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Genetic diversity and transmission dynamics of hepatitis C virus in Croatia

Implementation of successful interventions for hepatitis C virus (HCV) requires detailed understanding of molecular epidemiology and local viral transmission patterns. The aim of this study was to analyse distribution and transmission dynamics of the most common HCV genotypes and subtypes circulating in Croatia. This study included 300 patients with chronic hepatitis C receiving clinical care at the University Hospital for Infectious Diseases, Zagreb. Direct Sanger sequencing of the NS3, NS5A and NS5B region was performed and maximum likelihood trees were reconstructed in MEGA v.10.2.6 under 1000 bootstrap replicates. Identification of transmission clusters was performed using ClusterPicker v.1.2.3. with a genetic distance and bootstrap support threshold of 4, 5 % and 70 %, respectively. Transmission cluster associations for continuous variables were analysed by the Mann-Whitney test while categorical variables were compared by Pearson’s chi squared test or Fisher’s exact test using Statistica v.13.5. A p-value < 0, 05 was considered significant. Majority of patients were infected with HCV genotype 1 (189/300, 63, 0 %) followed by subtype 3a (111/300, 37 %) and had a median age of 45, 0 years (IQR: 40, 0 – 57, 0). Phylogenetic tree reconstructions showed two distinct clades within the subtype 1a - clade I (68/109, 62, 4 %) and clade II (41/109, 37, 6 %). Phylogenetic analysis across all regions demonstrated that 27 (27/300, 9, 0 %) HCV sequences had a presumed epidemiological link with another sequence and classified into 13 transmission clusters. Clustered individuals were significantly younger (median age (IQR) = 37, 0 (33 - 41) years) (p < 0, 001). Transmission clusters were the most common among patients infected with subtype 3a (17/111, 15, 3 %) (p = 0, 008). Among subtype 1a sequences, clustering was observed exclusively in clade I (8/68, 11, 8 %) (p = 0, 024). Sequenced obtained from patients who reported intravenous drug use (IDU) as a main risk factor for HCV acquisition more commonly formed transmission clusters compared to other reported HCV infection routes (14, 7 % (14/95) vs 6, 3 % (13/205), p = 0, 018). IDU- and subtype 3a- dominated transmission clusters suggests that despite the numerous preventative measures against the spread of HCV infection, needle-sharing and similar behaviors are still common in IDU population. Prevention of HCV among this population will remain a major challenge in the foreseeable future.

Hepatitis C virus ; Population-based sequencing ; Phylogenetics ; Transmission Clusters

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