engleski

Genetic diversity, transmission and resistance pattern of hepatitis C virus in treatment-naive patients in Croatia

Despite the great success of direct-acting antiviral (DAA) treatment, hepatitis C virus (HCV) related diseases still remain a major health burden. High genetic variability of HCV and fast intra-host evolution bring challenges to tracing HCV transmission events. The aim of this study was to provide up-to-date analysis of HCV quasispecies diversity, transmission and resistance patterns of the most common HCV subtypes in Croatia. The study included 119 consecutive treatment-naïve patients with chronic hepatitis C subtype 1a, 1b or 3a infection receiving clinical care at the University Hospital for Infectious Diseases, Zagreb in 2019. Sanger sequencing of the whole NS3 region, domain I of NS5A region and partial NS5B region was performed in serum samples, while resistance to direct-acting antivirals was evaluated using the Geno2pheno [HCV] algorithm. Separate phylogenetic analyses were performed for each subtype (1a, 1b and 3a) and region (NS3, NS5A, NS5B) in Mega-X program and model selection according to Bayesian Information Criterion (BIC). Transmission pairs were identified in the maximum likelihood tree using ClusterPicker v1.2.3. The majority of subtype 3a patients did not harbor viruses with resistance-associated supstitutions (RAS) conferring resistance to DAA - only 2.7% (1/37) in NS5A region and 2.7% (1/37) in NS3 region. Significantly more resistance conferring RAS were observed across all regions in genotype 1 patients, among which 42.2% (19/45) subtype 1a and 8.1% (3/37) subtype 1b patients had NS3 RAS while 4.4% (2/45) subtype 1a and 16.2% (6/37) subtype 1b patients had NS5A RAS. Only subtype 1b patients (32.4% ; 12/37) had RAS conferring reduced susceptibility to NS5B inhibitor sofosbuvir. Phylogenetic analysis showed segregation of subtype 1a sequences into clade I (62, 2% ; 28/45) or clade II (37, 8% ; 17/45) with NS3 RAS conferring resistance to DAA clustering exclusively in clade I. Two of the same transmission pairs were consistently identified for subtype 1a by clustering analysis across all regions, and a single transmission pair for subtype 1b and 3a. High resistance rate to NS3 inhibitors was observed in patients infected with clade I of HCV subtype 1a. Transmission events among individuals occurred mostly independently with no significant clustering of RAS.

hepatitis C virus ; resistance associated substitutions ; direct acting antivirals ; epidemiology ; phylogenetics ; genotypes ; subtypes

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