HIV treatment guidelines published by the US Department of Health and Human Services (DHHS) in 2021, the International Antiviral Society–USA (IAS) in 2020, and the European AIDS Clinical Society (EACS) in 2020 recommend integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) with either 1 or 2 nucleoside reverse transcriptase inhibitors for most previously untreated adults and adolescents [
1‐
3]. Considering the requirement for lifelong ART, the high prevalence of comorbidities among people with HIV (PWH), and the toxicities associated with ART, 2-drug regimens that maintain efficacy comparable to that of 3-drug regimens are of considerable interest and potential value, offering the possibility of reduced cumulative drug exposure, adverse effects, and potential drug interactions [
1,
2,
4]. The 2-drug regimen dolutegravir (DTG) + lamivudine (3TC) demonstrated non-inferior efficacy, a high barrier to resistance, and a comparable safety profile relative to the 3-drug regimen DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) at 144 weeks after treatment initiation in the GEMINI-1 and GEMINI-2 trials in ART-naive PWH [
5]. Notably, there was a lower risk of drug-related adverse events (AEs) through Week 144 with DTG + 3TC than DTG + TDF/FTC in the pooled safety population from these 2 studies [
5]. Efficacy and safety of the recommended 3-drug ART regimens have also been well established [
1,
2]. Although DTG in combination with 3TC has been directly compared with DTG + TDF/FTC in ART-naive PWH, this 2-drug regimen has not been directly compared with other second-generation INSTI-based, 3-drug combinations in randomized clinical trials, ie, those containing bictegravir [
5]. In the absence of randomized clinical trial data, indirect treatment comparisons can provide valuable supplementary information for clinicians, PWH, and other interested parties. Previous network meta-analyses have shown DTG + 3TC to have efficacy and safety comparable to those of guideline-recommended 3-drug regimens at Weeks 48 and 96 [
6,
7].
This indirect treatment comparison was undertaken to further assess the durability of efficacy and long-term safety of DTG + 3TC vs recommended second-generation, INSTI-based regimens 144 weeks after treatment initiation.