Ex vivo antiretroviral potency of newer integrase strand transfer inhibitors cabotegravir and bictegravir in HIV-1 non-B subtypes

OBJECTIVE:To determine the antiretroviral activity of the integrase strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), cabotegravir (CAB) and bictegravir (BIC), against different subtypes as well as primary and acquired drug resistance mutations (DRMs) in a patient-cohort infected with diverse subtypes. DESIGN:Biochemical and virological drug sensitivity analyses using patient-derived HIV type 1 (HIV-1) genes and cross-sectional/longitudinal clinical study. METHODS:Assays for 50% inhibition of 3'-end processing (IC50-3EP), strand transfer (IC50-ST) and drug sensitivity for five INSTIs were done using patient-derived integrase or gag-pol genes from subtypes A1, B, C, 01_AE and 02_AG. Integrase from INSTI-naive (n = 270) and experienced (n = 96) patients were sequenced. RESULTS:RAL had higher IC50-ST than the other INSTIs for all subtypes. EVG had higher IC50-ST for HIV 1 subtype C (P < 0.05) and 02_AG (P < 0.05) than HIV 1 subtype B (HIV-1B). DTG showed lower IC50-ST in HIV 1 subtype C than HIV-1B (P = 0.003). In CAB , the non-B subtypes showed lower IC50-ST (P < 0.05) than HIV-1B. In BIC, lower IC50-ST in 01_AE (P = 0.017) and 02_AG (P = 0.045) than HIV-1B. In drug sensitivity assay, inhibiting virus replication by 50% for DTG [median (IQR) 2.14 (1.3-2.56)], CAB [1.68 (1.34-2.55)] and BIC [1.07 (0.22-2.53)] were lower than RAL and EVG. One patient had a primary DRMs (0.3%, 1/270), but 17 (6.3%) had one major accessory DRM, of which 12 were E157Q. CONCLUSION:The equal or higher potency in non-B subtypes of DTG, CAB and BIC compared with RAL and EVG confirms their suitability for use in countries dominated by non-B subtypes. Any impact of the high prevalence of major accessory mutations, especially E157Q, requires long-term follow-up studies.