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. 2023 Jun 26:13:1187999.
doi: 10.3389/fcimb.2023.1187999. eCollection 2023.

Effectiveness and safety of integrase strand transfer inhibitors in Spain: a prospective real-world study

José Ramón Santos  1 , Maria Casadellà  2 , Marc Noguera-Julian  2 , Rafael Micán-Rivera  3 , Pere Domingo  4 , Antonio Antela  5 , Joaquin Portilla  6 , Jesús Sanz  7 , Marta Montero-Alonso  8 , Jordi Navarro  9 , Mar Masiá  10   11 , Nieves Valcarce-Pardeiro  12 , Antonio Ocampo  13 , Laura Pérez-Martínez  14 , Coral García-Vallecillos  15 , María Jesús Vivancos  11   16 , Arkaitz Imaz  17 , José Antonio Iribarren  18 , José Hernández-Quero  19 , Judit Villar-García  20 , Pilar Barrufet  21 , Roger Paredes  1   2 ; INSTINCT study group
Collaborators, Affiliations

Effectiveness and safety of integrase strand transfer inhibitors in Spain: a prospective real-world study

José Ramón Santos et al. Front Cell Infect Microbiol. .

Abstract

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.

Keywords: HIV; dolutegravir; elvitegravir; integrase strand transfer inhibitors (INSTI); raltegravir; real-world study.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
(A) Time to virological failure in ART-naïve patients according to INSTI-based regimen (genuine ITT analysis). (B) Time to virological failure or switching in ART-naïve patients according to INSTI-based regimen (ITT: S=F sensitivity analysis). (C) Time to virological failure or switching in ART-naïve patients or missing during the study according to INSTI-based regimen (ITT: M=F sensitivity analysis). Survival is presented as the mean (95% CI); p-values correspond to the log-rank test for intercurve differences. Patients at risk at each timepoint are shown below each graph.
Figure 2
Figure 2
(A) Time to virological failure in ART-switching patients according to INSTI-based regimen (genuine ITT analysis). (B) Time to virological failure or switching in ART-switching patients according to INSTI-based regimen (ITT: S=F sensitivity analysis). (C) Time to virological failure or switching in ART-switching patients or missing during the study according to INSTI-based regimen (ITT: M=F sensitivity analysis). Survival is presented as the mean (95% CI); p-values correspond to the log-rank test for intercurve differences. The number of patients at risk at each timepoint are shown below each graph.
Figure 3
Figure 3
(A) Time to virological failure in ART-salvage patients according to INSTI-based regimen (genuine ITT analysis). (B) Time to virological failure or switching in ART-salvage patients according to INSTI-based regimen (ITT: S=F sensitivity analysis). (C) Time to virological failure or switching in ART-salvage patients or missing during the study according to INSTI-based regimen (ITT: M=F sensitivity analysis). Survival is presented as the mean (95% CI); p-values correspond to the log-rank test for intercurve differences. The number of patients at risk at each timepoint are shown below each graph.
Figure 4
Figure 4
CD4+ T-cell counts in (A) ART-naïve, (B) ART-switching, and (C) ART-salvage groups according to INSTI-based regimen. Data points represent the mean at each time point and error bars represent the standard deviation; the number of patients at each time point for each regimen is shown below each graph. BL, baseline; ns, Not significant.
See this image and copyright information in PMC

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