Abstract
BackgroundWe evaluated the frequency of naturally occurring resistance associated substitutions (RASs) and their characteristic of polymorphic or non-polymorphic amino acid change to direct acting antivirals (DAAs) in NS5b HCV subtypes 1a and 1b according to different geographic origin of isolates.MethodsUsing a public database we retrieved 738 worldwide NS5b sequences (for which was available the geographic origin) from HCV genotype (G)1 infected patients naive to DAAs. NS5b sequences clustering with G1a were more conserved in regard of RASs than G1b isolates, (14% vs 57% RASs, P < 0.0001).ResultsIn G1a, RASs were differently distributed between isolates from Europe (24%) and USA, (12%) P = 0.0186. In particular, 421 V associated with resistance to non-nucleoside inhibitor beclabuvir was polymorphic in Europe and USA, being detected in 24% and 11% of sequences, respectively, P = 0.0140.In G1b, RASs were found in 45% of sequences from Europe, in 54% of isolates from USA and in 70% of sequences from Asia (P = 0.0051).The 316 N polymorphism was detected in 54% of Asian isolates and at lower frequency, in 28% of isolates from USA and in 20% of European sequences (P < 0.0001).ConclusionsIn conclusion, a higher prevalence of RASs in G1b respect to G1a was found and a geographical distribution of RASs and polymorphic aa changes was observed in G1a as well in G1b.The clinical and therapeutic impact of the geographic distribution of RASs to polymerase inhibitors remains to be established, particularly in patients with virologic failure to DAAs and/or advanced liver disease.
Highlights
We evaluated the frequency of naturally occurring resistance associated substitutions (RASs) and their characteristic of polymorphic or non-polymorphic amino acid change to direct acting antivirals (DAAs) in NS5b Hepatitis C virus (HCV) subtypes 1a and 1b according to different geographic origin of isolates
One other important viral factor is the genetic barrier to resistance related to the number and type of nucleotide substitutions required for the emergence of RASs during replication
Genotype distribution according to geographical origin of isolates The geographic distribution of genotype 1 according to subtypes, showed that of 432 G1a sequences analyzed 63 isolates were from Europe, 368 from USA and only 1 sequence was from Asia
Summary
We evaluated the frequency of naturally occurring resistance associated substitutions (RASs) and their characteristic of polymorphic or non-polymorphic amino acid change to direct acting antivirals (DAAs) in NS5b HCV subtypes 1a and 1b according to different geographic origin of isolates. One other important viral factor is the genetic barrier to resistance related to the number and type of nucleotide substitutions required for the emergence of RASs during replication. The genetic barrier varies with drug class specificity over than HCV genotype and subtype [1]. In addition to the genetic barrier, the in vitro resistance level, corresponding to fold change under effective concentration (EC50) of a single compound in the replicon system, is commonly used to define the resistance profile of Bagaglio et al Virology Journal (2018) 15:144 drug-selected variants [2,3,4]. The fitness of the variant under drug selection (replicative capacity of a resistant variant) may play a crucial role in the virologic outcome [5]
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