Variant of HCV Confers Resistance to NS5A Inhibitors, Susceptibility to Protease Inhibitors

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An NS5A mutation renders hepatitis C virus resistant to NS5A inhibitors but susceptible to protease inhibitors.
An NS5A mutation renders hepatitis C virus resistant to NS5A inhibitors but susceptible to protease inhibitors.

In resistance-associated variants (RAVs) of the hepatitis C virus (HCV), the Y93H mutation confers resistance to NS5A inhibitors but susceptibility to protease inhibitors, according to a study published in Scientific Reports.1

Direct-acting antivirals (DAAs), including protease inhibitors, polymerase inhibitors, and non-structural protein 5A (NS5A) inhibitors, can induce high sustained virological response rates during HCV infection, but their efficacy is limited by the development of resistance-associated variants (RAVs).

“The inhibitors of NS5A and NS5B play a pivotal role in HCV treatment,” Takanobu Kato, MD, PhD, of the National Institute of Infectious Diseases in Japan, told Infectious Disease Advisor. “While resistance-associated mutations for NS5B inhibitors have not yet been reported, resistance-associated mutations for NS5A inhibitors have been well-studied. NS5A mutations are considered a crucial factor for developing resistance to DAAs during HCV infection.”

Several NS5A mutations that confer resistance to NS5A inhibitors have been identified. When treated with single or combination DAAs, patients with these RAVs have been shown to have lower virological response rates than those without these RAVs. In contrast to variants with resistance to protease inhibitors or interferon, variants with resistance to NS5A inhibitors do not recede after treatment cessation, and have been found to persist for over 1 year after completion of daclatasvir therapy in some cases.

Y93H and L31M are among the most common NS5A mutations found in RAVs in treatment-naïve patients, with a prevalence of up to 23.2% and 3.3%, respectively.

Dr Kato and colleagues evaluated the characteristics of the NS5A mutations and their susceptibility to different anti-HCV therapies using JFH1-based recombinant virus in a cell culture system.

Compared with wild-type viruses, Y93H mutants had higher HCV core antigen levels while L31V and L31I mutants had lower HCV core antigen levels, which may be an indication that these mutations influence viral production or propagation. Infectivity titers were also higher with Y93H-mutant viruses.

Viruses with single mutation Y93H displayed 74-fold resistance to NS5A inhibitors compared with wild-type viruses, and resistance was increased up to 13300-fold by the presence of a second mutation, such as L31M, L31V, or L31I.

Exposure to protease inhibitors resulted in 2-fold lower HCV core antigen levels in cells transfected with Y93H-mutant HCV than in those transfected with wild type HCV. L31V mutants demonstrated greater susceptibility to polymerase inhibitors than wild type.

All variants with NS5A-resistant mutations and wild type HCV were similarly susceptible to interferons and ribavirin.

“We found that second-generation protease inhibitors are effective at reducing the replication of variants with resistance-associated NS5A mutations,” Dr Kato concluded. “Anti-HCV combination therapies that include protease inhibitors can be expected to demonstrate greater efficacy against these RAVs.”


  1. Nitta S, Asahina Y, Matsuda M, et al. Effects of resistance-associated NS5A mutations in hepatitis C virus on viral production and susceptibility to antiviral reagents. Sci Rep. 2016;6:34652. doi: 10.1038/srep34652.
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