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Hepatitis C Virus Resistance to Direct-Acting Antiviral Drugs in Interferon-Free Regimens.
Pawlotsky JM.
Gastroenterology 2016 ; 151:70-86

Treatment of HCV infection has made considerable progress with the approval of interferon-free, direct-acting antiviral (DAA) drug-based combination therapies. Although the majority of treated patients achieve virologic cure, HCV resistance to DAAs plays an important role in interferon-free treatment failure. The presence of viral variants resistant to NS5A inhibitors at baseline is associated with lower rates of virologic cure in certain groups of patients, such as those with genotype 1a, cirrhosis and/or prior nonresponders to pegylated interferon-based regimens. DAA-resistant viruses are generally dominant at virologic failure (most often relapse). Viruses resistant to NS3-4A protease inhibitors disappear from peripheral blood in a few weeks to months, whereas NS5A inhibitor-resistant viruses persist for years. Retreatment options are available, but first-line treatment strategies should be optimized to efficiently prevent treatment failure due to HCV resistance.

Expert's Commentary

This comprehensive, very complete and well documented paper presents the current state of the art on HCV resistance, and should be known by all physicians involved in chronic HCV infection care. The author, one of the leader expert in the field, reviews principles of resistance to anti-HCV drugs, as well as current prevalence of the various resistance-associated subtsitutions at the different targets of antivirals – NS3, NS5A and NS5B. The term “resistance-associated variant” or RAV, that has been often used to indifferently characterize substitutions that confer reduced susceptibility to a drug or drug class and the viral variants that carry these substitutions, must no longer be used. The substitutions (i.e., amino acid changes) that confer resistance should be called “resistance-associated substitutions”.
A very complete overview is also presented on available data regarding influence of baseline RASs on virologic outcome with the different combinations of antivirals, and on the selection of RASs in patients who fail to achieve SVR, mostly because of relapse.
The presence of more than 15% of NS5A RASs at baseline has an impact on SVR, especially in certain groups of patients such as those with genotype 1a, with cirrhosis and/or prior nonresponders to a pegylated IFN-based treatment.
Persistance or disappearance of RASs selected at relapse vary according to drugs and duration of treatment withdrawal. While sofosbuvir-associated RASs are poorly fit and rapidly disappear, NS5A RASs selected by anti-NS5A drugs are long-lasting, present as dominant species for several years (maybe forever), and are likely to impact the results of retreatment. In contrast, NS3 protease RASs progressively disappear after treatment has been withdrawn. Whether one should wait until resistant variants are undetectable to retreat if the regimen is to include an NS3-4A protease inhibitor is unclear. Also, whether RASs that were selected and subsequently disappeared will have an impact on retreatment with an NS3-4A protease inhibitor-containing regimen is unknown.
One of today debate is whether resistance testing in clinical practice should be done before treatment or whether treatment optmization is the best way to prevent treatment failure. Based on current guidelines, generalization of systematic pretreatment HCV resistance testing should not be recommended. Rather, treatment optimization and/or reinforcemet in difficult-to-treat patients (genotype 3, cirrrhosis, high baseline HCV RNA, prior non-responders) is the current recommended strategy. However, things are moving rapidly and HCV resistance testing at baseline (RASs at NS5A positions 28, 30, 31 or 93) is recommended in the US label for grazoprevir/elbasvir in treatment-naïve and pegylated IFN-ribavirin experienced patients infected with HCV genotype 1a.
The manuscript is illustrated by Tables and Figures providing a nice summary of impact and emergence of RASs in clinical trials.

Pr François Raffi, Nantes