Unraveling HCV Diversity and Resistance in Viet Nam: Implications for Treatment

BackgroundViet Nam has one of the worlds most diverse hepatitis C virus (HCV) epidemics, dominated by genotype 6. Understanding pre-treatment resistance-associated substitutions (RASs) particularly in under-studied genotype 6 is essential to protect cure rates and guide national elimination strategies. We aimed to evaluate the landscape of viral diversity and baseline drug resistance in Vietnam. MethodsWe utilized whole-genome sequencing to analyze HCV isolates from a cohort of 1,649 patients enrolled in six clinical studies in Viet Nam between 2013 and 2023. The study assessed genotype and subtype distribution, associations with demographic and clinical variables, and prevalence of known and putative RASs in NS3, NS5A, and NS5B relevant to DAAs used in Viet Nam. FindingsPhylogenetic analysis revealed that genotype 6 was dominant (50.3%, 829/1,649). We observed distinct geographical and demographic partitioning: genotype 2 was concentrated in the south and associated with older age and HIV co-infection, while genotype 3 was clustered in the north among younger males. Clinically relevant RASs were detected in 37.9% (617/1,630) of patients, with the highest burden in NS5A region. Genotypes 2 and 3 displayed near-universal intrinsic resistance. Among genotype 6 infections, subtype 6a frequently carried L28F mutation (43.3%, 181/418), whereas subtype 6e remained largely susceptible. InterpretationViet Nam is characterized by a complex, genotype 6-predominant HCV epidemic with significant reservoirs of natural resistance. The high-level resistance mutations in genotypes 2 and 3 suggests that "pan-genotypic" regimens may face efficacy gaps, highlighting the need for subtype-level molecular surveillance to guide national treatment policies.