Boceprevir for previously untreated patients with chronic hepatitis C Genotype 1 infection: a US-based cost-effectiveness modeling study

Infection with hepatitis C virus (HCV) is a major global public health problem. According to the World Health Organization statistics, approximately 130–170 million people are currently infected with chronic HCV worldwide [1]. In the United States (U.S.) and Europe, HCV is the leading cause of chronic liver disease and the leading indication for liver transplantation [2‐5]. HCV infection represents a substantial clinical and economic burden in the U.S. [6, 7]. For example, it is estimated that 3.2 million persons are chronically infected [6] and that HCV infection causes approximately 15,000 deaths annually [8]. The total 2011 healthcare cost associated with HCV in the U.S. was estimated at $6.5 ($4.3–$8.4) billion [9]. Generally, it takes several years – possibly decades – between infection with HCV and development of serious liver disease. Hence, although the incidence of acute HCV infection is declining, the prevalence of cirrhosis and incidence of HCV-related liver disease is expected to increase over the next 10–20 years [10].

There are 6 major HCV genotypes [11]. Approximately 70% of HCV infected people in the U.S. have genotype 1, which is the most difficult-to-treat [12]. Prior to 2011, the standard of care for chronic HCV genotype 1 infection was 48 weeks of antiviral (AV) treatment with a combination of a pegylated interferon alfa and ribavirin [13]. With peginterferon alfa-2a or alfa-2b and ribavirin treatment, less than 50% of treatment-naïve genotype 1 patients achieve a sustained virologic response (SVR) [14, 15]. Patients with advanced liver disease and of African-American descent have an even lower likelihood of attaining an SVR with this treatment regimen (20%–30%) [16].

In 2011, HCV protease inhibitors obtained regulatory approval and became available to treat patients infected with HCV genotype 1. The addition of HCV protease inhibitors, boceprevir and telaprevir, to peginterferon alfa and ribavirin have led to markedly higher SVR rates [17‐20]. As a result, the American Association for the Study of Liver Diseases (AASLD) guidelines were updated in 2011 to recommend including the protease inhibitors in the treatment regimens of patients infected with HCV genotype 1 [21]. The objective of this study was to assess the clinical impact and cost-effectiveness of the boceprevir-containing regimens that were studied in the Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial in treatment-naïve patients. The secondary objective was to evaluate the cost-effectiveness of boceprevir-based treatment strategies compared to treatment with dual therapy in pre-specified subsets of the population and in sensitivity analyses. The projections are based on a decision analytic model that integrates data from public sources, published literature, and clinical trial databases under a clearly specified set of assumptions.

In our model, we assumed that SVR is a cure for mild and moderate HCV and that patients who achieve an SVR through AV therapy will not be at risk for developing serious and costly complications associated with HCV. There are a small number of studies which suggest that patients with moderate HCV may develop HCC even after achieving an SVR with drug therapy [37, 38]. The limited data suggests that the probability of this transition is very close to zero. Because of the limited information and since the transition is negligible, we did not include it in our model. Data also suggests that cirrhotic patients may have a regression of fibrosis if they achieve an SVR, which would lower their risk of developing HCV-related liver complications. A recently published study by van der Meer et al. [58] showed that the all-cause mortality rates in patients who achieved SVR and who did not achieve SVR were 8.9% and 27% at 10 years, respectively. They also reported that 10-year cumulative incidence rates of HCC and decompensated cirrhosis in patients who achieved SVR were 5.1% and 2.1%, respectively. In our analysis, we also included a progression of disease in cirrhotic patients who achieved SVR, and the incidence rates reported by van der Meer et al. were included in our sensitivity analysis range.

SPRINT-2 demonstrated that the addition of boceprevir to peginterferon alfa-2b and ribavirin after a 4-week peginterferon─ribavirin lead-in period significantly increased SVR rate over treatment with peginterferon─ribavirin alone in previously untreated adult patients infected with HCV genotype 1. However, the boceprevir-based treatment regimens themselves are more costly than treatment with peginterferon and ribavirin alone. Given the scarce resources and competing demands, payers often need to consider the long-term impact that treatment will have on the clinical and economic burden of disease. Our modeling study assessed the cost-effectiveness of the boceprevir-based strategies studied in SPRINT-2 over the lifetime of patients from the payer perspective. We also examined the impact of the FDA-approved label-based strategies on the incidence of HCV-related complications, lifetime costs, QALYS, and assessed the cost-effectiveness of these regimens.

Our model estimates that treatment with PR48 is associated with considerable reductions on the incidence of serious liver complications compared to no treatment and is cost-effective at commonly used thresholds. However, our model projections indicate that treatment with boceprevir-based regimens offer substantial additional benefit.

A difference in the incidence rates of serious liver disease between boceprevir-based regimens and PR48 was projected to occur within 10 years following treatment (Figure 2). Hence, although the AV therapy costs of BOC/RGT and BOC/PR48 are considerably greater than the AV therapy costs of PR48, a savings in the projected costs of managing HCV-related liver disease is expected to offset some of the drug costs. The ICERs of the BOC/RGT and BOC/PR48 treatment regimens compared with PR48 were $16,792/QALY and $55,162/QALY, respectively. Thus both BOC/RGT and BOC/PR48 are considered cost-effective at commonly used thresholds [59]. In addition, the ICER of BOC/PR48 compared with BOC/RGT was $807,804/QALY, which implies that BOC/PR48 is not cost-effective at commonly used thresholds when compared to treatment with BOC/RGT. The high ICER obtained from comparing BOC/PR48 to BOC/RGT is mostly explained by the small difference in SVR rates between the two treatment strategies (BOC/PR48: 66% vs. BOC/RGT: 63%) and the difference in AV therapy costs (BOC/PR48:$69,928 vs. BOC/RGT: $47,582).

Describing the natural history of chronic HCV has been historically difficult because acute infection is often asymptomatic, and the duration between infection and development of advanced stages of liver disease is typically long [60]. Because of the variability of the estimates reported in literature and potential variability in treatment efficacy, we conducted sensitivity analyses on the majority of model inputs – treatment efficacy, transition rates, health state costs, and the quality of life associated with the health states. Results on the costs, benefits and cost-effectiveness of treatment varied widely across the different scenarios considered. The majority of one-way sensitivity analyses did not substantially impact the ICERs compared to the base case analyses. Only 5 of the 103 scenarios evaluated resulted in an ICER comparing BOC/RGT to PR48 that was more than $5000 different from the base case analysis ($16,792/QALY). Specifically, assumptions regarding the utility of the SVR-F1 health state, efficacy of PR48 and BOC/RGT, and the discount rates were most impactful on the ICER. Similarly, only 18 of the 103 scenarios evaluated resulted in an ICER comparing BOC/PR48 to PR48 that was more than $5,000 different from the base case analysis ($55,162/QALY). Specifically, assumptions regarding the transition rates from F4 to DC and F4 to HCC; utility of the F1-F4, SVR-F1, SVR-F2 health states; efficacy of PR48 and BOC/PR48; and the discount rates were most impactful on the ICER. These results imply that in comparison to treatment with dual therapy, the ICERs of BOC/RGT and BOC/PR48 are robust if a single model parameter is changed.

Multivariate sensitivity analyses found that there is more variability in the cost-effectiveness ratios associated with BOC/PR48 vs. PR48 treatment than in the cost-effectiveness ratios associated with BOC/RGT vs. PR48. The ICERs were most sensitive to assumptions concerning the quality of life of the HCV health states and least sensitive to assumptions concerning the quality of life of patients on treatment for those who receive BOC/RGT, and quality of life of the general population for patients who receive BOC/PR48. The most favorable results for BOC/RGT and BOC/PR48 were generated when a discount rate of 0% was applied to both costs and utilities, whereas the least favorable results were generated when the lower bounds of the SVR health states were assumed.

The PSA allowed us to evaluate the impact of varying the values of several parameters simultaneously on the projected long-term costs and QALYs of each treatment strategy at a variety of thresholds. Compared with PR48, BOC/RGT was cost-effective in nearly 100% of the 10,000 simulations when a threshold of $50,000 was chosen. This suggests that BOC/RGT offers the opportunity for a shorter duration of treatment than dual therapy that is significantly more efficacious and cost-effective at a threshold of $50,000 under a variety of assumptions.

Because of the differential treatment efficacy of dual therapy reported in non-black and black patients, data for these cohorts were collected and analyzed separately in the SPRINT-2 efficacy analyses. Although the reported SVR rates differed between the cohorts, the results of our cost-effectiveness study indicated similar trends within the results of the two subgroups. For both subgroup analyses by race cohort, compared to treatment with PR48, the ICER corresponding to the BOC/RGT treatment strategy was better than the ICER corresponding to the BOC/PR48 treatment strategy. The ICERs corresponding to BOC/PR48 compared with PR48 for both race cohorts were similar - $50,423 and $56,013 for the non-black and black cohorts, respectively. There was a greater difference in the ICERs between the boceprevir-based treatment strategies compared to dual therapy for the non-black subgroup than in the ICERs in the black subgroup. This is because the efficacies between the two boceprevir-based regimens are very similar even though the treatment cost of BOC/PR48 is much greater than the treatment cost of BOC/RGT. This implies that a longer duration of treatment may not result in additional clinical benefits. Conversely, treatment with BOC/PR48 resulted in an incremental gain of 0.21 QALYs compared to treatment with BOC/RGT in the black population. This implies that a longer duration of treatment with boceprevir may result in additional clinical benefit for black patients as is supported by the cost-effectiveness frontier (Figure 4).

The treatment strategies recommended in the FDA-approved boceprevir label include futility rules consistent with the guidelines of AASLD [21]. The ICER for the label-based treatment recommendation was $27,265 which implies that the label-based treatment recommendation is cost-effective at a reasonable threshold when compared with dual therapy. This indicates that the boceprevir-based treatment strategy offers great clinical benefit for the cost that is incurred.

Compared to previously published cost-effectiveness models [22‐26], our modeling study made several updates in the model structure and inputs. First, we incorporated treatment strategies that include boceprevir – a recently approved protease inhibitor which offers the opportunity for a shorter duration of therapy and significantly greater chance of attaining a cure. In addition, we updated the transition probabilities associated with progression of HCV, development of serious liver disease, the probability of receiving a liver transplant, and health state costs using data that was not previously available. Finally, unlike the majority of previous models, we included treatment of patients with cirrhosis in our model. We assumed that cirrhotic patients achieved a partial cure from HCV even if they attained SVR with treatment. This feature of our model –that patients with cirrhosis who achieve SVR are at risk of developing decompensated cirrhosis and hepatocellular carcinoma – was not incorporated in the majority of previous models.

After we developed our model, Liu et al. published a cost-effectiveness modeling study that included the costs and efficacy of recently approved protease inhibitors in the treatment regimen [27]. Our model differs from this modeling study in several ways. Specifically, the transition probabilities and health state costs included in our model are based on more recent data than those applied in the Liu model. Unlike Liu et al. which included cost for HCV with SVR and out-of-pocket expenses as part of the base case scenario, we only tested the influence of cost for HCV with SVR in the sensitivity analysis and we did not consider out-of-pocket expenses. Although the Liu model includes treatment of patients with cirrhosis, it was assumed that patients with cirrhosis who achieved an SVR were permanently cured of HCV. We assumed that patients with cirrhosis achieved a partial cure from HCV even if they attained SVR with treatment, which is consistent with recently published data [28]. Finally, we also evaluated the treatment regimen recommended by the FDA and AASLD for boceprevir, not just the treatment regimens studied in SPRINT-2.

Our study has several limitations. First, we did not model the possibility of retreatment with antiviral drugs that are currently available or might become available in the near future. Assumptions could be made concerning the timing of re-treatment in patients who received dual therapy in SPRINT-2 using data collected from a trial in previously treated patients (RESPOND-2) [18]. However, the efficacy of re-treatment for patients who did not achieve an SVR with one of the boceprevir-based regimens is unknown. Second, our model did not take into consideration the possibility of re-infection nor re-transplantation in patients who receive a liver transplant. These patients are at increased risk for developing future liver complications and receiving subsequent liver transplants. Since re-transplantation would occur further in the future, its influence on costs and benefits would be heavily discounted. This suggests that the inclusion of re-transplantation would have a favorable but small impact on the cost-effectiveness of boceprevir and that the current modeling study provides a conservative estimate of the cost-effectiveness of boceprevir-based regimens. Third, our model cannot be applied to special populations such as patients co-infected with HIV because of lack of data on the impact of treatment with boceprevir-based regimens at this time. Fourth, our study applies the all-cause mortality rate to patients with chronic HCV and to patients who attain an SVR. Subsets of this patient population are considered high-risk and the mortality rate of the general population may underestimate the mortality rate of the HCV treatment population. Our model also does not take into account that patients who attain an SVR are at risk for reinfection with HCV. This assumption may bias the results in favor of boceprevir-based regimens since the boceprevir-based regimens reported higher SVR rates. Sixth, our model does not take into account that patients who do not achieve an SVR with AV therapy may receive some benefit, such as a slower disease progression rate. The impact of relaxing this assumption on the results is not clear a priori. Seventh, this analysis was done from the payer perspective. Patients with chronic HCV or the sequelae of cirrhosis have been shown to experience increased work and productivity losses, suffer activity impairment, and incur increased indirect medical costs compared with people without HCV [61‐63]. Inclusion of such costs would result in lower ICERs for both boceprevir-regimens compared with dual therapy since the treatment efficacy of both BOC/RGT and BOC/PR48 are greater than the efficacy of treatment with PR48. Finally, all treatment characteristics are based entirely on clinical trial data. The discontinuation rates, which impact treatment efficacy, may differ in clinical practice.

In summary, boceprevir-based regimens were projected to substantially reduce the burden of liver-related complications such as decompensated cirrhosis, hepatocellular carcinoma, liver-related mortality, and liver-transplants in treatment-naïve patients infected with hepatitis C genotype 1. Our model also demonstrated that boceprevir-based regimens offer patients the possibility of experiencing great clinical benefit with a shorter duration of therapy that may minimize the time patients experience an HCV-treatment decrement to their quality of life. In addition both BOC/RGT and BOC/PR48 were projected to be cost-effective from the payer perspective at a reasonable threshold in comparison with treatment with peginterferon and ribavirin alone.