Importance of HCV genotype 1 subtypes for drug resistance and response to therapy

The treatment for patients infected with hepatitis C virus (HCV) genotype 1 has undergone major changes with the availability of direct-acting antivirals. Triple therapy, containing telaprevir or boceprevir, first-wave NS3 protease inhibitors, in combination with peginterferon and ribavirin, improved rates of sustained virologic response compared with peginterferon and ribavirin alone in patients with HCV genotype 1. However, the development of drug-resistant variants is a concern. In patients treated with telaprevir or boceprevir, different patterns of resistance are observed for the two major HCV genotype 1 subtypes, 1a and 1b. Genotype 1b is associated with a lower rate of resistant variant selection and better response to triple therapy compared with genotype 1a. Similar subtype-specific patterns have been observed for investigational direct-acting antivirals, including second-wave NS3 protease inhibitors, NS5A inhibitors and non-nucleoside NS5B inhibitors. This review explores resistance to approved and investigational direct-acting antivirals for the treatment of HCV, focusing on the differences between genotype 1a and genotype 1b. Finally, given the importance of HCV genotype 1 subtype on resistance and treatment outcomes, clinicians must also be aware of the tests currently available for genotype subtyping and their limitations.