Abstract
BACKGROUND: The National Viral Hepatitis Control Program (NVHCP) has a cure rate of 91.6% when using direct-acting antivirals (DAAs)-sofosbuvir with an NS5A inhibitor (ledipasvir, daclatasvir or velpatasvir) ± ribavirin in the Punjab hub-and-spoke model of hepatitis C virus (HCV) elimination. METHODS: We collected the clinical and virological data for the ∼8.4% treatment failure cases. Sanger nucleotide sequencing was performed to identify the resistance-associated substitutions (RAS) following treatment failure. We ascertained the clinical and virological predictors of treatment failure under the NVHCP. RESULTS: Between April 2019 and December 2023, 50865 patients with HCV were treated; median age 41.6 years, 65% men, 85.8% without cirrhosis, 8.5% treatment experienced, median viral load (x10(6)) of 4.1 (2.9-7.8),71.3% genotype (GT)-3, with cure rate of 89.5%. On multivariable analysis, age (aOR 1.5, 95% CI: 1.3-1.9, P = 0.021), presence of cirrhosis (aOR1.8, 95% CI: 1.3-2.5, P < 0.001), and poor drug compliance (aOR 0.3, 95% CI: 0.2-0.6, P < 0.001) predicted treatment failure. We enrolled a difficult-to-treat group of 640 persons for virological testing, aged 39.2 ± 15.1 years, median HCV viral load (x10(6)) of 1.98 (1.5-2.4). Of these, 56.6% were treatment-experienced, 11.1% were prior defaulters, with predominant GT3 (73.3%) and GT1 (18.7%) with coinfection rates of 3.8% and 4.4% for hepatitis B virus (HBV) and human immunodeficiency virus (HIV), respectively. Presumed modes of transmission in this subgroup were unsafe injections (57%), and injection drug use (32.8%). A total of 243 patient samples underwent RAS testing, with 45 patients having detectable variants, and finally 31 RAS mutations were detected in the NS5A gene, with no clinically significant resistance observed in the NS5B gene. In GT-3, the RAS observed were A30K, L31 M/R, A62S, A62T, and Y93H. In GT-1, the RAS observed were M28A, H58P, G30 H/R, H58D, and Y93K. Among these Y93K, L30R, G30 H/R confer resistance to velpatasvir; such patients received retreatment with voxilaprevir-containing regimens. CONCLUSION: Patient factors like compliance and the presence of cirrhosis predicted treatment failures. RAS do not appear to be a primary factor for treatment failure in a public health setting. CLINICAL TRIALS GOV NUMBER: NCT03488485 available from https://clinicaltrials.gov/study/NCT03488485.