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Viruses 2016, 8(4), 91; doi:10.3390/v8040091

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

1
Infectious Diseases Department, Scientific Institute Ospedale San Raffaele, 20127 Milan, Italy
2
Vita-Salute University, 20132 Milan, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Curt Hagedorn
Received: 4 December 2015 / Revised: 2 March 2016 / Accepted: 22 March 2016 / Published: 25 March 2016
(This article belongs to the Section Antivirals & Vaccines)
View Full-Text   |   Download PDF [679 KB, uploaded 25 March 2016]   |  

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. View Full-Text
Keywords: HCV natural resistance; HCV genotypes; NS5a inhibitors HCV natural resistance; HCV genotypes; NS5a inhibitors
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Bagaglio, S.; Andolina, A.; Merli, M.; Uberti-Foppa, C.; Morsica, G. 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. Viruses 2016, 8, 91.

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