Treatment of hepatitis C virus genotype 3-infection.

The treatment of hepatitis C virus (HCV) infection with pegylated interferon (PEG-IFN) alfa and ribavirin (800 mg daily) (RBV) is the standard of care (SOC) for hepatitis C virus genotype 3-infection leading to a sustained virological response (SVR) in around 65% of patients. A better understanding of the HCV life-cycle has recently resulted in the development of several potential direct-acting antiviral drugs (DAAs) targeting viral proteins (NS3/4A protease, NS5B nucleos(t)idic and non-nucleos(t)idic polymerase, NS5A viral replication complex). First generation protease inhibitors in combination with PEG-IFN/RBV are not efficient in genotype 3-infected patients. The combination of PEG-IFN/RBV with Daclatasvir, a NS5A inhibitor for 12-24 weeks results in a SVR in around 75% while the triple combination of PEG-IFN/RBV with the oral nucleotidic polymerase inhibitor Sofosbuvir (GS-7977) for 12 weeks in naïve patients results in a SVR in more than 95%. The results of the first oral combination of Sofosbuvir and RBV for 12 weeks in genotype 3-infected patients have been rather disappointing with a slightly lower SVR than after 24 weeks of PEG-IFN: around 60%, and only 30% in patients with cirrhosis. Extending treatment from 12 to 16 weeks in treatment experienced patients doubled the SVR rate and an 80% SVR rate is expected by extending treatment to 24 weeks. The best oral combination of new DAAs is probably the combination of Sofosbuvir and a NS5A inhibitor (Daclatasvir, Ledipasvir…) for 24 weeks, which resulted in a 100% SVR rate in a limited series. The use of cyclophilin inhibitors, a host-targeted antiviral, in association with DAAs and/or RBV may also be of interest. The oral combination of new DAAs (dual or triple combination of different antivirals) or of DAAs and host targets such as cyclophilin will probably become the SOC for genotype 3-infected treatment-naïve or -experienced patients.

Usefulness of viral kinetics for early prediction of a sustained virological response in HCV-1 non-responders re-treated with pegylated interferon and ribavirin.

BACKGROUND & AIMS: Undetectable HCV RNA at 12 weeks is the stopping rule recommended in HCV patients in whom previous treatment has failed. Whether earlier virological criteria may be useful for deciding treatment discontinuation remains subject of debate. The aim of this study was to identify, in HCV-1 non-responders and relapsers to IFN or Peg-IFN and ribavirin, the earliest and most accurate predictor of failure to respond to a new treatment combining Peg-IFN and ribavirin. METHODS: Prediction of SVR was assessed using the area under the ROC (AUROC) curve of reduction in viral load at different time points. RESULTS: This study included 151 patients (32% with extensive fibrosis or cirrhosis). A SVR was reached in 34% (21% in non-responders and 59% in relapsers). In non-responders, 1 month was the most accurate time point for predicting SVR (AUROC: 0.787 ± 0.075, p = 0.0001). Thirty-seven percent of non-responders did not have a 1-log drop in viral load at 1 month. All these patients had detectable HCV RNA at 3 months (p < 0.0001) and only 4% attained a SVR (p = 0.004). The same high negative predictive value for SVR was found in sensitivity analysis restricted to non-responders to Peg-IFN and ribavirin. In contrast, in relapsers, undetectable HCV RNA at 3 months was the earliest criterion with high negative predictive value (92%, p < 0.0001). CONCLUSIONS: All HCV-1 non-responders who did not have a 1-log drop in viral load at 1 month remained HCV-RNA-detectable at 3 months, and only 4% attained a SVR. This new criterion can be used early on as a first stopping rule.

Hepatitis C: epidemiology, diagnosis, natural history and therapy.

With an estimated prevalence of 3% in the world population (around 170 million infected individuals worldwide), hepatitis C virus (HCV) heavily burdens public health. Even though the incidence of new infections is declining, at least in industrialized countries where they are mainly restricted to intravenous drug users, morbidity and mortality (which means also HCV-induced costs) associated with HCV infection are expected to increase over the next decade. Models suggest that the incidence of hepatocellular carcinoma and HCV-related mortality will still increase until about 2015. The prevalence of the disease, the risk of progression of fibrosis to cirrhosis or hepatocellular carcinoma, mainly but not only in patients with liver comorbidities such as metabolic syndrome and/or heavy alcohol intake, evidences: (1) the need for a screening of chronic HCV infection as defined by both anti-HCV antibodies and detectable HCV RNA, (2) the evaluation of the extrahepatic (cryoglobulinemia-related vasculitis) or liver impact of chronic infection (by liver biopsy or noninvasive markers of fibrosis) and (3) the discussion of an antiviral treatment which is mainly the combination of pegylated interferon (one weekly subcutaneous injection) and ribavirin, a nucleosidic analogue with a twice daily oral intake. This 'standard of care' results in a mean of 60% of sustained virologic response corresponding to viral eradication, which allows the inactivation of necroinflammation and the remodeling of fibrosis. New antiviral treatments (direct-acting anti-virals like protease NS3/4, polymerase NS5B, NS5A, entry inhibitors or other drugs like cyclophilin inhibitors, new interferons, immune modulators or therapeutic vaccine) are being rapidly developed (the approval of the first generation protease inhibitors is expected for spring 2011). The next step appears to be the combination of these oral drugs allowing a better safety and efficacy of the treatment.