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Long-Term Changes in Hepatic Fibrosis following Hepatitis C Viral Clearance in Patients with and without HIV

Long-Term Changes in Hepatic Fibrosis following Hepatitis C Viral Clearance in Patients with and... Antiviral Therapy 2019; 24:451–457 (doi: 10.3851/IMP3327) Original article Long-term changes in hepatic fibrosis following hepatitis C viral clearance in patients with and without HIV 1 1 1 1 1 Julia B Balmaceda , Julia Aepfelbacher , Olivia Belliveau , Chloe S Chaudhury , Cheryl Chairez , 1 2 2 2 2 2 Mary McLaughlin , Rachel Silk , Chloe Gross , Sarah Kattakuzhy , Elana Rosenthal , Shyam Kottilil , 3 1 David E Kleiner , Colleen Hadigan * National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA Division of Clinical Care and Research, Institute of Human Virology, Department of Medicine, University of Maryland, Baltimore, MD, USA National Cancer Institute, NIH, Bethesda, MD, USA *Corresponding author e-mail: hadiganc@niaid.nih.gov Background: While acute changes in hepatic fibrosis are Results: Fibrosis progression occurred in 4% of subjects recognized shortly after achieving sustained virological while regression occurred in 7% and 89% were stable response (SVR) using direct-acting antiviral therapies, and did not differ by HIV coinfection. Fibrosis progression long-term outcomes for the growing population of suc- was associated with increased body mass index (BMI), cessfully treated patients with HCV remain uncertain. The hepatic steatosis and smoking pack-years. In a multivari- aim of this study is to characterize long-term changes in able logistic regression, HIV coinfection (P=0.009), lower fibrosis following SVR in patients with and without HIV steatosis score (P<0.05) and lower smoking pack-years and to identify potential factors associated with progres- (P=0.0007) were associated with a lower fibrosis score at sion or regression of fibrosis. last follow-up. Methods: We completed a prospective longitudinal study Conclusions: We identify potentially important relation- of 162 subjects with HCV (34% HIV-coinfected) with pre- ships between BMI, hepatic steatosis and smoking, and treatment fibrosis stage determined by liver biopsy and changes in hepatic fibrosis post-SVR in patients with and post-SVR transient elastography. Progression of fibrosis without HIV coinfection. Attention to modifiable risk fac- was defined as a two-stage or greater increase in fibrosis, tors such as body weight and smoking may reduce the risk while regression was defined as a two-stage or greater of liver disease progression in the growing population of decrease at last follow-up. The median duration of fol- successfully treated chronic HCV patients. low-up was 4.1 years. Introduction With the advent of highly effective direct-acting have demonstrated that while SVR is associated with antiviral therapy (DAA) for HCV infection, there a decreased risk of liver-related health complications has a been a dramatic increase in sustained virologi- such as hepatocellular carcinoma, the risk is not elimi- cal response (SVR) in patients with and without HIV. nated and remains present in patients with advanced SVR is associated with significant regression of hepatic fibrosis for at least 8–10 years [5,6]. Less is known fibrosis in monoinfected and coinfected (HIV –HCV) about the influence of HIV coinfection on long-term cohorts and fibrosis regression is linked with a reduc- outcomes and progression of liver disease after HCV tion of liver-related complications and mortality [1–4]. clearance, but previous research has linked HIV-spe- However, one cohort study of HCV-monoinfected cific factors to liver fibrosis progression due to long- patients treated with DAAs found progression of term exposure to antiretroviral therapy [7]. Because hepatic fibrosis in 17% of patients at 96 weeks despite liver fibrosis is a key predictor of adverse outcomes and achieving and maintaining SVR [3]. Furthermore, patient mortality, it is important to identify factors that long-term studies of mainly interferon-treated patients may lead to liver fibrosis progression in order to target ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 451 AVT-19-OA-4531_Balmaceda.indd 451 AVT-19-OA-4531_Balmaceda.indd 451 22/11/2019 13:44:17 22/11/2019 13:44:17 JB Balmaceda et al. patients that may require closer monitoring for these manufacturer programme recommendations; 36% of health complications. subjects had fibroscan completed with the XL probe and The aim of this study was to characterize regression and this did not differ by HIV coinfection (39% HCV-mono- progression of hepatic fibrosis in patients with chronic infected, 29% HIV-coinfected; P=0.2). Median kPa val- HCV following SVR and to identify potential factors asso- ues of ≤7 were scored as F0–F1, kPa >7 and ≤9 as F2, ciated with progression or regression of fibrosis. In addi- kPa >9 and ≤14 as F3, and kPa >14 as F4 [9]. Hepatic tion, we evaluated the potential role of HIV infection on steatosis grade 2 or greater was defined as a CAP score changes in fibrosis following HCV clearance. ≥311 dB/m [10]. For inclusion as valid determinations, Fibroscan data points were required to have at least 10 valid measurements and a minimum of 60% validity of Methods total measurements taken with a kPa IQR/median value Study population <30%. Progression of fibrosis was defined as a 2-stage Subjects participated in a prospective longitudinal study increase in fibrosis or greater from pre-treatment biopsy of long-term health outcomes of adults with viral hepa- to post-SVR transient elastography, while regression was titis (NCT01350648). Subjects were recruited from the defined as a 2-stage or greater decrease in fibrosis. Any local Maryland/Virginia/ Washington DC area. All sub- change in fibrosis less than a 2-stage change was consid- jects provided written informed consent and the proto- ered stable fibrosis. In order to account for the fact that col was approved by the National Institute of Allergy participants no longer had active HCV at follow-up and and Infectious Diseases Institutional Review Board. that non-HCV characteristics may influence transient For the purposes of the current study, a total of 162 elastography performance characteristics, a sensitivity subjects with a history of chronic HCV (n=55 with HIV analysis was performed using fibrosis cutoff values for coinfection) were identified who had pre-treatment liver transient elastography validated in patients with non- biopsy with fibrosis staging performed within 24 months alcoholic fatty liver disease (NAFLD). Median kPa val- of starting therapy, achieved SVR and had at least one ues of <7 were scored as F0–F1, kPa ≥7 and <8.7 as F2, follow-up visit with transient elastography. Three indi- kPa ≥8.7 and <10.3 as F3, and kPa ≥10.3 as F4 [11]. viduals had biopsies performed >24 months from start of therapy, however, these revealed clinical cirrhosis. Statistical analysis SVR was defined as undetectable HCV RNA 12 weeks All statistical analyses utilized laboratory and clinical after the end of treatment and maintained through fol- values obtained from the latest follow-up visit exclud- low-up. Subjects were excluded if they had a history of ing the pre-treatment fibrosis score. For the purpose of any hepatic malignancies or chronic hepatitis B. Partici- the pre- and post-HCV SVR analyses, pre-treatment pants were instructed to fast after midnight for annual baseline was defined as the fibrosis staging performed visits which included routine laboratory tests, HCV via liver biopsy preceding treatment. Post-SVR fibrosis RNA determinations and transient elastography. Study staging was based on transient elastography kPa values participants reported estimates of years smoking and at the latest follow-up visit. Data were analysed to deter- packs per day. Smoking pack-years was calculated by mine the possible factors associated with progression multiplying packs per day by the number of years smok- or regression of fibrosis post-SVR at last follow-up ing. Self-reported risk behaviours including alcohol con- and included age, transaminase levels, HIV coinfec- sumption and history of intravenous drug-use were also tion, body mass index (BMI), change in BMI, steatosis documented. Drinks per week was calculated using self- by CAP score, smoking pack years, estimated weekly reported drinking behaviour in the previous 12 months alcohol intake, CD4 T-cell count and diabetes. Statisti- (drinks/week based on frequency and number of alco- cal analysis was performed by t-tests and c likelihood holic drinks consumed). Diabetes was defined as having a ratio for group comparisons. All factors identified as medical diagnosis of diabetes and confirmed by either use significantly associated with regression/progression of of antidiabetic medication or haemoglobin A1c ≥6.5%. fibrosis were entered into a nominal logistic regression analysis of fibrosis score at last follow-up, which also Staging included baseline fibrosis score, age, HIV coinfection, Pre-treatment liver biopsies were staged using the duration of follow-up and alcohol intake. All analyses METAVIR system [8]. At annual follow-up visits, were completed using JMP statistical software (Version patients underwent transient elastography (Fibros- 13.0; SAS Institute Inc., Cary, NC, USA). can, Echosens, Paris, France) in order to evaluate liver stiffness (kPa) and steatosis (Controlled Attenuation Results Parameter [CAP]). Operators were trained and certi- fied by manufacturer representatives of Echosens. Use of Subjects had a mean age of 60 ±7 years at last follow-up, the medium (M) and extra-large (XL) probes followed were predominantly male (65%) and Black  (77%), 452 ©2019 International Medical Press AVT-19-OA-4531_Balmaceda.indd 452 AVT-19-OA-4531_Balmaceda.indd 452 22/11/2019 13:44:17 22/11/2019 13:44:17 Long-term change in fibrosis after HCV clearance with a mean duration of follow up of 4.1 ±1.7 years According to liver biopsy data at baseline, 57% (Table 1). Median treatment length was 12 weeks (IQR of subjects had a fibrosis score of F0–F1, whereas 9.5–16) and the HCV treatments resulting in SVR 26% had F3/F4 fibrosis and there was no difference included: 136 (84%) DAA only, 17 (10%) DAA plus between HCV-monoinfected and HIV-coinfected sub- ribavirin, 8 (5%) interferon and ribavirin and 1 (1%) jects (Table 2). With respect to steatosis grading, 10% interferon, ribavirin and DAA. The DAA treatment regi- had S2 or greater steatosis at baseline. At last follow- mens contained a wide spectrum of agents, including up using transient elastography, there was an overall asunaprevir, beclabuvir, daclatasvir, ledipasvir, sofos- reduction in those falling into the F3 and F4 category buvir and telaprevir. Approximately half (51%) of par- and an increase in those categorized with F0–1 and ticipants had chronic HCV infection for greater than F2 fibrosis (P<0.003 for pre- versus post-SVR fibro- 20 years and the majority had a history of intravenous sis). 45% of those with F3 or F4 at baseline had F2 or drug use (59%) based on self-reported risk behaviours. lower fibrosis at follow-up. The frequency of steatosis Most subjects had HCV genotype-1 A/B (96%) while as measured by CAP score at last follow-up increased only 4% had genotype-2 or 4. The mean BMI at follow- slightly from 10% to 12% for the entire cohort. The up was 28 ±6 kg/m . The monoinfected (HCV) group monoinfected group had an increase in the prevalence and coinfected (HIV–HCV) group were similar with of steatosis from 10% to 15%, whereas the HIV–HCV respect to age and demographic characteristics, how- group decreased in frequency of S2 steatosis at last fol- ever, the clinical characteristics varied slightly between low-up from 10% to 4%. the HCV and HIV–HCV groups. The HCV group had Next, we categorized subjects as stable, regressor or significantly higher mean BMI (P=0.03) and mean CAP progressor with respect to fibrosis. 89% of the cohort score (P=0.03) compared with the HIV–HCV group. had stable fibrosis, while 7% had regression and 4% The HIV–HCV group had slightly higher alanine had progression of fibrosis. There was no statistically aminotransferase (ALT) levels (P=0.03). 94% of the significant difference in the distribution of those who HIV–HCV subgroup were virally suppressed with an were stable, regressors or progressors between the HIV viral level <40 copies/ml at last follow-up and had HCV and HIV–HCV subgroups. HIV-coinfected sub- + 3 a mean CD4 T-cell count of 705 ±324 cell/mm . jects represented 34% of those with stable fibrosis, Table 1. Clinical characteristics at last follow-up Clinical characteristics Total (n=162) Monoinfected (HCV; n=107) Coinfected (HIV–HCV; n=55) Duration of follow-up, years 4.1 ±1.7 4.1 ±1.6 4.0 ±1.9 Age, years 60 ±7 60 ±7 60 ±8 2 a a BMI, kg/m 28 ±6 29 ±6 27 ±5 a a CAP, dB/m 247 ±59 254 ±58 232 ±59 Sex Male, n (%) 105 (65) 67 (63) 38 (69) Female, n (%) 57 (35) 40 (37) 17 (31) Race White, n (%) 36 (22) 22 (21) 14 (25) Black, n (%) 124 (77) 84 (79) 40 (73) Mixed race/other, n (%) 2 (1) 1 (1) 1 (2) Ethnicity: Hispanic or Latino, n (%) 11 (7) 4 (4) 7 (13) Risk Drinks per week 1 ±2 0 ±1 1 ±3 HCV infection >20 years, n (%) 81 (51) 50 (47) 31 (58) History of IVDU, n (%) 95 (59) 61 (58) 34 (62) Diabetes, n (%) 30 (19) 19 (18) 11 (20) Smoking pack years 10 ±10 11 ±11 9 ±9 Lab data AST, U/l 24 ±12 23 ±10 26 ±16 a a ALT, U/l 21 ±15 18 ±9 25 ±22 HIV viral load <40, n (%) 51 (94) + 3 CD4 T-cell count, cells/mm 705 ±324 Values are mean ±sd unless indicated otherwise. P<0.05 between HCV and HIV–HCV groups. ALT, alanine aminotransferase; AST, aspartate transaminase; BMI, body mass index; CAP, controlled attenuation parameter; IVDU, intravenous drug use. Antiviral Therapy 24.6 453 AVT-19-OA-4531_Balmaceda.indd 453 AVT-19-OA-4531_Balmaceda.indd 453 22/11/2019 13:44:17 22/11/2019 13:44:17 JB Balmaceda et al. Table 2. Baseline and follow-up fibrosis and steatosis grading Fibrosis scores Total (n=162) Monoinfected (HCV; n=107) Coinfected (HIV–HCV; n=55) Baseline liver biopsy F0–F1, n (%) 93 (57) 61 (57) 32 (58) F2, n (%) 27 (17) 17 (16) 10 (18) F3, n (%) 21 (13) 13 (12) 8 (15) F4, n (%) 21 (13) 16 (15) 5 (9) Steatosis ≥ Grade 2, n (%) 14 (10) 9 (10) 5 (10) Follow-up Fibroscan F0–F1, n (%) 104 (64) 69 (64) 35 (64) F2, n (%) 29 (18) 16 (15) 13 (24) F3, n (%) 16 (10) 10 (9) 6 (11) F4, n (%) 13 (8) 12 (11) 1 (2) a a Steatosis (CAP ≥311 dB/m), n (%) 17 (12) 15 (15) 2 (4) P<0.05 for HCV versus HIV–HCV comparison. Steatosis grade available n=146 at baseline and n=145 at follow-up. CAP, controlled attenuation parameter. 33% of regressors and 33% of progressors. There was In a sensitivity analysis using fibrosis stage cutoffs no difference in regression/progression groups with for NAFLD instead of hepatitis to categorize subjects respect to age, estimated weekly alcohol intake, dia- as progressors, regressors, or stable, BMI, CAP, and betes, aspartate transaminase, ALT, CD4 T-cell count smoking pack years remained significant factors asso- or change in BMI during follow-up (data not shown). ciated with fibrosis progression in univariate analyses However, BMI at last follow-up, CAP score and (Additional file 2). When using NAFLD cutoffs for fibro- smoking pack years differed significantly (Figure  1). sis stage in the multivariable regression, baseline fibro- Mean BMI of those with stable fibrosis or regression sis stage (P<0.0001) and smoking pack years (P=0.007) of fibrosis was significantly lower than the BMI of were the only significant factors associated with fibrosis. the progressor group (P=0.004, P=0.01, respectively). Similarly, mean CAP score among those with stable Discussion fibrosis was also significantly lower compared with the progressor group (P=0.005). In a sub-analysis Although chronic HCV is now a widely treatable excluding those without confirmed fasting prior to disease, questions remain regarding the long-term out- transient elastography measurements (n=14 excluded: comes for the many patients who achieve SVR follow- 1 progressor, 3 regressors and 10 with stable fibrosis), ing decades of infection. The majority of patients will difference in CAP score remained statistically signifi- be able to achieve and maintain SVR which has been cant. The progressor subgroup had a disproportion- shown to produce reductions in hepatic inflammation ately higher frequency of steatosis at last follow-up and subsequent regression of liver fibrosis in groups (50%) compared with the stable (9%) and regressor with and without HIV coinfection [1–3]. A few stud- (27%) subgroups (P=0.01). With regards to smoking, ies limited to individuals with advanced fibrosis (F3/F4 those with progression of fibrosis had significantly pre-treatment) using transient elastography demon- more pack years compared with those without pro- strated acute reductions in liver stiffness at the end of gression (P<0.0001). treatment or within 1 year post-SVR [12,13]. Further, In order to identify the key factors associated with Lledó et al. [14], showed that while there was no sig- fibrosis stage at last follow-up we performed a regres- nificant effect of HIV coinfection on change in elastog- sion analysis which included age, HIV coinfection, raphy at SVR, 40% of patients experienced a reduction BMI, CAP score, smoking pack years, weekly alcohol greater than 30% in liver stiffness (kPa) 12 weeks after intake, baseline fibrosis score, and duration of follow- treatment. However, few studies have characterized the up. We found that baseline fibrosis score (P<0.0001), factors associated with regression or progression of HIV coinfection (P=0.009), lower CAP score (P<0.05) hepatic fibrosis with up to 4 years of follow-up after and lower smoking pack-years (P=0.0007) were HCV clearance with contemporary therapies. The pre- associated with lower fibrosis score at last follow-up sent study prospectively examined factors associated (Additional file 1). When excluding subjects that were with regression and progression of hepatic fibrosis after not confirmed to have fasted for transient elastography, successful treatment of HCV in patients with and with- HIV (P=0.008) and smoking pack-years (P=0.003) and out HIV. Increased BMI, hepatic steatosis and smoking CAP (P=0.04) remained significant. were identified as significant co-factors in the subset of 454 ©2019 International Medical Press AVT-19-OA-4531_Balmaceda.indd 454 AVT-19-OA-4531_Balmaceda.indd 454 22/11/2019 13:44:17 22/11/2019 13:44:17 Long-term change in fibrosis after HCV clearance Figure 1. Clinical characteristics associated with changes in with chronic HCV, higher consumption of tobacco hepatic fibrosis after HCV clearance measured by smoking pack-years was related to greater severity of fibrosis [15]. Further, Xiong  et al. [16] found that a cigarette smoking history of 10 pack years or P=0.004 greater was associated with advanced fibrosis in chronic P=0.9 P=0.01 hepatitis B (CHB) infection and impaired fibrosis regres- sion with CHB treatment. The present study found that the relationship between smoking and hepatic fibrosis was also significant after HCV clearance. Studies suggest 20 that chemicals in cigarette smoke may have fibrogenic effects, specifically nicotine, which may affect hepatic cells via nicotinic acetylcholine receptors. In non-alco- holic steatohepatitis, nicotine has been shown to induce Stable Regressor Progressor fibrogenic pathways and upregulate collagen1-a 2 and the pro-fibrogenic cytokine transforming growth factor P=0.005 beta 1 (TGF-b1)  [17]. Most studies have not analysed P=0.3 P=0.1 other methods of nicotine and tobacco use, however, research trends are shifting to analysing the effects of e-cigarette use on the liver in animal models as this method of nicotine delivery grows in popularity. This novel observation linking smoking to fibrosis progres- sion after HCV clearance deserves further investigation and provides a potential modifiable target to optimize Stable Regressor Progressor liver health in the growing number of patients who have been successfully treated. In the present study, subjects categorized as progres- P<0.0001 sors had increased BMI compared with those who did P=0.2 P<0.0001 not progress in univariate analysis. Previous studies have identified obesity as a factor associated with rapid progression of liver disease in patients with active HCV infection [18]. Ortiz et al. [18] describes a BMI ≥25 kg/ m as the cutoff for risk of rapid hepatic fibrosis progres- 5 sion in a study of 114 patients with chronic HCV with- out SVR. Interestingly, BMI did not remain a significant Stable Regressor Progressor factor in multivariate analysis once hepatic steatosis was also included, indicating the potential mechanism by which increased adiposity promotes hepatic fibrosis. Participants categorized by change in fibrosis at last follow-up as stable We observed that the presence of hepatic steatosis (n=144), regressor (n=12) and progressor (n=6), comparing mean (A) body mass following viral clearance was an important indicator index (BMI), (B) controlled attenuation parameter (CAP) and (C) smoking pack- years between each group. of progression of fibrosis in multivariate analysis. One study by Noureddin et al. [19] evaluated a cohort of 101 subjects without HCV genotype-3 approximately patients who had progression of fibrosis despite HCV 1 year after SVR and identified a similar finding. The clearance. Somewhat unexpectedly, HIV coinfection study found that after achieving SVR, patients with ste- was not associated with worsening of fibrosis. These atosis (≥248 dB/m) continued to have clinically signifi- observations may be useful in determining how to cant liver fibrosis (defined as ≥7 kPa) while those with- monitor and counsel patients following HCV clearance. out steatosis did not have fibrosis [19]. While steatosis Smoking has been suggested as a cofactor for progres- has classically been associated with genotype-3, both sion of fibrosis in various organs including lungs, kidneys Noureddin et al. [19] and the present study did not and the liver in a variety of diseases including NAFLD, include patients with genotype-3. We observed a posi- primary biliary cholangitis, and HCV, possibly through tive relationship between BMI and steatosis measured increases in oxidative stress and inflammation. For by CAP scores. Interestingly, the present study did not example, Pessione et al. [15] found a strong independent find a relationship between CAP score and self-reported relationship between hepatic fibrosis score and tobacco alcohol use, although it is known that alcohol increases consumption. In this cross-sectional study of patients steatosis and also causes oxidative stress, inflammation Antiviral Therapy 24.6 455 AVT-19-OA-4531_Balmaceda.indd 455 AVT-19-OA-4531_Balmaceda.indd 455 22/11/2019 13:44:18 22/11/2019 13:44:18 CAP, dB/m Smoking pack-years BMI, kg/m JB Balmaceda et al. and damage to the liver [20]. Furthermore, there was no reports and the current understanding of liver disease. significant relationship between alcohol intake and pro- In addition, since participants, by definition, no longer gression or regression of fibrosis score at last follow- have HCV at follow-up, we repeated analyses using up, however, significant alcohol intake was not highly transient elastography fibrosis cutoffs established for prevalent in this cohort. NAFLD and all the key findings remained significant. Unexpectedly, HIV was associated with having a This study should be replicated in larger cohorts to fur- lower fibrosis score at last follow-up in multivariate ther validate these observations. analysis which accounted for fibrosis grade at baseline. In conclusion, we show a significant relationship This may be due to the fact that the coinfected group between BMI, hepatic steatosis, and smoking pack years as a whole was less enriched with co-factors associated and progression of hepatic fibrosis post-SVR in hepatitis with fibrosis progression (that is, BMI and CAP scores). C patients both with and without HIV. The influence of In a study of 214 patients who achieved SVR follow- BMI was largely attributable to the effect of adiposity on ing DAA therapy for HCV (60% coinfected with HIV), the increased risk of hepatic steatosis. The relationship Malin et al. [21] showed no difference in short-term between HIV coinfection and fibrosis change post-SVR changes in transient elastography between HCV-mono- should be further investigated. Our observations suggest infected and HIV-coinfected participants at a median that counselling and attention to modifiable risk factors follow-up of 12 weeks. Although HIV has been iden- such as maintaining a healthy body weight, avoidance of tified as a cofactor associated with rapid progression possible hepatoxic effects of tobacco and nicotine may of fibrosis in active HCV infection [22], observations benefit patients treated for chronic HCV and reduce the by Malin et al. [21], Lledó et al. [14], and the current risk of liver disease progression. study suggest that HIV may have less of an impact on fibrosis in the context of both acute and long-term viral Acknowledgements clearance. Further studies with a larger sample of HIV- infected patients are needed to understand the impact This work was support by the Intramural Research of HIV on the long-term regression or progression of program of the National Institute of Allergy and Infec- hepatic fibrosis following HCV viral therapy. tious Diseases and the National Cancer Institute. The present study had several limitations. It is Trial Registration Number: NCT01350648. important to recognize that while histopathologi- cal determination of severity of fibrosis was obtained Disclosure statement prior to HCV therapy, less invasive transient elastogra- phy was employed for longitudinal follow-up staging C Gross holds stock in Merck, Pfizer and Johnson & of fibrosis. Transient elastography, however, has been Johnson. S Kottilil has received research grants paid to well-established and validated to METAVIR staging as the university from Merck Inc. and Gilead Sciences Inc. a non-invasive method for evaluating liver fibrosis in and participated in advisory boards for Merck Inc. and chronic HCV and in HIV [23,24] and has been used Gilead Sciences Inc. The remaining authors declare no in other cohort studies to track changes in fibrosis competing interests. which was staged initially by liver biopsy pre-therapy [4]. Furthermore, we used conservative cutoffs for both Additional files fibrosis and steatosis as well as stringent definition of a 2-stage change in fibrosis for progression and regres- Additional file 1: A table showing nominal logistic sion to mitigate the potential variability in the continu- regression of fibrosis stage at last follow-up can be ous measurement scale of transient elastography. In found at https://www.intmedpress.com/uploads/ the current study only one quarter of the cohort had documents/4531_Balmaceda_Addfile1.pdf advanced fibrosis (F3–F4) pre-treatment and 29% of those showed regression of fibrosis; this may have lim- Additional file 2: A figure showing participants ited the ability to identify factors associated with fibro- categorized by change in fibrosis based on NAFLD sis regression. While research suggest that biopsy length established cutoffs for fibrosis stage at last follow-up and number of portal tracts are important to optimize can be found at https://www.intmedpress.com/uploads/ accuracy of histopathology determinations [25], lim- documents/4531_Balmaceda_Addfile2.pdf ited data on these characteristics prevented application of such criteria in the current study. Another limita- References tion in the study was the relatively small number of 1. ANRS CO13 HEPAVIH Cohort. Regression of liver stiffness subjects in the progressor group. Nonetheless, the risk after sustained hepatitis C virus (HCV) virological responses factors identified were statistically robust in multivari- among HIV/HCV-coinfected patients. 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Sustained virological hepatitis: the smaller the sample, the milder the disease. response by direct antiviral agents in HCV leads to an early J Hepatol 2003; 39:239–244. and significant improvement of liver fibrosis. Antivir Ther 2018; 23:129–138. 13. Giannini EG, Crespi M, Demarzo M, et al. Improvement in hepatitis C virus patients with advanced, compensated liver disease after sustained virological response to direct acting antivirals. Eur J Clin Invest 2019; 49:e13056. Accepted 15 July 2019; published online 30 July 2019 Antiviral Therapy 24.6 457 AVT-19-OA-4531_Balmaceda.indd 457 AVT-19-OA-4531_Balmaceda.indd 457 22/11/2019 13:44:18 22/11/2019 13:44:18 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antiviral Therapy SAGE

Long-Term Changes in Hepatic Fibrosis following Hepatitis C Viral Clearance in Patients with and without HIV

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SAGE
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© 2019 SAGE Publications
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1359-6535
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2040-2058
DOI
10.3851/imp3327
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Antiviral Therapy 2019; 24:451–457 (doi: 10.3851/IMP3327) Original article Long-term changes in hepatic fibrosis following hepatitis C viral clearance in patients with and without HIV 1 1 1 1 1 Julia B Balmaceda , Julia Aepfelbacher , Olivia Belliveau , Chloe S Chaudhury , Cheryl Chairez , 1 2 2 2 2 2 Mary McLaughlin , Rachel Silk , Chloe Gross , Sarah Kattakuzhy , Elana Rosenthal , Shyam Kottilil , 3 1 David E Kleiner , Colleen Hadigan * National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA Division of Clinical Care and Research, Institute of Human Virology, Department of Medicine, University of Maryland, Baltimore, MD, USA National Cancer Institute, NIH, Bethesda, MD, USA *Corresponding author e-mail: hadiganc@niaid.nih.gov Background: While acute changes in hepatic fibrosis are Results: Fibrosis progression occurred in 4% of subjects recognized shortly after achieving sustained virological while regression occurred in 7% and 89% were stable response (SVR) using direct-acting antiviral therapies, and did not differ by HIV coinfection. Fibrosis progression long-term outcomes for the growing population of suc- was associated with increased body mass index (BMI), cessfully treated patients with HCV remain uncertain. The hepatic steatosis and smoking pack-years. In a multivari- aim of this study is to characterize long-term changes in able logistic regression, HIV coinfection (P=0.009), lower fibrosis following SVR in patients with and without HIV steatosis score (P<0.05) and lower smoking pack-years and to identify potential factors associated with progres- (P=0.0007) were associated with a lower fibrosis score at sion or regression of fibrosis. last follow-up. Methods: We completed a prospective longitudinal study Conclusions: We identify potentially important relation- of 162 subjects with HCV (34% HIV-coinfected) with pre- ships between BMI, hepatic steatosis and smoking, and treatment fibrosis stage determined by liver biopsy and changes in hepatic fibrosis post-SVR in patients with and post-SVR transient elastography. Progression of fibrosis without HIV coinfection. Attention to modifiable risk fac- was defined as a two-stage or greater increase in fibrosis, tors such as body weight and smoking may reduce the risk while regression was defined as a two-stage or greater of liver disease progression in the growing population of decrease at last follow-up. The median duration of fol- successfully treated chronic HCV patients. low-up was 4.1 years. Introduction With the advent of highly effective direct-acting have demonstrated that while SVR is associated with antiviral therapy (DAA) for HCV infection, there a decreased risk of liver-related health complications has a been a dramatic increase in sustained virologi- such as hepatocellular carcinoma, the risk is not elimi- cal response (SVR) in patients with and without HIV. nated and remains present in patients with advanced SVR is associated with significant regression of hepatic fibrosis for at least 8–10 years [5,6]. Less is known fibrosis in monoinfected and coinfected (HIV –HCV) about the influence of HIV coinfection on long-term cohorts and fibrosis regression is linked with a reduc- outcomes and progression of liver disease after HCV tion of liver-related complications and mortality [1–4]. clearance, but previous research has linked HIV-spe- However, one cohort study of HCV-monoinfected cific factors to liver fibrosis progression due to long- patients treated with DAAs found progression of term exposure to antiretroviral therapy [7]. Because hepatic fibrosis in 17% of patients at 96 weeks despite liver fibrosis is a key predictor of adverse outcomes and achieving and maintaining SVR [3]. Furthermore, patient mortality, it is important to identify factors that long-term studies of mainly interferon-treated patients may lead to liver fibrosis progression in order to target ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 451 AVT-19-OA-4531_Balmaceda.indd 451 AVT-19-OA-4531_Balmaceda.indd 451 22/11/2019 13:44:17 22/11/2019 13:44:17 JB Balmaceda et al. patients that may require closer monitoring for these manufacturer programme recommendations; 36% of health complications. subjects had fibroscan completed with the XL probe and The aim of this study was to characterize regression and this did not differ by HIV coinfection (39% HCV-mono- progression of hepatic fibrosis in patients with chronic infected, 29% HIV-coinfected; P=0.2). Median kPa val- HCV following SVR and to identify potential factors asso- ues of ≤7 were scored as F0–F1, kPa >7 and ≤9 as F2, ciated with progression or regression of fibrosis. In addi- kPa >9 and ≤14 as F3, and kPa >14 as F4 [9]. Hepatic tion, we evaluated the potential role of HIV infection on steatosis grade 2 or greater was defined as a CAP score changes in fibrosis following HCV clearance. ≥311 dB/m [10]. For inclusion as valid determinations, Fibroscan data points were required to have at least 10 valid measurements and a minimum of 60% validity of Methods total measurements taken with a kPa IQR/median value Study population <30%. Progression of fibrosis was defined as a 2-stage Subjects participated in a prospective longitudinal study increase in fibrosis or greater from pre-treatment biopsy of long-term health outcomes of adults with viral hepa- to post-SVR transient elastography, while regression was titis (NCT01350648). Subjects were recruited from the defined as a 2-stage or greater decrease in fibrosis. Any local Maryland/Virginia/ Washington DC area. All sub- change in fibrosis less than a 2-stage change was consid- jects provided written informed consent and the proto- ered stable fibrosis. In order to account for the fact that col was approved by the National Institute of Allergy participants no longer had active HCV at follow-up and and Infectious Diseases Institutional Review Board. that non-HCV characteristics may influence transient For the purposes of the current study, a total of 162 elastography performance characteristics, a sensitivity subjects with a history of chronic HCV (n=55 with HIV analysis was performed using fibrosis cutoff values for coinfection) were identified who had pre-treatment liver transient elastography validated in patients with non- biopsy with fibrosis staging performed within 24 months alcoholic fatty liver disease (NAFLD). Median kPa val- of starting therapy, achieved SVR and had at least one ues of <7 were scored as F0–F1, kPa ≥7 and <8.7 as F2, follow-up visit with transient elastography. Three indi- kPa ≥8.7 and <10.3 as F3, and kPa ≥10.3 as F4 [11]. viduals had biopsies performed >24 months from start of therapy, however, these revealed clinical cirrhosis. Statistical analysis SVR was defined as undetectable HCV RNA 12 weeks All statistical analyses utilized laboratory and clinical after the end of treatment and maintained through fol- values obtained from the latest follow-up visit exclud- low-up. Subjects were excluded if they had a history of ing the pre-treatment fibrosis score. For the purpose of any hepatic malignancies or chronic hepatitis B. Partici- the pre- and post-HCV SVR analyses, pre-treatment pants were instructed to fast after midnight for annual baseline was defined as the fibrosis staging performed visits which included routine laboratory tests, HCV via liver biopsy preceding treatment. Post-SVR fibrosis RNA determinations and transient elastography. Study staging was based on transient elastography kPa values participants reported estimates of years smoking and at the latest follow-up visit. Data were analysed to deter- packs per day. Smoking pack-years was calculated by mine the possible factors associated with progression multiplying packs per day by the number of years smok- or regression of fibrosis post-SVR at last follow-up ing. Self-reported risk behaviours including alcohol con- and included age, transaminase levels, HIV coinfec- sumption and history of intravenous drug-use were also tion, body mass index (BMI), change in BMI, steatosis documented. Drinks per week was calculated using self- by CAP score, smoking pack years, estimated weekly reported drinking behaviour in the previous 12 months alcohol intake, CD4 T-cell count and diabetes. Statisti- (drinks/week based on frequency and number of alco- cal analysis was performed by t-tests and c likelihood holic drinks consumed). Diabetes was defined as having a ratio for group comparisons. All factors identified as medical diagnosis of diabetes and confirmed by either use significantly associated with regression/progression of of antidiabetic medication or haemoglobin A1c ≥6.5%. fibrosis were entered into a nominal logistic regression analysis of fibrosis score at last follow-up, which also Staging included baseline fibrosis score, age, HIV coinfection, Pre-treatment liver biopsies were staged using the duration of follow-up and alcohol intake. All analyses METAVIR system [8]. At annual follow-up visits, were completed using JMP statistical software (Version patients underwent transient elastography (Fibros- 13.0; SAS Institute Inc., Cary, NC, USA). can, Echosens, Paris, France) in order to evaluate liver stiffness (kPa) and steatosis (Controlled Attenuation Results Parameter [CAP]). Operators were trained and certi- fied by manufacturer representatives of Echosens. Use of Subjects had a mean age of 60 ±7 years at last follow-up, the medium (M) and extra-large (XL) probes followed were predominantly male (65%) and Black  (77%), 452 ©2019 International Medical Press AVT-19-OA-4531_Balmaceda.indd 452 AVT-19-OA-4531_Balmaceda.indd 452 22/11/2019 13:44:17 22/11/2019 13:44:17 Long-term change in fibrosis after HCV clearance with a mean duration of follow up of 4.1 ±1.7 years According to liver biopsy data at baseline, 57% (Table 1). Median treatment length was 12 weeks (IQR of subjects had a fibrosis score of F0–F1, whereas 9.5–16) and the HCV treatments resulting in SVR 26% had F3/F4 fibrosis and there was no difference included: 136 (84%) DAA only, 17 (10%) DAA plus between HCV-monoinfected and HIV-coinfected sub- ribavirin, 8 (5%) interferon and ribavirin and 1 (1%) jects (Table 2). With respect to steatosis grading, 10% interferon, ribavirin and DAA. The DAA treatment regi- had S2 or greater steatosis at baseline. At last follow- mens contained a wide spectrum of agents, including up using transient elastography, there was an overall asunaprevir, beclabuvir, daclatasvir, ledipasvir, sofos- reduction in those falling into the F3 and F4 category buvir and telaprevir. Approximately half (51%) of par- and an increase in those categorized with F0–1 and ticipants had chronic HCV infection for greater than F2 fibrosis (P<0.003 for pre- versus post-SVR fibro- 20 years and the majority had a history of intravenous sis). 45% of those with F3 or F4 at baseline had F2 or drug use (59%) based on self-reported risk behaviours. lower fibrosis at follow-up. The frequency of steatosis Most subjects had HCV genotype-1 A/B (96%) while as measured by CAP score at last follow-up increased only 4% had genotype-2 or 4. The mean BMI at follow- slightly from 10% to 12% for the entire cohort. The up was 28 ±6 kg/m . The monoinfected (HCV) group monoinfected group had an increase in the prevalence and coinfected (HIV–HCV) group were similar with of steatosis from 10% to 15%, whereas the HIV–HCV respect to age and demographic characteristics, how- group decreased in frequency of S2 steatosis at last fol- ever, the clinical characteristics varied slightly between low-up from 10% to 4%. the HCV and HIV–HCV groups. The HCV group had Next, we categorized subjects as stable, regressor or significantly higher mean BMI (P=0.03) and mean CAP progressor with respect to fibrosis. 89% of the cohort score (P=0.03) compared with the HIV–HCV group. had stable fibrosis, while 7% had regression and 4% The HIV–HCV group had slightly higher alanine had progression of fibrosis. There was no statistically aminotransferase (ALT) levels (P=0.03). 94% of the significant difference in the distribution of those who HIV–HCV subgroup were virally suppressed with an were stable, regressors or progressors between the HIV viral level <40 copies/ml at last follow-up and had HCV and HIV–HCV subgroups. HIV-coinfected sub- + 3 a mean CD4 T-cell count of 705 ±324 cell/mm . jects represented 34% of those with stable fibrosis, Table 1. Clinical characteristics at last follow-up Clinical characteristics Total (n=162) Monoinfected (HCV; n=107) Coinfected (HIV–HCV; n=55) Duration of follow-up, years 4.1 ±1.7 4.1 ±1.6 4.0 ±1.9 Age, years 60 ±7 60 ±7 60 ±8 2 a a BMI, kg/m 28 ±6 29 ±6 27 ±5 a a CAP, dB/m 247 ±59 254 ±58 232 ±59 Sex Male, n (%) 105 (65) 67 (63) 38 (69) Female, n (%) 57 (35) 40 (37) 17 (31) Race White, n (%) 36 (22) 22 (21) 14 (25) Black, n (%) 124 (77) 84 (79) 40 (73) Mixed race/other, n (%) 2 (1) 1 (1) 1 (2) Ethnicity: Hispanic or Latino, n (%) 11 (7) 4 (4) 7 (13) Risk Drinks per week 1 ±2 0 ±1 1 ±3 HCV infection >20 years, n (%) 81 (51) 50 (47) 31 (58) History of IVDU, n (%) 95 (59) 61 (58) 34 (62) Diabetes, n (%) 30 (19) 19 (18) 11 (20) Smoking pack years 10 ±10 11 ±11 9 ±9 Lab data AST, U/l 24 ±12 23 ±10 26 ±16 a a ALT, U/l 21 ±15 18 ±9 25 ±22 HIV viral load <40, n (%) 51 (94) + 3 CD4 T-cell count, cells/mm 705 ±324 Values are mean ±sd unless indicated otherwise. P<0.05 between HCV and HIV–HCV groups. ALT, alanine aminotransferase; AST, aspartate transaminase; BMI, body mass index; CAP, controlled attenuation parameter; IVDU, intravenous drug use. Antiviral Therapy 24.6 453 AVT-19-OA-4531_Balmaceda.indd 453 AVT-19-OA-4531_Balmaceda.indd 453 22/11/2019 13:44:17 22/11/2019 13:44:17 JB Balmaceda et al. Table 2. Baseline and follow-up fibrosis and steatosis grading Fibrosis scores Total (n=162) Monoinfected (HCV; n=107) Coinfected (HIV–HCV; n=55) Baseline liver biopsy F0–F1, n (%) 93 (57) 61 (57) 32 (58) F2, n (%) 27 (17) 17 (16) 10 (18) F3, n (%) 21 (13) 13 (12) 8 (15) F4, n (%) 21 (13) 16 (15) 5 (9) Steatosis ≥ Grade 2, n (%) 14 (10) 9 (10) 5 (10) Follow-up Fibroscan F0–F1, n (%) 104 (64) 69 (64) 35 (64) F2, n (%) 29 (18) 16 (15) 13 (24) F3, n (%) 16 (10) 10 (9) 6 (11) F4, n (%) 13 (8) 12 (11) 1 (2) a a Steatosis (CAP ≥311 dB/m), n (%) 17 (12) 15 (15) 2 (4) P<0.05 for HCV versus HIV–HCV comparison. Steatosis grade available n=146 at baseline and n=145 at follow-up. CAP, controlled attenuation parameter. 33% of regressors and 33% of progressors. There was In a sensitivity analysis using fibrosis stage cutoffs no difference in regression/progression groups with for NAFLD instead of hepatitis to categorize subjects respect to age, estimated weekly alcohol intake, dia- as progressors, regressors, or stable, BMI, CAP, and betes, aspartate transaminase, ALT, CD4 T-cell count smoking pack years remained significant factors asso- or change in BMI during follow-up (data not shown). ciated with fibrosis progression in univariate analyses However, BMI at last follow-up, CAP score and (Additional file 2). When using NAFLD cutoffs for fibro- smoking pack years differed significantly (Figure  1). sis stage in the multivariable regression, baseline fibro- Mean BMI of those with stable fibrosis or regression sis stage (P<0.0001) and smoking pack years (P=0.007) of fibrosis was significantly lower than the BMI of were the only significant factors associated with fibrosis. the progressor group (P=0.004, P=0.01, respectively). Similarly, mean CAP score among those with stable Discussion fibrosis was also significantly lower compared with the progressor group (P=0.005). In a sub-analysis Although chronic HCV is now a widely treatable excluding those without confirmed fasting prior to disease, questions remain regarding the long-term out- transient elastography measurements (n=14 excluded: comes for the many patients who achieve SVR follow- 1 progressor, 3 regressors and 10 with stable fibrosis), ing decades of infection. The majority of patients will difference in CAP score remained statistically signifi- be able to achieve and maintain SVR which has been cant. The progressor subgroup had a disproportion- shown to produce reductions in hepatic inflammation ately higher frequency of steatosis at last follow-up and subsequent regression of liver fibrosis in groups (50%) compared with the stable (9%) and regressor with and without HIV coinfection [1–3]. A few stud- (27%) subgroups (P=0.01). With regards to smoking, ies limited to individuals with advanced fibrosis (F3/F4 those with progression of fibrosis had significantly pre-treatment) using transient elastography demon- more pack years compared with those without pro- strated acute reductions in liver stiffness at the end of gression (P<0.0001). treatment or within 1 year post-SVR [12,13]. Further, In order to identify the key factors associated with Lledó et al. [14], showed that while there was no sig- fibrosis stage at last follow-up we performed a regres- nificant effect of HIV coinfection on change in elastog- sion analysis which included age, HIV coinfection, raphy at SVR, 40% of patients experienced a reduction BMI, CAP score, smoking pack years, weekly alcohol greater than 30% in liver stiffness (kPa) 12 weeks after intake, baseline fibrosis score, and duration of follow- treatment. However, few studies have characterized the up. We found that baseline fibrosis score (P<0.0001), factors associated with regression or progression of HIV coinfection (P=0.009), lower CAP score (P<0.05) hepatic fibrosis with up to 4 years of follow-up after and lower smoking pack-years (P=0.0007) were HCV clearance with contemporary therapies. The pre- associated with lower fibrosis score at last follow-up sent study prospectively examined factors associated (Additional file 1). When excluding subjects that were with regression and progression of hepatic fibrosis after not confirmed to have fasted for transient elastography, successful treatment of HCV in patients with and with- HIV (P=0.008) and smoking pack-years (P=0.003) and out HIV. Increased BMI, hepatic steatosis and smoking CAP (P=0.04) remained significant. were identified as significant co-factors in the subset of 454 ©2019 International Medical Press AVT-19-OA-4531_Balmaceda.indd 454 AVT-19-OA-4531_Balmaceda.indd 454 22/11/2019 13:44:17 22/11/2019 13:44:17 Long-term change in fibrosis after HCV clearance Figure 1. Clinical characteristics associated with changes in with chronic HCV, higher consumption of tobacco hepatic fibrosis after HCV clearance measured by smoking pack-years was related to greater severity of fibrosis [15]. Further, Xiong  et al. [16] found that a cigarette smoking history of 10 pack years or P=0.004 greater was associated with advanced fibrosis in chronic P=0.9 P=0.01 hepatitis B (CHB) infection and impaired fibrosis regres- sion with CHB treatment. The present study found that the relationship between smoking and hepatic fibrosis was also significant after HCV clearance. Studies suggest 20 that chemicals in cigarette smoke may have fibrogenic effects, specifically nicotine, which may affect hepatic cells via nicotinic acetylcholine receptors. In non-alco- holic steatohepatitis, nicotine has been shown to induce Stable Regressor Progressor fibrogenic pathways and upregulate collagen1-a 2 and the pro-fibrogenic cytokine transforming growth factor P=0.005 beta 1 (TGF-b1)  [17]. Most studies have not analysed P=0.3 P=0.1 other methods of nicotine and tobacco use, however, research trends are shifting to analysing the effects of e-cigarette use on the liver in animal models as this method of nicotine delivery grows in popularity. This novel observation linking smoking to fibrosis progres- sion after HCV clearance deserves further investigation and provides a potential modifiable target to optimize Stable Regressor Progressor liver health in the growing number of patients who have been successfully treated. In the present study, subjects categorized as progres- P<0.0001 sors had increased BMI compared with those who did P=0.2 P<0.0001 not progress in univariate analysis. Previous studies have identified obesity as a factor associated with rapid progression of liver disease in patients with active HCV infection [18]. Ortiz et al. [18] describes a BMI ≥25 kg/ m as the cutoff for risk of rapid hepatic fibrosis progres- 5 sion in a study of 114 patients with chronic HCV with- out SVR. Interestingly, BMI did not remain a significant Stable Regressor Progressor factor in multivariate analysis once hepatic steatosis was also included, indicating the potential mechanism by which increased adiposity promotes hepatic fibrosis. Participants categorized by change in fibrosis at last follow-up as stable We observed that the presence of hepatic steatosis (n=144), regressor (n=12) and progressor (n=6), comparing mean (A) body mass following viral clearance was an important indicator index (BMI), (B) controlled attenuation parameter (CAP) and (C) smoking pack- years between each group. of progression of fibrosis in multivariate analysis. One study by Noureddin et al. [19] evaluated a cohort of 101 subjects without HCV genotype-3 approximately patients who had progression of fibrosis despite HCV 1 year after SVR and identified a similar finding. The clearance. Somewhat unexpectedly, HIV coinfection study found that after achieving SVR, patients with ste- was not associated with worsening of fibrosis. These atosis (≥248 dB/m) continued to have clinically signifi- observations may be useful in determining how to cant liver fibrosis (defined as ≥7 kPa) while those with- monitor and counsel patients following HCV clearance. out steatosis did not have fibrosis [19]. While steatosis Smoking has been suggested as a cofactor for progres- has classically been associated with genotype-3, both sion of fibrosis in various organs including lungs, kidneys Noureddin et al. [19] and the present study did not and the liver in a variety of diseases including NAFLD, include patients with genotype-3. We observed a posi- primary biliary cholangitis, and HCV, possibly through tive relationship between BMI and steatosis measured increases in oxidative stress and inflammation. For by CAP scores. Interestingly, the present study did not example, Pessione et al. [15] found a strong independent find a relationship between CAP score and self-reported relationship between hepatic fibrosis score and tobacco alcohol use, although it is known that alcohol increases consumption. In this cross-sectional study of patients steatosis and also causes oxidative stress, inflammation Antiviral Therapy 24.6 455 AVT-19-OA-4531_Balmaceda.indd 455 AVT-19-OA-4531_Balmaceda.indd 455 22/11/2019 13:44:18 22/11/2019 13:44:18 CAP, dB/m Smoking pack-years BMI, kg/m JB Balmaceda et al. and damage to the liver [20]. Furthermore, there was no reports and the current understanding of liver disease. significant relationship between alcohol intake and pro- In addition, since participants, by definition, no longer gression or regression of fibrosis score at last follow- have HCV at follow-up, we repeated analyses using up, however, significant alcohol intake was not highly transient elastography fibrosis cutoffs established for prevalent in this cohort. NAFLD and all the key findings remained significant. Unexpectedly, HIV was associated with having a This study should be replicated in larger cohorts to fur- lower fibrosis score at last follow-up in multivariate ther validate these observations. analysis which accounted for fibrosis grade at baseline. In conclusion, we show a significant relationship This may be due to the fact that the coinfected group between BMI, hepatic steatosis, and smoking pack years as a whole was less enriched with co-factors associated and progression of hepatic fibrosis post-SVR in hepatitis with fibrosis progression (that is, BMI and CAP scores). C patients both with and without HIV. The influence of In a study of 214 patients who achieved SVR follow- BMI was largely attributable to the effect of adiposity on ing DAA therapy for HCV (60% coinfected with HIV), the increased risk of hepatic steatosis. The relationship Malin et al. [21] showed no difference in short-term between HIV coinfection and fibrosis change post-SVR changes in transient elastography between HCV-mono- should be further investigated. Our observations suggest infected and HIV-coinfected participants at a median that counselling and attention to modifiable risk factors follow-up of 12 weeks. Although HIV has been iden- such as maintaining a healthy body weight, avoidance of tified as a cofactor associated with rapid progression possible hepatoxic effects of tobacco and nicotine may of fibrosis in active HCV infection [22], observations benefit patients treated for chronic HCV and reduce the by Malin et al. [21], Lledó et al. [14], and the current risk of liver disease progression. study suggest that HIV may have less of an impact on fibrosis in the context of both acute and long-term viral Acknowledgements clearance. Further studies with a larger sample of HIV- infected patients are needed to understand the impact This work was support by the Intramural Research of HIV on the long-term regression or progression of program of the National Institute of Allergy and Infec- hepatic fibrosis following HCV viral therapy. tious Diseases and the National Cancer Institute. The present study had several limitations. It is Trial Registration Number: NCT01350648. important to recognize that while histopathologi- cal determination of severity of fibrosis was obtained Disclosure statement prior to HCV therapy, less invasive transient elastogra- phy was employed for longitudinal follow-up staging C Gross holds stock in Merck, Pfizer and Johnson & of fibrosis. Transient elastography, however, has been Johnson. S Kottilil has received research grants paid to well-established and validated to METAVIR staging as the university from Merck Inc. and Gilead Sciences Inc. a non-invasive method for evaluating liver fibrosis in and participated in advisory boards for Merck Inc. and chronic HCV and in HIV [23,24] and has been used Gilead Sciences Inc. The remaining authors declare no in other cohort studies to track changes in fibrosis competing interests. which was staged initially by liver biopsy pre-therapy [4]. Furthermore, we used conservative cutoffs for both Additional files fibrosis and steatosis as well as stringent definition of a 2-stage change in fibrosis for progression and regres- Additional file 1: A table showing nominal logistic sion to mitigate the potential variability in the continu- regression of fibrosis stage at last follow-up can be ous measurement scale of transient elastography. In found at https://www.intmedpress.com/uploads/ the current study only one quarter of the cohort had documents/4531_Balmaceda_Addfile1.pdf advanced fibrosis (F3–F4) pre-treatment and 29% of those showed regression of fibrosis; this may have lim- Additional file 2: A figure showing participants ited the ability to identify factors associated with fibro- categorized by change in fibrosis based on NAFLD sis regression. While research suggest that biopsy length established cutoffs for fibrosis stage at last follow-up and number of portal tracts are important to optimize can be found at https://www.intmedpress.com/uploads/ accuracy of histopathology determinations [25], lim- documents/4531_Balmaceda_Addfile2.pdf ited data on these characteristics prevented application of such criteria in the current study. Another limita- References tion in the study was the relatively small number of 1. ANRS CO13 HEPAVIH Cohort. Regression of liver stiffness subjects in the progressor group. Nonetheless, the risk after sustained hepatitis C virus (HCV) virological responses factors identified were statistically robust in multivari- among HIV/HCV-coinfected patients. 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Journal

Antiviral Therapy – SAGE

Published: Aug 1, 2019

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