NS5A resistance mutations in HCV monoinfection and HCV/HIV coinfection after ineffective therapy

Objective. To conduct a comparative analysis of the frequency and spectrum of resistance mutations to NS5A inhibitors in patients with hepatitis C virus (HCV) monoinfection and HCV/HIV coinfection after failed treatment with direct-acting antiviral drugs.

Materials and methods. The study included 180 patients with HCV/HIV coinfection and 180 patients with HCV monoinfection who relapsed or reinfected after therapy containing NS5A inhibitors. Frequency matching was performed across groups by gender, age, and HCV subtype. HCV genotyping and resistance mutation detection were performed using Sanger sequencing of Core/E1 and NS5A genome fragments.

Results. HCV subtype 3a was found to be dominant (53.9%) among the etiologic factors of virological failure in patients with HIV coinfection. The overall frequency of Resistance-Associated Substitutions (RAS) detection in the NS5A region was 60.6% in HIV coinfection and 66.1% in HCV monoinfection (p=0.283). Significant subtype-specific intergroup differences in the mutation spectrum were revealed for subtypes 1a, 1b, and 3a. In the case of subtype 3a, clinically significant highly resistant strains (A30K/S, Y93H, and their combinations with A62) prevailed in monoinfected patients, while polymorphisms associated with decreased sensitivity (mainly A62) prevailed in HIV coinfection. For subtype 1b, high-significance RAS with a leading role played by Y93H were more common in monoinfection, while complex profiles (A30Q+L31M±Y93H) were found in coinfection. For subtype 1a, highly resistant variants (Q30R, Y93C) predominated in coinfection, while mutations of moderate significance (M28T, L31V) predominated in monoinfection.

Conclusion. The overall frequency of detection of resistance mutations in the NS5A gene did not differ significantly between the HIV coinfection and HCV monoinfection groups. However, the patterns of these mutations significantly depended on both the viral subtype and the presence of HIV coinfection. These data indicate the need to identify resistance mutations before repeat courses of therapy in patients with prior virological failure.

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