Integrase strand-transfer inhibitor use and cardiovascular events in adults with HIV: an emulation of target trials in the HIV-CAUSAL Collaboration and the Antiretroviral Therapy Cohort Collaboration

Sophia M Rein*, Sara Lodi, Roger Logan, Giota Toulomi, Anastasia Antoniadou, Linda Wikktop, Fabrice Bonnet, Ard van Sighem, Marc van der Valk, Peter Reiss, Marina Klein, James Young, Antonella D Arminio Monforte, Alessandro Tavelli, Laurence Meyer, Laurent Tran, Michael Gill, Raynell Lang, Bernard Surial, Andreas D. HaasAmy Justice, Christopher T Rentsch, Andrew D Phillips, Caroline Sabin, Jose Miro, Adam J W Trickey, Suzanne M Ingle, Jonathan A C Sterne, Miguel A Hernan

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

6 Citations (Scopus)
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Abstract

Background
A recent observational study suggested that the risk of cardiovascular events could be higher among antiretroviral therapy (ART)-naive individuals with HIV who receive integrase strand-transfer inhibitor (INSTI)-based ART than among those who receive other ART regimens. We aimed to emulate target trials separately in ART-naive and ART-experienced individuals with HIV to examine the effect of using INSTI-based regimens versus other ART regimens on the 4-year risk of cardiovascular events.

Methods
We used routinely recorded clinical data from 12 cohorts that collected information on cardiovascular events, BMI, and blood pressure from two international consortia of cohorts of people with HIV from Europe and North America. For the target trial in individuals who had previously never used ART (ie, ART-naive), eligibility criteria were aged 18 years or older, a detectable HIV-RNA measurement while ART-naive (>50 copies per mL), and no history of a cardiovascular event or cancer. Eligibility criteria for the target trial in those with previous use of non-INSTI-based ART (ie, ART-experienced) were the same except that individuals had to have been on at least one non-INSTI-based ART regimen and be virally suppressed (≤50 copies per mL). We assessed eligibility for both trials for each person-month between January, 2013, and January, 2023, and assigned individuals to the treatment strategy that was compatible with their data. We estimated the standardised 4-year risks of cardiovascular events (myocardial infarction, stroke, or invasive cardiovascular procedure) via pooled logistic regression models adjusting for time and baseline covariates. In per-protocol analyses, we censored individuals if they deviated from their assigned treatment strategy for more than 2 months and weighted uncensored individuals by the inverse of their time-varying probability of remaining uncensored. The denominator of the weight was estimated via a pooled logistic model that included baseline and time-varying covariates.

Findings
The analysis in ART-naive individuals included 10 767 INSTI initiators and 8292 non-initiators of INSTI. There were 43 cardiovascular events in INSTI initiators (median follow-up of 29 months; IQR 15–45) and 52 in non-initiators (39 months; 18–47): standardised 4-year risks were 0·76% (95% CI 0·51 to 1·04) in INSTI initiators and 0·75% (0·54 to 0·98) in non-INSTI initiators; risk ratio 1·01 (0·57 to 1·57); risk difference 0·0089% (–0·43 to 0·36). The analysis in ART-experienced individuals included 7875 INSTI initiators and 373 965 non-initiators. There were 56 events in INSTI initiators (median follow-up 18 months; IQR 9–29) and 3103 events (808 unique) in non-INSTI initiators (26 months; 15–37) in non-initiators: standardised 4-year risks 1·41% (95% CI 0·88 to 2·03) in INSTI initiators and 1·48% (1·28 to 1·71) in non-initiators; risk ratio 0·95 (0·60 to 1·36); risk difference –0·068% (–0·60 to 0·52).

Interpretation
We estimated that INSTI use did not result in a clinically meaningful increase of cardiovascular events in ART-naive and ART-experienced individuals with HIV.

Funding
National Institute of Allergy and Infectious Diseases and National Institute on Alcohol Abuse and Alcoholism.
Original languageEnglish
Pages (from-to)e723-e732
JournalLancet HIV
Volume10
Issue number11
DOIs
Publication statusPublished - 1 Nov 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Ltd

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