Prevalence of resistance-associated substitutions to direct-acting antiviral agents in hemodialysis and renal transplant patients infected with hepatitis C virus

Rita Chelly Felix Tavares,1 Ana Cristina de Castro Amaral Feldner,1 João Renato Rebello Pinho,2,3 Fernanda de Mello Malta,3 Roberto José Carvalho-Filho,1 Rúbia Anita Ferraz Santana,2 Vanessa Fusco Duarte de Castro,2 Gregório Tadeu Fernando Dastoli,2 Juliana Custódio Lima,1 Maria Lucia Cardoso Gomes Ferraz1 1Gastroenterology Division, Federal University of Sao Paulo, São Paulo, SP, Brazil; 2Albert Einstein Diagnostic Medicine, Albert Einstein Hospital São Paulo, SP, Brazil; 3Laboratory of Tropical Gastroenterology and Hepatology “João Alves de Queiroz and Castorina Bittencourt Alves,” Institute of Tropical Medicine, Department of Gastroenterology, University of São Paulo, São Paulo, SP, Brazil Background: Direct-acting antiviral agents (DAAs) permit the use of interferon (IFN)-free regimens to treat hepatitis C (HCV) in patients with chronic kidney disease (CKD) on hemodialysis (HD) or renal transplant (RTx) recipients, with excellent response rates and safety. However, the occurrence of basal or therapy-induced resistance-associated substitutions (RASs) to DAAs can result in treatment failure. The aim of this study was to estimate the prevalence of RASs to NS3A, NS5A and NS5B inhibitors, and particularly the Q80K polymorphism, in CKD patients on HD and RTx recipients infected with HCV. Patients and methods: HD and RTx patients infected with HCV-genotype 1 (GT1) were subjected to sequencing of the NS3, NS5A and NS5B regions. Results: Direct sequencing of NS3 protease, NS5A and NS5B was performed in 76 patients (HD, n=37; RTx, n=39). The overall prevalence of RASs was 38.2%, but only 5.3% of the patients had mutations in more than one region. Substitutions were detected in NS3A (17.8%), NS5A (21.9%) and NS5B (8.4%). Q80K was detected in 1.5 % of the patients. Highly inhibitory RASs were uncommon (L31M, 2.6%; L159F+C316N, 2.6%). RASs were more prevalent in HCV-GT1a (42.9%) than in HCV-GT1b (32.4%), P=0.35. RASs were detected in 52.4% of treatment-naive patients and 27.8% of peg-IFN/ribavirin-experienced patients (P=0.12). The presence of RASs was associated with time of RTx (P=0.01). Conclusion: The Q80K polymorphism was uncommon in our sample of HD and RTx patients. Despite the high prevalence of naturally occurring RASs, most of the substitutions detected were associated with a low level of resistance to DAAs. Keywords: HCV, treatment, DAA resistance, hepatitis