Stay up To date

The importance of resistance to direct antiviral drugs in HCV infection in clinical practice.
Sarrazin C.
Journal of Hepatology, 2016; 64:486-504.

Treatment of chronic hepatitis C virus (HCV) infection with direct acting antiviral agents (DAA) is associated with high rates of sustained virologic response. Remaining factors associated with treatment failure include advanced stages of liver fibrosis, response to previous antiviral therapy and viral factors such as baseline viral load and suboptimal interaction of the DAA with the target based on viral variants. Heterogeneity within NS3, NS5A and NS5B areas interacting with DAAs exist between HCV genotypes and subtypes as well as HCV isolates of the same geno- and subtype. Amino acid polymorphisms associated with suboptimal efficacy of DAAs are termed resistance associated variants (RAVs). RAVs may be associated with virologic treatment failure. However, virologic treatment failure typically occurs only if other negative predictive host or viral factors are present at the same time, susceptibility to additional antiviral agents is reduced or duration of treatment is suboptimal. This review provides a very comprehensive analysis of genotypic and phenotypic resistance testing as well as clinical data on the importance of RAVs for conventional triple therapies with sofosbuvir, simeprevir and daclatasvir and available interferon-free DAA combinations are discussed.

In patients with failure to all-oral DAA regimens, more than 80% harbor HCV isolates with resistance to one, two or three DAA classes. A switch of drug classes can be explored. Due to the low likeliness of selection of major RAVs against the nucleotide inhibitors this class of drugs can be re-used. Other and/or additional options include longer treatment durations, the addition of ribavirin and finally, in patients with multiple resistance, also a combination with pegylated interferon alfa.

Perspectives :
For regimens with high antiviral activities and high genetic barrier to resistance based on single DAAs or the combination of different drug classes the presence of baseline resistance leads only to a small reduction of SVR rates. No general recommendation for baseline resistance testing can be given in subgroups of patients with certain HCV geno- or subtypes. However, in patients with shortened treatment duration or those with liver cirrhosis, resistance testing may be used to select optimal DAA regimens. Due the high costs of DAA regimens, future studies have to explore whether, in regions with economical restriction, baseline resistance testing for initial DAA combination regimens with the aim to avoid virologic treatment failure and the need of retreatment may be cost effective.