Telaprevir for retreatment of HCV infection.

BACKGROUND: Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. METHODS: In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. RESULTS: Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). CONCLUSIONS: Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.).

Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure.

BACKGROUND & AIMS: Nucleotide polymorphisms upstream of the interleukin 28B (IL28B) gene are strongly associated with hepatitis C virus (HCV) clearance in treatment-naïve patients treated with peginterferon/ribavirin (PegIFN/RBV). This subanalysis of the REALIZE study evaluated the impact of IL28B polymorphisms on sustained virologic response (SVR) in telaprevir-treated, HCV genotype 1-infected patients with prior PegIFN/RBV treatment failure. METHODS: Treatment-experienced patients were randomized to 12 weeks of telaprevir (750 mg every 8h) with/without a 4-week PegIFN/RBV lead-in, or placebo, each with PegIFN-α-2a (180 µg/week) and ribavirin (1000-1200 mg/day) for 48 weeks overall. Data from telaprevir arms were pooled. RESULTS: Eighty percent (527/662) of patients consented to genetic testing and were included. Similar proportions of patients had IL28B CC, CT and TT genotypes across treatment arms; baseline characteristics were generally well balanced. SVR rates were higher in the pooled telaprevir versus placebo group for all IL28B genotypes; CC: 79% versus 29%, respectively; CT: 60% versus 16%, respectively; TT: 61% versus 13%, respectively. Within each prior response category (relapse, partial or null response), SVR and viral breakthrough rates with telaprevir-based treatment were comparable across IL28B genotypes. IL28B genotype did not significantly affect SVR (2-step multivariate analyses; p >0.16 in pairwise comparison among CC, TT, and CT). Variations in rapid virologic response and relapse rates were noted in certain patient subgroups. CONCLUSIONS: Our findings suggest that IL28B genotype has a limited impact on SVR rates with telaprevir-based therapy in treatment-experienced patients. IL28B genotyping may have limited utility in the baseline evaluation of similar patients considered for telaprevir-based therapy.

Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or -2b to patients with chronic hepatitis C.

BACKGROUND & AIMS: Recent studies have shown that 12 weeks of treatment with telaprevir, administered every 8 hours (q8h), combined with pegylated interferon (peginterferon) alfa-2a plus ribavirin significantly increased the rate of hepatitis C virus (HCV) eradication (sustained virologic response [SVR]) in patients infected with HCV genotype 1 compared with approved therapy. We investigated the efficacy, safety, tolerability, and pharmacokinetics of telaprevir given q8h or every 12 hours (q12 h) in combination with peginterferon alfa-2a or alfa-2b. METHODS: Treatment-naive patients (n = 161) infected with HCV genotype 1 were randomly assigned to groups that were given open-label telaprevir (750 mg q8 h or 1125 mg q12 h) in combination with standard doses of peginterferon alfa-2a (180 µg/wk) and ribavirin (1000-1200 mg/day) or peginterferon alfa-2b (1.5 µg·kg(-1)·wk(-1)) and ribavirin (800-1200 mg/day). Patients received triple therapy for 12 weeks, followed by 12 or 36 additional weeks of treatment with peginterferon alfa and ribavirin, based on virologic response. RESULTS: Baseline characteristics were similar for all groups. SVR rates were 81.0% to 85.0% among groups; most patients received 24 weeks of therapy (68.0%). There were no significant differences in SVR rates (intent-to-treat analysis) among groups (P ≥ .787), between the pooled q8 h and q12 h groups (P = .997), or between the pooled peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin groups (P = .906). The safety profile was similar among all groups. CONCLUSIONS: A high proportion (>80%) of patients achieved an SVR regardless of the telaprevir dosing frequency (q8 h or q12 h) or type of peginterferon alfa used (alfa-2a or alfa-2b).

Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections.

BACKGROUND & AIMS: We evaluated antiviral activity of 2 weeks therapy with telaprevir alone, peginterferon alfa-2a and ribavirin (PR), or all 3 drugs (TPR) in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype 2 or 3 infections. METHODS: We performed a randomized, multicenter, partially blinded study of patients (23 with HCV genotype 2, 26 with genotype 3) who received telaprevir (750 mg every 8 h), placebo plus PR (peginterferon, 180 µg, once weekly and ribavirin, 400 mg, twice daily), or TPR for 15 days, followed by PR for 22 or 24 weeks. Plasma levels of HCV RNA were quantified. RESULTS: Levels of HCV RNA decreased in all patients with HCV genotype 2, including those who received telaprevir monotherapy. The decrease was more rapid among patients who received telaprevir. By day 15, 0% (telaprevir), 40% (TPR), and 22% (PR) of patients with HCV genotype 2 had undetectable levels of HCV RNA; rates of sustained virologic response were 56%, 100%, and 89%, respectively. Overall, 6 of 9 HCV genotype 2 patients that received only telaprevir had viral breakthrough within 15 days after an initial response. HCV RNA levels decreased slightly among patients with HCV genotype 3 who received telaprevir and decreased rapidly among patients given PR or TPR (telaprevir had no synergistic effects with PR). Sustained virologic response rates were 50%, 67%, and 44% among patients given telaprevir, TPR, or PR respectively; 7 patients with HCV genotype 3 relapsed after therapy (2 given telaprevir, 3 given TPR, and 2 given PR) and 3 patients with HCV genotype 3 had viral breakthrough during telaprevir monotherapy. The incidence of adverse events was similar among groups. CONCLUSIONS: Telaprevir monotherapy for 2 weeks reduces levels of HCV RNA in patients with chronic HCV genotype 2 infections, but has limited activity in patients with HCV genotype 3.

Telaprevir: pharmacokinetics and drug interactions.

Telaprevir is an inhibitor of the HCV NS3/4A protease. When used in combination with pegylated interferon and ribavirin, telaprevir has demonstrated a substantial increase in sustained virological response compared with pegylated interferon and ribavirin used alone. Telaprevir has good oral bioavailability, which is enhanced when administered with food. Telaprevir is extensively metabolized and primarily eliminated via faeces. No dose adjustment of telaprevir is needed in patients with mild to severe renal impairment or mild liver impairment. Telaprevir is a substrate and inhibitor of cytochrome P450 3A and P-glycoprotein and, thus, might interact with coadministered drugs that affect or are affected by these metabolic/transport pathways. This article reviews the pharmacokinetic and drug interaction profile of telaprevir.