Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial
Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection.
Available from: PubMed Central
- "With the approval of the viral NS3/4A protease inhibitor (PI) simeprevir and NS5B ribonucleic acid (RNA)-dependent RNA polymerase inhibitor (RdRpI) sofosbuvir, combination therapy offers new therapeutic options resulting in considerably higher SVR rates of 66% and 75% in treatment-naïve patients infected with HCV genotype 1 in the non-transplant setting [6,7]. However, the management of HCV reinfection after LT is complicated by drug interactions, tolerability and pre-treatment [8,9]. Therefore an individual treatment regimen is often required. "
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Hepatitis C virus reinfection occurs universally after liver transplantation with accelerated cirrhosis rates of up to 30% within 5 years after liver transplantation. Management of hepatitis C virus reinfection is complicated by drug interactions and pre-treatment. Dual antiviral therapy with pegylated interferon and ribavirin only reaches sustained virological response rates of approximately 30% after liver transplantation. With the approval of the viral NS3/4A protease and NS5B ribonucleic acid -dependent ribonucleic acid polymerase inhibitors, combination therapy offers new therapeutic options resulting in considerably higher sustained virological response rates in the non-transplant setting. However, silibinin has also shown potent antiviral activity in non-responders to dual therapy.
We report the first case of antiviral therapy with pegylated interferon and ribavirin in combination with silibinin post-liver transplantation in a 50-year-old Caucasian man with genotype 3 reinfection with prior non-response.
Silibinin was administered at a dose of 20mg/kg/day intravenously for 2 weeks and continued orally for 47 weeks in combination with a 48-week pegylated interferon and ribavirin therapy (180μg/week and 800mg/day), which was started on day 8. Pegylated interferon and ribavirin doses were adapted to 135μg/week and 600mg/day. After 4 weeks of therapy, the viral load declined 6 log10 and became undetectable in week 6, resulting in a sustained virological response 24 weeks after the end of therapy.
In general, antiviral therapy was well tolerated. Side effects included pruritus and anaemia leading to erythropoietin therapy.
Combination therapy with pegylated interferon, ribavirin and silibinin resulted in sustained virological response 24 weeks after the end of therapy in a patient reinfected with hepatitis C virus genotype 3 who was a prior non-responder after liver transplantation. Silibinin therapy may offer a new therapeutic option for patients reinfected with non-genotype 1 hepatitis C virus who have had a liver transplanted and are non-responders.
Available from: Catherine François
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ABSTRACT: Simeprevir (TMC435, Olysio™), a second-generation hepatitis C virus (HCV) protease inhibitor, has been recently approved for the treatment of genotype 1 chronic hepatitis C in combination with pegylated interferon and ribavirin. This molecule has very different characteristics from first-generation protease inhibitors. Results from trials show that simeprevir is highly effective and safe, with few adverse events. We discuss the specific features of this new treatment option for HCV infection, in terms of in vitro data, pharmacological data, and clinical trials. We also discuss the impact of Q80K polymorphism at baseline. Studies evaluating interferon-free regimens with simeprevir are ongoing. Future combinations of two or more direct-acting antiviral agents, targeting different viral enzymes and with synergistic antiviral effects, will be approved, allowing treatment of pan-genotypic HCV with optimized sustained virologic responses. Simeprevir will undoubtedly be part of future treatment strategies.
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ABSTRACT: Background & aims:
Chronic hepatitis C treatment for prior non-responders to peginterferon (PegIFN)/ribavirin remains suboptimal. The MATTERHORN study evaluated regimens containing ritonavir-boosted danoprevir (danoprevir/r) in prior PegIFN alfa/ribavirin non-responders.
Prior partial responders (N=152) were randomized to 24 weeks of twice-daily danoprevir/r 100/100mg, mericitabine 1000 mg and ribavirin 1000/1200 mg (IFN-free); danoprevir/r plus PegIFN alfa-2a/ribavirin (triple); or danoprevir/r, mericitabine and PegIFN alfa-2a/ribavirin (Quad). Prior null responders (N=229) were randomized to 24 weeks of IFN-free therapy, or quad alone (Quad 24) or quad plus 24-weeks of PegIFN alfa-2a/ribavirin (Quad 48). The primary endpoint was sustained virological response (HCV RNA <25 IU/ml) 24 weeks after end-of-treatment (SVR24). Due to high relapse rates, genotype (G) 1a patients in IFN-free arms were offered additional PegIFN alfa-2a/ribavirin.
Among prior partial responders, SVR24 rates were 46.2%, 51.0%, and 86.0%, in the IFN-free, Triple and Quad arms, respectively; among prior null responders, SVR24 rates were 45.5%, 80.5%, and 83.8% respectively. Relapse rates were lower and SVR24 rates higher in G1b-infected than G1a-infected patients. SVR24 rates in G1a and G1b patients randomized to Quad were 75.0% and 96.2%, respectively, in the partial Quad arm, and 68.1% and 100%, respectively, in the null Quad 24 arm. Treatment failure was associated with resistance to danoprevir, but not to mericitabine, and was more common in G1a infected patients. Treatment was well-tolerated.
Danoprevir/r, mericitabine plus PegIFN alfa-2a/ribavirin was well-tolerated and produced high overall SVR24 rates in prior partial and null responders to PegIFN alfa/ribavirin. In contrast, IFN-free regimens were associated with unacceptably high relapse rates.
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