Abstract
Hepatitis C virus (HCV) genotype (GT)3 is associated with increased risk of steatosis, development of cirrhosis and hepatocellular carcinoma. Limited data are available regarding genetic variability and use of direct-acting antiviral agents in these patients. non-structural protein 5A (NS5A) and non-structural protein 5B (NS5B) sequencing was performed on 45 HCV GT3-infected Italian patients subsequently treated with sofosbuvir ± daclatasvir (SOF ± DCV). Novel GT3a polymorphisms were observed by Sanger sequencing in three NS5A (T79S, T107K, and T107S) and three NS5B (G166R, Q180K, and C274W) baseline sequences in patients who achieved sustained virological response (SVR). Baseline NS5A resistance-associated substitutions (RASs) A30K and Y93H were detected in 9.5% of patients; one patient with A30K did not achieve SVR. Phylogenetic analyses of sequences showed no distinct clustering. Genetic heterogeneity of NS5A and NS5B was evaluated using ultra-deep pyrosequencing (UDPS) in samples longitudinally collected in patients not achieving SVR. Some novel NS5A and NS5B polymorphisms detected at baseline may not impact treatment outcome, as they were not enriched in post-failure samples. In contrast, the clinically novel GT3 NS5A-L31F RAS emerged in one treatment failure, and I184T, G188D and N310S, located on the same NS5B haplotype, became predominant after failure. These findings suggest a potential impact of these novel substitutions on the treatment outcome; however, their significance requires further investigation.
Highlights
Hepatitis C virus (HCV) has been classified into seven genotypes (GTs) by employing phylogenetic analysis of whole genomes [1]
During the era of pegylated interferon + ribavirin (RBV) therapy, GT3 was considered an “easy-to-treat” genotype, with high cure rates compared with other viral genotypes [4]; most failures were observed in cirrhotic patients [5]
In the era of direct-acting antivirals (DAA), a wide range of potent drugs are approved for HCV treatment, but only a few of them are effective against GT3: sofosbuvir (SOF), a nucleotide analog inhibitor of the non-structural protein 5B (NS5B)
Summary
Hepatitis C virus (HCV) has been classified into seven genotypes (GTs) by employing phylogenetic analysis of whole genomes [1]. Viruses 2017, 9, 212 risk of hepatic steatosis, development of cirrhosis and hepatocellular carcinoma (HCC). In a retrospective analysis of HCC occurrence in HCV positive patients, GT3 infection was a strong predictor of HCC development: 34% versus 17% in non-GT3 (p = 0.013) [3]. During the era of pegylated interferon (pegIFN) + ribavirin (RBV) therapy, GT3 was considered an “easy-to-treat” genotype, with high cure rates compared with other viral genotypes [4]; most failures were observed in cirrhotic patients [5]. In the era of direct-acting antivirals (DAA), a wide range of potent drugs are approved for HCV treatment, but only a few of them are effective against GT3: sofosbuvir (SOF), a nucleotide analog inhibitor of the non-structural protein 5B (NS5B)
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