PR treatment of naïve patients with chronic hepatitis C genotype 1 led to SVR rates of approximately 50%11
with substantial differences, according to the IL28B genotypes (80% in CC vs 40% in non-CC), liver fibrosis stage, and initial viremia.25
and Phase III studies17
provided clear evidences for the superiority of TVR combined with PR in the treatment of this patient population, both in terms of SVR rates and duration of therapy.
In the Phase II PROtease Inhibition for Viral Eradication (PROVE) trials 114
the efficacy and safety of TVR was assessed in association with PR in genotype 1a and 1b patients with mild to moderate liver disease only, since patients with bridging fibrosis or cirrhosis were excluded.
The PROVE-1 trial14
() was conducted in the USA on 250 HCV-1 naïve patients who were randomized to receive TVR (or placebo) according to one of the following arms: group 1 received T12PR24 (TVR + P + R for 12 weeks, followed by P + R for 12 weeks); group 2 received T12PR48 (TVR + P + R for 12 weeks, followed by P + R for 36 weeks); group 3 received T12PR12 (TVR + P + R for 12 weeks); and group 4 (control arm) received PR48 (placebo + P + R for 12 weeks, followed by P + R for 36 weeks). Patients in the T12PR24 and in the T12PR12 groups having a rapid virological response (RVR) were allocated to stop therapy at week 24 or 12, respectively; the SVR rates were 61% in the T12PR24 group, 67% in the T12PR48 group, 35% in the T12PR12 group, and 41% in the PR48 group. These higher SVR rates among patients in the TVR arms were the consequence of the higher RVR rates among these patients (ie, 81% in the T12PR24, 81% in the T12PR48, and 59% in the T12PR12 vs 35% in the PR48 arms). The optimal dosing was for the groups T12PR24 and T12PR48, who had rates of relapse of 2% and 6%, respectively. According to this study, however, the efficacy of a 24-week treatment in RVR patients was clearly demonstrated, thus building the basis for a response-guided therapy (RGT), whereas it demonstrated different responses to TVR by patients infected with subtype 1a or 1b, as a consequence of different rates of RAV-related virological failures.
Rates of SVR in the Phase II and Phase III trials among treatment-naïve patients with genotype 1 infection
The PROVE-2 study15
() confirmed high SVR rates among a similar cohort of European patients, who were randomly assigned to one of the following treatment arms: group 1 received T12PR24 (TVR + P + R for 12 weeks, followed by P + R for 12 weeks); group 2 received T12PR12 (TVR + P + R for 12 weeks); group 3 received T12P12 (TVR + P for 12 weeks, without RBV); and group 4 (control arm) received PR48 (placebo + P + R for 12 weeks, followed by P + R for 36 weeks). Patients in the T12PR24, T12PR12 and T12P12 were not required to have a RVR, but HCV-RNA had to test negative at week 20 (T12PR24) and week 10 (T12PR12, T12P12) to stop treatment. SVR rates were significantly higher among patients treated with the triple regimen (69% in T12PR24 and 60% in T12PR12) than among those treated with PR (38%) or without R (36%) as a consequence of high RVR rates, which were 69% in T12PR24, 80% in T12PR12, 50% in T12P12, and 13% in PR48. In the TVR groups, the higher rates of SVR were the consequence of reduced relapse rates, which were 14% in T12PR24, 30% in T12PR12, 48% in T12P12, and 22% in PR48. The PROVE-2, while confirming the effectiveness of TVR for treatment of naïve HCV-1 patients, highlighted the importance of R in preventing viral breakthrough and relapse following TVR regimens.
The efficacy and safety of TVR regimens in treatment-naïve subjects were evaluated in the ADVANCE and ILLUMINATE Phase III studies, which led to the registration of TVR for the treatment of adult patients with chronic hepatitis C genotype 1.
In the ADVANCE17
study (), 1088 patients, including 21% with bridging fibrosis or cirrhosis, were randomized to three arms, including the SOC with PR for 48 weeks (control group, PR48) or to one of the two combination treatment arms including TVR plus PR. The study included an arm with 8-week TVR associated with PR aimed to reduce the incidence of TVR-related skin rash (T8PR). Treatment-naïve subjects who achieved undetectable levels of HCV RNA at week 4 that extended to week 12 (ie, extended rapid virological response [eRVR]) stopped therapy at study week 24 (ie, after an additional 12 or 16 weeks of PR, respectively); otherwise, they received PR up to a complete 48-week course of therapy. In ADVANCE, the SVR rates were 75% in T12PR and 69% in T8PR, compared to the 44% in the control arm receiving PR48. The RVR rates were 68% in T12PR, 67% in T8PR, and 9% in PR48; similarly, eRVR rates were higher among patients treated with TVR than in controls (58% vs 57% vs 8%). SVR rates in patients with an eRVR were 89% in T12PR, 83% in T8PR, and 97% in PR48, whereas in patients without an eRVR were 54% in T12PR, 50% in T8PR, and 39% in PR48. Interestingly, the ADVANCE study also included patients with advanced liver disease, among whom the SVR rates were attenuated, ie, 62% in T12PR, 53% in T8PR, and 33% in PR48. In conclusion, the ADVANCE trial, while confirming high rates of SVR among patients exposed to TVR regimens, clearly suggested that 24 weeks of therapy could be sufficient to cure patients with an eRVR, mainly as a consequence of low rates of breakthrough and posttreatment relapse.
The ILLUMINATE trial18
was designed to investigate any additional benefit in extending therapy from 24 to 48 weeks in subjects with an eRVR exposed to TVR combination treatment. The answer was crystal clear, since the SVR rates were similar in patients randomized to 24 or 48 weeks of TVR, ie, 92% and 88%, respectively. This was not true, however, for patients with advanced fibrosis who may benefit from prolonged exposure to PR in order to efficiently clear all the infected hepatocytes. This was the message from a post hoc analysis of 30 patients enrolled in the ILLUMINATE study28
who achieved higher rates of SVR by following a 36-week tail of PR to complete 12 weeks of RGT with TVR than by following a shorter consolidation tail of 12 weeks with PR only (92% vs 67%). These findings, while calling for confirmation in a larger series of patients, still provided the rationale for recommending an extended tail of PR in naïve patients with advanced fibrosis receiving TVR-based regimens.