Sustained virologic response rates with telaprevir-based therapy in treatment-naive patients evaluated by race or ethnicity.

BACKGROUND: The phase 3 studies of telaprevir (T) in combination with peginterferon α-2a and ribavirin (PR) in treatment-naive genotype 1 chronic hepatitis C virus-infected patients (ADVANCE/ILLUMINATE) were not designed a priori to assess the effect of race and ethnicity on treatment response. However, these factors are important given the lower sustained virologic response (SVR) rates observed in black and Hispanic/Latino patients treated with PR. GOALS: This retrospective pooled analysis evaluated the effect of race or ethnicity on treatment-naive patient response to telaprevir-based therapy and assessed resistant variant profiles. MATERIALS AND METHODS: This analysis comprised patients enrolled in ADVANCE (N=363) and ILLUMINATE (N=540) who received 12 weeks of telaprevir in combination with PR followed by 12 or 36 weeks of PR alone and patients in ADVANCE (N=361) who received 48 weeks of PR alone. Race and ethnicity were self-reported and not mutually exclusive. RESULTS: Higher SVR rates were observed with telaprevir-based therapy compared with PR in blacks [n=99 (62%) vs. n=28 (29%), respectively] and in Hispanics/Latinos [n=89 (72%) vs. n=38 (39%)]. The SVR was lower in telaprevir-treated blacks [n=99 (62%)] compared with nonblacks [n=791 (78%)] and in Hispanic/Latinos compared with non-Hispanics/Latinos [n=89 (72%) vs. n=801 (76%)]. Low discontinuation rates due to adverse events, including rash and anemia, were observed across subgroups. Resistance profiles were similar among the subgroups. CONCLUSIONS: Treatment-naive black and Hispanic/Latino patients with genotype 1 chronic hepatitis C virus infection may benefit from telaprevir-based therapy, an important finding given the lower SVR rates observed in these patients when they are treated with PR alone.

Response-guided telaprevir combination treatment for hepatitis C virus infection.

BACKGROUND: Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, -10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations. METHODS: We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 µg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48. RESULTS: Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, -2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001). CONCLUSIONS: In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.).

Telaprevir for previously untreated chronic hepatitis C virus infection.

BACKGROUND: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. METHODS: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). RESULTS: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. CONCLUSIONS: Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).

Sustained virologic response rates with telaprevir by response after 4 weeks of lead-in therapy in patients with prior treatment failure.

BACKGROUND & AIMS: For hepatitis C virus (HCV)-infected patients who have not responded to previous PegIFN/ribavirin treatment, it is unclear whether subsequent direct-acting antiviral therapy outcomes are better predicted by prior treatment response or by on-treatment response to a PegIFN/ribavirin lead-in. METHODS: In REALIZE, treatment-experienced patients randomized to the lead-in telaprevir arm received 4 weeks of PegIFN-α-2a (180 µg/week) and ribavirin (1000-1200 mg/day), then 12 weeks of telaprevir (750 mg every 8h) plus PegIFN-α-2a/ribavirin, followed by 32 weeks of PegIFN-α-2a/ribavirin. This subanalysis only included patients in the lead-in telaprevir arm with available week 4 on-treatment response data (n=240). RESULTS: After 4weeks of PegIFN/ribavirin, 90% of relapsers, 60% of partial responders, and 41% of null responders in the lead-in telaprevir arm had ⩾1 log(10) HCV RNA reduction. Sustained virologic response (SVR) rates for telaprevir-treated patients with ≥1 versus <1 log(10) HCV RNA reduction after the PegIFN/ribavirin lead-in were 94% versus 62% in relapsers, 59% versus 56% in partial responders and 54% versus 15% in null responders. CONCLUSIONS: In prior relapsers and partial responders there is no apparent benefit of assessing response after a PegIFN/ribavirin lead-in with the aim of guiding telaprevir-based treatment. For patients known to be prior null responders, on-treatment response after a 4-week PegIFN/ribavirin lead-in may provide clinically useful prognostic information. However, withholding telaprevir-containing therapy in uncategorised treatment-experienced patient populations (i.e., that could include prior relapsers or partial responders), using response after a PegIFN/ribavirin lead-in could potentially exclude some patients with a high chance of SVR.

Telaprevir for previously treated chronic HCV infection.

BACKGROUND: Patients with genotype 1 hepatitis C virus (HCV) who do not have a sustained response to therapy with peginterferon alfa and ribavirin have a low likelihood of success with retreatment. METHODS: We randomly assigned patients with HCV genotype 1 who had not had a sustained virologic response after peginterferon alfa-ribavirin therapy to one of four treatment groups: 115 patients to the T12PR24 group, receiving telaprevir (1125-mg loading dose, then 750 mg every 8 hours) for 12 weeks and peginterferon alfa-2a (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 24 weeks; 113 patients to the T24PR48 group, receiving telaprevir for 24 weeks and peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group); 111 patients to the T24P24 group, receiving telaprevir and peginterferon alfa-2a for 24 weeks (at the same doses as in the T12PR24 group); and 114 patients to the PR48 (or control) group, receiving peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group). The primary end point was sustained virologic response (undetectable HCV RNA levels 24 weeks after the last dose of study drugs). RESULTS: The rates of sustained virologic response in the three telaprevir groups--51% in the T12PR24 group, 53% in the T24PR48 group, and 24% in the T24P24 group--were significantly higher than the rate in the control group (14%; P<0.001, P<0.001, and P=0.02, respectively). Response rates were higher among patients who had previously had relapses than among nonresponders. One of the most common adverse events in the telaprevir groups was rash (overall, occurring in 51% of patients, with severe rash in 5%). Discontinuation of study drugs because of adverse events was more frequent in the telaprevir groups than in the control group (15% vs. 4%). CONCLUSIONS: In HCV-infected patients in whom initial peginterferon alfa and ribavirin treatment failed, retreatment with telaprevir in combination with peginterferon alfa-2a and ribavirin was more effective than retreatment with peginterferon alfa-2a and ribavirin alone. (ClinicalTrials.gov number, NCT00420784.)

Telaprevir and peginterferon with or without ribavirin for chronic HCV infection.

BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment. METHODS: A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups. RESULTS: The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia. CONCLUSIONS: In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)

Retreatment with telaprevir combination therapy in hepatitis C patients with well-characterized prior treatment response.

UNLABELLED: Retreatment with peginterferon alpha and ribavirin (PR) offers a limited chance of sustained virologic response (SVR) in patients who did not achieve SVR with prior PR treatment. This study evaluated the safety and efficacy of telaprevir-based treatment in combination with PR in well-characterized patients who did not achieve SVR in the control arms of three Phase II clinical trials. Patients eligible to enroll in this open-label nonrandomized study either met on-treatment criteria for nonresponse or relapsed after 48 weeks of treatment in the control arm of the three Phase II PROVE studies. The initial protocol was a 24-week regimen: 12 weeks of telaprevir and PR followed by an additional 12 weeks of PR. During the study the protocol was amended to extend PR to 48 weeks for patients with previous null response. All other patients with undetectable hepatitis C virus (HCV) RNA at weeks 4 and 12 received 24 weeks of therapy. Those with detectable HCV RNA at weeks 4 or 12 received a total of 48 weeks of therapy. The overall SVR rate was 59% (69/117). SVR rates with T12PR were 37% (19/51) in prior null responders, 55% (16/29) in prior partial responders, 75% (6/8) in prior breakthroughs, and 97% (28/29) in prior relapsers. The overall relapse rate was 16% (13/83). Adverse events were similar to those in previous trials with telaprevir, with 9% of patients discontinuing due to an adverse event (most commonly rash and anemia). CONCLUSION: This study demonstrated the benefit of retreatment with a telaprevir-based regimen for patients with well-characterized nonresponse (null and partial) or relapse to a prior course of PR treatment.

VX-222, a non-nucleoside NS5B polymerase inhibitor, in telaprevir-based regimens for genotype 1 hepatitis C virus infection.

OBJECTIVE: To investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens for treatment of genotype 1 HCV. METHODS: In total, 152 treatment-naive patients received VX-222+telaprevir ('DUAL' regimen; n=47), with ribavirin ('TRIPLE' regimen; n=46), or with peginterferon+ribavirin ('QUAD' regimen; n=59) for 12 weeks. Patients with detectable HCV RNA at weeks 2 and/or 8 received peginterferon+ribavirin for 24 (DUAL and TRIPLE) or 12 (QUAD) additional weeks. RESULTS: VX-222 (100 or 400 mg twice daily) was well tolerated, with an increased rate of gastrointestinal adverse events observed with the higher dose. Across VX-222 400-mg twice-daily regimens, the QUAD was associated with the highest frequency of grade 3/4 adverse events. The DUAL was discontinued because of high viral breakthrough before week 12. Sustained virologic response (SVR) 24 weeks after end of treatment (SVR24), including patients treated with 12 or 24 additional weeks of peginterferon+ribavirin, was 67% for TRIPLE (VX-222 400 mg twice daily) and 79 and 90% for QUAD (VX-222 100 and 400 mg twice daily, respectively). CONCLUSION: These results provide valuable information regarding the safety, tolerability, and efficacy of telaprevir combined with a non-nucleoside polymerase inhibitor, as dual therapy or with ribavirin without or with peginterferon. Telaprevir and VX-222, alone or with ribavirin without or with peginterferon, were generally well tolerated, with improved tolerability without peginterferon. SVR24 rates achieved with TRIPLE and QUAD regimens containing telaprevir and VX-222 were comparable to those observed with telaprevir-based therapy.