Naturally Occurring Dominant Drug Resistance Mutations Occur Infrequently in the Setting of Recently Acquired Hepatitis C

Abstract

Background Directly Acting Antivirals (DAAs) are predicted to transform hepatitis C (HCV) therapy, yet little is known about the prevalence of naturally occurring resistance mutations in recently acquired HCV. This study aimed to determine the prevalence and frequency of drug resistance mutations in the viral quasispecies among HIV positive and negative individuals with recent HCV. Methods The NS3 protease, NS5A and NS5B polymerase genes were amplified from fifty genotype 1a participants of the Australian Trial in Acute Hepatitis C. Amino acid variations at sites known to be associated with possible drug resistance were analysed by ultra-deep pyrosequencing. Results Twelve percent of individuals harboured dominant resistance mutations, while 36% demonstrated non dominant resistant variants below that detectable by bulk sequencing (ie < 20%) but above a threshold of 1%. Resistance variants (< 1%) were observed at most sites associated with DAA resistance from all classes, with the exception of sofosbuvir. Conclusions Dominant resistant mutations were uncommonly observed in the setting of recent HCV. However, low level mutations to all DAA classes were observed by deep sequencing at the majority of sites, and in most individuals. The significance of these variants and impact on future treatment options remains to be determined.

Characterization of clinical predictors of naturally occurring NS3/NS4A protease polymorphism in genotype 1 hepatitis C virus mono and HIV co‐infected patients

“…HCV/HIV co‐infection was not associated with a greater frequency of substitutions. This result is in line with some published studies . Nevertheless, enrolled HCV/HIV co‐infected subjects had a good immune profile, as the great majority of these patients were on antiretroviral therapy.…”

“…This result is in line with some published studies. 19,20 Nevertheless, enrolled HCV/HIV co-infected subjects had a good immune profile, as the great majority of these patients were on antiretroviral therapy. This fact may have been influenced the equality in genomic variation between mono and co-infected patients.…”

Viral dynamic modelling of Hepatitis C and resistance‐associated variants in haemophiliacs

“…Baseline ultra‐deep sequence analysis shows that key mutations are indeed present at very low levels in most patients. However, the frequency of these mutations does not appear to be greater than that observed in non‐haemophilic patients with recently acquired infections . One subject had dominant Q80K mutations which confer a significant level of resistance to simeprevir‐containing regimens, even when those regimens are all oral DAAs .…”

Primer ID Ultra-Deep Sequencing Reveals Dynamics of drug Resistance-Associated Variants in Breakthrough Hepatitis C Viruses: Relevance to Treatment Outcome and Resistance Screening

“…The majority of these earlier studies utilized Sanger-based (population) sequencing technologies that resolve the major circulating viral strains within an individual but can underestimate the prevalence of such variants. More recently, the use of ultra-deep sequencing technologies has allowed a higher resolution snapshot of the circulating strains containing RAVs in treatmentnaive high-risk HCV exposure populations, and reveal that most individuals carry low frequency strains with at least one RAV within a DAA-targeted protein [21]. The clinical relevance of such low-frequency RAVs in the host's quasispecies is still not clear.…”