Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial, The Lancet, Volume 385, No. 9973, p1075–1086, 21 March 2015
Background There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response.
Methods The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326.
Findings We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with ribavirin and 29 with no ribavirin) and 63 to the 18-week regimen (32 with ribavirin and 31 with no ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with ribavirin and 33 with no ribavirin) and 65 to the 18-week regimen (33 with ribavirin and 32 with no ribavirin. High SVR12 rates were achieved irrespective of the use of ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74–98; 28/31; cohort 1, 12 weeks, ribavirin-containing) to 100% (95% CI 89–100; 33/33; cohort 2, 18 weeks, ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without ribavirin, 97% (95% CI 82–100, 28/29) of patients in cohort 1 and 91% (76–98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21–32]), headache (58 patients, 23% [95% CI 18–29]), and asthenia (35 patients, 14% [95% CI 10–19]).
Interpretation Treatment with grazoprevir plus elbasvir, both with and without ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir.
The direct-acting antiviral agents (DAAs), particularly NS3 protease inhibitors, telaprevir and boceprevir, which were approved in combination with current SOC (peg-IFN and ribavirin) for the treatment of HCV infection that significantly increased SVR, have opened a new window in HCV therapy. However, the side effects associated with this new therapy are a questionable maker. Anemia is the most frequent adverse effects with either telaprevir or boceprevir. They also exhibit strong inhibitory effect against an important drug metabolism enzyme, cytochrome P4503A4 (CYP3A4) resulting in the development of drug-drug interactions. In addition to drug resistance, the efficacies of these inhibitors differ significantly between HCV genotypes. It is well known that IFN itself has significant side effects. Another important issue arises with their short half-life and frequent dosing. With the advent of different small classes of DAAs, the future aim is to introduce an IFN-free regimen, oral cocktails of DAAs. The proof-of-concept studies presented some promising data confirming that the achievements of SVR without introducing IFN may be feasible. Thus, the combination of host and viral targeted inhibitors could be an attractive strategy in maximizing antiviral efficacy.
Reference: BioMed Research International, Volume 2013 (2013), Article ID 467869
telaprevir (Vertex) A significant proportion of patients with HCV who present particular challenges to treatment are not represented in the current clinical trials, including patients co-infected with HIV and patients with recurrent HCV following liver transplantation. These patients have a poorer response to pegIFN and ribavirin therapy and generally faster progression of liver disease. An interim analysis of a small phase II trial of telaprevir for treatment-naïve patients co-infected with genotype 1 HCV and HIV found considerably higher rates of RVR in patients receiving telaprevir (70% compared with 5% in those receiving pegIFN and ribavirin alone) [Sulkowski et al. 2011a]. The full results of this study are eagerly awaited to see if this translates to improved SVR rates for these patients. A trial of telaprevir for treatment-experienced genotype 1 HCV patients co-infected with HIV is also currently underway. A major challenge for telaprevir use in patients with HIV co-infection is the potential for drug– drug interactions. Telaprevir is a substrate and inhibitor of CYP3A, leading to significant interactions with protease inhibitors and nonnucleotide reverse transcriptase inhibitors used in the treatment of HIV. At present, this limits use of telaprevir to patients either not requiring antiretroviral therapy, or stably maintained on a limited number of treatment regimens with tested interactions with telaprevir (such as efavirenz, tenofovir and emtricitabine, or ritonavir-boosted atazanavir, tenofovir and emtricitabine or lamivudine) [Sulkowski et al. 2011a]. Drug interactions with immunosuppressant medications will also complicate the use of telaprevir in patients posttransplant. In healthy volunteers, co-administration of telaprevir substantially increased blood concentrations of both tacrolimus and ciclosporin [Garg et al. 2011]. No studies have yet been performed in organ transplant recipients, or with other commonly used immunosuppressants, so whether dose adjustment is required to allow safe co-administration with telaprevir is currently unknown. Although telaprevir clearly enhances response to treatment in genotype 1 HCV infection, its role in treatment of other viral genotypes is not clear. Interestingly, telaprevir appears to have equivalent antiviral efficacy in treatment-naïve patients with genotype 2 infection as genotype 1, but very limited efficacy in patients with genotype 3 infection [Foster et al. 2011a]. Whether telaprevir will play a role in shortening treatment duration for patients with genotype 2 infection, in retreatment of genotype 2 patients who have failed previous pegIFN and ribavirin therapy, or in treatment of genotype 4 infection remains to be established.
Conclusions The recent approval of telaprevir for treatment of chronic HCV infection is an exciting development. Although resistant viral variants emerge rapidly when telaprevir is used alone, in combination with pegIFN and ribavirin substantial increases in SVR are seen in both treatment-naïve and treatment-experienced patients. This benefit extends to those patients usually thought of as difficult to treat. The addition of telaprevir may allow shortening of treatment duration in treatment-naïve patients who show an early and sustained virological response. Knowledge of previous treatment response is important when considering telaprevir for treatment-experienced patients, as those with prior relapse have a greater chance of achieving SVR than prior null responders. A short lead-in phase of pegIFN and ribavirin could be considered for previous null responders, to estimate the likelihood of achieving SVR before commencing telaprevir-containing therapy. The efficacy and safety of telaprevir has yet to be established in some subgroups of patients who would greatly benefit from viral eradication but who respond poorly to pegIFN and ribavirin therapy, such as those co-infected with HIV or patients with recurrence of HCV infection following liver transplantation. Telaprevir is generally well tolerated, but significant side effects include rash, pruritis, anaemia and gastrointestinal disturbance. A strategy of sequential discontinuation of therapy, starting with telaprevir, may permit management of a severe adverse event whilst maximizing SVR rates. As experience of using telaprevir grows, local multidisciplinary strategies for the management of adverse events will need to be developed. In the majority of patients who do not achieve SVR following telaprevir-containing treatment, viral variants conferring telaprevir resistance can be detected. Although these variants are gradually replaced by wild-type virus over months following treatment, the implications of these variants on future treatment with telaprevir or other protease inhibitors is currently unknown. Successful treatment of these patients may await the development of further novel antiviral agents.
Reference: Ther Adv Gastroenterol. 2012;5(2):139-151
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