Evaluation of HIV-1 integrase resistance emergence and evolution in patients treated with integrase inhibitors

Abstract Objectives We evaluated the emergence of mutations associated to integrase strand transfer inhibitors (INSTI) resistance (INSTI-RMs) and the integrase evolution in HIV-1 infected patients treated with this drug class. Methods Emergence of INSTI-RMs and integrase evolution (estimated as genetic distance between integrase sequences under-INSTI and before-INSTI treatment) were evaluated in 107 INSTI-naive patients (19 drug-naive and 88 drug-experienced) with two plasma genotypic resistance tests available: one before and one under INSTI treatment. A logistic regression analysis was performed to evaluate factors associated with the integrase evolution under INSTI treatment. Results Patients were mainly infected by B subtype (72.0%). 87 patients were treated with raltegravir, 13 with dolutegravir and 7 with elvitegravir. Before INSTI treatment, one patient harboured the major INSTI-RM R263 K, and three patients the accessory INSTI-RMs T97A. Under INSTI treatment, the emergence of ≥1 INSTI-RM was found in 39 (36.4%) patients. The major INSTI-RMs which emerged more frequently were: N155H (17.8%), G140S (8.4%), Y143R (7.5%), Q148H (6.5%), Y143C (4.7%). Concerning integrase evolution, a higher genetic distance was found in patients with ≥1 INSTI-RM compared to those without emergence of resistance (0.024 [0.012-0.036] vs. 0.015 [0.009-0.024], p = 0.018). This higher integrase evolution was significantly associated with a longer duration of HIV-1 infection, a higher number of past regimens and non-B subtypes. Conclusions Our findings confirmed that in INSTI-naive patients, major INSTI-RMs occur very rarely. Under INSTI treatment, selection of drug-resistance follows the typical drug-resistance pathways; a higher evolution characterizes integrase sequences developing drug-resistance compared to those without any resistance.