Genomic surveillance uncovers regional variation in HCV transmission networks among people who use drugs in rural U.S. communities

Hepatitis C virus (HCV) remains a significant public health concern in the United States particularly in rural communities where the opioid epidemic has accelerated transmission among people who use drugs (PWUD)/ Despite, this growing burden the genetic features and transmission patterns of HCV in these settings are poorly understood. This study analyzed 692 HCV antibody-positive specimens collected from rural communities in ten U.S. states. Using amplicon-based deep sequencing and the Global Hepatitis Outbreak and Surveillance Technology (GHOST) platform, transmission networks were reconstructed. Among sequenced individuals, 29.5% were linked within clusters. The structure of these clusters varied by region—from sparse networks in Ohio to dense, interconnected clusters in New England. Phylogenetic analysis revealed that some transmission networks persisted for over a decade, highlighting long-term, sustained transmission. Nearly half of all clusters involved individuals connected through social recruitment, suggesting peer-referral strategies can effectively identify transmission chains. Younger age was independently associated with clustering, while recruitment by an intimate partner showed a weaker link. These findings emphasize the importance of ongoing genomic surveillance and social network-informed strategies to detect emerging HCV clusters and guide targeted public health interventions in underserved rural communities.