Risk of major adverse cardiovascular events with dolutegravir versus efavirenz-based antiretroviral therapy: emulated target trials using routine, de-identified data from South Africa

BackgroundIntegrase inhibitors, including dolutegravir, may increase risk of major adverse cardiovascular events (MACEs). However, limited data exists from low- and middle-income countries, where tenofovir disoproxil fumarate, lamivudine and dolutegravir (TLD) has largely replaced tenofovir disoproxil fumarate, emtricitabine and efavirenz (TEE). MethodsWe used de-identified data from a South African managed-healthcare organisation from people living with HIV (PLHIV) without cardiovascular disease, who either initiated TEE or TLD between April 2020-Dec 2023 (initiation cohort) or were receiving TEE in April 2020 and eligible for TLD (transition cohort). In the initiation cohort, we emulated a target trial using pooled logistic regression models with inverse probability of treatment weights and bootstrapped confidence intervals to compare standardised 3-year MACE risk between TLD versus TEE. In the transition cohort, we used similar methods in 44 emulated monthly sequential trials, comparing MACE risk in people transitioned to TLD with those remaining on TEE. FindingsIn the initiation cohort, 7310 PLHIV initiated TLD (n=3711) or TEE (n=3599). Median follow-up was 21 months (IQR 10-33), with 18 MACEs with TLD (3-year risk 0.78%, 95%CI 0.37-1.32) and 28 with TEE (3-year risk 0.96%, 0.60-1.40; RR 0.81, 0.35-1.59; RD -0.18, -0.82-0.50). In the transition cohort, 22338 people contributed to 2837 person-trials with TLD and 706615 with TEE. Median follow-up was 25 months (14-36), with 19 MACEs with TLD (3-year risk 1.09%, 0.48-1.99) and 5420 with TEE (3-year risk 1.21%, 1.05-1.41; RR 0.90, 0.41-1.64; RD -0.12, -0.75-0.75). InterpretationAmong PLHIV in South Africa we found no increased MACE with TLD. FundingGates Foundation; National Institute of Health and Social Care Research RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed with no language restrictions on March 6th, 2025, with the terms "(dolutegravir) AND (cardiovascular disease OR coronary heart disease OR cerebrovascular disease OR stroke)" and identified additional studies using hand searches of reference lists and citing papers. We found no randomised trials which were adequately powered to directly assess the risk of major adverse cardiovascular events (MACEs) between dolutegravir (or integrase strand transferase inhibitors [INSTIs]) and efavirenz (or non-nucleoside reverse transcriptase inhibitors). We identified one systematic review from 2018 of eight trials, predominantly from high-income settings, which found 15/2202 (0.7%) serious adverse cardiovascular events with dolutegravir versus 8/2215 (0.4%) with other antiretrovirals (relative risk 1.69, 95% CI 0.71 to 4.03). We identified five observational studies which assessed risk of cardiovascular events with INSTIs versus non-INSTI antiretroviral therapy (ART). A study using medical insurance claims data from the United States between 2008 and 2015 found initiating an INSTI was associated with fewer cardiovascular events compared to non-INSTI initiation, while a later study using the same dataset from 2013 to 2021 found no difference in MACE between INSTI versus non-INSTI initiation, although INSTI use was associated with increased myocardial infarction. An observational study using 17 European and Australian cohorts found an association between cumulative INSTI exposure up to 24 months and increased risk of cardiovascular events, although the study design has been questioned. Two studies used observational data to emulate target trials comparing risk of cardiovascular events among people using INSTI versus non-INSTI ART. In a Swiss cohort, people initiating INSTIs were not found to be at increased risk of cardiovascular events, while in a larger study using data from European and North American cohorts, 4-year cardiovascular risk was similar between INSTI and non-INSTI users in both ART naive and ART experienced individuals. Added value of this studyOur study is the first to evaluate risks of MACEs with tenofovir disoproxil fumarate, lamivudine and dolutegravir (TLD), the most widely used INSTI-based regimen in low- and middle-income countries (LMICs), where the majority of people living with HIV (PLHIV) live. This is important as this regimen has been recommended by the World Health Organisation (WHO) for first-line ART since 2018, replacing the previously recommended regimen of tenofovir disoproxil fumarate, emtricitabine and efavirenz (TEE). Using robust emulated target trial methods, we found no evidence of increased risk of MACEs with TLD versus TEE in both people initiating ART, or people already ART-experienced, in a large South African cohort. These findings are relevant for the over 20 million people estimated to be taking TLD in LMICs, where risk factors for cardiovascular disease may differ from high-income settings. Implications of all the available evidenceWe found no large increased risk of MACEs in the short-to medium term with TLD, which is supported by the majority of evidence investigating risks with INSTIs from high-income settings. These findings support the ongoing use of dolutegravir-based ART as part of the WHO public health approach in LMICs, although studies with greater follow-up time are required.