Boceprevir for previously treated chronic HCV genotype 1 infection

Abstract

Background: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.

Methods: To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.

Results: A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls.

Conclusions: The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).

Figure 1. Study Design

For 13 patients for whom the HCV RNA measurement at the end of the follow-up period was missing, the measurement obtained at 12 weeks of follow-up was carried forward; of these patients, a sustained virologic response was achieved in 2 (1 in group 2 and 1 in group 3). Patients with a detectable HCV RNA level at week 12 were considered to have had treatment failure (according to the stopping rule). Patients in group 1 were offered the opportunity to receive treatment with boceprevir plus peginterferon–ribavirin by means of an access study or to proceed to the follow-up phase of this study. Patients in groups 2 and 3 proceeded to the follow-up phase of this study. The primary efficacy end point was assessed at the end of the follow-up phase. The x-axis numbers are not to scale.

Figure 2. Patients with a Sustained Virologic Response, According to Treatment Group and Analysis

The percentages of patients with a sustained virologic response are shown. The prespecified primary analysis involved all patients who were randomly assigned to a treatment group and received at least one dose of any study medication. The prespecified secondary analysis involved all patients who were randomly assigned to a treatment group and received at least one dose of boceprevir or placebo. Prior relapse was defined as an undetectable HCV RNA level at the end of prior therapy without subsequent attainment of a sustained virologic response. Prior nonresponse was defined as a decrease in the HCV RNA level of at least 2 log₁₀ IU per milliliter by week 12 of prior therapy but a detectable HCV RNA level throughout the course of prior therapy, without subsequent attainment of a sustained virologic response. Poor response to interferon was defined as a decrease in the HCV RNA level of less than 1 log₁₀ IU per milliliter after the 4-week lead-in period (treatment week 4). Good response to interferon was defined as a decrease in HCV RNA level of 1 log₁₀ IU per milliliter or more after the lead-in period. For the primary analysis, the absolute difference between group 2 and group 1 was 37.4 percentage points (95% confidence interval [CI], 25.7 to 49.1; P<0,001), and between group 3 and group 1, 45.2 percentage points (95% CI, 33.7 to 56.8; P<0.001). For the secondary analysis, the absolute difference between group 2 and group 1 was 39.1 percentage points (95% CI, 27.2 to 51.0; P<0.001), and between group 3 and group 1, 45.1 percentage points (95% CI, 33.4 to 56.8; P<0.001). The P values were calculated with the use of the Cochran-Mantel-Haenszel chi-square test after adjustment for baseline stratification factors. I bars are 95% confidence intervals.

Figure 3. Odds Ratios for a Sustained Virologic Response in Group 2 versus Group 1 and Group 3 versus Group 1, According to Subgroup

Odds ratios are shown for group 3 versus group 1 (solid circles) and group 2 versus group 1 (open circles) on a log₁₀ scale. The dashed vertical line at unity indicates no difference between the two groups (odds ratio of 1). The dashed horizontal arrows indicate odds ratios and confidence intervals that exceed the x-axis scale. Race was self-reported. The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. For the Metavir fibrosis score, presence or absence of cirrhosis, and percent steatosis, a total of 28 patients (4 in group 1, 13 in group 2, and 11 in group 3) had missing data. Data on sustained virologic response for other subgroups are listed in Table S2 of the Supplementary Appendix. P values for the interaction between treatment group and baseline characteristic are given in Table 6 of the Supplementary Appendix. The HCV genotype 1 subtype was determined with the use of the Trugene assay (Bayer Diagnostics). ALT denotes alanine aminotransferase.