An average of 150 millions people are chronically infected by Hepatitis C virus (HCV) worldwide resulting in significant morbidity and mortality (1.4 millions yearly), related to hepatic and extra-hepatic manifestations. The virologic sustained virologic response (SVR) which is allowed by antiviral treatments significantly reduces both morbidity (hepatocellular carcinoma, liver transplantation) and hepatic as well as extra-hepatic mortality. The overall mortality in those patients achieving SVR was reduced by 75%, especially in cirrhotic patients but also in HIV/HCV co-infected patients and the occurrence of hepatocellular carcinoma at 5 years of follow-up dropped from 15 to 5% and need of liver transplantation from 10 to 1.2%, respectively in a recent meta-analysis of patients receiving interferon-including regimen. In a prospective study of more than 1300 HCV-infected patients with biopsy-proven cirrhosis in the Cirvir ANRS CO12 cohort, a significant decrease in the occurrence of hepatocellular carcinoma, of bacterial spontaneous peritoneal infection or other cirrhosis complications has been reported in cirrhotic patients with vs. without SVR at 3 or 5 years of follow-up but also a decrease in the occurrence of vascular disease (cardio- or cerebro-vascular disease). All these data underline the need of achieving SVR in most of HCV-infected patients which means a large screening, an improvement of access to care of infected patients.
The combination of pegylated interferon alfa and ribavirin) which led to a sustained virologic response (or SVR which corresponds to a complete recovery) in around 45% of patients with HCV genotype 1, 65% with HCV genotype 4, 70% with HCV genotype 3 and around 85% with HCV genotype 2 which was the standard of care for two decades has been replaced from 2011 to 2013 by a combination with first generation NS3/4A protease inhibitors (Telaprevir or Boceprevir) in genotype 1-infected patients, allowing around 70% of SVR with a reduction of the duration of therapy from 48 to 24 weeks in half of treated patients (23). These first-generation regimens unexpectedly disappeared in 2014 with the rapid availability of interferon-free regimens combining different direct-acting antiviral drugs (DAAs). These DAAs target the main viral proteins involved in the replication cycle of HCV and combine NS3/4A protease inhibitors (Simeprevir or Paritaprevir boosted by ritonavir), NS5B nucleos(t)idic (Sofosbuvir) and non nucleos(t)idic (Dasabuvir) polymerase inhibitors, NS5A replication complex inhibitors (Dacalatasvir, Ledipasvir, Elbasvir, Velpatasvir). This therapeutic revolution combines 2 or 3 second wave DAAs, with or without ribavirin but without interferon. The combinations are given (for 8 to 24 weeks) according to baseline factors including fibrosis stage, genotype and subtype, baseline viral load, prior therapeutic history of the patient (naïve or experienced) and pre-existing resistance-associated variants, result in a SVR rate greater than 90% with a good tolerance. The SVR rates (and the safety) are similar in the clinical trials and in the real-life, usually higher than 95% in per-protocol analysis.
Despite these great achievements, new treatments are about to be launched (Grazoprevir/elbasvir: Zepatier) and next generation are finalizing their phase III (Sofbuvir/velpatasvir in the Polaris program or the Abbvie 2nd gen with Endurance). To be competitive, these new combinations need to prove an added value regarding the pill burden (a single tablet regimen STR appears to be a pre-requisite), the reduced duration of treatment (6 or 8 weeks instead of 12 weeks) and/or a ribavirin-free regimen with drugs with a low drug-drug interaction profile and a fair safety/tolerance.
Disclosure of Interest S. Pol Grant/research support from: Bristol-Myers Squibb, Gilead, Roche and MSD, Consultant for: Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Vertex, Gilead, Roche, MSD, Novartis, Abbvie, Sanofi and Glaxo Smith Kline