Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Antiviral drug Utilization and Annual Expenditures for Patients with Chronic HBV Infection in Guangzhou, China, in 2008–2015

Antiviral drug Utilization and Annual Expenditures for Patients with Chronic HBV Infection in... Antiviral Therapy 2019; 24:405–416 (doi: 10.3851/IMP3326) Original article Antiviral drug utilization and annual expenditures for patients with chronic HBV infection in Guangzhou, China, in 2008–2015 1† 2† 1 1 1 2 2 1 Feng Zhou , Weidong Jia , Shuo Yang , Ge Chen , Guanhai Li , Yueping Li , Yingfang Liang , Yi Yang *, 1 3 Yanhui Gao *, Yue Chen Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China Guangzhou Eighth People’s Hospital, Guangzhou, China Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada These authors contributed equally to this work *Corresponding author e-mails: gao_yanhui@163.com; yangyigz@163.com Background: The aims of this study were to describe The patients with medical insurance were more likely to antiviral drug (AD) utilization and costs in patients with use AD than patients without insurance, and the adjusted chronic HBV infection. OR was 1.11 (95% CI: 1.03, 1.19) for inpatients and 1.66 Methods: We conducted a retrospective study of patients (1.59, 1.73) for outpatients. With the disease progress- in the hospital and calculated annual proportions of AD ing, the proportion of antiviral costs in total direct medi- utilization and costs among patients. A two-part model cal costs decreased from 13.91% to 4.07% (71.29% to was used to estimate adjusted odds ratio (OR) for antiviral 49.29%) for inpatients (outpatients). therapy and cost ratios for antiviral costs associated with Conclusions: The use of AD for chronic HBV infection was demographics. less than expected based on established guidelines, and Results: Of a total of 14,920 records, 143,658 records only half of patients received antiviral treatment. How- were involved in the analysis. The annual proportions ever, the AD utilization, especially ETV, increased annu- of AD utilization were 56.99% (45.65%) for inpatients ally. Reimbursement policy was the most important factor (outpatients) during 2008–2015 and increased annually. affecting antiviral treatment. Antiviral therapy was an Entecavir (ETV), in particular, increased from 11.08% to important part of the direct medical costs, especially in 70.26% (11.05% to 49.35%) for inpatients (outpatients). the early stage of disease. Introduction HBV infection is one of the most important public higher than the national level. Chronically infected health problems in the world. An estimated 240 million individuals are at increased risk of developing hepatic people are chronically infected with HBV with a vary- decompensation, cirrhosis and hepatocellular carcinoma ing prevalence geographically in the world, the highest (HCC) [4]. These complications substantially reduce the in Africa and Asia [1]. In China, a meta-analysis showed quality of life and life expectancy, as well as imposing that hepatitis B surface antigen (HBsAg)-positive rate great demands on health-care resources [5]. Thus, pre- was 5.7% in the general population aged 1–59 years in vention or delay of disease progression would improve 2007–2016 [2], and there were considerable numbers of the prognosis and save medical resources [6]. patients with chronic HBV (CHB) infection due to the Antiviral treatment can achieve sustained suppres- large population in China. Guangzhou, as the capital sion of HBV DNA replication, and then prevent fur- city of Guangdong Province, is one of the most economi- ther disease progression [7]. It has been recommended cally developed cities in Southeast China. A community- by multiple international guidelines of prevention and based study showed the prevalence of positive HBsAg treatment for CHB [8–11]. Currently, there are seven was 8.76% in Guangdong Province in 2014–2015 [3], agents widely used to treat patients with CHB infection ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 405 AVT-19-OA-4525_Zhou.indd 405 AVT-19-OA-4525_Zhou.indd 405 22/11/2019 11:32:50 22/11/2019 11:32:50 F Zhou et al. in China, including conventional alpha-interferon of clinic visit or hospital admission. According to the (IFN-a), pegylated interferon-alpha-2a (alpha-2b; PEG- frequencies of the drug use, we combined IFN with IFN-a2a [a2b]), lamivudine (LAM), adefovir dipivoxil PEG-IFN-a2a and separated the made-in-China adefo- (ADV), entecavir (ETV), telbivudine (LdT) and tenofo- vir dipivoxil (ADV_C). The subjects prescribed any of vir (TDF). Several clinical trials have confirmed that the the seven antiviral drugs (IFN, ETV, ADV, LAM, LdT, recommended first-line antiviral agents such as ETV TDF and ADV_C) were considered as users of anti- and TDF have a potent antiviral effect, low incidence of viral drugs. The proportion of utilization of each of drug resistance and good safety [12–14]. However, use seven antiviral drugs was computed as the number of of the antiviral drugs are impacted by factors like their patients treated for a particular antiviral drug divided costs, coverage of reimbursement and others [15,16]. by the total number of patients in a year for the study Persistent and normative antiviral therapy will bring period. A user of hepato-protective drugs and tradi- a substantial financial burden for HBV-related patients. tional Chinese drugs was defined as a patient who was In this study, we assessed the utilization and costs of prescribed at least one kind of the drugs in the year of antiviral drugs and their affecting factors, which will visit/admission. The types of hepato-protective and tra- help optimize standardized protocols for therapy and ditional Chinese medicines included were determined follow-up management for the patients with HBV after consulting with senior clinicians. Annual direct infection. medical costs and annual costs for antiviral drugs were calculated by accumulating the expenses of all hospi- tal admissions (or clinic visits) during the year. In this Methods study, the direct medical costs included items of labo- Data source and study population ratory tests and imaging examinations, antiviral drugs We used the electronic medical record databases from and other medicines including liver protector or tra- the hospital information system of the Guangzhou ditional Chinese medicine, bed and nursing (only for Eighth People’s Hospital and constructed separate ret- inpatients), registration and consultation (only for out- rospective cohorts for outpatients and inpatients with patients), radiation therapy, anaesthesia, surgery and CHB infection. The hospital is the largest specialized blood transfusion (only for inpatients). The cost of each infection hospital in Guangdong Province, China. antiviral drug used was estimated separately and annual The target populations of this study were adult inpa- expected cost of each antiviral drug was also estimated tients and outpatients with CHB infection and related based on the price published on the Chinese medicine complications for the period from 1 January 2008 to price network [17], assuming that patients were given 31 December 2015. These patients were classified into standardized treatment. There are multiple specifica- three disease stages: CHB, cirrhosis (including com- tions and dosages for each type of antiviral drugs, and pensated and decompensated cirrhosis) and HCC. All the Chinese medicine price network lists a range of unit the patients were identified through clinical diagnosis price for each drug. An interval for the annual expected according to the International Classification of Disease, costs for each drug was provided based on this range of 10th Revision (ICD-10). Patients coinfected with hepa- unit price. All costs were expressed in RMB in the year titis A, hepatitis C, hepatitis D, hepatitis E, HIV infec- of 2015 and were adjusted by a discount rate of 5% per tion or cytomegalovirus (CMV) infection were excluded year [18,19]. from this study. Patients admitted to the hospital due to pregnancy or diseases including glomerulonephritis, Statistical analyses uraemia, metabolic syndrome, tumour and severe car- The distributions of person-years (based on calendar diovascular diseases were excluded. The details of sam- year) were described according to demographic charac- pling and data collection are shown in Figure 1. teristics of inpatients and outpatients including age, gen- der, payment mode, year of visit/admission and disease Study variables stage. Meanwhile, expenditure data of antiviral therapy Demographic characteristics, treatment of CHB were typically right-skewed and zero-inflated because infection and associated costs were extracted from elec- many patients did not use antiviral drugs and ordinary tronic medical records for all the patients. The demo- least squares estimation is usually biased and inefficient graphic information of patients such as age, gender, because of this. We used a two-part model approach [20] payment mode, admission (or visit) date and disease to simultaneously model the probability of antiviral uti- stage were included in our analysis datasets. Payment lization and costs of antiviral therapy [21,22]. In the first mode was categorized into four groups: self-payment, part, a logistic regression model was used to estimate the medical insurance, free medical service and other insur- probability of antiviral drug utilization. The ORs and ance. Antiviral treatment was defined as a patient pre- their 95% CIs were used to describe the association of rel- scribed at least one kind of antiviral drugs in the year evant factors with antiviral drug utilization. The second 406 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 406 AVT-19-OA-4525_Zhou.indd 406 22/11/2019 11:32:50 22/11/2019 11:32:50 Antiviral drug utilization and costs for CHB, China 2008–2015 Figure 1. Flowchart of records selection Patients potentially eligible for inclusion, diagnosed including ‘hepatitis’ during the period of 1 January 2008 to 31 December 2015 (inpatients: 52,369 records; outpatients: 1,540,015 records) Patients rst diagnosed with hepatitis A, hepatitis C, hepatitis D, hepatitis E or alcoholic hepatitis, autoimmune hepatitis, drug-induced hepatitis, HBV carriers, severe hepatitis excluded (inpatients: 31,616 records; outpatients: 387,334 records) Patients rst diagnosed CHB, CHB-related cirrhosis or HCC (inpatients: 20,753 records; outpatients: 1,152,681 records) Patients coinfected with hepatitis A, hepatitis C, hepatitis D, hepatitis E, HIV or cytomegalovirus; or the patients admitted to hospital due to pregnancy, glomerulonephritis, uraemia, metabolic syndrome, tumour, severe cardiovascular diseases excluded (inpatients: 1,628 records; outpatients: 13,679 Patients meet inclusion criteria (inpatients: records) 19,125 records; outpatients: 1,139,002 records) Records of no basic characteristics, prescription or costs information excluded (inpatients: 1,082 records; outpatients 218,238 records) Inpatients: 18,043 records; outpatients: 920,764 records Sum up prescription and costs information of patients by year (inpatients: 15,216 records; outpatients: 148,289 records) Younger than 18 years old excluded (inpatients: 296 records; outpatients: 4,631 records) Inpatients: 14,920 records; outpatients: 143,658 records CHB, chronic hepatitis B; HCC, hepatocellular carcinoma. part estimated the nonzero antiviral expenditures for the was conducted separately for outpatients and inpatients antiviral drug users using a generalized linear model with using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and a gamma distribution and a log link. The cost ratios (CR) P<0.05 was considered statistically significant. and their 95% CIs were used to analyse the difference in antiviral drug expenditures among patients with differ- Results ent characteristics. The method of maximum likelihood Descriptive characteristics estimation was used to estimate the ORs and the CRs in two-part models. In addition, we also described aver- A total of 14,920 records from 12,433 inpatients and age annual costs for antiviral drugs and the proportion in 143,658 records from 22,802 outpatients were involved direct medical costs for patients by different disease stages. in the analysis. Among the inpatients, the mean age The cost of each antiviral drug and the expected cost of was 42.1 ±14.6 years old, and 11,405 (76.44%) were normative treatment based on the Chinese medicine price male and 3,515 (23.56%) were female. There were network [17] were also compared. All statistical analysis 105,195 (73.25%) male and 38,410 (26.75%) female Antiviral Therapy 24.6 407 AVT-19-OA-4525_Zhou.indd 407 AVT-19-OA-4525_Zhou.indd 407 22/11/2019 11:32:51 22/11/2019 11:32:51 F Zhou et al. outpatients with mean age of 38.1 ±13.0 years. Self- respectively. The annual proportion of antiviral drug payment and medical insurance were the main pay- utilization increased from 45.61% in 2008 to 62.60% ment modes. Approximately 53% inpatients and 86% in 2015 for inpatients, and from 29.44% to 53.99% outpatients visited/admitted to hospital due to CHB. for outpatients. More than half of inpatients with Table 1 shows the distribution of person-years (based CHB (54.63%, 4,308/7,886), 64.03% (2,896/4,523) on calendar year) according to the study variables. The of inpatients with cirrhosis and 56.31% (1,414/2,511) median number of visits/admissions per case per year of HCC inpatients had received antiviral treatment. was 1 for inpatients and 3 for outpatients. For outpatients, antiviral drugs were taken by 43.44% (53,358/122,841) for CHB, 60.14% (11,641/19,357) Antiviral drug utilization and expenditures using for cirrhosis and 39.66% (579/1,460) for HCC. two-part model Tables 2 and 3 present the results from the two- The overall annual antiviral drug utilization for part models for inpatients and outpatients, respec- inpatient and outpatients were 56.99% and 45.65%, tively. Table 2 shows the annual proportion of anti- viral drug utilization in the first part of the model. A higher probability of antiviral drug utilization was Table 1. Distribution of PY (based on calendar year) according observed in male and older inpatients. Inpatients to the characteristics of patients with medical insurance and free medical service were Inpatients Outpatients more likely to use antiviral drugs than self-payment (PY=14,920) (PY=143,658) inpatients, with the ORs (95% CI) being 1.11 (1.03, Characteristics PY % PY % 1.19) and 1.24 (1.13, 1.36), respectively. As com- pared with inpatients with CHB, cirrhosis inpatients Age were more likely to use antiviral drugs (OR=1.18, 18–29 years 3,589 24.05 43,080 29.99 95% CI: 1.06, 1.30). Inpatients receiving traditional 30–39 years 3,664 24.56 45,683 31.80 Chinese medication had a higher proportion of anti- 40–49 years 3,006 20.15 27,578 19.20 viral drug use than those who did not (OR=2.00, 50–59 years 2,508 16.81 16,046 11.17 ≥60 years 2,153 14.43 11,271 7.85 95% CI: 1.83, 2.18). The second part was used to Gender estimate the annual average expenditures of anti- Male 11,405 76.44 105,195 73.25 viral drug treatment among inpatients prescribed Female 3,515 23.56 38,410 26.75 antiviral drugs. Women and young inpatients had Payment mode higher antiviral drug expenditures than men and Self-payment 9,789 65.61 92,354 64.29 old inpatients. Inpatients with free medical service Medical insurance 4,370 29.29 40,217 27.99 had a 1.32-fold higher expenditure than inpatients Free medical service 663 4.44 11,043 7.69 with self-payment. However, inpatients with medi- Others 98 0.66 44 0.03 cal insurance had a lower expenditure than those Traditional Chinese medicine with self-payment (OR=0.79; 95% CI: 0.75, 0.84). No 6,413 42.98 94,557 65.82 Inpatients receiving traditional Chinese medicine and Yes 8,507 57.02 49,101 34.18 Hepatoprotective drugs hepato-protective drugs had a 1.30-fold and 1.14- No 14,269 95.64 90,578 63.05 fold higher antiviral drug expenditure than inpatients Yes 651 4.36 53,080 36.95 who did not. Annual average antiviral drug costs for Year of visit/admission inpatients increased first and then decreased for the 2008 1,561 10.46 13,777 9.59 period from 2008 to 2015. 2009 1,598 10.71 13,729 9.56 Table 3 showed male and older outpatients had a 2010 1,575 10.56 13,187 9.18 higher probability of antiviral drug utilization. It was 2011 1,665 11.16 19,036 13.25 also seen that outpatients with medical insurance were 2012 1,611 10.8 21,393 14.89 more likely to use antiviral drugs than self-payment 2013 2,264 15.17 20,152 14.03 outpatients (OR=1.66, 95% CI: 1.59, 1.73). Outpa- 2014 2,280 15.28 20,919 14.56 tients who used hepato-protective drugs had a lower 2015 2,366 15.86 21,465 14.94 Disease stage proportion of antiviral use than those who did not CHB 7,886 52.86 122,841 85.51 (36.00% versus 51.30%; OR=0.44, 95% CI: 0.42, Cirrhosis 4,523 30.32 19,357 13.47 0.46). As compared with outpatients with CHB, out- HCC 2,511 16.83 1,460 1.02 patients with cirrhosis were more likely to use anti- Median number of hospital 1.0 3.0 viral drugs (OR=1.58, 95% CI: 1.53, 1.63). Among visits/admissions (P –P ) (1.0–1.0) (1.0–7.0) 25 75 outpatients with antiviral drug expenditure, men had higher antiviral drug expenditures than women. Including commercial insurance and cooperative medical service, etc. CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; PY, person-years. As compared with outpatients with self-payment, 408 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 408 AVT-19-OA-4525_Zhou.indd 408 22/11/2019 11:32:51 22/11/2019 11:32:51 Antiviral drug utilization and costs for CHB, China 2008–2015 Table 2. Utilization of antiviral drugs and corresponding annual antiviral drugs costs and associated factors for inpatients First part: description First part: binary Second part: description Second part: gamma a b b Characteristics n % OR 95% CI P-value Mean (sd ) Median Cost ratio 95% CI P-value Age 18–29 years 1,838 51.21 Reference 2,324.94 (4,904.22) 921.58 Reference 30–39 years 2,105 57.45 1.17 1.05, 1.30 0.0035 2,351.87 (4,198.35) 1,123.84 1.09 1.02, 1.17 0.0122 40–49 years 1,880 62.54 1.30 1.15, 1.47 <0.0001 1,878.36 (3,005.04) 1,097.89 1.00 0.93, 1.08 0.9414 50–59 years 1,530 61.00 1.21 1.06, 1.38 0.0052 1,656.21 (2,350.83) 991.31 0.95 0.87, 1.03 0.1962 ≥60 years 1,265 58.76 1.06 0.92, 1.23 0.4065 1,595.10 (2,230.99) 921.58 0.91 0.83, 1.00 0.0540 Gender Female 1,827 51.98 Reference 2,226.21 (4,013.65) 1,001.05 Reference Male 6,791 59.54 1.38 1.28, 1.51 <0.0001 1,949.60 (3,523.97) 1,016.05 0.96 0.90, 1.01 0.4591 Payment mode Self-payment 5,507 56.26 Reference 1,959.88 (3,217.88) 1,115.55 Reference Medical insurance 2,650 60.64 1.11 1.03, 1.19 0.0152 1,946.16 (4,175.00) 850.02 0.79 0.75, 0.84 <0.0001 Free medical service 415 62.59 1.24 1.13, 1.36 0.0084 3,129.45 (4,917.14) 1,303.34 1.32 1.19, 1.48 <0.0001 Others 46 46.94 1.05 0.68, 1.64 0.8142 1,259.74 (1,327.08) 786.70 1.01 0.74, 1.38 0.9517 Traditional Chinese medicine No 2,948 45.97 Reference 1,550.37 (2,749.21) 704.51 Reference Yes 5,555 65.30 2.00 1.83, 2.18 <0.0001 2,273.17 (4,031.93) 1,209.58 1.30 1.23, 1.38 <0.0001 Hepatoprotective drugs No 8,158 57.17 Reference 2,034.41 (3,700.54) 1,016.05 Reference Yes 345 53.00 0.93 0.77, 1.12 0.4443 1,742.68 (2,311.42) 1,037.68 1.14 1.07, 1.21 0.0244 Year of visit/admission 2008 712 45.61 Reference 1,428.92 (2,326.03) 709.18 Reference 2009 793 49.62 1.20 1.03, 1.40 0.0214 1,363.63 (2,120.32) 696.89 1.04 0.93, 1.16 0.4773 2010 847 53.78 1.29 1.10, 1.50 0.0017 1,837.26 (3,621.43) 977.50 1.29 1.16, 1.44 <0.0001 2011 907 54.47 1.21 1.03, 1.41 0.0189 2,078.61 (3,874.95) 979.64 1.32 1.19, 1.48 <0.0001 2012 1,031 64.00 1.44 1.22, 1.70 <0.0001 3,075.53 (5,860.67) 1,403.16 1.55 1.39, 1.74 <0.0001 2013 1,463 64.62 1.33 1.14, 1.56 0.0004 2,542.53 (4,319.37) 1,270.06 1.33 1.19, 1.47 <0.0001 2014 1,384 60.70 1.21 1.03, 1.41 0.0188 1,741.27 (2,533.46) 967.66 1.11 1.00, 1.23 0.0587 2015 1,481 62.60 1.23 1.05, 1.44 0.0089 1,665.30 (2,287.85) 951.26 1.04 0.94, 1.16 0.4306 Disease stage CHB 4,308 54.63 Reference 2,286.30 (4,461.05) 1,016.05 Reference Cirrhosis 2,896 64.03 1.18 1.06, 1.30 0.0015 1,911.27 (2,804.20) 1,151.98 0.84 0.80, 0.90 <0.0001 HCC 1,414 56.31 0.79 0.70, 0.89 0.0001 1,359.69 (1,767.34) 812.77 0.56 0.52, 0.60 <0.0001 The number of hospital visits/ admissions 1 7,019 54.36 Reference 1,418.91 (1,793.83) 897.39 Reference 2 1,175 78.65 2.90 2.52, 3.35 <0.0001 3,276.99 (4,474.96) 1,883.62 2.32 2.17, 2.49 <0.0001 ≥3 424 82.33 3.20 2.48, 4.11 <0.0001 8,248.15 (10,531.53) 4,129.85 5.53 4.96, 6.15 <0.0001 Intercept 0.61 0.54, 0.69 <0.0001 1,154.01 1,055.08, <0.0001 1,262.22 a b n, the number of antiviral drug use. Description: RMB (yuan). CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; OR, odds ratio. outpatients with medical insurance had a 1.07-fold higher probability of antiviral drug use and higher higher antiviral drug expenditure. Furthermore, out- antiviral drug costs. patients receiving traditional Chinese medicine had a higher antiviral drug expenditure but those receiving Proportion of utilization and annual expenditure for hepato-protective drugs had a lower antiviral drug each antiviral drug expenditure than outpatients who did not, respec- As shown in Figure 2, IFN, ETV, LAM and ADV_C were tively. Outpatients with more hospital visits had a the primary antiviral drugs for inpatients and outpatients. Antiviral Therapy 24.6 409 AVT-19-OA-4525_Zhou.indd 409 AVT-19-OA-4525_Zhou.indd 409 22/11/2019 11:32:51 22/11/2019 11:32:51 F Zhou et al. Table 3. Utilization of antiviral drugs and corresponding annual antiviral drugs costs and associated factors for outpatients First part: description First part: binary Second part: description Second part: gamma a b b Characteristics n % OR 95% CI P-value Mean (sd ) Median Cost ratio 95% CI P-value Age 18–29 years 16,346 37.94 Reference 5,295.95 (6,401.34) 3,657.12 Reference 30–39 years 20,947 45.85 1.19 1.15, 1.23 <0.0001 5,219.27 (6,096.92) 3,675.27 1.04 1.02, 1.06 0.0004 40–49 years 14,390 52.18 1.43 1.37, 1.48 <0.0001 4,475.06 (4,706.03) 3,169.65 0.95 0.92, 0.97 <0.0001 50–59 years 8,311 51.79 1.38 1.32, 1.45 <0.0001 4,017.63 (4,024.97) 2,833.40 0.87 0.85, 0.90 <0.0001 ≥60 years 5,584 49.54 1.23 1.16, 1.30 <0.0001 3,591.28 (3,695.81) 2,380.06 0.79 0.76, 0.81 <0.0001 Gender Female 16,320 42.49 Reference 4,492.66 (5,448.98) 2,975.07 Reference Male 49,233 46.80 1.20 1.18, 1.23 <0.0001 4,882.20 (5,545.02) 3,421.26 1.06 1.04, 1.29 <0.0001 Payment mode Self-payment 37,536 40.64 Reference 4,629.85 (5,449.05) 3,144.90 Reference Medical insurance 23,284 57.90 1.66 1.59, 1.73 <0.0001 5,406.79 (5,659.13) 4,118.42 1.07 1.04, 1.10 <0.0001 Free medical service 4,758 43.09 1.05 1.02, 1.08 0.0243 2,954.61 (4,903.79) 1,257.11 0.62 0.59, 0.65 <0.0001 Traditional Chinese medicine No 42,347 44.81 Reference 4,607.22 (4,952.90) 3,240.37 Reference Yes 23,206 47.27 0.97 0.92, 1.02 0.7758 5,110.06 (6,423.79) 3,474.43 1.07 1.03, 1.11 <0.0001 Hepatoprotective drugs No 46,451 51.30 Reference 4,790.14 (5,191.06) 3,405.63 Reference Yes 19,102 36.00 0.44 0.42, 0.46 <0.0001 4,773.25 (6,259.68) 3,116.74 0.87 0.86, 0.89 <0.0001 Year of visit/admission 2008 4,056 29.44 Reference 4,627.36 (5,932.92) 2,986.88 Reference 2009 4,702 34.25 1.21 1.14, 1.28 <0.0001 4,620.16 (5,758.29) 2,996.43 1.00 0.95, 1.04 0.8321 2010 5,028 38.13 1.32 1.24, 1.40 <0.0001 4,785.42 (6,011.24) 3,280.64 1.05 1.01, 1.10 0.0226 2011 8,176 42.95 1.88 1.79, 1.97 <0.0001 4,103.87 (5,551.22) 2,456.93 0.97 0.93, 1.01 0.1001 2012 10,506 49.11 1.97 1.84, 2.10 <0.0001 4,068.79 (5,299.55) 2,589.32 0.98 0.94, 1.01 0.2235 2013 10,430 51.76 2.31 1.19, 2.43 <0.0001 5,186.13 (5,864.40) 3,804.73 1.15 1.11, 1.20 <0.0001 2014 11,091 53.02 2.48 2.34, 2.62 <0.0001 5,023.65 (5,220.26) 3,744.49 1.12 1.08, 1.17 <0.0001 2015 11,589 53.99 2.49 2.35, 2.63 <0.0001 5,442.55 (5,050.31) 4,179.96 1.21 1.17, 1.26 <0.0001 Disease stage CHB 53,358 43.44 Reference 4,848.03 (5,801.32) 3,308.20 Reference Cirrhosis 11,641 60.14 1.58 1.53, 1.63 <0.0001 4,561.88 (4,093.37) 3,486.61 1.00 0.98, 1.02 0.9555 HCC 579 39.66 0.81 0.71, 0.92 <0.0001 3,367.31 (3,638.20) 2,007.65 0.84 0.78, 0.92 <0.0001 The number of hospital visits/ admissions 1 7,083 16.94 Reference 1,041.06 (1,231.30) 598.47 Reference 2–3 13,121 35.18 2.54 2.41, 2.67 <0.0001 2,371.84 (2,752.24) 1,342.54 2.24 2.20, 2.27 <0.0001 4–7 18,395 59.36 3.56 3.42, 3.70 <0.0001 4,228.52 (3,788.88) 3,134.84 4.24 4.18, 4.30 <0.0001 >7 26,954 80.57 5,37 5.21, 5.53 <0.0001 7,323.87 (6,866.60) 5,810.09 8.79 8.65, 8.93 <0.0001 Intercept 0.10 0.10, 0.11 <0.0001 1,042.73 1,021.13, <0.0001 1,064.79 a b n, the number of antiviral drug use. Description: RMB (yuan). CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; OR, odds ratio. From 2008 to 2015, the annual proportion of utilization 2008 to 19.35% in 2011 and then decreased gradually for IFN dropped from 57.16% to 8.71% for inpatients to 9.24% in 2015. For outpatients, however, it remained and from 24.77% to 3.25% for outpatients, whereas the at a higher level from 2008 to 2015. The proportion of proportion for ETV gradually increased from 11.08% LAM utilization increased from 2008 to 2011 and then to 70.26% for inpatients and from 11.05% to 49.35% gradually decreased for both in- and outpatients. for outpatients, respectively. In addition, the proportion Figure 3 showed annual average actual costs for of ADV_C utilization increased initially from 10.14% in inpatients and outpatients using various antiviral drugs 410 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 410 AVT-19-OA-4525_Zhou.indd 410 22/11/2019 11:32:51 22/11/2019 11:32:51 Antiviral drug utilization and costs for CHB, China 2008–2015 Figure 2. Utilization prevalence of antiviral drugs for inpatients and outpatients using antiviral drugs from 2008 to 2015 Inpatients (n=8,618) IFN ETV ADV LAM LdT TDF ADV_C 2008 2009 2010 2011 2012 2013 2014 2015 Outpatients (n=65,578) IFN ETV ADV LAM LdT TDF ADV_C 2008 2009 2010 2011 2012 2013 2014 2015 ADV, adefovir dipivoxil; ADV_C, made-in-China adefovir dipivoxil; ETV, entecavir; IFN, interferon; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir disoproxil fumarate. during the 8-year period and the corresponding annual antiviral costs achieved the expected costs of norma- expected costs when normative antiviral therapy was tive therapy were found in outpatients (Table 4). assumed. Annual expected costs range from 11,260 to 13,766 RMB for ETV and 5,292 to 6,474 RMB for The proportion of annual antiviral drug costs in TDF. However, actual annual costs were about 5,000 average annual direct medical costs RMB for outpatients using ETV and about 5,500 Figure 4 summarized annual average direct medical RMB for TDF (only the years of 2013, 2014 and 2015, costs and the proportion of annual average antivi- because this drug was launched in 2013) from 2008 to ral drug costs for patients in different disease stages 2015. The actual costs were far less than the annual for the period from 2008 to 2015. The annual direct expected costs for outpatients who received ETV treat- medical costs for inpatients and outpatients were as fol- ment. Less than 40% of patients whose annual actual lows: CHB: 16,439.84 and 6,800.56 RMB; cirrhosis: Antiviral Therapy 24.6 411 AVT-19-OA-4525_Zhou.indd 411 AVT-19-OA-4525_Zhou.indd 411 22/11/2019 11:32:51 22/11/2019 11:32:51 % % F Zhou et al. Figure 3. Annual average costs of various antiviral drugs for inpatients and outpatients from 2008 to 2015 and annual expected costs of normative antiviral therapy Inpatients 14,000 12,000 10,000 8,000 6,000 4,000 2,000 ETV ADV LAM LdT TDF ADV_C Annual simulated costs of normative antiviral therapy 2008 2009 2010 2011 2012 2013 2014 2015 Outpatients 14,000 12,000 10,000 8,000 6,000 4,000 2,000 ETV ADV LAM LdT TDF ADV_C Annual simulated costs of normative antiviral therapy 2008 2009 2010 2011 2012 2013 2014 2015 ADV, adefovir dipivoxil; ADV_C, made-in-China adefovir dipivoxil; ETV, entecavir; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir disoproxil fumarate. 25,379.39 and 8,156.47 RMB; HCC: 33,371.09 and Discussion 6,831.00 RMB, respectively. Among them, antiviral drug costs represented 13.91% and 71.29% of direct In the present study, using electronic medical data from medical costs for inpatients and outpatients with CHB, the largest specialized infection hospital in Guang- respectively. And with the progress of disease, this pro- dong, China, antiviral drug utilization for 14,920 portion decreased to 4.07% for HCC inpatients and inpatients and 143,658 outpatients with CHB infec- 49.29% for HCC outpatients. tion were analysed for the period from 2008 to 2015. 412 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 412 AVT-19-OA-4525_Zhou.indd 412 22/11/2019 11:32:52 22/11/2019 11:32:52 Annual costs of various antiviral drugs, RMB Annual costs of various antiviral drugs, RMB The proportion of antiviral drugs costs in direct medical costs, % Antiviral drug utilization and costs for CHB, China 2008–2015 Table 4. The proportion of outpatients whose annual actual antiviral costs achieved the annual expected antiviral costs of normative therapy from 2008 to 2015 (%) Antiviral drug 2008 2009 2010 2011 2012 2013 2014 2015 ETV 15.63 14.31 11.99 11.35 9.92 16.32 15.39 17.01 (73/467) (77/538) (80/667) (185/1,630) (275/2,773) (619/3,794) (747/4,853) (979/5,755) ADV 16.16 21.07 25.82 16.8 15.62 15.48 14.93 0.3 (74/458) (118/560) (150/581) (171/1,018) (221/1,415) (232/1,499) (200/1,340) (3/993) LAM 3.28 6.61 8.26 7.27 5.16 5.47 5.15 5.94 (15/458) (37/560) (48/581) (74/1,018) (73/1,415) (82/1,499) (69/1,340) (59/993) LdT 25.09 16.67 13.46 7.99 8.66 19.74 19.44 20.23 (143/570) (89/534) (58/431) (48/601) (108/1,247) (328/1,662) (370/1,903) (458/2,264) TDF – – – – – 36.36 40.43 36.23 (8/22) (19/47) (100/276) ADV_C 26.61 27.89 27.84 20.77 19.59 21.96 17.68 5.32 (393/1,477) (509/1,825) (600/2,155) (701/3,375) (795/4,059) (806/3,670) (602/3,405) (211/3,967) ADV, adefovir dipivoxil; ADV_C, made-in-China adefovir dipivoxil; ETV, entecavir; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir disoproxil fumarate. Figure 4. The annual average direct medical costs and the proportion of antiviral drugs costs in direct medical costs for inpatients and outpatients by different disease stages 35,000 33,371.09 80.00 71.29 70.00 30,000 25,379.39 60.00 55.93 25,000 50.00 49.29 20,000 16,439.84 40.00 15,000 30.00 10,000 8,156.47 20.00 6,800.56 6,831.00 13.91 5,000 10.00 7.53 4.07 0 0.00 CHB Cirrhosis HCC CHB Cirrhosis HCC Inpatients Outpatients Direct medicine costs Proportion, % CHB, chronic hepatitis B; HCC, hepatocellular carcinoma. Nearly half of the infected patients did not receive year, including ETV and TDF, as the first-line antiviral antiviral treatment in Guangzhou. The overall propor- drugs [8–11]. tion of antiviral drug utilization was 56.99% for inpa- Antiviral treatment can achieve sustained suppres- tients and 45.65% for outpatients. However, the pro- sion of HBV DNA replication, and slow disease pro- portion of antiviral drug utilization increased every gression. The WHO Global Health Sector Strategy on Antiviral Therapy 24.6 413 AVT-19-OA-4525_Zhou.indd 413 AVT-19-OA-4525_Zhou.indd 413 22/11/2019 11:32:52 22/11/2019 11:32:52 Mean direct medical costs per patient per year, RMB F Zhou et al. Viral Hepatitis with the purpose of an elimination of which needs to be further evaluated. In addition to the HBV in 2030, targets to provide antiviral treatment for effect of reimbursement policy, our results showed that 80% of those diagnosed and eligible for treatment [23]. outpatients receiving hepato-protective drugs were less China has the largest number of patients with hepati- likely to use antiviral drugs than outpatients who did tis B infections in the world. However, a large number not receive hepato-protective drugs. of the patients did not receive antiviral treatment in WHO estimated that the most important part of the this country. Research form Beijing You’an Hospital in total costs was hepatitis screening fees and antivirus 2008–2012 and from 10 hospitals in western China in treatment costs for CHB in low and middle-income 2011 also demonstrated a low proportion of using anti- countries [31]. In this study, the costs of antiviral ther- viral drugs [24,25]. This phenomenon was also observed apy were an important part of the economic burden, in some Western countries. A study of electronic health especially in the early stage of disease progression. records in the United States found that antiviral therapy Annual average antiviral drug costs for outpatients with was received by 57.90% of HBV-infected patients [26]. CHB was 4,848.03 RMB, and it accounted for 71.29% It was even lower (25%) in Belgium [27]. One possible of annual direct medical costs. When the disease pro- explanation was that there were increased numbers of gresses to HCC, the hospitalization risk increases and patients with HBV infection who did not meet antivi- the medical costs also increase substantially [32–34]. ral indications in areas with a low prevalence. It was a The annual direct medical cost for HCC inpatients was concern that only 5% of individuals eligible for treat- 3,3371.09 RMB, but the antiviral drugs accounted for ment actually received antiviral therapy globally, and only 4.07%. Normative antiviral therapy in early stage this rate was about 11% in China [28]. of disease progression slows down the disease progres- Given the importance of antiviral therapy in patients sion, improves the quality of life and reduces other with CHB infection, it is imperative to identify the influ- medical expenses caused by disease progression. How- encing factors of antiviral therapy. From the perspec- ever, we found that the actual annual antiviral drug tive of macro-management, reimbursement policy is the costs were significantly lower than normative treat- most critical positive factor. In this study, the antiviral ment costs based on the Chinese medicine price net- utilization increased in inpatients with medical insur- work [17]. Taking TDF as an example, less than 40% ance more than those with self-payment. A study by of outpatients with antiviral drug treatment achieved Liaw [7] revealed that lack of reimbursement for treat- the expected costs of normative therapy. This may be ment is an obstacle to the proper management of HBV related to poor persistence and adherence of patients. disease. Another study from South Korea also showed A large-scale study of patient adherence with antiviral that the number of patients receiving oral antiviral ther- therapy for CHB infection reported a persistence rate apy for HBV precipitously increased since life-long reim- of 85.5% in the United States [35]. In China, the adher- bursement of oral antiviral agents was approved [29]. ence rate to antiviral therapy in China is far from opti- Since 2008, health insurance policy has experienced a mistic [36]. Non-adherence can result in poor virology series of changes in Guangzhou. The Outpatient Medi- suppression, breakthrough resistance and progression cal Insurance Fund Policy was implemented in Guang- of disease [37]. zhou on 1 August 2008 that provided a monthly quota This study included a large study population from payment for patients. Until 1 October 2013, both urban 8-year retrospective inpatient and outpatient cohorts and rural residents were paid with CHB patients receiv- and used novel two-part model methodology. How- ing 100 RMB per month by this Fund. The payment ever, there are some limitations. First, there were increased to 400 RMB per month on 1 January 2015. possible selection biases in our study, owing to study In this study, the effect of reimbursement policy on the individuals coming from one hospital. However, the proportion of antiviral drug use tended to increase with Guangzhou Eighth People’s Hospital is the largest time, especially for first-line treatment drug ETV. IFN specialized infection hospital in Guangdong Prov- and NAs (ETV, ADV, LAM and LdT) have been listed ince, and most patients with HBV-related diseases on the National Reimbursement Catalog of Drugs would usually seek their medical care services from for Basic Medical Insurance since 1 July 2011, which large hospitals rather than county-level hospitals and increases the affordability as well as allows patients to community clinics [38]. Our study population had a use more expensive drugs such as first-line treatment similar distribution of demographic characteristics of drug ETV, which offered better therapeutic efficacy, and subjects as compared with others [16,32,34]. Second, fewer side effects and drug resistance [5,30]. Therefore, there was a lack of information on other influenc- medical insurance optimized the availability of antiviral ing factors at the individual level, such as education, drugs. Additionally, in May 2016, TDF was included household income and lifestyle. Third, we were not in the National Medical Insurance, which would sig- able to distinguish between treatment-naive patients nificantly increase the use of first-line antiviral drugs, (patients who had not received antiviral therapy 414 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 414 AVT-19-OA-4525_Zhou.indd 414 22/11/2019 11:32:52 22/11/2019 11:32:52 Antiviral drug utilization and costs for CHB, China 2008–2015 9. Korean Association for the Study of the Liver. KASL clinical before the study) and treatment-experienced patients practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol 2016; 22:18–75. (patients who had received antiviral therapy before the study), thus initiation, switch or add-on treat- 10. Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a ments were not considered and compared with estab- 2015 update. Hepatol Int 2016; 10:1–98. lished guidelines in this study. Fourth, HCC patients 11. Terrault NA, Bzowej NH, Chang KM, et al. AASLD were likely to be underrepresented since it is not a guidelines for treatment of chronic hepatitis B. Hepatology 2016; 63:261–283. cancer hospital. 12. Chang TT, Gish RG, de Man R, et al. A comparison of In conclusion, nearly half of the patients with CHB entecavir and lamivudine for HBeAg-positive chronic infection received antiviral treatment from 2008 to hepatitis B. N Engl J Med 2006; 354:1001–1010. 2015 in Guangzhou, China. The proportion of antivi- 13. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic ral drug utilization increased annually, especially ETV hepatitis B. N Engl J Med 2008; 359:2442–2455. and TDF as first-line treatment drugs. Reimbursement 14. Yao G, Chen C, Lu W, et al. Efficacy and safety of entecavir policy was the most important factor affecting antivi- compared to lamivudine in nucleoside-naive patients with chronic hepatitis B: a randomized double-blind trial in ral treatment. The costs of antiviral therapy were an China. Hepatol Int 2007; 1:365–372. important part of the direct medical costs, especially 15. Chan HL, Jia J. Chronic hepatitis B in Asia-new insights in the early stage of disease progression. However, the from the past decade. J Gastroenterol Hepatol 2011; 26 Suppl 1:131–137. actual annual average costs of antiviral drugs were 16. Qiu Q, Duan XW, Li Y, et al. Impact of partial lower than expected, suggesting that the dosage of reimbursement on hepatitis B antiviral utilization and antiviral drugs might not be enough for patients with adherence. World J Gastroenterol 2015; 21:9588–9597. antiviral therapy. 17. Chinese medicine price network. (Accessed 16 July 2017.) Available from http://www.zgyyjgw.com/front/cn/retailPrice 18. Smith DH, Gravelle H. The practice of discounting in Acknowledgements economic evaluations of healthcare interventions. Int J Technol Assess Health Care 2001; 17:236–243. Funding: this study was supported by the National 19. Chinese Pharmacoeconomics Evaluation Guide Research Group, Liu GE, Hu SH, Wu JH. [Chinese Natural Science Foundation of China (No.71573059); pharmacoeconomics evaluation guide (2011 edition)]. and The Medical Scientific Research Foundation of Chin Pharmacoeconom 2011; 3:1–23. Chinese. Guangdong Province, China (No. A2017036). 20. Manning WG, Basu A, Mullahy J. Generalized modeling approaches to risk adjustment of skewed outcomes data. J Health Econ 2005; 24:465–488. Disclosure statement 21. Buntin MB, Zaslavsky AM. Too much ado about two- part models and transformation? Comparing methods of modeling Medicare expenditures. J Health Econ 2004; No conflict of interest exits in the submission of this 23:525–542. manuscript, and manuscript is approved by all authors 22. Duan N, Manning WG, Jr. A comparison of alternative for publication. models for the demand for medical care. J Bus Econ Stat 1983; 1:115–126. 23. WHO. Global Health Sector Strategies for viral hepatitis References 2016–21. 2016. (Accessed 1 July 2016.) Available from http://www.who.int/hepatitis/strategy2016-2021/ghss-hep/en 1. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of 24. Qiu Q, Li Y, Duan XW, et al. Impact of a new age-specific HBsAg seroprevalence and endemicity. Vaccine reimbursement program on hepatitis B antiviral medication cost and utilization in Beijing, China. PLoS One 2014; 2012; 30:2212–2219. 9:e109652. 2. Zhang WL, Ji Z, Fu T, Zhang L, Su H, Yan Y. [Meta analysis 25. Sun YT, Zhang YX, Tang H, et al. Clinical characteristics on HBsAg-positive rate among general populations aged and current management of hepatitis B and C in China. 1–59 years, 2007–2016, China]. Zhonghua Liu Xing Bing World J Gastroenterol 2014; 20:13582–13590. Xue Za Zhi 2017; 38:1278–1284. Chinese. 26. Moorman AC, Gordon SC, Rupp LB, et al. Baseline 3. Zeng F, Guo P, Huang Y, et al. Epidemiology of hepatitis B characteristics and mortality among people in care for virus infection: results from a community-based study of 0.15 chronic viral hepatitis: the chronic hepatitis cohort study. million residents in South China. Sci Rep 2016; 6:36186. Clin Infect Dis 2013; 56:40–50. 4. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009; 27. De Vroey B, Moreno C, Laleman W, et al. Hepatitis B virus 373:582. and hepatitis C virus infections in Belgium: similarities 5. Yuen MF, Lai CL. Treatment of chronic hepatitis B: and differences in epidemics and initial management. Eur J evolution over two decades. J Gastroenterol Hepatol 2011; Gastroenterol Hepatol 2013; 25:613–619. 26 Suppl 1:138–143. 28. Razavi-Shearer D, Gamkrelidze I, Nguyen MH, et al. Global 6. Sun J, Hou JL. Management of chronic hepatitis B: experience prevalence, treatment, and prevention of hepatitis B virus from China. J Viral Hepat 2010; 17 Suppl 1:10–17. infection in 2016: a modelling study. Lancet Gastroenterol Hepatol 2018; 3:383–403. 7. Liaw YF. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia. J Hepatol 2009; 51:403–410. 29. Choi J, Han S, Kim N, Lim YS. Increasing burden of liver cancer despite extensive use of antiviral agents in a hepatitis B 8. Chinese Society of Hepatology CMA, Hou JL, Lai W. [The virus-endemic population. Hepatology 2017; 66:1454–1463. guideline of prevention and treatment for chronic hepatitis B: a 2015 update]. Zhonghua Gan Zang Bing Za Zhi 2015; 30. Osborn M. Safety and efficacy of entecavir for the treatment of chronic hepatitis B. Infect Drug Resist 2011; 4:55–64. 23:888. Chinese. Antiviral Therapy 24.6 415 AVT-19-OA-4525_Zhou.indd 415 AVT-19-OA-4525_Zhou.indd 415 22/11/2019 11:32:52 22/11/2019 11:32:52 F Zhou et al. 31. WHO. Combating hepatitis B and C to reach elimination 35. Chotiyaputta W, Peterson C, Ditah FA, Goodwin D, Lok by 2030: advocacy brief. (Accessed 16 July 2017.) Available ASF. Persistence and adherence to nucleos(t)ide analogue from http://www.who.int/hepatitis/publications/hep- treatment for chronic hepatitis B. J Hepatol 2011; 54:12–18. elimination-by-2030-brief/en/ 36. Xu K, Liu LM, Farazi PA, et al. Adherence and perceived 32. Che YH, Chongsuvivatwong V, Li L, et al. Financial burden barriers to oral antiviral therapy for chronic hepatitis B. on the families of patients with hepatitis B virus-related liver Glob Health Action 2018; 11:1433987. diseases and the role of public health insurance in Yunnan 37. European Association For The Study Of The Liver. EASL province of China. Public Health 2016; 130:13–20. Clinical Practice Guidelines: management of chronic 33. Hu M, Chen W. Assessment of total economic burden of hepatitis B. J Hepatol 2012; 57:167–185. chronic hepatitis B (CHB)-related diseases in Beijing and 38. Zhang S, Ma Q, Liang S, et al. Annual economic burden Guangzhou, China. Value Health 2009; 12:S89. of hepatitis B virus-related diseases among hospitalized 34. Lu J, Xu A, Jian W, et al. Direct economic burden of patients in twelve cities in China. J Viral Hepat 2016; hepatitis B virus related diseases: evidence from Shandong, 23:202–210. China. BMC Health Serv Res 2013; 13:37. Accepted 27 June 2019; published online 26 July 2019 416 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 416 AVT-19-OA-4525_Zhou.indd 416 22/11/2019 11:32:52 22/11/2019 11:32:52 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antiviral Therapy SAGE

Antiviral drug Utilization and Annual Expenditures for Patients with Chronic HBV Infection in Guangzhou, China, in 2008–2015

Download PDF
12 pages

Loading next page...
 
/lp/sage/antiviral-drug-utilization-and-annual-expenditures-for-patients-with-JkaWKPItij

References (47)

Publisher
SAGE
Copyright
© 2019 SAGE Publications
ISSN
1359-6535
eISSN
2040-2058
DOI
10.3851/imp3326
Publisher site
See Article on Publisher Site

Abstract

Antiviral Therapy 2019; 24:405–416 (doi: 10.3851/IMP3326) Original article Antiviral drug utilization and annual expenditures for patients with chronic HBV infection in Guangzhou, China, in 2008–2015 1† 2† 1 1 1 2 2 1 Feng Zhou , Weidong Jia , Shuo Yang , Ge Chen , Guanhai Li , Yueping Li , Yingfang Liang , Yi Yang *, 1 3 Yanhui Gao *, Yue Chen Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China Guangzhou Eighth People’s Hospital, Guangzhou, China Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada These authors contributed equally to this work *Corresponding author e-mails: gao_yanhui@163.com; yangyigz@163.com Background: The aims of this study were to describe The patients with medical insurance were more likely to antiviral drug (AD) utilization and costs in patients with use AD than patients without insurance, and the adjusted chronic HBV infection. OR was 1.11 (95% CI: 1.03, 1.19) for inpatients and 1.66 Methods: We conducted a retrospective study of patients (1.59, 1.73) for outpatients. With the disease progress- in the hospital and calculated annual proportions of AD ing, the proportion of antiviral costs in total direct medi- utilization and costs among patients. A two-part model cal costs decreased from 13.91% to 4.07% (71.29% to was used to estimate adjusted odds ratio (OR) for antiviral 49.29%) for inpatients (outpatients). therapy and cost ratios for antiviral costs associated with Conclusions: The use of AD for chronic HBV infection was demographics. less than expected based on established guidelines, and Results: Of a total of 14,920 records, 143,658 records only half of patients received antiviral treatment. How- were involved in the analysis. The annual proportions ever, the AD utilization, especially ETV, increased annu- of AD utilization were 56.99% (45.65%) for inpatients ally. Reimbursement policy was the most important factor (outpatients) during 2008–2015 and increased annually. affecting antiviral treatment. Antiviral therapy was an Entecavir (ETV), in particular, increased from 11.08% to important part of the direct medical costs, especially in 70.26% (11.05% to 49.35%) for inpatients (outpatients). the early stage of disease. Introduction HBV infection is one of the most important public higher than the national level. Chronically infected health problems in the world. An estimated 240 million individuals are at increased risk of developing hepatic people are chronically infected with HBV with a vary- decompensation, cirrhosis and hepatocellular carcinoma ing prevalence geographically in the world, the highest (HCC) [4]. These complications substantially reduce the in Africa and Asia [1]. In China, a meta-analysis showed quality of life and life expectancy, as well as imposing that hepatitis B surface antigen (HBsAg)-positive rate great demands on health-care resources [5]. Thus, pre- was 5.7% in the general population aged 1–59 years in vention or delay of disease progression would improve 2007–2016 [2], and there were considerable numbers of the prognosis and save medical resources [6]. patients with chronic HBV (CHB) infection due to the Antiviral treatment can achieve sustained suppres- large population in China. Guangzhou, as the capital sion of HBV DNA replication, and then prevent fur- city of Guangdong Province, is one of the most economi- ther disease progression [7]. It has been recommended cally developed cities in Southeast China. A community- by multiple international guidelines of prevention and based study showed the prevalence of positive HBsAg treatment for CHB [8–11]. Currently, there are seven was 8.76% in Guangdong Province in 2014–2015 [3], agents widely used to treat patients with CHB infection ©2019 International Medical Press 1359-6535 (print) 2040-2058 (online) 405 AVT-19-OA-4525_Zhou.indd 405 AVT-19-OA-4525_Zhou.indd 405 22/11/2019 11:32:50 22/11/2019 11:32:50 F Zhou et al. in China, including conventional alpha-interferon of clinic visit or hospital admission. According to the (IFN-a), pegylated interferon-alpha-2a (alpha-2b; PEG- frequencies of the drug use, we combined IFN with IFN-a2a [a2b]), lamivudine (LAM), adefovir dipivoxil PEG-IFN-a2a and separated the made-in-China adefo- (ADV), entecavir (ETV), telbivudine (LdT) and tenofo- vir dipivoxil (ADV_C). The subjects prescribed any of vir (TDF). Several clinical trials have confirmed that the the seven antiviral drugs (IFN, ETV, ADV, LAM, LdT, recommended first-line antiviral agents such as ETV TDF and ADV_C) were considered as users of anti- and TDF have a potent antiviral effect, low incidence of viral drugs. The proportion of utilization of each of drug resistance and good safety [12–14]. However, use seven antiviral drugs was computed as the number of of the antiviral drugs are impacted by factors like their patients treated for a particular antiviral drug divided costs, coverage of reimbursement and others [15,16]. by the total number of patients in a year for the study Persistent and normative antiviral therapy will bring period. A user of hepato-protective drugs and tradi- a substantial financial burden for HBV-related patients. tional Chinese drugs was defined as a patient who was In this study, we assessed the utilization and costs of prescribed at least one kind of the drugs in the year of antiviral drugs and their affecting factors, which will visit/admission. The types of hepato-protective and tra- help optimize standardized protocols for therapy and ditional Chinese medicines included were determined follow-up management for the patients with HBV after consulting with senior clinicians. Annual direct infection. medical costs and annual costs for antiviral drugs were calculated by accumulating the expenses of all hospi- tal admissions (or clinic visits) during the year. In this Methods study, the direct medical costs included items of labo- Data source and study population ratory tests and imaging examinations, antiviral drugs We used the electronic medical record databases from and other medicines including liver protector or tra- the hospital information system of the Guangzhou ditional Chinese medicine, bed and nursing (only for Eighth People’s Hospital and constructed separate ret- inpatients), registration and consultation (only for out- rospective cohorts for outpatients and inpatients with patients), radiation therapy, anaesthesia, surgery and CHB infection. The hospital is the largest specialized blood transfusion (only for inpatients). The cost of each infection hospital in Guangdong Province, China. antiviral drug used was estimated separately and annual The target populations of this study were adult inpa- expected cost of each antiviral drug was also estimated tients and outpatients with CHB infection and related based on the price published on the Chinese medicine complications for the period from 1 January 2008 to price network [17], assuming that patients were given 31 December 2015. These patients were classified into standardized treatment. There are multiple specifica- three disease stages: CHB, cirrhosis (including com- tions and dosages for each type of antiviral drugs, and pensated and decompensated cirrhosis) and HCC. All the Chinese medicine price network lists a range of unit the patients were identified through clinical diagnosis price for each drug. An interval for the annual expected according to the International Classification of Disease, costs for each drug was provided based on this range of 10th Revision (ICD-10). Patients coinfected with hepa- unit price. All costs were expressed in RMB in the year titis A, hepatitis C, hepatitis D, hepatitis E, HIV infec- of 2015 and were adjusted by a discount rate of 5% per tion or cytomegalovirus (CMV) infection were excluded year [18,19]. from this study. Patients admitted to the hospital due to pregnancy or diseases including glomerulonephritis, Statistical analyses uraemia, metabolic syndrome, tumour and severe car- The distributions of person-years (based on calendar diovascular diseases were excluded. The details of sam- year) were described according to demographic charac- pling and data collection are shown in Figure 1. teristics of inpatients and outpatients including age, gen- der, payment mode, year of visit/admission and disease Study variables stage. Meanwhile, expenditure data of antiviral therapy Demographic characteristics, treatment of CHB were typically right-skewed and zero-inflated because infection and associated costs were extracted from elec- many patients did not use antiviral drugs and ordinary tronic medical records for all the patients. The demo- least squares estimation is usually biased and inefficient graphic information of patients such as age, gender, because of this. We used a two-part model approach [20] payment mode, admission (or visit) date and disease to simultaneously model the probability of antiviral uti- stage were included in our analysis datasets. Payment lization and costs of antiviral therapy [21,22]. In the first mode was categorized into four groups: self-payment, part, a logistic regression model was used to estimate the medical insurance, free medical service and other insur- probability of antiviral drug utilization. The ORs and ance. Antiviral treatment was defined as a patient pre- their 95% CIs were used to describe the association of rel- scribed at least one kind of antiviral drugs in the year evant factors with antiviral drug utilization. The second 406 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 406 AVT-19-OA-4525_Zhou.indd 406 22/11/2019 11:32:50 22/11/2019 11:32:50 Antiviral drug utilization and costs for CHB, China 2008–2015 Figure 1. Flowchart of records selection Patients potentially eligible for inclusion, diagnosed including ‘hepatitis’ during the period of 1 January 2008 to 31 December 2015 (inpatients: 52,369 records; outpatients: 1,540,015 records) Patients rst diagnosed with hepatitis A, hepatitis C, hepatitis D, hepatitis E or alcoholic hepatitis, autoimmune hepatitis, drug-induced hepatitis, HBV carriers, severe hepatitis excluded (inpatients: 31,616 records; outpatients: 387,334 records) Patients rst diagnosed CHB, CHB-related cirrhosis or HCC (inpatients: 20,753 records; outpatients: 1,152,681 records) Patients coinfected with hepatitis A, hepatitis C, hepatitis D, hepatitis E, HIV or cytomegalovirus; or the patients admitted to hospital due to pregnancy, glomerulonephritis, uraemia, metabolic syndrome, tumour, severe cardiovascular diseases excluded (inpatients: 1,628 records; outpatients: 13,679 Patients meet inclusion criteria (inpatients: records) 19,125 records; outpatients: 1,139,002 records) Records of no basic characteristics, prescription or costs information excluded (inpatients: 1,082 records; outpatients 218,238 records) Inpatients: 18,043 records; outpatients: 920,764 records Sum up prescription and costs information of patients by year (inpatients: 15,216 records; outpatients: 148,289 records) Younger than 18 years old excluded (inpatients: 296 records; outpatients: 4,631 records) Inpatients: 14,920 records; outpatients: 143,658 records CHB, chronic hepatitis B; HCC, hepatocellular carcinoma. part estimated the nonzero antiviral expenditures for the was conducted separately for outpatients and inpatients antiviral drug users using a generalized linear model with using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and a gamma distribution and a log link. The cost ratios (CR) P<0.05 was considered statistically significant. and their 95% CIs were used to analyse the difference in antiviral drug expenditures among patients with differ- Results ent characteristics. The method of maximum likelihood Descriptive characteristics estimation was used to estimate the ORs and the CRs in two-part models. In addition, we also described aver- A total of 14,920 records from 12,433 inpatients and age annual costs for antiviral drugs and the proportion in 143,658 records from 22,802 outpatients were involved direct medical costs for patients by different disease stages. in the analysis. Among the inpatients, the mean age The cost of each antiviral drug and the expected cost of was 42.1 ±14.6 years old, and 11,405 (76.44%) were normative treatment based on the Chinese medicine price male and 3,515 (23.56%) were female. There were network [17] were also compared. All statistical analysis 105,195 (73.25%) male and 38,410 (26.75%) female Antiviral Therapy 24.6 407 AVT-19-OA-4525_Zhou.indd 407 AVT-19-OA-4525_Zhou.indd 407 22/11/2019 11:32:51 22/11/2019 11:32:51 F Zhou et al. outpatients with mean age of 38.1 ±13.0 years. Self- respectively. The annual proportion of antiviral drug payment and medical insurance were the main pay- utilization increased from 45.61% in 2008 to 62.60% ment modes. Approximately 53% inpatients and 86% in 2015 for inpatients, and from 29.44% to 53.99% outpatients visited/admitted to hospital due to CHB. for outpatients. More than half of inpatients with Table 1 shows the distribution of person-years (based CHB (54.63%, 4,308/7,886), 64.03% (2,896/4,523) on calendar year) according to the study variables. The of inpatients with cirrhosis and 56.31% (1,414/2,511) median number of visits/admissions per case per year of HCC inpatients had received antiviral treatment. was 1 for inpatients and 3 for outpatients. For outpatients, antiviral drugs were taken by 43.44% (53,358/122,841) for CHB, 60.14% (11,641/19,357) Antiviral drug utilization and expenditures using for cirrhosis and 39.66% (579/1,460) for HCC. two-part model Tables 2 and 3 present the results from the two- The overall annual antiviral drug utilization for part models for inpatients and outpatients, respec- inpatient and outpatients were 56.99% and 45.65%, tively. Table 2 shows the annual proportion of anti- viral drug utilization in the first part of the model. A higher probability of antiviral drug utilization was Table 1. Distribution of PY (based on calendar year) according observed in male and older inpatients. Inpatients to the characteristics of patients with medical insurance and free medical service were Inpatients Outpatients more likely to use antiviral drugs than self-payment (PY=14,920) (PY=143,658) inpatients, with the ORs (95% CI) being 1.11 (1.03, Characteristics PY % PY % 1.19) and 1.24 (1.13, 1.36), respectively. As com- pared with inpatients with CHB, cirrhosis inpatients Age were more likely to use antiviral drugs (OR=1.18, 18–29 years 3,589 24.05 43,080 29.99 95% CI: 1.06, 1.30). Inpatients receiving traditional 30–39 years 3,664 24.56 45,683 31.80 Chinese medication had a higher proportion of anti- 40–49 years 3,006 20.15 27,578 19.20 viral drug use than those who did not (OR=2.00, 50–59 years 2,508 16.81 16,046 11.17 ≥60 years 2,153 14.43 11,271 7.85 95% CI: 1.83, 2.18). The second part was used to Gender estimate the annual average expenditures of anti- Male 11,405 76.44 105,195 73.25 viral drug treatment among inpatients prescribed Female 3,515 23.56 38,410 26.75 antiviral drugs. Women and young inpatients had Payment mode higher antiviral drug expenditures than men and Self-payment 9,789 65.61 92,354 64.29 old inpatients. Inpatients with free medical service Medical insurance 4,370 29.29 40,217 27.99 had a 1.32-fold higher expenditure than inpatients Free medical service 663 4.44 11,043 7.69 with self-payment. However, inpatients with medi- Others 98 0.66 44 0.03 cal insurance had a lower expenditure than those Traditional Chinese medicine with self-payment (OR=0.79; 95% CI: 0.75, 0.84). No 6,413 42.98 94,557 65.82 Inpatients receiving traditional Chinese medicine and Yes 8,507 57.02 49,101 34.18 Hepatoprotective drugs hepato-protective drugs had a 1.30-fold and 1.14- No 14,269 95.64 90,578 63.05 fold higher antiviral drug expenditure than inpatients Yes 651 4.36 53,080 36.95 who did not. Annual average antiviral drug costs for Year of visit/admission inpatients increased first and then decreased for the 2008 1,561 10.46 13,777 9.59 period from 2008 to 2015. 2009 1,598 10.71 13,729 9.56 Table 3 showed male and older outpatients had a 2010 1,575 10.56 13,187 9.18 higher probability of antiviral drug utilization. It was 2011 1,665 11.16 19,036 13.25 also seen that outpatients with medical insurance were 2012 1,611 10.8 21,393 14.89 more likely to use antiviral drugs than self-payment 2013 2,264 15.17 20,152 14.03 outpatients (OR=1.66, 95% CI: 1.59, 1.73). Outpa- 2014 2,280 15.28 20,919 14.56 tients who used hepato-protective drugs had a lower 2015 2,366 15.86 21,465 14.94 Disease stage proportion of antiviral use than those who did not CHB 7,886 52.86 122,841 85.51 (36.00% versus 51.30%; OR=0.44, 95% CI: 0.42, Cirrhosis 4,523 30.32 19,357 13.47 0.46). As compared with outpatients with CHB, out- HCC 2,511 16.83 1,460 1.02 patients with cirrhosis were more likely to use anti- Median number of hospital 1.0 3.0 viral drugs (OR=1.58, 95% CI: 1.53, 1.63). Among visits/admissions (P –P ) (1.0–1.0) (1.0–7.0) 25 75 outpatients with antiviral drug expenditure, men had higher antiviral drug expenditures than women. Including commercial insurance and cooperative medical service, etc. CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; PY, person-years. As compared with outpatients with self-payment, 408 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 408 AVT-19-OA-4525_Zhou.indd 408 22/11/2019 11:32:51 22/11/2019 11:32:51 Antiviral drug utilization and costs for CHB, China 2008–2015 Table 2. Utilization of antiviral drugs and corresponding annual antiviral drugs costs and associated factors for inpatients First part: description First part: binary Second part: description Second part: gamma a b b Characteristics n % OR 95% CI P-value Mean (sd ) Median Cost ratio 95% CI P-value Age 18–29 years 1,838 51.21 Reference 2,324.94 (4,904.22) 921.58 Reference 30–39 years 2,105 57.45 1.17 1.05, 1.30 0.0035 2,351.87 (4,198.35) 1,123.84 1.09 1.02, 1.17 0.0122 40–49 years 1,880 62.54 1.30 1.15, 1.47 <0.0001 1,878.36 (3,005.04) 1,097.89 1.00 0.93, 1.08 0.9414 50–59 years 1,530 61.00 1.21 1.06, 1.38 0.0052 1,656.21 (2,350.83) 991.31 0.95 0.87, 1.03 0.1962 ≥60 years 1,265 58.76 1.06 0.92, 1.23 0.4065 1,595.10 (2,230.99) 921.58 0.91 0.83, 1.00 0.0540 Gender Female 1,827 51.98 Reference 2,226.21 (4,013.65) 1,001.05 Reference Male 6,791 59.54 1.38 1.28, 1.51 <0.0001 1,949.60 (3,523.97) 1,016.05 0.96 0.90, 1.01 0.4591 Payment mode Self-payment 5,507 56.26 Reference 1,959.88 (3,217.88) 1,115.55 Reference Medical insurance 2,650 60.64 1.11 1.03, 1.19 0.0152 1,946.16 (4,175.00) 850.02 0.79 0.75, 0.84 <0.0001 Free medical service 415 62.59 1.24 1.13, 1.36 0.0084 3,129.45 (4,917.14) 1,303.34 1.32 1.19, 1.48 <0.0001 Others 46 46.94 1.05 0.68, 1.64 0.8142 1,259.74 (1,327.08) 786.70 1.01 0.74, 1.38 0.9517 Traditional Chinese medicine No 2,948 45.97 Reference 1,550.37 (2,749.21) 704.51 Reference Yes 5,555 65.30 2.00 1.83, 2.18 <0.0001 2,273.17 (4,031.93) 1,209.58 1.30 1.23, 1.38 <0.0001 Hepatoprotective drugs No 8,158 57.17 Reference 2,034.41 (3,700.54) 1,016.05 Reference Yes 345 53.00 0.93 0.77, 1.12 0.4443 1,742.68 (2,311.42) 1,037.68 1.14 1.07, 1.21 0.0244 Year of visit/admission 2008 712 45.61 Reference 1,428.92 (2,326.03) 709.18 Reference 2009 793 49.62 1.20 1.03, 1.40 0.0214 1,363.63 (2,120.32) 696.89 1.04 0.93, 1.16 0.4773 2010 847 53.78 1.29 1.10, 1.50 0.0017 1,837.26 (3,621.43) 977.50 1.29 1.16, 1.44 <0.0001 2011 907 54.47 1.21 1.03, 1.41 0.0189 2,078.61 (3,874.95) 979.64 1.32 1.19, 1.48 <0.0001 2012 1,031 64.00 1.44 1.22, 1.70 <0.0001 3,075.53 (5,860.67) 1,403.16 1.55 1.39, 1.74 <0.0001 2013 1,463 64.62 1.33 1.14, 1.56 0.0004 2,542.53 (4,319.37) 1,270.06 1.33 1.19, 1.47 <0.0001 2014 1,384 60.70 1.21 1.03, 1.41 0.0188 1,741.27 (2,533.46) 967.66 1.11 1.00, 1.23 0.0587 2015 1,481 62.60 1.23 1.05, 1.44 0.0089 1,665.30 (2,287.85) 951.26 1.04 0.94, 1.16 0.4306 Disease stage CHB 4,308 54.63 Reference 2,286.30 (4,461.05) 1,016.05 Reference Cirrhosis 2,896 64.03 1.18 1.06, 1.30 0.0015 1,911.27 (2,804.20) 1,151.98 0.84 0.80, 0.90 <0.0001 HCC 1,414 56.31 0.79 0.70, 0.89 0.0001 1,359.69 (1,767.34) 812.77 0.56 0.52, 0.60 <0.0001 The number of hospital visits/ admissions 1 7,019 54.36 Reference 1,418.91 (1,793.83) 897.39 Reference 2 1,175 78.65 2.90 2.52, 3.35 <0.0001 3,276.99 (4,474.96) 1,883.62 2.32 2.17, 2.49 <0.0001 ≥3 424 82.33 3.20 2.48, 4.11 <0.0001 8,248.15 (10,531.53) 4,129.85 5.53 4.96, 6.15 <0.0001 Intercept 0.61 0.54, 0.69 <0.0001 1,154.01 1,055.08, <0.0001 1,262.22 a b n, the number of antiviral drug use. Description: RMB (yuan). CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; OR, odds ratio. outpatients with medical insurance had a 1.07-fold higher probability of antiviral drug use and higher higher antiviral drug expenditure. Furthermore, out- antiviral drug costs. patients receiving traditional Chinese medicine had a higher antiviral drug expenditure but those receiving Proportion of utilization and annual expenditure for hepato-protective drugs had a lower antiviral drug each antiviral drug expenditure than outpatients who did not, respec- As shown in Figure 2, IFN, ETV, LAM and ADV_C were tively. Outpatients with more hospital visits had a the primary antiviral drugs for inpatients and outpatients. Antiviral Therapy 24.6 409 AVT-19-OA-4525_Zhou.indd 409 AVT-19-OA-4525_Zhou.indd 409 22/11/2019 11:32:51 22/11/2019 11:32:51 F Zhou et al. Table 3. Utilization of antiviral drugs and corresponding annual antiviral drugs costs and associated factors for outpatients First part: description First part: binary Second part: description Second part: gamma a b b Characteristics n % OR 95% CI P-value Mean (sd ) Median Cost ratio 95% CI P-value Age 18–29 years 16,346 37.94 Reference 5,295.95 (6,401.34) 3,657.12 Reference 30–39 years 20,947 45.85 1.19 1.15, 1.23 <0.0001 5,219.27 (6,096.92) 3,675.27 1.04 1.02, 1.06 0.0004 40–49 years 14,390 52.18 1.43 1.37, 1.48 <0.0001 4,475.06 (4,706.03) 3,169.65 0.95 0.92, 0.97 <0.0001 50–59 years 8,311 51.79 1.38 1.32, 1.45 <0.0001 4,017.63 (4,024.97) 2,833.40 0.87 0.85, 0.90 <0.0001 ≥60 years 5,584 49.54 1.23 1.16, 1.30 <0.0001 3,591.28 (3,695.81) 2,380.06 0.79 0.76, 0.81 <0.0001 Gender Female 16,320 42.49 Reference 4,492.66 (5,448.98) 2,975.07 Reference Male 49,233 46.80 1.20 1.18, 1.23 <0.0001 4,882.20 (5,545.02) 3,421.26 1.06 1.04, 1.29 <0.0001 Payment mode Self-payment 37,536 40.64 Reference 4,629.85 (5,449.05) 3,144.90 Reference Medical insurance 23,284 57.90 1.66 1.59, 1.73 <0.0001 5,406.79 (5,659.13) 4,118.42 1.07 1.04, 1.10 <0.0001 Free medical service 4,758 43.09 1.05 1.02, 1.08 0.0243 2,954.61 (4,903.79) 1,257.11 0.62 0.59, 0.65 <0.0001 Traditional Chinese medicine No 42,347 44.81 Reference 4,607.22 (4,952.90) 3,240.37 Reference Yes 23,206 47.27 0.97 0.92, 1.02 0.7758 5,110.06 (6,423.79) 3,474.43 1.07 1.03, 1.11 <0.0001 Hepatoprotective drugs No 46,451 51.30 Reference 4,790.14 (5,191.06) 3,405.63 Reference Yes 19,102 36.00 0.44 0.42, 0.46 <0.0001 4,773.25 (6,259.68) 3,116.74 0.87 0.86, 0.89 <0.0001 Year of visit/admission 2008 4,056 29.44 Reference 4,627.36 (5,932.92) 2,986.88 Reference 2009 4,702 34.25 1.21 1.14, 1.28 <0.0001 4,620.16 (5,758.29) 2,996.43 1.00 0.95, 1.04 0.8321 2010 5,028 38.13 1.32 1.24, 1.40 <0.0001 4,785.42 (6,011.24) 3,280.64 1.05 1.01, 1.10 0.0226 2011 8,176 42.95 1.88 1.79, 1.97 <0.0001 4,103.87 (5,551.22) 2,456.93 0.97 0.93, 1.01 0.1001 2012 10,506 49.11 1.97 1.84, 2.10 <0.0001 4,068.79 (5,299.55) 2,589.32 0.98 0.94, 1.01 0.2235 2013 10,430 51.76 2.31 1.19, 2.43 <0.0001 5,186.13 (5,864.40) 3,804.73 1.15 1.11, 1.20 <0.0001 2014 11,091 53.02 2.48 2.34, 2.62 <0.0001 5,023.65 (5,220.26) 3,744.49 1.12 1.08, 1.17 <0.0001 2015 11,589 53.99 2.49 2.35, 2.63 <0.0001 5,442.55 (5,050.31) 4,179.96 1.21 1.17, 1.26 <0.0001 Disease stage CHB 53,358 43.44 Reference 4,848.03 (5,801.32) 3,308.20 Reference Cirrhosis 11,641 60.14 1.58 1.53, 1.63 <0.0001 4,561.88 (4,093.37) 3,486.61 1.00 0.98, 1.02 0.9555 HCC 579 39.66 0.81 0.71, 0.92 <0.0001 3,367.31 (3,638.20) 2,007.65 0.84 0.78, 0.92 <0.0001 The number of hospital visits/ admissions 1 7,083 16.94 Reference 1,041.06 (1,231.30) 598.47 Reference 2–3 13,121 35.18 2.54 2.41, 2.67 <0.0001 2,371.84 (2,752.24) 1,342.54 2.24 2.20, 2.27 <0.0001 4–7 18,395 59.36 3.56 3.42, 3.70 <0.0001 4,228.52 (3,788.88) 3,134.84 4.24 4.18, 4.30 <0.0001 >7 26,954 80.57 5,37 5.21, 5.53 <0.0001 7,323.87 (6,866.60) 5,810.09 8.79 8.65, 8.93 <0.0001 Intercept 0.10 0.10, 0.11 <0.0001 1,042.73 1,021.13, <0.0001 1,064.79 a b n, the number of antiviral drug use. Description: RMB (yuan). CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; OR, odds ratio. From 2008 to 2015, the annual proportion of utilization 2008 to 19.35% in 2011 and then decreased gradually for IFN dropped from 57.16% to 8.71% for inpatients to 9.24% in 2015. For outpatients, however, it remained and from 24.77% to 3.25% for outpatients, whereas the at a higher level from 2008 to 2015. The proportion of proportion for ETV gradually increased from 11.08% LAM utilization increased from 2008 to 2011 and then to 70.26% for inpatients and from 11.05% to 49.35% gradually decreased for both in- and outpatients. for outpatients, respectively. In addition, the proportion Figure 3 showed annual average actual costs for of ADV_C utilization increased initially from 10.14% in inpatients and outpatients using various antiviral drugs 410 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 410 AVT-19-OA-4525_Zhou.indd 410 22/11/2019 11:32:51 22/11/2019 11:32:51 Antiviral drug utilization and costs for CHB, China 2008–2015 Figure 2. Utilization prevalence of antiviral drugs for inpatients and outpatients using antiviral drugs from 2008 to 2015 Inpatients (n=8,618) IFN ETV ADV LAM LdT TDF ADV_C 2008 2009 2010 2011 2012 2013 2014 2015 Outpatients (n=65,578) IFN ETV ADV LAM LdT TDF ADV_C 2008 2009 2010 2011 2012 2013 2014 2015 ADV, adefovir dipivoxil; ADV_C, made-in-China adefovir dipivoxil; ETV, entecavir; IFN, interferon; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir disoproxil fumarate. during the 8-year period and the corresponding annual antiviral costs achieved the expected costs of norma- expected costs when normative antiviral therapy was tive therapy were found in outpatients (Table 4). assumed. Annual expected costs range from 11,260 to 13,766 RMB for ETV and 5,292 to 6,474 RMB for The proportion of annual antiviral drug costs in TDF. However, actual annual costs were about 5,000 average annual direct medical costs RMB for outpatients using ETV and about 5,500 Figure 4 summarized annual average direct medical RMB for TDF (only the years of 2013, 2014 and 2015, costs and the proportion of annual average antivi- because this drug was launched in 2013) from 2008 to ral drug costs for patients in different disease stages 2015. The actual costs were far less than the annual for the period from 2008 to 2015. The annual direct expected costs for outpatients who received ETV treat- medical costs for inpatients and outpatients were as fol- ment. Less than 40% of patients whose annual actual lows: CHB: 16,439.84 and 6,800.56 RMB; cirrhosis: Antiviral Therapy 24.6 411 AVT-19-OA-4525_Zhou.indd 411 AVT-19-OA-4525_Zhou.indd 411 22/11/2019 11:32:51 22/11/2019 11:32:51 % % F Zhou et al. Figure 3. Annual average costs of various antiviral drugs for inpatients and outpatients from 2008 to 2015 and annual expected costs of normative antiviral therapy Inpatients 14,000 12,000 10,000 8,000 6,000 4,000 2,000 ETV ADV LAM LdT TDF ADV_C Annual simulated costs of normative antiviral therapy 2008 2009 2010 2011 2012 2013 2014 2015 Outpatients 14,000 12,000 10,000 8,000 6,000 4,000 2,000 ETV ADV LAM LdT TDF ADV_C Annual simulated costs of normative antiviral therapy 2008 2009 2010 2011 2012 2013 2014 2015 ADV, adefovir dipivoxil; ADV_C, made-in-China adefovir dipivoxil; ETV, entecavir; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir disoproxil fumarate. 25,379.39 and 8,156.47 RMB; HCC: 33,371.09 and Discussion 6,831.00 RMB, respectively. Among them, antiviral drug costs represented 13.91% and 71.29% of direct In the present study, using electronic medical data from medical costs for inpatients and outpatients with CHB, the largest specialized infection hospital in Guang- respectively. And with the progress of disease, this pro- dong, China, antiviral drug utilization for 14,920 portion decreased to 4.07% for HCC inpatients and inpatients and 143,658 outpatients with CHB infec- 49.29% for HCC outpatients. tion were analysed for the period from 2008 to 2015. 412 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 412 AVT-19-OA-4525_Zhou.indd 412 22/11/2019 11:32:52 22/11/2019 11:32:52 Annual costs of various antiviral drugs, RMB Annual costs of various antiviral drugs, RMB The proportion of antiviral drugs costs in direct medical costs, % Antiviral drug utilization and costs for CHB, China 2008–2015 Table 4. The proportion of outpatients whose annual actual antiviral costs achieved the annual expected antiviral costs of normative therapy from 2008 to 2015 (%) Antiviral drug 2008 2009 2010 2011 2012 2013 2014 2015 ETV 15.63 14.31 11.99 11.35 9.92 16.32 15.39 17.01 (73/467) (77/538) (80/667) (185/1,630) (275/2,773) (619/3,794) (747/4,853) (979/5,755) ADV 16.16 21.07 25.82 16.8 15.62 15.48 14.93 0.3 (74/458) (118/560) (150/581) (171/1,018) (221/1,415) (232/1,499) (200/1,340) (3/993) LAM 3.28 6.61 8.26 7.27 5.16 5.47 5.15 5.94 (15/458) (37/560) (48/581) (74/1,018) (73/1,415) (82/1,499) (69/1,340) (59/993) LdT 25.09 16.67 13.46 7.99 8.66 19.74 19.44 20.23 (143/570) (89/534) (58/431) (48/601) (108/1,247) (328/1,662) (370/1,903) (458/2,264) TDF – – – – – 36.36 40.43 36.23 (8/22) (19/47) (100/276) ADV_C 26.61 27.89 27.84 20.77 19.59 21.96 17.68 5.32 (393/1,477) (509/1,825) (600/2,155) (701/3,375) (795/4,059) (806/3,670) (602/3,405) (211/3,967) ADV, adefovir dipivoxil; ADV_C, made-in-China adefovir dipivoxil; ETV, entecavir; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir disoproxil fumarate. Figure 4. The annual average direct medical costs and the proportion of antiviral drugs costs in direct medical costs for inpatients and outpatients by different disease stages 35,000 33,371.09 80.00 71.29 70.00 30,000 25,379.39 60.00 55.93 25,000 50.00 49.29 20,000 16,439.84 40.00 15,000 30.00 10,000 8,156.47 20.00 6,800.56 6,831.00 13.91 5,000 10.00 7.53 4.07 0 0.00 CHB Cirrhosis HCC CHB Cirrhosis HCC Inpatients Outpatients Direct medicine costs Proportion, % CHB, chronic hepatitis B; HCC, hepatocellular carcinoma. Nearly half of the infected patients did not receive year, including ETV and TDF, as the first-line antiviral antiviral treatment in Guangzhou. The overall propor- drugs [8–11]. tion of antiviral drug utilization was 56.99% for inpa- Antiviral treatment can achieve sustained suppres- tients and 45.65% for outpatients. However, the pro- sion of HBV DNA replication, and slow disease pro- portion of antiviral drug utilization increased every gression. The WHO Global Health Sector Strategy on Antiviral Therapy 24.6 413 AVT-19-OA-4525_Zhou.indd 413 AVT-19-OA-4525_Zhou.indd 413 22/11/2019 11:32:52 22/11/2019 11:32:52 Mean direct medical costs per patient per year, RMB F Zhou et al. Viral Hepatitis with the purpose of an elimination of which needs to be further evaluated. In addition to the HBV in 2030, targets to provide antiviral treatment for effect of reimbursement policy, our results showed that 80% of those diagnosed and eligible for treatment [23]. outpatients receiving hepato-protective drugs were less China has the largest number of patients with hepati- likely to use antiviral drugs than outpatients who did tis B infections in the world. However, a large number not receive hepato-protective drugs. of the patients did not receive antiviral treatment in WHO estimated that the most important part of the this country. Research form Beijing You’an Hospital in total costs was hepatitis screening fees and antivirus 2008–2012 and from 10 hospitals in western China in treatment costs for CHB in low and middle-income 2011 also demonstrated a low proportion of using anti- countries [31]. In this study, the costs of antiviral ther- viral drugs [24,25]. This phenomenon was also observed apy were an important part of the economic burden, in some Western countries. A study of electronic health especially in the early stage of disease progression. records in the United States found that antiviral therapy Annual average antiviral drug costs for outpatients with was received by 57.90% of HBV-infected patients [26]. CHB was 4,848.03 RMB, and it accounted for 71.29% It was even lower (25%) in Belgium [27]. One possible of annual direct medical costs. When the disease pro- explanation was that there were increased numbers of gresses to HCC, the hospitalization risk increases and patients with HBV infection who did not meet antivi- the medical costs also increase substantially [32–34]. ral indications in areas with a low prevalence. It was a The annual direct medical cost for HCC inpatients was concern that only 5% of individuals eligible for treat- 3,3371.09 RMB, but the antiviral drugs accounted for ment actually received antiviral therapy globally, and only 4.07%. Normative antiviral therapy in early stage this rate was about 11% in China [28]. of disease progression slows down the disease progres- Given the importance of antiviral therapy in patients sion, improves the quality of life and reduces other with CHB infection, it is imperative to identify the influ- medical expenses caused by disease progression. How- encing factors of antiviral therapy. From the perspec- ever, we found that the actual annual antiviral drug tive of macro-management, reimbursement policy is the costs were significantly lower than normative treat- most critical positive factor. In this study, the antiviral ment costs based on the Chinese medicine price net- utilization increased in inpatients with medical insur- work [17]. Taking TDF as an example, less than 40% ance more than those with self-payment. A study by of outpatients with antiviral drug treatment achieved Liaw [7] revealed that lack of reimbursement for treat- the expected costs of normative therapy. This may be ment is an obstacle to the proper management of HBV related to poor persistence and adherence of patients. disease. Another study from South Korea also showed A large-scale study of patient adherence with antiviral that the number of patients receiving oral antiviral ther- therapy for CHB infection reported a persistence rate apy for HBV precipitously increased since life-long reim- of 85.5% in the United States [35]. In China, the adher- bursement of oral antiviral agents was approved [29]. ence rate to antiviral therapy in China is far from opti- Since 2008, health insurance policy has experienced a mistic [36]. Non-adherence can result in poor virology series of changes in Guangzhou. The Outpatient Medi- suppression, breakthrough resistance and progression cal Insurance Fund Policy was implemented in Guang- of disease [37]. zhou on 1 August 2008 that provided a monthly quota This study included a large study population from payment for patients. Until 1 October 2013, both urban 8-year retrospective inpatient and outpatient cohorts and rural residents were paid with CHB patients receiv- and used novel two-part model methodology. How- ing 100 RMB per month by this Fund. The payment ever, there are some limitations. First, there were increased to 400 RMB per month on 1 January 2015. possible selection biases in our study, owing to study In this study, the effect of reimbursement policy on the individuals coming from one hospital. However, the proportion of antiviral drug use tended to increase with Guangzhou Eighth People’s Hospital is the largest time, especially for first-line treatment drug ETV. IFN specialized infection hospital in Guangdong Prov- and NAs (ETV, ADV, LAM and LdT) have been listed ince, and most patients with HBV-related diseases on the National Reimbursement Catalog of Drugs would usually seek their medical care services from for Basic Medical Insurance since 1 July 2011, which large hospitals rather than county-level hospitals and increases the affordability as well as allows patients to community clinics [38]. Our study population had a use more expensive drugs such as first-line treatment similar distribution of demographic characteristics of drug ETV, which offered better therapeutic efficacy, and subjects as compared with others [16,32,34]. Second, fewer side effects and drug resistance [5,30]. Therefore, there was a lack of information on other influenc- medical insurance optimized the availability of antiviral ing factors at the individual level, such as education, drugs. Additionally, in May 2016, TDF was included household income and lifestyle. Third, we were not in the National Medical Insurance, which would sig- able to distinguish between treatment-naive patients nificantly increase the use of first-line antiviral drugs, (patients who had not received antiviral therapy 414 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 414 AVT-19-OA-4525_Zhou.indd 414 22/11/2019 11:32:52 22/11/2019 11:32:52 Antiviral drug utilization and costs for CHB, China 2008–2015 9. Korean Association for the Study of the Liver. KASL clinical before the study) and treatment-experienced patients practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol 2016; 22:18–75. (patients who had received antiviral therapy before the study), thus initiation, switch or add-on treat- 10. Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a ments were not considered and compared with estab- 2015 update. Hepatol Int 2016; 10:1–98. lished guidelines in this study. Fourth, HCC patients 11. Terrault NA, Bzowej NH, Chang KM, et al. AASLD were likely to be underrepresented since it is not a guidelines for treatment of chronic hepatitis B. Hepatology 2016; 63:261–283. cancer hospital. 12. Chang TT, Gish RG, de Man R, et al. A comparison of In conclusion, nearly half of the patients with CHB entecavir and lamivudine for HBeAg-positive chronic infection received antiviral treatment from 2008 to hepatitis B. N Engl J Med 2006; 354:1001–1010. 2015 in Guangzhou, China. The proportion of antivi- 13. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic ral drug utilization increased annually, especially ETV hepatitis B. N Engl J Med 2008; 359:2442–2455. and TDF as first-line treatment drugs. Reimbursement 14. Yao G, Chen C, Lu W, et al. Efficacy and safety of entecavir policy was the most important factor affecting antivi- compared to lamivudine in nucleoside-naive patients with chronic hepatitis B: a randomized double-blind trial in ral treatment. The costs of antiviral therapy were an China. Hepatol Int 2007; 1:365–372. important part of the direct medical costs, especially 15. Chan HL, Jia J. Chronic hepatitis B in Asia-new insights in the early stage of disease progression. However, the from the past decade. J Gastroenterol Hepatol 2011; 26 Suppl 1:131–137. actual annual average costs of antiviral drugs were 16. Qiu Q, Duan XW, Li Y, et al. Impact of partial lower than expected, suggesting that the dosage of reimbursement on hepatitis B antiviral utilization and antiviral drugs might not be enough for patients with adherence. World J Gastroenterol 2015; 21:9588–9597. antiviral therapy. 17. Chinese medicine price network. (Accessed 16 July 2017.) Available from http://www.zgyyjgw.com/front/cn/retailPrice 18. Smith DH, Gravelle H. The practice of discounting in Acknowledgements economic evaluations of healthcare interventions. Int J Technol Assess Health Care 2001; 17:236–243. Funding: this study was supported by the National 19. Chinese Pharmacoeconomics Evaluation Guide Research Group, Liu GE, Hu SH, Wu JH. [Chinese Natural Science Foundation of China (No.71573059); pharmacoeconomics evaluation guide (2011 edition)]. and The Medical Scientific Research Foundation of Chin Pharmacoeconom 2011; 3:1–23. Chinese. Guangdong Province, China (No. A2017036). 20. Manning WG, Basu A, Mullahy J. Generalized modeling approaches to risk adjustment of skewed outcomes data. J Health Econ 2005; 24:465–488. Disclosure statement 21. Buntin MB, Zaslavsky AM. Too much ado about two- part models and transformation? Comparing methods of modeling Medicare expenditures. J Health Econ 2004; No conflict of interest exits in the submission of this 23:525–542. manuscript, and manuscript is approved by all authors 22. Duan N, Manning WG, Jr. A comparison of alternative for publication. models for the demand for medical care. J Bus Econ Stat 1983; 1:115–126. 23. WHO. Global Health Sector Strategies for viral hepatitis References 2016–21. 2016. (Accessed 1 July 2016.) Available from http://www.who.int/hepatitis/strategy2016-2021/ghss-hep/en 1. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of 24. Qiu Q, Li Y, Duan XW, et al. Impact of a new age-specific HBsAg seroprevalence and endemicity. Vaccine reimbursement program on hepatitis B antiviral medication cost and utilization in Beijing, China. PLoS One 2014; 2012; 30:2212–2219. 9:e109652. 2. Zhang WL, Ji Z, Fu T, Zhang L, Su H, Yan Y. [Meta analysis 25. Sun YT, Zhang YX, Tang H, et al. Clinical characteristics on HBsAg-positive rate among general populations aged and current management of hepatitis B and C in China. 1–59 years, 2007–2016, China]. Zhonghua Liu Xing Bing World J Gastroenterol 2014; 20:13582–13590. Xue Za Zhi 2017; 38:1278–1284. Chinese. 26. Moorman AC, Gordon SC, Rupp LB, et al. Baseline 3. Zeng F, Guo P, Huang Y, et al. Epidemiology of hepatitis B characteristics and mortality among people in care for virus infection: results from a community-based study of 0.15 chronic viral hepatitis: the chronic hepatitis cohort study. million residents in South China. Sci Rep 2016; 6:36186. Clin Infect Dis 2013; 56:40–50. 4. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009; 27. De Vroey B, Moreno C, Laleman W, et al. Hepatitis B virus 373:582. and hepatitis C virus infections in Belgium: similarities 5. Yuen MF, Lai CL. Treatment of chronic hepatitis B: and differences in epidemics and initial management. Eur J evolution over two decades. J Gastroenterol Hepatol 2011; Gastroenterol Hepatol 2013; 25:613–619. 26 Suppl 1:138–143. 28. Razavi-Shearer D, Gamkrelidze I, Nguyen MH, et al. Global 6. Sun J, Hou JL. Management of chronic hepatitis B: experience prevalence, treatment, and prevention of hepatitis B virus from China. J Viral Hepat 2010; 17 Suppl 1:10–17. infection in 2016: a modelling study. Lancet Gastroenterol Hepatol 2018; 3:383–403. 7. Liaw YF. Antiviral therapy of chronic hepatitis B: opportunities and challenges in Asia. J Hepatol 2009; 51:403–410. 29. Choi J, Han S, Kim N, Lim YS. Increasing burden of liver cancer despite extensive use of antiviral agents in a hepatitis B 8. Chinese Society of Hepatology CMA, Hou JL, Lai W. [The virus-endemic population. Hepatology 2017; 66:1454–1463. guideline of prevention and treatment for chronic hepatitis B: a 2015 update]. Zhonghua Gan Zang Bing Za Zhi 2015; 30. Osborn M. Safety and efficacy of entecavir for the treatment of chronic hepatitis B. Infect Drug Resist 2011; 4:55–64. 23:888. Chinese. Antiviral Therapy 24.6 415 AVT-19-OA-4525_Zhou.indd 415 AVT-19-OA-4525_Zhou.indd 415 22/11/2019 11:32:52 22/11/2019 11:32:52 F Zhou et al. 31. WHO. Combating hepatitis B and C to reach elimination 35. Chotiyaputta W, Peterson C, Ditah FA, Goodwin D, Lok by 2030: advocacy brief. (Accessed 16 July 2017.) Available ASF. Persistence and adherence to nucleos(t)ide analogue from http://www.who.int/hepatitis/publications/hep- treatment for chronic hepatitis B. J Hepatol 2011; 54:12–18. elimination-by-2030-brief/en/ 36. Xu K, Liu LM, Farazi PA, et al. Adherence and perceived 32. Che YH, Chongsuvivatwong V, Li L, et al. Financial burden barriers to oral antiviral therapy for chronic hepatitis B. on the families of patients with hepatitis B virus-related liver Glob Health Action 2018; 11:1433987. diseases and the role of public health insurance in Yunnan 37. European Association For The Study Of The Liver. EASL province of China. Public Health 2016; 130:13–20. Clinical Practice Guidelines: management of chronic 33. Hu M, Chen W. Assessment of total economic burden of hepatitis B. J Hepatol 2012; 57:167–185. chronic hepatitis B (CHB)-related diseases in Beijing and 38. Zhang S, Ma Q, Liang S, et al. Annual economic burden Guangzhou, China. Value Health 2009; 12:S89. of hepatitis B virus-related diseases among hospitalized 34. Lu J, Xu A, Jian W, et al. Direct economic burden of patients in twelve cities in China. J Viral Hepat 2016; hepatitis B virus related diseases: evidence from Shandong, 23:202–210. China. BMC Health Serv Res 2013; 13:37. Accepted 27 June 2019; published online 26 July 2019 416 ©2019 International Medical Press AVT-19-OA-4525_Zhou.indd 416 AVT-19-OA-4525_Zhou.indd 416 22/11/2019 11:32:52 22/11/2019 11:32:52

Journal

Antiviral Therapy – SAGE

Published: Aug 1, 2019

There are no references for this article.