Elsevier

Current Opinion in Virology

Volume 32, October 2018, Pages 115-127
Current Opinion in Virology

Viral resistance in HCV infection

https://doi.org/10.1016/j.coviro.2018.10.005Get rights and content

The introduction of new multi-genotypic direct acting antivirals (DAA) in clinical practice has revolutionized HCV treatment, permitting the achievement of >95% rates of sustained virological response in many patients. However, virological failures can occur particularly if the treatments are sub optimal and/or with too short duration. Failure is often associated with development of resistance. The wide genetic variability in terms of different genotypes and subtypes, together with the natural presence and/or easy development of resistance during treatment, are intrinsic characteristics of HCV that may affect the treatment outcome and the chances of achieving a virological cure. This review explores in detail the aspects of HCV innate and treatment-induced resistance to new interferon-free DAA regimens.

Introduction

Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide. The global prevalence of anti-HCV positive people has been estimated at 1–3%, which equates to 62–170 million people [1, 2, 3]. Considering only HCV chronically infected people, around 71 million were estimated to have a viremic infection in 2015 [1]. Nevertheless, the asymptomatic course of HCV chronic infection, and inadequate surveillance programs in many countries, lead to a substantial underestimation of worldwide prevalence of HCV viremic population. HCV has highly divergent sequences which can be classified into 8 genotypes (GTs) with a large number of subtypes, and circulating in infected individuals as a continuously evolving quasispecies destined to easily escape host immune responses and applied antivirals [4,5]. The introduction of direct-acting antiviral agents (DAAs) in clinics has revolutionized the management of HCV infection. DAAs target different viral non-structural proteins, including the NS3/4A protease, the NS5A protein and the NS5B polymerase.

Currently, several highly effective, well-tolerated interferon and ribavirin free DAA combinations are approved for the treatment of HCV infection [6,7]. The high rate of sustained virologic response (SVR), obtained with the treatment for 8–12 weeks with the new multi-genotypic regimens (>95%), has for the first time introduced the possibility of using antiviral therapy as a strategy to achieve HCV-elimination. However, treatment failures can occur, particularly if the treatments are sub optimal. Currently, all HCV clinical-practice guidelines list several treatment options for initial treatment and retreatment of prior non-responders, depending on baseline factors including HCV-GT, liver cirrhosis, prior treatment history, and presence of specific resistance-associated-substitutions (RASs). Even if viral failure is much less frequent than in the past, it still represents a concern, especially when resistance is present [8,9].

The characterization of HCV resistance can be performed by a genotypic resistance test (GRT), by using the standard Sanger sequencing (the simplest and most popular approach) or by deep sequencing (next generation sequencing, NGS). The first assay allows the identification of viral variants with a prevalence >15–20%, while NGS is characterized by high throughput and high sensitivity, allowing the identification of viral variants with a prevalence >0.1–1%. However, if NGS is used, the proposed clinical cutoff for reporting resistant variants is their prevalence >15% [6,7]. This review explores in detail the aspects of HCV resistance before and after treatment with new interferon-free DAA regimens.

Section snippets

The role of HCV genotype and subtypes

When the term ‘pan-genotypic’ was used for the first time to describe an anti-HCV agent, the hope of all physicians treating HCV-infected patients was to eliminate the problem of viral GT for the choice of therapeutic regimen. However, viral genetics is still one of the main determinants of treatment responsiveness. Assessment of HCV-GT, including GT1-subtype (1a or 1b), helps in tailoring treatment-protocols in terms of DAA combination, duration, and possible ribavirin association [6,7]. The 8

Treatment-induced resistance

In the majority of DAA failing patients, failure is often associated with specific RASs related to the HCV-GT and therapeutic regimen [21,36••,41]. The risk of developing these variants depends mainly on host and virus-related factors, and the genetic barrier of the individual DAAs [25,26,42••]. Real-world studies confirmed a high prevalence of RASs at failure, particularly in NS5A (75%–90%) [21,36••]. Notably, in contrast to treatment emergent substitutions found in NS3 and NS5B, which

Conclusions

Even if viral failures represent (will represent) a minority of the DAA treated patients, overall in the next years a large number of people will harbour HCV-resistance worldwide. Indeed, according to the different availability between countries of new potent multi-genotypic regimens with high barrier of resistance, virological failures can range from 2% of patients [41,51] to 5–10% [9].

Indeed, HCV-resistance is a frequent phenomenon associated with DAA-failure, and, until the uptake of new

Conflict of interest

Francesca Ceccherini-Silberstein reports personal fees from Gilead Sciences, Bristol-Myers Squibb, Abbvie, Roche Diagnostics, Janssen-Cilag, Abbott Molecular, ViiV Healthcare; grants and personal fees from Merck Sharp & Dohme; grants from Italian Ministry of Instruction, University and Research (MIUR). Valeria Cento reports personal fees from Abbvie, Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen-Cilag. Velia Chiara di Maio has nothing to declare. Carlo Federico Perno reports grants from

Funding

This work was supported by the Italian Ministry of Instruction, University and Research (MIUR) (Bandiera InterOmics Protocollo PB05 1°). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

•• of outstanding interest

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