A real‐world impact of cost‐effectiveness of pegylated interferon/ribavarin regimens on treatment‐naïve chronic hepatitis C patients in Taiwan

Abstract

Treatments with pegylated interferon/ribavirin (PEG‐IFN/RBV) has been standard‐of‐care in patients with chronic hepatitis C virus (HCV) (CHC) infection and reimbursed in Taiwan. However, the actual cost‐effectiveness remains unclear. We aimed to evaluate a real‐world cost‐effectiveness for CHC patients treated with PEG‐IFN/RBV by using a clinical cohort with linkage to the National Health Insurance Research Database of Taiwan. The total and itemized medical‐care expenses of outpatient visits of 117 treatment‐naïve CHC patients with linkage to the two million sampling of the National Health Insurance Research Database were collected. Four components of costs were assessed, including antiviral agents, nonantiviral agents, laboratory testing and consultation costs. The cost per sustained virological response (SVR) achieved was calculated to evaluate the cost‐effectiveness. The average cost per treatment in 117 naïve Taiwanese CHC patients was $4620. With an overall SVR rate of 78.6%, the average cost per SVR was $5878. The average medical‐care cost per treatment for 52 Genotype 1 (G1) patients was $5133, including $4420 for antivirals, $380 for nonantivirals, $302 for laboratory, and $78 for consultation, compared to $4209, $3635, $317, $233, and $56 for 65 Genotype 2 (G2) patients. With an SVR rate at 67.3% for G1 and 87.7% for G2 patients, the cost per SVR achieved was significantly higher in G1 patients than those in G2 patients ($7627 vs. $4799, p = 0.001). In the current study, we provided the real‐world cost‐effectiveness of PEG‐IFN/RBV for treatment‐naïve CHC patients. The genotype‐specific cost‐effectiveness could enhance decision‐making for policy‐makers in the coming era of directly acting antiviral therapy.

Introduction

There are approximately 180 million people infected with the hepatitis C virus (HCV) worldwide [1]. In Taiwan, a recent study showed that around 0.6 million people are chronically infected with HCV with a prevalence rate of approximately 3.8% [[2], [3]]. In the natural course of untreated HCV patients, 20% eventually develop liver cirrhosis. Once cirrhosis is established, hepatocellular carcinoma (HCC) and hepatic decompensation will develop with an incidence of 1–4% and 2–5%, respectively [4]. A large community cohort study showed that the 18‐year all‐cause mortality and specific mortality due to HCC were 30.1% and 10.4%, respectively, in the patients with HCV viremia [5]. Successful antiviral therapy has been associated with greater reduction of liver cirrhosis, HCC, and liver‐related mortality [[6], [7], [8], [9]].

Pegylated interferon (PEG‐IFN) plus ribavirin (RBV) combination therapy has been the standard‐of‐care in the past two decades, which could achieve high sustained virological response (SVR) rates in Taiwan. A 48‐week or 24‐week regimen of peg‐IFN‐α (PEG‐IFN‐α2a or PEG‐IFN‐α2b) plus RBV could achieve an SVR rate of 70–75% and 85–90% for HCV Genotype 1/4 (HCV‐1/4) and HCV‐2/3, respectively, in Taiwan [[10], [11], [12]]. However, PEG‐IFN/RBV might cause significant adverse events, dose reduction, and early discontinuation in the treatment of chronic hepatitis C (CHC) [13], leading to a huge gap between high clinical efficacy (80%) and low community effectiveness (13%) in Taiwan [3]. Recently, the introduction of new directly acting antiviral agent (DAA) regimens (mostly IFN‐free) greatly improved the treatment efficacy and reduced the adverse events [[14], [15], [16]]. However, DAAs are expensive [17] and necessitate a cost‐effectiveness analysis to compare the different regimens for the treatment of HCV, especially in countries where PEG‐IFN/RBV could provide high treatment efficacy, such as Taiwan and East Asia [10]. Nevertheless, most of the cost‐effectiveness analysis only counted the cost of antivirals without taking the other costs, such as nonantivirals and laboratory tests, into consideration [[18], [19], [20], [21], [22], [23], [24], [25]]. Therefore, a real‐world cost‐effective analysis including all of the real‐world costs is very important to provide the evidence for decision‐making of nation‐level policy.

In Taiwan, the National Health Insurance Program, with coverage rate up to 99.6% population, provides comprehensive database for real‐world cost‐effectiveness analysis [26]. We hereby conducted a real‐world cost‐effectiveness analysis for CHC patients treated with PEG‐IFN/RBV based on the National Health Insurance Research Database (NHIRD) in Taiwan.

Methods

Study population

In the hospital‐based cohort study, a total of 4740 CHC patients receiving PEG‐IFN/RBV regimens were consecutively enrolled in a medical center and two core regional hospitals from 1991 to 2014. All consecutive treatment courses with available on‐treatment clinical data were assessed. Patients who had HCC before antiviral treatment, with hepatitis B virus dual infections or human immunodeficiency virus dual infection, were excluded. Therefore, 3781 CHC patients were enrolled in this further study.

All patients were provided written informed consent. The institutional review board at the participating hospitals approved the protocols, which conformed to the guidelines of the International Conference on Harmonization for Good Clinical Practice costs.

Clinical data (laboratory examinations and SVR assessment)

Serum HCV RNA was detected using qualitative real‐time polymerase chain reaction (COBAS AMPLICOR HCV Test, ver. 2.0; Roche, Branchburg, NJ, USA) and quantification branched DNA assay (Versant HCV RNA 3.0, Bayer, Tarrytown, NJ, USA; quantification limit: 615 IU/mL). The HCV genotypes were determined using the Okamoto method [27]. The liver histology, which was obtained within 1 year before antiviral therapy, was graded and staged according to the scoring system described by Scheuer [28].

The treatment efficacy, SVR, was defined as seronegativity of HCV RNA throughout a 24‐week post‐antiviral treatment follow‐up period.

Cost measurement from NHIRD

Costs were sourced from real‐world retrospective HCV clinic data to link the 2 million sampling of NHIRD during 1998–2011. The 2 million sampling of NHIRD derived from the universal compulsory national health insurance program, which was conducted by the Taiwan government in March 1995, provided information for approximately one‐eleventh of the total 23 million of the national population.

The four components of medical‐care in outpatient clinics were: medication (antiviral agents and nonantiviral agents) costs, laboratory testing costs, and consultation costs. All of the costs were based on the records of prescribed medication, laboratory tests, and consultation retrieved from linked NHIRD. The assessed period for the medical care costs was retrieved from 3 months before starting antiviral treatment to 6 months after stopping antiviral treatment. All medical costs were expressed in US Dollars with a currency rate at 32 New Taiwan Dollars to US $1.

Statistical analyses

Number/percentage and mean/standard deviation were, respectively, presented in the calculation of SVR rate and medical‐care costs. The average total cost per SVR achieved was calculated as (the summation of total cost for all HCV‐treated patients)/number of SVR cases. The average cost per SVR will be additionally performed by HCV genotype. All analyses will be conducted by SAS software (SAS Institute Inc., Carey, NC, USA). All statistical analyses were based on two‐sided hypothesis tests with a significance level of p < 0.05.

Results

Patients profile

A total of 3781 CHC patients (3365 naïve and 416 treatment) were initially enrolled in this study. After linking to two million outpatient expenditure and order of NHIRD, we used the five criteria to screen targeting outpatient visits: (1) the date of outpatient visits was not located on the assessed HCV management period; (2) treatment starting date later than January 1, 2011, due to limited NHIRD dataset; (3) patients did not use PEG‐IFN/RBV drugs on each visit; (4) there was no SVR information; and (5) patients who were treatment‐experienced. Patients who met the criteria listed above were excluded in the further outpatient‐cost analysis. Finally, 117 treatment‐naive CHC patients were enrolled for further analysis (Figure 1).

Figure 1.

Study cohort enrolled. CHC = chronic HCV; HCC = hepatocellular carcinoma; NHIRD = National Health Insurance Research Database; PEG‐IFN = pegylated interferon; RBV = ribavirin; SVR = sustained virological response.

The basic demographical, virological, and histological features are shown in Table 1. A total of 92 (78.6%) of 117 patents achieved an SVR with a mean follow‐up period of 27.1 weeks, whereas 25 (21.4%) patients treated failure with a longer follow‐up period of 32.1 weeks. The mean age was 50.2 years for patients with SVR and 55.5 years for patients without SVR. Males accounted for 53.3% of the patients with SVR and 36.0% of the patients without SVR. The percentages of patients in the groups of Fibrosis F0–2, F3–4 were 76.4% and 23.6% for patients with SVR and 76.2% and 23.8% for patients without SVR. The mean HCV RNA was 5.4 (KIU/mL) for patients with SVR and 5.8 (KIU/mL) for patients without SVR. In addition, the frequency of HCV genotype distribution was significantly different between the patients with SVR and without SVR. Some 62% of SVR patients were HCV Genotype 2 and 68% of non‐SVR patients were HCV Genotype 1 (p = 0.0075).

Table 1.

Baseline clinic demographic profiles of CHC patients.

		n	SVR a		p
			Yes (n = 92)	No (n = 25)
Age	< 60 y	94	77 (83.7)	17 (68.0)	0.10
	≥ 60 y	23	15 (16.3)	8 (32.0)
Sex	Female	59	43 (46.7)	16 (64.0)	0.18
	Male	58	49 (53.3)	9 (36.0)
Fibrosis score b	0–2	58	42 (76.4)	16 (76.2)	0.99
	3–4	18	13 (23.6)	5 (23.8)
AST (IU/L)		117	93.6 ± 53.8	102.3 ± 46.3	0.46
ALT (IU/L)		117	148.1 ± 88.0	158.1 ± 91.0	0.62
HCV RNA (KIU/mL)		117	5.4 ± 0.9	5.8 ± 0.7	0.09
HCV genotype	Genotype 1	52	35 (38.0)	17 (68.0)	0.0075
	Genotype 2	65	57 (62.0)	8 (32.0)
Treatment duration (wk)		117	27.1 ± 11.1	32.1 ± 12.3	0.06
Cost per treatment (US $)		117	4569 ± 1417	4810 ± 1941	0.49
Cost per SVR (US $)		117	5878 ± 1955

^aData are presented as n (%) or mean ± SD.

^bForty‐one patients had no liver histology available.

Cost analysis

The average medical‐care cost per treatment was $4620 (standard deviation, 1537), including $3984 for antivirals, $345 for nonantivirals, $264 for laboratory testing, and $65 for consultation (Supplementary Table 1). The average cost per treatment was higher in non‐SVR patients when compared to that in SVR patients ($4810 and $4569, respectively, Table 1).

Since HCV genotype is the most important predictor of the HCV treatment efficacy to PEG‐IFN/RBV, we further analyzed the cost‐effectiveness according to the viral genotype. Among the 117 treatment‐naïve CHC patients, there were 52 HCV Genotype 1 (G1) and 65 Genotype 2 (G2) patients. The SVR rate was 67.3% in G1 patients, which was significantly lower than 87.7% in G2 patients (p = 0.012). The average medical‐care cost per treatment for G1 patients was $5133 (standard deviation, 1589) including $4420 for antivirals, $380 for nonantivirals, $302 for laboratory testing, and $78 for consultation, compared to $4209, $3635, $317, $233, and $56, respectively, for G2 patients (p = 0.0038 for antivirals, p = 0.47 for nonantivirals, p = 0.018 for laboratory testing, and p = 0.016 for consultation). Among these medical‐care costs, the antiviral cost, laboratory testing, and consultation cost per treatment for G1 patients were significantly higher than those for G2 patients. The medical‐care cost per treatment for G1 patients was $4913 and $5239 for non‐SVR and SVR patients, respectively. By contrast, the medical‐care cost per treatment for G2 patients was $4582 and $4157 for non‐SVR and SVR patients, respectively (p = 0.49 for G1, p = 0.42 for G2) (Supplementary Table 1).

Cost‐effectiveness analysis

We further analyzed the cost per SVR achieved. For all naïve patients with an SVR rate at 78.6%, the cost per SVR achieved was $5878 (standard deviation, 1955) (Table 1). With an SVR rate at 67.3% for G1 and 87.7% for G2 patients, the cost per SVR achieved was $7627 (standard deviation, 2361) and $4799 (standard deviation, 1566) for G1 and G2 patients, respectively (p < 0.001) (Table 2). The average itemized cost per SVR for G1 patients was $6568 for antivirals, $565 for nonantivirals, $449 for laboratory testing, and $116 for consultation, compared to $4145, $361, $266, and $64, respectively for G2 patients (p < 0.0001 for antivirals, p = 0.074 for non‐antivirals, p < 0.0001 for laboratory testing, p < 0.0001 for consultation) (Figure 2). Among naïve G1 patients, younger age and mild hepatic fibrosis had significantly better real‐world cost effectiveness to PEG‐IFN/RBV therapy when compared to their counterparts (p = 0.0004 for age < 60 vs. ≥ 60 and p < 0.0001 for fibrosis 0–2 vs.3–4). However, there was no group‐specific difference of cost‐effectiveness in naïve G2 patients, in terms of age, sex and hepatic fibrosis (Table 2).

Table 2.

The number/percentage and average cost per sustained virological response (SVR) achieved (US $) on hepatitis C virus (HCV) genotype 1 and HCV genotype 2 patients stratified by age, sex and liver fibrosis.

		No. (%)			Average cost per SVR (US $)
		All patients	Non‐SVR	SVR
Naïve G1		52	17 (32.7)	35 (67.3)	7627
Age	< 60 y	42	12 (28.6)	30 (71.4)	7,313*
	≥ 60 y	10	5 (50.0)	5 (50.0)	9,510*
Sex	Female	28	10 (35.7)	18 (64.3)	8,074
	Male	24	7 (29.1)	17 (70.8)	7,152
Fibrosis	0–2	30	7 (30.0)	21 (70.0)	6,182**
	3–4	8	4 (50.0)	4 (50.0)	10,099**
Naïve G2		65	8 (12.3)	57 (87.7)	4,799
Age	< 60 y	52	5 (9.6)	47 (90.4)	4,835
	≥ 60 y	13	3 (23.1)	10 (76.9)	4,647
Sex	Female	31	6 (19.3)	25 (80.7)	5,093
	Male	34	2 (5.9)	32 (94.1)	4,569
Fibrosis	0–2	28	7 (25.0)	21 (75.0)	5,686
	3–4	10	1 (10.0)	9 (90.0)	4,351

* p = 0.0004.

** p < 0.0001.

Figure 2.

Antiviral and nonantiviral agents cost, laboratory testing cost, and consultation cost (US $) and effectiveness evaluated as sustained virological response (SVR) on treatment naïve, hepatitis C virus (HCV) Genotype 1 and HCV Genotype 2.

Discussion

In this present study, we provided the real‐world cost‐effectiveness of PEG‐IFN/RBV in Taiwan. The average cost per SVR achieved was $5878. When stratified according to viral genotype, the results showed that the cost per SVR of $7627 in G1 CHC patients was 1.5 fold of $4799 in G2 CHC patients. Among these medical‐care costs, the antiviral cost, laboratory testing, and consultation cost per treatment for G1 patients was significantly higher than those for G2 patients.

Interestingly, the cost per treatment between SVR and non‐SVR patients was paradoxical between HCV G1 and G2 patients. HCV G1 non‐SVR patients had lower cost of medical‐care costs, antiviral agents and nonantiviral agents, and higher costs of laboratory testing than HCV G1 SVR patients. By contrast, almost of the components of medical‐care cost were higher in HCV G2 non‐SVR than HCV G2 SVR patients. The standard care of HCV G1 patients with PEG‐IFN/RBV is 48 weeks. Nevertheless, around 5–10% of HCV G1 patients could not achieve an early virological response at week 12, for whom early termination of PEG‐IFN/RBV treatment was recommended due to little chance of achieving an SVR [10]. This might therefore lead to the lower costs for HCV G1 non‐SVR patients. However, most of the HCV G2 patients could achieve a rapid virological response at week 4, for whom treatment duration shortened to 16 weeks do not compromising the treatment efficacy [12].

As expected, the average cost per SVR was much higher in HCV G1 patients than in HCV G2 patients ($7627 vs. $4799, respectively, in Taiwan). This was due to a longer period of antiviral therapy and lower SVR rate in HCV G1 patients when compared to HCV G2 patients. Thus, at our real‐world medical‐care costs, the PEG‐IFN/RBV had much better cost‐effectiveness in the treatment of HCV G2 than in the HCV G1 patients. We demonstrated that not only antiviral agents, but also nonantiviral agents, laboratory testing, and consultation costs were higher in HCV G1 patients than in HCV G2 patients. This indicated longer treatment duration, more adverse events, and outpatient visits in HCV G1 patients than in HCV G2 patients.

There were limitations in this study. First, the result was preliminary as it connects the 2 million out of 23 million patient profiles, which was one‐eleventh of the Taiwan whole population. However, the randomized sampling will reduce the bias. Secondly, our analysis was limited to direct medical‐care costs; indirect costs such as lost productivity and caregiver salaries were not hard to assess and not included in the present study.

In this study, we provided the real‐world cost‐effectiveness of PEG‐IFN/RBV according to viral genotype. Our results enhance the formation of a future strategy of HCV therapy for policy‐makers in the era of DAA IFN‐free therapy.

Acknowledgments

This work was supported by grants from the Ministry of Science Technology (MOST 103‐2314‐B‐037‐061‐MY3), Kaohsiung Medical University Hospital (KMUH‐103‐10V04, KMUH‐104‐4R04), and Kaohsiung Medical University (105‐P027 and 105‐P025). We are also grateful for the help from the Taiwan Liver Research Foundation (TLRF). All linkage databases were supported from Health and Welfare Data Science Center, Taiwan.

Supporting information

Supplementary data

Supplementary data

Supplementary data related to this article can be found at https://doi.org/10.1016/j.kjms.2016.10.008.