Approximately 140 million people worldwide are infected with hepatitis C virus (HCV), 11 million of whom are <15 years of age.1 The prevalence of HCV infection in children ranges widely by region, varying from 0% to 0.4% in developed regions and up to 14.5% in developing regions.2 There is a relative paucity of epidemiologic data regarding the disease course and morbidity and mortality of HCV in children. A more favorable prognosis was observed in children than in infected adults because of more frequent spontaneous recovery and fewer risks of fulminant hepatitis and fibrosis progression in children.2–4 However, approximately 4%–6% of children develop compensated cirrhosis (CC) or decompensated cirrhosis (DC), and 4–5 children undergo liver transplantation (LT) annually in the United States for DC and hepatocellular carcinoma (HCC) as a consequence of HCV.5–7 Despite these findings, the assessment and treatment of HCV in children are implemented in a manner similar to that used for adults based on the current guidelines8 in which pegylated interferon α plus ribavirin (PR) treatment is recommended. For children receiving PR treatment, the sustained virologic response (SVR) for genotypes 1/4 and 2/3 is approximately 52% and 89%, respectively.2,9 However, many infected children do not complete PR treatment due to its shortcomings.3
The regimen of ledipasvir/sofosbuvir (LS) is currently used in adults and is well tolerated in adolescents because of its appropriate pharmacokinetic profile.10,11 In adolescents with HCV genotype 2 and 3 infections, the regimen of sofosbuvir/ribavirin (SR) also demonstrates clinical efficacy and good patient-reported outcomes.12 In 2017, LS and SR were approved for managing adolescents with HCV genotype 1, 4, 5, and 6 infections and genotype 2 and 3 infections, respectively.13 A position paper published by the Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition addressed therapeutic management issues related to direct-acting antiviral combinations, including goals, endpoints, indications, contraindications, and the optimal treatment regimen, in children with chronic HCV infection.13 However, it is unclear whether these novel oral regimens represent a cost-effective strategy for treating adolescents with HCV infection.
This study aimed to examine the health and economic outcomes of novel oral regimens and pegylated interferon α–based treatments for managing HCV genotype 1, 2, 3, and 4 infections in adolescents in the United States and China. We compared the cost-effectiveness of these regimens in the world’s 2 largest economies, representing developed (United States) and resource-constrained (China) settings.
MATERIALS AND METHODS
Analytic and Model Overview
A previously published state-transition Markov model was adopted to examine the lifetime cost-effectiveness of novel oral regimens for adolescents with HCV infection relative to the cost-effectiveness of currently available regimens in the United States and China,14 including the following: the pegylated interferon with PR strategy for genotypes 1–4 (reference strategy); the LS strategy for genotypes 1 and 4; the SR strategy for genotypes 2 and 3; and the ledipasvir/sofosbuvir/ribavirin (LSR) strategy for genotype 3.
The Markov model reflected the natural disease course of HCV infection, which included 14 exclusive health states (Fig. 1): 5 METAVIR liver fibrosis states [no fibrosis (F0), portal fibrosis without septa (F1), portal fibrosis with few septa (F2), numerous septa without fibrosis (F3), or cirrhosis (F4)] and 5 METAVIR liver fibrosis states (SVR F0–F4) with SVR if active treatment was administered, CC, DC, HCC, LT, and death. The Markov cycle length was 12 weeks with a lifetime horizon. During each Markov cycle, patients remained in their current health state or moved to another health state, as shown by arrows at the end of each cycle. The source of the transition probabilities and their details are described in the following paragraph. At the beginning of the model, a hypothetic patient cohort of adolescents was assigned to the 5 stages of fibrosis (F0–F4) based on the proportions reported in the literature. If patients in stages F0–F2 transited to SVR, they were assumed to be cured and not incur recurrence again; however, those in stages SVR F3 and SVR F4 who achieved SVR were allowed to progress to DC and HCC, albeit at a slower rate based on a recent cohort study that compared patients in stages F3 and F4. After patients entered into the DC and HCC states, they incurred disease-specific mortality or received LT. Patients in health states other than DC, HCC, and LT experienced natural mortality.
The health endpoints included the cumulative probability of CC, DC, and HCC; expected life years; and quality-adjusted life years (QALYs). Cost and QALYs are annually discounted at 3% in the United States and 5% in China.15 Because adolescents might have a longer expected life year from the new treatment than adults, a wide range of discount rates (0%–8%) was adopted to determine the impact of the discount rate in the 1-way sensitivity analysis. We measured the incremental cost-effectiveness ratio (ICER; US $ per additional QALY gained) of competing strategies compared with that of the control strategy. We used US $50,000 and $27,351 (3× the per capita gross domestic product of China in 2017) as the local cost-effectiveness thresholds.16,17 The Consolidated Health Economic Evaluation Reporting Standards checklist is attached in the Appendix (Supplemental Digital Content 1, http://links.lww.com/INF/D939).
Our base-case patients were diagnosed with chronic HCV genotype 1, 2, 3 or 4 infections. The baseline characteristics were obtained from clinical trials,10–12,18 where patients had a mean age of 15 years (range, 12–17 years) and a median weight of 68 kg (range, 47–87 kg). In adolescents with chronic hepatitis C, the distribution of METAVIR fibrosis stages (F0–F4) was 24.6% (F0), 66.2% (F1), 7.1% (F2), 2.1% (F3), and 0% (F4).14
Treatment Regimens and Scenarios
The current analysis used SVR as the surrogate endpoint, which was stratified by treatment-naive and treatment-experienced adolescent patients (Appendix Table 1, Supplemental Digital Content 1, http://links.lww.com/INF/D939). The PR strategies used for the 48-week treatment in HCV genotype 1 and 4 infections and the 24-week treatment in HCV genotype 2 and 3 infections were derived from a meta-analysis9 that examined the efficacy and safety of PR therapy in children and adolescents with HCV in 8 trials. In HCV genotype 1, the efficacy and safety of the LS strategy were collected from a multicenter, open-label, phase 2 trial.11 In HCV genotype 4, the efficacy and safety of the LS strategy were collected from a real-world study.10 Because of the similarity between chronic HCV infection in children and adults with genotype 1, the efficacy data in this study and comparable exposure results suggest the possibility for extrapolation to other genotypes.11 Thus, the clinical data of LSR for genotype 3 in adolescents were assumed to be similar to those of adults, which were derived from published trials.19,20 The impact of efficacy data in adults was assessed with sensitivity analyses.
Appendix Table 2 (Supplemental Digital Content 1, http://links.lww.com/INF/D939) summarizes the Markov transition parameters used in the model that were taken from published literature. Because of the absence of adolescent-specific disease progression data, we assumed that the transition probabilities between fibrosis states in adults would also apply to children because infected adolescents follow a clinical disease pattern similar to that of adults.6,21 The probabilities of liver fibrosis progression in a population with HCV were derived from a systematic review22 that reported the liver fibrosis progression rate in 3 age groups: age <20 years, age 20–29 years, and age ≥30 years. The progression rate for individuals <20 years of age was used for adolescents. One recent cohort study showed that Asians were significantly more likely to develop cirrhosis [adjusted hazard ratio, 1.28; confidence interval: 1.02–1.61; P = 0.034] than Caucasians. The fibrosis progression rate in Chinese HCV patients without SVR was adjusted using this hazard ratio.23 If patients achieved SVR, the risks of fibrosis progression and liver complications were reduced by >90%. Those who did not achieve SVR were assumed to remain in their current health state or transition to sequential health states as if untreated. Spontaneous recovery was observed in patients without SVR. Spontaneous resolution in children was documented in a cohort study.3 The probabilities of developing HCC from DC, receiving a liver transplant, and dying due to HCC, DC, and liver transplant were country specific and derived from previous reports.24,25 The natural mortality data were obtained from the life tables of the World Health Organization member states (2011).
Cost and Utility Inputs
This analysis adopted the third-party payer and health care perspectives in the United States and China, respectively, which considered only direct medical costs, including antiviral therapy and the management of complications associated with HCV (Appendix Table 3, Supplemental Digital Content 1, http://links.lww.com/INF/D939). For comparison, Chinese costs were reported in 2017 US dollars (1 US $ = 6.5 Chinese Yuan). The US costs associated with health care services were inflated to 2013 values according to the US consumer price index.26
The dosages used were 15 mg/kg for ribavirin, 180 μg/1.73 m2 per week for peginterferon α-2a in genotypes 1 and 4, and 60 μg/m2 per week for peginterferon α-2b in genotypes 2 and 3.14 The costs of peginterferon α-2a, peginterferon α-2b, ribavirin, LS, and sofosbuvir were obtained from local charges.27 The reported annual direct medical costs of managing patients with a METAVIR score of F0–F4, DC, HCC, and LT were country specific and taken from previous economic evaluations.24,25 It was assumed that patients in stages F0–F2 with SVR would not incur direct medical costs due to the cured health states and that patients in stages F3–F4 with SVR used fewer health resources. The relative ratio of the costs in stages F3–F4 with SVR versus without SVR was 0.709.28
Utility scores were assigned for each health state, and they were gathered from the literature.25,29–31 Disutility scores caused by treatment-related adverse events were also taken into account in the duration of therapy (Appendix Table 4, Supplemental Digital Content 1, http://links.lww.com/INF/D939).
In the probabilistic sensitivity analysis, 1000 Monte Carlo simulations were run by inputting parameters sampled from their statistical distributions (ie, γ distribution for costs; normal distribution for log relative ratios and health resource utilization; and β distribution for utilities, probabilities, and proportions). A cost-effectiveness acceptability curve representing the uncertainty in the model was generated to show the probability of the cost-effective simulations at various willingness-to-pay (WTP) thresholds. In the 1-way sensitivity analysis, the gaps in the ICERs of an individual parameter between a low and high value, as shown in Appendix Tables 1–4 (Supplemental Digital Content 1, http://links.lww.com/INF/D939), were measured, and the results are shown as a tornado chart. Model development and all analyses were performed with R version 3.4.1 (R Core Team, Vienna, Austria).
HCV Genotypes 1 and 4
In HCV genotype 1 infection, the LS strategy reduced the cumulative probabilities of CC, DC, and HCC by 47.08%, 30.49%, and 15.69%, respectively, relative to PR treatment in the United States and 48.57%, 31.07%, and 26.59%, respectively, in China (Table 1). LS therapy also increased the marginal overall life expectancy by 9.31 and 11.23 years in the United States and China, respectively, and increased QALYs by 3.69 and 2.37, respectively, with marginal costs of $54,185 and saved costs of $11,730, which yielded ICERs of $14,699/QALY and $4958/QALY, respectively, relative to PR therapy.
In HCV genotype 1 infection, the LS strategy reduced the cumulative probabilities of CC, DC, and HCC by 42.81%, 27.73%, and 14.27%, respectively, relative to PR treatment in the United States and 44.45%, 28.43%, and 24.34%, respectively, in China. LS therapy also increased the marginal overall life expectancy by 8.46 and 10.28 years in the United States and China, respectively, and discounted QALYs by 3.31 and 2.12, respectively, with marginal costs of $49,493 and saved costs of $10,995, which yielded ICERs of $14,946/QALY and $5179/QALY, respectively, relative to PR therapy.
In HCV genotype 1 and 4 infections, the 1-way sensitivity analysis demonstrated that the ICERs of LS versus PR were robust to the adjustment of model parameters in the United States and China (Fig. 2A, D and Appendix Figure 1A, D, Supplemental Digital Content 1, http://links.lww.com/INF/D939). Based on the probabilistic sensitivity analysis, a cost-effectiveness acceptability plot showed a 100% probability that the LS strategy would be more cost-effective than the PR strategy at a WTP threshold of $50,000/QALY and $9117/QALY in the United States and China (Fig. 3), respectively.
HCV Genotype 2
In the United States, SR therapy increased the marginal overall life expectancy by 4.07 years (Table 1) and discounted QALYs by 1.59, with marginal costs of $67,608, which yielded an ICER of $42,472/QALY relative to PR therapy. In China, the SR strategy is superior to the PR strategy due to its greater health benefits and saved costs.
The 1-way sensitivity analysis also demonstrated that the ICER of SR versus PR was most sensitive to the discount rate in the United States (Fig. 2B). The cost-effectiveness acceptability plot showed that the probability that the SR strategy would be more cost-effective in the United States than the PR strategy was 58% at a WTP threshold of $50,000/QALY (Fig. 3). In China, the probability that the SR strategy would be more cost-effective than the PR strategy was nearly 100% at a local threshold.
HCV Genotype 3
In the United States, LSR and SR therapies increased the marginal overall life expectancy by 3.96 and 3.61 years, respectively, and discounted QALYs by 1.58 and 1.42, respectively, with respective marginal costs of $77,836 and $153,990, which yielded ICERs of $49,409/QALY and $108,666/QALY, respectively, relative to PR therapy. In China, LS and SR strategies are superior to the PR strategy due to their greater health benefits and saved costs.
The 1-way sensitivity analysis also demonstrated that the ICER of LS versus PR was most sensitive to the discount rate in the United States (Fig. 2C). The cost-effectiveness acceptability plot showed that the probabilities that LSR and SR strategies would be more cost-effective in the United States than the PR strategy were 50% and 1%, respectively, at a WTP threshold of $50,000/QALY and 97% and 40%, respectively, at a WTP threshold of $100,000/QALY (Fig. 3). In China, the probabilities that LSR and SR strategies would be more cost-effective than the PR strategy were nearly 100% at a local threshold.
The findings of this analysis revealed that the treatment with oral regimens is expected to notably reduce the risks of liver complications associated with HCV compared with those associated with traditional PR treatments in adolescents with HCV genotype 1–4 infections, which may result in the consumption of fewer health resources and better health outcomes. The different natural mortality and transition probabilities of disease progression have led to a paucity of different liver complications in the United States and China. The cost-utility analysis indicated that compared with conventional PR therapy, the newly approved peginterferon-free regimen of LS for genotypes 1 and 4 and LSR for genotype 3 was more cost-effective in the United States and cost saving in China. However, the regimen of SR for adolescents with HCV genotype 3 infection did not provide relatively good value due to the high cost of 24 weeks of treatment. These findings were generally comparable to those of other economic evaluations, which suggested that direct-acting antivirals were more cost-effective than no treatment and conventional PR therapy.32
The economic outcomes in the United States are most sensitive to the discount rate. In genotypes 2 and 3, the ICERs of SR and LSR versus PR exceeded $100,000/QALY if the discount rate was adjusted to 8%. This finding aptly explains the influence of discounting on the economic outcomes of regimens for genotypes 2 and 3, in which most costs occur early in treatment, and most health benefits are grasped in the future. However, the adjustment of the discount rate could not drive the ICERs of LS against PR to exceed $100,000/QALY for genotypes 1 and 4, although it is the most sensitive parameter. The sensitivity analysis also revealed that the model outcomes were considerably influenced by the cost of LS, which led to the distinguished cost-effective results in the United States and cost-saving results in China. This finding indicates that the lower price of new oral regimens would be helpful for local decision-makers, especially in a health resource–limited setting.
This study has several strengths. To the best of our knowledge, this is the first economic evaluation to quantitatively compare a novel oral regimen composed of sofosbuvir plus ledipasvir or ribavirin in adolescents with HCV infection. The current analysis also used or adjusted specific clinical efficacy data to project health outcomes, such as the efficacy of oral regimens and spontaneous resolution, in adolescents. Second, the present evaluation assessed economic outcomes from the perspectives of the United States and China as representatives of high- and middle-income countries, respectively; therefore, these findings could be easily applied to other regions.
The analysis has several limitations. First, the efficacy data of LSR for genotype 3 were derived from trials conducted in adults because of the lack of such data in adolescents. Fortunately, the 1-way sensitivity analyses showed that the ICERs of the new oral regimens over the PR strategy did not exceed $100,000/QALY, even when their SVR was reduced to 80%. Second, only genotypes 1, 2, 3, and 4 were considered in the current analysis, and other genotypes, such as 5 and 6, were not included because thus far, no clinical trials have been carried out to demonstrate the effectiveness of oral regimens in adolescents. Finally, the analysis did not consider special populations, such as drug users and hepatitis B virus or HIV coinfections, due to limited and weak epidemiologic data. However, because the findings of this study reflected the common clinical conditions of managing HCV in adolescents, we hope that this study provides relevant information for clinical and health policy decision-makers.
In summary, novel oral regimens for adolescents with HCV can improve patient health outcomes and might also be more cost-effective than traditional PR therapy in the context of the United States and China.
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