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

• Main Authors: Rossana Scutari, Claudia Alteri, Ilaria Vicenti, Domenico Di Carlo, Valentina Zuccaro, Francesca Incardona, Vanni Borghi, Antonia Bezenchek, Massimo Andreoni, Andrea Antinori, Carlo Federico Perno, Antonio Cascio, Andrea De Luca, Maurizio Zazzi, Maria Mercedes Santoro
• Format: Article
• Language: English
• Published: Elsevier 2020-03-01
• Series: Journal of Global Antimicrobial Resistance
• Subjects: HIV-1 integrase resistance; Genetic distance; Integrase inhibitors; Polymorphisms; Subtype
• Online Access: http://www.sciencedirect.com/science/article/pii/S221371651930181X

Objectives: This study evaluated the emergence of mutations associated with integrase strand transfer inhibitors (INSTI) resistance (INSTI-RMs) and the integrase evolution in human immunodeficiency virus type 1 (HIV-1) infected patients treated with this drug class. Methods: The emergence of INSTI-RMs and integrase evolution (estimated as genetic distance between integrase sequences under INSTI treatment and before INSTI treatment) were evaluated in 107 INSTI-naïve patients (19 drug-naïve and 88 drug-experienced) with two plasma genotypic resistance tests: one before INSTI treatment and one under INSTI treatment. A logistic regression analysis was performed to evaluate factors associated with the integrase evolution under INSTI treatment. Results: The patients were mainly infected by B subtype (72.0%). Eighty-seven patients were treated with raltegravir, 13 with dolutegravir and seven with elvitegravir. Before INSTI treatment one patient harboured the major INSTI-RM R263K 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 that more frequently emerged were: N155H (17.8%), G140S (8.4%), Y143R (7.5%), Q148H (6.5%), and Y143C (4.7%). Concerning integrase evolution, a higher genetic distance was found in patients with ≥1 INSTI-RM compared with 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: These findings confirm that major INSTI-RMs very rarely occur in INSTI-naïve patients. Under INSTI treatment, selection of drug-resistance follows the typical drug-resistance pathways; a higher evolution characterises integrase sequences developing drug-resistance compared with those without any resistance.