Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naïve patients

Stefania Paolucci,Loretta Fiorina,Fausto Baldanti,Roberto Gulminetti,Stefano Novati,Raffaele Bruno,Bianca Mariani,Giorgio Barbarini

doi:10.1186/1743-422x-10-355

Abstract

BackgroundDirect-acting antiviral (DAA) agents target HCV proteins; some of these have already been approved for the treatment of HCV infection, while others are in development. However, selection of DAA-resistant viral variants may hamper treatment. The aim of this study was to illustrate potential natural DAA-resistance mutations in the HCV NS5A and NS5B regions of HCV genotypes 1a and 1b from DAA-naïve patients.MethodsDirect sequencing of HCV NS5A and NS5B regions was performed in 32 patients infected with HCV genotype 1a and 30 patients infected with HCV genotype 1b; all subjects were naïve to DAAs.ResultsIn genotype 1a strains, resistance mutations in NS5A (M28V, L31M and H58P) were observed in 4/32 (12.5%) patients, and resistance mutations in NS5B (V321I, M426L, Y448H, Y452H) were observed in 4/32 (12.5%) patients. In genotype 1b, resistance mutations in NS5A (L28V, L31M, Q54H, Y93H and I280V) were observed in 16/30 (53.3%) patients, while resistance mutations in NS5B (L159F, V321I, C316N, M426L, Y452H, R465G and V499A) were observed in 27/30 (90%) patients.ConclusionsMutations conferring DAA resistance were detected in NS5A and NS5B of HCV genotypes 1a and 1b from DAA-naïve patients. Although some mutations confer only a low level of resistance, the presence at baseline of mutated HCV variants should be taken into consideration in the context of DAA therapy.

Highlights

Direct-acting antiviral (DAA) agents target Hepatitis C virus (HCV) proteins; some of these have already been approved for the treatment of HCV infection, while others are in development
Most patients (26/32, 81%) were naive to PegIFN and RBV, while none had ever been treated with HCV NS3, NS5A or NS5B inhibitors
Ten out of 62 (16.2%) patients were co-infected with HIV and under treatment with highly active antiretroviral therapy (HAART), while 52/62 (83.8) were HCV mono-infected (Table 2)

Summary

Introduction

Direct-acting antiviral (DAA) agents target HCV proteins; some of these have already been approved for the treatment of HCV infection, while others are in development. The aim of this study was to illustrate potential natural DAA-resistance mutations in the HCV NS5A and NS5B regions of HCV genotypes 1a and 1b from DAA-naïve patients. Peginterferon/ribavirin (PegIFN/RBV) for the treatment of HCV infection is burdened by adverse reactions in at least 10% of patients [2]. A sustained virological response is achieved in only 50% of patients infected with HCV genotype 1 [3]. PegIFN/RBV treatment failure is mainly attributed to its low efficacy against genotypes 1 and 4, and, to some extent to its side effects [3,4]. Developed direct-acting antiviral agents (DAAs) are predicted to have a major impact both in combination

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