Abstract
Any successful strategy to prevent and control HCV infection requires an understanding of the epidemic behaviour among the different genotypes. Here, we performed the first characterization of the epidemic history and transmission dynamics of HCV subtypes in Portugal. Direct sequencing of NS5B was performed on 230 direct-acting antiviral drugs (DAA)-treatment naïve patients in Lisbon. Phylogenetic analysis was used for subtyping and transmission cluster identification. Bayesian methods were used to reconstruct the epidemic history of HCV subtypes. Sequences were analysed for resistance-associated substitutions (RAS). The majority of strains were HCV-GT1 (62.6%), GT3 (18.3%, all subtype 3a) and GT4 (16.1%). Among GT1, the most frequent were subtypes 1a (75.5%) and 1b (24.5%). Polyphyletic patterns were found in all but 12 lineages suggesting multiple introductions of the different subtypes in this population. Five distinct epidemics were identified. The first significant HCV epidemic in Portugal occurred between 1930s and 1960s, was caused almost exclusively by GT1b and was likely associated with blood transfusions. Rapid expansion of GT3a occurred in the 1960s and GT1a in the 1980s, associated with intravenous drug use. The most recent epidemics were caused by GT4a and GT4d and seem to be associated with the resurgence of opioid use. The C316N substitution was found in 31.4% of GT1b-patients. Close surveillance of patients bearing this mutation and undergoing dasabuvir-based regimens will be important to determine its impact on treatment outcome.
Highlights
Hepatitis C virus (HCV) infection continues to be a major public health problem globally despite the introduction of new treatment modalities based on a combination of direct-acting antiviral drugs (DAA)
Two drugs targeting the viral NS5B RNA polymerase have been approved in Europe and the US for clinical use, the nucleotide analogue sofosbuvir and the nonnucleoside inhibitor dasabuvir[27,28], while others are in the pipeline[29]
Since 2014, the combination of sofosbuvir/simeprevir/ribavirin and the new fixed-dose combinations ledipasvir/sofosbuvir and sofosbuvir/velpatasvir resulted in sustained virological response (SVR) rates of 92–100% in trials enrolling patients infected with HCV GT134–40 and 85–100% in other genotypes[40,41,42,43]
Summary
Hepatitis C virus (HCV) infection continues to be a major public health problem globally despite the introduction of new treatment modalities based on a combination of direct-acting antiviral drugs (DAA). The high genetic heterogeneity exhibited by HCV has given rise to seven major genotypes (1–7)[2] that differ on average by 30% at nucleotide level[3], and 86 subtypes[4] that differ between 15–25% at nucleotide level[3]. Palladino and Ifeanyi Jude Ezeonwumelu contributed to this work. The current treatment landscape based on a combination of direct-acting antiviral drugs (DAA) has increased dramatically the cure rate of chronic HCV infection[26]. The presence of resistance-associated substitutions (RAS) as natural polymorphisms in the NS5B gene affects HCV susceptibility to sofosbuvir and dasabuvir and may limit the clinical effectiveness of DAA combinations containing these drugs[45,46]
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