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Dynamic evolution of hepatitis C virus resistance-associated substitutions in the absence of antiviral treatment.

ABSTRACT: Resistance against new hepatitis C virus (HCV) antivirals is an area of increasing interest. Resistance-associated substitutions (RASs) have been identified in treatment-naïve individuals, but pressures driving treatment-independent RAS emergence are poorly understood. We analysed the longitudinal evolution of RASs in twelve participants with early acute HCV infections. Full-genome deep sequences were analysed for changes in RAS frequency within NS3, NS5A and NS5B-coding regions over the course of the infection. Emergence of RASs relevant only to the polymerase non-nucleoside inhibitors (NNI) was detected, and these lay within CD8+ T-cell epitopes. Conversely, the loss of NNI RASs over time appeared likely to be driven by viral fitness constraints. These results highlight the importance of monitoring CD8+ T cell epitope-associated RASs in populations with dominant HLA types.

SUBMITTER: Eltahla AA

PROVIDER: S-EPMC5282498 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Dynamic evolution of hepatitis C virus resistance-associated substitutions in the absence of antiviral treatment.

Eltahla Auda A AA Leung Preston P Pirozyan Mehdi R MR Rodrigo Chaturaka C Grebely Jason J Applegate Tanya T Maher Lisa L Luciani Fabio F Lloyd Andrew R AR Bull Rowena A RA

Scientific reports 20170131

Resistance against new hepatitis C virus (HCV) antivirals is an area of increasing interest. Resistance-associated substitutions (RASs) have been identified in treatment-naïve individuals, but pressures driving treatment-independent RAS emergence are poorly understood. We analysed the longitudinal evolution of RASs in twelve participants with early acute HCV infections. Full-genome deep sequences were analysed for changes in RAS frequency within NS3, NS5A and NS5B-coding regions over the course ...[more]

PMID: 28139734

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Project description:Background & aimsWe aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections.MethodsA total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing.ResultsFailure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (p <0.01), which was similar to that seen with L31-RAS and Y93-RAS. The prevalence of patients with RASs in either NS3 or NS5A, or in both, increased significantly with increasing numbers of failed regimens. The P32del, which is unique to patients for whom DAA had failed, was linked to the absence of Y93H, the presence of L31F, and previous exposure to IFN plus protease inhibitor regimens.ConclusionsFailure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV.Lay summaryResistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.

Project description:BackgroundDirect-Acting agents (DAAs) target and inhibit essential viral replication proteins. They have revolutionized the treatment of Hepatitis C virus (HCV) infection reaching high levels of sustained virologic response. However, the detection of basal resistance-associated substitutions (RASs) to DAAs in naïve patients could be important in predicting the treatment outcome in some patients exhibiting failures to DAA-based therapies. Therefore, the aim of this work was to evaluate the presence of RASs as minority variants within intra-host viral populations, and assess their relationship to response to therapy on a multiple times relapser patient infected chronically with HCV.Case presentationA male HCV infected-patient with a genotype 1a strain was evaluated. He had previously not responded to dual therapy (pegylated interferon-α plus ribavirin) and was going to start a direct-acting agent-based therapy (DAAs). He showed no significant liver fibrosis (F0). Viral RNA was extracted from serum samples taken prior and after therapy with DAAs (sofosbubir/ledipasvir/ribavirin). NS5A and NS5B genomic regions were PCR-amplified and the amplicons were sequenced using Sanger and next-generation sequencing (NGS) approaches. RASs were searched in in-silico translated sequences for all DAAs available and their frequencies were determined for those detected by NGS technology. Sanger sequencing did not reveal the presence of RASs in the consensus sequence neither before nor after the DAA treatment. However, several RASs were found at low frequencies, both before as well as after DAA treatment. RASs found as minority variants (particularly substitutions in position 93 within NS5A region) seem to have increased their frequency after DAA pressure. Nevertheless, these RASs did not become dominant and the patient still relapsed, despite perfect adherence to treatment and having no other complications beyond the infection (no significant fibrosis, no drug abuse).ConclusionsThis report shows that some patients might relapse after a DAA-based therapy even when RASs (pre- and post-treatment) are detected in very low frequencies (< 1%) within intra-host viral populations. Increased awareness of this association may improve detection and guide towards a personalized HCV treatment, directly improving the outcome in hard-to-treat patients.

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Dynamic evolution of hepatitis C virus resistance-associated substitutions in the absence of antiviral treatment.

Publications

Dynamic evolution of hepatitis C virus resistance-associated substitutions in the absence of antiviral treatment.

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