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Impact of a New Reimbursement Program on Hepatitis B Antiviral Medication Cost and Utilization in Beijing, China

Impact of a New Reimbursement Program on Hepatitis B Antiviral Medication Cost and Utilization in... Background: Hepatitis B virus (HBV) infection is a significant clinical and financial burden for chronic hepatitis B (CHB) patients. In Beijing, China, partial reimbursement on antiviral agents was first implemented for the treatment of CHB patients in July 1, 2011. Aims: In this study, we describe the medical cost and utilization rates of antiviral therapy for CHB patients to explore the impact of the new partial reimbursement policy on the medical care cost, the composition, and antivirals utilization. Methods: Clinical and claims data of a retrospective cohort of 92,776 outpatients and 2,774 inpatients with non-cirrhotic CHB were retrieved and analyzed from You’an Hospital, Beijing between February 14, 2008 and December 31, 2012. The propensity score matching was used to adjust factors associated with the annual total cost, including age, gender, medical insurance type and treatment indicator. Results: Compared to patients who paid out-of-pocket, medical cost, especially antiviral costs increased greater among patients with medical insurance after July 1, 2011, the start date of reimbursement policy. Outpatients with medical insurance had 16% more antiviral utilization; usage increased 3% among those who paid out-of-pocket after the new partial reimbursement policy was implemented. Conclusions: Direct medical costs and antiviral utilization rates of CHB patients with medical insurance were higher than those from paid out-of-pocket payments, even after adjusting for inflation and other factors. Thus, a new partial reimbursement program may positively optimize the cost and standardization of antiviral treatment. Citation: Qiu Q, Li Y, Duan X-w, Yang L-k, Chen Y, et al. (2014) Impact of a New Reimbursement Program on Hepatitis B Antiviral Medication Cost and Utilization in Beijing, China. PLoS ONE 9(10): e109652. doi:10.1371/journal.pone.0109652 Editor: Xiaoping Miao, MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, China Received July 4, 2014; Accepted September 2, 2014; Published October 16, 2014 Copyright:  2014 Qiu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper. Funding: This study was supported by the Ministry of National Science and Technology of China (2012ZX10004904), Bristol-Myers Squibb Company (AI463-961), Beijing Municipal and Technology Commission (Z131100004613030) and Innovative Foundation of Beijing Union Medical College. The funders had no rolein study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: This study was supported by the Ministry of National Science and Technology of China (2012ZX10004904), Bristol-Myers Squibb Company (AI463-961), Beijing Municipal and Technology Commission (Z131100004613030), and Innovative Foundation of Beijing Union Medical College. Although some funding we received was from a commercial source "Bristol-Myers Squibb Company", which is the manufacturer of BARACLUDE (entecavir), one of the antiviral agents studied in our study for research grants, this does not alter our adherence to PLOS ONE policies on sharing data and materials. Also, the authors have not signed an agreement with Bristol-Myers Squibb Company of the research reported in the contribution that prevents them from publishing both positive and negative results or that forbids them from publishing this research without the prior approval of the sponsor. ZPD and LW have received research support from Bristol-Myers Squibb. QQ, YL, XWD, LKY, YC and HL have no conflicts. * Email: liwang@ibms.pumc.edu.cn (LW); duan2517@163.com (ZPD) . These authors contributed equally to this work. Individuals with chronic HBV have a 15–40% probability for Introduction developing compensated cirrhosis, decompensated cirrhosis and Hepatitis B viral (HBV) infection is a global public health hepatocellular carcinoma, which significantly affect patient treat- problem. A universal vaccination program against HBV has been ment outcomes and quality of life measures. Also, healthcare costs carried out in China since 1992, contributing significantly to can increase with disease progression [3,4]. Thus prevention or reduced HBV surface antigen (HBsAg)-positive rate (9.75% in delay of hepatic HBV progression may offer better outcomes and 1992 to 7.18% in 2006) [1]. However there were still estimated 20 significant savings. million individuals with HBV in China [2], representing a At this time, antiviral treatment can reduce fibrosis progression financial burden to themselves and their families. and cirrhosis and prevent further disease progression, including PLOS ONE | www.plosone.org 1 October 2014 | Volume 9 | Issue 10 | e109652 Reimbursement on Hepatitis B Cost hepatocellular carcinoma [5,6,7]. Over the past 10 years, and other kinds of insurance that included the new rural cooperative medical scheme (NCMS), free medical service, considerable improvement in HBV treatment has occurred, including development of antivirals such as interferon (IFN)-based commercial insurance for medical care which was voluntary paid therapy and nucleos(t)ide analogs (NAs). Four NAs: lamivudine by patients themselves and compensated by insurance companies, (LAM), adefovir (ADV), entecavir (ETV) and telbivudine (LdT) and so on. Baseline and laboratory tests were also retrieved from have been approved in China. The costs and utilization of these the electronic medical record to identify treatment indicator. drugs in China have yet to be described, especially in the setting of These tests included routine biochemical tests (serum alanine a new reimbursement program in Beijing. aminotransferase), virological markers (serum HBV DNA) and In Beijing, no reimbursement was available for HBV antivirals hepatitis B e antigen (HBeAg) status. Direct medical expenses included any expenditure from registration, lab tests, imaging tests, prior to July 1, 2011: all drug expenses were paid by the individual medications, hospital stays and hospital supplies. Indirect cost, patients. This may have resulted in low compliance due to cost [8]. including medical leave, time off, and productivity loss, was not At this time, IFN and NAs are listed with the National collected. We also collected detailed antiviral utilization, including Reimbursement Catalog of Drugs for Basic Medical Insurance and partial reimbursement has been available since July 1, 2011 in drug names, dosage, costs, and treatment durations. Indirect costs, reflecting the value of lost productivity but other losses, such as Beijing, mainly designed for civil residents. Patients could receive a 75–85% reimbursement of the cost between a deductible of 1,800 patient travel and medical assistance expenditures, however, were not included. yuan and a ceiling of 20,000 yuan. This should increase affordability and patient compliance but data have not been collected and studied. Thus, we investigated this new partial Cost estimation reimbursement program on cost, patient demographics, and All costs were inflated to Dollars in the year 2012 using the antiviral utilization. Consumer Price Index for Health in Beijing [10] and also With inpatient and outpatient electronic data from Beijing expressed in US dollars in the year of 2012. The exchange rate of You’an Hospital, a university affiliated infectious disease hospital RMB to USD was 6.3 to 1. Annual inpatient and outpatient costs in Beijing, China, we estimated average annual treatment costs for each patient were calculated according to the following and the proportion of costs of drugs (including antivirals), formula: laboratory tests, and related fees to describe the current treatment patterns for CHB patients to understand how the new partial Annual inpatient (outpatient) cost~S (a,b,c,:::,n) reimbursement policy affects healthcare costs, patients affected and utilization of antiviral drugs. Where a, b, c…, z represents actual costs occurred for each Materials and Methods visit/hospital admission of that year, such as drug costs, lab and Ethics statement imaging tests, registration, and all related costs. Finally, n The study protocol was approved by the Ethical Review represents visit times for each patient each year. Committee of Beijing You’an Hospital, Capital Medical Univer- Because the electronic medical record system in You’an sity and Institute of Basic Medical Sciences Chinese Academy of Hospital was established on February 14, 2008, records prior to Medical Sciences. The team obtained informed consent from this date could not be collected, which may lead to an artificially hospital authorities for data collection. No informed consent, lower annual cost per person. Thus, the average proportion of written or oral, was obtained from the participants because only visits before February 14 from 2009 to 2012 was used to adjust the the electronic medical records were retrieved to do the analysis visit time and the corresponding annual cost per person in 2008. and only necessary data for study objectives were extracted. To explore the effect of the new partial reimbursement program Deidentification was done to assure confidentiality of the study on care costs, patient composition, and antiviral utilization, we data. divided 2011 data into two parts: costs in the first and second half of the year. Each half-year cost was adjusted by the corresponding half-year cost in 2010 and 2012 using the following formula: Study population A retrospective cohort study was conducted on CHB patients at You’an Hospital, Beijing, between February 14, 2008 and first half year cost in 2010 first half year cost in 2011 December 31, 2012. Patients were diagnosed by the ‘‘Asian- cost in 2010 cost in 2011 Pacific consensus statement on the management of CHB [9]’’. Patients co-infected with hepatitis A, C, D and E, human immunodeficiency virus, cytomegalovirus or those admitted to first half year cost in 2011 first half year cost in 2012 the hospital due to diagnosed liver cirrhosis or hepatocellular cost in 2011 cost in 2012 carcinoma or other diseases or conditions, including pregnancy, glomerulonephritis, uremia, complications of metabolic syndrome, tumors, and cardiovascular diseases, were excluded. Also, non- residents of Beijing were excluded. Propensity score matching The treatment cost was greatly influenced by the socio- Data collection economic status, medical technology, the health care system, the Demographic characteristics, clinical information and medical patients’ disease severity and healthcare awareness [8]. Logistic expenses for each patient visit were retrieved from electronic regression was adopted to estimate the propensity score (PS). The medical records. Demographic characteristics included, gender, dependent variable was admission year and the independent birth date, admission (or visit) date, inpatient discharge date, and variable (covariates) were age, gender, medical insurance type and health insurance type were documented. Health insurance type treatment indicator (patients were considered treatment indicated was categorized into 3 groups: out-of-pocket, medical insurance if met one of the following conditions: (1) serum alanine PLOS ONE | www.plosone.org 2 October 2014 | Volume 9 | Issue 10 | e109652 Reimbursement on Hepatitis B Cost Figure 1. Patient selection procedure. doi:10.1371/journal.pone.0109652.g001 aminotransferase over two times upper limit of normal (40 U/L); characteristics would be comparable among the six time periods. For inpatients, the smallest sample size was from the first half of (2) log DNA. = 5 copies/ml for HBeAg (+) patients; (3) log 10 10 DNA. = 4 copies/ml for HBeAg (2) patients [11]). All covariates 2011. So, this was used as the control group. were entered into the logistic regression model and the probability of being in the case group (known as PS) was then calculated for Statistical analysis each patient. As a 1:1 matching was adopted thus outpatients in The average annual cost for inpatients and outpatients was 2008 were considered as the control group due to the smallest expressed as median (first quartile and third quartile). The sample size. Outpatients in 2009, 2010, 2011 (first half-year), 2011 proportion of the cost of laboratory tests, medications (especially (second half-year) and 2012, were matched as the case group to the antivirals) was calculated by the annual total cost of laboratory control group by PS within a range of 0.1 standard deviation tests and medications divided by the total costs for all patients. respectively. Then, data from 2008 that had been matched to all Chi-square test was used to detect differences in the proportion five years and corresponding pairs were selected so that baseline of antiviral therapy among outpatients with different medical PLOS ONE | www.plosone.org 3 October 2014 | Volume 9 | Issue 10 | e109652 Reimbursement on Hepatitis B Cost insurance types. SAS 9.2 (Windows, SAS Institute Inc., Cary, NC) was used to perform the statistical analysis. Results A total of 444,900 outpatients and 4,759 inpatients medical records of CHB patients were documented from February 14, 2008 to December 31, 2012. A total of 1,428 medical records with no treatment, 128,467 cases admitted to the hospital with other diseases or conditions, as well as 3,339 cases from outside of Beijing who were covered by different local reimbursement policies from those in Beijing were excluded, leaving 313,411 outpatients and 3,014 inpatients medical records. Figure 1 depicts the selection procedure. Subject characteristics Patient demographics among different admission years are depicted in Table 1. Age, gender, health insurance type and treatment indicator was significantly different among admission years. Patients in each admission year were predominantly male and the mostly male was in 2008 for outpatients and 2009 for inpatients. The proportion of patients who paid out-of-pocket decreased and those with medical insurance increased annually. To allow a common ground for comparison among different admission year, PS matching were conducted by selected key characteristics. PS matching resulted in a matched sample size of 10,587 for outpatients and 186 for inpatients for each admission year and the distribution of key confounders, including age, gender, insurance status and treatment indicator, was similar in outpatients and inpatients in different admission years (Table 2). Cost analysis The direct costs and cost composition from year 2008–2012 after PS matching were shown in Table 3. Two apparent inflection points may have explained the outpatients cost changes in 2009 and the second half of 2011. For inpatients, the annual average costs were higher than outpatients in the same year and annual costs for inpatients increased yearly, peaking in the second half of 2011. Composition analysis revealed that the proportion of drug costs nearly identical (,80%) for outpatients and 60% for inpatients during the study period. After a steady growth prior to July 1, 2011, the implementation of the partial reimbursement policy, antiviral costs jumped from 53 to 64% for outpatients and from 8 to 13% for inpatients. The proportion of laboratory costs increased from 11 to 15% for outpatients but decreased from 21 to 14% for inpatients. Anti-viral drug and medical service utilization Because inpatients focused on symptomatic treatment, we only analyzed antiviral drug utilization for outpatients. We found that the antiviral utilization had grown rapidly since the second half year of 2011 (Figure 2). The antiviral utilization was around 40% before July 1, 2011 and jumped to 50% after then. Among outpatients who received antiviral treatment, ADV was the most frequently prescribed antiviral, comprising 50% of those prescribed during the 5-year period, even though utilization of this compound decreased slightly. IFN usage decrease from 20 to 12% after the new policy was implemented. However the proportion of patients using ETV increased 4% before July 1, 2011 and increased 10% after that time. LdT and LAM did not change much regarding usage (Figure 3). PLOS ONE | www.plosone.org 4 October 2014 | Volume 9 | Issue 10 | e109652 Table 1. Demographic characteristic of CHB patients from 2008 to 2012. Age(year) Gender Insurance type (%) Treatment indicated Out-of- Medical Year N Mean±Sd p Male% p Else p % P pocket insurance Outpatient 2008 11222 39.0613.7 ,0.0001 68.6 ,0.0001 68.3 23.8 7.9 ,0.0001 12.8 ,0.0001 2009 16767 38.2613.5 67.5 67.1 22.8 10.1 22.8 2010 20737 38.1612.9 65.5 61.0 26.3 12.7 23.9 2011 22070 39.2612.3 63.4 52.6 36.6 10.8 20.3 2012 21980 39.4612.8 62.8 49.1 42.7 8.2 20.0 Inpatient 2008 383 34.5612.1 ,0.0001 71.0 ,0.0001 67.6 25.6 6.8 ,0.0001 36.0 ,0.0001 2009 666 35.7612.4 77.3 67.8 23.9 8.3 37.8 2010 606 36.1612.9 74.6 58.1 21.9 20.0 40.1 2011 570 41.7613.6 71.4 43.3 36.1 20.6 47.0 2012 549 41.1612.8 69.0 27.0 53.9 19.1 42.1 doi:10.1371/journal.pone.0109652.t001 Reimbursement on Hepatitis B Cost PLOS ONE | www.plosone.org 5 October 2014 | Volume 9 | Issue 10 | e109652 Table 2. Demographic characteristic of CHB patients from 2008 to 2012 after PS matching. Age(year) Gender Insurance type (%) Treatment indicated Out-of- Medical Year N Mean±Sd p Male% p Else p % P pocket insurance Outpatient 2008 10587 39.1613.0 0.8306 67.9 0.4289 66.4 25.2 8.4 0.7495 13.5 0.7192 2009 10587 39.0612.8 68.7 67.3 24.3 8.4 13.5 2010 10587 39.0612.7 68.0 66.6 25.1 8.3 13.5 First half of 2011 10587 39.0612.3 67.7 66.8 25.1 8.1 14.0 Second half of 2011 10587 39.2612.8 67.5 66.6 25.2 8.2 13.4 2012 10587 39.4612.6 68.4 67.0 25.2 7.8 13.6 Inpatient 2008 186 39.0611.5 0.5171 74.7 0.682 61.8 26.4 11.8 0.0244 41.4 0.1364 2009 186 39.0612.5 77.4 53.2 37.1 9.7 43.0 2010 186 38.5612.6 76.9 53.2 28.5 18.3 43.0 First half of 2011 186 38.5612.0 72.6 55.9 33.9 10.2 44.1 Second half of 2011 186 41.2612.1 73.1 47.3 38.2 14.5 47.9 2012 186 40.8612.3 71.0 46.8 37.1 16.1 50.0 doi:10.1371/journal.pone.0109652.t002 Reimbursement on Hepatitis B Cost Table 3. Annual total cost and the composition among CHB patients from 2008 to 2012. Total Year Antiviral cost (%) Medicine without antivirals (%) Test (%) Others (%) Median(p25,p75) Outpatient 2008 179.2 (67.0,481.5) 53.1 32.3 10.9 3.7 2009 219.9 (74.4,709.1) 57.7 28.2 10.8 3.3 2010 201.1 (66.7,689.6) 56.4 27.0 12.8 3.8 First half of 2011 170.1 (66.9,483.1) 56.8 23.4 15.8 4.0 Second half of 2011 219.5 (82.0,605.1) 63.0 19.6 14.1 3.3 2012 217.1 (77.0,729.1) 63.9 17.3 15.4 3.4 Inpatient 2008 1274.8 (529.5,2409.8) 8.3 52.3 20.6 18.8 2009 1590.7 (614.0,2854.8) 11.5 49.8 20.6 18.1 2010 1612.2 (679.6,2491.0) 12.5 49.4 20.7 17.4 First half of 2011 1357.4 (299.2,2851.1) 9.2 52.7 14.1 24.0 Second half of 2011 2060.1 (641.7,3623.6) 9.5 54.7 14.4 21.4 2012 1697.9 (496.8,3616.4) 13.2 48.8 13.6 24.4 doi:10.1371/journal.pone.0109652.t003 pocket. This rate increased from 43.0 to 45.1% after the new Effect of partial reimbursement policy on patients with policy was implemented (Figure 2). For patients with medical different insurance insurance, however, the difference between different admission The new partial reimbursement program was only available to years before July 1, 2011 did not exceed 8% and increased from patients with medical insurance, so we divided patients into three 49.1 to 65.9% after that time. Among patients with other insurance groups (out-of-pocket, medical insurance, and other insurance types, most were covered by NCMS or had free types of insurance) to investigate the effect of the new partial medical services. Antiviral utilization ranged from 41.3–45.2% for reimbursement policy. those with free medical care and from 39–45% for those with Total cost. Data indicate that the total annual cost was NCMS from 2008–2011 and this increased from 41.2 to 51.9% higher among both outpatients and inpatients with medical and from 45.2 to 60.9% after July 1, 2011, respectively. These insurance compared to those who paid out-of-pocket, especially increases were lower than experienced by those with medical since the second half year of 2011. The total cost for outpatients insurance but higher than the costs for those who paid out-of- with medical insurance increased 50% after the second half of pocket (data not shown). 2011, compared to before. For patients who paid out-of-pocket, The proportion of outpatients with medical insurance treated rates increased only 19% (Table 4). with ETV increased from 30% to more than 40% with an annual Cost composition. Among outpatients, the proportion of growth of 34% since July 1, 2011, higher than before July 1, 2011. costs for lab tests among the three insurance groups increased Annual growth of no more than 20% was observed among those somewhat during the study period; drug costs increased more who paid out-of-pocket and this was not different to costs prior to rapidly among those with medical insurance than those who paid July 1, 2011. Decreased use of ADV among patients with medical out-of-pocket after the second half of 2011. Non-antiviral drug insurance during the second half of 2011 was 8.3% of the previous costs were not different between the two groups. For inpatients, a year, which was twice that of patients who paid out-of-pocket. The yearly decrease in lab costs was observed among all three groups yearly utilization trend for the other three antivirals was not and drug costs rose annually among the three groups (Table 4). different between patients with medical insurance and those who Antiviral utilization. Before the first half of 2011, antiviral paid out-of-pocket (Figure 3). utilization fluctuated ,2% for outpatients who paid out-out- For outpatients with free medical care, ADV use decreased from 50.0 to 38.8% and ETV use increased from 36.8 to 51.0% after July 1, 2011. For those with NCMS, ADV use decreased during the study period and ETV use was 10% lower than the use observed by individuals with free medical care in the same year before July 1, 2011. After the implementation of the new policy, this use was still lower than that of outpatients who paid out-of- pocket. Over time, ETV utilization grew among those with NCMS compared to outpatients with other insurance types (data not shown). Medical service utilization was observed higher among those with medical insurance compared to those who paid out-out- pocket. Proportion of patients who visited hospital three or more than three times a year increased from 39.2% in 2008 to 55.9% in 2012 among insured patients during the study period, while Figure 2. Antiviral utilization among CHB patients with increased slightly from 26.8% in 2008 to 36.4% in 2012 for those different insurance types from 2008–2012. paid out-of-pocket (data not shown). doi:10.1371/journal.pone.0109652.g002 PLOS ONE | www.plosone.org 6 October 2014 | Volume 9 | Issue 10 | e109652 Reimbursement on Hepatitis B Cost Figure 3. Antiviral composition of outpatients prescribed antivirals with different insurance types from 2008–2012. *Note: some patients treated with more than one antiviral at the same time may increase the sum of antiviral composition to more than 1 in each year. doi:10.1371/journal.pone.0109652.g003 utilization among outpatients, specifically in the second half of Discussion 2011 and 2012, when a new partial reimbursement policy was Approximately 20 million Chinese live with HBV, and antiviral offered in China. We noted that antiviral use increased and these therapy is one of the effective ways of improving their lives even drugs represented a large proportion of all medication costs that though cost is a significant barrier [7]. Using electronic data from increased annually as other drug costs decreased over the same a university affiliated infection specialty hospital in Beijing, China, time. Also, outpatients were more likely to choose antiviral costs and antiviral utilization for 92,776 outpatients and 2,774 treatment after the new reimbursement policy was offered. inpatients with HBV from 2008 to 2012 were analyzed. Inpatients, however, chose antivirals less often and other Outpatient costs were less than inpatients in Beijing, Guangzhou medication costs were significant. Perhaps inpatients required in 2007 [12] and Shandong in 2010. Economic and social issues more drugs other than antivirals. After the partial reimbursement may explain these cost differences as well as technological policy in Beijing, utilization of antivirals may increase due to advancements in each area. Estimating a disposable personal greater affordability, a concept supported by the fact that antiviral income of $5,353 in Beijing in 2012, the annual total cost for CHB utilization in the second half of 2011 and 2012 among CHB patients was estimated to be ,5–40% of that income. Thus, outpatients with medical insurance increased more than those who annual costs for CHB patients were significant burdens for patients paid out-of-pocket. Liaw and colleagues arrived at a similar and their families. Creating a practical reimbursement policy was conclusion: they reported a lack of adequate reimbursement was needed to reduce this financial burden and increase care correlated to lack of adherence to treatment guidelines [8]. affordability for all patients so that they may receive adequate In our study patients, almost 50% of outpatients were and timely treatment to prevent or reduce disease progression and prescribed ADV which was cheaper compared to the other NAs ultimately extend survival. approved in China. From 2008–2012, ADV utilization decreased Antiviral treatment is a priority for CHB patients to reduce the and ETV utilization increased and this was more pronounced for risk of complications and delay HBV infection progression people with medical insurance after the new partial reimburse- [13,14,15]. Here, we studied the yearly growth of antiviral PLOS ONE | www.plosone.org 7 October 2014 | Volume 9 | Issue 10 | e109652 Reimbursement on Hepatitis B Cost PLOS ONE | www.plosone.org 8 October 2014 | Volume 9 | Issue 10 | e109652 Table 4. Annual total cost and the composition among CHB patients with different insurance types from 2008 to 2012. Total Antivirals (%) Medicine without antivirals (%) Lab test (%) Median (p25,p75) Out-of- Medical Out-of- Medical Out-of- Medical Out-of- Medical Others Others Others Others pocket insurance pocket insurance pocket insurance pocket insurance Out-patient 2008 153.9 (60.2,429.3) 255.4 (100.4,649.8) 178.3 (67.2,480.6) 55.7 48.8 50.6 29.6 37.1 34.0 11.0 10.7 11.4 2009 183.8 (64.8,589.9) 359.2 (120.3,1040.4) 227.1 (79.9,705.3) 59.0 55.9 56.2 26.1 31.4 30.0 11.5 9.8 10.5 2010 175.9 (60.7,599.1) 293.5 (91.8,960.0) 192.4 (69.7,598.1) 59.7 51.3 51.1 23.1 33.4 31.3 13.4 11.7 13.2 First half of 2011 153.5 (61.2,460.1) 227.8 (90.9,564.7) 155.1 (66.0,380.8) 59.8 54.0 53.5 20.2 26.9 25.1 15.9 15.3 17.3 Second half of 2011 182.6 (70.8,530.6) 338.5 (120.6,838.7) 219.3 (97.5,556.7) 63.7 65.2 60.3 15.8 20.1 20.5 16.6 11.8 15.3 2012 176.7 (63.9,586.5) 407.1 (127.2,1111.1) 237.8 (82.8,730.6) 60.6 68.9 65.0 17.9 16.3 17.1 17.7 11.9 14.6 In-patient 2008 1175 (483.3,2074.3) 1453 (836.0,2928.0) 1336.8 (469.3,1867.6) 8.1 8.1 9.9 53.6 51.7 46.8 20.1 20.9 22.9 Total Antivirals (%) Medicine without antivirals (%)Lab test (%) Median (p25,p75) Out-of- Medical Out-of- Medical Out-of- Medical Out-of- Medical Others Others Others Others pocket insurance pocket insurance pocket insurance pocket insurance In-patient 2009 1152.6 (280.9,2671.9) 2134.3 (1342.8,2949.1) 2097.7 (925.8,2923.0) 17.8 5.5 7.1 45.7 54.0 51.1 19.0 22.1 22.2 2010 1466.6 (557.8,2230.7) 2194.4 (1482.2,3415.5) 1323.3 (372.9,2254.0) 18.8 7.5 4.9 43.3 56.1 52 20.9 19.5 23.2 First half of 2011 1270.9 (212.9,2796.8) 1660.7 (594.9,3338.5) 1128.9 (297.2,2751.1) 16.5 3.0 10.8 46.6 55.8 55.3 14.1 13.4 15.5 Second half of 2011 1098.2 (237.8,2524.8) 2706.6 (1685.7,4903.3) 2117.8 (1242.6,3281.3) 10.3 9.1 9.3 48.0 56.1 60.6 16.6 13.7 13.2 2012 1351.7 (231.4,2677.5) 1794.1 (700.7,5188.8) 2236.5 (1572.1,4006.9) 10.9 15.8 11.3 50.1 45.2 54.2 17.0 12.5 11.0 doi:10.1371/journal.pone.0109652.t004 Reimbursement on Hepatitis B Cost ment policy was implemented. Thus, the new policy may have as well as antiviral selection and utilization, which may result in increased the antiviral utilization by increasing the affordability as the different stage of HBV infection for different admitting years. well as enabling the use of more expensive drugs such as ETV, Although we used a PS to match the factors that would affect the which offers better therapeutic efficacy and fewer side effects and treatment and cost, other observed confounding factors, such as drug resistance [16,17,18]. Further analysis showed that for those income, education level, were not adjusted. Third, we estimated with free medical care ADV was less used, and ETV was more the cost for outpatients and inpatients separately for each popular, compared to patients with NCMS and medical insur- admission year. But it can represent the annually cost for CHB ance. The NCMS was established in rural areas with lower patients because a less than 10% overlap were observed among household income, likely poorer medical technology and lower outpatients and inpatients for each admission year. Finally, the new drug coverage rates, compared with urban patients. Thus, direct cost and medical service frequency data may be underes- these rural individuals may have chosen less expensive and more timated because only electronic medical records were used. The common antivirals.. direct costs of patient who visited other hospitals or pharmacies Our study also showed that outpatients with medical insurance would not be included. had more medical visits, indicating that a reimbursement policy In conclusion, direct medical costs and antiviral utilization for may standardize antiviral treatment patterns, improve patient CHB patients with medical insurance increased more than those outcomes finally for those with medical insurance compared to who paid out-of-pocket annually, especially after the new partial those who paid out-of-pocket. reimbursement was put into lace and after adjusting for inflation There are several limitations in our study. First, our patients and patients’ baseline characteristics. Thus, the new partial were recruited from Beijing You’an hospital, one of the two largest reimbursement policy positively optimized the cost and standard- infectious and liver disease hospital in Beijing, they might not have ization of antiviral treatment, offering improved patient outcomes. been representative of the general CHB population in Beijing. But the demographic characteristic in our study population showed Author Contributions that male to female ratios were 2 to 4, and the mean of age range was 38–42 years, facts consistent with the age and gender Conceived and designed the experiments: LW ZPD HL. Analyzed the data: QQ. Wrote the paper: QQ. Retrieved the electronic data: YL XWD distribution of HBV infection in other studies [19,20,21,22,23]. LKY YC. Reviewed the manuscript: QQ YL XWD LKY YC HL LW Second, real-world based electronic medical records from You’an ZPD. Hospital over a 5-year period from 2008 to 2012 were used to evaluate the effect of reimbursement policy on medical care cost, References 1. Liang X, Bi S, Yang W, Wang L, Cui G, et al. (2009) Epidemiological serosurvey 14. Kobashi H, Miyake Y, Ikeda F, Yasunaka T, Nishino K, et al. (2011) Long-term of hepatitis B in China—declining HBV prevalence due to hepatitis B outcome and hepatocellular carcinoma development in chronic hepatitis B or vaccination. Vaccine 27: 6550–6557. cirrhosis patients after nucleoside analog treatment with entecavir or lamivudine. 2. Lu FM, Zhuang H (2009) Management of hepatitis B in China. Chin Hepatol Res 41: 405–416. Med J (Engl) 122: 3–4. 15. Janssen HL, Reijnders JG (2009) Treatment with nucleos(t)ide analogues in 3. Lu J, Xu A, Wang J, Zhang L, Song L, et al. (2013) Direct economic burden of chronic hepatitis B: where does the road map lead us? J Hepatol 51: 1–3. hepatitis B virus related diseases: evidence from Shandong, China. BMC Health 16. Osborn M (2011) Safety and efficacy of entecavir for the treatment of chronic Serv Res 13: 37. hepatitis B. Infect Drug Resist 4: 55–64. 4. Yang BM, Kim DJ, Byun KS, Kim HS, Park JW, et al. (2010) The societal 17. Buti M, Morillas RM, Prieto M, Diago M, Perez J, et al. (2012) Efficacy and burden of HBV-related disease: South Korea. Dig Dis Sci 55: 784–793. safety of entecavir in clinical practice in treatment-naive Caucasian chronic 5. Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, et al. (2006) A hepatitis B patients. Eur J Gastroenterol Hepatol 24: 535–542. treatment algorithm for the management of chronic hepatitis B virus infection in 18. Yuen MF, Lai CL (2011) Treatment of chronic hepatitis B: Evolution over two the United States: an update. Clin Gastroenterol Hepatol 4: 936–962. decades. J Gastroenterol Hepatol 26 Suppl 1: 138–143. 6. EASL (2009) EASL Clinical Practice Guidelines: management of chronic 19. Fattovich G (2003) Natural history and prognosis of hepatitis B. Semin Liver Dis hepatitis B. J Hepatol 50: 227–242. 23: 47–58. 7. Chinese Society of Hepatology and Chinese Society of Infectious Diseases CMA 20. Brunetto MR, Oliveri F, Coco B, Leandro G, Colombatto P, et al. (2002) (2011) The guideline of prevention and treatment for chronic hepatitis B (2010 Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated version). Zhonghua Gan Zang Bing Za Zhi 19: 13–24. and untreated patients: a long term cohort study. J Hepatol 36: 263–270. 8. Liaw YF (2009) Antiviral therapy of chronic hepatitis B: opportunities and 21. Fattovich G, Giustina G, Christensen E, Pantalena M, Zagni I, et al. (2000) challenges in Asia. J Hepatol 51: 403–410. Influence of hepatitis delta virus infection on morbidity and mortality in 9. Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, et al. (2008) Asian-Pacific compensated cirrhosis type B. The European Concerted Action on Viral consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatitis (Eurohep). Gut 46: 420–426. Hepatol Int 2: 263–283. 22. Yoon EL, Yim HJ, Lee HJ, Lee YS, Kim JH, et al. (2011) Comparison of 10. Available: http://www.bjstats.gov.cn/Accessed 2014 Sep 17. clevudine and entecavir for treatment-naive patients with chronic hepatitis B 11. Liaw YF, Kao JH (2012) Asian-Pacific consensus statement on the management virus infection: two-year follow-up data. J Clin Gastroenterol 45: 893–899. of chronic hepatitis B: a 2012 update. Hepatol Int: 531–561. 23. Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, et al. (2011) 12. Min H, Wen C (2009) Assessment of Total Economic Burden of Chronic Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in Hepatits B (CHB)-Related Disease in Beijing and Guangzhou, China. Value in patients with decompensated chronic hepatitis B liver disease. Hepatology 53: health 12: S89–S92. 62–72. 13. Chang TT, Suh DJ (2008) Current approaches for treating chronic hepatitis B: when to start, what to start with, and when to stop. Hepatol Int 2: 19–27. PLOS ONE | www.plosone.org 9 October 2014 | Volume 9 | Issue 10 | e109652 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png PLoS ONE Pubmed Central

Impact of a New Reimbursement Program on Hepatitis B Antiviral Medication Cost and Utilization in Beijing, China

PLoS ONE , Volume 9 (10) – Oct 16, 2014

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1932-6203
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1932-6203
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10.1371/journal.pone.0109652
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Abstract

Background: Hepatitis B virus (HBV) infection is a significant clinical and financial burden for chronic hepatitis B (CHB) patients. In Beijing, China, partial reimbursement on antiviral agents was first implemented for the treatment of CHB patients in July 1, 2011. Aims: In this study, we describe the medical cost and utilization rates of antiviral therapy for CHB patients to explore the impact of the new partial reimbursement policy on the medical care cost, the composition, and antivirals utilization. Methods: Clinical and claims data of a retrospective cohort of 92,776 outpatients and 2,774 inpatients with non-cirrhotic CHB were retrieved and analyzed from You’an Hospital, Beijing between February 14, 2008 and December 31, 2012. The propensity score matching was used to adjust factors associated with the annual total cost, including age, gender, medical insurance type and treatment indicator. Results: Compared to patients who paid out-of-pocket, medical cost, especially antiviral costs increased greater among patients with medical insurance after July 1, 2011, the start date of reimbursement policy. Outpatients with medical insurance had 16% more antiviral utilization; usage increased 3% among those who paid out-of-pocket after the new partial reimbursement policy was implemented. Conclusions: Direct medical costs and antiviral utilization rates of CHB patients with medical insurance were higher than those from paid out-of-pocket payments, even after adjusting for inflation and other factors. Thus, a new partial reimbursement program may positively optimize the cost and standardization of antiviral treatment. Citation: Qiu Q, Li Y, Duan X-w, Yang L-k, Chen Y, et al. (2014) Impact of a New Reimbursement Program on Hepatitis B Antiviral Medication Cost and Utilization in Beijing, China. PLoS ONE 9(10): e109652. doi:10.1371/journal.pone.0109652 Editor: Xiaoping Miao, MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, China Received July 4, 2014; Accepted September 2, 2014; Published October 16, 2014 Copyright:  2014 Qiu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper. Funding: This study was supported by the Ministry of National Science and Technology of China (2012ZX10004904), Bristol-Myers Squibb Company (AI463-961), Beijing Municipal and Technology Commission (Z131100004613030) and Innovative Foundation of Beijing Union Medical College. The funders had no rolein study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: This study was supported by the Ministry of National Science and Technology of China (2012ZX10004904), Bristol-Myers Squibb Company (AI463-961), Beijing Municipal and Technology Commission (Z131100004613030), and Innovative Foundation of Beijing Union Medical College. Although some funding we received was from a commercial source "Bristol-Myers Squibb Company", which is the manufacturer of BARACLUDE (entecavir), one of the antiviral agents studied in our study for research grants, this does not alter our adherence to PLOS ONE policies on sharing data and materials. Also, the authors have not signed an agreement with Bristol-Myers Squibb Company of the research reported in the contribution that prevents them from publishing both positive and negative results or that forbids them from publishing this research without the prior approval of the sponsor. ZPD and LW have received research support from Bristol-Myers Squibb. QQ, YL, XWD, LKY, YC and HL have no conflicts. * Email: liwang@ibms.pumc.edu.cn (LW); duan2517@163.com (ZPD) . These authors contributed equally to this work. Individuals with chronic HBV have a 15–40% probability for Introduction developing compensated cirrhosis, decompensated cirrhosis and Hepatitis B viral (HBV) infection is a global public health hepatocellular carcinoma, which significantly affect patient treat- problem. A universal vaccination program against HBV has been ment outcomes and quality of life measures. Also, healthcare costs carried out in China since 1992, contributing significantly to can increase with disease progression [3,4]. Thus prevention or reduced HBV surface antigen (HBsAg)-positive rate (9.75% in delay of hepatic HBV progression may offer better outcomes and 1992 to 7.18% in 2006) [1]. However there were still estimated 20 significant savings. million individuals with HBV in China [2], representing a At this time, antiviral treatment can reduce fibrosis progression financial burden to themselves and their families. and cirrhosis and prevent further disease progression, including PLOS ONE | www.plosone.org 1 October 2014 | Volume 9 | Issue 10 | e109652 Reimbursement on Hepatitis B Cost hepatocellular carcinoma [5,6,7]. Over the past 10 years, and other kinds of insurance that included the new rural cooperative medical scheme (NCMS), free medical service, considerable improvement in HBV treatment has occurred, including development of antivirals such as interferon (IFN)-based commercial insurance for medical care which was voluntary paid therapy and nucleos(t)ide analogs (NAs). Four NAs: lamivudine by patients themselves and compensated by insurance companies, (LAM), adefovir (ADV), entecavir (ETV) and telbivudine (LdT) and so on. Baseline and laboratory tests were also retrieved from have been approved in China. The costs and utilization of these the electronic medical record to identify treatment indicator. drugs in China have yet to be described, especially in the setting of These tests included routine biochemical tests (serum alanine a new reimbursement program in Beijing. aminotransferase), virological markers (serum HBV DNA) and In Beijing, no reimbursement was available for HBV antivirals hepatitis B e antigen (HBeAg) status. Direct medical expenses included any expenditure from registration, lab tests, imaging tests, prior to July 1, 2011: all drug expenses were paid by the individual medications, hospital stays and hospital supplies. Indirect cost, patients. This may have resulted in low compliance due to cost [8]. including medical leave, time off, and productivity loss, was not At this time, IFN and NAs are listed with the National collected. We also collected detailed antiviral utilization, including Reimbursement Catalog of Drugs for Basic Medical Insurance and partial reimbursement has been available since July 1, 2011 in drug names, dosage, costs, and treatment durations. Indirect costs, reflecting the value of lost productivity but other losses, such as Beijing, mainly designed for civil residents. Patients could receive a 75–85% reimbursement of the cost between a deductible of 1,800 patient travel and medical assistance expenditures, however, were not included. yuan and a ceiling of 20,000 yuan. This should increase affordability and patient compliance but data have not been collected and studied. Thus, we investigated this new partial Cost estimation reimbursement program on cost, patient demographics, and All costs were inflated to Dollars in the year 2012 using the antiviral utilization. Consumer Price Index for Health in Beijing [10] and also With inpatient and outpatient electronic data from Beijing expressed in US dollars in the year of 2012. The exchange rate of You’an Hospital, a university affiliated infectious disease hospital RMB to USD was 6.3 to 1. Annual inpatient and outpatient costs in Beijing, China, we estimated average annual treatment costs for each patient were calculated according to the following and the proportion of costs of drugs (including antivirals), formula: laboratory tests, and related fees to describe the current treatment patterns for CHB patients to understand how the new partial Annual inpatient (outpatient) cost~S (a,b,c,:::,n) reimbursement policy affects healthcare costs, patients affected and utilization of antiviral drugs. Where a, b, c…, z represents actual costs occurred for each Materials and Methods visit/hospital admission of that year, such as drug costs, lab and Ethics statement imaging tests, registration, and all related costs. Finally, n The study protocol was approved by the Ethical Review represents visit times for each patient each year. Committee of Beijing You’an Hospital, Capital Medical Univer- Because the electronic medical record system in You’an sity and Institute of Basic Medical Sciences Chinese Academy of Hospital was established on February 14, 2008, records prior to Medical Sciences. The team obtained informed consent from this date could not be collected, which may lead to an artificially hospital authorities for data collection. No informed consent, lower annual cost per person. Thus, the average proportion of written or oral, was obtained from the participants because only visits before February 14 from 2009 to 2012 was used to adjust the the electronic medical records were retrieved to do the analysis visit time and the corresponding annual cost per person in 2008. and only necessary data for study objectives were extracted. To explore the effect of the new partial reimbursement program Deidentification was done to assure confidentiality of the study on care costs, patient composition, and antiviral utilization, we data. divided 2011 data into two parts: costs in the first and second half of the year. Each half-year cost was adjusted by the corresponding half-year cost in 2010 and 2012 using the following formula: Study population A retrospective cohort study was conducted on CHB patients at You’an Hospital, Beijing, between February 14, 2008 and first half year cost in 2010 first half year cost in 2011 December 31, 2012. Patients were diagnosed by the ‘‘Asian- cost in 2010 cost in 2011 Pacific consensus statement on the management of CHB [9]’’. Patients co-infected with hepatitis A, C, D and E, human immunodeficiency virus, cytomegalovirus or those admitted to first half year cost in 2011 first half year cost in 2012 the hospital due to diagnosed liver cirrhosis or hepatocellular cost in 2011 cost in 2012 carcinoma or other diseases or conditions, including pregnancy, glomerulonephritis, uremia, complications of metabolic syndrome, tumors, and cardiovascular diseases, were excluded. Also, non- residents of Beijing were excluded. Propensity score matching The treatment cost was greatly influenced by the socio- Data collection economic status, medical technology, the health care system, the Demographic characteristics, clinical information and medical patients’ disease severity and healthcare awareness [8]. Logistic expenses for each patient visit were retrieved from electronic regression was adopted to estimate the propensity score (PS). The medical records. Demographic characteristics included, gender, dependent variable was admission year and the independent birth date, admission (or visit) date, inpatient discharge date, and variable (covariates) were age, gender, medical insurance type and health insurance type were documented. Health insurance type treatment indicator (patients were considered treatment indicated was categorized into 3 groups: out-of-pocket, medical insurance if met one of the following conditions: (1) serum alanine PLOS ONE | www.plosone.org 2 October 2014 | Volume 9 | Issue 10 | e109652 Reimbursement on Hepatitis B Cost Figure 1. Patient selection procedure. doi:10.1371/journal.pone.0109652.g001 aminotransferase over two times upper limit of normal (40 U/L); characteristics would be comparable among the six time periods. For inpatients, the smallest sample size was from the first half of (2) log DNA. = 5 copies/ml for HBeAg (+) patients; (3) log 10 10 DNA. = 4 copies/ml for HBeAg (2) patients [11]). All covariates 2011. So, this was used as the control group. were entered into the logistic regression model and the probability of being in the case group (known as PS) was then calculated for Statistical analysis each patient. As a 1:1 matching was adopted thus outpatients in The average annual cost for inpatients and outpatients was 2008 were considered as the control group due to the smallest expressed as median (first quartile and third quartile). The sample size. Outpatients in 2009, 2010, 2011 (first half-year), 2011 proportion of the cost of laboratory tests, medications (especially (second half-year) and 2012, were matched as the case group to the antivirals) was calculated by the annual total cost of laboratory control group by PS within a range of 0.1 standard deviation tests and medications divided by the total costs for all patients. respectively. Then, data from 2008 that had been matched to all Chi-square test was used to detect differences in the proportion five years and corresponding pairs were selected so that baseline of antiviral therapy among outpatients with different medical PLOS ONE | www.plosone.org 3 October 2014 | Volume 9 | Issue 10 | e109652 Reimbursement on Hepatitis B Cost insurance types. SAS 9.2 (Windows, SAS Institute Inc., Cary, NC) was used to perform the statistical analysis. Results A total of 444,900 outpatients and 4,759 inpatients medical records of CHB patients were documented from February 14, 2008 to December 31, 2012. A total of 1,428 medical records with no treatment, 128,467 cases admitted to the hospital with other diseases or conditions, as well as 3,339 cases from outside of Beijing who were covered by different local reimbursement policies from those in Beijing were excluded, leaving 313,411 outpatients and 3,014 inpatients medical records. Figure 1 depicts the selection procedure. Subject characteristics Patient demographics among different admission years are depicted in Table 1. Age, gender, health insurance type and treatment indicator was significantly different among admission years. Patients in each admission year were predominantly male and the mostly male was in 2008 for outpatients and 2009 for inpatients. The proportion of patients who paid out-of-pocket decreased and those with medical insurance increased annually. To allow a common ground for comparison among different admission year, PS matching were conducted by selected key characteristics. PS matching resulted in a matched sample size of 10,587 for outpatients and 186 for inpatients for each admission year and the distribution of key confounders, including age, gender, insurance status and treatment indicator, was similar in outpatients and inpatients in different admission years (Table 2). Cost analysis The direct costs and cost composition from year 2008–2012 after PS matching were shown in Table 3. Two apparent inflection points may have explained the outpatients cost changes in 2009 and the second half of 2011. For inpatients, the annual average costs were higher than outpatients in the same year and annual costs for inpatients increased yearly, peaking in the second half of 2011. Composition analysis revealed that the proportion of drug costs nearly identical (,80%) for outpatients and 60% for inpatients during the study period. After a steady growth prior to July 1, 2011, the implementation of the partial reimbursement policy, antiviral costs jumped from 53 to 64% for outpatients and from 8 to 13% for inpatients. The proportion of laboratory costs increased from 11 to 15% for outpatients but decreased from 21 to 14% for inpatients. Anti-viral drug and medical service utilization Because inpatients focused on symptomatic treatment, we only analyzed antiviral drug utilization for outpatients. We found that the antiviral utilization had grown rapidly since the second half year of 2011 (Figure 2). The antiviral utilization was around 40% before July 1, 2011 and jumped to 50% after then. Among outpatients who received antiviral treatment, ADV was the most frequently prescribed antiviral, comprising 50% of those prescribed during the 5-year period, even though utilization of this compound decreased slightly. IFN usage decrease from 20 to 12% after the new policy was implemented. However the proportion of patients using ETV increased 4% before July 1, 2011 and increased 10% after that time. LdT and LAM did not change much regarding usage (Figure 3). PLOS ONE | www.plosone.org 4 October 2014 | Volume 9 | Issue 10 | e109652 Table 1. Demographic characteristic of CHB patients from 2008 to 2012. Age(year) Gender Insurance type (%) Treatment indicated Out-of- Medical Year N Mean±Sd p Male% p Else p % P pocket insurance Outpatient 2008 11222 39.0613.7 ,0.0001 68.6 ,0.0001 68.3 23.8 7.9 ,0.0001 12.8 ,0.0001 2009 16767 38.2613.5 67.5 67.1 22.8 10.1 22.8 2010 20737 38.1612.9 65.5 61.0 26.3 12.7 23.9 2011 22070 39.2612.3 63.4 52.6 36.6 10.8 20.3 2012 21980 39.4612.8 62.8 49.1 42.7 8.2 20.0 Inpatient 2008 383 34.5612.1 ,0.0001 71.0 ,0.0001 67.6 25.6 6.8 ,0.0001 36.0 ,0.0001 2009 666 35.7612.4 77.3 67.8 23.9 8.3 37.8 2010 606 36.1612.9 74.6 58.1 21.9 20.0 40.1 2011 570 41.7613.6 71.4 43.3 36.1 20.6 47.0 2012 549 41.1612.8 69.0 27.0 53.9 19.1 42.1 doi:10.1371/journal.pone.0109652.t001 Reimbursement on Hepatitis B Cost PLOS ONE | www.plosone.org 5 October 2014 | Volume 9 | Issue 10 | e109652 Table 2. Demographic characteristic of CHB patients from 2008 to 2012 after PS matching. Age(year) Gender Insurance type (%) Treatment indicated Out-of- Medical Year N Mean±Sd p Male% p Else p % P pocket insurance Outpatient 2008 10587 39.1613.0 0.8306 67.9 0.4289 66.4 25.2 8.4 0.7495 13.5 0.7192 2009 10587 39.0612.8 68.7 67.3 24.3 8.4 13.5 2010 10587 39.0612.7 68.0 66.6 25.1 8.3 13.5 First half of 2011 10587 39.0612.3 67.7 66.8 25.1 8.1 14.0 Second half of 2011 10587 39.2612.8 67.5 66.6 25.2 8.2 13.4 2012 10587 39.4612.6 68.4 67.0 25.2 7.8 13.6 Inpatient 2008 186 39.0611.5 0.5171 74.7 0.682 61.8 26.4 11.8 0.0244 41.4 0.1364 2009 186 39.0612.5 77.4 53.2 37.1 9.7 43.0 2010 186 38.5612.6 76.9 53.2 28.5 18.3 43.0 First half of 2011 186 38.5612.0 72.6 55.9 33.9 10.2 44.1 Second half of 2011 186 41.2612.1 73.1 47.3 38.2 14.5 47.9 2012 186 40.8612.3 71.0 46.8 37.1 16.1 50.0 doi:10.1371/journal.pone.0109652.t002 Reimbursement on Hepatitis B Cost Table 3. Annual total cost and the composition among CHB patients from 2008 to 2012. Total Year Antiviral cost (%) Medicine without antivirals (%) Test (%) Others (%) Median(p25,p75) Outpatient 2008 179.2 (67.0,481.5) 53.1 32.3 10.9 3.7 2009 219.9 (74.4,709.1) 57.7 28.2 10.8 3.3 2010 201.1 (66.7,689.6) 56.4 27.0 12.8 3.8 First half of 2011 170.1 (66.9,483.1) 56.8 23.4 15.8 4.0 Second half of 2011 219.5 (82.0,605.1) 63.0 19.6 14.1 3.3 2012 217.1 (77.0,729.1) 63.9 17.3 15.4 3.4 Inpatient 2008 1274.8 (529.5,2409.8) 8.3 52.3 20.6 18.8 2009 1590.7 (614.0,2854.8) 11.5 49.8 20.6 18.1 2010 1612.2 (679.6,2491.0) 12.5 49.4 20.7 17.4 First half of 2011 1357.4 (299.2,2851.1) 9.2 52.7 14.1 24.0 Second half of 2011 2060.1 (641.7,3623.6) 9.5 54.7 14.4 21.4 2012 1697.9 (496.8,3616.4) 13.2 48.8 13.6 24.4 doi:10.1371/journal.pone.0109652.t003 pocket. This rate increased from 43.0 to 45.1% after the new Effect of partial reimbursement policy on patients with policy was implemented (Figure 2). For patients with medical different insurance insurance, however, the difference between different admission The new partial reimbursement program was only available to years before July 1, 2011 did not exceed 8% and increased from patients with medical insurance, so we divided patients into three 49.1 to 65.9% after that time. Among patients with other insurance groups (out-of-pocket, medical insurance, and other insurance types, most were covered by NCMS or had free types of insurance) to investigate the effect of the new partial medical services. Antiviral utilization ranged from 41.3–45.2% for reimbursement policy. those with free medical care and from 39–45% for those with Total cost. Data indicate that the total annual cost was NCMS from 2008–2011 and this increased from 41.2 to 51.9% higher among both outpatients and inpatients with medical and from 45.2 to 60.9% after July 1, 2011, respectively. These insurance compared to those who paid out-of-pocket, especially increases were lower than experienced by those with medical since the second half year of 2011. The total cost for outpatients insurance but higher than the costs for those who paid out-of- with medical insurance increased 50% after the second half of pocket (data not shown). 2011, compared to before. For patients who paid out-of-pocket, The proportion of outpatients with medical insurance treated rates increased only 19% (Table 4). with ETV increased from 30% to more than 40% with an annual Cost composition. Among outpatients, the proportion of growth of 34% since July 1, 2011, higher than before July 1, 2011. costs for lab tests among the three insurance groups increased Annual growth of no more than 20% was observed among those somewhat during the study period; drug costs increased more who paid out-of-pocket and this was not different to costs prior to rapidly among those with medical insurance than those who paid July 1, 2011. Decreased use of ADV among patients with medical out-of-pocket after the second half of 2011. Non-antiviral drug insurance during the second half of 2011 was 8.3% of the previous costs were not different between the two groups. For inpatients, a year, which was twice that of patients who paid out-of-pocket. The yearly decrease in lab costs was observed among all three groups yearly utilization trend for the other three antivirals was not and drug costs rose annually among the three groups (Table 4). different between patients with medical insurance and those who Antiviral utilization. Before the first half of 2011, antiviral paid out-of-pocket (Figure 3). utilization fluctuated ,2% for outpatients who paid out-out- For outpatients with free medical care, ADV use decreased from 50.0 to 38.8% and ETV use increased from 36.8 to 51.0% after July 1, 2011. For those with NCMS, ADV use decreased during the study period and ETV use was 10% lower than the use observed by individuals with free medical care in the same year before July 1, 2011. After the implementation of the new policy, this use was still lower than that of outpatients who paid out-of- pocket. Over time, ETV utilization grew among those with NCMS compared to outpatients with other insurance types (data not shown). Medical service utilization was observed higher among those with medical insurance compared to those who paid out-out- pocket. Proportion of patients who visited hospital three or more than three times a year increased from 39.2% in 2008 to 55.9% in 2012 among insured patients during the study period, while Figure 2. Antiviral utilization among CHB patients with increased slightly from 26.8% in 2008 to 36.4% in 2012 for those different insurance types from 2008–2012. paid out-of-pocket (data not shown). doi:10.1371/journal.pone.0109652.g002 PLOS ONE | www.plosone.org 6 October 2014 | Volume 9 | Issue 10 | e109652 Reimbursement on Hepatitis B Cost Figure 3. Antiviral composition of outpatients prescribed antivirals with different insurance types from 2008–2012. *Note: some patients treated with more than one antiviral at the same time may increase the sum of antiviral composition to more than 1 in each year. doi:10.1371/journal.pone.0109652.g003 utilization among outpatients, specifically in the second half of Discussion 2011 and 2012, when a new partial reimbursement policy was Approximately 20 million Chinese live with HBV, and antiviral offered in China. We noted that antiviral use increased and these therapy is one of the effective ways of improving their lives even drugs represented a large proportion of all medication costs that though cost is a significant barrier [7]. Using electronic data from increased annually as other drug costs decreased over the same a university affiliated infection specialty hospital in Beijing, China, time. Also, outpatients were more likely to choose antiviral costs and antiviral utilization for 92,776 outpatients and 2,774 treatment after the new reimbursement policy was offered. inpatients with HBV from 2008 to 2012 were analyzed. Inpatients, however, chose antivirals less often and other Outpatient costs were less than inpatients in Beijing, Guangzhou medication costs were significant. Perhaps inpatients required in 2007 [12] and Shandong in 2010. Economic and social issues more drugs other than antivirals. After the partial reimbursement may explain these cost differences as well as technological policy in Beijing, utilization of antivirals may increase due to advancements in each area. Estimating a disposable personal greater affordability, a concept supported by the fact that antiviral income of $5,353 in Beijing in 2012, the annual total cost for CHB utilization in the second half of 2011 and 2012 among CHB patients was estimated to be ,5–40% of that income. Thus, outpatients with medical insurance increased more than those who annual costs for CHB patients were significant burdens for patients paid out-of-pocket. Liaw and colleagues arrived at a similar and their families. Creating a practical reimbursement policy was conclusion: they reported a lack of adequate reimbursement was needed to reduce this financial burden and increase care correlated to lack of adherence to treatment guidelines [8]. affordability for all patients so that they may receive adequate In our study patients, almost 50% of outpatients were and timely treatment to prevent or reduce disease progression and prescribed ADV which was cheaper compared to the other NAs ultimately extend survival. approved in China. From 2008–2012, ADV utilization decreased Antiviral treatment is a priority for CHB patients to reduce the and ETV utilization increased and this was more pronounced for risk of complications and delay HBV infection progression people with medical insurance after the new partial reimburse- [13,14,15]. Here, we studied the yearly growth of antiviral PLOS ONE | www.plosone.org 7 October 2014 | Volume 9 | Issue 10 | e109652 Reimbursement on Hepatitis B Cost PLOS ONE | www.plosone.org 8 October 2014 | Volume 9 | Issue 10 | e109652 Table 4. Annual total cost and the composition among CHB patients with different insurance types from 2008 to 2012. Total Antivirals (%) Medicine without antivirals (%) Lab test (%) Median (p25,p75) Out-of- Medical Out-of- Medical Out-of- Medical Out-of- Medical Others Others Others Others pocket insurance pocket insurance pocket insurance pocket insurance Out-patient 2008 153.9 (60.2,429.3) 255.4 (100.4,649.8) 178.3 (67.2,480.6) 55.7 48.8 50.6 29.6 37.1 34.0 11.0 10.7 11.4 2009 183.8 (64.8,589.9) 359.2 (120.3,1040.4) 227.1 (79.9,705.3) 59.0 55.9 56.2 26.1 31.4 30.0 11.5 9.8 10.5 2010 175.9 (60.7,599.1) 293.5 (91.8,960.0) 192.4 (69.7,598.1) 59.7 51.3 51.1 23.1 33.4 31.3 13.4 11.7 13.2 First half of 2011 153.5 (61.2,460.1) 227.8 (90.9,564.7) 155.1 (66.0,380.8) 59.8 54.0 53.5 20.2 26.9 25.1 15.9 15.3 17.3 Second half of 2011 182.6 (70.8,530.6) 338.5 (120.6,838.7) 219.3 (97.5,556.7) 63.7 65.2 60.3 15.8 20.1 20.5 16.6 11.8 15.3 2012 176.7 (63.9,586.5) 407.1 (127.2,1111.1) 237.8 (82.8,730.6) 60.6 68.9 65.0 17.9 16.3 17.1 17.7 11.9 14.6 In-patient 2008 1175 (483.3,2074.3) 1453 (836.0,2928.0) 1336.8 (469.3,1867.6) 8.1 8.1 9.9 53.6 51.7 46.8 20.1 20.9 22.9 Total Antivirals (%) Medicine without antivirals (%)Lab test (%) Median (p25,p75) Out-of- Medical Out-of- Medical Out-of- Medical Out-of- Medical Others Others Others Others pocket insurance pocket insurance pocket insurance pocket insurance In-patient 2009 1152.6 (280.9,2671.9) 2134.3 (1342.8,2949.1) 2097.7 (925.8,2923.0) 17.8 5.5 7.1 45.7 54.0 51.1 19.0 22.1 22.2 2010 1466.6 (557.8,2230.7) 2194.4 (1482.2,3415.5) 1323.3 (372.9,2254.0) 18.8 7.5 4.9 43.3 56.1 52 20.9 19.5 23.2 First half of 2011 1270.9 (212.9,2796.8) 1660.7 (594.9,3338.5) 1128.9 (297.2,2751.1) 16.5 3.0 10.8 46.6 55.8 55.3 14.1 13.4 15.5 Second half of 2011 1098.2 (237.8,2524.8) 2706.6 (1685.7,4903.3) 2117.8 (1242.6,3281.3) 10.3 9.1 9.3 48.0 56.1 60.6 16.6 13.7 13.2 2012 1351.7 (231.4,2677.5) 1794.1 (700.7,5188.8) 2236.5 (1572.1,4006.9) 10.9 15.8 11.3 50.1 45.2 54.2 17.0 12.5 11.0 doi:10.1371/journal.pone.0109652.t004 Reimbursement on Hepatitis B Cost ment policy was implemented. Thus, the new policy may have as well as antiviral selection and utilization, which may result in increased the antiviral utilization by increasing the affordability as the different stage of HBV infection for different admitting years. well as enabling the use of more expensive drugs such as ETV, Although we used a PS to match the factors that would affect the which offers better therapeutic efficacy and fewer side effects and treatment and cost, other observed confounding factors, such as drug resistance [16,17,18]. Further analysis showed that for those income, education level, were not adjusted. Third, we estimated with free medical care ADV was less used, and ETV was more the cost for outpatients and inpatients separately for each popular, compared to patients with NCMS and medical insur- admission year. But it can represent the annually cost for CHB ance. The NCMS was established in rural areas with lower patients because a less than 10% overlap were observed among household income, likely poorer medical technology and lower outpatients and inpatients for each admission year. Finally, the new drug coverage rates, compared with urban patients. Thus, direct cost and medical service frequency data may be underes- these rural individuals may have chosen less expensive and more timated because only electronic medical records were used. The common antivirals.. direct costs of patient who visited other hospitals or pharmacies Our study also showed that outpatients with medical insurance would not be included. had more medical visits, indicating that a reimbursement policy In conclusion, direct medical costs and antiviral utilization for may standardize antiviral treatment patterns, improve patient CHB patients with medical insurance increased more than those outcomes finally for those with medical insurance compared to who paid out-of-pocket annually, especially after the new partial those who paid out-of-pocket. reimbursement was put into lace and after adjusting for inflation There are several limitations in our study. First, our patients and patients’ baseline characteristics. Thus, the new partial were recruited from Beijing You’an hospital, one of the two largest reimbursement policy positively optimized the cost and standard- infectious and liver disease hospital in Beijing, they might not have ization of antiviral treatment, offering improved patient outcomes. been representative of the general CHB population in Beijing. But the demographic characteristic in our study population showed Author Contributions that male to female ratios were 2 to 4, and the mean of age range was 38–42 years, facts consistent with the age and gender Conceived and designed the experiments: LW ZPD HL. Analyzed the data: QQ. Wrote the paper: QQ. Retrieved the electronic data: YL XWD distribution of HBV infection in other studies [19,20,21,22,23]. LKY YC. Reviewed the manuscript: QQ YL XWD LKY YC HL LW Second, real-world based electronic medical records from You’an ZPD. 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Chang TT, Suh DJ (2008) Current approaches for treating chronic hepatitis B: when to start, what to start with, and when to stop. Hepatol Int 2: 19–27. PLOS ONE | www.plosone.org 9 October 2014 | Volume 9 | Issue 10 | e109652

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