542A Unique Non-Nucleoside RT Inhibitor Resistance Mutation in Epidemic Russian Subtype A HIV-1 Strains

Background. The Russian HIV-1 epidemic is caused by several virus variants with strong founder effects. The most common variant, subtype A-FSU (Former Soviet Union), which began spreading among intravenous drug users in the 1990s, causes most of the 800,000 Russian infections. The spectrum of drug-resistance mutations (DRMs) in ARV-treated patients with this strain has not been studied. Methods. We performed genotypic resistance testing of 444 samples from 383 patients with virological failure on initial or salvage ARV therapy in the Siberian Federal District (2010 to 2013). NRTI, NNRTI, and PI DRMs were correlated with HIV-1 subtype and the ARVs of patients from whom virus samples were obtained. Results. 316 patients (82%) had subtype A-FSU; 59 (16%) had CRF02_AG; and 8 (2%) had subtype B strains. 62% of patients received an NNRTI: 36% efavirenz (EFV), 17% nevirapine (NVP), and 9% EFV ±NVP ± etravirine. 65% received a PI. The pattern of HIV-1 DRMs was concordant with patient ARV treatments with one striking exception. G190S, the sixth most common major NNRTI-DRM worldwide, was the most common subtype A-FSU NNRTI-DRM occurring in 63 of 121 (52%) viruses from NNRTI-treated patients with ≥1 NNRTI-DRM. In contrast, K103N occurred in 36 of 121 (30%; p < 0.001) viruses. Among CRF02_AG viruses, G190S occurred in 0 of 40 NNRTI-treated patients (52% vs 0%; p<0.001). The codon usage for wildtype glycine and mutant serine at RT190 showed that in subtype A-FSU, G190S results from a single G to A transition: G (GGC) to S (AGC) whereas two mutations are required for other subtypes: G (GGA) to S (AGC). RT G190 is encoded by GGC in >95% of 600 published subtype A strains in Russia and FSU countries. In contrast, RT G190 is encoded by GGA in ∼85% of 750 subtype A strains in Europe, Asia, and North America, and 99% of subtype A strains in Africa. Conclusion. The predisposition of subtype A-FSU to G190S is of concern because G®A transitions are the most common RT enzyme errors, G190S causes >4-fold higher levels of resistance to NVP and EFV than K103N, and G190S is included in the etravirine genotypic susceptibility score. Further studies are warranted to verify that NRTI/ NNRTI regimens are as efficacious in treating subtype A-FSU viruses as they are in treating viruses belonging to other subtypes. Disclosures. All authors: No reported disclosures.