Future hepatitis C virus treatment: interferon-sparing combinations

An estimated million people have chronic hepatitis C virus (HCV) infection. With current treatment success rates, by 2030, more than 40% will be cirrhotic and the number of cases with end-stage liver disease is projected to treble. Current standard-of-care is the combination of pegylated interferon plus ribavirin for 24-48 weeks. Unfortunately this is associated with poor efficacy (45% in HCV GT1; 75% in GT2 and 65% in GT 3) and tolerability. Many patients are either unsuitable for or decline current treatment infection because of the significant side-effects associated with this treatment, including those with decompensated cirrhosis or sever psychiatric illness. It is hoped that the development of direct acting antiviral agents (DAAs) will address this huge unmet medical need. The addition of a protease inhibitor to pegylated interferon plus ribavirin is associated with increase in efficacy and shortened duration of therapy in patients with HCV GT1 and is likely to become the new standard-of-care. However, triple therapy will not be suitable for patients with non-1 HCV infection, or contraindications to interferon. It is hoped that the combination of multiple DAAs which target different steps of HCV replication should provide interferon-free treatment regimen. Current and planned studies will determine which combination (protease, nonnucleoside polymerase, nucleoside polymerase, NS5A, cyclophyllin B inhibitors), how many DAAs and duration of therapy will be required to optimise cure. It will also be important to minimise the emergence of multi-resistance, which would jeopardise future retreatment options.