The Molecular Basis of Anti-HCV Drug Resistance

Abstract

Hepatitis C virus (HCV) is a significant medical problem and has become one of the leading causes of chronic liver disease. HCV replicates at a high rate, and due to inherently inaccurate nucleotide incorporation and lack of proofreading and post-replication repair, mutations are inevitable. In the era of direct acting antivirals (DAAs), treatment for HCV has become highly effective, but there are still about 5-10% of treated patients who do not achieve sustained virological response (SVR). There are many factors that affect SVR rates including the absorption and metabolism of DAAs, genetic make-up, the presence or absence of cirrhosis, and severity and resistance of HCV to DAAs. An important factor influencing treatment failure is HCV resistance. The majority of treatment failures while on DAAs are not due to on-treatment failures, but due to relapses. The exact mechanism for mutation-associated relapse is unclear, but possible theories include persistent intrahepatocytic viral replication and/or differences in the levels of host immune response.