Natural polymorphisms associated with resistance to new antivirals against HCV in newly diagnosed HIV-HCV-coinfected patients

Background: Direct acting antivirals (DAA) targeting the HCV serine protease and RNA polymerase have recently entered clinical development. Information about primary resistance to these compounds in HIV-HCV-coinfected patients is scarce. Methods: All individuals newly diagnosed with HIV-1 at several clinics in Madrid between 2000 and 2010 were tested for serum HCV antibody and HCV RNA. The NS3 protease and NS5B polymerase genes were sequenced in all HCV viraemic patients with genotype 1 (G1). Results: From 1,684 individuals newly diagnosed with HIV-1 during the 10-year study period, 141 (8.4%) were positive for serum HCV RNA. Overall, 58% were infected with G1, being 1a in 64.2% of them. Altogether, 62% of G1a and 30% of G1b harboured HCV drug-resistant changes, with the most common being prQ80K (n=9), prV55A (n=2), polC316Y/N (n=3) and polV499A (n=24). Although no primary resistance mutations were identified for HCV protease inhibitors or nucleoside analogues, mutations C316Y/N and V499A conferring resistance to some non-nucleoside analogues were found in 6% and 51% of G1 patients, respectively. Conclusions: Natural DAA resistance-associated mutations are frequently seen in HIV-HCV-coinfected individuals. Changes polV499A and prQ80K seem to be natural polymorphisms and their effect on treatment outcomes warrants further examination. However, drug resistance testing in HCV drug-naive individuals coinfected with HIV currently does not seem to be warranted before using HCV protease inhibitors and nucleoside analogues. More information is needed for HCV non-nucleoside analogues.