A total of 165 patients were enrolled in Austria, Germany, Hungary, Poland, Romania, and Spain; the majority of patients were enrolled from Eastern European countries (70%). All 165 patients received at least one dose of study medication and were included in the efficacy analysis (Fig. 1). The first patient was enrolled in July 2012 and the last patient completed follow-up in June 2014. The mean age was 46 years, the mean body mass index was 26 kg/m2, 50% of the patients were male, and a majority were Caucasian (99%), infected with HCV genotype 1b (86%), and had a host IL28B non-CC genotype (79%) (Table 1).
A total of 14 patients (8.5%) had protocol deviations: two patients had contraindications to treatment; nine patients received a dosing regimen that differed from the recommendations for response-guided therapy in the protocol; two patients received less than the recommended initial dose of boceprevir (<2400 mg/day); one patient did not receive boceprevir and did not have a post-baseline HCV RNA test result.
All treatment was discontinued prematurely in 26 (16%) patients (Fig. 1). Of note, discontinuation for lack of efficacy at Weeks 12 or 24 occurred in 10 patients overall. A further six patients (4%) did not complete 24 weeks of follow-up.
A total of 12 patients (7%) had a virological response by the end of the 4-week lead-in phase, and 100 (61%) and 143 (87%) of patients had undetectable HCV RNA after 4 (Week 8) and 12 (Week 16) weeks of triple therapy, respectively (Fig. 2).
The overall SVR12 rate was 81% (133/165, CI 74–86%) (Fig. 3a). Among patients with HCV genotype 1a and 1b infection, the SVR12 rates were 86% (19/22, CI 65–97%) and 80% (114/142, CI 73–86%), respectively, and among patients with host IL28B CC, CT, and TT genotypes the SVR12 rates were 94% (33/35, CI 81–99%), 77% (71/92, CI 67–85%), and 78% (29/37, CI 62–90%), respectively (Supplementary figure 2).
A total of 78 non-cirrhotic patients (47%) had an early response (undetectable HCV RNA at Weeks 8 and 24) and were eligible to stop all therapy at Week 28. Among these patients, the SVR12 rate was 95% (74/78, CI 87–99%). A further 24 patients had a late response (detectable HCV RNA at Week 8, undetectable HCV RNA at Week 24) of whom 21 (88%, CI 68–97%) had an SVR12. Among those patients with a poor response (<1-log10 decrease in HCV RNA) at the end of the 4-week lead-in phase, the SVR12 rate was 75% (18/24, CI 53–90%), and among all patients with cirrhosis the SVR12 rate was 67% (14/21, CI 43–85%). The baseline characteristics of patients with an early and late response are shown in Supplementary Table 1. The characteristics in these two groups were generally similar with the exception of a higher prevalence of a host IL28B CC genotype in early responders (31% versus 8% in late responders) and a lower proportion of patients with a high baseline HCV RNA level in early responders (69% versus 88%, respectively).
The overall relapse rate was 7% (10/143) (CI 3–12%) (Fig. 3b). All patients who relapsed harbored HCV genotype 1b and had a non-CC genotype (eight CT and two TT). Among patients with an early and late response the relapse rates were 4% and 9%, respectively, and among patients with cirrhosis the relapse rate was 13%.
A ≥3-log10 decrease in serum HCV RNA after 4 weeks of triple therapy (Week 8) was associated with both a positive predictive value and negative predictive value of 86% for SVR (Supplementary figure 3).
Rebound, defined as 1-log10 increase above nadir, was observed in 6% (10/164) of patients with an on-treatment decrease in HCV RNA, and breakthrough was observed in 3% (4/151) of patients with an on-treatment virological response.
A total of 18 serious AEs (SAEs) were reported in 15 patients (13 of 18 SAEs were considered to be related to study treatment in the investigator’s opinion), and 5 (3%) patients discontinued treatment for AEs (Table 2). Discontinuation of peginterferon alfa-2a, ribavirin, and boceprevir was attributed to neutropenia in 1, 1, and 4 patients, respectively, and to anemia in 0, 2, and 3 patients, respectively. A total of 10 patients (6%) received treatment with a hematopoietic stimulant (epoetin) and a total of 14 patients (8%) received treatment with a colony-stimulating factor. A total of five patients received transfusions of whole blood or packed red blood cells for anemia during the study.
The incidence of individual AEs was similar in the overall study population and in patients with cirrhosis (Table 2). However, when compared with the overall study population, the incidence of SAEs was higher in cirrhotic patients as was the incidence of study drug discontinuation for AEs and of certain laboratory abnormalities (low hemoglobin concentrations and platelet count) (Table 2). Of note, the incidence of thrombocytopenia was 12% overall (20/165), but was 33% (7/21) in patients with cirrhosis. Consistent with this observation, a higher proportion of cirrhotic patients had platelet counts of <50 × 109/L (48% versus 8% in the overall study population).