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Introduction: Second-generation integrase strand transfer inhibitors (INSTIs) are preferred treatment options worldwide, and dolutegravir (DTG) is the treatment of choice in resource-limited settings. Nevertheless, in some resource-limited settings, these drugs are not always available. An analysis of the experience with the use of INSTIs in unselected adults living with HIV may be of help to make therapeutic decisions when second-generation INSTIs are not available. This study aimed to evaluate the real-life effectiveness and safety of dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), and raltegravir (RAL) in a large Spanish cohort of HIV-1-infected patients., Methods: Real-world study of adults living with HIV who initiated integrase INSTIs DTG, EVG/c, and RAL-based regimens in three settings (ART-naïve patients, ART-switching, and ART-salvage patients). The primary endpoint was the median time to treatment discontinuation after INSTI-based regimen initiation. Proportion of patients experiencing virological failure (VF) (defined as two consecutive viral loads (VL) ≥200 copies/mL at 24 weeks or as a single determination of VL ≥1,000 copies/mL while receiving DTG, EVG/c or RAL, and at least 3 months after INSTI initiation) and time to VF were also evaluated., Results: Virological effectiveness of EVG/c- and RAL-based regimens was similar to that of DTG when given as first-line and salvage therapy. Treatment switching for reasons other than virological failure was more frequent in subjects receiving EVG/c and, in particular, RAL. Naïve patients with CD4+ nadir <100 cells/μL were more likely to develop VF, particularly if they initiated RAL or EVG/c. In the ART switching population, initiation of RAL and EVG/c was associated with both VF and INSTI discontinuation. There were no differences in the time to VF and INSTI discontinuation between DTG, EVG/c and RAL. Immunological parameters improved in the three groups and for the three drugs assessed. Safety and tolerability were consistent with expected safety profiles., Discussion: Whereas second-generation INSTIs are preferred treatment options worldwide, and DTG is one of the treatment of choices in resource-limited settings, first-generation INSTIs may still provide high virological and immunological effectiveness when DTG is not available., Competing Interests: JRS, AA, AO, and JP have received research funding, consultancy fees and lecture sponsorships from, and have served on advisory boards for Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme and ViiV Healthcare. JP and JS have received research funding and consultancy fees from, and have served on advisory boards for Gilead Sciences, Merck Sharp & Dohme and ViiV Healthcare. PD has received honoraria for speaking or participating in advisory boards and/or research grants from the following pharmaceutical companies: Glaxo SmithKline GSK, Abbvie, Boehringer-Ingelheim, Bristol-Myers Squibb, Jansen & Cilag, Merck & Dohme, Gilead Sciences, Pfizer Inc, Thera technologies, ViiV Healthcare, Roche, and Ferrer International. MM has received research funding, consultancy fees and lecture sponsorships from, and has served on advisory boards for Janssen-Cilag, Merck Sharp & Dohme and ViiV Healthcare. MM-A has received consultancy fees and lecture sponsorships from and has served on advisory boards for Gilead Sciences, Janssen-Cilag, ViiV Healthcare and Merck Sharp & Dohme. JN has received fees for educational activities and/or consultancies and/or financial support for attending conferences from Abbvie, Gilead Science, Janssen-Cilag, Merck Sharp & Dohme and ViiV Healthcare out of the submitted work. MV has received research funding, consultancy fees and lecture sponsorships from, and has served on advisory boards for Gilead and ViiV Healthcare. AI has received research funding, consultancy fees, and lecture sponsorships from, or has served on advisory boards for Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme, Thera Technologies and ViiV Healthcare. PB has received consultancy fees from, and has served on advisory boards for Gilead Sciences, Merck Sharp & Dohme, Janssen-Cilag and ViiV Healthcare. RP has received research funding and consultancy fees and/or has served on advisory boards for Boehringer-Ingelheim, Gilead Sciences, Glaxo Smith-Kline, Merck Sharp & Dohme, Pfizer, and ViiV Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Santos, Casadellà, Noguera-Julian, Micán-Rivera, Domingo, Antela, Portilla, Sanz, Montero-Alonso, Navarro, Masiá, Valcarce-Pardeiro, Ocampo, Pérez-Martínez, García-Vallecillos, Vivancos, Imaz, Iribarren, Hernández-Quero, Villar-García, Barrufet, Paredes and INSTINCT study group.)

Background: Transmission of resistance mutations to integrase strand transfer inhibitors (INSTIs) in HIV-infected patients may compromise the efficacy of first-line antiretroviral regimens currently recommended worldwide. Continued surveillance of transmitted drug resistance (TDR) is thus warranted., Objectives: We evaluated the rates and effects on virological outcomes of TDR in a 96 week prospective multicentre cohort study of ART-naive HIV-1-infected subjects initiating INSTI-based ART in Spain between April 2015 and December 2016., Methods: Pre-ART plasma samples were genotyped for integrase, protease and reverse transcriptase resistance using Sanger population sequencing or MiSeq™ using a ≥ 20% mutant sensitivity cut-off. Those present at 1%-19% of the virus population were considered to be low-frequency variants., Results: From a total of 214 available samples, 173 (80.8%), 210 (98.1%) and 214 (100.0%) were successfully amplified for integrase, reverse transcriptase and protease genes, respectively. Using a Sanger-like cut-off, the overall prevalence of any TDR, INSTI-, NRTI-, NNRTI- and protease inhibitor (PI)-associated mutations was 13.1%, 1.7%, 3.8%, 7.1% and 0.9%, respectively. Only three (1.7%) subjects had INSTI TDR (R263K, E138K and G163R), while minority variants with integrase TDR were detected in 9.6% of subjects. There were no virological failures during 96 weeks of follow-up in subjects harbouring TDR as majority variants., Conclusions: Transmitted INSTI resistance remains rare in Spain and, to date, is not associated with virological failure to first-line INSTI-based regimens., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)