Frequency of Natural Resistance within NS5a Replication Complex Domain in Hepatitis C Genotypes 1a, 1b: Possible Implication of Subtype-Specific Resistance Selection in Multiple Direct Acting Antivirals Drugs Combination Treatment

Abstract

Different HCV subtypes may naturally harbor different resistance selection to anti-NS5a inhibitors. 2761 sequences retrieved from the Los Alamos HCV database were analyzed in the NS5a domain 1, the target of NS5a inhibitors. The NS5a resistance-associated polymorphisms (RAPs) were more frequently detected in HCV G1b compared to G1a. The prevalence of polymorphisms associated with cross-resistance to compounds in clinical use (daclatasvir, DCV, ledipasvir, LDV, ombitasvir, and OMV) or scheduled to come into clinical use in the near future (IDX719, elbasvir, and ELV) was higher in G1b compared to G1a (37/1552 (2.4%) in 1b sequences and 15/1209 (1.2%) in 1a isolates, p = 0.040). Interestingly, on the basis of the genotype-specific resistance pattern, 95 (6.1%) G1b sequences had L31M RAP to DCV/IDX719, while 6 sequences of G1a (0.5%) harbored L31M RAP, conferring resistance to DCV/LDV/IDX719/ELV (p < 0.0001). Finally, 28 (2.3%) G1a and none of G1b isolates harbored M28V RAP to OMV (p < 0.0001). In conclusion, the pattern of subtype-specific resistance selection in the naturally occurring strains may guide the treatment option in association with direct acting antivirals (DAAs) targeting different regions, particularly in patients that are difficult to cure, such as those with advanced liver disease or individuals who have failed previous DAAs.

Prevalence of hepatitis C virus-resistant association substitutions to direct-acting antiviral agents in treatment-na&iuml;ve hepatitis C genotype 1b-infected patients in western China

“… 29 In addition, the variant combination of L28M and L31F has been shown to have a higher level of resistance to ombitasvir than either of the variants separately did. 30 In this study, L28M was detected without the presence of L31F.…”

Prevalence of NS5A resistance associated substitutions in patients with hepatitis C virus genotypes 1a and 3: Impact on current therapeutic strategies

“…There are scarce data regarding the prevalence of NS5A RASs in G1a and G3 CHC population outside clinical trials and none evaluating the impact of the presence of clinically relevant mutations for the current treatment options . Indeed, in the absence of a standard globally available methodology for testing HCV RASs, the latest AASLD and EASL recommendations highlight the usefulness of HCV resistance to NS5A inhibitors to guide physician's decisions in case of access to reliable resistance tests .…”

Factors Influencing the Prevalence of Resistance-Associated Substitutions in NS5A Protein in Treatment-Naive Patients with Chronic Hepatitis C

“…At the same time, the M28V polymorphism in the Russian strains of HCV genotype 1a was found to be unexpectedly frequent (57.9%). This particular RAS is associated with resistance of HCV 1a to ombitasvir and, to lesser extent, to ledipasvir, velpatasvir, and pibrentasvir [7,19,33,34]. The usual incidence of M28V polymorphism in treatment-naïve HCV 1a patients is 4-8% [8,9].…”