Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial.

BACKGROUND: Telaprevir (TVR) plus peginterferon-α2a (PEG-IFN-α2a) and ribavirin substantially increases treatment efficacy for genotype 1 chronic hepatitis C virus (HCV) infection versus PEG-IFN-α2a-ribavirin alone. Its safety and efficacy in patients with HCV and HIV-1 are unknown. OBJECTIVE: To assess the safety and efficacy of TVR plus PEG-IFN-α2a-ribavirin in patients with genotype 1 HCV and HIV-1 and to evaluate pharmacokinetics of TVR and antiretrovirals during coadministration. DESIGN: Phase 2a, randomized, double-blind, placebo-controlled study. (ClinicalTrials.gov: NCT00983853). SETTING: 16 international multicenter sites. PATIENTS: 62 patients with HCV genotype 1 and HIV-1 who were HCV treatment-naive and receiving 0 or 1 of 2 antiretroviral regimens were randomly assigned to TVR plus PEG-IFN-α2a-ribavirin or placebo plus PEG-IFN-α2a-ribavirin for 12 weeks, plus 36 weeks of PEG-IFN-α2a-ribavirin. MEASUREMENTS: HCV RNA concentrations. RESULTS: Pruritus, headache, nausea, rash, and dizziness were higher with TVR plus PEG-IFN-α2a-ribavirin during the first 12 weeks. During this period, serious adverse events occurred in 5% (2 in 38) of those receiving TVR plus PEG-IFN-α2a-ribavirin and 0% (0 in 22) of those receiving placebo plus PEG-IFN-α2a-ribavirin; the same number in both groups discontinued treatment due to adverse events. Sustained virologic response occurred in 74% (28 in 38) of patients receiving TVR plus PEG-IFN-α2a-ribavirin and 45% (10 in 22) of patients receiving placebo plus PEG-IFN-α2a-ribavirin. Rapid HCV suppression was seen with TVR plus PEG-IFN-α2a-ribavirin (68% [26 in 38 patients] vs. 0% [0 in 22 patients] undetectable HCV RNA levels by week 4). Two patients had on-treatment HCV breakthrough with TVR-resistant variants. Patients treated with antiretroviral drugs had no HIV breakthroughs; antiretroviral exposure was not substantially modified by TVR. LIMITATION: Small sample size and appreciable dropout rate. CONCLUSION: In patients with HCV and HIV-1, more adverse events occurred with TVR versus placebo plus PEG-IFN-α2a-ribavirin; these were similar in nature and severity to those in patients with HCV treated with TVR. With or without concomitant antiretrovirals, sustained virologic response rates were higher in patients treated with TVR versus placebo plus PEG-IFN-α2a-ribavirin.

Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial.

BACKGROUND: Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin. METHODS: In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1.5 mug/kg plus ribavirin 800-1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400-1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00423670. FINDINGS: Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 [54%, 95% CI 44-64], p=0.013 for PRB28; 58/103 [56%, 44-66], p=0.005 for PR4/PRB24; 69/103 [67%, 57-76], p<0.0001 for PRB48; and 77/103 [75%, 65-83], p<0.0001 for PR4/PRB44; vs 39/104 [38%, 28-48] for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]). Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group. INTERPRETATION: In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone. FUNDING: Merck.

Twice-Daily Telaprevir for Posttransplant Genotype 1 Hepatitis C Virus: A Prospective Safety, Efficacy, and Pharmacokinetics Study.

OBJECTIVES: Our objective was to determine the safety, efficacy, and pharmacokinetics of telaprevir plus pegylated interferon alfa 2a and ribavirin for chronic, posttransplant genotype 1 hepatitis C virus infection. MATERIALS AND METHODS: A prospective, single-arm, multicenter, open-label, phase 2b study was conducted at 22 North American sites to assess the safety, efficacy, and pharmacokinetics of pegylated interferon alfa 2a, ribavirin, and twice daily telaprevir in liver transplant recipients with recurrent, chronic hepatitis C without cirrhosis. Baseline liver biopsies were read by a central pathologist. There were planned safety reviews after a sentinel cohort reached treatment weeks 4 and 16. Serial pharmacokinetic sampling was performed for calcineurin inhibitors, telaprevir, and ribavirin. RESULTS: Sixty-one patients were enrolled and received ≥ 1 dose of study medication; 37 (61%) achieved sustained virologic response. Thirteen of 18 treatment-naive patients (72%), 10 of 11 patients with no or minimal fibrosis (91%), 13 of 15 patients (87%) with interleukin 28B genotype CC, and 36 of 45 patients (80%) with either undetectable or unquantifiable hepatitis C virus RNA at treatment week 4 achieved sustained virologic response. Nine patients (15%) had ≥ 1 drug-related serious adverse event and 7 (11%) discontinued all study drugs due to an adverse event. There were no deaths or acute cellular rejection episodes. During telaprevir treatment, median doses of tacrolimus and cyclosporine were 0.5 mg weekly and 25 mg daily. Target exposures were achieved for telaprevir with twice daily dosing and for ribavirin with reduced initial dosing. CONCLUSIONS: Telaprevir combination therapy for posttransplant hepatitis C virus infection yielded superior efficacy than historical controls. Adverse events were similar to, but exceeded, those in immunocompetent patients. Calcineurin inhibitor dosing levels were substantially reduced with telaprevir.