ObjectivesRapid initiation of antiretroviral therapy (ART) is important for individuals with high baseline viral loads, such as in primary HIV‐1 infection (PHI). Four‐drug regimens are sometimes considered; however, data are lacking on tolerability. We aimed to evaluate the tolerability of four‐drug regimens used in the Research in Viral Eradication of HIV‐1 Reservoirs (RIVER) study.MethodsAt enrolment, ART‐naïve adult participants or those newly commenced on ART were initiated or intensified to four‐drug regimens within 4 weeks of PHI. Rapid start was defined as pre‐confirmation or ≤ 7 days of confirmed diagnosis. Primary and secondary outcomes were patient‐reported adherence measured by 7‐day recall and regimen switches between enrolment and randomization, respectively.ResultsOverall, 54 men were included: 72.2% were of white ethnicity, with a median age of 32 years old, 42.6% had a viral load of ≥ 100 000 HIV‐1 RNA copies/mL, and in 92.6% sex with men was the mode of acquisition of HIV‐1. Twenty (37%) started a four‐drug regimen and 34 (63%) were intensified. Rapid ART initiation occurred in 28%, 100% started in ≤ 4 weeks. By weeks 4, 12, and 24, 37.0%, 69.0%, and 94.0% were undetectable (viral load < 50 copies/mL), respectively. Adherence rates of 100% at weeks 4, 12, 22 and 24 were reported in 88.9%, 87.0%, 82.4% and 94.1% of participants, respectively. Five individuals switched to three drugs, four changed their regimen constituents, and two switched post‐randomization.ConclusionsOverall, four‐drug regimens were well tolerated and had high levels of adherence. Whilst their benefit over three‐drug regimens is lacking, our findings should provide reassurance if a temporarily intensified regimen is clinically indicated to help facilitate treatment.