatment was provided. [106]. The overall evaluation was that these screening programs In countries with high endemicity, [90 % of new had at best screened modest numbers of patients, consid- infections occurred among infants and young children as ering the global burden of disease. The authors felt that the the result of perinatal or household transmission, while in most successful programs achieved significant buy-in from countries of low endemicity (i.e., HBsAg prevalence of target communities, delivering culturally appropriate edu- \2 %), the majority of new infections occur among ado- cational initiatives and offering comprehensive care pack- lescents and adults as a result of sexual and injection-drug ages, not just screening alone. use exposures. In countries of intermediate HBV Whichever screening strategy is employed, the logistics of endemicity, multiple modes of transmission operate, i.e., implementation need to be established. A key aspect of this is perinatal, household, sexual, injection-drug use, and the consent and information to be provided to the patient. health-care related. Counseling is crucial to educate and inform patients about Screening of the general population may be cost effec- chronic HBV infection, the consequences and sequelae of tive in finding new cases in countries with high prevalence, chronic infection and the treatment options available. Also, but it is not in regions with low prevalence. In countries advice on what is to be done if the test is positive and the with intermediate prevalence, it would depend upon the linkage to care need to be established. Aids such as flyers, socioeconomic status. However, it is worth doing screening leaflets, websites, trained counselors and trusted community of ‘high-risk groups’ irrespective of prevalence and contacts can be used to help patients understand this better. socioeconomic status. Proper clinical studies are needed to test whether such The following groups should be tested for HBV infec- methods are useful in increasing screening uptake. tion [7, 107–110]: • Persons with liver disease Risk factor screening • Persons needing immunosuppressive or cancer chemotherapy Certain groups are at higher risk of acquisition of HBV and • Injection drug users (IDU) of becoming chronically infected. There is a need for tar- • Persons who have received unsafe injections (used geted screening for HBV infection in high-risk individuals syringes or needles) because the infection remains asymptomatic in a vast • Men who have sex with men (MSM) majority of infected individuals, especially those who • Persons with multiple sexual partners or history of acquire infection at birth or during childhood. Moreover, sexually transmitted infection chronic infection leads to the development of cirrhosis, • Family members, household contacts and sex partner of liver failure, or HCC. Identification of a HBV-infected a person with hepatitis B person is helpful to [7, 105]: • Inmates of correctional facilities 123 Hepatol Int (2016) 10:1–98 15 • Dialysis patients The total hepatitis B core antibody (total anti-HBc) test • HCV- or HIV-infected individuals tells if a person has been previously exposed to HBV [119]. • Pregnant female (preferably during the first trimester to The test by itself does not indicate whether immunity or vaccinate unprotected mothers) chronic infection has developed as a result of exposure. • Infants born to females with chronic HBV This test can be utilized for screening, but anti-HBc posi- • Blood or organ donors tive individuals should be further tested for both HBsAg • Health care workers and anti-HBs to differentiate infection from immunity. However, both HBsAg and ant-HBs may be negative. In such a case, patients with immunity show anamnestic Screening in special populations response after one dose of HBV vaccine, while patients with occult infection do not [120]. This test may be false- Antenatal screening for hepatitis B in pregnant females to positive in low prevalence areas. Patients with false-posi- identify newborns who require prophylaxis against perinatal tive results will need a full course of vaccine to have an infection is a well-established, evidence-based standard of immune response. Anti-HBc antibody is also positive practice [111]. This has become even more important, as new during the window phase of acute hepatitis B, i.e., after the strategies to even further reduce perinatal transmission using disappearance of HBsAg and before the anti-HBs develop. nucleos(t)ide analogues in the last trimester of pregnancy Individuals with past HBV infection (anti-HBc reactive) haves been established through randomized control trials should not donate blood even if they have recovered. [112, 113]. However, the effectiveness of such screening programs in real life is not ideal. In a large prospective study 3:1 Recommendations (screening for chronic HBV [114], the impact of the GAVI project on reducing perinatal infection). HBV infection was evaluated. This included a proportion of 3:1:1 Screening for hepatitis B infection is an pregnant females screened for HBV. Between 2002 and important tool to discover new cases of 2009, using a cluster sampling methodology in Eastern, chronic infection (A1). Central and Western regions of China, 244 facilities were 3:1:2 There is insufficient evidence to recommend assessed with 71,694 live births in 2002 and 125,874 live any specific screening strategy for CHB and births in 2009. The HBV screening rate increased from 64 % further research is needed in this crucial area in 2002 to 85 % in 2009. Consequently, there is still room for (C1). improvement. With regard to blood safety, this is clearly an 3:1:3 Existing screening strategies in antenatal care important area to ensure high compliance. A recent report in and blood supply should be strengthened (A1). Morbidity and Mortality Weekly Report (MMWR) [115] 3:1:4 Screening in high-risk populations should indicates that the number of countries in Africa and sub- continue to be a high priority (A1). Saharan Africa testing at least 95 % of donations for HBV 3:1:5 Strategies to enhance screening acceptance increased from 76 to 94 %. Nucleic acid testing (NAT) is not and uptake should be undertaken (C1). widely available in the developing world [116], and is now 3:1:6 High-risk persons who are most likely to be considered a standard of care in blood safety. In Asia, there infected with HBV and should be tested for are few audits of blood safety measures in developing chronic HBV infection include (B1): countries; consequently, it is unclear to what extent is blood safety is established. Persons with liver disease Family members, household contacts, Tests used for screening Screening tests are inexpensive infants, sex partners of a person infected and cost effective in populations at higher prevalence, as with hepatitis B cost per case identified decreases, and they have the Persons needing immunosuppressive or potential to reduce HBV-associated morbidity and mor- cancer chemotherapy tality [117]. The individuals found to be negative during Injection drug users (IDU) the screening should be vaccinated, and cases identified Persons who receive unsafe injections (used should be counseled and treated. syringes or needles) The HBsAg test is the primary way to definitively Persons who have sex with males (MSM), diagnose chronic HBV infection. The anti-HBs test will tell with multiple sexual partners, STDs if your patient is protected against HBV. Anti-HBs anti- Inmates of correctional facilities body can be produced in response to vaccination, recovery Dialysis patients from an acute hepatitis B infection, or the presence of less HCV- or HIV-infected individuals common pre-S mutants [118]. 123 16 Hepatol Int (2016) 10:1–98 Pregnant females (preferably during the first immune status of the recipients [123]. If anti-HBc-positive trimester, to vaccinate unprotected mothers) donor organs are used for HBV seronegative recipients, Health care workers antiviral therapy should be administered to prevent de novo Blood or organ donors HBV infection. While the optimal duration of prophylactic therapy has not been determined, a limited duration, such 3:1:7 Testing should include a serological assay for as 6–12 months, may be sufficient for transplantation of HBsAg (A1), anti-HBs (B2) and total anti- non-hepatic solid organs. For transplantation of livers, life- HBc (B2). long antiviral therapy is recommended, but whether HBIG 3:1:8 Screening should be linked to appropriate is necessary is unclear [124]. counseling and referral for further care includ- HBsAg-positive female who are pregnant should be ing clinical evaluation, need for treatment and counseled to make sure they inform their providers so that vaccination (if found to be negative for HBV appropriate decisions regarding administering hepatitis B infection) (C1). immune globulin (HBIG) and hepatitis B vaccine can be made for their newborn immediately after delivery. HBIG 3.2 Counseling and prevention of transmission and concurrent hepatitis B vaccine have been shown to be of hepatitis B from individuals with chronic HBV 95 % efficacious in the prevention of perinatal transmis- infection sion of HBV; the efficacy is lower for mothers with very high serum HBV DNA levels ([7–8 log10 IU/ml) [125, Patients with chronic HBV infection should be counseled 126]. In a recent analysis comparing the cost-effectiveness regarding lifestyle modifications and prevention of trans- of HBV control strategies combining universal vaccination mission, as well as the importance of lifelong monitoring. with hepatitis B immunoglobulin (HBIG) treatment for No specific dietary measures have been shown to have neonates of chronically HBV-infected mothers, it was any effect on the progression of CHB. However, heavy concluded that HBIG treatment for neonates of HBsAg use of alcohol ([20 g/day in female and [30 g/day in positive mothers is likely to be a cost-effective addition to male) may be a risk factor for the development of cir- universal vaccination, particularly in settings with adequate rhosis [121]. health care infrastructure. Targeting HBIG to neonates of Persons chronically infected with HBV should be higher risk, HBeAg-positive mothers may be preferred counseled regarding transmission to others (Table 4). where willingness to pay is moderate. However, in very Household members and steady sexual partners are at resource-limited settings, universal vaccination alone is increased risk of HBV infection and therefore should be optimal [127]. vaccinated if they test negative for HBV serological Transmission of HBV from infected health care workers markers. For sex partners who have not been tested or have to patients may occur in rare instances (see ‘‘3.13.4 Health not completed the full immunization series, barrier pro- care workers’’ section). tection methods should be employed. 3:2 Recommendations: counseling and prevention of The risk of infection after blood transfusion and trans- transmission of hepatitis B from individuals with plantation of nonhepatic solid organs (kidneys, lungs, chronic HBV infection: heart) from persons with isolated anti-HBc is low: 0–13 % [122]. The risk of infection after transplantation of liver 3:2:1 Chronic HBV-infected persons should be from HBsAg-negative, anti-HBc-positive donors has been counseled regarding prevention of transmis- reported to be as high as 75 % and is related to the HBV sion of HBV (Table 4) (A1). Table 4 Recommendations for infected persons regarding prevention of transmission of HBV to others Have sexual contacts vaccinated Use barrier protection during sexual intercourse if partner not vaccinated or naturally immune Do not share toothbrushes or razors Cover open cuts and scratches Clean blood spills with detergent or bleach Do not donate blood, organs or sperm Can participate in all activities including contact sports Children should not be excluded from daycare or school participation and should not be isolated from other children Can share food, utensils, or kiss others 123 Hepatol Int (2016) 10:1–98 17 3:2:2 Sexual and household contacts of chronic choosing therapeutic strategies and for monitoring the HBV-infected persons who are negative for responses to anti-viral or anti-fibrotic treatment. Knowl- HBV seromarkers should receive hepatitis B edge of the underlying histology can help guide therapeutic vaccination (A1). decisions when patients do not meet the clinical practice 3:2:3 Abstinence of alcohol is recommended in guidelines and treatment may be helpful. Aminotransferase chronic HBV-infected subjects (A1). levels may fluctuate with time, and single measurements of 3:2:4 Chronic HBV-infected subjects should not be ALT and AST do not indicate disease stage. Usually, the discriminated and stigmatized in the society or ALT concentrations are higher than those of AST, but with in their work place (A1). disease progression to cirrhosis, the AST/ALT ratio may be 3:2:5 HBV-infected children should not be isolated reversed. A progressive decline in serum albumin con- in the educational and social environment centrations, rise in bilirubin and prolongation of the pro- (A1). thrombin time are characteristically observed as decompensated cirrhosis develops. In chronic HBV infec- tion, a liver biopsy is usually recommended to determine 3.3 Assessment of persons with chronic HBV the stage of fibrosis and/or the grade of activity in patients infection with a high viral load and high-normal or minimally raised ALT levels and in those older than 30 years without clin- The initial evaluation of an individual with HBV infec- ical evidence of cirrhosis. Liver biopsy is considered the tion should include a detailed history and physical reference standard for the histological evaluation of liver disease. However, it is important to remember that a liver examination. Alcohol consumption, family history of HBV and HCC, and assessment of risk factors to biopsy represents just *1/50,000 of the entire liver, and determine the likely mode of HBV acquisition and that liver injury is typically irregularly distributed in the possible superinfection with other hepatitis virus(es) liver. Thus, liver biopsy is an imperfect reference standard; should be part of the history taking. Comorbidities such taking into account a range of accuracies of the biopsy, as obesity, diabetes mellitus and metabolic syndrome even in the best possible scenario, an area under the should be assessed. Hepatic steatosis in individuals with receiver operating characteristic (AUROC) [0.90 cannot CHB is related to co-existent metabolic factors rather be achieved even for a perfect marker of liver disease than being virally induced [128, 129]. The physical [133]. The diagnostic accuracy of liver biopsy decreases examination focuses on identifying presence of cirrhosis because it is often subject not only to sampling error, but or decompensated liver disease, as it has an impact on also to intra- and inter-observer variability in histological interpretation [134]. Moreover, even if it is generally prognosis. A complete blood count, biochemical tests, serological and virological markers of HBV, and hepatic accepted to be a safe procedure, it is invasive and can be ultrasound should be part of the initial evaluation. The associated with rare but potentially serious complications, biochemical tests include ALT, AST, GGT, alkaline including hemorrhage, pneumothorax, and procedure-re- phosphatase, serum albumin and prothrombin time. The lated mortality. Thus, although there is still an important virological assessment consists of HBeAg, anti-HBe role for liver biopsy among chronic HBV infection, there is antibodies and Hepatitis B DNA measurement, the latter an obvious need to develop and use noninvasive, accurate, being the best marker of viral replication [130]. A real- and reproducible tests for detecting liver injury. For time PCR quantification assay should be used to measure example, noninvasive tests are helpful in assessing the serum HBV DNA levels [131, 132]. stage of fibrosis in chronic HBV infection with no clear Other causes of chronic liver disease should be sys- indication for a liver biopsy, or in those who require fol- low-up assessment of the stage of fibrosis during or after tematically looked for, including coinfections with HDV, HCV and/or HIV. Comorbidities, including alcoholic, treatment. autoimmune, and metabolic liver disease with steatosis or Several noninvasive tests based on serum fibrosis steatohepatitis should be assessed. markers or radiographic techniques have been introduced, In addition, all first-degree relatives and sexual partners and they are being increasingly used to assess the severity of patients with chronic HBV infection should be advised of liver disease in clinical practice. These include serum to get tested for HBV serological markers (HBsAg, anti- biochemical parameters, such as the ratio of aspartate HBc, anti-HBs) and to be vaccinated, if they are negative aminotransferase (AST) to ALT, the fibrosis score-4 (FIB- for these markers. 4), the AST to platelet ratio index (APRI), the age-spleen- In subjects with chronic HBV infection, accurate platelet index, the Forns index, and the Hui index. Spe- assessment of the extent of hepatic fibrosis and/or the cialized tests include Fibrotest, Hepascore, the enhanced severity of necroinflammatory activity is essential for liver fibrosis test and, for elasticity imaging, magnetic 123 18 Hepatol Int (2016) 10:1–98 resonance (MR) elastography and transient elastography frequently presents as fluctuating patterns associated with (TE) [135, 136]. necroinflammatory activity, serum levels of ALT and The APRI is a simple test that is readily available, is bilirubin must be considered as a potential confounder inexpensive, does not require particular expertise in inter- when interpreting the TE values of chronic HBV-infected pretation, and can be performed in an outpatient setting. patients. APRI uses two cutoff points for diagnosing specific fibrosis Liver fibrosis is a dynamic process. Beyond the cross- stages, as the use of a single cutoff would result in sub- sectional studies, recent evaluations of noninvasive tests optimal sensitivity and specificity. A high cutoff with high have focused on their ability to predict the risk of disease specificity is used to diagnose persons with a particular progression or liver-related death, and on their use in stage of fibrosis, and a low cutoff with high sensitivity (i.e., monitoring the treatment response during long-term, fol- fewer false-negative results) is used to rule out the presence low-up longitudinal assessments [141, 142]. A major of a particular stage of fibrosis. Some persons will fall in advantage of noninvasive tests is that they allow repeated the indeterminate range of test results (i.e., their score will serial measurements of liver fibrosis. Indeed, the role of be between the low and the high cutoff) and will need noninvasive tests is no longer confined to the detection of future re-testing and evaluation. Most commonly reported the severity of liver fibrosis; rather, noninvasive approa- cutoff values for APRI for the detection of significant ches provide a surveillance tool that predicts clinical out- fibrosis and cirrhosis are as follows: For significant fibrosis come and long-term prognosis, thus helping to determine (METAVIR CF2), low and high cutoffs for APRI are 0.5 treatment strategies. Furthermore, to improve the overall and 1.5; and for cirrhosis (METAVIR F4), low and high diagnostic performance, the advantages of combining TE cutoffs for APRI are 1.0 and 2.0. Sensitivity, specificity, and serum markers have been established in several studies PPV and NPV for diagnosing significant fibrosis (META- [143–145], but further validation is still required. VIR CF2) were 71–84, 50–69, 52–61 and 76–84 % for Neither noninvasive testing nor liver biopsy alone is APRI low cutoff; and 28–45, 90–95, 68–81 and 65–72 % sufficient to make a definitive decision in clinical prac- for APRI high cutoff. Sensitivity, specificity, PPV and tice, and regardless of specific methodological advances, NPV for diagnosing cirrhosis (METAVIR F4) were 55–73, all of the available clinical and biological data must be 70–80, 18–28 and 93–97 % for APRI low cutoff; and taken into account in therapeutic decision-making. The 22–49, 81–94, 19–34 and 91–94 % for APRI high cutoff utilization of noninvasive tests for assessing liver his- [137]. tology can significantly reduce, but not completely Emerging technologies utilizing ultrasound and MR replace, the need for liver biopsy and should be seen as imaging platforms, such as acoustic radiation force a complementary tool in the management of chronic impulse imaging and diffusion-weighted MR imaging HBV-infected patients. have been developed as well. These approaches make up for the weak points in the liver biopsy by improving the Use of risk calculators histology results, but they also reduce the need for liver biopsy. Chronic HBV infection remains an important cause of Liver stiffness measurement using TE (Fibroscan ) was HCC development. HCC causes poor quality of life and first developed in 2003 and is the most extensively evalu- shortened survival, and is thus regarded as a major health ated method of this type. Following vigorous validations in challenge. The risk of CHB progressing to HCC may be many studies, TE was shown to be a reliable and accurate reduced by antiviral therapy [146], and surveillance with surrogate for liver biopsy in assessing the severity of liver abdominal ultrasonography and serum alpha-fetoprotein fibrosis [138–140]. In recent years, many patients in Asia- tests can be used to screen patients for early HCC treat- Pacific countries have been evaluated by TE, resulting in ment. Although, the global number of individuals infected extensive accumulated experience. The performances of with CHB is extensive, especially in endemic areas such as TE in diagnosing significant fibrosis (CF2 stage) and cir- Asian-Pacific and sub-Saharan African regions, only a rhosis (F4 stage) are good, with AUROC of 0.81–0.95 and small number of patients develop end-stage liver diseases. 0.8–0.98, respectively. Most studies report estimated cutoff Therefore, the identification and triage of patients who are ranges of 6.3–7.9 and 9.0–13.8 kPa for the diagnosis of at high risk of HCC development is important. Several significant fibrosis and cirrhosis, respectively. However, factors, such as gender, age, family history of HCC, pres- although TE has displayed reliable diagnostic accuracy in ence of hepatic inflammation/fibrosis, alcohol consump- this setting, it can be influenced by factors such as tion, elevated viral load, hepatitis Be antigen (HBeAg) necroinflammation, edema, food intake, and cholestasis, positivity, and specific HBV genotypes (e.g., genotype C), resulting in an overestimation of TE values. Because of the have been identified to be independently associated with complex natural history of chronic HBV infection, which elevated risk of HCC development [13, 67, 147]. These 123 Hepatol Int (2016) 10:1–98 19 factors, including patient, viral, and environmental factors, patients with low levels of HBV DNA (\2000 IU/ml) interact with one another and lead to HCC development in [154], the original REVEAL nomograms were upgraded by patients with chronic HBV infection. From the individu- incorporating qHBsAg into the HCC risk prediction model alized medicine point of view, these factors should be used [155]. In addition to HCC, this study also provided a pre- to reveal the future risk of HCC progression in patients diction model for predicting the long-term development of with viral hepatitis so that preventive measures can be cirrhosis. The risk prediction model for HCC included age, applied to those at high risk [148]. sex, family history of HCC, and a combined variable encompassing HBeAg serostatus, serum HBV DNA and Risk calculators for HCC in chronic HBV-infected patients ALT levels, quantitative serum HBsAg level, and HBV without antiviral treatment Many Asian study groups genotype as the predicting parameters. The projected 5-, established prediction models that incorporated several 10-, and 15-year HCC risk for each score was pre-calcu- clinical variables to estimate HCC risk for chronic HBV- lated and depicted in a nomogram. This upgraded HCC risk infected patients. These included IPM from Korea (hospital calculator was internally validated using a third of the based using gender, HCV infection, HBV infection, AFP population from which the model was derived, and showed levels, chronic hepatitis, cirrhosis, alcohol use and ALT excellent prediction accuracy and discriminatory ability. levels) [149]; GAG-HCC risk score from Hong-Kong Since serum HBV DNA measurement is relatively (hospital based using gender, age, HBV DNA levels, core expensive compared to all other risk predictors in the risk promoter mutations and cirrhosis) [150]; CUHK clinical calculator, a risk calculator might be generated in which scoring system from Hong-Kong (hospital based using age, quantitative serum HBsAg levels can be used in lieu of serum HBV DNA levels. albumin, bilirubin, HBV DNA levels and cirrhosis) [151]; and REVEAL nomograms from Taiwan (community based The REACH-B scoring system has been used to classify using gender, age, ALT levels, family history of HCC, anti-viral treatment eligibility of CHB patients according to alcohol consumption, HBV DNA levels, HBeAg and HBV the 2012 Asian Pacific Association for the Study of the genotype) [152]. The most important issue with these was Liver (APASL) treatment guidelines [156]. In this study, a the lack of external validation. All these groups then col- total of 904 noncirrhotic CHB patients were enrolled, and it laborated to develop a HCC risk score (REACH-B) showed that for patients to be eligible for anti-viral treat- incorporating gender, age, serum alanine transaminase ment, the minimal REACH-B score should be 7 and 6, (ALT) concentration, HBeAg status, and serum HBV DNA respectively, for HBeAg-seropositive and HBeAg- level as the predicting parameters [153]. This study derived seronegative patients. Additionally, in HBeAg-seronega- a 17-point risk model from 3584 treatment-free and cir- tive patients, the REACH-B score could predict treatment eligibility, with an adjusted OR (95 % CI) of 1.78 rhosis-free CHB patients in a community-based Taiwanese cohort (REVEALHBV), and validated its use in a com- (1.61–1.98). In HBeAg-seropositive patients, however, this posite hospital-based cohort (n = 1505) from Hong Kong same score-dependent eligibility of treatment was not and Korea. This risk score could predict HCC with a wide observed. In this study, the authors also showed that the range of risks, ranging from 0.0 to 23.6 % at 3 years, 0.0 to REACH-B score was excellent in discriminating treatment 47.4 % at 5 years, and 0.0 to 81.6 % at 10 years for eligibility for young (\40 years) HBeAg-seropositive patients with the lowest through the highest scores. patients (AUC 0.903) and in both young (\45 years; AUC Although the derivation and validation cohorts were quite 0.907) and older (C45 years; AUC 0.883) HBeAg- different in their distributions of sex, age, HBeAg seronegative patients; but the discriminatory capability for serostatus, ALT concentration, HBV DNA level, and cir- older (C40 years) HBeAg-seropositive patients was poor rhosis, the risk score developed from the derivation cohort (AUC 0.664). They also found that 46.4 % of HBeAg- accurately and reliably estimated the HCC risk at 3, 5 and seropositive patients older than 40 years of age with high 10 years of follow-up in the validation cohort. The area risk of HCC, as estimated by a REACH score C11, would under the receiver operating characteristic curve (AUROC) be erroneously excluded from treatment, mainly because and the corresponding 95 % CI were 0.811 (0.790–0.831), their ALT levels never exceeded 29 ULN, even after 0.796 (0.775–0.816), and 0.769 (0.747–0.790), respec- frequent blood tests during follow-up. tively, in predicting 3-, 5- and 10-year HCC risk, indicating These risk calculators can be used for evidence-based a fair discriminatory capability. The performance of the decisions during clinical management of chronic HBV-in- risk score was improved when cirrhotic patients were fected patients. Based on patient’s personalized HCC risks, excluded from the validation cohort [153]. their follow-up intervals, surveillance patterns, and referral With recent studies showing utility of quantitative serum strategies can be tailored. Also, timely antiviral therapy in HBsAg levels (which are reproducible and low cost) in high-HCC-risk patients may lead to improvement in qual- providing additional predictability of HCC, especially in ity of life and prolonged survival. The potential cutoff risk 123 20 Hepatol Int (2016) 10:1–98 and corresponding management strategies still remain an 3:3:5 Accurate assessment of the degree of fibrosis issue. is essential not only to determine prognosis, Although the risk calculators are easy-to-use and the but also to identify patients who require REACH-B predictive score was externally validated to be antiviral treatment (AI). 3:3:6 A liver biopsy is recommended to determine an applicable tool for HCC risk estimation, several pre- cautions are warranted. Because surveillance strategies the stage of fibrosis and/or the grade of activity in patients with a high viral load and derived from a Taiwanese population might not apply globally, further validation is still needed in patients of high-normal or minimally raised ALT levels without clinical evidence of cirrhosis (AI). different ethnicities, geographical areas, ages at infection, genetic background, HBV genotypes or species, comor- 3:3:7 Noninvasive tests such as transient elastog- bidities, and exposures to environmental factors such as raphy can be a useful, reliable and practical aflatoxin and alcohol [157]. It has been shown that the tool for the diagnosis, and for decision- applicability and predictability of HCCrisk scores devel- making for treatment and monitoring clinical oped in Asians are poor or modest in Caucasian CHB outcome (BI). patients, for whom different risk scores are required [158]. 3:3:8 Transient elastography is especially useful in the assessment of liver fibrosis in patients Since current HCC risk prediction tools were generated from a natural history cohort without history of antiviral with normal ALT and bilirubin levels (AI). In a patient infected with hepatitis B, a liver therapy, the inference of predicted risks under circum- stances of antiviral therapy should theoretically be inap- stiffness measurement\6 generally excludes propriate; although these risk calculators have been also a significant liver disease, above 8 indicates used for predicting HCC risk among patients on anti-virals significant fibrosis (F C2 by METAVIR [159]. fibrosis score) and above 11 raises suspicion Besides HCC, several other clinical outcomes and of cirrhosis. These cutoffs may have regional milestones of chronic HBV infection, such as cirrhosis, and and population variations (A1). liver-related mortality, as well as the seroclearance of 3:3:9 Risk calculators may be used to assess HCC HBeAg, HBsAg, and HBV DNA, can also be suitable for risk in chronic HBV-infected patients and make decisions to manage such patients (B2). the development of risk prediction tools. 3:3:10 Specific risk calculators need to be developed 3:3 Recommendations (assessment of persons with and validated in patients of different ethnic- chronic HBV infection) ities, geographical areas, ages at infection, 3:3:1 The initial evaluation of an individual with genetic backgrounds, HBV genotypes, HBV infection should include assessment of comorbidities, and exposures to environmen- the level of viremia, degree of inflammation tal factors such as aflatoxin and alcohol (B1). and the presence and stage of liver disease. A detailed history to investigate the possible 3.4 Goals and endpoints of therapy in chronic HBV source of HBV transmission, as well as infection physical examination, biochemical tests [in- cluding aspartate aminotransferase (AST) Goal of therapy and ALT, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase, bilirubin, and The ultimate goal is global eradication of HBV infection by serum albumin and globulins, and prothrom- various strategies, including vaccination, treatment and bin time], complete blood count and hepatic prevention of transmission. The goal of therapy for chronic ultrasound should be performed (A1). HBV infection is to improve quality of life and survival of 3:3:2 Measurement of HBV DNA is essential for the infected person by preventing progression of the dis- the diagnosis, assessment for initiating treat- ease to cirrhosis, decompensated cirrhosis, end-stage liver ment and subsequent monitoring of infected disease, HCC and death; and prevention of transmission of subjects (A1). HBV to others. This goal can be achieved if HBV repli- 3:3:3 Other causes of chronic liver disease should cation can be suppressed in a sustained manner. Then, the be looked for, including coinfections with accompanying reduction in histological activity of CHB HDV, HCV and/or HIV (A1). lessens the risk of cirrhosis and decreases the risk of HCC, 3:3:4 Comorbidities, including alcoholic, autoim- particularly in noncirrhotic patients. However, chronic mune, metabolic liver disease with steatosis HBV infection cannot be completely eradicated due to the or steatohepatitis should be assessed (A1). 123 Hepatol Int (2016) 10:1–98 21 persistence of covalently closed circular DNA (cccDNA) in support increased, and financial concerns decreased the nucleus of infected hepatocytes, and also, the HBV (p\ 0.05) [163]. genome integrates into the host genome and might favour 3:4 Recommendations: goals and endpoints of therapy in oncogenesis and the development of HCC [160]. chronic HBV infection Endpoints of therapy 3:4:1 The overall goal is global eradication of HBV infection by various strategies including vac- Therapy must ensure a degree of virological suppression cination, treatment and prevention of trans- mission (A1). that will lead to biochemical remission, histological improvement and prevention of complications. The ideal 3:4:2 The goal of therapy for CHB is to improve endpoint in both HBeAg-positive and HBeAg-negative quality of life and survival of the infected patients is sustained off-therapy HBsAg loss, with or person by preventing development of disease, without seroconversion to anti-HBs. This is associated with progression of the disease to cirrhosis, decom- a complete and definitive remission of the activity of CHB pensated cirrhosis, end-stage liver disease, and an improved long-term outcome. This endpoint, how- HCC and death; and by prevention of trans- ever, is infrequently achievable with the currently available mission of HBV to others (A1). anti-HBV agents. A more realistic endpoint is the induction 3:4:3 The ideal endpoint in both HBeAg-positive and HBeAg-negative patients is sustained off- of sustained or maintained virological remission [25]. Induction of sustained off-therapy virological response in therapy HBsAg loss, with or without serocon- both HBeAg-positive (with sustained anti-HBe serocon- version to anti-HBs (A1). version) and HBeAg-negative patients is a satisfactory 3:4:4 Induction of sustained off-therapy virological endpoint, because it has been shown to be associated with response in both HBeAg-positive (with sus- improved prognosis. If sustained off-therapy response not tained anti-HBe seroconversion) and HBeAg- achievable, then a maintained virological remission (un- negative patients is a satisfactory endpoint detectable HBVDNA by a sensitive PCR assay) under (A1). long-term antiviral therapy in HBeAg-positive patients 3:4:5 If sustained off-therapy response is not achiev- who do not achieve anti-HBe seroconversion and in able, then a maintained virological remission HBeAg-negative patients is the next most desirable (undetectable HBV DNA by a sensitive PCR assay) under long-term antiviral therapy in endpoint. Health-related quality of life (HRQOL) is significantly HBeAg-positive patients who do not achieve anti-HBe seroconversion, and in HBeAg-neg- affected in CHBV patients, particularly in those with more severe forms of the disease. Prevention of disease pro- ative patients, is the next most desirable gression with early treatment or liver transplantation can endpoint (A1). certainly improve HRQOL. Even though some antiviral medications decrease HRQOL during the acute treatment 3.5 Indications of therapy in chronic HBV infection period, the HRQOL of CHBV patients improves after completion of antiviral treatment [161]. In order to The indications for treatment are generally based mainly on improve HRQOL of CHB patients, attention should be paid the combination of three criteria: serum HBV DNA levels, to the reduction of patients’ treatment cost burden and the serum ALT levels and severity of liver disease (assessed by provision of early health education accompanied with clinical evaluation, liver biopsy or noninvasive methods). proper treatments [162]. A recent Chinese study evaluated Indications for treatment should also take into account age, the effect of comprehensive intervention on health-related health status, family history of HCC or cirrhosis and quality of life and provided guidance on improving extrahepatic manifestations (Table 5). HRQOL for patients with CHB. Comprehensive interven- Patients with decompensated cirrhosis and tion included government support, technical guidance from detectable HBV DNA require urgent antiviral treatment the Chinese Center for Disease Control and Prevention, with NA(s). Significant clinical improvement can be standardized medical care, and community involvement. associated with control of viral replication [164, 165]. HRQOL before and 1 year after intervention was measured However, antiviral therapy may not be sufficient to rescue with the Short Form 36 and HBV-specific health surveys. all decompensated patients and they should be considered After comprehensive intervention, the HRQOL in patients for liver transplantation at the same time (Fig. 1). with CHB showed significant improvements in body pain, Patients with compensated cirrhosis and HBV DNA vitality, social functioning, and mental as well as physical [2000 IU/ml should also be considered for treatment even and mental component score (p \ 0.05). Family and social 123 22 Hepatol Int (2016) 10:1–98 Table 5 Treatment indications for chronic HBV-infected patients HBsAg positive patient HBV DNA ALT Treatment (IU/ml) Decompensated Detectable Any Treat. Histology not needed. Consider LT of no stabilization cirrhosis Compensated cirrhosis [2000 Any Treat. Histology should be obtained or assess fibrosis noninvasively Severe reactivation of Detectable Elevated Treat immediately chronic HBV Noncirrhotic HBeAg- [20,000 [29 ULN Observation for 3 months if no hepatic decompensation concerns. positive chronic Treat. Histology should be obtained or assessed noninvasively hepatitis B 1–29 ULN Assess fibrosis noninvasively. Monitor every 3 months. Biopsy if noninvasive tests suggest evidence of significant fibrosis, ALT is persistently elevated, age [35 years or family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis Persistently normal (age Assess fibrosis noninvasively. Monitor every 3 months. Biopsy if \30) (immune tolerant noninvasive tests suggest evidence of significant fibrosis, or there is a phase) family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis 2000–20,000 Any ALT Rule out other causes of elevated ALT.Assess fibrosis noninvasively. Monitor every 3 months. Biopsy if noninvasive tests suggest evidence of significant fibrosis, age[35 years, ALT is persistently elevated, or there is a family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis \2000 \ULN Assess fibrosis noninvasively. Monitor every 3 months. Biopsy if ALT becomes elevated, noninvasive tests suggest evidence of significant fibrosis, age[35 years or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis [ULN Rule out other causes of elevated ALT. Assess Fibrosis noninvasively. Monitor every 3 months. Biopsy if noninvasive tests suggest evidence of significant fibrosis, ALT is persistently elevated, age[35 years or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis Noncirrhotic HBeAg- [2000 [29 ULN Observation for 3 months if no hepatic decompensation concerns. negative chronic Treat. Histology should be obtained or assess fibrosis noninvasively hepatitis B 1–29 ULN Rule out other causes of elevated ALT.Assess fibrosis noninvasively. Monitor every 3 months. Biopsy if noninvasive tests suggest evidence of significant fibrosis, age[35 years, ALT is persistently elevated, or there is a family h/o HCC or cirrhosis. Treat, if moderate to severe inflammation or significant fibrosis Persistently normal Assess fibrosis noninvasively. Monitor every 3 months. Biopsy if ALT becomes elevated, noninvasive tests suggest evidence of significant fibrosis, age[35 years or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis \2000 [ULN Rule out other causes of elevated ALT. Assess fibrosis noninvasively. Monitor every 3 months. Biopsy, if noninvasive tests suggest evidence of significant fibrosis, ALT is persistently elevated, age [35 years or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis Persistently normal Assess Fibrosis noninvasively. Monitor ALT every 3–6 months and/or DNA every 6–12 months. Biopsy if noninvasive tests suggest evidence of significant fibrosis, ALT becomes elevated, age [35 years or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis Moderate to severe inflammation on liver biopsy means either hepatic activity index by Ishak activity score[3/18 or METAVIR activity score A2 or A3; significant fibrosis means F C2 by METAVIR fibrosis score or Ishak fibrosis stage C3. Significant fibrosis by noninvasive markers means liver stiffness C8 kPa (by Fibroscan) or APRI C1.5. Cirrhosis by noninvasive markers means liver stiffness C11 kPa (by Fibroscan) or APRI C2.0 123 Hepatol Int (2016) 10:1–98 23 Fig. 1 Treatment indications for chronic HBV-infected Chronic HBV Infected Paent patients with cirrhosis or reactivation of chronic HBV infection Severe reacvaon of Decompensated Cirrhosis Compensated Cirrhosis* Chronic HBV • HBV DNA > 2000 IU/ml if normal ALT, HBV DNA Detectable � HBV DNA detectable if elevated ALT � Treat � Treat Treat � Histology not needed � Histology should be immediately � Consider LT of no obtained or assess stabilizaon fibrosis noninvasively.* * Cirrhosis by non-invasive markers means Liver sffness ≥ 11 kPa (by Fibroscan) or APRI ≥2.0 if ALT levels are normal. Liver biopsy is recommended, may be followed by disease remission. Thus, it is reason- but noninvasive assessment of fibrosis is another option able to delay treatment for an observation period of (Fig. 1). 3 months, if there is no concern about hepatic Treatment may be started in pre-cirrhotic chronic HBV- decompensation. infected patients if they have persistently elevated ALT Patients with severe reactivation of chronic HBV levels [2 times the upper limit of normal (ULN) (at least infection [reactivation with the presence of coagulopathy 1 month between observations) and HBV DNA with prolonged prothrombin time (prolonged by more than [20,000 IU/ml if HBeAg positive and [2000 IU/ml if 3 s) or INR increased to [1.5] with impending or overt HBeAg negative. In such patients, liver biopsy may pro- hepatic decompensation should be treated immediately vide additional useful information, especially in those with with antiviral agents to prevent the development or dete- doubtful causes of hepatic necroinflammation. A nonin- rioration of hepatic decompensation (see ‘‘Treatment of vasive method for the estimation of the extent of fibrosis is patients with reactivation of chronic HBV infection useful in patients who start treatment without liver biopsy. including those developing acute on chronic liver failure’’ There is lack of sufficient data to start antiviral therapy section) (Fig. 1). in the sub-groups of patients where there is significant Available information suggests that patients with per- fibrosis, but the ALT levels are normal or minimally ele- sistently normal alanine aminotransferase levels (PNALT) vated or the DNA levels are below the defined limits. or minimally raised ALT levels (1–2 times the ULN) These group of patients are not uncommon and the experts respond poorly, in terms of HBeAg seroconversion, when deliberated on the treatment options for them. It was treated with currently available drugs. A recent article unanimously agreed that these patients do merit antiviral evaluating the effects of tenofovir disoproxil fumarate therapy, in order to prevent further progression of fibrosis (TDF) in HBeAg-positive patients with normal levels of and other complications of liver disease. In addition, ALT and high levels of HBV DNA in a double-blinded therapy might help in stabilizing their disease or even way was reported. The authors demonstrated that both TDF regression of fibrosis. In these cases, serial noninvasive monotherapy and the combination of TDF and emtric- assessment of fibrosis and bio-chemical assessment of itabine are effective in the suppression of HBV DNA in inflammation and disease severity should be done. patients with normal ALT and high viral load. However, Patients with a rising trend in ALT or bilirubin may be only 5 % of patients achieved HBeAg seroconversion after developing an exacerbation, and even severe hepatitis or 192 weeks of therapy with combination of TDF and hepatic decompensation. They should be monitored closely emtricitabine [166]. Therefore, no drug treatment is rec- with weekly or biweekly serum ALT, bilirubin, and pro- ommended for this group of patients unless they have thrombin time measurement. Such exacerbations, particu- evidence of significant fibrosis, cirrhosis, or are under a larly in patients with declining serum HBV DNA level, protocol. One recent meta-analysis showed that nearly half may also precede spontaneous HBeAg seroconversion, and (48 %) of the 683 CHB patients with minimally increased 123 24 Hepatol Int (2016) 10:1–98 Non-cirrhoc HBeAg posive Chronic HBV infected paent HBV DNA VIRAL HBV DNA HBV DNA LOAD 2000 -20,000IU/mL <2000IU/mL >20,000 IU/mL Any Any ALT1-2x ULN or N ALT>2x ULN ALT � If elevated ALT, exclude � If elevated ALT, other causes exclude other causes � Observe for 3 months, � Assess fibrosis � Assess fibrosis � Assess fibrosis if no concerns of noninvasively noninvasively noninvasively hepac Fibrosis � Monitor 3 monthly � Monitor 3 monthly � Monitor 3 monthly decompensaon � Individualize liver � Individualize liver � Individualize liver � Treat if no biopsy@ biopsy@ biopsy@ seroconversion � Treat if moderate to � Treat if moderate to � Treat if moderate to � Obtain histology or severe inflammaon or severe inflammaon or severe inflammaon assess fibrosis non- significant fibrosis. $ significant fibrosis.$ or significant fibrosis.$ invasively.$ @ Biopsy if non-invasive tests suggest evidence of significant fibrosis, ALT persistently elevated, Age >35 yr. or family h/o HCC or cirrhosis. � Moderate to severe inflammaon on liver biopsy means either Hepac acvity index by Ishak acvity score >3/18 or METAVIR acvity score A2 or A3 � Significant fibrosis on liver biopsy means F≥2 by METAVIR fibrosis score or Ishak fibrosis stage ≥ 3 � Liver sffness ≥ 8 kPa ( by Fibroscan) or APRI ≥1.5 indicates significant fibrosis; Liver sffness ≥ 11 kPa (by Fibroscan) or APRI ≥2.0 indicates cirrhosis Fig. 2 Treatment indications for noncirrhotic HBeAg-positive chronic HBV-infected patients Non-cirrhoc HBeAg negave Chronic HBV infected paent VIRAL HBV DNA <2000IU/mL HBV DNA>2000 IU/mL LOAD ALT>2x ULN ALT ALT > ULN Persistently normal ALT1-2x ULN or N � If elevated ALT, exclude � Assess fibrosis � Observe for 3 � Assess fibrosis Fibrosis other causes noninvasively months, if no noninvasively � Assess fibrosis � Monitor ALT 3-6 � Individualize liver concerns of hepac noninvasively biopsy@ decompensaon monthly and DNA 6-12 � Monitor 3 monthly � Treat if moderate to � Treat if no monthly � Individualize liver � Individualize liver severe inflammaon seroconversion biopsy@ or significant fibrosis* � Obtain histology or biopsy@ � Treat if moderate to assess fibrosis non- � Treat if moderate to severe inflammaon or severe inflammaon or invasively.$ significant fibrosis.$ significant fibrosis.$ @ Biopsy if non-invasive tests suggest evidence of significant fibrosis, ALT persistently elevated, Age >35 yr. or family h/o HCC or cirrhosis. � Moderate to severe inflammaon on liver biopsy means either Hepac acvity index by Ishak acvity score >3/18 or METAVIR acvity score A2 or A3 � Significant fibrosis on liver biopsy means F≥2 by METAVIR fibrosis score or Ishak fibrosis stage ≥ 3 � Liver sffness ≥ 8 kPa ( by Fibroscan) or APRI ≥1.5 indicates significant fibrosis; Liver sffness ≥ 11 kPa (by Fibroscan) or APRI ≥2.0 indicates cirrhosis Fig. 3 Treatment indications for noncirrhotic HBeAg-negative chronic HBV-infected patients 123 Hepatol Int (2016) 10:1–98 25 ALT levels (levels 1–2 times the ULN) from nine recruited fetoprotein determinations every 3–6 months and ultra- studies had stage 2 or higher fibrosis (95 % CI 36–61 %). sonography and/or HBV DNA every 6–12 months is A subgroup of HBeAg-positive and HBeAg-negative needed (Fig. 3). patients showed similar rates of fibrosis (41 vs. 47 %; 3:5 Recommendations: indications of therapy in chronic p = nonsignificant) [167]. Another study tried to explore HBV infection the hepatic histological changes after long-term antiviral therapy in CHB patients with persistently normal ALT 3:5:1 HBsAg positive patients with decompensated levels and advanced hepatic fibrosis [168]. The authors cirrhosis and detectable HBV DNA require immediate antiviral treatment with NA(s). compared paired liver biopsies before and after lamivudine treatment in CHB and normal ALT levels. Of them, 82.4 % Liver transplantation should be considered if of patients had a baseline fibrosis score of 4 by Scheuer patients do not stabilize with medical man- scoring system and this was reduced to 17.6 % after a agement (A1). median duration of 44.5 months of therapy. 3:5:2 Patients with compensated cirrhosis and HBV If patients are not considered for treatment, they should DNA [2000 IU/ml should be considered for be followed up every 3–6 months. HBeAg-positive patients treatment even if ALT levels are normal (A1). with serum HBV DNA[20,000 IU/ml and PNALT should Patients with compensated cirrhosis should be also be followed up every 3 months. A liver biopsy should treated irrespective of the ALT and HBV DNA levels (C2). be considered in viremic patients older than 35–40 years, especially those with high normal or minimally raised ALT 3:5:3 Patients with suspected severe reactivation levels or family history of HCC or cirrhosis, with intent to [reactivation with the presence of coagulopa- identify the group of patients with significant fibrosis thy with prolonged prothrombin time (pro- requiring treatment (Fig. 2). longed by more than 3 s) or INR increased to Patients with active HBV replication (HBV DNA [1.5] of chronic HBV infection should be [2000 IU/ml) and minimally elevated (1–29 ULN) or started on antiviral therapy immediately after persistently normal ALT should have liver fibrosis asses- sending tests for quantitative HBV DNA, but sed. Liver biopsy may be needed before therapy to assess without waiting for the results (B1). the necroinflammatory grade, determine the fibrotic stage, 3:5:4 Treatment may be started in pre-cirrhotic and exclude other possible causes of raised ALT levels as a chronic HBV-infected patients if they have persistently elevated ALT levels [2 times guide for consideration of antiviral treatment. Treatment should be instituted if moderate to severe hepatic upper limit of normal (ULN) (at least 1 month between observations) and HBV DNA necroinflammation or significant fibrosis is found. If liver biopsy is not feasible, noninvasive assessment of liver [20,000 IU/ml if HBeAg positive and fibrosis should be considered as an alternative. [2000 IU/ml if HBeAg negative (B1). Immunotolerant patients need special attention. HBeAg- 3:5:5 Patients with high HBV DNA levels positive patients under 30 years of age with persistently ([20,000 IU/ml if HBeAg positive and normal ALT levels and a high HBV DNA level, without [2000 IU/ml if HBeAg negative) but ALT any evidence of liver disease and without a family history \29 ULN should obtain assessment of fibro- of HCC or cirrhosis, generally do not require immediate sis noninvasively, and should be monitored therapy. In these cases, noninvasive assessment of liver every 3 months. Biopsy should be considered if noninvasive tests suggest evidence of sig- fibrosis should be done. Follow-up should be done at least every 3–6 months. A liver biopsy should be considered if nificant fibrosis, ALT becomes persistently significant fibrosis is suspected or if there is family history elevated, if age is[35 years or there is family of HCC or cirrhosis. h/o HCC or cirrhosis. They should be consid- HBeAg-negative patients with persistently normal ered for treatment if biopsy shows moderate to ALT levels (ALT determinations every 3 months for at severe inflammation or significant fibrosis least 1 year) and HBV DNA levels below 2000 IU/ml, (B1). without any evidence of liver disease, do not require 3:5:6 HBeAg-positive patients with HBV DNA immediate therapy. Evaluation of the severity of fibrosis \20,000 IU/ml, should be evaluated for other by a noninvasive method might be useful as the first causes if ALT is elevated, should obtain screening test in such cases. A suspicion of significant assessment of fibrosis noninvasively, and should be monitored every 3 months. Biopsy fibrosis should help identify patients for liver biopsy. There is however, limited data using such an algorithmic should be considered if noninvasive tests approach in CHB. Follow-up with ALT and alpha- suggest evidence of significant fibrosis, ALT 123 26 Hepatol Int (2016) 10:1–98 becomes persistently elevated, if age is Korea and the Philippines, while its development has been [35 years or there is family h/o HCC or stopped in others countries due to myopathy. cirrhosis. They should be considered for treatment if biopsy shows moderate to severe L-Nucleoside analogues Lamivudine In the Asian inflammation or significant fibrosis (B1). lamivudine (LAM) trial and a multi-center trial in China, 3:5:7 HBeAg-negative patients with HBV DNA HBeAg seroconversion was achieved in approximately \2000 IU/ml, should be evaluated for other 44–47 % after 4–5 years of therapy [169]. In a long-term causes if ALT is elevated, should obtain follow-up study among 95 CHB patients (43 HBeAg-pos- assessment of fibrosis noninvasively, and itive) on lamivudine for at least 10 years with maintained should be monitored every 3 months if ALT viral suppression (HBV DNA\2000 IU/ml), seven (10 %) is elevated (if ALT is normal, monitoring patients had HBsAg seroclearance. Baseline HBsAg should be done with ALT every 3–6 months \1000 IU/ml and on-treatment reduction of HBsAg and with DNA every 6–12 months). Biopsy [0.166 log IU/ml were optimal cutoffs to predict HBsAg should be considered if noninvasive tests seroclearance (negative predictive values 98.1 and 97.8 %, suggest evidence of significant fibrosis, ALT respectively), but in general, the HBsAg decline was slow remains persistently elevated, if age is at 0.104 log IU/ml/year [170]. [35 years or there is family h/o HCC or In a Korean study including 178 patients with HBeAg cirrhosis. They should be considered for seroconversion and discontinued lamivudine, the relapse treatment if biopsy shows moderate to severe (defined as HBV DNA [140,000 copies/ml) rate after inflammation or significant fibrosis (C1). More 12-month consolidation was 8.7 % in 5 years, in contrast to long-term data using antiviral therapy is 61.9 % in those with consolidation therapy \12 months needed for these groups of patients. [171]. In another study including 101 patients from Taiwan 3:5:8 Noninvasive methods for the estimation of the and Hong Kong, longer consolidation of lamivudine was extent of fibrosis are useful in selecting associated with a higher combined response (HBeAg patients for liver biopsy. Patients with the seroconversion and undetectable HBV DNA) 6 months suggestion of significant fibrosis by noninva- post-treatment; 25.6, 39.0 and 71.4 % with consolidation sive markers [mean liver stiffness C8 kPa (by therapy for \12, 12–18 and [18 months, respectively Fibroscan) or APRI C1.5] should be consid- [172]. A study among 83 Taiwanese patients found that ered for liver biopsy followed by treatment, if HBsAg level \300 IU/ml at the end of lamivudine treat- biopsy shows moderate to severe inflammation ment could predict HBsAg seroclearance after stopping or significant fibrosis (C1) (Table 5). Patients lamivudine (five of nine patients, 55.5 %) at a median with suspected significant fibrosis but unwill- follow-up of 4 years [173]. More data is needed for the use ing to undergo liver biopsy may be considered of HBsAg level to guide treatment cessation. for treatment (C2) or should be kept on regular In HBeAg-negative patients, studies among Chinese follow-up (B1). patients who stopped LAM after a minimum of 24 months 3:5:9 Patients who are not considered for treatment of treatment with at least three results of undetectable HBV should be followed up regularly by measure- DNA 6 months apart showed a post-treatment relapse ment of ALT levels, HBV DNA, AFP, ultra- (HBV DNA C10 copies/ml) rate of 37–50 % at 1 year sonography and fibrosis assessment (Table 5) [174, 175]. A study from Hong Kong including 53 HBeAg- (B1). negative patients treated with LAM for a mean of 34 (12–76) months and stopped LAM therapy for 3.6 Results of currently available therapies, 47 ± 35 months showed that end-of-treatment HBsAg predictors of response to therapy, follow-up B100 IU/ml plus reduction by[1 log from baseline could and stopping rules during therapy in chronic HBV predict sustained response (HBV DNA B200 IU/ml) of infection 100 % (five of five patients) at 12 months and HBsAg loss at 5 years post-treatment [176]. Another Taiwanese study 3.6.1 Results of and predictors of response to nucleos(t)ide including 107 HBeAg-negative patients treated by LAM analogues for 93 ± 35 months showed that end of treatment HBsAg \120 and \200 IU/ml were associated with HBsAg loss Lamivudine, adefovir dipivoxil, entecavir, telbivudine and (19 of 24 patients, 79.2 %) and sustained response (HBV tenofovir disoproxil fumarate have been approved in most DNA \2000 IU/ml; 28 of 30, 93.3 %) at a median of Asia Pacific countries. Clevudine has been approved in 4 years post-treatment [177]. 123 Hepatol Int (2016) 10:1–98 27 LAM is well tolerated, even in patients with decom- seroconversion, 28 (46 %) had HBV DNA \4 log copies/ pensated cirrhosis or in pediatric patients [178]. The key ml (14 patients had undetectable HBV DNA), and four LAM resistant mutant is at the YMDD locus in the cat- (6.5 %) had HBsAg loss [184]. alytic domain of the HBV polymerase gene (rtM204I/V/S), The most common LdT resistant substitution is rtM204I, which may confer cross-resistance to other drugs in the L- and rtA181T/V [179]. The 2-year risk of LdT resistance nucleoside group, such as telbivudine and entecavir. The was 25.1 % in HBeAg-positive patients and 10.8 % in compensatory mutation, rtL180M, is frequently associated HBeAg-negative patients, which is lower than that of with rtM204V/S and will reduce the susceptibility to lamivudine [180]. In the subgroup that had no genotypic entecavir. Another LAM resistant mutation, rtA181T/V, resistance at year 2 and received LdT up to year 4, the may confer cross-resistance to adefovir and telbivudine, cumulative virological breakthrough/resistance rate was and has partial resistance to tenofovir. Compensatory 18.8/10.6 % for HBeAg-positive and 15.9/10.0 % for codon substitutions that increase viral replication may also HBeAg-negative patients [184]. be found, such as rtL80V/I, rtV173L, rtT184S/G [179]. The In a multi-centered Chinese study among HBeAg-posi- incidence of rtM204V/I substitution increased from 24 % tive patients on LdT, patients who had HBV DNA C300 in 1 year to 70 % in 5 years. Undetectable HBV DNA at copies/ml at week 24 were randomized to add-on adefovir week 24 was associated with 9 and 5 % of LAM resistance treatment versus continuation of telbivudine until week at 2 years among HBeAg-positive and HBeAg-negative 104. The add-on adefovir group had a higher chance of patients, respectively [180]. HBV DNA\300 copies/ml (76.7 vs. 61.2 %), a lower risk Although prolonged lamivudine (LAM) therapy is of genotypic resistance (2.7 vs. 25.8 %) and comparable associated with the emergence of LAM-resistant mutations, rate of HBeAg seroconversion (23.7 vs. 22.7 %) compared it is still a commonly used therapy in many Asian countries to the continued LdT group at week 104 [185]. In a real-life because of its established long-term safety and low cost. In cohort in Hong Kong, among the 25 patients who had one recent multicenter study on 838 patients, an individual detectable HBV DNA but\2000 IU/ml after 6–12 months prediction model for lamivudine treatment response in of telbivudine, 24 (96 %) could achieve undetectable HBV HBeAg-positive CHB patients was suggested. In the mul- DNA after switching to entecavir for a median follow-up of tivariate analysis, age [odds ratio (OR) 0.974, p\ 0.001], 2 years [186]. LdT is generally well tolerated, including in baseline alanine aminotransferase level (OR 1.001, patients with decompensated liver cirrhosis [178]. Based p = 0.014), and baseline HBV DNA level (OR 0.749, on the databases of the GLOBE study as well as other p \ 0.001) were independent factors for HBeAg serocon- studies including compensated and decompensated version. Based on the predictors, an IPM was established. patients, LdT was found to improve renal function, as Patients were classified into high ([50 %), intermediate measured by calculated eGFR after 24 weeks of therapy, (30–50 %), or low (B30 %) response groups based on their and this benefit was seen among patient who were aged probability of HBeAg seroconversion according to the [50 years and those with eGFR B90 at baseline [187]. The IPM. The cumulative HBeAg seroconversion rate at improvement in eGFR was confirmed in another Korean 6 years for the high, intermediate, and low response groups study with 43 patients on LdT and adefovir combination was 66.0, 48.5, and 21.8 %, respectively (p \ 0.001). This therapy for 24 weeks [188]. Among patients who received model may allow screening of LAM responders prior to the LdT for 4 years, creatine kinase increase was reported in commencement of antiviral treatment, but needs further 10.1 % of patients and muscle symptoms in 6.1 % of validation [181]. patients (myopathy and myositis in 0.6 %) [187]. Telbivudine Telbivudine (LdT) 600 mg daily has been shown to have more potent HBV DNA suppression than Acyclic nucleotide phosphonates Adefovir dipivoxil In HBeAg-positive patients, HBeAg seroconversion can be LAM and ADV [182, 183]. After excluding patients who had drug resistance at year 2 in the GLOBE study, con- achieved in 30–37 % after 3–5 years of adefovir (ADV) treatment [189, 190]. In HBeAg-negative patients, 67 % of tinuation of LdT until year 4 was associated with unde- tectable HBV DNA in 76 % of HBeAg-positive and 86 % patients had HBV DNA\200 IU/ml and 75 % had fibrosis of HBeAg-negative patients, HBeAg seroconversion in regression after 240-week treatment with ADV [191]. 53 % of HBeAg-positive patients, and HBsAg loss in The safety profile of 10 mg ADV daily was similar to 1.9 % of HBeAg-positive patients and 0.6 % in HBeAg- placebo in patients with compensated CHB. Reversible negative patients [184]. Among the 61 patients who had increase in serum creatinine of more than 0.5 mg/dl telbivudine stopped because of HBeAg loss for[6 months (maximum 1.5 mg/dl) was reported in up to 3 % of patients and HBV DNA \5 log copies/ml (98 % had HBV DNA when the therapy is extended to 5 years [191]. \300 copies/ml), 50 (82 %) had sustained HBeAg 123 28 Hepatol Int (2016) 10:1–98 The primary drug resistance mutations against ADV are there was a small decline in the bone mineral density of the rtA181V/T and rtN236T. The cumulative incidence of spine (-1.4 %) and hip (-1.8 %) at week 96 of treatment genotypic resistance to ADV was 29 % after 5 years of [198]. Rare cases of Fanconi syndrome that readily therapy in HBeAg-negative patients [191]. The substitution resolved with cessation of tenofovir have been reported rtN236T has partial cross-resistance to tenofovir, but it is [199]. sensitive to LAM, LdT and entecavir [179]. No TDF resistance has been reported up to 7 years ADV is effective in suppressing HBV DNA in patients [200]. Tenofovir monotherapy is sufficient in the treatment with rtM204I/V HBV substitution. In a 5-year follow-up of rtM204V/I ± rtL180M HBV variants; 89.4 % patients cohort of 165 LAM-resistant patients, add-on ADV therapy on TDF versus 86.3 % patients on a combination of TDF resulted in undetectable HBV DNA in 74 % and genotypic and emtricitabine achieved undetectable HBV DNA ADV resistance in 10.2 % of patients [192]. Unde- (\69 IU/ml) after 96 weeks of treatment [198]. In vitro tectable HBV DNA at month 6 is the best predictor of studies showed that a single mutation of the ADV resistant maintained HBV DNA suppression; 87–100 % of patients mutations, A181T/V or N236T, had little reduced suscep- with undetectable HBV DNA at month 6 had unde- tibility to TDF. On the other hand, presence of the double tectable HBV DNA at 3–5 years on continuous ADV add- mutant rtA181V/T ? rtN236T had low level, reduced on therapy [193, 194]. susceptibility to TDF [201]. In a post hoc analysis of a multi-center study comparing TDF versus TDF and Tenofovir disoproxil fumarate Tenofovir disoproxil emtricitabine combination among ADV refractory patients, fumarate (TDF) is an acyclic adenine nucleotide analogue patients with rtN236T showed a similar decline in HBV effective for both HBV and HIV. Five-year continuous DNA as of those with wild-type HBV in the initial TDF therapy was associated with HBV DNA\400 copies/ 24 weeks by either regime [202]. Another European multi- ml in 65 % of HBeAg-positive and 83 % of HBeAg-neg- center study showed that TDF monotherapy and TDF/ ative patients; HBeAg seroconversion in 40 % and HBsAg emtricitabine combination were equally effective in sup- loss in 10 % (all but one were HBeAg-positive; 96 % HBV pressing the HBV DNA to \400 copies in 168 weeks (82 genotype A and D) patients [195]. On paired liver biopsy at and 84 %, respectively) among ADV refractory patients, 5 years, 87 % of the 348 patients had histological and there was no difference in the response with regard to improvement and 74 % of the 96 cirrhotic patients had the baseline LAM/ADV resistance profile [197]. In a case regression of liver cirrhosis [195]. Patients who had high series of 57 patients who failed to achieve complete HBV viral load ([9 log copies/ml) took a longer time to reach DNA suppression by antiviral drugs including entecavir or HBV DNA\400 copies/ml than those with lower baseline TDF due to the presence of multi-drug resistant HBV, a HBV DNA levels, but overall, 96.9 % of patients who combination of TDF and entecavir (0.5 mg for naıve or completed 240 weeks of therapy could achieve HBV DNA 1 mg for LAM experienced patients daily) could achieve \169 copies/ml [196]. Among immune-tolerant patients undetectable HBV DNA (\80 IU/ml) in 90 % of patients (HBeAg-positive, HBV DNA [1.7 9 10 IU/ml, normal after treatment for a median of 21 months [203]. ALT), a combination of tenofovir with emtricitabine was associated with a higher rate of undetectable HBV DNA D-Cyclopentanes than tenofovir monotherapy (76 vs. 55 %) after treatment for 4 years, but the overall rate of HBeAg seroconversion Entecavir Entecavir (ETV) is a cyclopentyl guanosine was only 5 % (all in patients on combination therapy) analogue with potent selective inhibition of the priming, [166]. Among the 52 patients who stopped treatment after DNA-dependent synthesis, and reverse transcription func- 4 years, 51 of them had rapid increase in HBV DNA within tions of HBV polymerase. In Asian cohorts treated with 4 weeks and one patient had an ALT flare within 24 weeks. ETV 0.5 mg daily, approximately 83–92 % patients had TDF is generally well tolerated, including in patients undetectable HBV DNA, 26–49 % patients had HBeAg with decompensated liver disease [165]. Reduction of seroconversion and \1 % of patients had HBsAg sero- creatinine clearance to \50 ml/min is extremely uncom- clearance at year 3 of treatment [204, 205]. Among 222 mon among patients with normal baseline renal function treatment-naı ¨ve patients treated with entecavir in Hong (\1 %) after 3–5 years of continuous TDF treatment [197, Kong, 97.1 % patients had undetectable HBV DNA, 198]. Approximately 1 % of patients developed 66.9 % had HBeAg seroconversion and only one patient hypophosphatemia (\2 mg/dl or 0.65 mmol/l), and most of achieved HBsAg seroclearance after 5 years [206]. The them resolved without dosage modification, treatment rate of HBsAg decline is approximately 0.125 log IU/ml/ interruption or phosphate supplementation. In a multi- year, which explains the need for long-term therapy and centered study comparing TDF (n = 141) with TDF and low rate of HBsAg clearance in ETV-treated patients [206]. emtricitabine (n = 139) in lamivudine-resistant CHB, Among HBeAg-positive patients with high viral load ([10 123 Hepatol Int (2016) 10:1–98 29 IU/ml), a combination of tenofovir and entecavir could ETV is well tolerated. The US Food and Drug Admin- achieve a higher rate of undetectable HBV DNA than istration (FDA) requires all approved NAs to carry the entecavir monotherapy at week 96 (78.8 vs. 62.0 %, ‘‘black box’’ warning for the potential development of respectively) [207]. However, this study lacks the tenofovir lactic acidosis as a result of mitochondrial toxicity. Most of monotherapy arm for comparison. the reports of lactic acidosis for LAM and TDF have been In a Korean study, approximately 14–16 % of treat- when they were used in combination with other antiretro- ment-naıve patients had primary nonresponse as defined by viral agents in HIV-infected patients. Isolated cases have AASLD (\2 log reduction in HBV DNA at month 6) or been reported for TEL and ADV in HBV patients [219, EASL (\1 log reduction in HBV DNA at month 3), but all 220]. Reports of cases have also been observed in patients primary non-responders could achieve undetectable HBV treated with ETV, in particular those with impaired liver DNA after 54 months of treatment [208]. On the other function and high model for end-stage liver disease hand, partial virological response (detectable HBV DNA at (MELD) score [221, 222]. Interestingly, only the MELD month 12) was predictive of a lower probability of com- and not the Child–Pugh score was correlated with the plete HBV DNA suppression and higher risk of virological development of lactic acidosis, suggesting that renal breakthrough. Approximately 18–26 % of treatment-naı ¨ve impairment may be an important contributor. In a series of patients had partial virological response on entecavir; the 11 patients treated with ETV before liver transplant for cumulative rate of virological response (undetectable HBV acute flares of CHB with decompensation, none had evi- DNA) at year 3 is 45–58 % and virological breakthrough is dence of lactic acidosis [223]. This highlights the impor- 5.1–6.3 % [205, 209]. For some of these patients, viro- tance of appropriate dose adjustment of NAs according to logical breakthrough might be related to poor drug the calculated CrCl. Lactic acidosis is rarely reported adherence. among Asian patients with decompensated cirrhosis [164]. Long-term cohort studies among entecavir-treated Although it is likely to be a rare event, clinical vigilance patients compared with historic untreated controls in Japan must be adopted for this potentially fatal complication, and Hong Kong demonstrated reduction in mortality, liver- especially for those who are receiving combination ther- related complication and HCC, especially among patients apy, and for those with impaired liver function and multi- with liver cirrhosis [210–212]. Patients who achieved organ failure. undetectable HBV DNA during treatment had better ETV has a high genetic barrier to resistance. Drug prognosis [213, 214]. Over 97 % of treatment-naı ¨ve resistance requires at least three codon substitutions, patients could achieve maintained HBV DNA suppression including rtL180M, rtM204I/V, plus a substitution at one on entecavir after 2–3 years, while most patients who of the following amino acids: rtT184S/G, rtS202I/G and/or failed to achieve undetectable HBV DNA were exposed to rtM250V [179]. Among treatment-naıve patients, ETV previous antiviral agents [214]. Among patients who failed resistance is very rare. In the long-term follow-up of the to have complete HBV DNA suppression with entecavir, international trial on HBeAg-positive and HBeAg-negative switching or add-on tenofovir was associated with patients and in a long-term follow-up study in Hong Kong, 97–100 % undetectable HBV DNA after 12 months [215, the cumulative probability of ETV resistance was 1.2 % 216]. after 5 years of ETV treatment [218]. In a retrospective Taiwanese study among 95 HBeAg- ETV is effective in the treatment of ADV resistance negative patients who discontinued ETV therapy after [179]. Switching to ETV monotherapy (1 mg daily) in undetectable HBV DNA had been documented on three LAM resistant patients is associated with a [50 % cumu- occasions, each 6 months apart, the cumulative clinical lative risk of ETV, as rtM204I/V and rtL180M reduce the relapse (ALT[2 time upper limit of normal and HBV DNA genetic barrier of resistance to ETV [224]. Among lami- [2000 IU/ml) was 45.3 % in 1 year [217]. Nine patients vudine resistant patients who had HBV DNA[2000 IU/ml had spontaneous remission while the remaining 34 patients on LAM and ADV combination therapy, a combination of were retreated by ETV with good HBV DNA suppression. entecavir 1 mg daily and ADV could achieve unde- In another prospective study from Hong Kong, ETV was tectable HBV DNA (\60 IU/ml) in 29 % in 1 year and stopped in 184 HBeAg-negative patients, fulfilling the 42 % in 2 years [225]. same stop treatment criteria. The cumulative rate of viro- Other direct antiviral agents Clevudine is an L-nucle- logical relapse (HBV DNA [2000 IU/ml) was 72.4 % at oside pyrimidine analogue with potent antiviral activity 6 months and 91.2 % at 1 year; 25.8 % of patients had against HBV. With clevudine 30 mg daily, the cumulative elevated ALT level before ETV retreatment was recom- rate of undetectable HBV DNA is 67–83 % and HBeAg menced [218]. No baseline or on-treatment factors were seroconversion is 23–31 % after 2–3 years [226, 227]. found to be consistently predictive of post-treatment Virological breakthrough occurs in approximately 25 % of relapse after stopping ETV. 123 30 Hepatol Int (2016) 10:1–98 patients, and is primarily related to rtM204I ± rtL180M 48 weeks, the combination group had superior virological mutants. Myopathy was reported in up to 13 % of patients response rates compared to the ETV group (90.0 vs. after being treated for a mean of 14 (range 78.9 %, p = 0.01). At week 96, LAM ? ADV was more 9.3–23.5) months, but it was resolved spontaneously after effective than ETV in ALT normalization [RR 1.11, 95 % stopping clevudine [226]. The global development of cle- CI (1.02, 1.21), p = 0.01] and HBeAg seroconversion [RR vudine was terminated in 2009 because of case reports of 2.00, 95 % CI (1.26, 3.18, p = 0.003)], and no significant serious myopathy related to myonecrosis. difference was found in the virological response (p = 0.23). No viral resistance occurred in combination Besifovir (LB80380) is an acyclic nucleotide phospho- therapy and six patients in the ETV group were experi- nate with chemistry similar to ADV and TDF. In a phase enced with viral breakthrough [231]. In a recent clinical IIb, open-label, multicenter study among 114 treatment- trial, 379 treatment-naı ¨ve patients were randomized to naı ¨ve patients randomized to besifovir 90 mg daily, besi- receive entecavir monotherapy (n = 186) or entecavir plus fovir 150 mg daily and entecavir 0.5 mg daily for tenofovir (n = 198) [232]. By week 96, 76 % in the 48 weeks, undetectable HBV DNA was found in 63.6, 62.9 monotherapy arm and 83 % in the combination arm had and 58.3 %, and HBeAg seroconversion was found in 11.1, HBV DNA below 50 IU/ml (p = 0.088). In a post hoc 15 and 9.5 %, respectively [228]. No drug resistance or subgroup analysis, combination therapy was superior to elevated serum creatinine was found among patients on entecavir monotherapy in patients with positive HBeAg besifovir. Ninety-four percent of patients on besifovir had and baseline HBV DNA over 8 log IU/ml. However, reduced serum L-carnitine, but the L-carnitine levels because the subgroup analysis was not planned a priori, the returned to normal with supplement. findings can only be considered exploratory and have to be Tenofovir alafenamide fumarate (TAF) is a nucleotide confirmed in another study focusing on patients with high reverse transcriptase inhibitor and a novel prodrug of viral load. The efficacy of tenofovir monotherapy and tenofovir. Closely related to the commonly used reverse- higher dose entecavir (1.0 mg) has to be evaluated before transcriptase inhibitor tenofovir disoproxil fumarate, it has combination therapy can be recommended for this group of greater plasma stability than tenofovir disoproxil fumarate, patients. and provides efficient delivery of active drug to hepato- cytes at reduced systemic tenofovir exposures. In a recent Monitoring treatment and guidance for stopping therapy study, noncirrhotic, treatment-naıve subjects with CHB in chronic HBV-infected patients treated with nucleos(t)ide were randomized (1:1:1:1:1) to receive tenofovir alafe- analogues namide 8, 25, 40, or 120 mg, or tenofovir disoproxil fumarate 300 mg for 28 days and were assessed for safety, Efficacy and safety of NA therapy should be monitored antiviral response, and pharmacokinetics, followed up by regularly. Primary non-response, defined as\1 log IU/ml off-treatment for 4 weeks. Tenofovir alafenamide was safe decline in HBV DNA level from baseline at month 3 of and well tolerated; declines in HBV DNA were similar to therapy, is rare with NA therapy [233]. Checking patient’s tenofovir disoproxil fumarate at all doses evaluated. compliance is recommended in patients with primary non- Tenofovir alafenamide 25 mg has been selected for further response. Virological response at 6 months of lamivudine hepatitis B clinical development [229]. or telbivudine therapy and at 12 months of adefovir ther- Combination of NAs De novo combination of lamivudine apy is associated with the risk of emergence of drug and adefovir does not improve viral suppression over resistance and virological and serological response with lamivudine alone, although this reduces, but does not long-term therapy [234, 235]. HBV DNA level should be abolish, lamivudine resistance. Furthermore, adefovir measured at month 3 and 6 of therapy and then every resistance was not reported in this study. Combining tel- 3–6 months if agents with low genetic barrier are used bivudine and lamivudine does not achieve greater reduc- (lam, Adefo, telbivudine), and every 6 months in patients tion in HBV DNA than telbivudine monotherapy, but may treated with a high genetic barrier to resistance, such as even increase the risk of telbivudine resistance [230]. This entecavir or tenofovir. Serum ALT and HBeAg and anti- suggests that NAs with the same resistance pattern should HBe (in patients with HBeAg-positive CHB) should be not be combined. monitored every 3 months. Checking compliance and testing for genotypic resis- In one meta-analysis evaluating the effectiveness and tance should be done in patients with virological break- resistance of de novo combination of lamivudine and through during NA therapy. Due to potential adefovir dipivoxil compared with entecavir monotherapy nephrotoxicity, monitoring serum creatinine and serum for nucleos(t)ide-naive patients with chronic HBV infec- phosphate levels should be done every 3 months during tion (five studies, 328 patients), it was found that at adefovir or tenofovir therapy [236, 237]. Muscle symptoms 123 Hepatol Int (2016) 10:1–98 31 or muscle weakness should be monitored during tel- follow-up ranged from 6 months to 8 years, 4–96 weeks bivudine or clevudine therapy [180, 238]. A decline of and 6–80 months, respectively, and patients were moni- HBsAg level during therapy may predict HBeAg or HBsAg tored with serum ALT and HBV DNA monthly in the first loss with long-term telbivudine, entecavir or tenofovir 1–3 months and every 3–6 months thereafter in most therapy [239–241]. However, more data is needed to con- studies), the 1-year off-therapy ‘virological relapse’ (HBV firm the results before making a recommendation. DNA [2000 IU/ml)and ‘clinical relapse’ (HBV DNA In HBeAg-positive CHB patients who achieve HBeAg [2000 IU/ml ? ALT elevation) occurred in \70 % and seroconversion with undetectable HBV DNA, the relapse \50 % of the patients, respectively, and \40 % of the rates depend on the duration of consolidation therapy patients received re-treatment. These rates were higher in [242]. One recent study described 94 patients who stopped patients with shorter treatment, shorter consolidation ther- NA after at least 1 year of therapy. Patients could be apy (\2 years) and those treated with less potent HBeAg-positive or HBeAg-negative at the start of therapy, nucleos(t)ide analogues. Off-therapy severe flares were but all were HBeAg-negative and had undetectable HBV rare and hepatic decompensation was reported in only one DNA (\200 IU/ml) at the time of discontinuation. Con- patient with cirrhosis. Biochemical relapse reflecting solidation therapy was defined as treatment duration enhanced immune-mediated hepatocyte killing may lead to between the first undetectable HBV DNA (in case of a higher chance for off-therapy HBsAg seroclearance and HBeAg-positive patients after HBeAg loss) and NA dis- possibly be desirable. Thus, with an appropriate stopping continuation. Relapse was defined as HBV DNA rule and a proper off-therapy monitoring plan, cessation of [2000 IU/ml measured twice 6 months apart within long-term nucleos(t)ide analogue therapy prior to HBsAg 1 year, or retreatment after an initial HBV DNA elevation. seroclearance in HBeAg-negative CHB is a feasible alter- At the start of therapy, 35 patients were HBeAg-positive native to indefinite treatment [246]. and 59 were HBeAg-negative. The cumulative relapse rate Hepatitis relapse with hepatic decompensation and death was 33 % at 6 months, 42.7 % at 1 year, and 64.4 % at is an important issue after cessation of NAs therapy in 5 years. Patients with at least 3 years of consolidation cirrhotic patients. The advantages of stopping NA therapy therapy (n = 37) had a 1-year relapse rate of 23.2 % are a finite duration of treatment, with improved adherence compared to 57.2 % for 1–3 years of consolidation therapy and retention in care, reduced costs, and minimization of (n = 32), and 55.5 % for\1 year of consolidation therapy renal and bone toxicity. The disadvantages are the risk of (n = 20) (p = 0.002). For each additional year of consol- reactivation of suppressed disease with discontinuation of idation therapy, patients were 1.3-fold more likely to lose therapy, resulting in an unpredictable worsening of disease HBsAg (hazard ratio 1.34; 95 % CI 1.02–1.75). Consoli- and possible development of fulminant hepatitis and acute- dation therapy of at least 3 years decreased the rate of on-chronic liver failure, as well as the risk of developing relapse and increased the rate of HBsAg loss significantly resistance with ‘‘stop–start’’ therapy. Cirrhotics have much [243]. less hepatic reserve for life-threatening hepatic decom- Due to the high relapse rate after NA treatment dis- pensation after an exacerbation. However, one recent meta- continuation in patients with HBeAg-negative chronic analysis suggested that NAs withdrawel is safe even in hepatitis, treatment until HBsAg loss is generally recom- cirrhotics, that off-therapy severe flares were rare and that mended [218]. HBsAg levels may be a potential marker to hepatic decompensation was rarely observed in patients guide treatment cessation. HBsAg levels of\2 log IU/ml with cirrhosis [246]. at the end of treatment are associated with a lower relapse 3:6:1 Recommendations (results of currently available rate at 1–2 years post-treatment discontinuation (15 vs. therapies, predictors of response to therapy, follow- 85 % in those with HBsAg level[2 log IU/ml at end of up and stopping rules during NA therapy in patients treatment) [244]. In one recent study to assess the outcome with chronic HBV infection) of patients withdrawing from NA therapy after HBsAg clearance, 27 (5 %) out of 520 CHB patients who received 3:6:1:1 Treatment-naı ¨ve patients can be treated NA for prolonged periods ultimately lost serum HBsAg with TDF 300 mg daily (A1), ETV 0.5 mg and were followed for 44 (12–117) months thereafter. It daily (A1), ADV 10 mg daily (A2), LdT was concluded that patients reaching the therapeutic end- 600 mg daily (A2) or LAM 100 mg daily point of HBsAg clearance can be safely withdrawn from (A2). NA following either anti-HBs seroconversion or at least 3:6:1:2 TDF or ETV are the preferred NAs and 12 months of a post-clearance consolidation period [245]. should be used as first-line therapy (A1). 3:6:1:3 During NA therapy, HBeAg, anti-HBe (in However, in one recent meta-analysis including 22 studies with a total of 1732 HBeAg-negative patients (median patients with HBeAg-positive) and ALT duration of therapy, consolidation therapy and off-therapy should be monitored every 3 months (A1). 123 32 Hepatol Int (2016) 10:1–98 3:6:1:4 The HBV DNA level should be measured countries. However, clevudine was only approved in Korea at month 3 and 6 of therapy and then every and the Philippines. 3–6 months if agents with a low genetic Immunomodulatory agents include conventional inter- barrier are used (lamivudine, adefovir, feron-a (IFN), pegylated interferon (Peg-IFN), and thy- telbivudine), and every 6 months in mosin a . These agents have dual actions: enhancing host patients treated with a high genetic barrier immunity to mount a defense against HBV and modest to resistance, such as entecavir or teno- antiviral action. Over the past two decades, IFN-based fovir (A1). therapy has been the mainstay of CHB treatment 3:6:1:5 Renal function and bone profile should be worldwide. monitored at least every 3 months if TDF or ADV is used (A1). Conventional interferon 3:6:1:6 Muscle symptoms and muscle weakness should be monitored during telbivudine or HBeAg-positive chronic hepatitis B Meta-analyses of clevudine therapy (A1). controlled trials in HBeAg-positive patients showed that 3:6:1:7 For HBeAg-positive patients without liver treatment with conventional interferon-alfa (IFN) at a dose cirrhosis, the optimal duration of NA of 5 MU daily or 10 MU three times weekly for therapy is unknown, and the therapy can 4–6 months achieved higher HBeAg loss (33 vs. 12 %), be stopped after at least 1 year (A1), but HBV DNA suppression (37 vs. 17 %) and ALT normal- preferably after 3 years (C1) of additional ization than untreated controls with a risk difference of therapy after HBeAg seroconversion with around 25 % for each parameter. The rate of HBsAg undetectable HBV DNA by PCR and seroclearance was also higher (7.8 vs. 1.8 %) in IFN- persistently normal ALT levels. treated patients, with a risk difference of 5.6 %. Asian 3:6:1:8 The optimal duration of NA therapy is patients with elevated baseline ALT have IFN response unknown in patients with HBeAg-negative rates comparable to Western patients. The efficacy of IFN CHB. In patients without liver cirrhosis, treatment in children with elevated ALT was also similar to the treatment can be withdrawn (1) after that in adults. Re-treatment of patients who failed previous HBsAg loss following either anti-HBs IFN therapy could achieve HBeAg loss in 20–40 % of seroconversion or at least 12 months of a cases. A study of tailored regimen of IFN in 247 HBeAg- post-HBsAg clearance consolidation per- positive patients showed a higher sustained response than iod (B1), or (2) after treatment for at least fixed 6-month treatment (40.5 vs. 28.3 %, p = 0.013). 2 years with undetectable HBV DNA HBeAg seroconversion is durable in over 90 % and documented on three separate occasions, delayed HBeAg seroconversion could occur in 10–15 % at 6 months apart (B1). 1–2 years post-therapy, and there was up to a 15-year 3:6:1:9 After stopping of NAs, patients should be cumulative incidence of 75 % HBeAg seroconversion (vs. monitored monthly for the initial 3 months 52 % in control). In addition, IFN-treated patients have a and then every 3–6 months thereafter for lower likelihood of cirrhosis and HCC development, as relapse (A2). well as better overall survival, especially among responders 3:6:1:10 The stopping of NA therapy may also be [19]. considered in cirrhotic patients with a careful off-therapy monitoring plan (A1). HBeAg-negative chronic hepatitis B A 12-month IFN therapy showed the end-of-treatment biochemical and virological response rates in 60–90 %; however, sustained 3.6.2 Results of and predictors of response response rate was only 22 %. Extending IFN treatment for to therapy with interferons 24 months in Italian patients induced sustained response in 30 % and HBsAg clearance in 18 % at 6 years post-ther- Currently, conventional interferon-alfa (IFN), lamivudine, apy. IFN treatment improved long-term outcomes, includ- adefovir, entecavir, telbivudine, tenofovir and pegylated ing reduction of HCC and survival and hepatic interferona2a (Peg-IFN-2a) have been approved for the complication-free survival in patients with sustained treatment of CHB globally. Table 1 shows the comparison response [19]. between these two treatment strategies (immune control vs. viral control). Peg-IFN-2b has been approved for the Compensated cirrhosis Previous studies showed that treatment of chronic HBV infection in a few countries. compensated cirrhosis patients treated with IFN had com- Thymosin a has also been licensed in some Asian parable or even better response and a similar side effect 123 Hepatol Int (2016) 10:1–98 33 profile as those without cirrhosis, with reduced risk of A recent prospective study with mostly Asian patients hepatic decompensation, HCC and prolonged survival in compared the treatment response of different doses and responders. However, IFN is contraindicated in patients durations of Peg-IFN a-2a in HBeAg-positive patients with overt decompensated cirrhosis because it can precip- [254]. The data showed that 180 lg/week of Peg-IFN a-2a itate hepatic decompensation, resulting in fatal complica- for 48 weeks was superior to regimens with shorter dura- tions [19]. Long-term follow-up studies showed that IFN tion or lower dose. Therefore, the currently recommended treatment increased HBsAg seroclearance over time in dose and duration of Peg-IFN a-2a therapy is 180 lg/week patients with HBeAg loss. Two meta-analysis studies have for 48 weeks. The recommended dose of Peg-IFN a-2b confirmed these long-term benefits of IFN treatment in therapy is 1.5 lg/kg/week for 48 weeks. reducing liver disease progression to cirrhosis and HCC [247]. HBeAg-negative chronic hepatitis B With 1 year of Peg- IFN a-2a therapy, the data revealed that HBV DNA Pegylated interferon alfa alone Pegylation of interferon- \4000 IU/ml occurred in 43 % of patients and HBsAg loss a (Peg-IFN) improves its pharmacokinetic and prolongs its was reported in 4 % at 6 months post-therapy [255]. After half-life, which allows weekly injection. Two types of Peg- 3 years of follow-up, 28 % of HBeAg-negative patients IFN have been developed: Peg-IFN a-2a (40 KD) and Peg- had HBV DNA \2000 IU/ml, and HBsAg clearance rate IFN a-2b (12 KD). In an early phase 2 study on Asian increased to 8.7 % [256]. In addition, the two studies using HBeAg-positive patients, the combined sustained viral Peg-IFN a-2a therapy also found that Peg-IFN–based response (SVR) (HBeAg loss, HBV DNA suppression, and therapy was superior to lamivudine alone in inducing ALT normalization) of Peg-IFN a-2a was twice that with HBeAg seroconversion in HBeAg-positive patients and in conventional IFN a-2a (24 vs. 12 %; p = 0.036) at suppressing viral replication in HBeAg-negative patients. 24 weeks post-therapy [248]. A previous study of 24-week All three studies showed that the therapeutic efficacy was Peg-IFN a-2b in Chinese HBeAg-positive patients also comparable between Peg-IFN monotherapy and combina- confirmed a higher HBeAg loss rate than conventional IFN tion therapy of Peg-IFN plus lamivudine. A recent study on a-2b [249]. 120 Caucasian HBeAg-negative patients with genotype D infection explored whether longer treatment duration could HBeAg-positive chronic hepatitis B Two large phase 3 lead to a better response, and the results showed that trials on HBeAg-positive patients showed that 1 year of extending treatment duration to 96 weeks increased Peg-IFN a-2a and Peg-IFN a-2b monotherapy resulted in response rate (HBV DNA level \2000 IU/ml at 1 year HBeAg seroconversion in 32 % and 29 % of patients at post-therapy) from 11.8 to 28.8 % [257]. 6 months post-therapy, respectively. The virological response based on HBV DNA suppression was found to be Chronic hepatitis B with cirrhosis A prior study on 24 modest with Peg-IFN. HBV DNA suppression to \400 HBeAg-positive patients with well-compensated cirrhosis copies/ml was only obtained in 14 % of patients with Peg- treated with 52 weeks of Peg-IFN a-2b with or without IFN a-2a and 7 % with Peg-IFN a-2b, respectively. lamivudine showed a higher rate of HBeAg serconversion However, HBsAg seroconversion was achieved in 3–5 % and HBV DNA \10,000 copies/ml at 26 weeks post-ther- of patients at 6 months post-therapy [250, 251]. In an apy than those without cirrhosis (30 vs. 14 %, p = 0.02) analysis of the long-term effects of Peg-IFN, 83 % of 150 [258]. In addition, improvement of liver fibrosis was found Asian HBeAg-positive patients treated with Peg-IFN a-2a more frequently in patients with advanced fibrosis than in for 48 weeks who achieved HBeAg seroconversion at those without (66 vs. 22 %, p \ 0.001). The side effects 6 months post-therapy had sustained seroconversion at were comparable between patients with and without 12 months. Furthermore, 38 % of the patients who advanced fibrosis. achieved HBeAg seroconversion at 12 months post-ther- apy had serum HBV DNA levels \400 copies/ml [252]. Combination therapy of IFN and NAs Moreover, long-term (mean follow-up of 3 years) sustained negativity of HBeAg and HBsAg in 172 European HBeAg- With current antiviral agents, most CHB patients fail to positive patients treated with Peg-IFN a-2b was 37 and obtain HBsAg seroclearance, which is the ultimate goal of 11 %, respectively. In particular, sustained negativity of HBV therapy. Furthermore, relapse is common during post HBeAg and HBsAg was observed in 81 and 30 % of 64 NA therapy follow-up. Therefore, combination therapy patients with an initial serological response (HBeAg neg- could be considered the ideal treatment for CHB. There are ativity at 26 weeks post-therapy) [253]. Of note, most of three approaches for administering combination therapy: the patients who cleared HBsAg were infected by HBV NA followed by addition of Peg-IFN and continuation of genotype A. NA; starting with Peg-IFN followed by addition of NA; or 123 34 Hepatol Int (2016) 10:1–98 simultaneous administration of NA and Peg-IFN. There is undetectable HBV viral load and greater reductions in lack of data to recommend one over the other. However, HBeAg and HBsAg levels than either drug alone [263]. most investigators have used the first approach and scien- Another study compared the efficacy and safety of two tifically prefer the basis of viral load reduction followed by sequential regimens: Peg-IFN for 24 weeks followed by immune modulation as a logical step. The three approaches LdT for 24 weeks (Peg-IFN first), or vice versa (LdT first), have been used with different NAs and Peg-IFN with in 30 HBeAg-negative patients. At the end of follow-up improved results compared to monotherapy with either (week 72), more patients treated with LdT first had HBV group of drugs. DNA \2000 IU/ml (47 vs. 13 %, p = 0.046). Sequential treatment with Peg-IFN followed or preceded by 24 weeks Combination of Peg-IFN with lamivudine However, in of LdT was safe; only one patient dropped out because of both HBeAg-positive and HBeAg-negative subjects, myalgia [264]. However, presently the combinations of simultaneous commencement of Peg-IFN and LAM tends Peg-IFN with LdT should be avoided, as a high risk of to provide a more profound treatment effect on viral sup- severe polyneuropathy development was reported in those pression without superior sustained virological off-treat- treated with the combination therapy, leading to an early ment response, compared with Peg-IFN monotherapy [250, discontinuation of one study [263]. 251, 255]. A study on 36 treatment-naive HBeAg-positive patients Combination of Peg-IFN with entecavir One recent study who received LAM 100 mg per day for 4 weeks before (the OSST study) reported on 100 Chinese HBeAg-positive adding Peg-IFN for the following 24 weeks showed that patients with maintained virological response on ETV who they achieved higher sustained (6 months after end of switched to a finite course of Peg-IFN a-2a and achieved treatment) virological responses compared with the 27 significantly higher rates of HBeAg seroconversion and patients who received Peg-IFN from the start (unde- HBsAg clearance than 100 patients who continued ETV tectable HBV DNA and HBeAg losses 50 vs. 15 %; [265]. p = 0.028; 39 vs. 15 %; p = 0.05, respectively) [259]. Another global randomized trial (the ARES study) was However, another study found no difference in efficacy conducted in European and Chinese HBeAg-positive between32-week Peg-IFN started simultaneously with patients. In this open-label, multicenter randomized trial, LAM and that started 8 weeks before LAM or 8 weeks HBeAg-positive CHB patients with compensated liver after commencement of LAM, 24 weeks after the end of disease started on ETV monotherapy (0.5 mg/day) and therapy. All patients received lamivudine until week 104 were randomized in a 1:1 ratio to either Peg-IFN add-on [260]. therapy (180 lg/week) from week 24 to 48 (n = 85), or to continue ETV monotherapy (n = 90). Response was Combination of Peg-IFN with adefovir In a multicenter defined as HBeAg loss with HBV DNA \200 IU/ml at prospective study, 160 HBeAg-positive patients were ran- week 48. Responders discontinued ETV at week 72. All domized to Peg-IFNa-2a monotherapy or to individualized patients were followed until week 96. Response was combination therapy with Peg-IFNa-2a ? adefovir dip- achieved in 16/85 (19 %) patients allocated to the add-on ivoxil (ADV) based on the baseline features and treatment arm versus 9/90 (10 %) in the monotherapy arm response. At week 96, combined response (ALT normal- (p = 0.095). Adjusted for HBV DNA levels prior to ran- ization and undetectable HBV DNA), HBeAg clearance, domized therapy, the Peg-IFN add-on was significantly and seroconversion rates were higher in those patients associated with response (OR 4.8, 95 % CI 1.6–14.0, treated with the combination than in those treated with Peg- p = 0.004). Eleven (13 %) of add-on treated patients IFNa-2a alone [261]. An Italian multicenter study in 60 achieved disease remission after ETV cessation, versus 2/90 (2 %) of patients treated with monotherapy HBeAg-negative patients showed a similar sustained virological response (i.e., HBV DNA \2000 IU/ml (p = 0.007), which was 79 % (11/14) versus 25 % (2/8) of 24 weeks) after the EOT among those treated with a those who discontinued ETV (p = 0.014). At week 96, 22 48-week combination of Peg-IFNa-2a ? ADV or Peg- (26 %) patients assigned add-on versus 12 (13 %) assigned IFNa-2a alone (23 vs. 20 %, p = 0.75), with only one monotherapy achieved HBeAg seroconversion patient (3 %) in the combination group achieving HBsAg (p = 0.036). Peg-IFN add-on led to significantly more loss [262]. decline in HBsAg, HBeAg and HBV DNA (all p\ 0.001). Add-on therapy resulted in more viral decline and appeared Combination of Peg-IFN with telbivudine A study in 159 to prevent relapse after stopping ETV. Hence Peg-IFN add- HBeAg-positive patients reported that a combination of on therapy may facilitate the discontinuation of nucleos(- Peg-IFNa-2a and telbivudine (LdT) led to a higher rate of t)ide analogues [266]. 123 Hepatol Int (2016) 10:1–98 35 Combination of Peg-IFN with tenofovir In one study on of Peg-IFN in chronic HBV-infected patients is to add on HBeAg-positive CHB, raised ALT (48–200 IU/ml) Peg-IFN to NAs responders to accelerate the HBsAg patients, all patients received tenofovir (300 mg/day for decline. One study reported HBsAg kinetics in 12 patients 12 weeks), followed by randomization to tenofovir plus (nine HBeAg-negative) having undetectable HBV DNA peg-interferon a2b 1.5 mcg/kg/weekly for 24 weeks (se- (\116 copies/ml) for more than 6 months on NAs quential therapy; n = 30) or tenofovir monotherapy (LAM = 1, LAM ? ADV = 2, ETV = 7, (n = 30). Daily tenofovir was continued thereafter until ETV ? TDF = 2), and who additionally received Peg- HBsAg loss. At 48 weeks, 60 % in the sequential therapy IFN as an individualized therapy. After add-on of group and 30 % in tenofovir monotherapy had normal ALT PegIFN, a rapid decline of HBsAg occurred in two (p = 0.02). Patients receiving sequential therapy had patients, to HBsAg levels of 0.14 and 0.02 IU/ml at week higher HBV DNA loss (80 vs. 53 %; p = 0.028), mean 48, respectively (corresponding to a maximal reduction of HBV DNA reduction [6.70 ± 1.64 vs. 4.43 ± 2.44 log10 2.9 log10 and 4.25 log10). Three patients discontinued (p\ 0.001)], and HBeAg seroconversion (53.3 vs. 23.3 %; Peg-IFN early due to side effects, whereas seven patients p = 0.017), compared to the tenofovir monotherapy group. withdrew from treatment after a mean of 16 weeks due to Two patients on sequential therapy had HBsAg loss by a suboptimal HBsAg response (decline of 0.09 log10 48 weeks compared with none in tenofovir monotherapy only) [269]. In one randomized controlled trial (PEGON [267]. study) conducted in Europe and China, 82 HBeAg-posi- In a recent open-label study (Study 149), a total of 740 tive patients with compensated liver disease were treated CHB patients (60 % positive for HBeAg) without for at least 12 months with entecavir (ETV) or tenofovir advanced bridging fibrosis or cirrhosis were randomly (TDF) with subsequent HBV DNA \2000 IU/ml at ran- assigned to receive tenofovir ? pegylated interferon for domization. Patients were randomized to 48 weeks of 48 weeks, tenofovir ? pegylated interferon for 16 weeks, Peg-IFN addition, or 48 weeks of continued NA continuing on Tenofovir alone through week 48, tenofovir monotherapy. Response (HBeAg seroconversion with monotherapy for 120 weeks (continuous monotherapy) or HBV DNA \200 IU/ml) was assessed at week 48. pegylated interferon monotherapy for 48 weeks. At the Responders will discontinue treatment after 24 weeks end of treatment, HBsAg levels declined most in the consolidation treatment (week 72), with subsequent off- 48-week tenofovir plus pegylated interferon arm (-1.1 treatment follow-up until week 96. Week 48 results were log ), followed by interferon monotherapy (-0.8.1 presented at AASLD 2014. Ninety-six percent of patients log ), the 16-week tenofovir combination regimen (-0.5 were of Asian ethnicity, with an average age of 33 years. log ) and tenofovir monotherapy (-0.3 log ). At Response, as well as HBeAg seroconversion alone, was 10 10 48 weeks, 7.3 % of patients taking the 48-week tenofovir achieved in 17 % of patients who received Peg-IFN add- plus pegylated interferon regimen showed HBsAg loss. on compared to 5 % of patients who continued NA Response rates were substantially lower in the 16-week monotherapy (p = 0.15). HBeAg loss was achieved in tenofovir combination arm and interferon monotherapy 33 % of patients who received Peg-IFN add-on compared arm (both 2.8 %). None taking tenofovir alone experi- to 18 % in the NA monotherapy group (p = 0.14). Peg- enced HBsAg loss. By 72 weeks, the rate of HBsAg loss IFN add-on resulted in significantly more HBsAg decline rose to 9.0 % in the 48-week tenofovir plus pegylated at week 48 (0.59 vs. 0.29 log IU/ml, p = 0.021). HBsAg interferon group, while remaining the same in the other decline [1 log IU/ml was achieved in 19 % of the Peg- three arms. A total of seven patients experienced HBsAg IFN add-on group compared to 0 % in the NA seroreversion, or reappearance after loss (four in the monotherapy group (p = 0.005). One patient who 48-week combination arm and three in the 16-week received Peg-IFN add-on had clearance of HBsAg at combination arm) [268]. week 48 [270]. Preliminary results of the multicenter, Taken together, simultaneous combination of Peg-IFN randomized controlled phase III trial ANRS-HB06 plus tenofovir or sequential combination therapy using PEGAN study presented at AASLD 2014 suggested that entecavir first followed by Peg-IFN shows promising addition of a 48-week course of Peg-IFN alfa-2a to oral results; however, future large studies are needed to confirm anti-HBV therapy in HBeAg-negative CHB patients with these results. undetectable serum HBV DNA for at least 1 year results in a low rate of HBsAg clearance (6.6 %), and that low Peg-IFN add-on treatment in NAs responders baseline HBs Ag titers and a history of HBeAg sero- conversion, either spontaneously or under HBV therapy, Because it has been observed that during effective NAs may increase HBsAg clearance rate [history of HBeAg therapy, HBsAg decline is very slow and may require seroconversion prior to randomization (23.5 vs. 3.3 %) decades to achieve undetectable levels, an alternative use (p = 0.0185)] [271]. 123 36 Hepatol Int (2016) 10:1–98 Baseline and on-treatment predictors of response to Peg- showed that genotype A had the highest rate of HBsAg loss IFN (Table 6) compared to other genotypes [272]. For HBeAg-negative patients, the data comparing the sustained response among Lower serum HBV DNA level and elevated ALT levels In patients receiving Peg-IFN a-2a ± lamivudine showed that CHB patients receiving IFN or Peg-IFN treatment, lower there was no difference between genotypes A and D or HBV DNA level and higher ALT level are known as genotypes B and C after a long-term follow-up of 3 years baseline predictors for a better response. For HBeAg-pos- [256]. itive patients receiving Peg-IFN-based treatment, a pooled Taking these lines of evidence together, it is concluded analysis showed that a lower level of HBV DNA (\9 log that with a standard 12-month Peg-IFN treatment, HBeAg- copies/ml) and an elevated ALT level ([2 times of upper positive patients infected with genotype A have the best limit of normal) were associated with a higher sustained response, followed by genotypes B and C, who have a response rate (HBeAg loss and HBV-DNA level similar response, while those infected with genotype D \2000 IU/ml at 6 months post-therapy) [272]. For have the lowest response. For HBeAg-negative patients, HBeAg-negative patients, a lower HBV DNA level and a the role of HBV genotype may be minimal. higher ALT level were both associated with a higher treatment response to Peg-IFN-based therapy [256]. HBeAg level, precore and basal core promoter mutants A retrospective analysis on 271 HBeAg-positive patients who HBV genotype In a pooled analysis on two large clinical received 48-week Peg-IFN a-2a ± lamivudine showed that trials with HBeAg-positive patients who received HBeAg seroconverters have a lower baseline and on- 12-month Peg-IFN-based therapy, Buster et al. [272] found treatment levels of HBeAg [275]. However, thus far, there that patients with genotype A infection had the best is no commercial assay available for measuring HBeAg response, followed by genotypes B and C, which had concentrations in clinical practice. Two Asian studies similar responses, while those with genotype D had the indicated that pre-therapy BCP mutations could increase worst response. These results lend support to the recom- HBeAg clearance rate in patients receiving Peg-IFN mendation that Peg-IFN therapy is suitable for patients treatment [273, 276]. These results highlight that further with genotype A rather than genotype D infection. In studies are needed to confirm the predictive value of patients with genotype B or C infection, Asian studies HBeAg-associated factors in HBeAg-positive patients with reported that in a shorter 6-month Peg-IFN treatment, Peg-IFN therapy. A recent study quantified the proportion response was better in genotype B infection compared to of precore (PC) and BCP mutants at baseline and during genotype C infection [273, 274]. However, the HBeAg IFN or Peg-IFN treatment in 203 HBeAg-positive patients, seroconversion rate is similar between genotypes B and C and found a dose response relationship between the pro- after 12-month Peg-IFN-based treatment, which is the portion of PC/BCP mutants and HBeAg seroconversion current standard of care. When HBsAg clearance is defined rate [277]. These data suggested that both PC and BCP as treatment endpoint in HBeAg-positive patients, sub- mutants were qualitatively and quantitatively associated group analysis from the clinical trial using Peg-IFN a-2b with a higher response rate to IFN or Peg-IFN therapy in Table 6 Baseline predictors and stopping rules of 48-week pegylated interferon therapy in Asian and Caucasian chronic hepatitis B patients HBeAg-positive HBeAg-negative Asian Caucasian Asian Caucasian Lower HBV DNA level Better response Better response Not clear Not clear Higher ALT level Better response Better response Not clear Not clear Genotype B and C are A is better than D B and C are comparable Not clear comparable Precore stop codon (PC) and Mutant better Wild type better Not clear Not clear basal core promoter (BCP) than wild type than mutant mutants IL28b SNP No predictive Controversial Not clear Controversial value Lower level HBeAg Better response Better response Not applied Not applied Stopping rule at 12-weeks No decline of HBsAg level No rule could achieve Only in genotype D patients: without HBsAg level at [20,000 IU/ml 95 % of negative HBsAg decline and with \2log HBV week 12 at week 12 predictive value DNA decline 123 Hepatol Int (2016) 10:1–98 37 Asian HBeAg-positive patients. However, a European with genotype D infection, a week 12 stopping rule is also study with 214 HBeAg-positive patients receiving Peg-IFN clinically applicable. However, for HBeAg-negative a-2b ± lamivudine showed that the presence of either PC patients with non-genotype D infection, more studies are or BCP mutants lowered the rate of sustained response warranted. (wild-type vs. presence of mutant: 34 vs. 11 %) [278]. Taken together, PC and BCP mutant may play different Quantitative serum anti-HBc level Quantitative serum roles in Asians and Caucasians, which may be anti-HBc level has been reported to reflect host immune attributable to different HBV genotypes. status and hepatitis activity. However, its clinical signifi- cance in CHB therapy remains limited. In a retrospective Quantitative serum HBsAg level Since serum HBsAg cohort study consisting of 231 and 560 patients enrolled in level varies depending on the balance between viral two phase IV, multicenter, randomized, controlled trials replication and host immunity, it is hypothesized that treated with Peg-IFN or NA-based therapy, the role of HBsAg may serve as a biomarker to predict treatment quantitative serum anti-HBc level in predicting HBeAg response to Peg-IFN. A French study first reported that a seroconversion was evaluated. The data showed that at the decline in serum HBsAg level of 0.5 log IU/ml at week end of trials, 99 (42.9 %) and 137 (24.5 %) patients 12 could differentiate sustained responders from relapser in achieved HBeAg seroconversion in the Peg-IFN and NA HBeAg-negative patients [279]. From then on, several cohorts, respectively. Baseline anti-HBc level of 4.4 log retrospective studies proposed the role of HBsAg level as a IU/ml was the optimal cutoff value to predict HBeAg ‘‘stopping rule’’ at week 12 of Peg-IFN treatment in both seroconversion for both Peg-IFN and NA. Patients with HBeAg-positive and HBeAg-negative patients. However, baseline anti-HBc C4.4 log IU/ml and baseline HBV further prospective studies are still required to validate DNA \9 log copies/ml had 65.8 % (50/76) and 37.1 % these findings. (52/140) rates of HBeAg seroconversion in the Peg-IFN In a study enrolling 202 HBeAg-positive Caucasian and NA cohorts, respectively. In pooled analysis, other patients with genotype A or D infection [280], only 3 % of than treatment strategy, the baseline anti-HBc level was the patients without decline of HBsAg level at week 12 could best independent predictor for HBeAg seroconversion (OR achieve sustained response [negative predictive value 2.178; 95 % CI 1.577–3.009; p \ 0.001). Therefore, (NPV) of 97 %]. However, this was not validated well in baseline anti-HBc titer may serve as a useful predictor of another study with 399 HBeAg-positive Asian patients Peg-IFN and NA therapy efficacy in HBeAg-positive CHB with genotype B or C infection (NPV of 82 %) [281]. patients, which could be used for optimizing the antiviral Instead, the Asian study proposed an alternate stopping therapy of CHB [285]. rule, HBsAg [20,000 IU/ml at week 12. To investigate which stopping rule was more universally applicable across Quantitative hepatic HBsAg level In addition to serum HBV genotypes, data from three large-scale clinical trials HBsAg level, the relationship between hepatic HBsAg were pooled, and it was concluded that if treatment level and treatment response of IFN-based therapy has response was defined as sustained response, then the been explored in 45 HBeAg-positive patients, and there 12-week stopping rule can be defined as no decline of was a positive correlation between baseline serum HBsAg HBsAg level for genotype A and D, but HBsAg level level and hepatic HBsAg level [286]. [20,000 IU/ml for genotype B and C patients; while HBsAg [20,000 IU/ml at 24 week could be applied to all Interleukin-28B genotype Several interleukin-28B patients as the 24 week stopping rule, irrespective of HBV (IL28B)-associated single nucleotide polymorphisms genotype [282]. (SNPs), including CC genotype of rs12979860 and TT Most data regarding HBeAg-negative patients included genotype of rs8099917, are associated with a higher genotype D infection. When using HBV DNA level response rate in Peg-IFN-based treatment for chronic \2000 IU/ml combined with normal ALT level at hepatitis C. Whether the IL-28B SNPs could also predict 6 months post-therapy as the treatment endpoint, the Peg-IFN-based treatment response in CHB has been stopping rule of no HBsAg decline plus\2 log HBV DNA actively investigated. Nevertheless, the results remain decline at week 12 had NPV of 100 % [283]. For patients controversial. The first study enrolled 115 patients receiv- with non-genotype D infections, HBsAg decline of 10 % ing 6-month Peg-IFN treatment, and there was no corre- has been shown to predict treatment response at 1-year lation noted between IL28B SNPs and treatment response post-therapy (47.2 and 16.4 % for HBsAg decline C10 vs. [273]. In contrast, a multicenter study, which enrolled 205 \10 %, respectively) [284]. In summary, a stopping rule HBeAg-positive patients receiving Peg-IFN ± lamivudine for Peg-IFN therapy at week 12 or 24 is clinically useful in from 11 European and Asian centers, yielded contradictory HBeAg-positive patients. For HBeAg-negative patients results [287]. In this study, around 65 % of the patients 123 38 Hepatol Int (2016) 10:1–98 were of Asian descendants. They found that the CC is not recommended for patients who have hepatic genotype of rs12979860 was highly associated with decompensation, immunosuppression or medical or psy- HBeAg seroconversion. However, this is the only study chiatric contraindications. Peg-IFN is more appropriate for showing a positive correlation in HBeAg-positive patients. young patients, those who can better tolerate side effects Most of the subsequent studies failed to confirm these and those who are reluctant to receive indefinite treatment. findings [288]. With regard to HBeAg-negative patients, During treatment, Peg-IFN could be stopped at week 12 or only one retrospective study has been reported. The authors 24 if the patients are found to be primary non-responders, included 101 Caucasian patients receiving IFN or Peg-IFN which is defined by the genotype-specific HBsAg stopping for 24 months and were followed for a median of 11 years rule. Finally, useful and reliable viral and host factors [289]. They found that the CC genotype of rs12979860 was predictive of treatment outcomes need further exploration associated with higher rates of SVR (HBV DNA level to guide individualized Peg-IFN therapy in the future. \2000 IU/ml) and HBsAg clearance. In summary, most studies involving Asian patients failed to identify IL28B Monitoring treatment and guidance for stopping genotype as a possible predictor for HBV treatment therapy in chronic HBV-infected patients treated response. In Caucasian patients, further investigations are with interferons needed. The currently recommended dose and duration of Peg-IFN SNPs near HLA-DP region Two SNPs near HLA-DP a-2a therapy for both HBeA-positive and HBeA-negative regions rs3077 and rs9277535 were shown to play a role in CHB is 180 lg/week for 48 weeks. In patients receiving Peg-IFN therapy, full blood cell counts and serum ALT spontaneous HBsAg clearance in patients with chronic HBV infection. Since spontaneous clearance of HBsAg is a levels should be monitored monthly and thyroid function result of host immune activity, which could be enhanced by should be monitored every 3 months. All patients should Peg-IFN treatment, it seems reasonable to investigate the be monitored for safety through 12 months of treatment. association between the HLA-DP SNPs and the treatment In HBeAg-positive patients, HBeAg, anti-HBe anti- response to Peg-IFN. In fact, it has been shown that rs3077 bodies and serum HBV DNA levels should be checked at 6 GG genotype was associated with a better treatment and 12 months of therapy and at 6 and 12 months post- response in HBeAg-positive patients receiving Peg-IFN therapy. Sustained HBeAg seroconversion together with therapy in Asian studies [290]. Although both were retro- ALT normalization and serum HBV DNA below 2000 IU/ spective and small-scale studies, these encouraging data ml post-therapy is the desired therapeutic endpoint. still suggested that the role of HLA-DP SNPs in Peg-IFN HBeAg-positive patients who develop HBeAg serocon- therapy are worthy of further studies. version with Peg-IFN therapy require long-term follow-up because of the possibility of HBeAg seroreversion or Side effects of IFN-based therapy progression to HBeAg-negative CHB. HBsAg should be checked at 12-month intervals after HBeAg seroconversion The most frequently reported side effects of IFN-based if HBV DNA is undetectable, as the rate of HBsAg loss therapy are flu-like symptoms, headache, fatigue, myalgia, increases over time. Patients who become HBsAg sero- alopecia, and local reaction at the injection site. IFN and clearance should be tested for anti-HBs antibodies. Patients Peg-IFN have myelosuppressive effects; however, neu- treated with Peg-IFN who achieve significant decline of tropenia \1000/mm and thrombocytopenia \500,000/ HBV DNA and/or HBsAg levels through 3 or 6 months of mm are not common unless patients already have cirrhosis therapy have an increased likelihood of treatment response. or low cell counts prior to IFN-based treatment. Neu- In contrast, HBeAg-positive patients treated with Peg-IFN tropenia and thrombocytopenia induced by IFN or Peg-IFN who fail to achieve serum HBsAg levels below 20,000 IU/ do not significantly increase the risk of infection and ml or any decline in serum HBsAg levels by month 3 have bleeding, except in patients with cirrhosis or immunosup- a low likelihood of HBeAg seroconversion [274]. Thus, pression. Although IFN and Peg-IFN have many side cessation of Peg-IFN therapy may be considered. effects, they are well tolerated. Premature discontinuation In HBeAg-negative patients, serum HBV DNA levels due to patient’s intolerability has been reported in 2–8 % of should be checked at 6 and 12 months of therapy and at 6 patients treated with Peg-IFN. and 12 months post-therapy. A sustained virological response with HBV DNA \2000 IU/ml post-therapy is Therapy with pegylated interferon: overall conclusions generally associated with the remission of disease activity. HBsAg should be checked at 12-month intervals if HBV Currently, monotherapy with a potent NA or Peg-IFN is DNA remains undetectable during the follow-up. Patients who become HBsAg seroclearance should be tested for recommended as the first-line therapy. However, Peg-IFN 123 Hepatol Int (2016) 10:1–98 39 anti-HBs antibodies. HBeAg-negative patients who C infection), or any decline in serum HBsAg achieve sustained response at 12 months post-therapy still levels (genotype A and D infection) by week require long-term follow-up because of the risk of future 12 and serum HBsAg levels below disease reactivation. HBeAg-negative patients, especially 20,000 IU/ml by week 24 (genotype A–D infection), stopping Peg-IFN therapy should those with genotype D infection, who fail to achieve any decline in serum HBsAg levels and a [2 log10 IU/ml be considered (B2). 3:6:2:7 In HBeAg-negative patients, serum HBV decline in serum HBV DNA levels by month 3 of Peg-IFN therapy, have a very low likelihood of treatment response DNA levels should be measured at 6 and 12 months of treatment and at 6 and [274, 291, 292]. Thus, cessation of Peg-IFN therapy should be considered. 12 months post-treatment (A1). HBsAg levels should be checked every 3 months 3:6:2 Recommendations: results of currently available (A1). therapies, predictors of response to therapy, follow- 3:6:2:8 For HBeAg-negative patients, especially up and stopping rules during interferon therapy in those with genotype D infection, who fail chronic HBV infection to achieve any decline in serum HBsAg ¨ levels and a [2 log10 IU/ml decline in 3:6:2:1 Treatment-naıve patients can be treated with Peg-IFN-a2a 180 lg weekly or Peg-IFN-a2b serum HBV DNA levels by month 3 of 1–1.5 lg/kg weekly (A1). Peg-IFN therapy, discontinuation of Peg-IFN 3:6:2:2 For Peg-IFN, the recommended duration is therapy should be considered (B2). 48 weeks for both HBeAg-positive and– negative patients (A1). 3.7 Treatment strategies for first-line therapy in pre- 3:6:2:3 In patients treated with Peg-IFN, full blood cirrhotic chronic hepatitis B: nucleos(t)ide counts and serum ALT levels should be analogues or interferons or a combination monitored monthly and TSH should be monitored every 3 months. All patients The two therapeutic approaches available for the suppres- should be monitored for safety through sion of HBV replication include antiviral agents [nu- 12 months of treatment (A1). cleos(t)ide analogues, NAs] and immune-based therapies 3:6:2:4 In regions endemic for HBV genotype A and (IFN-a or pegylated-IFN-a) (Table 7). D infection, HBV genotyping should be done The main theoretical advantages of Peg-IFN are the among patients being considered for IFN absence of resistance and the potential for immune-medi- therapy (A1). ated control of HBV infection with an opportunity to obtain 3:6:2:5 In HBeAg-positive patients, HBeAg and a sustained virological response off-treatment, and a anti-HBe antibodies and serum HBV DNA chance of HBsAg loss in patients who achieve and main- levels should be checked at 6 and 12 months tain undetectable HBV DNA, and thus potential of finite of treatment and at 6 and 12 months post- treatment duration. Peg-IFN-induced HBeAg seroconver- treatment (A1). HBsAg levels should be sion might be more durable than NA-induced HBeAg checked every 3 months (A1). seroconversion. Frequent side effects and subcutaneous 3:6:2:6 For HBeAg-positive patients treated with injection are the main disadvantages of (PEG-) IFN treat- Peg-IFN who fail to achieve serum HBsAg ment. (PEG-) IFN is contraindicated in patients with levels below 20,000 IU/ml (genotype B and Table 7 Comparison of two treatment strategies for chronic hepatitis B Pegylated interferon Nucleos(t)ide analogues Strategy Sustained off-therapy response (immune control) Maintained on-treatment response (viral control) Goal Low HBV DNA level (\2000 IU/ml) and normal ALT Undetectable HBV DNA level and normal ALT level level Duration Finite Prolonged or indefinite Effectiveness Sustained response in *30 % of patients after Successful suppression of viral replication with continued 48 weeks of therapy treatment, but high relapse rate after stopping the treatment Contraindication Hepatic decompensation, immunosuppression, Nil pregnancy, psychiatric or medical contraindications 123 40 Hepatol Int (2016) 10:1–98 decompensated HBV-related cirrhosis or autoimmune dis- decreases the rate of relapse and increases the rate of ease, in patients with uncontrolled severe depression or HBsAg loss significantly [243]. psychosis, and in female patients during pregnancy. Orally Long-term treatment with NA(s) This strategy is neces- administered NAs are well tolerated, but the rate of viral sary for patients who are not expected to or fail to achieve a relapse is common once the treatment is ceased, which sustained off-treatment virological response and require necessitates long-term or even life-long treatment. Current extended therapy, i.e., for HBeAg-positive patients who do data show that long-term ETV or TDF therapy is relatively not develop HBeAg seroconversion and HBeAg-negative safe and has minimal risk of drug resistance. Therefore, patients. This strategy is also recommended in patients with Peg-IFN should be highly considered in young people who cirrhosis, irrespective of HBeAg status or anti-HBe sero- are planning to have babies and patients with a high chance conversion on treatment. The most potent drugs with the of achieving sustained off-therapy response, such as optimal resistance profile, i.e., tenofovir or entecavir, HBeAg-positive patients who have high pre-treatment ALT should be used as first-line monotherapies. levels, genotype A infection or those with more favorable There are as yet no data to indicate an advantage of de predictors. novo combination treatment with NAs in NA naive patients Finite-duration treatment with (PEG-) IFN This strategy receiving either entecavir or tenofovir. is intended to achieve a sustained off-treatment virological 3:7 Recommendations: treatment strategies for first-line response. Peg-IFN, if available, has replaced standard IFN therapy in pre-cirrhotic CHB: nucleos(t)ide ana- in the treatment of CHB, mostly due to its easier applica- logues or interferons or a combination bility (once weekly administration). A 48-week course of Peg-IFN is mainly recommended for HBeAg-positive 3:7:1 A course of Peg-IFN may be the most patients with the best chance of HBeAg seroconversion. It appropriate first-line treatment strategy when can also be used for HBeAg-negative patients, as it is the purpose of treatment is to achieve a practically the only option that may offer a chance for sustained response after a defined treatment sustained off-treatment response after a finite duration of course compared with NAs requiring long- therapy. Full information about the advantages, adverse term administration (B2). events and inconveniences of Peg-IFN versus NAs 3:7:2 A 48-week course of Peg-IFN is mainly (Table 7) should be provided so the patient can participate recommended for HBeAg-positive patients in the decision. Simultaneous combinations of Peg-IFN with the best chance of HBeAg seroconver- sion (B1). It can also be used for HBeAg- with NAs such as entecavir and tenofovir have been shown to be safe with promising results. Sequential combination negative patients, as it is practically the only option that may offer a chance for sustained therapies using viral load reduction followed by addition of Peg-IFN have been found to be safe with improved sero- off-treatment response after a finite duration conversion rates compared to monotherapies. These of therapy (B2). approaches need to be confirmed in larger studies before 3:7:3 Despite the tolerability and the higher rates they are recommended. of off-therapy response compared to NAs, the Finite-duration treatment with a NA This strategy can be benefits of Peg-IFN are restricted to a is feasible for HBeAg-positive patients who seroconvert to subgroup of patients, especially with raised anti-HBe on treatment. However, treatment duration is ALT and low to moderate levels of serum unpredictable prior to therapy, as it depends on the timing HBV DNA. To increase the rates of patients who may benefit from this treatment while of HBeAg seroconversion and the treatment continuation post-HBeAg seroconversion. HBeAg seroconversion may minimizing the adverse events, a careful not be durable after NAs discontinuation, at least with less patient selection and individualized treatment potent agents, in a substantial proportion of these patients decisions to achieve treatment optimization requiring close virological monitoring after treatment are required (A1). cessation. 3:7:4 Full information about the advantages, An attempt for finite NA treatment should use the most adverse events and inconveniences of Peg- potent agents with the highest barrier to resistance, to IFN versus NAs should be provided, so that the rapidly reduce levels of viremia to undetectable levels and patient can participate in the decision (A1). avoid breakthroughs due to HBV resistance. Once HBeAg 3:7:5 Simultaneous combinations of Peg-IFN with seroconversion occurs during NA administration, treatment NAs such as lamivudine, entecavir and tenofovir have been shown to be safe, but should be prolonged for at least 1 year and preferably an additional 3 years to try to achieve a durable off-treatment safety needs to be confirmed in larger studies response. Consolidation therapy of at least 3 years before recommendation (B2). 123 Hepatol Int (2016) 10:1–98 41 3:7:6 Sequential combination therapies using viral virological response. Primary nonresponse is defined as\1 load reduction followed by addition of Peg- log reduction in plasma HBV DNA levels after 24 weeks IFN or add-on Peg-IFN after response to NAs of therapy. In the absence of noncompliance, primary have been found to be safe with improved nonresponse is rare and is now only observed during ade- seroconversion rates compared to monother- fovir therapy due to suboptimal efficacy of this agent. The apies (B2). These approaches need to be appropriate action is to switch to a more potent drug (en- confirmed in larger studies. ¨ tecavir in treatment-naıve patients, tenofovir in treatment- 3:7:7 Finite-duration treatment with a NA is experienced patients). Partial virological response is achievable for HBeAg-positive patients who defined as detectable HBV DNA in plasma after 24 weeks seroconvert to anti-HBe on treatment. How- of therapy. Partial virological response may be encountered ever, treatment duration is unpredictable prior with all available NAs, especially in those patients with to therapy, as it depends on the timing of high baseline viraemia. The previous APASL HBV Man- HBeAg seroconversion and the treatment agement Guidelines recommended that treatment be mod- continuation post anti-HBe seroconversion ified (switch or add a second, more potent drug without (A1). cross-resistance) if HBV DNA remained detectable after 3:7:8 Strategy of long-term treatment with NA(s) is 24 weeks. However, this ‘‘Roadmap Approach’’ really only necessary for patients who are not expected pertains to patients receiving lamivudine or telbivudine to or fail to achieve a sustained off-treatment (drugs with a low genetic barrier to resistance), and should virological response and require extended become obsolete with the shift towards primary therapy therapy, i.e., for HBeAg-positive patients with more potent drugs with a high genetic barrier to who do not develop HBeAg seroconversion resistance. In patients receiving entecavir or tenofovir and HBeAg-negative patients (A1). monotherapy with detectable HBV DNA after 24 weeks, 3:7:9 The most potent drugs with the optimal continuation of the same treatment is recommended, given resistance profile, i.e., tenofovir or entecavir, the steady rise in rates of virological response over time should be used as first-line long-term and the very low risk of resistance with both of these agents monotherapies (A1). [213]. 3:7:10 As of yet, there are no data to indicate an Viral breakthrough is either due to noncompliance or the advantage of de novo combination treatment emergence of drug resistance. Because antiviral therapy with two NAs in NA-naive patients receiving with NA does not completely inhibit the replication of the either entecavir or tenofovir (C2). virus, the emergence of HBV drug resistance is almost inevitable with long-term monotherapy. Like HIV, the HBV reverse transcriptase lacks a proofreading function, 3.8 Treatment failure to therapy and its which allows for viral mutations to occur spontaneously management in chronic HBV infection during viral replication. This results in a pool of viral quasi-species that coexist in different proportions depend- The goals of hepatitis B treatment are to eliminate or ing on their relative replicative fitness. The dominant permanently suppress viral replication, normalize serum species at any one time is the ‘‘fittest’’ virus, capable of ALT levels and improve liver histology, thereby reducing replicating in the presence of selection pressure provided the risk of disease progression in patients chronically by the antiviral therapy. Factors that may impact the risk of infected with hepatitis B and reducing the long-term risk of selecting resistant HBV variants during antiviral therapy liver-related complications such as HCC, decompensation include the baseline viral load and diversity, the replicative and death. In recent years, the treatment of chronic hep- fitness of variants and the number of specific mutations that atitis has greatly improved with the development of new are required to confer resistance, which is the genetic therapeutic options. To date, two immunomodulators, barrier of that antiviral agent to resistance. interferon alpha and pegylated interferon, and five There are five NAs approved for clinical use, and a sixth nucleos(t)ide analogues (NA), lamivudine, adefovir, ente- agent, clevudine, which is approved in Korea but devel- cavir, telbivudine and tenofovir (not all countries), are opment elsewhere, has been halted because of risk of approved therapies for HBV. myopathy. All NAs target the active site of the HBV The long term efficacy of NAs is determined by the reverse transcriptase of the HBV polymerase and have ability to achieve and maintain viral suppression. Treat- potent antiviral activity, with between 4 and 6 log IU ment failure may be either primary virological failure or reduction in HBV DNA levels over 12 weeks. Single secondary viral breakthrough. Primary virological failure amino acid substitutions within the reverse transcriptase may be either primary nonresponse or partial (suboptimal) domain can significantly reduce NA binding and antiviral 123 42 Hepatol Int (2016) 10:1–98 Fig. 4 Reverse transcriptase mutations associated with drug Terminal resistance Spacer POL/RT RNaseH Protein 1 183 349 (rt1) 692 (rt 344) 845 a.a. F__V__LLAQ_YMDD I(G) II(F) AC B D E L-Nucleoside Resistance LMV rtA181T/V rtM204V/I L-dT rtA181T/V rtM204I Acyclic Phosphonate Resistance ADV/TFV rtA181T/V rtN236T D-Cyclopentane Resistance ETV rtL180M plus rtM204V/I rtI169 rtM250 rtT184 rtS202 Fig. 5 Cumulative incidence of Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 8 antiviral resistance in long-term studies of NA therapy 72 Weeks LAM 23% 46% 55% 71% 80% - ǂ1 ADV 0% 3% 11% 18% 29% ƚ2,3 LdT 25% 5% 29% 35% - - §4 § § TDF 0% 0% 0% 0% 0% 0% 0% *5 6 ETV <1% <1% 1.2% 1.2% 1.2% 1.2% efficacy, whilst preserving replication capacity. The long- NA resistance include changes to the overlapping envelope term benefit of these agents is lost following the selection region, resulting in altered HBsAg antigenicity, possible of these resistant mutants, resulting in viral breakthrough surface escape mutants, reduced binding to HBIG and and subsequent treatment failure. associated increased risk of HBV recurrence following Viral breakthrough due to drug resistance is defined as liver transplantation. an increase in HBV DNA levels (C19 log10 IU/ml) in Primary resistance mutations have been identified for patients who initially responded to antiviral therapy and are five out of the six currently approved NAs (Fig. 4). compliant with therapy [293]. This will lead to ALT ele- Although all five currently available NAs target the vations with occasional hepatitis flares and clinical same active site of the reverse transcriptase, they exhibit decompensation. Occasionally, the emergence of drug very different genetic barriers to resistance rates in long- resistance may result in acute liver failure and death, even term follow-up studies of each (Fig. 5). in patients with minimal liver disease. Antiviral resistance Lamivudine: L-nucleoside analogue The first approved is also associated with loss of long-term efficacy of NA for HBV. Lamivudine has potent antiviral efficacy, but antiviral therapy, with reduced HBeAg seroconversion and also has the lowest barrier to resistance. The cumulative histological progression. Other potential consequences of rate of emergence of lamivudine resistance is 15–20 %/ 123 Hepatol Int (2016) 10:1–98 43 year, and it plateaus around 60 % after 5 years. Higher receiving up to 8 years continuous tenofovir therapy. In baseline viral load, HBeAg positivity and immunosup- addition, no tenofovir resistance has been observed in pression are all factors associated with increase rate of patients with prior lamivudine resistance in studies of resistance, whilst HBV genotype and fibrosis stage are not. tenofovir salvage therapy. In a large Phase IIb study, 280 The primary mutations associated with lamivudine resis- patients with documented resistance to lamivudine were tance are the rtM204I and rtM204V mutations randomized to either tenofovir monotherapy or the fixed- (±rtL180M). dose combination of tenofovir plus emtricitabine (an L- Telbivudine: L-nucleoside analogue Tenfold more nucleoside analogue similar to lamivudine) for 96 weeks potent than lamivudine. Slower rate of drug emergence [198]. Both treatments were safe and well tolerated. The than LAM, around 10 %/year in HBeAg-positive and 5 %/ addition of emtricitabine did not improve efficacy—HBV year in HBeAg-negative patients. In the Globe study, at the DNA levels were suppressed below LOQ in 86 % of the end of 2 years, resistance was observed in 21.6 % of combination group and 89 % of the monotherapy group. HBeAg-positive patients and 8.6 % of HBeAg-negative No tenofovir resistance was observed in either treatment patients. The primary mutations associated with tel- group. Prior exposure or documented resistance to ente- bivudine resistance are the rtM204I and rtM204V muta- cavir or adefovir was documented at baseline in 12 % and tions. Therefore, lamivudine resistance is assumed to 22 %, respectively, all of who achieved and maintained confer cross-resistance with telbivudine. complete viral suppression on tenofovir ± emtricitabine. Adefovir: acyclic nucleoside phosphonate The first In a second Phase IIb study, 105 patients with documented approved NA for the rescue of lamivudine resistance. It is resistance to adefovir were randomized to tenofovir also effective against telbivudine and entecavir resistance. monotherapy or to tenofovir plus emtricitabine for Unfortunately, the dose-limiting nephrotoxicity of this 168 weeks [197]. Again, adding emtricitabine did not agent has resulted in suboptimal dosing (10 mg) with improve efficacy, with HBV DNA levels were suppressed reduced antiviral potency compared to other NAs. Around below LOQ in 84 % of the combination group and 82 % of 20 % of patients have primary treatment failure to this the monotherapy group maintaining HBV DNA levels agent. Factors that contribute to primary nonresponse below LOQ at the end of 168 weeks. The baseline geno- include the inadequate dose of 10 mg, individual differ- typic resistance mutations did not predict response—in ences in ADV metabolism and prior lamivudine resistance. particular, the presence of lamivudine and/or adefovir In treatment-naı ¨ve patients who had an adequate primary resistance-associated mutations at baseline had no impact virological response, the rate of adefovir resistance is on long-term treatment response. around 3–5 % per annum. This is increased to almost 10 % Because all the NAs share the same target (HBV poly- per annum in patients with prior lamivudine resistance (i.e., merase), cross resistance is a major issue (Table 8), and sequential monotherapy). The primary mutations associ- therefore the emergence of resistance may limit future ated with adefovir resistance are rt N236T ± rtA181V/T. treatment options (Fig. 5). Therefore, the optimal first-line The latter also confers cross resistance to lamivudine. treatment will be with an NA with high antiviral potency Entecavir: deoxyguanosine analogue 100-fold more and a high barrier to resistance. Unfortunately, in many potent than LAM and has a very high genetic barrier to countries within the Asia-Pacific region, the less expensive resistance—only 1 % over 5 years in treatment-naı ¨ve NAs with low barrier to resistance have remained as first- patients. Much higher rates of resistance in LAM-experi- line therapies because of cost and access barriers. As enced (refractory) patients, around 10 % per annum. This patients receive and fail sequential monotherapy, multi- difference reflects the pathway to resistance for entecavir. drug resistant HBV variants are becoming more prevalent, The primary mutations are those associated with lamivu- for which there are very limited salvage options available. dine resistance—L180M ? m204I/V. However, secondary Combining two or more of these older NAs with low mutations are needed to confer resistance to entecavir. barriers to resistance from different classes may help delay These include rtT184G ± rtS202I ± rtM250V. It has no or prevent the emergence of antiviral resistance to each cross resistance to adefovir, so entecavir monotherapy can drug (e.g., LAM plus ADV) [294]. However, such a be used to treat adefovir resistance. strategy is associated with increased cost and non- Tenofovir Acyclic nucleoside phosphonate: 1000-fold adherence. more potent than adefovir and has a very high barrier to resistance. This is the only approved NA without any Summary associated clinical resistance. Although reduced suscepti- bility to tenofovir has been produced in vitro with site- The best first-line strategy will always be selection of an directed mutagenesis, no primary mutations associated agent with both a high barrier to resistance (requires mul- with tenofovir resistance have been detected in any patient tiple mutations before emergence of resistance) and high 123 44 Hepatol Int (2016) 10:1–98 Table 8 Cross-resistance profiles amongst the five NAs [332] Pathway HBV variants LAM LdT ETV ADV TDF Wild-type SS S S S L-Nucleoside (LAM/LdT) M204 l/V RR I SS Acyclic phosphonate (ADV) N236T SS S R I Shared (LAM, LdT, ADV) A181T/V R SS R I Double (ADV, TDF) A181T/V ? N236T RR S RR D-Cyclopentane (ETV) L181M ? M204V/I ± I169 ± T184 ± S202 ± M250 RR R SS Multi-drug resistance A181T ? N236T ? M204V RR R R R 3:8:2 Regular monitoring for viral breakthrough Table 9 Strategies to manage treatment failure—first and second line should be performed in patients receiving an LAM/LdT resistance Switch to TDF agent with low barrier to resistance (lamivu- Add ADV dine, telbivudine and adefovir) (A1). LAM then ETV resistance Switch to TDF 3:8:3 Patients with viral breakthrough evident by Add ADV more than 1 log IU/ml increase of HBV DNA ADV resistance (no previous LAM) Switch to ETV from the nadir should be counseled about Switch to TDF compliance. In the compliant patient, appro- ADV resistance (previous LAM/LdT) Switch to TDF priate testing to confirm genotypic drug resis- Switch to LAM/TDF tance should be performed with a validated ETV resistance (no previous LAM/LdT) Switch to TDF test. Rescue therapy should be instituted as Add ADV early as possible in case of drug resistance Multidrug resistance Switch to ETV/TDF (A1). Switch to Peg-IFN 3:8:4 For patients who develop drug resistance while on LAM or LdT, switching to TDF is indicated (A1). antiviral potency (achieves complete viral suppression 3:8:5 For patients who develop drug resistance while within the first 6 months). Patient education and monitor- on ADV therapy, without prior lamivudine ing is also important to prevent treatment interruption. exposure, switching to either ETV or TDF The availability of tenofovir and entecavir as first line monotherapy is indicated (A1). drugs has made the two previous APASL recommenda- 3:8:6 For patients who develop drug resistance while tions—(1) that combination of NAs without cross-resis- on ADV rescue therapy for prior lamivudine/ tance should be used in highest risk patients (those who telbivudine resistance, switching to TDF have already failed one class, those with highest viral load monotherapy is indicated (B1). and those on immunosuppression), and (2) that the treat- 3:8:7 For patients who develop drug resistance while ment be modified (switch or add a second agent) after on ETV, switching to TDF is indicated (B1). 24 weeks, if HBV DNA is still detectable (so-called 3:8:8 For patients who develop drug resistance ‘‘Roadmap Approach’’)—invalid. associated with multidrug resistant mutations In patients receiving long-term therapy with lamivudine, (A181T ? N236T ? M204V), combination telbivudine and adefovir monotherapy, appropriate viro- ETV plus TDF is indicated (C2). logical monitoring should be performed to detect viral breakthrough and genotypic resistance. Early detection and 3.9 Treatment of patients with chronic HBV modification of antiviral therapy should optimize long-term infection with severe liver disease outcomes (Table 9). 3:8 Recommendations: treatment failure to therapy and 3.9.1 Treatment of patients with compensated cirrhosis its management in chronic HBV infection Peg-IFN in regimens similar to those used in CHB can be 3:8:1 The best strategy for drug resistance is used for the treatment of well-compensated cirrhosis [258]. prevention through patient education on com- Among NAs, monotherapies with tenofovir or entecavir are pliance and selection of an agent with high preferred because of their potency and minimal risk of potency and high barrier to resistance (ente- resistance. Close monitoring of HBV DNA levels every cavir and tenofovir) (A1). 123 Hepatol Int (2016) 10:1–98 45 3 months during the first year of therapy and until HBV closely monitored in this setting. The dose of all NAs needs DNA undetectability is important, as exacerbations of to be adjusted in patients with low creatinine clearance hepatitis B may occur in patients with cirrhosis requiring (\50 ml/min). urgent management. Thus, patients with cirrhosis require Patients with decompensated cirrhosis may show slow long-term therapy, with careful monitoring for resistance clinical improvement over a period of 3–6 months under and flares. NA(s) and then transplantation may be avoided. In such Clinical studies indicate that prolonged and adequate cases, life-long treatment is recommended. The HCC risk suppression of HBV DNA can stabilize patients and pre- is high in these patients even under effective NA therapy, vent the progression to decompensated liver disease [86]. and therefore long-term HCC surveillance is mandatory Regression of fibrosis and even reversal of cirrhosis have [299]. Some patients with advanced hepatic disease with a been reported in patients with prolonged suppression of high Child–Pugh or MELD score may have progressed viral replication [295]. beyond the point of no return, and may not benefit, thus Nonetheless, long-term monitoring for HCC is manda- requiring liver transplantation. In that situation, treatment tory despite virological remission under NA(s), since there with NA(s) inducing HBV DNA undetectability at trans- is still a risk of developing HCC [296, 297]. plantation will decrease the risk of HBV recurrence in the NA therapy should usually be continued for life in cir- graft (see ‘‘3.12 Prevention and treatment of recurrent rhotic patients. hepatitis B after liver transplantation’’ section). 3:9:1 Recommendations: treatment of patients with com- 3:9:2 Recommendations (treatment of patients with pensated cirrhosis decompensated cirrhosis) 3:9:1:1 Peg-IFN in regimens similar to those used 3:9:2:1 Patients with decompensated cirrhosis in CHB can be used for the treatment of should preferably be treated in specialized well-compensated cirrhosis (A1). However, liver units, as the application of antiviral extra caution and monitoring is recom- therapy is complex, and these patients may mended to prevent and diagnose hepatic be candidates for liver transplantation (A1). decompensation (A1). 3:9:2:2 Antiviral treatment is indicated in all 3:9:1:2 Among NAs, monotherapies with tenofovir HBsAg positive cirrhotic patients with or entecavir are preferred (A1). hepatic decompensation, irrespective of 3:9:1:3 NA therapy should usually be continued for HBV DNA levels (A1). life in cirrhotic patients (B1). 3:9:2:3 Peg-IFN is contraindicated in decompen- 3:9:1:4 Monitoring for HCC is mandatory despite sated cirrhosis (A1). virological remission under NA(s) (A1). 3:9:2:4 Among NAs, monotherapies with tenofovir or entecavir are preferred (A1). The antivi- ral treatment should not be delayed while 3.9.2 Treatment of patients with decompensated cirrhosis waiting for the HBVDNA results. 3:9:2:5 The dose of all NAs needs to be adjusted in Patients with decompensated cirrhosis should be treated in patients with low creatinine clearance specialized liver units, as the application of antiviral ther- (\50 ml/min) (A1). apy is complex, and these patients may be candidates for 3:9:2:6 NA therapy should usually be continued for liver transplantation. Antiviral treatment is indicated irre- life in decompensated cirrhotic patients (B1). spective of HBV DNA level, in order to prevent reactiva- 3:9:2:7 Monitoring for HCC is mandatory, despite tion. Peg-IFN is contraindicated in this setting. Entecavir or virological remission under NA(s) (A1). tenofovir should be used. The licensed entecavir dose for patients with decompensated cirrhosis is 1 mg (instead of 0.5 mg for patients with compensated liver disease) once 3.10 Treatment of patients with reactivation daily. of chronic HBV infection including those developing Recent studies have shown that both drugs are not only acute on chronic liver failure effective, but are generally safe in these patients [164, 298]. Upon exposure to HBV, individuals with a vigorous and Lactic acidosis has been reported to develop with some broad immune response to the virus develop an acute self- NAs, particularly entecavir, in treated patients with limited infection that may result in acute hepatitis. Indi- advance decompensated cirrhosis (MELD score [20). viduals who do not mount a broad and vigorous immune Therefore, clinical and laboratory parameters should be response do not clear the virus, but develop persistent 123 46 Hepatol Int (2016) 10:1–98 infection and become chronically infected with HBV. HBV Spontaneous reactivation hepatitis B persists in the body even after serological recovery from acute hepatitis B; so individuals who have been exposed to Spontaneous reactivation of hepatitis B can occur in both HBV are at risk for reactivation of hepatitis B replication HBeAg-positive and -negative patients [302, 303]. Spon- taneous reactivation of chronic HBV infection can occur in when the immune imbalance occurs, which can lead to flare or exacerbation of hepatitis [300]. The severity of the the immune clearance phase affecting 40–50 % of HBeAg- positive patients, and can be prolonged when there is flare depends on the state of underlying liver disease and may range from mild flare of hepatitis to acute on chronic repeated unsuccessful clearance of HBeAg [304]. Reacti- vation of chronic HBV infection at the HBeAg-negative liver failure. As patients suffering from severe acute exacerbation of CHB may not have underlying liver cir- phase is seen in 15–30 % of HBeAg-negative patients, and rhosis, they may recover to a relatively normal liver is occasionally associated with HBeAg seroreversion function, in contrast to those suffering from end-stage liver [301]. cirrhosis. It is therefore important to recognize this In Far Eastern regions, 23–38 % of patients have been important clinical presentation of CHB. reported to develop jaundice and hepatic decompensation Reactivation of chronic HBV infection has two com- (acute on chronic liver failure) during biochemical exac- erbation of CHB [305, 306]. These exacerbations may be ponents, i.e., reactivation of HBV replication and flare (or exacerbation) of hepatitis. Reactivation of HBV replication associated with significant mortality. should be defined as a marked increase in HBV replication (C2 log increase from baseline levels or a new appearance Pathogenesis of spontaneous reactivation of hepatitis B of HBV DNA to a level of C100 IU/ml) in a person with virus infection previously stable or undetectable levels or detection of HBV DNA with levelss C20,000 IU/ml in a person with no Acute hepatitis flare is precipitated by the reactivation of baseline HBV DNA [22, 300]. The types of reactivation HBV infection. The reasons for reactivated infection are should be described as follows: exacerbation of CHB or unknown, but are likely explained by changes in the immunological control of viral replication. reactivation of past hepatitis B. The latter can be further defined as reverse HBsAg seroconversion (reappearance of Influence of HBV genotypes on reactivation has also been assessed. There is a possibility that the immuno- HBsAg), or appearance of HBV DNA in serum in the absence of HBsAg. genicity of the different genotypes is different. Genotype B HBV may associate with more vigorous immune response This reactivation of HBV replication may lead to flare (or exacerbation) of hepatitis, which is characterized by an that leads to a higher chance of successful immune clear- ance, but also a higher risk of hepatic decompensation abrupt elevation of the serum ALT level, although there is no consensus definition or diagnostic criterion. It usually during the hepatitis flare. On the contrary, genotype C refers to an abrupt increase in serum ALT to[5 times the HBV is associated with less vigorous and prolonged, upper limit of normal and more than twice the baseline abortive immune clearance, which is more likely to cause value [23, 301]. Severe hepatitis flare means reactivation progressive liver damage, and eventually, liver cirrhosis with the presence of coagulopathy with prolonged pro- and HCC [307]. thrombin time (prolonged by more than 3 s) or INR Several HBV mutant strains, including mutations in precore, core promoter, and deletion mutation in pre-S/S increased to[1.5. Severe hepatitis flare may lead to ACLF. Flare (or exacerbation) of hepatitis in CHB infected genes, have been reported. Viral populations in the immune tolerance phase mostly consist of exclusively wild-type patients is common and may be caused by a number of factors (Table 10). virus or HBeAg-positive strains with little or no Table 10 Causes of acute hepatitis flares of hepatitis in chronic hepatitis B virus infected patients Spontaneous reactivation of hepatitis B virus replication Due to immunosuppressive medications: cancer chemotherapy, antirejection drugs, corticosteroids Cessation of anti-viral agents Emergence of drug resistance Due to antiviral therapy: interferon, corticosteroid withdrawal Due to superimposed infections with other hepatotropic viruses: hepatitis A/E virus, hepatitis C virus, hepatitis delta virus Caused by interaction with HIV infection: reactivated hepatitis, effect of immune reconstitution therapy Other hepatotropic insults: drugs, alcohol 123 Hepatol Int (2016) 10:1–98 47 precore/core promoter mutants or HBeAg-negative strains endemicity, the possibility of reactivation of chronic HBV [308]. Spontaneous reactivation of CHB may also occur in infection is high, which may be the first presentation of response to HBV genotypic variation. Chronic infection CHB or compensated cirrhosis, which was asymptomatic with precore mutant is often associated with multiple flares before exacerbation. Hence, a possibility exists that a interspersed with periods of asymptomatic infection [309]. proportion of patients with suspected acute hepatitis B It is possible that the absence of HBeAg in patients har- might actually be suffering from CHB and manifesting boring precore mutant HBV may permit a more vigorous clinically for the first time during a period of severe reac- immunological response to core peptides expressed on the tivation [23]. In areas of intermediate to high HBV surface of hepatocytes. Episodic flares have been attributed endemicity, endemic for chronic HBV infection, reactiva- to increases in the concentration of precore mutants and tion (flare or exacerbation) accounts for 27–70 % of pre- changes in the proportion of precore to wild-type HBV sumed acute hepatitis [23, 317, 318]. [310]. It has been suggested that disease exacerbations are The symptoms and biochemical parameters of severe uncommon during the earliest phase of chronic HBV at a acute reactivationof CHB can be very similar to those of time when wild-type HBV predominates, and that flares acute hepatitis B [23]. Hence, severe acute reactivation of become common with the gradual emergence of the pre- CHB might be misdiagnosed as acute hepatitis B in some core variant [310]. These flares have been thought to sub- cases. Patients with severe spontaneous acute reactivation side with time as the genetic heterogeneity disappears and of CHB can have positive IgM anti-HBc, which may again patients become exclusively infected with precore HBV be confused with the diagnosis of acute hepatitis B. Levels [311]. Multiple exacerbations of hepatitis due to reacti- [600 Paul–Ehrlich units/ml or IgM anti-HBc ([1:1000) vated HBV infection have been described in patients with suggest an acute HBV infection with high inflammatory BCP mutation, either alone, or in association with precore activity. In all other situations, concentrations are lower or mutation [312, 313]. undetectable [23, 319]. One study suggests that a low titer Reactivation seems to occur more commonly in male of IgM anti-HBc (\1:1000) and high HBV DNA level homosexuals, patients who are infected with human ([0.5 pg/ml, which equals *141,500 copies/ml) are useful immunodeficiency virus (HIV), concurrent with bacterial to identify severe acute reactivation (flare or exacerbation) infections or surgery, and when there is emotional or of CHB from acute hepatitis B [23]. However, HBV DNA physical stress [314]. Pregnancy and postpartum may also may sometimes become undetectable at the peak of the be a risk factor [315]. Liver injury during these sponta- biochemical exacerbation due to vigorous immune clear- neous flares appears to be mediated by expanded numbers ance. The presence of BCP mutation and precore stop of T cells that are reactive to HBeAg and HBcAg which codon mutations have been suggested to differentiate sev- are cross-reactive at the T cell level. Measurement of ere acute exacerbation of CHB from acute hepatitis B in lymphocyte proliferation in response to these viral anti- Japanese series, but its use in clinical practice needs further gens has shown that increased T-cell responses occur in validation [319]. the early phase of acute flares and subside after recovery A previous history of CHB or a positive family history from acute exacerbation and HBeAg seroconversion of CHB may suggest reactivation (flare or exacerbation); [316]. whereas recent history of at-risk blood, percutaneous or Once acute on chronic liver failure (ACLF) develops, sexual exposure may suggest acute hepatitis B. the immunological changes seen in the inflammatory pro- Liver biopsy showing evidence of chronicity may sug- cess are very similar to those of severe sepsis [317]. As the gest chronic infection. ACLF progresses, the resulting inflammatory responses in In uncertain cases of acute hepatitis B versus severe the liver and its associated cellular immune dysfunction reactivation of CHB, one can manage these patients as can result in multi-organ failure. severe reactivation cases and repeat hepatitis B surface antigen testing (HBsAg) 6 months later. In over 95 % of Diagnosis acute hepatitis B acquired in adulthood, HBsAg will be cleared on the follow-up testing; however, a small per- The typical presentation of severe spontaneous reactivation centage of patients with acute reactivation of chronic HVB in a patient with CHB is a short onset of jaundice and very infection may also clear HBsAg. high ALT level, sometimes preceded by prodromal con- As CHB infected patients still can acquire another viral stitutional symptoms. If signs of chronic liver disease are infection that causes acute hepatitis, other viral hepatitis present, the diagnosis could be easy, however, some (A, C, D and E) must be excluded by serological assays. If patients presenting with severe acute reactivation of CHB suspected, other etiologies (Table 1) should also be may not have had an earlier diagnosis of chronic HBV excluded before a diagnosis of spontaneous reactivation of infection. In countries with intermediate and high CHB is made. 123 48 Hepatol Int (2016) 10:1–98 Outcome been described. One regression model, using the presence of hepatorenal syndrome, liver cirrhosis, positive HBeAg, The clinical presentation of acute spontaneous reactivation low albumin and prolonged PT, was found to be superior to of CHB infection depends on the underlying severity of the MELD score in predicting 3-month mortality [329]. liver disease and other factors. Another model based on the presence of hepatic In a Chinese study on evaluation of prognostic factors in encephalopathy, hepatorenal syndrome, positive HBeAg, severe reactivation (flare or exacerbation) of chronic HBV liver cirrhosis and prolonged PT was also found to be infection, at admission the following parameters were superior to both the MELD and Child–Pugh score [325]. In independently associated with adverse outcome: pre-ex- a recent study from China compared a logistic regression isting cirrhosis, high Child–Pugh score, low albumin level, based model (based on presence of hepatic encepahalopa- high bilirubin level, prolonged PT and low platelet count. thy, hepatorenal syndrome, cirrhosis, HBeAg status, For the subsequent stay in the hospital, these factors were Prothrombin time and age) with Child–Turcotte–Pugh as follows: high peak bilirubin level, long peak PT, long (CTP) classification, King’s College Hospital (KCH) cri- duration to reach the peak PT, development of teria, model for end-stage liver disease (MELD), MELD encephalopathy, and presence of ascites. There was also a combined with serum sodium (Na) concentration trend for a longer time to reach peak bilirubin level to be an (MELDNa), and integrated MELD (iMELD) for predicting independent factor associated with adverse outcome [320]. short-term prognosis of patients with HBV-related acute- In one study from Taiwan on HBeAg-positive noncir- on-chronic liver failure (ACLF). It was found that the rhotic patients with acute exacerbation, 5.1 % of the regression model, MELD, MELDNa and iMELD had exacerbation episodes resulted in hepatic decompensation, similar accuracy in predicting the short-term prognosis in and serum HBV DNA level was the only significant risk patients with liver cirrhosis, while regression model was factor (p = 0.003). A serum HBV DNA cutoff value of superior to MELD, MELDNa and iMELD in predicting the 1.55 9 10 copies/ml predicted decompensation with a short-term prognosis of HBV-ACLF patients without liver sensitivity of 85.7 %, a specificity of 85.5 %, a negative cirrhosis. CPT score and KCH criteria fared poorly [330]. prediction value of 99.1 %, and a positive prediction value Further studies to externally validate these models would of 24.0 % [321]. be needed. Owing to their limited hepatic reserve, cirrhotic patients Acute Physiology and Chronic Health Evaluation are expected to recover more slowly from the hepatic insult (APACHE) II and III, Simplified Acute Physiology Score and are more prone to complications including sepsis, (SAPS) II, and Mortality Prediction Model II, SOFA and gastrointestinal bleeding and acute renal failure. Many its modifications have been used to prognosticate critically studies have found that patients with pre-existing liver ill patients with liver failure [331, 332]. cirrhosis and more serious hepatic dysfunction (prolonged prothrombin time, elevated serum bilirubin and high Treatment Child–Pugh score) have a higher risk of mortality [322, 323]. Patients need intensive supportive care, including close Once the disease reaches the stage of acute on chronic monitoring and treatment of complications. liver failure (ACLF), the prognosis is extremely poor, with In severe spontaneous reactivation of CHB when 3-month mortality rates without liver transplantation immune activity is already excessive, interferon-based reported to be around 50–55 % [324]. Different predictive treatment may aggravate the hepatic decompensation, and models have been used in prognosticating acute-on-chronic is thus contraindicated. Oral nucleos(t)ide analogs are the liver failure due to reactivation of CHB. MELD is the most treatment of choice. commonly used prediction model. MELD score has been In initial case series or cohort studies of Lamivudine in found in many studies to be more objective when compared patients with severe acute exacerbation, some showed to Child–Pugh score in predicting survival in chronic HBV dramatic effects [333], whereas others could not demon- infection patients with ACLF [325, 326]. It has been found strate any survival benefit of lamivudine treatment [323, that a MELD score of[30 is associated with high mortality 334, 335], possibly related to the delayed commencement ([90 % despite using antivirals), a MELD \20–23 is of lamivudine. A study from Taiwan suggests that the associated with low mortality with use of antivirals beneficial effect of antiviral therapy on short-term survival (16–17 %) and MELD in between these ranges is associ- depends on the timing of treatment. Among consecutive ated with intermediate mortality (44–51 %) with antiviral CHB patients with severe acute exacerbation treated with treatment [327, 328]. lamivudine, all 25 patients who had baseline bilirubin A number of logistic regression models based on both below 20 mg/dl survived. Among patients with low laboratory parameters and organ dysfunction have also (\20 mg/dl) baseline serum bilirubin level, lamivudine 123 Hepatol Int (2016) 10:1–98 49 treatment has definite survival benefit as compared to his- lamivudine [36.4 vs. 40.5 %, RR 0.77, 95 % CI (0.45, toric controls who did not receive lamivudine (5/20 1.32), p = 0.35] [339]. One study has found entecavir to patients died, 20 %, p = 0.013). On the other hand, the have similar survival benefit as compared to telbivudine, mortality rate of the patients who received lamivudine although telbivudine had a better renoprotective effect when bilirubin was above 20 mg/dl (23/35, 67 %) was [347]. similar to that of the untreated historical controls (9/11, One RCT from India found improved 3-month survival 82 %) [336]. A more recent study found a survival benefit with tenofovir (57 %) in comparison to placebo (15 %) in lamivudine-treated patients when compared to controls among patients with acute exacerbation of chronic HBV in patients with a MELD score of 30 or less; however, infection presenting as acute-on-chronic liver failure. A those treated with lamivudine still had a 3-month mortality more than 2-log reduction in HBV DNA levels at 2 weeks of 50.7 %. A low pre-treatment HBV DNA and a rapid was found to be an independent predictor of survival [348]. decline in viral load were predictors of good outcome In one study, 69 patients of severe spontaneous reacti- [337]. vation of hepatitis B were randomized to receive either Once ACLF develops, the prognosis of spontaneous tenofovir monotherapy or dual therapy of tenofovir plus reactivation of HBV infection is poorer as compared to telbivudine. Of all patients, 25 patients had ACLF (13 patients who don’t develop features of ACLF. In one meta- patients received tenofovir and 12 received tenofovir plus analysis of antiviral therapy in ACLF due to spontaneous telbivudine). Patients with ACLF receiving tenofovir plus reactivation of HBV infection that included 11 randomized telbivudine against tenofovir alone had significant controlled trials (including 654 patients; 340 treated with improvement in MELD score at week 4 and week 12 and NAs such as lamivudine entecavir, telbivudine, or teno- improvement in acute kidney injury compared to baseline. fovir disoproxil fumarate, and 314 treated with NAs or Of the 69 patients enrolled into study, 11 patients died at placebo), it was found that nucleoside analogues signifi- the end of the 3-month follow-up period. Among ten deaths cantly improved 1-month [OR 2.10; 95 % CI (1.29, 3.41); in ACLF, eight had received tenofovir alone (p = 0.02). A p = 0.003], 3-month [OR 2.15; 95 % CI (1.26, 3.65); predictor of mortality in univariate analysis in ACLF-B at p = 0.005] and 12-month survival [OR 4.62; 95 % CI 24–36 weeks of follow-up was presence of septic shock, (1.96, 10.89); p = 0.0005] [338]. Another meta-analysis of tenofovir monotherapy, e antibody positivity and high five studies on nucleos(t)ide analogues in ACLF due to baseline MELD score [349]. spontaneous reactivation of HBV infection concluded that The definitive treatment for severe reactivation (flare or antiviral treatment with nucleos(t)ide analogues signifi- exacerbation) with ACLF is liver transplantation. Both cantly lowered 3-month mortality [44.8 vs. 73.3 %, RR deceased and living donor transplants are viable and very 0.68, 95 % CI (0.54, 0.84), p \ 0.01] as well as incidence useful options with very good results [350]. Liver trans- of reactivation [1.80 vs. 18.4 %, RR 0.11, 95 % CI (0.03, plantation results from the East in patients with HBV 0.43), p \ 0.01] compared to those who did not. There was reactivation have shown successful 5-year survival above no significant difference in the prognosis of patients treated 90 % [350, 351]. with entecavir or lamivudine [36.4 vs. 40.5 %, RR 0.77, In a DDLT setting, the availability of the organ becomes 95 % CI (0.45, 1.32), p = 0.35] [339]. a major concern. In living donor transplant cases, there are Several studies have found that despite a faster sup- no waiting list constraints, and survival has been shown to pression of HBV replication, entecavir treatment was either be comparable to DDLT. not associated with improved short-term survival as com- Recently, a lot research has been conducted in an pared to patients receiving no treatment [340], or had attempt to improve the dreadful outcome in HBV ACLF. higher overall mortality as compared to lamivudine treat- One randomized placebo-controlled trial found that the ment [341], or higher mortality when treatment was started administration of granulocyte-colony stimulating factor early but with high DNA levels (bilirubin \15 mg/dl and improved survival after 2 months [352]. Use of bioartificial HBV DNA higher than 10 copies/ml) compared with liver support systems is controversial and the results of a lamivudine [342]. Lactic acidosis has been hypothesized as randomized controlled multicenter study in ACLF patients a possible cause of increased mortality with entecavir failed to identify any survival benefit [353]. Corticos- [341]. This finding needs further confirmation. However, teroids, based on their anti-inflammatory activity, have other studies have found comparable efficacy of entecavir been used in chronic HBVinfection with ACLF. In a recent and lamivudine in the short term [329, 343, 344], and long study, 56 patients received intravenous dexamethasone term [345], or better long-term (52 weeks) survival but not 10 mg daily for 5 days, together with continuous lamivu- short-term survival as compared to lamivudine [346]. One dine. When compared with controls, dexamethasone meta analysis found that there was no significant difference treatment was an independent factor influencing survival, in the prognosis of patients treated with entecavir or with a rapid decline in serum bilirubin in the first 5 days 123 50 Hepatol Int (2016) 10:1–98 being predictive of survival [354]. In a more recent study, that of normal population [358]. As a result, surveillance corticosteroid treatment in combination with nucleotide for HCC has been widely applied in patients with chronic analogue has sufficient virological effect against severe HBV infection. acute exacerbation of chronic HBVinfection, and a rapid An important issue related to the surveillance program is decline of HBV DNA is conspicuous in survived patients cost-effectiveness. In many Western countries, interven- [355]. tions that can be achieved at a cost of\$50,000/year of life gained are considered cost-effective [359]. Obviously, this 3:10 Recommendations: treatment of patients with reac- threshold cost is not applicable in most Asian countries, tivation of chronic HBV infection, including those and should be determined depending on the economic sit- developing acute on chronic liver failure uation of each country. As a matter of course, the efficacy 3:10:1 Reactivation of HBV replication should be of surveillance unambiguously depends on the incidence of defined as a marked increase in HBV HCC in the target population. replication (C2 log increase from baseline levels or a new appearance of HBV DNA Who should be screened? to a level of C100 IU/ml) in a person with previously stable or undetectable levels or In determining the target population for surveillance, two detection of HBV DNA, with levels points should be taken into consideration: the incidence of C20,000 IU/ml in a person with no base- HCC, and the degree of benefit from a treatment in terms of line HBV DNA (B1). patient’s survival. According to several cost-effectiveness 3:10:2 Flare (or exacerbation) of hepatitis usually models, surveillance becomes cost-effective when the risk refers to an abrupt increase in serum ALT to of HCC is 1.5 %/year or greater in patients with cirrhosis [5 times the upper limit of normal and [359, 360]. However, surveillance with USG and AFP more than thrice the baseline value (B1). becomes cost-effective once the incidence of HCC exceeds 3:10:3 Other causes of hepatitis flares, such as 0.2 %/year in hepatitis B infected subjects without cir- superimposed hepatotropic viruses, toxins or rhosis [361]. drugs, should be excluded (Table 10) (A1). All patients with HBV-related cirrhosis should be 3:10:4 The severity of such reactivation depends screened for HCC. However, the benefit of surveillance on the severity of underlying liver disease, seems to be absent or minimal in Child–Pugh class C and once ACLF develops, the prognosis is patients. Trevisani et al. [362] reported that a surveillance very poor (A1). program could prolong the patient’s survival in Child–Pugh 3:10:5 Nucleos(t)ide analogs should be started class B patients. However, in Child–Pugh class C patients, immediately without delay or waiting for although cancer stage and treatment distribution were the HBV DNA results (A1). better in those under a surveillance program than those 3:10:6 Liver transplantation should be considered without it, there was no difference in overall survival (7.1 among patients with severe liver failure vs. 6.0 months). The anticipated survival benefit from early (e.g., MELD [30) (B1). detection of HCC was offset by a high incidence of liver- 3:10:7 Assessment of reduction of HBV DNA failure-related mortality. level at week 2 after nucleos(t)ide analogs Defining the population who should be screened among should be done; if there is a \2 log chronic HBV-infected subjects without cirrhosis is some- reduction, it suggests poor prognosis and what complicated. As mentioned above, surveillance the patient should be considered for liver becomes cost-effective in chronic HBV-infected subjects transplantation (B1). without cirrhosis, if the cutoff cost-benefit is $50,000/year of life gained and the incidence of HCC exceeds 0.2 %/ year. However, each Asian country differs greatly in the 3.11 HCC screening in chronic HBV infection economic situation, and therefore the result of cost-effec- tiveness analysis performed in a specific country is not HCC screening and surveillance in patients with HBV applicable to other countries. Since the cost-effectiveness infection have been covered in detail in APASL consensus greatly depends on the incidence of HCC, the threshold recommendations on HCC [356]. incidence of HCC for surveillance should be determined More than 50 % of HCC cases worldwide and 70–80 % individually in each country. of those in HBV-endemic regions are attributable to chronic HBV infection [357]. The relative risk of HCC in Outcome calculators for predicting HCC Until now, chronic HBV-infected subjects was about 100–223 times several prediction scores have been developed and 123 Hepatol Int (2016) 10:1–98 51 validated to calculate the risk of HCC in patients with patients with chronic HBV infection and chronic HBV infection in the community and clinic be used to determine the target population settings. for surveillance (B1). 3:11:3 The threshold incidence of HCC for surveillance should be determined individ- Liver stiffness as predictor of HCC development Liver stiffness, measured by transient elastography, has been ually based on the economic situation of each country (B1). used to assess the degree of liver fibrosis and it correlates well with liver fibrosis stage. Jung et al. [363] reported that 3:11:4 Surveillance for HCC should be performed by USG and AFP (B2). the incidence rates of HCC are significantly associated with the degree of elevated liver stiffness measurement (LSM). 3:11:5 Surveillance by USG and AFP should be The discordance rate in the diagnosis of cirrhosis between performed every 6 months (B2), and clinical criteria and LSM was 13.4 %, and the incidence of preferably every 3 months in cirrhotics HCC was higher in patients without clinical cirrhosis who and those at high risk of HCC (C2). showed LSM[13 kPa than in those with clinical cirrhosis 3:11:6 Contrast enhanced CT and MRI should be who showed LSM B13 kPa. These results strongly sug- used regularly for confirmation of suspicious lesions on US screening (A1). Their use is gested that LSM can be a complement or alternative to the clinical diagnosis of cirrhosis in developing models for the also recommended in the screening of patients with advanced cirrhosis with high prediction of HCC. However, LSM per se was not useful in determining the subgroup of patients for surveillance in suspicion of development of HCC (C2). 3:11:7 A baseline CECT or CEMRI should be this study population. The observed incidence of HCC was 0.54 %/person-year even in patients with the lowest LSM obtained in all cirrhotics at presentation (B1). value (\8 kPa), which is much higher than the threshold incidence (0.2 %/year) for surveillance in noncirrhotic 3.12 Prevention and treatment of recurrent hepatitis chronic HBV-infected subjects. Recently, Wong et al. B after liver transplantation [364] modified their CU–HCC score with LSM (LSM– HCC score), and the AUROCs of LSM–HCC score were Antiviral therapy using newer nucleos(t)ide analogues with higher than those of CU–HCC score (0.83–0.89 vs. lower resistance rates such as entecavir or tenofovir could 0.75–0.81). By applying the cutoff value of 11, the score suppress HBV replication, improve liver function, and excluded future HCC with high negative predictive value delay or obviate the need for liver transplantation in some (99.4–100 %) at 5 years. patients. Antiviral therapy before LT may prevent HBV recurrence after LT by reducing the level of viremia to Modalities and frequency for screening extremely low levels. After LT, the primary goal of antiviral therapy is to prevent HBV recurrence and to USG, AFP, des-c-carboxyprothrombin (DCP, prothrombin prevent graft loss. induced by vitamin K absence-II), Lens culinaris agglu- tinin-reactive fraction of AFP (AFP-L3), or their combi- Diagnosis, mechanisms, and risk factors for HBV nations have long been used as surveillance tests for HCC recurrence after LT- in Asian countries. Detailed review on the diagnostic per- formance of each test as a surveillance test is beyond the Recurrence of HBV infection after LT is defined as the scope of this guideline for the management of CHB. They reappearance of circulating hepatitis B surface antigen were well summarized in APASL consensus recommen- (HBsAg) with or without detectable HBV DNA. However, dations on HCC [356]. only patients who develop persistently detectable HBV The APASL consensus recommendations on HCC rec- DNA are shown to be at risk for clinical disease and graft ommended USG and AFP every 6 months as surveillance loss [365]. HBV reinfection is the consequence of an tests for HCC [356]. immediate reinfection of the graft by circulating HBV 3:11 Recommendations: HCC screening in chronic HBV particles, or a later reinfection from HBV particles coming infection from extrahepatic sites such as peripheral blood mononu- clear cells, or both. 3:11:1 Surveillance for HCC is recommended in There is a direct relationship between HBV viral load at high-risk populations with chronic HBV transplantation (i.e., [10 copies/ml) and the rate of HBV infection (B2). recurrence [366]. Thus, antivirals should be used before 3:11:2 Current HCC risk prediction scores can transplantation to achieve undetectable HBV DNA levels accurately stratify the risk of HCC in 123 52 Hepatol Int (2016) 10:1–98 to reduce the risk of HBV recurrence. Other factors asso- prophylaxis regimen is necessary for those patients with a ciated with low rates of recurrence include surrogate high risk of HBV recurrence: high pretransplant HBV markers for low levels of viral replication (including DNA levels, those with limited antiviral options if HBV HBeAg-negative status, fulminant HBV, and HDV coin- recurrence occurs (i.e., HIV or HDV coinfection, preex- fection). In addition, HCC at LT, HCC recurrence, or isting antiviral drug resistance), those with a high risk of chemotherapy used for HCC are independently associated HCC recurrence, and those with a risk of noncompliance to with an increased risk of HBV recurrence [367]. antiviral therapy [373]. Combination prophylaxis with low-dose IM HBIG Prevention of HBV recurrence after LT- (400–800 IU IM) plus lamivudine decreases costs by more than 90 % compared to an IV regimen, with a recurrence Prior to the availability of effective HBV prophylaxis in the rate as low as 4 % at 4 years [374]. Subcutaneous regimens 1980s, LT for CHB was a relative contraindication. High of HBIG administered 6 months after LT have also been rates of graft reinfection leading to severe flares and loss of shown to be effectivel, with some advantage in tolerability graft occurred in the absence of antiviral therapy. The use and the possibility of self-administration by patients at of hepatitis B immune globulin (HBIG) after LT was the home [375]. In one study on 183 patients receiving com- first major milestone in the prevention of post-transplant bination prophylaxis with antiviral therapy (mostly LAM HBV recurrence. HBIG monotherapy reduced HBV monotherapy) plus HBIG given either IV high-dose recurrence by a rate of approximately 70 % [368]. The (10,000 IU monthly), IV low-dose (3000–6000 IU advent of antiviral therapy further changed the landscape of monthly), IM low-dose (1000–1500 IU every 1–2 months), post-LT prophylaxis. Several meta-analyses have shown or for a finite duration (median duration 12 months). that combination prophylaxis was significantly superior to Cumulative rates of HBV recurrence at 1, 3, and 5 years antivirals or HBIG alone in preventing HBV recurrence were 3, 7, and 9 %, respectively. Multivariate analysis [369–371]. showed that positivity for HBeAg and high viral load at transplant, but not the post transplant HBIG regimen, were HBIG containing prophylaxis regimens In conventional associated with HBV recurrence [376]. Also, the combi- protocols, HBIG is used at high dose to neutralize HBsAg nation of HBIG and a newer nucleos(t)ide analogue during the anhepatic phase and the first postoperative week (tenofovir or entecavir) was shown to be superior to the (i.e., generally 10,000 IU/day) . In the early post transplant combination of HBIG and LAM in reducing the risk of period, some studies reported that high IV HBIG dosage HBV recurrence in one systematic review (1 vs. 6.1 %, (C10,000 IU/day) versus low HBIG dosage p = 0.0004) [371]. Indefinite combination therapy with HBIG plus a (\10,000 IU/day) was associated with a lower frequency of HBV recurrence [368]. In medium-term and long-term nucleos(t)ide analogue may not be required in all liver follow-up, IV HBIG has been administered in two different transplant recipients. Strategy of HBIG withdrawal after a ways: at a frequency dictated by the maintenance of defined period of combination prophylaxis has been stud- specific anti-HBs levels, or on a fixed schedule. The latter ied. In a study of 29 patients, high-dose HBIG and LAM approach is simpler and requires less monitoring, but is were used in the first month, after which the patients were more expensive [372]. The target levels for anti-HBs titers randomized to receive either LAM monotherapy or LAM vary with time after LT: generally, anti-HBs levels are plus IMHBIG at 2000 IU monthly [377]. None of the maintained at [500 IU/l during 1–3 months, [250 IU/l patients developed HBV recurrence during the first until 6–12 months, and at [100 IU/l thereafter. 18 months, but later recurrences developed in four patients The use of IV HBIG has limitations; namely, the high after 5 years of follow-up, which was related to poor LAM cost, parenteral administration, limited supply, need for compliance [378]. An alternative approach is to switch frequent clinic visits and laboratory monitoring, lower after HBIG withdrawal to a combination of LAM/ADV effectiveness in patients with high levels of HBV replica- [379] or a combination of emtricitabine/TDV [380]or tion before LT, and the potential selection of HBsAg entecavir [381]. escape mutants. Alternative approaches have been studied, which include the use of low-dose intramuscular (IM) HBIG-free prophylactic regimens LAM, when used as a HBIG, subcutaneous HBIG, withdrawal of HBIG after a prophylactic monotherapy (started before transplantation finite period or prophylaxis regimens without HBIG. The and continued after transplantation without HBIG), showed ability to achieve undetectable HBV DNA before LT in the a 10 % recurrence rate at 1 year, but 22–41 % at 3 years majority of patients using potent antivirals allows the use after LT, due to the emergence of escape mutations in the of prophylaxis regimens that minimize the dose or duration YMDD motif of the polymerase gene [382]. Recurrence of HBIG. However, a more cautious approach to a was observed mainly in patients with a high level of HBV 123 Hepatol Int (2016) 10:1–98 53 replication prior to drug exposure [382]. In a study on 61 with limited antiviral options if HBV recurrence occurs LAM-resistant patients treated with ADV on the wait-list (i.e., HIV or HDV coinfection, pre-existing drug resistance, who underwent LT (40 % of these patients received ADV or intolerance), those with a HCC at LT, and those with a plus/minus LAM prophylaxis without HBIG), no patient risk of noncompliance to antiviral therapy [373]. Among had recurrent HBV infection [383]. In another study on use them, HBIG withdrawal may be considered if high potency of a combination prophylaxis using LAM and ADV with- NAs are used. The timing of HBIG withdrawal is still out BIG in 18 patients who had HBV DNA below 3 log controversial; however, 1-year post-transplantation seems 10 IU/ml before LT, no cases of HBV recurrence were to be safe and feasible [379, 390]. A recent study from observed after a median follow-up of 22 months [384]. India included 176 patients (at least [12 months follow- The availability of more potent antivirals with a higher up) with HBV cirrhosis/HCC who received secondary barrier to resistance could increase the proportion of prophylaxis with indefinite entecavir/tenofovir after living- patients with undetectable HBV DNA before transplanta- donor LT. All patients received 10,000 IU intravenous tion and decrease the risk of recurrent disease after trans- HBIG in anhepatic phase followed by 600–1000 IU intra- plantation. In a study investigating the efficacy of ETV as muscularly daily for 7 days, weekly for 3 weeks, and then monoprophylaxis in 80 patients, there were no episodes of monthly, to keep antiHBs levels [100 mIU/ml for 1 year. HBV flares or graft loss secondary to recurrent HBV Thirty-five patients (19.8 %) had HBV DNA[2000 IU/ml infection. A total of 18 patients (22.5 %) had persistent before LT. After LT, patients received entecavir (n = 126, HBsAg positivity after transplant without seroclearance 71.5 %), tenofovir (n = 20, 11.3 %), or a combination of (n = 8) or reappearance of HBsAg after initial seroclear- entecavir and tenofovir (n = 30, 17 % for 3 months, fol- ance (n = 10). One of these patients had a very low HBV lowed by entecavir alone). During follow-up of 43 DNA level. The pre-LT HBsAg level was significantly (12–117) months, two patients (including one with non- higher in those who had HBV recurrence/persistence compliance) had HBV recurrence [391]. compared with those who did not [223]. A recent large 3:12 Recommendations: prevention and treatment of long-term cohort study of 362 CHB post-LT patients recurrent hepatitis B after liver transplantation receiving only NAs without HBIG showed that at year 8 after LT, 98 % had undetectable HBV DNA. Moreover, the 3:12:1 Antivirals (tenofovir or entecavir) should survival was excellent at 83 % at 8 years, with no mortality be used before transplantation to achieve related to HBV recurrence [385]. This clearly shows that undetectable HBV DNA levels to reduce the risk of HBV recurrence (A1). HBIG-free regimen is safe and effective, and many studies have also demonstrated the efficacy of this therapeutic 3:12:2 A lifelong prophylactic therapy is needed (A1). approach [386, 387]. However, HBIG remains part of the antiviral prophy- 3:12:3 Among low risk patients (i.e., with unde- laxis in many transplant centers. The use of HBIG is likely tectable HBV DNA levels at the time of to result in a higher rate of HBsAg negativity due to the transplant), HBIg free regimens can be used. fact that the passive anti-HBs antibodies will bind with High potency NAs (entecavir or tenofovir) HBsAg, leading to a further reduction in detection rate should be used for life (B1) (Fig. 6). when compared with HBIG-free protocols. HBV DNA persists in serum, liver, or peripheral blood mononuclear cells even 10 years after LT in a proportion of HBV Assess risk status transplanted patients who are HBsAg-negative. These reservoirs may serve as a source of HBV reinfection in the Low-risk paents High-risk paents future, supporting the use of long-term prophylactic ther- -Undetectable HBV DNA levels at LT - Detectable HBV DNA levels at LT - Presence of drug-resistant HBV apy in most patients [388, 389]. Therefore, life-long - HIV /HDV coinfecon - HCC at LT antiviral therapy is currently the standard of care after LT - Poor compliance to anviral therapy for CHB. In the early post transplant period, some studies � 10,000 IU IV HBIG in an-hepac phase No HBIg reported that a high IV HBIG dosage (C10,000 IU/day) followed by 600-1000 IU High potency NAs[ Tenofovir or intramuscularly/ IV daily for 7 days, versus a low HBIG dosage (\10,000 IU/day) was associ- Entecavir] weekly for 3 weeks, and then monthly, ated with a lower frequency of HBV recurrence [369]. to keep an-HBs levels >100 mIU/mL for 1 year Patients with undetectable HBV DNA levels at the time of � High potency NAs [Tenofovir or transplant can be considered for HBIG free regimens by Entecavir] using high potency NAs [tenofovir or entecavir]. However, HBIG free prophylaxis should not be used for those Fig. 6 Prophylaxis for prevention of HBV graft recurrence following patients with high pretransplant HBV DNA levels, those LT 123 54 Hepatol Int (2016) 10:1–98 3:12:4 Among high-risk patients (detectable HBV significantly impaired CD4 recovery during the first DNA levels at LT, presence of drug- 3 years of HAART, despite similar virological effective- resistant HBV, HIV or HDV coinfection, ness of antiretroviral therapy compared to patients without HCC at LT or poor compliance to antiviral HBV infection [504 cells/ll (95 % CI 496–511) vs. 449 therapy) 10,000 IU IV HBIG in anhepatic cells/ll (95 % CI 428–469)] [402]. phase should be given, followed by Compared to HIV-uninfected subjects, patients with 600–1000 IU intramuscularly/IV daily for HIV infection have a higher risk of chronicity after acute 7 days, then weekly for 3 weeks, and then HBV infection [403]. Clinical observational studies have monthly, to keep antiHBs levels[100 mIU/ demonstrated that HIV/HBV-coinfected patients may have ml for 1 year. After 1 year, HBIg may be faster progression of hepatic fibrosis and a higher risk of discontinued. High potency NAs (entecavir cirrhosis, end-stage liver disease, and HCC than HBV- or tenofovir) should be continued monoinfected patients [395, 404]. Similarly, compared simultaneously. with HIV-monoinfected patients, those with HIV/HBV coinfection, especially HBV genotype B, had a higher risk of acute hepatitis, hepatic decompensation, and liver-re- 3.13 Treatment of chronic HBV infection in special lated mortality [405]. Superinfection or coinfection with patient groups hepatitis D virus may further exacerbate the complications in patients with HIV/HBV coinfection [406]. 3.13.1 Coinfection with HBV and HIV Treatment of HIV may lead to flares of hepatitis B due to immune reconstitution, but the risk of developing cir- Approximately 15–25 % of the HIV infected population in rhosis is negligible in HBV/HIV coinfected patients on Asia and Africa has concurrent chronic HBV infection, long-term tenofovir combined with emtricitabine or lami- with coinfection more common in areas of high prevalence vudine therapy [407]. for both viruses [392] and rates approaching 25 % in Given the faster progression of liver disease in HIV– countries where the viruses are highly endemic [393]. In HBV coinfected patients, there is a strong rationale for areas where HBV is less endemic (North America, Europe, early dual anti-HIV and anti-HBV therapy, irrespective of and Australia), the overall prevalence of chronic HBV immunological, virological or histological considerations infection among HIV-infected persons is estimated to be [408]. Most coinfected patients should be simultaneously 6–14 % [394–396]. treated for both HIV and HBV de novo [409]. Lamivudine A persistent state of immune activation in patients with (LAM), emtricitabine (FTC) and and tenofovir (TDF) have chronic HBV infection could upregulate HIV replication. both anti-HBV and anti-HIV activities. For most patients, Early prospective cohort studies of HIV/HBV-coinfected the best option is triple combination of antiretrovirals, patients revealed a 3.6-fold–6.8-fold relative risk of pro- including two reverse transcriptase inhibitors with anti- gression to AIDS compared to those without coinfection HBV activity. Tenofovir combined with emtricitabine or [397, 398]. However, other reports failed to confirm these lamivudine plus a third agent active against HIV are indi- results [399]. This discrepancy was likely related to the cated [409, 410] (Fig. 7). duration of HIV infection. To minimize the influence of Other NAs, such as adefovir (ADV) or telbivudine duration of HIV infection, a prospective observational (LdT) therapy, do not fit in the HIV setting due to the lack cohort of adult patients with primary HIV infection (sero- of or residual activity of these molecules against HIV and conversion window B6 months) has shown that HBV their relatively weak activity against HBV. Treatment with coinfection (adjusted hazards ratio 3.46; 95 % CI entecavir (ETV) may be needed in case TDF cannot be 1.16–10.32) was an independent predictor of immunolog- used, mostly due to kidney toxicity. Because ETV displays ical progression that was defined as the occurrence of a weak activity against HIV and may select for resistance CD4 cell count \350 cells/ll 3 months or more after mutations, it should be administered only in the context of diagnosis of primary HIV infection [400]. In another study a fully suppressive HIV treatment [411]. examining the interactions of HBV and HIV using the Lamivudine, entecavir and tenofovir have activity composite endpoint of AIDS defining illnesses and death against both HIV and HBV, and are contraindicated as among HIV-infected individuals who had a seroconversion single agents for hepatitis B in coinfected patients because window of B3 years in a large cohort, it was found that the of the risk of HIV resistance. Thus, all HBsAg-positive hazards ratio for an AIDS or death event was almost double patients should be screened for HIV before these drugs are (adjusted hazards ratio 1.80; 95 % CI 1.20–2.69) for those used in the treatment of HBV infection. with HBV coinfection [401]. In the Swiss HIV Cohort Among patients with CD4 count [500/ml who are Study, patients who tested positive for HBsAg had unwilling to start HAART, HBV can be treated before the 123 Hepatol Int (2016) 10:1–98 55 Fig. 7 Treatment of CHB infection in HIV infected HIV/HBV Co-infecon individuals Among paents with CD4 count Consider early dual an-HIV and an-HBV >500/ml unwilling to start therapy, irrespecve of immunological, HAART, HBV can be treated virological or histological consideraons before the instuon of an- HIV therapy; PEGIFN,* Adefovir# and Telbivudine#, which are not proven to be Lamivudine naive Lamivudine acve against HIV, should be experienced used. HAART including Tenofovir plus Add or Substute Lamivudine or one NRTI with Tenofovir Emtricitabine as part of HAART * Peg-IFN may be used if genotype A, low HBV-DNA and high ALT # However, if Adefovir or Telbivudine use does not lead to the goal of undetectable HBV DNA aer 12 months of therapy, treatment of HIV infecon should be considered. institution of anti-HIV therapy; PegIFN, adefovir and tel- interventions due to cross-resistance with other antivirals. bivudine, which are not proven to be active against HIV, Additionally, because of overlapping polymerase and should be preferred [409]. Peginterferon (Peg-IFN) alpha envelope genes in the HBV genome, LAM resistance could be considered as therapy for CHB in coinfected mutations may result in changes in the HBsAg, causing patients in very specific situations, such as in patients diminished HBs antigen–antibody binding. This may unwilling to start HAART who have normal CD4 counts translate into failure in diagnostic tests, vaccine escape, or [500, HBeAg(?), low HBV-DNA, elevated ALT, and both [414]. Transmission of drug-resistant HBV strains lack of decompensated cirrhosis. However, if any of these has also been reported [415]. two NAs (adefovir and telbivudine) with a low barrier to HIV-infected adults without protective HBsAb titers resistance do not reach the goal of undetectable HBV DNA should be vaccinated. The response rate and durability of after 12 months of therapy, treatment of HIV infection the vaccine are poorer in HIV infected persons compared should be envisaged. with HIV-negative persons, and they are influenced by both CD4 counts and plasma HIV-RNA levels [416, Oral anti-HBV drugs may select changes at the HBV polymerase, leading to loss of susceptibility to the corre- 417]. Accordingly, in patients with low CD4 counts sponding drug and cross-resistance to other antivirals. (\200 cells/ml) and uncontrolled HIV replication, the Changes in M204 I or V are usually responsible for LAM, success of HBV immunization is low. In these individ- FTC, and LdT resistance, whereas more changes (L180M uals, previous antiretroviral therapy for at least 6 months plus M204V plus T250) are usually needed for ETV may increase HBV vaccine response rates. An initial resistance. Accordingly, cross-resistance is almost univer- conventional HBV vaccination schedule should be used; sal with LAM, FTC, LdT, and to a lesser extent, with ETV. in the case of lack of achievement of protective anti-HBs There is some cross-resistance to ADV in the presence of titers ([10 mIU/ml) revaccination using double-dose and/ A181S plus M204 I mutations in patients who have failed or 3–4 injections (months 0, 1, 6, and 12) is recom- LAM therapy. No mutations have been uniformly associ- mended [418]. Some protection from HBV vaccine may ated with significant loss of susceptibility to TDF in vivo, be expected even in the case of anti-HBs titers dropping although anecdotal reports have pointed out that A194T in to \10 mIU/ml. the context of LAM resistance mutations might account for 3:13:1 Recommendations: coinfection with HBV and HIV TDF resistance in HBV [412]. Resistance to LAM in HBV is more common and 3:13:1:1 In HIV/HBV-coinfected patients, HBV develops more quickly in HIV-HBV coinfected patients coinfection accelerates immunological [413]. Selection of LAM resistance in CHB is associated and clinical progression of HIV infection with poor outcomes, including the occurrence of liver and increases the risk of hepatotoxicity enzyme flares, which occasionally may be life-threaten- when combination antiretroviral therapy is initiated, while HIV infection increases ing, and preclude the success of rescue antiviral 123 56 Hepatol Int (2016) 10:1–98 Fig. 8 Treatment of HBV– HCV coinfected patients HBsAg-posive An-HCV-posive Acve HCV / Acve HCV / Acve HBV / Inacve HCV / Inacve HBV Acve HBV Inacve HCV Inacve HBV � Treat HCV: P+R � Treat HCV: P+R � Observe HBV Treat HBV: P or NUC Observaon Observe HBV reacvaon response & reacvaon Or � Treat HCV & HBV: P+R+NUC P: Peg-IFN α R: ribavirin NUC: nucleos(t)ide analogue the risk of hepatitis events, cirrhosis, and 3.13.2 Coinfection with HBV and HCV end-stage liver disease related to chronic HBV infection (A1). Most patients with chronic hepatitis C have a hepatitis C 3:13:1:2 Given the faster progression of liver virus (HCV) monoinfection. However, in areas where the HBV is endemic, a substantial proportion of the patients disease in HIV-HBV coinfected patients, early dual anti-HIV and anti-HBV ther- are coinfected with hepatitis C and B [419]. If the preva- apy should be considered, irrespective of lence of anti-HCV positivity worldwide is approximately immunological, virological or histologi- 1–4 % in the general population, the number of individuals cal considerations (B1). with HCV/HBV coinfection among the 320 million chronic 3:13:1:3 Tenofovir combined with emtricitabine HBV positive subjects would be approximately 3.2–12.8 or lamivudine plus a third agent active million. Moreover, HCV/HBV coinfections can also be against HIV should be used (A1). found in people at risk of parenteral hepatotropic viral 3:13:1:4 Peg-IFN can be used in a highly selected transmissions, such as people who use intravenous drugs, group of coinfected patients (B1) (Fig. 5). patients with thalassemia, and patients with hemophilia. 3:13:1:5 Lamivudine, entecavir and tenofovir In patients with dual chronic hepatitis B and C, the have activity against both HIV and disease outcomes, including the development of liver cir- HBV and are contraindicated as single rhosis (LC) and HCC, are generally more severe than those agents for hepatitis B in coinfected in patients with either hepatitis B or hepatitis C [420, 421]. patients because of the risk of HIV In addition to cross-sectional data, a long-term community- resistance (A1). Thus, all HBsAg-posi- based study finding supported the effect of HCV/HBV tive patients should be screened for HIV coinfection on the cumulative incidences of HCC [422]. before these drugs are used in the treat- Therefore, patients dually infected with hepatitis C and B ment of HBV infection (A1). need attention and require effective antiviral treatments. 3:13:1:6 Adefovir and telbivudine should not be used in coinfected patients (A1). Treatment goals and strategies The primary goal of the 3:13:1:7 HIV-infected adults without protective treatment of HCV and HBV coinfection is to eliminate or HBsAb titers should be vaccinated (A1). permanently suppress both viruses [419]. Simultaneously, 3:13:1:8 In HBV-HIV coinfected patients, an the long-term goal is to reduce or terminate hepatic initial conventional HBV vaccination necroinflammation, prevent progression to cirrhosis and the schedule should be used; in the case of development of HCC, and ultimately prolong the survival lack of achievement of protective anti- of patients. HBs titers ([10 mIU/ml), revaccination These goals can be achieved by eradicating both viruses using double-dose and/or three to four after providing an effective antiviral therapy for dually injections (months 0, 1, 6, and 12) is infected patients. Accumulating data exist to reach firm recommended (B1). conclusions on the management of patients with HCV 123 Hepatol Int (2016) 10:1–98 57 coinfection. It is generally agreed that the dominant virus 3.13.3 Coinfection with HBV and HDV should be identified before designing a therapeutic strategy (Fig. 8)[423]. HBV and HCV replicate in the same hep- Although HDV can only infect HBsAg positive patients atocyte without interference [424]. A proportion of coin- and HBV vaccine has been available for a long time, the prevalence of HDV has not shown a significant decline. fected patients may have fluctuating serum HBV DNA levels, thus indicating the need for longitudinal evaluation Recent studies also confirm that even in countries like United States, Australia and some European countries, the of viral loads before starting any antiviral therapy, in order to clarify the respective pathogenic role of each virus prevalence of HDV is showing an increasing trend [430]. In the coinfected host, it is generally HDV which is the [423]. HBV DNA levels are often low or undetectable and HCV is usually responsible for the activity of chronic dominant virus because it suppresses HBV through repli- hepatitis in most patients. If HBV is dominant, treatment cation, but can cause severe liver injury that may result in should be aimed toward this virus. If HCV is dominant, fulminant hepatic failure and rapid progression to cirrhosis Peg-IFN therapy in combination with ribavirin can achieve and hepatic decompensation, as well as an increased risk of a sustained HCV clearance rate comparable to that in HCV liver cancer [431]. Chronic infection after acute HBV- mono-infection [425–428]. This has been demonstrated in HDV hepatitis is less common, while chronic delta hep- atitis develops in 70–90 % of patients with HDV superin- an open-label, comparative, multicenter study involving 321 Taiwanese patients with active HCV infection, in fection [430]. Active coinfection with HDV is confirmed by detectable HDV RNA, immuno-histochemical staining which patients with HCV genotype 1 infection received Peg-IFN alfa 2a 180 lg weekly and ribavirin for HDV antigen, or IgM anti-HDV [432]. However, (1000–1200 mg) daily for 48 weeks [426]. Patients with diagnosis of active HDV infection may be difficult, as HCV genotypes 2 or 3 received Peg-IFN alfa 2a 180 lg HDV RNA assays are not standardized and HDV antigen weekly and ribavirin 800 mg daily for 24 weeks. The and IgM anti-HDV assays are not widely available. sustained virological response in HCV genotype 1-infected Peg-IFN is effective against HDV. The efficacy of Peg- patients was comparable between 161 HBV/HCV patients IFN therapy can be assessed during treatment (after and 160 HCV mono-infection patients (72.2 vs. 77.3 %). 3–6 months) by measuring HDV RNA levels. Weekly For patients with HCV genotype 2/3 infections, the sus- injection of pegylated interferon is currently used for 12–18 months [433]. More than 1 year of therapy may be tained virological response values were 82.8 and 84.0 %, respectively. The HCV sustained virological response necessary, as there may be some benefit from treatment prolongation [434]. However, the optimal duration of (SVR) was durable in approximately 97 % of the patients during a 5-year post-treatment follow-up [427]. Further- therapy is not well defined [432]. So long as the hepatitis B surface antigen stays positive, HDV patients remain more, approximately 30 % of dually infected patients lost HBsAg within 5 years after the start of Peg-IFN-based infective even if the HBV or HDV viral titers are low or therapy. The benefit of anti-HCV therapy in dually infected undetected. patients was further confirmed in another large population- Around 25–40 % of treated patients have a sustained based survey in Taiwan [429]. Compared with the patients off-treatment virological response with undetectable HDV in an untreated dually infected cohort, the risk of devel- RNA and accompanying improvement in histology, while oping HCC, all-cause mortality, and liver-related mortality some also lose HBsAg [430, 432]. Although late relapses have been documented, in a study decreased by 35, 62, and 59 %, respectively, in patients who received active anti-HCV therapy. performed by Hedrich and colleagues in patients who were HDV RNA negative 6 months after pegylated interferon 3:13:2 Recommendations: coinfection with HBV and treatment, pegylated interferon alfa 2a treatment was given HCV for 48 weeks with or without adefovir and resulted in 28 % 3:13:2:1 It is important to determine the viral of the patients having undetectable HDV RNA 6 months loads of individual viral infections and post-treatment [435]. In long-term follow-up of patients for which virus is dominant before designing approximately 4 years, a significant number of patients the treatment strategy, and then to treat were tested HDV RNA positive at least once during further follow-up, and it was also concluded by the investigators to the patients accordingly (B1) (Fig. 6). 3:13:2:2 In HBV–HCV coinfected patients who closely monitor patients post-Peg interferon therapy, even those who are HDV RNA negative 6 months after therapy are HCV viremic, antiviral treatment may be selected using the same criteria as for with interferon alfa 2a therapy. those patients with HCV mono-infection When standard interferon was used at nine million units (A1). compared to no treatment or low dose at three million units given three times a week for 48 weeks, 50 % of the high- 123 58 Hepatol Int (2016) 10:1–98 dose group had a complete biochemical response defined significant decline in HBsAg titers using adefovir [444], by normalization of ALT, in addition to virological which could be significant as a predictor for successful response negative HDV RNA at the end of the treatment, treatment of HBeAg-positive CHB [280]. Case reports compared to no complete responses in any of those in the have appeared in which successful treatment of HBV and low-dose or no treatment group. The long term follow-up HDV have been reported using pegylated interferon and up to 12 years demonstrated significantly improved sur- entecavir [445] and pegylated interferon and tenofovir and vival and liver histology for the high dose treatment group, emtricitabine [446]. Thus, NAs treatment might be con- although most of them relapsed after clearance of HDV sidered in some patients who have active HBV replication RNA [436]. with persistent or fluctuating serum HBV DNA levels Although no head-to-head comparison trials have been above 2000 IU/ml [447]. carried out, two major reviews have not been able to def- 3:13:3 Recommendations: coinfection with HBV and initely show that either type of interferon therapy is supe- HDV rior to the other. However, one recent systematic review of randomized trials found that 1 year of high dose interferon 3:13:3:1 In patients with coinfection of HBV and alfa monotherapy achieved higher levels of unde- HDV, it is important to determine which tectable HDV RNA and normalization of ALT at the end of virus is dominant and the patient should be treatment when compared with pegylated interferon alfa 2a treated accordingly with pegylated inter- feron alfa for 12–18 months. Patients monotherapy. However levels of HDV RNA suppression 24 weeks after the end of therapy were not significantly should be monitored for 6 months post- different [437]. A systematic review by Alavian and col- treatment and beyond (A1). leagues comparing standard and pegylated interferon alfa found sustained virological response rates in 19 and 29 % 3.13.4 Health care workers of patients, respectively [438]. In a study from Turkey using entecavir for chronic hepatitis D, after 1 year of HBV can survive in dried blood outside the body for up to entecavir treatment, it was found to be ineffective in CHD. 7 days, and is significantly more infectious than either It was also concluded from the study that any beneficial hepatitis C or HIV, with a reported transmission rate of up effect of nucleoside–nucleotide analogue treatment may to 30 % from needlestick injuries. This rate seems to cor- necessitate prolonged treatment [439]. In a recent study relate with serum HBV DNA concentrations. The con- from Pakistan, sustained virological response, which was centration of HBV varies across body fluids, with blood, defined as negative HDVRNA at 24 weeks post-treatment, serum and wound exudates carrying the highest concen- was seen in 23.1 % for virological and biochemical trations; semen, vaginal fluid and saliva carrying moderate responses and in only 12.5 % as a combined response concentrations; and urine, feces, sweat and breast milk [440]. A Cochrane review concluded that interferon alfa containing the lowest concentrations, which translates into does not seem to cure Hepatitis D in most patients. It was the lowest risk of HBV transmission. Percutaneous injuries also concluded from this review that more randomized sustained by health-care workers during certain surgical, trials with large sample sizes and less risk of bias were obstetrical, and dental procedures provide a potential route needed before interferon can be recommended or refuted of HBV transmission to patients as well as to heath care [441]. In a recent study from Germany by Nikongolo [442], workers (HCWs). Therefore, it is important to prevent it was suggested that HBV and HDV entry via sodium operator injuries and blood exposures during exposure- taurocholate co transporting polypeptide is inhibited by prone surgical, obstetrical, and dental procedures. cyclosporine A. In the future, this drug may help reduce the Chronic HBV infection in itself should not preclude the incidence of HBV and HDV after more studies demonstrate practice or study of medicine, surgery, dentistry, or allied its usefulness and where it would actually fit in the man- health professions. Standard precautions should be adhered agement of HBV and HDV coinfection. Myrcludex-B, a to rigorously in all health-care settings for the protection of myristoylated a preS/2–48my2 peptide, has been shown to both patient and provider [448]. limit the establishment of HDV infection in vivo and HCWs and students of surgery, dentistry, medicine, or delayed the increase in HBV viremia. The real role of its allied health fields should be screened for HBV infection. use is yet to be determined in HBV-HDV management Testing should include a serological assay for HBsAg, ant- [443]. HBs and Total anti-HBc. All noninfected health-care pro- Lamivudine, adefovir and entecavir have been found to viders and students should receive hepatitis B vaccine. be ineffective in the management of Hepatitis D alone or in Vaccination (three-dose series) should be followed by combination with interferon; however, Wedemeyer, in his assessment of hepatitis B surface antibody to determine study using pegylated interferon and adefovir, showed 123 Hepatol Int (2016) 10:1–98 59 vaccination immunogenicity, and providers who do not procedure is considered to be non-exposure-prone (NEPP) have protective concentration of anti-HBs ([10 mIU/ml) when the hands and fingertips of the physician are visible should undergo, revaccination [448]. and outside the patient’s body throughout, even when there Exposure of a HCW to the blood of an HBV-infected is handling of sharp instruments. A NEPP can become an patient in the performance of any procedure, should be EPP if a patient is uncooperative [451]. handled with standard post-exposure prophylaxis. Expo- Retrospective studies have evaluated the rate of HBV sure of a patient to the blood of an HBV-infected health- transmission from affected physicians through blood con- care provider, in the performance of any procedure, should tact during specific types of EPPs. Percutaneous injuries be handled with post-exposure prophylaxis and testing of have been reported to occur in 6.9 % of operations, and in the patient in a manner similar to the reverse situation (i.e., 32 % of these instances, the instigating sharp instrument prophylaxis for providers exposed to the blood of an HBV- touches the patient wound once again [452]. The risk of infected patient) [449]. HBV transmission is not negligible; the rate in cardiotho- racic surgery is reported to be 6–13 % [453, 454], up to Transmission of HBV by HCWs to patients In the health 9 % in gynecological surgery [455, 456], and 2 % in care setting, transmission may occur via several routes, but general surgery [457, 458]. The proportion of patients the most frequent route leading to establishment of HBV infected with HBV secondary to transmission from an infection is through needlestick injury. Invasive surgical infected HCW is between 0.5 and 13.1 % [459]. procedures are another route of HBV transmission; in fact, CDC has classified patient care procedures into two surgeons represent the largest group of HCWs involved in categories (Table 11). Most effective transmissions have occurred when the provider-to-patient HBV transmission [450]. It is the regular performance of an exposure-prone HCW carried HBV DNA [1.9 9 105 IU/ml (10 copies/ procedure (EPP) that is mainly of concern. EPPs are ml, with conversion factor of 5.26 copies/IU). Establishing defined as procedures in which there is a risk that injury to a threshold for the limitation of EPPs would have to the physician may result in the exposure of the patient’s account for a 3 log10 safety margin to account for assay open tissues to the blood of the physician. Any type of variability [452]. HCWs who are HBsAg positive should invasive surgery is, thus, an EPP, wherein the affected be tested for HBeAg and anti-HBe and for HBV viremia. physician’s gloved hand is in constant contact with sharp HCWs, and medical and dental students who are instruments, needle tips or sharp tissues (spicules of bone HBsAg-positive, who do not perform exposure-prone or teeth) inside a patient’s open body cavity. Surgery procedures but who practice non- or minimally invasive performed within a confined anatomical space, where the procedures (Category II, table) should not be subject to any hands or fingertips may not always be completely visible, restrictions of their activities or study. They do not need to also carries an elevated risk of transmission, given the achieve low or undetectable levels of circulating HBV paucity of surgical precision and control in this context. A DNA, hepatitis e-antigen negativity, or have review and Table 11 Classification of patient care procedures Procedures known or likely to pose an increased risk of percutaneous Category II—all other invasive and noninvasive procedures injury to a HCW that have resulted in provider-to-patient transmission of hepatitis B virus (HBV) These procedures are limited to major abdominal, cardiothoracic, and These and similar procedures are not included in Category I as they orthopedic surgery, repair of major traumatic injuries, abdominal and pose low or no risk for percutaneous injury to a health-care provider, vaginal hysterectomy, caesarean section, vaginal deliveries, and or, if a percutaneous injury occurs, it usually happens via provider-to- major oral or maxillofacial surgery (e.g., fracture reductions). patient blood exposure. These include surgical and obstetrical/ Techniques that have been demonstrated to increase the risk for gynecological procedures that do not involve the techniques listed for health-care provider percutaneous injury and provider digital Category I; and provider’s hands are outside a body cavity (e.g., palpation of a needle tip in a body cavity and/or the simultaneous phlebotomy, placing and maintaining peripheral and central presence of a health care provider’s fingers and a needle or other intravascular lines, administering medication by injection, sharp instrument or object (e.g., bone spicule) in a poorly visualized performing needle biopsies, or lumbar puncture) or highly confined anatomic site Category I procedures, especially those that have been implicated in Dental procedures other than major oral or maxillofacial surgery HBV transmission, are not ordinarily performed by students fulfilling Insertion of tubes (e.g., nasogastric, endotracheal, rectal, or urinary the essential functions of a medical or dental school education rectal catheters) examination; and procedures that involve external physical touch Endoscopic or bronchoscopic procedures (e.g., general physical or eye examinations or blood pressure checks) Internal examination with a gloved hand that does not involve the use of sharp devices (e.g., vaginal, oral) 123 60 Hepatol Int (2016) 10:1–98 oversight by an expert review panel, as recommended for from 7.3 to 3.7 log10 copies/ml within approximately those performing exposure-prone procedures. However, 12 weeks, while patients with [9.0 log10 baseline level they should receive medical care for their condition by needed roughly 52 weeks [196]. In a direct comparison of appropriate clinicians [460]. tenofovir and entecavir, decreases of -4.0 or -4.5 HCWs who perform exposure-prone procedures, i.e., log10 units/ml, respectively, were found after 3 months of those listed under Category I activities (Table 11), should therapy [464]. Thus, viremia can be suppressed to accept- be guided by an institutional expert review panel regarding able levels in the majority HCWs by 3 months of entecavir the procedures that they can perform and prospective or tenofovir therapy. HCWs with very high viremia oversight of their practice [461]. Confidentiality of the [10 IU/ml may need longer therapy, but most of them health-care provider’s or student’s HBV serological status will reach acceptable or even undetectable levels within should be maintained. HBV-infected HCWs can conduct 1 year [465]. exposure-prone procedures if a low or undetectable HBV 3:13:4 Recommendations (health care workers) viral load is documented by regular testing at least every 6 months unless higher levels require more frequent test- 3:13:4:1 Chronic HBV infection in itself should ing; for example, as drug therapy is added or modified, not preclude anyone from the practice or testing is repeated to determine if elevations above a study of medicine, surgery, dentistry, or threshold are transient [460]. An HBV DNA level of allied health professions (A1). Such HCWs should not be isolated or discrim- 1000 IU/ml or its equivalent is an appropriate threshold to adopt [460]. Spontaneous fluctuations of HBV DNA levels inated, but should be encouraged to be and treatment failures might both present as higher-than- investigated and treated (A1). threshold (1000 IU/ml) values. This will require the HBV- 3:13:4:2 HCWs and students of surgery, dentistry, infected HCW to abstain from performing exposure-prone medicine, or allied health fields should be procedures, while subsequent retesting occurs, and if nee- screened for HBV infection. Testing ded, modifications or additions to the health-care provi- should include a serological assay for der’s drug therapy and other reasonable steps are taken HBsAg, anti-HBs and total anti-HBc (A1). [460]. 3:13:4:3 All non-infected health-care providers Hospitals, medical and dental schools, and other insti- and students should receive hepatitis B tutions should have written policies and procedures for the vaccine and their immunization status be confirmed (A1). identification and management of HBV-infected health- care providers, students, and school applicants. 3:13:4:4 Standard precautions should be adhered to rigorously in all health-care settings Treatment of HCWs for reduction of Infectivity Health- for the protection of the patient and the care workers also need special attention regarding starting provider (A1). antiviral therapy, as they may require antiviral therapy 3:13:4:5 HCWs who perform exposure-prone pro- even if they do not fulfill the typical indications for treat- cedures, i.e., those listed under Category ment, to reduce direct transmission during exposure-prone I activities (Table 11), should be guided procedures to patients. by an institutional expert review panel Published evidence for the efficacy of antiviral ther- regarding the procedures that they can apy on the transmission rate to patients is limited. One perform and prospective oversight of their practice (B1). The status of the Dutch study reported reduction of viremia to \1000 copies/ml in 18 HCPs with either interferon-a or various individual could vary depending on the NAs [462]. response to therapy. DNA levels \1000 IU/ml are reached more often and 3:13:4:6 HBV-infected HCWs can conduct expo- much faster in HBeAg-negative chronic HBV-infected sure-prone procedures if a low subjects, because they have lower baseline levels of vir- (\1000 IU/ml) or undetectable HBV emia and possibly a higher turnover of HBV-containing viral load is documented by regular hepatocytes, as compared to HBeAg-positive subjects. The testing at least every 6 months (B1). immunotolerant HBeAg-positive subjects typically have baseline viremia levels[10 IU/ml. The mean reduction of 3.13.5 Chronic HBV infection and pregnant females viremia obtained in HBeAg-positive patients with ente- cavir within 1 year was reported to be 6.9 log10 copies/ml When females in the childbearing age require antiviral [463]. One study on tenofovir therapy showed that the therapy, the issue of pregnancy must be discussed before mean value in patients with moderately high viremia fell 123 Hepatol Int (2016) 10:1–98 61 starting treatment. If pregnancy is planned in approaching postpartum. Some studies reported increased rates of ALT years, IFN-based therapy is preferable for its finite duration flares in the LdT or LAM treated group [476], and other of treatment. Pregnancy is discouraged during IFN therapy studies using TDF reported comparable or possibly bene- because of IFN’s anti-proliferative effect. Contraception is ficial effects for the mothers [472, 481]. Several issues are suggested during IFN treatment. In pregnant females with still not well understood, such as the long-term safety of chronic HBV infection who need antiviral therapy, or in the mothers and child beyond 1 year post delivery, optimal females who have unexpected pregnancy during antiviral large-scale screening methods, and cost-effectiveness of treatment, the treatment plan should be fully discussed, such prevention strategy for the population. considering risks and benefits for the mother and fetus on 3:13:5 Recommendations: chronic HBV infection and issues regarding risks of maternal disease progression, pregnant female maternal ALT flares, fetal development, vertical trans- mission of HBV, long-term plan for treatment and next 3:13:5:1 The issue of pregnancy and maternal– pregnancy [466, 467]. Among the currently available NAs, fetal–child health should be notified in LdT and TDF are classified as category B drugs (no risk in chronically HBV-infected female in the animal studies, but unknown in humans), whereas LAM, childbearing age, especially when antivi- ADV, and ETV are classified as category C drugs (ter- ral treatment is considered. The treatment atogenic in animals, but unknown in humans) by the US plan should be fully discussed with the patient and relatives, especially regarding FDA. Category B NAs (LdT and TDF) may be considered for mothers indicated for antiviral treatment during the first the risks of maternal liver disease status, through third trimester of pregnancy. TDF has more safety fetal development, vertical transmission data in HIV-positive females, and the least chance of viral of HBV, long-term plan for treatment and resistance. Safety data from the Antiretroviral Pregnancy pregnancy. Maternal HBeAg, HBV DNA Registry has demonstrated no increased rates of birth status, and ALT level should be checked defects (2.8 % 46/1982) with TDF exposure during the first during pregnancy (A1). trimester [468]. Despite postnatal active/passive immu- 3:13:5:2 In pregnant females with chronic HBV nization of the newborns, mother-to-infant transmission of infection who need antiviral therapy, HBV still occurs; major risk factors are maternal HBeAg tenofovir is the drug of choice for and high viral load [469, 470]. For prevention of mother- mothers indicated for antiviral treatment during the first through third trimester of to-infant transmission that occurrs during theperinatal period, short-term maternal NAs used in mothers of pregnancy. It is a pregnancy category B drug with adequate safety data in HIV- stable liver disease, starting from the second or third tri- mester, has been documented to reduce maternal viral load positive females and least chance of viral and decrease perinatal mother-to-infant transmission. The resistance (B1). results are based on non-randomized, open label clinical 3:13:5:3 For reduction of risk of mother-to-infant studies using either LAM, LdT or TDF [471–478]. The transmission that occurs during perinatal target population for short-term NAs treatment for preg- period, short-term maternal NAs starting nant females to reduce maternal HBV transmission is from 28 to 32 weeks of gestation is maternal HBV viral load above 6–7 log IU/ml [469]. The recommended using either tenofovir or starting point of maternal treatment in most studies is telbuvidine for those mothers with HBV DNA above 6–7 log IU/ml (B2). Since, 28–32 weeks of gestation, after careful examination to exclude maternal systemic disorder and fetal anomalies. the HBV transmission could occur even Cessation of NAs therapy (at delivery or 4–12 weeks after with lower maternal HBV DNA levels, delivery) is recommended in females without ALT flares NAs could be administered after discus- and without pre-existing advanced liver fibrosis/cirrhosis. sion with the patient, even in patients Continuation of NAs treatment after delivery may be with lower DNA levels. The NAs could necessary according to maternal liver disease status. be stopped at birth and when breastfeed- Breastfeeding is not discouraged in mothers with chronic ing starts, if there is no contraindication HBV infection if newborns have received appropriate to stopping NAs (B2). postnatal immunoprophylaxis. However, breastfeeding is 3:13:5:4 Breast-feeding is discouraged during not generally encouraged during NAs therapy because of maternal NAs treatment. For those with ALT flares detected during the treatment uncertainty of safety to newborns [479, 480]. There has been insufficient data regarding maternal ALT flare rates period, continuation of antiviral before and after delivery, especially after cessation of NAs 123 62 Hepatol Int (2016) 10:1–98 treatment according to maternal liver 3.13.7 Extrahepatic manifestations of chronic hepatitis B disease status may be indicated (B2). Several extrahepatic conditions have been described during 3.13.6 Chronic HBV infection in patients with CKD, acute and chronic HBV infection. While the pathogenesis on dialysis and in renal transplant patients remains controversial, it is largely attributed to an immune- mediated injury of organs other than the liver. Viral antigen- Chronic HBV infection has a pivotal influence on induced induction and deposition of immune complexes, patients with CKD undergoing haemodialysis and renal reaction with tissue antigens by HBV-induced auto anti- transplant with complex issues [482]. Patients with renal bodies, or a direct viral reaction may occur in extrahepatic disease should be screened for HBV infection and tissues such as the skin, muscles, joints and kidneys. though vaccine responsiveness is impaired, HBV seronegative patients should be vaccinated. In particular, Glomerulonephritis The incidence of HBV-related renal patients under anti-HBV therapy should be fol- glomerulonephritis is from 0.1 to 25 % and may present lowed not only for the treatment efficacy, but also the clinically in three forms, i.e., membranous, membranopro- stage of liver disease and the renal disease status. Peg- liferative, and IgA nephropathy. Membranous glomeru- IFN or NAs can be used for chronic HBV infection lonephritis (MGN) is the most common type, especially in patients with renal dysfunction. However, NAs represent areas endemic for HBV infection, and usually presents as the first-line treatment option for chronic HBV-infected nephrotic syndrome, with proteinuria, edema and hyperten- patients with any level of renal dysfunction and renal sion. Immune complexes are deposited only in the basement replacement therapy. Physicians should be aware of the membrane where HBV antigens, i.e., HBsAg, may be iden- necessary drug dose adjustments according to creatinine tifiable in the glomerular capillary wall. In children, up to clearance as well as the potential nephrotoxicity and 60 % may experience spontaneous remission, usually asso- long-term drug efficacy. ciated with HBeAg seroconversion. However, in adults it can In general, entecavir, an agent without signs of lead to chronic renal failure in up to 30–50 % of cases [483, nephrotoxicity, and telbivudine, an agent with promising 484]. Membranoproliferative glomerulonephritis (MPGN) data for even improvement in creatinine clearance, seem is characterized by deposition of HBsAg in both the to be the preferred options for NA-naive patients with mesangial and capillary walls; HBeAg and HBcAg have also any renal dysfunction, depending on the HBV viremia been identified in the glomeruli. In chronic HBV infection, levels and the severity of renal dysfunction. Although, the heightened immune response results in increased there are no definite conclusions about the risk of amounts of circulating immune complexes containing HBV tenofovir-associated nephrotoxicity, most clinicians are antigens, complement components, immunoglobulins, etc., concerned and therefore avoid using this agent in this which are deposited in sites outside the liver [485]. HBV- setting. However, tenofovir remains the agent of choice related IgA nephropathy is a less severe form of renal disease for patients with renal dysfunction and prior resistance to and usually evolves with an indolent course, although an other NAs. aggressive course with progression to acute renal failure has HBsAg positive patients who undergo renal transplan- been reported. Tubulo-reticular inclusions in the endoplas- tation and receive immunosuppressive agents should mic reticulum of endothelial cells of the glomerular and receive anti-HBV prophylaxis with NAs. However, Peg- peritubular capillaries have been identified on electron IFN should be avoided in renal transplant patients because microscopy [486]. It has been suggested that both humoral of the risk of rejection. and cellular immune injury, mediated by HBAg-HBAb immune complexes in the former and by HBV originating 3:13:6 Recommendations: chronic HBV infection in from renal cells in the latter, may be involved in the patho- patients with CKD, on dialysis and renal trans- genesis of IgA nephropathy [487]. Remission of clinical and plant patients laboratory manifestations of nephropathy with successful 3:13:6:1 NAs (entecavir or telbivudine) represent antiviral treatment have been demonstrated [488–491]. the first-line treatment options for chronic HBV-infected patients with any level of Polyarteritis nodosa Polyarteritis nodosa (PAN) is a gen- renal dysfunction and renal replacement eralized necrotizing vasculitis, and HBV-associated PAN therapy. NAs should be dose adjusted (HBV-PAN) represents a typical form of classic PAN. The based on creatinine clearance rates (A1). pathogenesis HBV-PAN is largely attributed to immune- 3:13:6:2 Peg-IFN should be avoided in renal complex deposition (with antigen excess) in the vessel walls transplant patients because of the risk of of the skin, kidneys, heart and nervous system. A recent study rejection (A1). of 348 patients with PAN revealed that patients with HBV- 123 Hepatol Int (2016) 10:1–98 63 PAN had more frequent peripheral neuropathy, abdominal immune complex deposition, neutrophilic infiltration and pain, cardiomyopathy, orchitis, and hypertension compared small vessel necrosis. They present typically as palpable to patients with non-HBV-related PAN. PAN is observed purpura. Lichen planus, a chronic recurrent rash composed more frequently in European and North American patients, of small, flat-topped, polygonal bumps that may coalesce but rarely in Asian patients [492]. Constitutional symptoms together into rough, scaly plaques on the skin and mucous include malaise, anorexia, weakness, fever, and weight loss. membranes, has been found to be highly prevalent in Erythematous skin lesions and palpable purpura and nodules Turkish patients who are seropositive with HBsAg [502]. are not uncommon. Prior reports have estimated the inci- The Gianotti-Crosti syndrome, or papular acrodermatitis of dence of HBV infection in PAN patients to be between 30 childhood, is characterized by small, flat, erythematous, and 70 %; however, in the West, these figures have declined papular or papulovesicular rash that occurs in the face and remarkably in parallel with those of HBV infection [493]. distal extremities of infants and young children. Other than Antiviral therapy, combined with corticosteroids and plasma HBV, the Epstein–Barr virus, hepatitis A virus, cytome- exchanges, has demonstrated good efficacy in the manage- galovirus, coxsackie, adenovirus, enterovirus, HIV are also ment of HBV-PAN [494, 495]. implicated as etiological agents. While the association of this syndrome with HBV infection was reported as early as Cryoglobulinemia Patients with chronic HBV infection 1976, this association remains controversial [503]. may present with mixed cryoglobulinemia, i.e., type II (monoclonal IgM and polyclonal IgG) and type III (poly- Guillain–Barre´ syndrome Guillain–Barre syndrome clonal IgM and monoclonal IgG). The prevalence of HBV- (GBS) is a rare extrahepatic involvement associated with associated cryoglobulinemia ranges from 0 to 15 % [496, both acute and chronic HBV infection. While both HBsAg 497]. Clinically, it may present with protracted purpura, and HBV DNA have been detected in cerebrospinal fluid, it is with or without ulcerative skin lesions, arthralgia, and unclear whether the virus itself or an immune-mediated weakness. It may be associated also with the sicca syn- assault or a vasculitis-related injury to the myelin sheath is drome, Raynaud phenomenon, as well as renal and neu- responsible for these symptoms of the central nervous system rological complications. When nephritis is present, the [504]. A recent case report described a patient with GBS clinical course can rapidly be fatal. Effective treatment of associated with acute hepatitis B responding to nucleoside the underlying chronic HBV infection with currently analogue and intravenous immunoglobulin treatment [505]. available nucleos(t)ide analogues generally leads to clinical 3:13:7 Recommendations: extrahepatic manifestations of and serological resolution of cryoglobulinemia [498, 499]. CHB 3:13:7:1 Extrahepatic manifestations may be asso- Serum sickness-like syndrome A transient serum sick- ness-like ‘‘arthritis–dermatitis’’ syndrome occurs in ciated with both CHB infection approximately 10–20 % of patients during the prodrome of (glomerulonephritis, polyarteritis nodosa, acute hepatitis B [500]. The pathogenesis is related also to mixed cryoglobulinemia, and skin man- circulating immune complexes, and during the acute phase, ifestations) and acute HBV infection high concentrations of HBsAg have been detected in the (Guillain–Barre syndrome and, a serum synovial fluid with associated reduction in complement sickness-like syndrome) (B1). levels. The manifestations can range from fever, myalgia, 3:13:7:2 HBsAg positive patients with extra-hepatic polyarthralgia or overt arthritis with joint swelling and manifestations and active HBV replication may respond to antiviral therapy (B1). edema of small joints of the hands and feet, as well as large joints of the knees, ankles and wrists. The polyarthritis is 3:13:7:3 Peg-IFN may worsen some immune medi- ated extra-hepatic manifestations (B1). characteristically asymmetrical and is often associated with erythematous skin lesions. Morning stiffness and a ‘‘gel’’ 3:13:7:4 Plasmapheresis, corticosteroids or IVIG phenomenon are present; thus, it can be mistaken for acute can be useful in addition to NA therapy in rheumatoid arthritis. However, it typically disappears when severe immune-mediated cases (C2). jaundice sets in and leaves no demonstrable permanent joint destruction. The resolution of arthritic lesions paral- 3.13.8 Patients before and/or after curative or local– lels those of HBsAg clearance. This serum sickness-like regional therapy of HCC syndrome ends abruptly with the onset of clinical hepatitis with few significant sequelae, and does not recur [501]. Once HCC develops, treatment for HBV will depend on the stage of disease. Mostly patients will be on antiviral ther- Dermatological manifestations The skin rashes in apy, as the majority will have underlying cirrhosis. patients with chronic HBV infection are usually related to 123 64 Hepatol Int (2016) 10:1–98 For non-surgical patients, a high viral load prior to independently associated with a significantly lower HCC chemotherapy or locoregional therapy results in higher recurrence risk (HR 0.67, 95 % CI 0.55–0.81, p\ 0.001). rates of severe hepatitis during chemotherapy [506]. A meta-analysis also demonstrated the beneficial effects of Longer survival has been shown in patients receiving antiviral therapy with regards to HCC recurrence (OR 0.59, TACE with the additional of antiviral therapy [507]. 95 % CI 0.35–0.97, p = 0.04), and liver-related mortality For the overwhelming majority of patients with HCC, (OR 0.13, 95 % CI 0.02–0.69, p = 0.02) [518]. Two recent surgical removal of the tumor by resection or LT is the only meta-analyses including 20 studies demonstrated that the curative option. HCC recurrence occurs in up to 41–50 % presence of high viral load significantly increased overall of patients within 2 years after resection (early recurrence) HCC recurrence risk after curative therapy, whereas and in up to 20 % of patients more than 2 years later (late antiviral therapy had potential beneficial effects in pre- recurrence) [508]. Most early recurrence appears to reflect venting recurrence [519, 520]. diffusion of primary tumors, while most late recurrence There is also improvement in recurrence-free survival stems from de novo tumors spontaneously arising in the and overall survival with NAs treatment among patients remnant diseased liver. Antiviral therapy is important for undergoing resection for HBV-related HCC. In a recent patients undergoing resection, as the hepatic reserves will systematic review of 19 studies, the NA group (1468 be limited and compromised in the post-operative period. patients) showed a median recurrence-free survival of Therefore, flares of hepatitis may lead to decompensation 85.0 % (range 19.7–90.0 %) at 1 year, 57.0 % (range for untreated patients [509]. Surgery and anesthesia may 11.4–90.0 %) at 3 years, and 54.0 % (range 42.6–81.3 %) also impart a state of immunosuppression in the early post- at 5 years. These median survival rates were significantly operative period, thereby increasing the risk of HBV higher than the corresponding values in the non-NA group reactivation [510]. A high pre-operative viral load has been (5541 patients): 78.0 % (range 4.5–86.6 %) at 1 year, associated with worse overall and recurrence free survivals 56.0 % (range 0–56.0 %) at 3 years, and 47.0 % (range after curative resection [511]. There is also the potential 0–47.0 %) at 5 years (all p \ 0.001) [521]. In the same increased risk of recurrent HCC due to the process of review on 15 studies reporting overall survival, the overall necrosis and regeneration of remaining hepatocytes, which median survival in the NA group (1468 patients) was may induce DNA mutations and instability. Upregulation 94.0 % (range 24.0–100.0 %) at 1 year, 81.0 % (range of adhesion molecules on cells lining sinusoids may 60.0–100.0 %) at 3 years, and 73.0 % (range 59.0–89.7 %) increase the risk of distant metastasis [512]. at 5 years. These values were significantly higher than the Viral load and hepatic inflammatory activity have been corresponding ones for the non-NA group (5200 patients): associated with late recurrences after HCC resection [513]. 91.0 % (range 0–100.0 %) at 1 year, 74.0 % (range A cohort of 72 resected patients with HBV-relatedHCC 0–85.0 %) at 3 years, and 62.0 % (range 0–70.0 %) at showed that the absence of antiviral treatment was a risk in 5 years (all p \ 0.001) [521]. tumor recurrence [514]. An HBV DNA of[2000 IU/ml at Thus, use of antiviral therapy improves the long-term the time of resection was a significant risk factor (RR 22.3, post-hepatectomy recurrence and survival in patients with 95 % CI 3.3–150.5, p = 0.001). HBV-related HCC. With a better liver function reserve at Routine prophylactic NA therapy for HCC patients with the time of recurrence, a greater proportion of patients in HBV-DNA levels\2000 IU/ml before liver resection may the antiviral group could receive curative treatment for also be considered. The aim is to prevent HBV reactivation recurrence [522]. after liver resection, which occurs in as many as 19 % of Interferon treatment as tertiary prevention of HBV-re- patients within the first 1 year, and which can severely lated HCC recurrence remains controversial [523–525]. reduce liver function and survival [515]. Use of interferon treatment in HCC patients may be com- Since NAs cannot completely eradicate HBV, lifelong plicated and even risky, as these patients are more vul- treatment should be pursued as long-term therapy may help nerable to the development of hepatic decompensation with prevent hepatitis flare-ups and inhibit hepatocarcinogenesis life-threatening complications such as hepatic to the greatest extent [516]. encephalopathy and ascites. In contrast, nucleos(t)ide Various studies have found that antiviral therapy analogues are, in general, safer and better tolerated than decreases HCC recurrence after resection. In a nationwide interferon. cohort study from Taiwan of 4051 untreated versus 518 HBV recurrence after liver transplantation has always NA-treated CHB patients with resected HCC, even though been a major problem for HBV-related HCC. Pre-trans- there was a higher rate of cirrhosis in the latter (38.7 vs. plant HBV DNA level and antiviral treatment was a major 48.6 % respectively, p \ 0.001), the risk of HCC recur- risk factor associated with HBV recurrence after liver rence was lower in the NA-treated patients (43.6 vs. transplantation [526]. For all recipients with high load of 20.5 % respectively, p\ 0.001) [517]. NA use was HBV DNA, a potent, high resistance NAs should be given 123 Hepatol Int (2016) 10:1–98 65 as early as possible before transplantation. HBIG should be related infections have become very rare because of given during the anhepatic phase. NAs in combination with improved blood screening [531]. The age at the time of low dose HBIG have been proved to reduce HBV recur- HBV acquisition is the major determinant of chronicity, as rence after transplantation [527]. The most recent data about 90 % of newborns who acquire HBVperinatally showed entecavir or tenofovir were more effective NAs develop chronic HBV infection In contrast, only 25–50 % using this strategy [528] (see ‘‘3.12 Prevention and treat- of children who acquire the virus in the first 6 years of life ment of recurrent hepatitis B after liver transplantation’’ and 5 % of adults become chronically infected [532]. section). Natural history of chronic HBV infection in children The 3:13:8 Recommendations: patients before and/or after vast majority of children infected at birth are immune- curative or local–regional therapy of HCC tolerant with high HBV DNA levels in serum and the 3:13:8:1 NAs treatment should be given to presence of HBeAg for years, typically into late childhood patients with HBV-related HCC (at least or adolescence. Generally, in this phase, despite the high- 1–2 weeks before, during and after level HBV replication, the host T-cell response is sup- chemotherapy, locoregional therapies, pressed, and infected hepatocytes are therefore not resection or LT), if they have attacked. Alanine aminotransferase (ALT) levels are fre- detectable serum HBV-DNA (B1). quently normal or slightly increased, and histological 3:13:8:2 Because NA therapy cannot completely changes are minimal. Transplacental transfer of maternal eradicate HBV, lifelong treatment is HBeAg can induce tolerance of helper T cells of newborns needed (B2). to HBeAg [309]. The affected children are usually 3:13:8:3 HBIG should be given to recipients with asymptomatic and have normal growth. high viral loads in anhepatic phase, The immune-active phase is characterized by elevation followed by combination therapeutic of aminotransferase and fluctuating serum HBV-DNA modalities with NAs and low-dose HBIG levels. This phase may lead to seroconversion. Sponta- after LT to prevent HBV recurrence (B1). neous seroconversion rates (loss of HBeAg and develop- ment of anti-HBe) in these perinatally infected children are low, occurring in fewer than 2 %/year of children younger 3.13.9 Chronic HBV infection in children than 3 years and in 4–5 % of children older than 3 years [533]. These rates are much lower than those (14–16 %/ The Oxford dictionary states that ‘A young human being year) observed in children infected horizontally after the below the age of puberty or below the legal age of majority perinatal period [534, 535]. should be regarded as ‘child’. On the other hand, The After achievement of anti-HBe seroconversion, serum Nations Convention defines child as ‘a human being below HBsAg persists, but aminotransferase levels return to the age of 18 years’ [529]. The UN convention has been normal and HBV DNA becomes very low or undetectable. ratified by 192 of 194 member countries. However, dif- This state is the low replicative phase, and in this phase, ferent countries may have different age settings for chil- liver disease progresses very slowly. Available data on dren in medical set-up. Also, the age of voting rights differ long-term follow-up of children in low replicative phase in different countries, ranging from 18 to 20 years. The without signs of cirrhosis at the time of seroconversion definition of ‘child’ is of utmost importance for the treat- have demonstrated no progression to cirrhosis over about ment of chronic HBV-infected patients, as the pathogenesis 30 years [536, 537]. The complete resolution of HBV of HBV takes critical clinical turns in ‘child’, especially infection is characterized by loss of HBsAg and appearance around 16–18 years of age. Transmission modalities for of anti-HBs. This spontaneous vent is rarely observed in HBV infection vary between different regions of the world. children (0.6–1 %/year) [538]. Although in children and In highly endemic areas, most infections are transmitted adolescents, chronic HBV infection is generally a mild from mother to child vertically/perinatally (mainly in Asian disease with a benign course, 1–5 % of HBeAg-positive countries) or through horizontal transmission from child to children develop cirrhosis [536, 537]. child during early childhood (mainly in African countries) Between 0.01 and 0.03 % of children with chronic HBV [530]. In countries of intermediate endemicity, HBV infection develop HCC during childhood (32 per 100,000 infection occurs in all age groups, whereas in areas of low person-year) [538, 539]. Children developing HCC are endemicity, infection occurs primarily in adult life through more likely to be males (70 %), with cirrhosis (80 %), and sexual or parenteral transmission (e.g., drug use). In these to have undergone early seroconversion (suggesting that countries, surgery, dental care, tattooing, and body piercing necroinflammation during seroconversion to anti-HBe may may be relevant sources of infection, while transfusion- be severe enough to lead to cirrhosis and HCC) [538]. In 123 66 Hepatol Int (2016) 10:1–98 adult patients, the long-term risk of both HCC and cirrhosis In HBeAg-positive children with elevated serum ALT is directly correlated to serum HBV DNA levels and levels ([19 upper normal limit), an observation period of HBeAg positivity, but no conclusion can be drawn from 12 months is recommended, as raised ALT levels and pediatric studies because of the rarity of HCC during variable levels of HBV-DNA may indicate imminent childhood. The role of viral genotype in the risk of seroconversion that would not require treatment. developing HCC is still to be clarified in the pediatric In HBeAg-negative children, ALT and HBV DNA population. The risk of HCC is higher in individuals with a levels should be measured every 3 months within the first family history of HCC [71]. year to rule out HBeAg-negative hepatitis. After confir- mation of the low replicative phase (normal ALT and HBV Indications of treatment in children with chronic HBV DNA \2000 IU/ml), patients should be monitored with infection Decision to treat must take into account the ALT every 3 months and HBV DNA every 6–12 months. mild evolution of the disease during childhood, the risk of HCC surveillance with liver ultrasound and AFP should disease progression later in life, the development of severe be done every 6 months, as in adults. complications in few, not yet well-identified children, the efficacy of current antivirals, their side effects, and the Treatment options for children with chronic HBV infec- limited number of drugs labelled for use in this age group tion The US Food and Drug Administration (FDA) [540]. approved five medications for treatment of children with The need for treatment should be evaluated at each CHB: IFN-a, lamivudine, adefovir, entecavir, and recently, follow-up visit, in order to initiate antiviral drugs at the tenofovir. IFN-a can be used in children older than earliest signs of liver damage. Currently, decision to start 12 months of age, lamivudine starting at 3 years of age, treatment is based on ALT levels, HBeAg positivity, HBV adefovir and tenofovir in children aged 12 years and older, DNA levels, assessment of liver disease severity (either and entecavir starting from 16 years of age. histology and/or noninvasive methods), family history of IFN-a Results of a large, multinational, randomized, HCC, and co-existing liver diseases (Table 12). controlled trial of IFN-a in children with HBV infection As the upper limit of normal (ULN) for ALT levels in showed a virological response (defined as negativeHBeAg pediatric age has not yet been established, it is advised that and HBV-DNA) in 26 % of treated patients versus 11 % of the normal limit should be as per the local laboratory ULN. controls (p = 0.03) after 24 weeks of therapy. Loss of In the presence of high ALT levels, assessment of serum HBsAg occurred in 10 % of treated patients versus 1.2 % HBV DNA levels is important, as high HBV DNA values of controls [542]. Various studies have shown that factors warrant antiviral treatment, whereas low levels should associated with response to treatment are elevated ALT levels ([29 upper normal limit), low-serum HBV-DNA instigate investigations to exclude other causes of liver disease. levels, female gender, and age \5 years [543, 544]. As response to currently available antivirals in children However, long-term follow-up studies suggest that is partial and limited to specific subgroups, histological untreated children may have similar rates of HBeAg assessment of the degree of inflammation and of the stage seroconversion as IFN-a-treated children, although the of fibrosis is recommended before considering treatment in seroconversion may lag by 1–3 years [545, 546]. With certain groups (Table 12). Response to both interferon respect to nucleoside analogs, IFN-a has the advantages of (IFN)-a and NA is more likely when at least moderate a long-lasting response and no risk of mutants induction; necroinflammation or moderate fibrosis is found at liver however, major disadvantages are the high-cost, frequent histology [541, 542]. Although the benefit of treatment has side-effects, and the need for thrice-weekly injections. The not been established for children with mild inflammation or latter could be reduced by the use of pegylated IFN-a, fibrosis, a family history of HCC may warrant treatment which requires a single weekly administration because of even in children with mild histological changes, as they are its prolonged half-life. It is not yet approved for use in at increased risk of developing HCC [71]. Although still children, although studies in adults HBV patients have not fully validated, noninvasive methods to assess the shown a higher efficacy with respect o IFN-a. In summary, degree of hepatic fibrosis, such as FibroScan, could prove HBeAg seroconversion occurs earlier in IFN-a-treated useful to avoid liver biopsy, especially during follow-up. children with elevated ALT levels at the time of starting However, sufficient data is lacking in children, and at therapy compared with controls. It remains to be estab- present, these noninvasive methods cannot substitute for lished whether shifting the time to seroconversion by liver biopsy in the decision to treat a child or an adolescent 12–36 months reduces long-term damage to the liver [531]. with CHB, as these methods evaluate more fibrosis than Lamivudine A large multicenter trial of LAM in children necroinflammatory activity. [547] showed that 23 % of the children in the treatment 123 Hepatol Int (2016) 10:1–98 67 Table 12 Indications of treatment in children with chronic HBV infection HBV DNA ALT Treatment (IU/ml) Decompensated Detectable Any Treat. Histology not needed. Consider LT of no stabilization cirrhosis Compensated Detectable Any Treat cirrhosis Severe reactivation Detectable Elevated Treat immediately of chronic HBV Noncirrhotic [20,000 [29 ULN Follow-up for 1 year to see for spontaneous seroconversion. Treat if no HBeAg-positive seroconversion. Histology not t needed CHB 1–29 ULN Follow-up for 1 year to see for spontaneous seroconversion. If no seroconversion, assess severity of liver disease by biopsy. Treat if moderate to severe inflammation or significant fibrosis Persistently normal Monitor every 3 months. Biopsy if ALT persistently elevated or family h/o (immune tolerant HCC or cirrhosis. Treat if moderate to severe inflammation or significant phase) fibrosis 2000–20,000 Any ALT Rule out other causes of elevated ALT if normal ALT. Monitor every 3 months. Biopsy if ALT persistently elevated, or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis \2000 \ULN Monitor every 3 months. Biopsy if ALT persistently elevated or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis [ULN Rule out other causes of elevated ALT. Monitor every 3 months. Biopsy if ALT persistently elevated, or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis Noncirrhotic [2000 [29 ULN Treat. Histology not needed HBeAg-negative CHB 1–29 ULN Rule out other causes of elevated ALT. Monitor every 3 months. Biopsy if ALT persistently elevated, or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis Persistently normal Monitor every 3 months. Biopsy if ALT persistently elevated, or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis \2000 [ULN Rule out other causes of elevated ALT. Monitor every 3 months. Biopsy if ALT persistently elevated, or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis Persistently normal Monitor ALT every 3 months and DNA 6–12 monthly. Biopsy if ALT persistently elevated, or with family h/o HCC or cirrhosis. Treat if moderate to severe inflammation or significant fibrosis A family history of HCC may warrant treatment even in children with mild histological changes, as they are at increased risk of developing HCC group cleared HBV-DNA and HBeAg, compared to 13 % Adefovir ADV dipivoxil is approved for the treatment in the placebo group. of adolescents ([12 years) with CHB, but not in The response to treatment was especially in children younger children after beneficial virological effects were with higher ALT values and histological activity (among not observed in children between 2 and 12 years of age children with ALT greater than five times the upper limit of in the primary efficacy, multicenter, randomized trial normal, HBeAg loss occurred in 50 % vs. 24 % in the where 23 % of adolescents reached a virological placebo group). However, 19 % of children developed response after 12 months of ADV treatment compared LAM resistant mutants. Other smaller studies of LAM with 0 % in the placebo group [550]. ADV is safe and treatment in children have confirmed both the efficacy in well tolerated in children, and no important resistance- reducing serum HBV DNA and the high mutation rate associated mutations have been observed in the pediatric [548, 549]. setting [551]. 123 68 Hepatol Int (2016) 10:1–98 Entecavir ETV is more effective than LAM and ADV in Although not yet approved for the treatment of CHB the treatment of CHB in adults. On the basis of these inpatients \12 years of age, the use of tenofovir might be encouraging results and a good safety profile, ETV has safe in younger children, as it is already widely used (and been approved by the FDA for treatment of adolescents FDA licensed) for patients older than 2 years of age with over the age of 16. Clinical trials in children younger than HIV infection. Since the approval of tenofovir for adoles- 16 years are ongoing. cents, adefoviris is no longer recommended because of the Tenofovir In a recent double-blind, placebo-controlled higher risk of resistance and the lower response rate. trial on the use of tenofovir (300 mg once daily for A finite-duration treatment with tenofovir or entecavir is 72 weeks vs. placebo) in CHB adolescents 12 to\18 years possible if seroconversion to anti-HBe is achieved on of age, a virological response in 89 % of treated patients treatment. Duration of treatments with NA has not been was seen regardless of previous HBV therapies [552]. established, but the recommendations should be as for the Normalization of ALT levels occurred in 74 % of treated adults. Patients should be monitored after discontinuation patients. No resistance to tenofovir developed through because of the possibility of post-treatment flares. week 72. Tenofovir therefore appears to be a promising Patients who do not undergo HBeAg seroconversion on agent for the treatment of CHB in adolescents, although treatment, the rare children with HBeAg-negative chronic long-term studies are needed to evaluate the rate of sero- hepatitis and cirrhotic patients need long-term treatment conversion and the impact on the development of HCC. with NA. Tenofovir or entecavir, if allowed by the age, are the Treatment strategy for chronic HBV infection in children first choice. Lamivudine is the only NA currently approved for younger children. Its use should be limited to the rare Currently, a finite-duration IFN-a therapy remains the young children unresponsive to IFN-a and requiring treatment strategy of choice for HBeAg-positive children immediate treatment, and to special populations with with elevated ALT levels, as seroconversion to anti-HBe contraindications to IFN. The recommended treatment dose is the main aim in this patient population. IFN-a is the for lamivudine is 3 mg/kg/day (maximum 100 mg/day), only available treatment offering a chance of sustained administered orally once daily. off-treatment response. It is likely that, as soon as results of trials using Peg-IFN in children are available, it will Treatment failure and antiviral resistance become the recommended drug. The recommended regi- men is 5–10 million units per square meter, three times The basic principles remain the same as for adults. Because weekly for 6 months. For Peg-IFN, studies in adults show of the low number of effective drugs that are approved, when resistance to an NA develops in children, the decision the highest HBeAg seroconversion rate with 48-week treatment schedules. IFN-a is the only treatment licensed of therapy adjustment is based on the patient’s age for treating children younger than 3 years of age, who, (Table 13). however, rarely require therapy. In case of non-response 3:13:9 Recommendations: chronic HBV infection in at the end of IFN treatment, wait for at least 12 months children before considering other therapies, as response may be achieved during the 6 months following the end of IFN-a 3:13:9:1 Any person up to the age of 18 years treatment. will be considered as a child (A1). The recent FDA approval of tenofovir and entecavir, 3:13:9:2 The need for treatment should be eval- uated at each follow-up visit, in order to which have high genotypic barriers to resistance, has made them the first-line NA treatments for adolescents. In initiate antiviral drugs at the earliest patients older than 12 years of age, tenofovir (or entecavir signs of liver damage (C2). for patients [16 years old) is the best choice, as response 3:13:9:3 Children with decompensated cirrhosis rate is high and resistance is less likely. The recommended and detectable HBV DNA require urgent dose for tenofovir is 300 mg once daily, and for entecavir antiviral treatment with NA(s). Liver is 0.5 mg once daily (for nucleoside-naı ¨ve patients). transplantation should be considered if Table 13 Management of antiviral resistance in children with chronic HBV infection Lamivudine Switch to tenofovir (for [12 years old) resistance Switch to IFN (\12 years of age) Adefovir If the patient was NA-naive before adefovir, switch to entecavir (for [16 years age) or tenofovir (for [12 years age); resistance entecavir for ([16 years age) may be preferred in such patients with high viremia 123 Hepatol Int (2016) 10:1–98 69 patients do not stabilize with medical changes, as they are at increased risk of management (A1). developing HCC (B2). 3:13:9:4 Patients with moderate to severe activity 3:13:9:13 No sufficient data are available for use or significant fibrosis with any ALT of noninvasive markers in children and, level should be considered for treatment at present, these noninvasive methods (A1). cannot substitute for liver biopsy in the 3:13:9:5 Children with severe reactivation of decision to treat a child or an adolescent chronic HBV infection should be treated with CHB, as these methods evaluate without delay and irrespective of HBV more fibrosis than necroinflammatory DNA levels (A1). activity (C2). 3:13:9:6 As the upper limit of normal (ULN) for 3:13:9:14 The US FDA approved five medications ALT levels in pediatric age has not yet for treatment of children with CHB: been established, it is advised that the IFN-a, lamivudine, adefovir, entecavir, normal limit should be as per the local and recently, tenofovir. IFN-a can be laboratory ULN (C2). used in children older than 12 months of 3:13:9:7 In HBeAg-positive children with ele- age, lamivudine starting at 3 years of vated serum ALT levels ([19 upper age, adefovir and tenofovir in children normal limit), an observation period of aged 12 years and older, and entecavir 12 months is recommended, as raised starting from 16 years of age (A1). ALT levels and variable levels of HBV- 3:13:9:15 Currently, a finite-duration IFN-a ther- DNA may indicate imminent serocon- apy remains the treatment strategy of version that would not require treatment choice for HBeAg-positive children (C1). with elevated ALT levels (A1). 3:13:9:8 In HBeAg-negative children, ALT and 3:13:9:16 In case of no response at the end of IFN HBV DNA levels should be measured treatment, at least 12 months should every 3-months within the first year to elapse before considering other thera- rule out HBeAg-negative hepatitis. pies, as response may be achieved After confirmation of the low replicative during the 6 months following the end phase (normal ALT and HBV DNA of IFN-a treatment (B1). \2000 IU/ml), patients should be mon- 3:13:9:17 Patients who do not undergo HBeAg itored with ALT every 3 months and seroconversion on treatment, the rare HBV DNA every 6–12 months (B1). children with HBeAg-negative chronic 3:13:9:9 Treatment may be started in pre-cir- hepatitis and cirrhotic patients need rhotic chronic HBV-infected patients if long-term treatment with NA (B1). they have persistently elevated ALT 3:13:9:18 The recent FDA approval of tenofovir levels [2 times upper limit of normal ([12 years of age) and entecavir (for (ULN) (at least 1 month between obser- [16 year of age), which have high vations) and HBV DNA[20,000 IU/ml genotypic barriers to resistance, has if they are HBeAg-positive and made them the first-line NA treatments [2000 IU/ml if HBeAg-negative, even for adolescents (A1). without a liver biopsy (B1). 3:13:9:19 Although not yet approved for the 3:13:9:10 Patients with compensated cirrhosis and treatment of CHB in patients\12 years detectable HBV DNA should be con- of age, the use of tenofovir might be sidered for treatment even if ALT levels safe in younger children, as it is already are normal (B1). widely used (and FDA-licensed) for 3:13:9:11 Patients who are not considered for patients older than 2 years of age with treatment should be followed up regu- HIV infection (B1). larly (Table 13) (B1). 3:13:9:12 Although the benefit of treatment has 3.14 Treatment of acute HBV infection not been established for children with mild inflammation or fibrosis, a family The natural course of HBV infection is determined by the history of HCC may warrant treatment interplay between virus replication and the host’s immune even in children with mild histological 123 70 Hepatol Int (2016) 10:1–98 response. Upon exposure to HBV, individuals with a vig- resolution, small amounts of cccDNA persist in the liver orous and broad immune response to the virus develop an for years, decades and possibly for life. T cell immunity acute self-limited infection that may result in acute hep- suppresses viral replication originating from these cccDNA atitis; an aberrant response can lead to fulminant hepatitis. copies to very low levels [554]. Anti-HBc appears with the Individuals who do not mount a broad and vigorous onset of the disease as the first anti-HBV antibody, then immune response do not clear the virus, but develop per- anti-HBe, anti-pre-S, and finally, anti-SHBs. These anti- sistent infection and become chronically infected with bodies probably contribute neither to virus elimination HBV. from the liver nor to the pathogenesis of hepatitis. How- ever, anti-HBs formed during convalescence and later may Clinical manifestations enhance opsonization of HBsAg and block de novo infection of hepatocytes by released HBV. In contrast to During the acute phase of hepatitis B (AVH-B), manifes- the other HBV antibodies, anti-HBc induction is partially T tations range from subclinical or anicteric hepatitis to cell independent. This explains the presence of anti-HBc icteric hepatitis, and in some cases, fulminant hepatitis. even in those patients who do not build up an efficient Approximately 70 % of patients with acute hepatitis B immune response. Serological resolution is defined by the have subclinical or anicteric hepatitis, while 30 % develop disappearance of HBsAg, which may take months after icteric hepatitis. The course of acute hepatitis B is divided onset. into the incubation period, and preicteric, icteric and con- In subjects who have been previously vaccinated, there valescence phases. From the incubation period to the onset is earlier engagement of innate and adaptive immunity at of symptoms or jaundice, it averages 75 days (range much lower viral loads, leading to blunted viral load 40–140 days). The onset of hepatitis B is typically insidi- increase and rapid clearance of virus, thus preventing ous, with nonspecific symptoms of malaise, poor appetite, development of clinically significant acute and chronic nausea and pain in the right upper quadrant. With the onset HBV infection [555]. of the icteric phase, symptoms of fatigue and anorexia typically worsen. Jaundice can last from a few days to Diagnosis several months, the average being 2–3 weeks. Itching and pale stools may occur. The convalescent phase of hepatitis The differential diagnosis of HBsAg-positive acute hep- B begins with the resolution of jaundice. Fatigue is gen- atitis includes reactivation (flare or exacerbation) of hep- erally the last symptom to abate and may persist for many atitis in chronic HBV-infected patients. months into convalescence. Laboratory testing during the acute phase of acute hepatitis B reveals elevations in the concentration of ala- The physical signs of typical acute hepatitis B are not prominent. Variable degrees of jaundice are present. The nine and aspartate aminotransferase levels (ALT and AST); only other common physical finding in acute hepatitis B is values up to 1000–2000 IU/l are typically seen during the a mild and slightly tender hepatomegaly. Mild enlargement acute phase, with ALT being higher than AST. The serum of the spleen or lymph nodes occur uncommonly. alkaline phosphatase and lactic dehydrogenase are usually only mildly elevated (less than threefold). The bilirubin is Pathogenesis variably increased, in both direct and indirect fractions. The serum bilirubin concentration may be normal in It is clear that replication and persistence of HBV is not patients with anicteric hepatitis. Serum albumin rarely falls cytopathic per se. Studies in acutely HBV-infected chim- except with protracted severe disease. The prothrombin panzees and woodchucks showed that no host response to time can increase and is the most reliable marker of viral replication occurred during the incubation phase, as severity of injury. In patients who recover, normalization HBV infection does not stimulate the innate immune sys- of serum aminotransferases usually occurs within tem, which recognizes pathogen-associated molecular 1–4 months. Persistent elevation of serum ALT for more patterns. In contrast, later in the infection period, most of than 6 months may indicate progression to chronic hep- the effector molecules associated with the adaptive cellular atitis. Various auto-antibodies can appear during the course immune response are induced, followed by HBV antibod- of acute hepatitis B, most typically to smooth muscle. ies. HBV elimination starts several weeks before onset of The diagnosis of acute hepatitis B is based upon the the disease with T-cell-dependent noncytolytic mecha- detection of HBsAg and IgM anti-HBc. During the initial nisms, but later cytolytic immune responses follow and phase of infection, markers of HBV replication, HBeAg generate the symptoms of acute hepatitis [553]. and HBV DNA, are also present. Recovery is accompanied High disease activity usually leads to clinical and by the disappearance of HBV DNA, HBeAg to anti-HBe serological resolution. However, even after serological seroconversion, and subsequently HBsAg to anti-HBs 123 Hepatol Int (2016) 10:1–98 71 seroconversion. During resolving acute hepatitis B, anti- acute flare from acute hepatitis B. Bilirubin, AST and HBe appears after anti-HBc, but before anti-HBs. It usually platelet count (BAP) score was calculated, and a score of disappears earlier than anti-HBs. [2 strongly suggested an acute flare of CHB [560]. Rarely, patients present during the window period when The meaning of the term anti-HBs is somewhat HBsAg has become negative but anti-HBs is not yet pos- ambiguous. Some understand it to mean antibodies only itive. In this setting, which is more common in patients against the small HBsAg protein (SHBs), others the entire with fulminant hepatitis B in whom virus clearance tends to antibody spectrum against all three surface proteins be more rapid, IgM anti-HBc is the sole marker of acute including pre-S1 and pre-S2. During acute infection, anti- HBV infection. pre-S antibodies appear before anti-SHBs, and they often In acute infections, HBsAg concentrations rise loga- coexist with HBsAg. rithmically for weeks–months from undetectable to typical final concentrations of 10,000–100,000 ng/ml with Outcome of acute hepatitis B 2–4 days of doubling time [556]. If the acute HBV infec- tion is resolved, HBsAg decreases with an initial half-life Fulminant hepatitis B is an atypical course for acute hep- of 8 days until it has been completely removed from serum atitis B infection, occurring in \1 % of icteric cases. after weeks–months. In about 25 % of acute resolving Typically, in fulminant disease, HBV DNA and HBeAg hepatitis B cases, the elimination of HBsAg proceeds much become undetectable as hepatic failure supervenes. faster, with the consequence that samples taken in the late The rate of progression from acute to chronic hepatitis B acute phase may be HBsAg negative [557]. A decrease in is determined primarily by the age at infection. The rate is HBsAg concentration by more than 50 % within the first approximately 90 % for a perinatally acquired infection, 4 weeks indicates resolving acute infection in [95 % of 20–50 % for infections between the age of 1 and 5 years cases [558]. Hence, quantitative analysis of highly con- and \5 % for an adult-acquired infection [561]. Genotype centrated HBsAg is an excellent prognostic marker, indi- A was an independent risk factor for progression to chronic cating progression to chronicity if the values remain infection following AVH-B in Japan [562]. In Japanese stable or increase. patients, high levels of HBsAg at 12 weeks and HBV DNA Anti-HBc immunoglobulin (Ig)M (anti-HBc IgM) may at 8 weeks were useful for discriminating between the be useful in two situations: (1) to distinguish an acute patients who lost HBsAg within 12 months and those who hepatitis caused by HBV from a hepatitis of different eti- did not. Only those who fail to clear HBV within ology in a chronic HBV-infected patient; and (2) to identify 12 months from the onset may develop chronic infection an acute hepatitis in some hepatitis B patients, particularly [563]. those with fulminant hepatitis B or HDV coinfection, where HBsAg may have been eliminated very rapidly. Treatment Predominant TH1 immune response in AVH-B favors cell- mediating viral clearance, while TH2-mediated immune Treatment for acute HBV is mainly supportive. In addition, response in chronic HBV infection favors antibody pro- appropriate measures should be taken to prevent infection duction. HBV antigens elicit immune-mediated liver injury in exposed contacts. in a dose-dependent manner; therefore, low viral antigen Patients who have a coagulopathy, are deeply jaundiced, load and subsequent resolution of infection in AVH-B as are encephalopathic or cannot tolerate oral intake should compared to persistent viral antigenemia in chronic HBV generally be hospitalized. infection leads to significantly increased production of Whether patients should be treated with nucleos(t)ide HBV specific antibodies (mainly Anti HBe/Anti HBc) in therapy is unsettled since few studies have addressed the chronic HBV infection or its exacerbation in comparison to benefits of antiviral therapy during acute infection. One AVH-B [559]. Tests should be quantitative because anti- prospective case series treated 15 patients with severe AHB HBc IgM is also positive in CHB and during convales- (INR [1.6, serum bilirubin levels [10 mg/dl or hepatic cence. Levels[600 Paul–Ehrlich units/ml or IgM anti-HBc encephalopathy) with 100 mg of lamivudine, achieving a ([1:1000) suggest an acute HBV infection with high response rate of 86 % [564]. The first randomized clinical inflammatory activity. In all other situations, concentra- trial included a total of 71 patients with AHB (31 ran- tions are lower or undetectable [23, 319]. In a study on domized to lamivudine for 3 months and 40 to placebo) patients with a protracted clinical course of [2 months and showed no biochemical or clinical benefit to lamivu- with elevated liver enzymes and positive HBV DNA, it was dine; the lack of response to therapy was also observed in found that peak bilirubin level, peak AST levels and least the subset of patients with severe AHB. There was also no platelet count within the first 8 weeks had the highest difference in HBsAg loss after 12 months (94 vs. 97 % in predictive power for differentiating patients with CHB with the groups that received lamivudine and placebo, 123 72 Hepatol Int (2016) 10:1–98 respectively) [565]. However, another RCT that included 3:14:2 More than 95–99 % of adults with acute 80 AVH-B patients showed statistically significant differ- HBV infection will recover spontaneously ences in mortality (7.5 % lamivudine vs. 25 % placebo) and seroconvert to anti-HBs without antivi- and incidence of acute liver failure (20 vs. 42.5 %). The ral therapy (A1). 3:14:3 Patients with fulminant hepatitis B must be study also showed that the sooner the treatment is initiated, the better the results obtained, and a rapid decline of HBV evaluated for liver transplantation (A1). 3:14:4 Treatment is only indicated for patients DNA load was a good predictor for the treatment outcome [566]. In a few other studies, patients with severe acute or with fulminant hepatitis B or for those with severe or protracted acute hepatitis B (C2). fulminant hepatitis B were treated with lamivudine, demonstrating the safety and efficacy of this antiviral drug, 3:14:5 Tenofovir, entecavir, telbivudine, lamivu- with a capacity for improving the prognosis of these dine or adefovir are acceptable options patients [567–569]. Antivirals other than lamivudine have when given as monotherapy, as the duration been investigated so far, in small case reports or series of of treatment should be short (C2). acute severe hepatitis B, with some promising preliminary 3:14:6 The duration of treatment is not estab- results with the use of entecavir [570, 571], tenofovir [572, lished. However, treatment should be con- tinued until HBsAg clearance is confirmed, 573], and telbivudine [574]. Thus, antiviral therapy is not indicated in the vast or indefinitely in those who undergo liver transplantation (C2). majority of patients with acute hepatitis B, but may be indicated in certain subgroups of patients as follows: 3:14:7 Interferon is contraindicated (A1). (a) patients with fulminant acute hepatitis B; (b) severe 3:14:8 When the distinction between true severe AVH-B: individuals who fulfill any two of the following acute hepatitis B and spontaneous reactiva- criteria: (1) hepatic encephalopathy; (2) serum bilirubin tion of chronic HBV infection is difficult, [10.0 mg/dl; and (3) international normalized ratio NA treatment should be administered (A1). (INR) [1.6, especially if it is increasing; and (c) a pro- tracted course [such as persistent symptoms or marked 3.15 Antiviral prophylaxis jaundice (bilirubin[10 mg/dl) for more than 4 weeks after before immunosuppressive therapy presentation]. or chemotherapy These indications outline the limitations in differentiat- ing AVH-B from reactivation of chronic HBV infection. Chemotherapy-induced HBV reactivation and hepatitis An argument can be made for treating all of the above flare is a common complication in HBsAg(?) cancer groups of patients using an NA, given its safety and the fact patients, with the incidence ranging from 20 to 70 % in that many of these patients may ultimately need liver previous reports [575]. Increased incidence of HBV reac- transplantation and reduction of HBV DNA levels would tivation was associated with cancer types (lymphoma, reduce the risk of recurrent hepatitis B after transplant. breast cancer, HCC), viral factors (high baseline HBV Interferon should be avoided because of the increased DNA, HBeAg positivity), and types of anti-cancer therapy risk of hepatic necro-inflammation. Telbivudine, lamivu- (steroid, anthracyclines). All candidates for chemotherapy dine, adefovir, entecavir or tenofovir are acceptable options and immunosuppressive therapy should be screened for- when given as monotherapy, as the duration of treatment HBsAg and anti-HBc prior to initiation of treatment. should be short. Treatment can be stopped after confir- Vaccination of HBV seronegative patients should be con- mation that the patient has cleared HBsAg. sidered. Higher vaccine doses may be required to achieve 3:14 Recommendations (acute viral hepatitis B) anti-HBs response in immunocompromised patients. The efficacy of prophylactic anti-viral therapy in pre- 3:14:1 Establishing a diagnosis of acute HBV is venting HBV reactivation in HBsAg(?) patients was firmly important, as majority of adult patients established by two randomized trials in lymphoma patients presenting as acute hepatitis B have reac- and meta-analysis involving clinical trials and cohort tivation of CHB. A definite history of studies of various cancer types [576–578]. Lamivudine was exposure, positive HBeAg and IgM used in all of these studies and was shown to reduce the antiHBc with low HBV DNA levels and risk of HBV reactivation [risk ratio (RR) 0.13, 95 % CI liver biopsy in doubtful cases can help to 0.07–0.24], reactivation-related mortality (RR 0.30, 95 % establish the diagnosis of acute HBV CI 0.1–0.94), and to reduce the delay/premature termina- infection and exclude the diagnosis of tion of chemotherapy (RR 0.41, 95 % CI 0.27–0.63) [579]. HBV reactivation (B1). The optimal duration of lamivudine prophylaxis was not 123 Hepatol Int (2016) 10:1–98 73 explored in these studies, and current recommendation for HBV DNA reactivation was confirmed) entecavir treatment the duration of anti-viral prophylaxis is 6–12 months after in lymphoma patients who received rituximab-CHOP completion of chemotherapy [25, 105]. It is not known chemotherapy, and confirmed that prophylactic entecavir whether more potent anti-viral agents, such as entecavir treatment significantly reduced the risk of HBV reactiva- and tenofovir, can further improve the prophylactic effi- tion. In these studies, the incidence of HBV-related hep- cacy in reducing the risk of HBV reactivation or reacti- atitis flare in patients with HBV DNA reactivation was vation-related mortality. However, these agents should be \50 %, and no HBV-related liver decompensation or considered if prolonged anti-viral therapy is indicated, death was noted. No risk factors for HBV reactivation were because of their lower rate of treatment-induced HBV identified, though baseline anti-HBs titer was proposed. resistance. Physicians should be aware of the potential life-threatening HBV reactivation has also been reported in HBsAg(?) consequence of HBV reactivation in this patient popula- cancer patients who received other molecular target ther- tion. However, the optimal preventive strategy remains apies. In the case of mTOR (mammalian target of rapa- undetermined. RCT has clearly demonstrated the efficacy mycin) inhibitor, everolimus is approved for the treatment of prophylactic anti-HBV in high-risk lymphoma patients of neuroendocrine tumor and renal cell carcinoma (as with resolved HBV infections. Further studies to identify single-agent), and breast cancer (in combination with host and viral risk factors for HBV reactivation and cost- hormonal therapy) [580, 581]. This may be due to the effectiveness of different preventive strategies are clearly effects of everolimus (and other mTOR inhibitors) on needed. immune suppression or on HBV synthesis [582]. Incidence and severity of HBV reactivation in patients Immunosuppressive therapy is required for patients who with resolved HBV infection who received other undergo solid organ transplantation, and long-term anti- immunosuppressive agents are not well defined [596]. viral therapy is recommended for HBsAg(?) organ trans- HBsAg-negative patients with positive anti-HBc antibodies plant recipients [583]. Immunosuppressive therapy, should be tested for HBV DNA. HBsAg-negative, anti- including steroid, cytotoxics, and biological agents (e.g., HBc positive patients with detectable serum HBV DNA tumor necrosis factor-a-blocking agents), is also com- should be treated similarly to HBsAg positive patients. monly used in patients with inflammatory bowel disease HBsAg-negative, anti-HBc positive patients with unde- and rheumatic diseases. Although prospective studies in tectable serum HBV DNA, and who receive chemotherapy these patient populations are lacking, the incidence and and/or immunosuppression regardless of anti-HBs status, severity of HBV reactivation has generally correlated with should be followed carefully by means of ALT and HBV the extent of immune suppression, and fatal HBV reacti- DNA testing, and be treated with NA therapy upon con- vation has been reported [584–586]. Therefore, despite the firmation of HBV reactivation before ALT elevation [25]. lack of randomized clinical trials, prophylactic anti-viral The frequency of monitoring can range from 1 to 3 months, therapy is recommended for HBsAg(?) patients who depending on the type of immunosuppressive therapy and received immunosuppressive agents for auto-immune and comorbidities. Some experts recommend prophylaxis in all rheumatic diseases. However, the duration may be long- HBsAg-negative, anti-HBc positive patients who receive term, and its cost-effectiveness is not yet established. rituximab and/or combined regimens for hematological Chemotherapy-induced HBV reactivation in patients malignancies, if they are anti-HBs negative and/or if close with ‘resolved’ HBV infection (i.e., patients who are neg- monitoring of HBV DNA is not guaranteed [597–599]. ative for HBsAg but positive for anti-surface (anti-HBs) or NA prophylaxis is also recommended for anti-HBc anti-core (anti-HBc) antibodies) is also mostly reported in positive patients receiving bone marrow or stem cell lymphoma patients who received rituximab-containing transplantation [599, 600]. The optimal duration of pro- regimens [587–592]. The cumulative risk of hepatitis-re- phylaxis for these indications is not known. lated mortality in these early, retrospective series, in which 3:15 Recommendations: antiviral prophylaxis before no preventive strategies were adopted, was about 1 %. Two immunosuppressive therapy or chemotherapy prospective studies exploring different preventive strate- gies were recently reported. Hsu et al. reported prospective 3:15:1 All candidates for chemotherapy and follow-up of HBV DNA and entecavir therapy upon HBV immunosuppressive therapy should be DNA reactivation in lymphoma patients who received screened for HBsAg and anti-HBc prior to rituximab-based chemotherapy [593, 594]. The incidence initiation of treatment (A1). of HBV DNA reactivation was 10–40 %, depending on the 3:15:2 Prophylactic anti-viral therapy should be given to HBsAg(?) cancer patients who sensitivity of the HBV DNA test and the diagnostic criteria for HBV reactivation. Huang et al. [595] compared pro- receive cytotoxic or immunosuppressive phylactic entecavir treatment and therapeutic (started when therapy, both during therapy (regardless of 123 74 Hepatol Int (2016) 10:1–98 HBV DNA levels) and for 12 months after with the use of potent immunosuppressors, especially anti- cessation of therapy to reduce the incidence CD20s such as rituximab and ofatumumab, it becomes and severity of HBV reactivation (A1). increasingly important for transfusion services to screen for 3:15:3 Physicians should be aware of the risk of occult hepatitis B, since such recipients may develop sev- HBV reactivation in lymphoma patients ere/fulminant hepatitis B. This would require the use of a with resolved HBV infection [HBsAg(-) nucleic acid test (NAT) to quantify small amount of HBV and anti-HBc(?) who receive rituximab- DNA [601]. The great expense for such testing is a containing chemotherapy]. Further studies potential limitation, but NAT has become mandatory in are needed to compare the efficacy and more developed countries. cost-effectiveness of different preventive strategies (prophylactic antiviral therapy vs. Prevention of maternal to child transmission regular HBV DNA monitoring) (B1). of the hepatitis B virus: vaccination and antiviral treatment 3:15:4 HBsAg-negative patients with positive anti- HBc antibodies should be tested for HBV The risk of maternal to child transmission of HBV had DNA. HBsAg-negative, anti-HBc positive been well documented, mostly from studies from Taiwan, patients with detectable serum HBV DNA prior to the development of the hepatitis B vaccine in 1981 should be treated similarly to HBsAg- [602]. Up to 63 % of infants born of HBsAg-positive positive patients (C1). mothers became HBsAg-positive during the first 6 months 3:15:5 HBsAg-negative, anti-HBc positive patients of life. Six percent of fathers and 67 % of siblings were with undetectable serum HBV DNA and also HBsAg-positive. Infants born of HBeAg-positive who receive chemotherapy and/or immuno- mothers have a higher chronic HBV positivity rate com- suppression regardless of anti-HBs status pared to those born of HBeAg-negative mothers, proving should be followed carefully by means of that transmission is related to high viral load. However, up ALT and HBV DNA testing, and be treated to 25–30 % of infants born of HBeAg-negative mothers with NA therapy upon confirmation of HBV also become chronic HBsAg positive, showing that reactivation before ALT elevation (C1). HBeAg-negative mothers can also have high viral load. It has subsequently also been shown by sequence analysis of HBV mutations that post-natal transmission can occur from 3.16 Public health issues for HBV: prevention HBsAg-positive fathers and even aunts [603]. With the and management availability of both hepatitis B immune globulin (HBIG) and hepatitis B vaccine (at first plasma-derived, later Needles and other sharp instruments recombinant), there was marked reduction in the infant infection rate [125]. In one of the most carefully planned It has been well established that HBV can be spread by studies, the infant chronic HBV positivity state was contaminated needles, including intravenous drug use, reduced from 73.2 % in the control group to 21.0 % in the accupuncture, tattoos, ear piercing and needle prick injuries vaccine alone group, 6.8 % in the group receiving vaccine in hospital situation. This can be prevented by raising plus one dose of HBIG and 2.9 % in the group receiving awareness and by public education. In more developed vaccine plus multiple doses of HBIG (p B 0.0001 for all countries, disposable needles are used for accupuncture and groups) [604]. With increased knowledge of, and better ear piercing. The use of disposable needles/instruments is assays for, HBV DNA, it has recently been shown in a more difficult to implement. The importance of imple- retrospective study of 869 HBsAg-positive mothers and menting safe sharps practices in the hospital setting cannot their infants who had received HBIG with three does of be over emphasized. Other than the use of disposable hepatitis B vaccine, that 27 infants (3.1 %) were HBsAg- needles and sharps boxes, education and surveillance positive at age 7–12 months [605]. Multivariate analysis concerning the disposal of sharps, the banning of recapping showed that maternal HBV DNA levels and needles, the transfer of blood from syringes into containers, detectable HBV DNA in the cord blood were independent and needle disassembly should be enforced. risk factors for immunoprophylaxis failure. All failures occurred in infants born of HBeAg-positive mothers with Transfusion services pre-delivery HBV DNA C6 log copies/ml. Other smaller studies also confirm that high maternal viral load (in the There has been widespread implementation of screening study of Wiseman et al. HBV DNA of[8 log copies/ml) for HBsAg (and anti-HCV as well as anti-HIV) in the is associated with failure of prophylaxis [126, 606]. Since it transfusion services in most countries in Asia. However, is possible that mothers with HBV DNA levels between 6 123 Hepatol Int (2016) 10:1–98 75 and 8 log copies/ml can still induce immuonprophylaxis 3:16:3 Transfusion services should be encouraged failure in their infants, it is advisable to treat mothers with to use NAT as screening tests (B1). antiviral therapy when their HBV DNA levels are C6 log 3:16:4 Universal hepatitis B vaccination of new- copies/ml. There have been long-term follow-up studies of borns should be enforced (A1). 3:16:5 Increasing the awareness of the public and vaccinated infants, one of which follow the vaccine recipients for 22 years [606]. Booster doses are probably medical personnel should be a priority (A1). 3:16:6 Appropriate training for medical personnel not necessary for immune competent subjects, because of good anamnestic responses even after the anti-HBs titers at various levels is important (A1). 3:16:7 A shift in focus from tertiary care to have fallen to very low levels (\10 mIU/ml). community and primary care settings is Increasing the awareness of the public and medical needed (A1). personnel 3.17 Occult HBV infection Education of public and health care professionals will help in identification of persons at risk for viral hepatitis, and Definition and patient category ensure appropriate counseling, diagnosis, medical man- agement, and treatment [607]. Appropriate training for Occult hepatitis B (OBI) infection is defined by medical personnel is important. detectable HBV DNA in serum and/or liver in patients who are tested negative for serum HBsAg by the most sensitive Shift in focus from tertiary care to community and primary commercial assays [609]. There are three groups of sub- care settings jects in whom HBV DNA is detectable with concomitant undetectable serum HBsAg. The management of CHB requires a shift in focus from For the first group, subjects are in the window phase of tertiary care to community and primary care settings. This HBV infection, exposed recently. Depending on the could also include an exploration of alternative arrange- immune status at the time of contacting HBV, the subjects ments for care, including possible roles for nurse practi- may have acute hepatitis B with resolution of the disease or tioners or hepatitis coordinators besides primary care become chronically infected with hepatitis B. They are doctors. Primary care services, particularly those working therefore regarded as subjects with past infection and in high prevalence areas, and community organizations subjects with chronic HBV infection, respectively, in providing support and advice to priority populations will subsequent follow-ups. In the former group, subjects would need to play an increasingly important role in hepatitis B have positive or negative anti-HBs and anti-HBc in sub- screening, testing and monitoring. Better understanding of sequent follow-ups. It is, however, important to note that hepatitis B and C and its management is also required for studies have shown that HBV DNA may still be some primary care practitioners and non-hepatology spe- detectable in some of these subjects even after years of so- cialists such as those involved in antenatal care, where in called acute HBV infection [610, 611]. These subjects may some cases, maternal treatment can significantly reduce the also be having OBI. More longitudinal studies are required risk of transmission of HBV to the baby. A 6-year study to delineate the outcome of acute HBV infection in this from China reported that the training of general practi- regard. tioners (GPs) of village clinics in Hebei province improved For the second group, patients are considered as having their practice, for instance, the sterilization of needles, primary OBI. These patients have been identified only by syringes and transfusion sets. The chronic HBV positivity persistently detectable HBV DNA without prior docu- rate of 2-year-old children (mothers are HBsAg negative) mentation of HBsAg positivity before the presentation. dropped from 11.6 to 2.1 %, which indicates that the For the third group, patients have known chronic HBV training of GPs decreases the transinfection rate of HBV infection with previous documentation of HBsAg positivity [608]. for at least 6 months and are undergoing subsequent 3:16 Recommendations: public health issues for HBV- HBsAg seroclearance, i.e., entering into the last phase of prevention and management chronic HBV infection. Around 50–60 % of these patients are positive for anti-HBs [612]. 3:16:1 The general public should be educated OBI can also be serologically classified into sero-posi- concerning care in using needles and other tive (anti-HBs and/or anti-HBc positive) or sero-negative sharp instruments (A1). (both anti-HBs and anti-HBc negative). It is estimated that 3:16:2 Hospitals should strongly enforce the imple- upto a total of 20 % of OBI patients are negative for all mentation of safe sharps practices (A1). 123 76 Hepatol Int (2016) 10:1–98 serological markers of HBV infection [613]. These sero- HBV disease activity [628] and also the chance of loss of logically negative OBI patients may likely be infected with HBsAg seroclearance [629]. minute amounts of HBV which are insufficient to mount intense and specific immune responses. Clinical scenarios of OBI Prevalence of OBI OBI is of particularly interest in three main clinical areas. First, whether HBV is transmissible from OBI patients. There is a wide range of estimation of the prevalence of Second, what are the clinical manifestations of OBI, OBI reported in different countries. It ranges from \1to including liver function, histological features, and long- 18 % [614–618]. These data are grossly underestimated, term complications, e.g., liver cirrhosis and HCC? Finally, and this is related to the fact that most of the OBI patients what is the risk of reactivation of HBV from OBI patients have extremely low HBV DNA levels in the serum (and who have undergone immunosuppressive therapy? liver tissues are generally not easily assessible). Although There are several studies addressing the issue of trans- the viremia level (HBV DNA) is generally quoted as lower missibility of HBV through the blood products from OBI than 200 IU/ml [613], at least more than 90 % of OBI subjects. It has been shown that while HBV transmission is patients will have HBV DNA levels of \20 IU/ml in the possible, the risk is relatively low (1–3 %) [630]. Factors serum [616]. These low levels of HBV DNA as well as affecting the chance of infection of recipients include the their fluctuations make the detection of this condition dif- anti-HBs status in the donors and the recipients, the blood/ ficult even when using existing standardized and sensitive product volume received by the recipients, and the immune HBV DNA assays. status of the recipients [631]. There has been a practice of anti-viral prophylaxis being given to recipients receiving Pathogenesis of OBI bone marrow or solid organ donations from OBI subjects. Many centers advocate the use of nucleos(t)ide analogs for Mechanisms leading to OBI remain obscure. Proposed recipients who received bone marrow/organs from donors mechanisms include mutations of viral genomes, espe- who are anti-HBc positive with or without detectable HBV cially over the surface gene (e.g., G145R), such that they DNA. escape detection by commercial HBsAg assays [619]. There are many studies examining the possible patho- However, studies have shown that there is an absence of genic role of OBI. According to several studies, nearly all relevant mutations in the genomic HBsAg coding region OBI patients will have normal liver biochemistry and [620, 621]. Another better accepted postulation is that in minimal or no necroinflammation and fibrosis in liver OBI patients, the HBV is replicating at an extremely low histology [632, 633]. However, OBI may still be associated rate [622]. This can either be due to intrinsically low viral with the development of liver cirrhosis and HCC. OBI as replicative activities or extrinsic factors; namely, an the etiology for development of cirrhosis and HCC is well immense immune suppressive effect on the HBV. Several reported in the setting of coinfection with chronic hepatitis studies have found that there are significantly more C infection [634]. The estimated frequency of OBI in genomic mutations and rearrangement in splice donor patients with cryptogenic liver cirrhosis ranges from 4.8 to sites of the pre-S1, pre-S2, and S genes and their regu- 40 % [635, 636]. latory regions [623, 624]. Other studies reported greater 45–80 % of patients with apparently unidentifiable nucleoside and amino acid diversities in OBI compared to cause of HCC have had HBV detected in the liver, sug- those of overt chronic HBV infection [621, 623]. Additive gesting that OBI is associated with increased risk of HCC effects from these mutations may restrain the virus [637, 638]. A longitudinal follow-up study conducted in replication capacity. Post-transcriptional mechanism Japan confirmed OBI increased the risk of HCC [639]. A involving the Pre-S2/S RNA splicing has also been pro- recent meta-analysis recruiting 16 studies revealed that posed to explain the marked decrease in pre-S2/S tran- OBI increased the risk of development of HCC, with an script and HBsAg [625]. On the other hand, reactivation adjusted odds ratio of 2.9 from five prospective studies of HBV from OBI during and after immunosuppressive [634]. This was confirmed by another meta-analysis that therapy (including anti-CD20) indirectly suggests that the included 14 studies showing increased risk of HCC in OBI OBI state is kept by immune-mediated suppression of subjects with an OR of 8.9 [640]. Possible mechanisms for virus replication [626]. In fact, it has been shown that OBI leading to these complications include (1) persistent human genomic constitutions, in particular, the HLA DP low-grade inflammation leading to or continuing with region as illustrated by studies using single nucleotide existing cirrhosis [641]; (2) persistent oncogenic role of the polymorphisms (SNP) affecting the immune responses, HBV genome with its possible integration into the human are associated with the chance of HBV chronicity [627], genome as well as with its free episome [642]; and (3) low 123 Hepatol Int (2016) 10:1–98 77 levels of HBV transcriptional activities with viral protein 3:17:3 HBV DNA measurement in serum and liver synthesis (e.g., X protein and truncated preS–S protein) (if available) by highly sensitive assays with transforming properties [643]. should be performed in patients with HBV reactivation in OBI subjects undergoing cirrhosis and/or HCC in which no causes are identifiable (B1). immunosuppressive therapy has recently gained increasing attention because of the potential fatal hepatic decompen- 3:17:4 Chronic hepatitis B patients with HBsAg seroclearance still require continuous fol- sation if the condition is not treated promptly (see ‘‘3.15 Antiviral prophylaxis before immunosuppressive therapy low-up for the development of cirrhosis- related complications and HCC (A1). or chemotherapy’’ section). Concerning the antiviral treatment, it is recommended 3:17:5 HBsAg negative, anti-HBc positive subjects that whenever HBV DNA is detectable in the serum of with or without positive anti-HBs should be HBsAg-negative and anti-HBc/anti-HBs-positive patients closely monitored by HBV DNA during and at baseline, antiviral treatment should be given as in the at least 12 months after immunosuppressive case of HBsAg-positive patients. Patients who are negative therapy. Monitoring should be more frequent for HBV DNA at baseline should have HBV DNA and in patients receiving potent B cell depletion agents, e.g., anti-CD20. Antiviral treatment liver function checked at regular intervals of 1–3 months unil at least 12 months after the last cycle of immuno- should be started once the HBV DNA is detectable (B1). suppressive therapy. The frequency of monitoring depends on which agents are being used (for example patients on rituximab should be checked more frequently). HBV DNA levels are more sensitive indices of reactivation than liver 4 Newer therapies and future perspectives function since they become detectable before ALT levels start to increase. For those with undetectable HBV DNA at 4.1 Newer therapies and immunomodulatory baseline, once HBV DNA is detectable on follow-up, therapies patients should be treated with nucleos(t)ide analogues. It has also been suggested that patients should be treat pre- The limited efficacy of the currently available antiviral emptively if they are anti-HBs negative or if close follow- treatments requires the development of new therapeutic up cannot be assured [597, 598]. tools for the treatment of CHB. Promising therapies have To date, there are insufficient data to recommend whe- recently been developed that directly target HBV-infected ther routine antiviral prophylaxis right at the initiation of hepatocytes by inducing cccDNA degradation or by immunosuppressive therapy or postponement of antiviral inhibiting HBV entry or the expression of viral proteins. agents until HBV DNA becomes undetectable is more HBV-infected hepatocytes may also be targeted by appropriate. In addition, there is no good data on the fre- immunotherapeutic approaches designed to either boost the quency of monitoring of HBV DNA and HBsAg during HBV-specific T cell component of the immune response or and after immunosuppressive therapy. According to a to directly stimulate the intrahepatic innate response [644]. recent study adopting 4 weekly HBV DNA monitoring in The efficacy and feasibility of these approaches will, HBsAg-negative, anti-HBc positive patients receiving however, need to be carefully evaluated in humans. rituximab and prompt entecavir treatment once the HBV DNA is detectable, all of the patients achieved excellent Antiviral therapies targeting hepatitis B virus-infected control [594]. hepatocytes 3:17 Recommendations: occult HBV infection The life cycle of the virus begins with its attachment to the 3:17:1 Occult hepatitis B infection is not an appropriate hepatocyte receptor, which is now recognized uncommon disease entity. Suspicion should to be a bile salt transporter known as sodium taurocholate be raised in all HBsAg-negative subjects co-transporting polypeptide (NTCP) [645]. The region with or without positive anti-HBs or anti- between amino acids 21–47 of the Pre-S1 present in L- HBc (C1). HBsAg in virus binds to the hepatocyte membrane. 3:17:2 Sensitive nucleic acid tests should be used Cyclosporine (known to inhibit NTCP) analogues without to screen all blood donations from HBsAg- its immunosuppressive properties and oxysterols [646] may negative subjects. Transfusion products thus constitute possible drugs for development against should be discarded if HBV DNA is HBV for the future. Myrcludex-B, a synthetic lipopeptide detectable in these products (A1). ligand derived from the pre-S1 domain of L-HBsAg blocks 123 78 Hepatol Int (2016) 10:1–98 de novo HBV infection both in vitro and in vivo, as life cycle of the virus are Bay 41-4109 [653], GLS4 [654] demonstrated after pretreatment of human chimeric uPA/ and NVR-1221 [655]. SCID mice [647]. Six weeks of Myrcludex administration, Following encapsidation of the polymerase and pgRNA initiated either 3 days or 3 weeks post infection in the same complex, the subsequent steps in virus nucleic acid repli- animal model, efficiently blocked cell-to-cell virus spread cation take place within the nucleocapsid and involve and cccDNA amplification [648]. Although the above RNAse H. A potential drug targeting RNase H is b-thu- drugs appear to block HBV at the point of entry and japlicinol, which inhibited the enzyme from genotypes D therefore prevent the infection of new hepatocytes, their and H in biochemical assays with IC50 values of 5.9 ± 0.7 use as monotherapy regimens is unlikely to prove very and 2.3 ± 1.7 lM, respectively. It also blocked replication effective unless there is an obvious effect on already of HBV genotypes A and D in culture by inhibiting RNase infected hepatocytes harboring transcriptionally active H activity with an estimated EC50 of 5 lM and a CC50 of cccDNA. Therefore, future regimens may include such 10.1 ± 1.7 lM. Thus, if chemical derivatives of b-thu- drugs only in combination with others. japlicinol with improved efficacy and reduced toxicity can Following attachment, the processes of endocytosis, be identified, such compounds could be used in future uncoating and delivery of the resulting naked nucleocap- regimens of combined therapy with nucleos(t)ide ana- sids to the nuclear pores are initiated. Ezetimibe was tested logues [656]. using the HepaRG cell model and was shown to inhibit the Maturing nucleocapsids in the final stages of morpho- establishment of intrahepatic cccDNA and expression of genesis bud through the endoplasmic reticulum membrane. viral replication markers when the cells were infected with Peptidomimetic compounds that would prevent HBsAg- HBV. These findings indicate that the drug acts at early nucleocapsid interaction and glucosidase inhibitors pre- stages in the life cycle of the virus by modulating hepatic venting glycosylation of HBsAg are potential drugs at this cholesterol uptake and interfering with lipid transport, stage of the viral life cycle [657]. pathways that may represent new targets for antiviral therapy in the case of HBV infection [649]. Immunotherapeutic approaches: restoration of adaptive Nucleocapsid disassembly occurs at the nuclear pore, immunity followed by translocation to the nucleoplasm of the released HBV-DNA. Within the nucleus, the rcDNA is During CHB infection, HBV-specific T cells are deleted converted into a double-stranded cccDNA molecule. This or functionally exhausted, most likely due to the repeated involves a number of stages. In this form, cccDNA is quite exposure of these cells to large quantities of HBsAg and stable and behaves as a minichromosome, being the tem- HBeAg. Exhausted virus specific T cells express inhibi- tory molecules, such as PD-1 (programmed cell death plate for viral transcript synthesis by host RNA polymerase II. Most HBV-specific antiviral agents have thus far been protein 1), CTLA-4 (cytotoxic T-lymphocyte-associated unable to prevent the replenishment of the cccDNA pool protein 4), SLAM (signalling lymphocyte activation from maturing HBV-DNA containing nucleocapsids, molecule), and TIM-3 (T-cell immunoglobulin domain which are recycled to the nucleus from the cytoplasm, or to and mucin domain 3), and acquire a progressive and effect efficient clearance of cccDNA-containing hepato- step-wise loss of their effector functions [658]. Blocking cytes. In the last few years, new strategies aimed at inhibitory receptors has been shown to partially recover improving cccDNA clearance have been developed. These the exhausted T cells of CHB patients in vitro [659], but include lymphotoxin-b receptor (LT-b R) activation of the in vivo efficacy of this approach is still uncharac- HBV-infected cells [650], and cccDNA-specific transcrip- terized. Therapeutic vaccination aimed at eliciting the tion activator-like effector nucleases (TALENs) [651]. An patient’s immune system represents another attractive alternative approach is to modulate the expression of viral therapy for HBV. Potential approaches include HBV proteins, such as HBsAg and HBeAg, which are believed to therapeutic vaccines targeting different HBV proteins play a role in induction of T cell exhaustion. This could [660, 661], vaccine based on immunogenic complexes potentially be achieved by using RNA interference-based composed of HBsAg and antihuman HBsAg antibodies therapeutics that target expression of specific viral RNAs [662], or TLR-mediated or anti CD40-mediated stimu- [652]. lation of intrahepatic monocytes or dendritic cells [663, Viral messenger RNAs are translated in the cytoplasm to 664]. Improving HBV-specific T cell immunity by yield viral proteins. Once synthesized, the polymerase engineering HBV-specific T cells through the transfer of engages, an event that leads to recruitment of core protein HBV-specific T cell receptors (TCR) or HBV-specific dimers triggering encapsidation of the complex into the chimeric antigen receptors (CARs) represents another nucleocapsid. Three inhibitors that act at this stage in the novel approach [665, 666]. 123 Hepatol Int (2016) 10:1–98 79 Immunotherapeutic approaches: direct stimulation There is the need for novel therapies—antiviral agents of innate intrahepatic immunity with new targets in the HBV replication cycle combined with immunotherapies that can restore the host immune Therapeutic strategies aimed at increasing innate immunity response to HBV. exploit the antiviral efficacy of distinct cytokines (tumour The persistence of cccDNA in HBV-infected cells necrosis factor-a, IFN-a, IFN-c and interleukin-1b), mimic remains one of the main obstacles to complete eradication the activation of innate immunity during the early phase of of the virus during chronic infection. In that respect, a acute HBV infection and induce a correct maturation of the better understanding of the biochemical steps of cccDNA adaptive immunity [667]. Strategies include boosting biosynthesis and epigenetic control of cccDNA is needed. intrahepatic IFN- a levels by TCR-like antibodies conju- The characterization of the complex interaction between gated with IFN- a that specifically target HBV-infected viral and host cellular proteins and/or genomes represent hepatocytes [668], use of TLR7 agonists to induce IFN- a other research challenges that may pave way to identifi- production in pDCs (plasmacytoid dendritic cells) [669], cation of new treatment targets. stimulating NK and NKT cells by IL-12 and IL-18 [670, Further confirmatory studies need to be done on the use 671], and use of TLR8 agonists [672]. of potent NAs from the time of listing to provide a com- However, these new therapeutic approaches have mainly pletely HBIG-free oral prophylaxis regimen and thus fur- been tested in animal models and await lrarge-scale human ther improve the outcomes, tolerability and cost studies. A cure for chronic HBV infection requires agents effectiveness of liver transplantation for CHB. that can target different stages in the life cycle of the virus. Compliance with ethical standards However, this requirement must deal effectively with the cccDNA pool by either inhibiting the cccDNA complex Conflict of interest S. K. Sarin, M. Kumar, G. K. Lau, Z. Abbas, H. formation or destroying infected hepatocytes. The latter is L. Y. Chan, C. J. Chen, D. S. Chen, H. L. Chen, P. J. Chen, R. only achievable through immune-mediated mechanisms, a N. Chien, A. K. Dokmeci, Ed Gane, J. L. Hou, W. Jafri, J. Jia, J. H. Kim, C. L. Lai, H. C. Lee, S. G. Lim, C. J. Liu, S. Locarnini, M. Al fact that strongly suggests a combination therapy approach Mahtab, R. Mohamed, M. Omata, J. Park, T. Piratvisuth, B. for the future [657]. C. Sharma, J. Sollano, F. S. Wang, L. Wei, M. F. Yuen, S. S. Zheng, J. H. Kao declare that they have no conflict of interest. 4.2 Unresolved issues and unmet needs Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://crea The challenges in the management of hepatitis B are still tivecommons.org/licenses/by/4.0/), which permits unrestricted use, very daunting, and despite significant advances, cure from distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a HBV infection is a far cry. We need to improve our link to the Creative Commons license, and indicate if changes were understanding of the natural history of chronic HBV made. infection, including the role of serum HBsAg levels in the evaluation of the natural history. The role of noninvasive methods for the evaluation of References the severity of liver disease and for the follow-up of treated 1. 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