The following is a summary of the “Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure,” published in the January 2023 issue of Hepatology by Dietz, et al.

They know little about the long-term persistence of HCV resistance-associated substitutions (RASs) following therapy with direct-acting antivirals (DAAs). This research examined how long NS3, NS5A, and NS5B RASs lingered end of treatment (EOT): up to 5 years. They used data from the European Resistance Database, which contained samples from 678 people with HCV infection of either genotype (GT) 1 or GT 3 who had failed to respond to virologic DAA treatment. Clinical indicators were assessed after sequencing NS3, NS5A, and NS5B.

Totaling 242 people, 36% had HCV GT1a, 35% had GT1b, and 29% had GT3 and a DAA failure. About 40% to 90% of NS3 RASs were detected following EOT without protease inhibitors. Q80K allowed NS3 RASs in GT1a to remain consistent (60%), but in GT1b and GT3, they drastically declined after month 3. GT3a patients only have the SOF-resistant NS5B RAS S282T mutation. Non-nucleoside NS5B RASs were found at high frequencies in GT1 (56-80%), reduced to 30% in GT1a, and persisted in GT1b. 

After NS5A inhibitor failure, NS5A RASs were found in most GTs (88-95%), and their prevalence remained high (65% or higher) through month 24 of follow-up. While RASs in GT1b remained stable, they gradually decreased in GT1a and GT3 after month 24 of follow-up (68% in GT1a, 95% in GT1b, and 65% in GT3). This was due mostly to the progressive elimination of highly resistant Y93H. They discovered that RASs at the lower and middle levels remained, whereas those at the higher levels gradually faded. Retreatment with first-generation DAAs and worldwide HCV elimination goals could be affected by the varying patterns of RAS persistence shown among HCV subtypes.

Source: sciencedirect.com/science/article/pii/S0168827822030161