Tolerability of Four-Drug Antiretroviral Combination Therapy in Primary HIV-1 Infection

JE Burns; W Stöhr; S Kinloch-De Loes; J Fox; A Clarke; M Nelson; J Thornhill; A Babiker; J Frater; SL Pett; S Fidler


HIV Medicine. 2021;22(8):770-774. 

In This Article

Abstract and Introduction


Objectives: Rapid 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.

Methods: At 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.

Results: Overall, 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.

Conclusions: Overall, 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.


Following the findings of the START and TEMPRANO trials in 2015,[1,2] HIV-1 treatment guidelines are unified in their recommendation to initiate antiretroviral therapy (ART) irrespective of CD4 count.[3,4] There is also a consensus that the rapid initiation of ART (ideally ≤ 7days after confirmed HIV-1 diagnosis) is feasible,[5] can achieve faster virological suppression,[6] minimizes the HIV-1 reservoir[7] and subsequent immune recovery,[1] and improves uptake of ART and retention of care.[8] Rapid ART initiation is particularly important for individuals with primary HIV-1 infection (PHI) to mitigate the elevated risk of onward transmission due to very high HIV-1 viral loads.[9,10]

Current guidelines for rapidly starting ART in PHI recommend triple ART regimens comprising a tenofovir-based, dual nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone combined with integrase strand transfer inhibitors (INSTIs), or a boosted protease inhibitor (PI) such as darunavir/ritonavir (DRV/r).[4] Some physicians elect to start all four components, particularly with high viral loads in PHI. The rationale for four drugs is to access the benefits of faster viral suppression seen with INSTIs[11,12] combined with the higher genetic barrier to resistance associated with PIs.[13] This also safely negates the need to await genotype resistance and HLA-B*5701 results.

Despite the recommendations for rapid start of ART in PHI, there is a paucity of data on the tolerability and adherence in this setting, a time when patients are dealing with the burden of a new diagnosis of HIV-1, potentially compounded by symptoms of seroconversion. As such, our aim was to review the tolerability of four-drug regimens in the Research in Viral Eradication of HIV-1 Reservoirs (RIVER) trial (NCT02336074).[14]