Rare and Novel Hepatitis C Virus Genotype Subtypes and Response to Sofosbuvir/Velpatasvir in A5360 ( MINMON ) Clinical Trial

The introduction of potent, well‐tolerated direct‐acting antivirals (DAAs) has transformed hepatitis C virus (HCV) therapy and spurred global elimination efforts. However, the extensive genetic diversity of HCV may affect antiviral efficacy, particularly in low and middle‐income regions where limited data currently exist. Using samples from the ACTG A5360 (MINMON) trial, which evaluated a minimal‐monitoring strategy with 12 weeks of sofosbuvir/velpatasvir (SOF/VEL) across five countries, we characterized rare and novel HCV subtypes and assessed baseline resistance‐associated substitutions (RASs) and treatment response. Genotype/subtype assignments were obtained by NS5B short‐fragment sequencing and confirmed through next‐generation and whole‐genome sequencing. Among 399 participants, 389 (97.5%) were successfully genotyped; whole‐genome sequencing in unresolved genotypes identified several provisional novel genotype 4 subtypes and a putative new genotype 7 subtype (7c). Despite the presence of baseline NS5A RASs, all participants with initially unsubtyped infections achieved sustained virologic response (SVR12). Reduced SVR was observed primarily among genotype 3b infections (78%), consistent with prior data linking A30K + L31M RASs to decreased NS5A inhibitor susceptibility. Overall, SOF/VEL achieved high SVR across genotypes, including rare and novel subtypes. These findings underscore both the increased recognition of global HCV genetic diversity and the robust performance of pangenotypic DAA regimens, supporting universal adoption of simplified treatment strategies, as proposed by the MINMON trial, towards HCV elimination. Trial Registration: ClinicalTrials.gov , NCT03512210.