Among treatment-naïve adults with HIV who are initiating antiretroviral therapy (ART), a regimen containing doravirine, lamivudine, and tenofovir disoproxil fumarate (DOR/3TC/TDF) is as good as the dolutegravir, emtricitabine, and tenofovir alafenamide (DTG/FTC/TAF) regimen in terms of viral suppression but is associated with less weight gain, according to the open-label, head-to-head OPTI-DOR study conducted in South Africa.
By week 48, 89 percent of patients who received DOR/3TC/TDF had achieved viral suppression (HIV RNA level <50 copies/mL) compared with 90.7 percent of those who received DTG/FTC/TAF. The between-group difference was −1.7 percentage points (95 percent confidence interval [CI], −6.6 to 3.1), meeting the prespecified noninferiority margin of −10 percentage points. [JAMA 2026;doi:10.1001/jama.2026.14762]
First author Joana Woods, MBChB, MPH, from the University of the Witwatersrand, Johannesburg, South Africa, and colleagues noted in their paper that while both ART regimens were associated with weight gain, increases were greater with DTG/FTC/TAF. Over 48 weeks, the median weight gain was 3 kg in the DOR/3TC/TDF group vs 5 kg in the DTG/FTC/TAF group, for a difference of 2 kg (p<0.001).
Virologic failure occurred in nine patients in the DOR/3TC/TDF group and six in the DTG/FTC/TAF group. In the DOR/3TC/TDF group, seven patients in the DOR/3TC/TDF group developed high-level resistance to doravirine during follow-up, and six achieved viral suppression after switching to dolutegravir-based therapy. None of the patients in the DTG/FTC/TAF group had emergent treatment resistance.
Preventing weight gain
“Second-generation integrase strand transfer inhibitor (InSTI)–based regimens, particularly dolutegravir and bictegravir, are the global standard for first-line HIV treatment because of their high potency, tolerability, and high barrier to treatment resistance… [But these] regimens, particularly when combined with tenofovir alafenamide, are also associated with substantial weight gain that is most pronounced during the first 1 to 2 years of treatment and disproportionately affects women, Black populations, and people with advanced HIV disease,” according to Woods and colleagues.
“The DOR/3TC/TDF regimen is one of the few currently available fixed-dose combinations that pair a non-InSTI anchor with a tenofovir disoproxil fumarate backbone, offering a biologically plausible strategy to attenuate ART-associated weight gain,” they added.
Wood and colleagues argued that preventing weight gain at ART initiation may be critical, because switching ART regimens later in treatment appears to do little to reverse established weight gain. [Clin Infect Dis 2024;79:999-1005; Open Forum Infect Dis 2024;11:ofae485; Ann Epidemiol 2026;113:13-22; Lancet HIV 2026;13:e306-e315]
During her presentation at the 2026 AIDS conference, Woods acknowledged that while the findings from OPTI-DOR support DOR/3TC/TDF as an alternative regimen to prevent weight gain and potentially modify cardiometabolic risk, the doravirine-based regimen is not a universal ART replacement.
“Viral suppression will always be the priority. But we have alternative regimens that can still suppress the virus in a targeted population where preventing obesity and cardiometabolic risk is a priority,” she said.
The OPTI-DOR trial
OPTI-DOR was conducted at two South African sites and included 600 ART-naïve adults (median age 34 years, 68.8 percent assigned female at birth, 99.5 percent Black African) with an HIV RNA level >500 copies/mL and no detectable high-level doravirine resistance at baseline.
The patients were randomly assigned to receive a once-daily, fixed-dose regimen containing 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate (n=299) or 50 mg of dolutegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide (n=301).
Over 48 weeks, CD4 cell count increased by a mean of 180 cells/μL in DOR/3TC/TDF group vs 185 cells/μL in the DTG/FTC/TAF group (p=0.72). Total body fat percentage increased by a median of 1.5 percent vs 2.2 percent (p<0.001), respectively, while visceral adipose tissue area increased by a median of 8.4 vs 11.6 cm2 (p=0.04), respectively. A ≥25-percent decline in creatinine clearance occurred in 10.7 percent of patients in the DOR/3TC/TDF group vs 23.9 percent in the DTG/FTC/TAF group (p<0.001).
Bone mineral density decreased by a median of 2.1 percent with DOR/3TC/TDF vs 0.5 percent with DTG/FTC/TAF at the hip and by a median of 3.2 percent vs 1.3 percent, respectively, at the spine. Both groups showed minimal changes in fasting glucose level, HbA1c level, fasting insulin level, and homeostatic model assessment of insulin resistance. However, lipid changes were more favourable in the DOR/3TC/TDF group.
Safety outcomes were similar between the two groups. Grade 3 or 4 adverse events (AEs) occurred in 8.4 percent of patients in the DOR/3TC/TDF group vs 12.3 percent in the DTG/FTC/TAF group, while serious AEs occurred in 3.7 percent vs 2.3 percent, respectively. AEs led to treatment discontinuation in only one patient who received DTG/FTC/TAF. There were two deaths reported in the DOR/3TC/TDF group, and both were deemed unrelated to the study regimen.
Not practice-changing
“I don’t think this is going to be a practice-changing study here in the US,” wrote Dr Paul Sax from Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, US, in his blog post on NEJM Voices.
“The resistance is clinically significant, and all of the non-virologic findings can be linked to the known off-target effects of TDF, including weight suppression, lipid lowering, and bone mineral density loss; long-term we could expect renal issues, especially in those with other risk factors for this problem,” Sax added.
“The best way to manage excess weight gain in people with HIV is not through ART manipulation, but through strategies that we use in people without HIV: diet, exercise, GLP-1s,” he concluded.