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.).

Pharmacokinetic interaction between telaprevir and methadone.

Hepatitis C virus (HCV) antibody is present in most patients enrolled in methadone maintenance programs. Therefore, interactions between the HCV protease inhibitor telaprevir and methadone were investigated. The pharmacokinetics of R- and S-methadone were measured after administration of methadone alone and after 7 days of telaprevir (750 mg every 8 h [q8h]) coadministration in HCV-negative subjects on stable, individualized methadone therapy. Unbound R-methadone was measured in predose plasma samples before and during telaprevir coadministration. Safety and symptoms of opioid withdrawal were evaluated throughout the study. In total, 18 subjects were enrolled; 2 discontinued prior to receiving telaprevir. The minimum plasma concentration in the dosing interval (C(min)), the maximum plasma concentration (Cmax), and the area under the plasma concentration-time curve from h 0 (time of administration) to 24 h postdose (AUC(0-24)) for R-methadone were reduced by 31%, 29%, and 29%, respectively, in the presence of telaprevir. The AUC0-24 ratio of S-methadone/R-methadone was not altered. The median unbound percentage of R-methadone increased by 26% in the presence of telaprevir. The R-methadone median (absolute) unbound C(min) values in the absence (10.63 ng/ml) and presence (10.45 ng/ml) of telaprevir were similar. There were no symptoms of opioid withdrawal and no discontinuations due to adverse events. In summary, exposure to total R-methadone was reduced by approximately 30% in the presence of telaprevir, while the exposure to unbound R-methadone was unchanged. No symptoms of opioid withdrawal were observed. These results suggest that dose adjustment of methadone is not required when initiating telaprevir treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT00933283.).

Short-term randomized proof-of-principle trial of TMC278 in patients with HIV type-1 who have previously failed antiretroviral therapy.

BACKGROUND: In vitro, TMC278, an investigational next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), has shown activity against wild-type and NNRTI-resistant HIV type-1 (HIV-1) and a higher genetic barrier to the development of resistance than efavirenz or nevirapine. This Phase II open-label trial evaluated the short-term (7-day) antiviral activity of TMC278 administered at three different doses replacing either the protease inhibitor (PI) or NNRTI of an ongoing failing treatment regimen in HIV-1-infected patients. METHODS: A total of 36 patients on failing antiretroviral therapy containing either an NNRTI or a PI (with evidence of > or =1 NNRTI resistance-associated mutation at screening for the PI group) and plasma viral load (VL)>1,000 copies/ml were randomized to one of three once-daily TMC278 doses (25 mg, 50 mg or 150 mg) for 7 days, while continuing NRTIs used at screening. The primary efficacy parameter was the change on day 8 in log(10) plasma VL from baseline. RESULTS: On day 8, median (min, max) changes from baseline in plasma VL were -0.87 (-2.3, 0.0), -0.95 (-1.8, 0.4) and -0.66 (-1.3, -0.2) log(10) copies/ml for the 25 mg, 50 mg and 150 mg once-daily TMC278 groups, respectively (P<0.001-<0.01). Overall, the median change from baseline was -1.19 log(10) copies/ml in the PI-substituted therapy group and -0.71 log(10) copies/ml in the NNRTI-substituted therapy group. TMC278 was generally safe and well tolerated with no apparent differences in safety among the three dose groups. CONCLUSIONS: Once-daily TMC278 showed significant antiviral activity against HIV-1 in treatment-experienced patients with NNRTI failure and/or resistance, and was generally safe and well tolerated.

Short-term antiviral activity of TMC278--a novel NNRTI--in treatment-naive HIV-1-infected subjects.

OBJECTIVE: To evaluate antiviral activity, pharmacokinetics, tolerability and safety of TMC278, a non-nucleoside reverse transcriptase inhibitor (NNRTI), when given as a 25, 50, 100 or 150 mg once-daily dose for 7 days to antiretroviral-naive HIV-infected subjects. DESIGN: Randomized, double-blind, placebo-controlled, phase IIa clinical trial. METHODS: Participants were 47 antiretroviral naive HIV-infected subjects. Primary outcome was the change in plasma HIV-1 RNA viral load from baseline to day 8. Secondary outcomes were evaluation of pharmacokinetics of TMC278, immunologic changes, safety and tolerability, and evolution of viral genotypic and phenotypic patterns. RESULTS: Patients treated with TMC278 achieved a median decrease in plasma viral load from baseline of 1.199 log10 copies/ml compared with a 0.002 log10 copies/ml gain in the placebo group (P < 0.01). A significantly higher proportion of subjects in the TMC278 groups obtained a viral load decrease of > 1.0 log10 compared with the placebo group (25/36 versus 0/11) (P < 0.01). No significant dose differences were noted in either antiviral effect or safety. No genotypic changes associated with antiretroviral resistance were detected between baseline and the end of the trial. Plasma concentrations of TMC278 were above the target concentration (13.5 ng/ml) at all time points for all TMC278-treated subjects. The most common reported adverse event was headache (TMC278 14%; placebo 18%). CONCLUSIONS: TMC278 showed antiviral activity when given as monotherapy for 7 days at all doses studied and the drug was safe and well tolerated. Trials of longer treatment duration with TMC278, in combination with other antiretroviral drugs, are underway to assess the long-term durability of antiviral response, safety and tolerability.