Abstract
Sustained virologic response rates have increased dramatically following direct acting antiviral (DAA) therapy in chronic HCV infection. However, resistance-associated substitutions (RASs) may occur either prior to DAA or following drug exposure. The aim of this study was to determine RASs in DAA treatment-failing patients and the role of RASs in failure treatment. Six hundred and twenty HCV patients were evaluated. Direct sequencing of HCV genes was performed at breakthrough in all 31 patients failing DAAs, and in 19 baseline patients. Deep sequencing analysis was performed in 15/19 baseline patients. RASs were detected at breakthrough in 17/31 patients and at baseline in 11/19 patients, although, only 8/19 patients carried RASs associated with the prescribed regimen. Deep sequencing analysis showed RASs at baseline in 10/15 treatment-failing patients. No significant difference was observed with the Sanger sequencing. Treatment failure in the 14/31 patients without RASs was associated with suboptimal treatment. In 54.8% of treatment-failing patients one of the causes of failure might be the presence of RASs. In the majority of patients with RASs, mutations were present at baseline. Direct resistance test is advocated before treatment and at breakthrough in order to optimize retreatment regimens.
Highlights
Chronic infection with hepatitis C virus (HCV) affects more than 70 million individuals worldwide, with genotype distribution varying according to different geographic areas[1]; these subjects are at risk of developing advanced liver disease and hepatocellular carcinoma[1,2]
Thirty-one/620 (5%) patients failed to achieve sustained virologic response (SVR) during direct-acting antivirals (DAAs) treatment, 5/31 (16.1%) patients were non responders with detectable HCV RNA for the entire treatment period, while 26/31 (83.9%) patients relapsed during the first month following treatment completion
HCV RNA levels during treatment were significantly different at week 1, week 4 and week 8, between responders and treatment-failing patients, while no difference was observed at baseline, and at week 2 of therapy (Fig. 1)
Summary
Chronic infection with hepatitis C virus (HCV) affects more than 70 million individuals worldwide, with genotype distribution varying according to different geographic areas[1]; these subjects are at risk of developing advanced liver disease and hepatocellular carcinoma[1,2]. New antiviral drugs that target specific steps of the HCV lifecycle have been developed. These drugs, termed direct-acting antivirals (DAAs), include NS3/4 A protease inhibitors, NS5B polymerase inhibitors (nucleotide analogues and non-nucleoside inhibitors), and NS5A inhibitors; these are associated with a sustained virologic response (SVR) in ≥90% patients[5,6,7,8,9]. Resistance-associated substitutions (RASs) to DAAs might impair viral response to treatment due to baseline presence and early selection of resistant HCV strains. Gender Male Female Race Italian Other Genotype 1a 1b 2 3 4 1b/2k recombinant No of HIV-1 co-infected patients Advanced fibrosis/cirrhosis Baseline median HCV viral load (UI/ml log10) IL28B polymorphism CC CT TT Unknown Naïve Peg RBV experienced DAA experienced. The aim of this study was to illustrate potential DAA-resistant variants in HCV NS3, NS5A and NS5B in treated patients at baseline and at breakthrough as well as to underscore the role of RASs in the failure of the firstline DAA treatment or in the re-treatment of patients failing DAAs
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