Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure

Abstract

Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A and NS5B RASs for up to 5 years after the end of treatment (EOT). We included samples from n=678 patients with a HCV GT (genotype) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A and NS5B were sequenced and clinical parameters were evaluated. A total of 242 patients with HCV GT1a (36%), 237 with GT1b (35%) and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after end of treatment (EOT) and RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 (FU3), while in GT1a RASs were stable (≥ 60%) due to Q80K. The SOF-resistant NS5B RAS S282T was only found in individual GT3a patients. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after FU24 their frequency was 65% and higher. However, RASs in GT1b had a stable course, while RASs in GT1a and GT3 declined slightly after FU24 (GT1a, 68%; GT1b, 95%; GT3, 65%), mainly due to the slow decline of high-level resistant Y93H. We found that low to medium-level RASs persisted, while high-level resistant RAS disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first generation DAAs and for global HCV elimination goals. The long-term persistence of RASs after DAA failure is largely unknown. RASs in NS3 (with exception of Q80K) and S282T in NS5B generally declined rapidly. NS5A RASs persisted beyond two years after end of treatment, with a slight decrease in GT1a and GT3 compared to GT1b. The different patterns of RAS persistence could be of importance for re-treatment especially in countries with limited medical resources.