Analysis of resistance‐associated substitutions in acute hepatitis C virus infection by deep sequencing across six genotypes and three continents

Abstract

Several direct-acting antivirals (DAAs) have been approved for the treatment of chronic hepatitis C virus (HCV) infections, opening the door to highly effective interferon-free treatment regimens. Resistance-associated substitutions (RASs) have been reported both in treatment-naïve patients and following treatment with protease (NS3), phosphoprotein (NS5A) and polymerase (NS5B) inhibitors. The prevalence of naturally occurring RASs in untreated HCV-infected individuals has mostly been analysed in those infected with genotype 1 (GT1), in the late phase of infection, and only within limited regions of the genome. Furthermore, the geographic distribution of RASs remains poorly characterized. In this study, we used next-generation sequencing to analyse full-length HCV genomes for the prevalence of RASs in acute HCV infections identified in nine international prospective cohorts. RASs were analysed in 179 participants infected with all six major HCV genotypes (GT1-GT6), and the geographic distribution of RASs was assessed in 107 GT1a and GT3a samples. While RASs were detected at varied frequencies across the three genomic regions, and between genotypes, RASs relevant to multiple DAAs in the leading IFN-free regimens were rarely detected in combination. Low-frequency RASs (<10% of the viral population) were also shown to have a GT-specific distribution. The main RASs with geographic associations were NS3 Q80K in GT1a samples and NS5B N142T in GT3a. These data provide the backdrop for prospective surveillance of RASs during DAA treatment scale-up.

A Prospective Italian Study on Baseline NS3 and NS5A Resistance to Direct-Acting Antivirals in a Real-World Setting of HIV-1/HCV Coinfected Patients and Association with Treatment Outcome

“…With regard to the RASs in NS5A, we showed that the NS5A domain was more conserved across GT1 to GT4 than the NS3 region. NS5A RASs were observed in 7/62 (11.3%) sequences, which is in line with the 6-16% reported in previous studies [19][20][21]. Carrasco et al [6], who explored NS5A RASs across different genotypes, showed that 36.1% of their patients had NS5A RASs.…”

B cell immunodominance in primary hepatitis C virus infection

“…Sequencing was performed on the Illumina MiSeq platform. 29 In total 44 sequences were available for analysis, covering a range of HCV subtypes, including GT1a (n = 19), GT3a (n = 17), GT1b (n = 4), GT6a (n = 3) and GT2b (n = 1). E1E2 sequences were analysed for enrichment of amino acid residues in patients that mounted epitope-specific responses compared to those that did not, response was defined by the GT1 E1E2 mapped data.…”

Dynamic evolution of hepatitis C virus resistance-associated substitutions in the absence of antiviral treatment

“…As a consequence of an error-prone viral polymerase, and a high replication rate, a swarm of mutations constantly get generated during HCV infection. Some of these natural mutations encode for RASs and have been reported in many studies in treatment-naïve patients 3 4 5 6 . Such naturally occurring RASs could negatively impact treatment success rates, particularly in patients with cirrhosis, those infected with genotype 3, and those who have failed interferon-based therapies.…”