A treatment regimen anchored by doravirine worked as well as a dolutegravir-based approach but led to significantly less weight gain among patients starting antiretroviral therapy (ART) for HIV, an open-label randomized trial showed.
Among 600 treatment-naive patients in South Africa, 89% of those who took once-daily doravirine, lamivudine, and tenofovir disoproxil fumarate (Delstrigo) achieved HIV RNA levels of less than 50 copies/mL at 48 weeks compared with 90.7% of those taking once-daily dolutegravir, emtricitabine, and tenofovir alafenamide, meeting the prespecified noninferiority margin of -10 percentage points.
Both regimens were linked with weight gain, but the median weight gain was lower with the doravirine-anchored regimen: 3.0 kg versus 5.0 kg with the dolutegravir-based approach (P<0.001), reported Joana Woods, MBChB, MPH, of the University of the Witwatersrand in Johannesburg, at the International AIDS Conference in Rio de Janeiro.
The study results were also published simultaneously in JAMA.
The doravirine-based regimen isn’t a universal ART replacement, Woods cautioned. But the findings support this alternative regimen to prevent weight gain and potentially modify cardiometabolic risk, she said.
“Viral suppression will always be the priority,” she noted. “But we have alternative regimens that can still suppress the virus in a targeted population where preventing obesity and cardiometabolic risk is a priority.”
Standard first-line HIV treatments include second-generation integrase strand transfer inhibitors (INSTI) such as dolutegravir and bictegravir. While potent and not prone to treatment resistance, these INSTI-based regimens are linked to substantial weight gain during the initial treatment period, particularly when paired with tenofovir alafenamide.
Patients who are Black, female, or with advanced HIV are at greater risk for that initial weight gain, which can be irreversible, even after switching from an INSTI-based ART to regimens based on protease inhibitors or non-nucleoside reverse transcriptase inhibitors such as doravirine. Preventing weight gain during initial ART may be easier than trying to lose weight later during treatment.
To avoid weight gain risks, Woods and colleagues combined doravirine with two nucleoside reverse transcriptase inhibitors, lamivudine and tenofovir disoproxil fumarate.
The Opti-DOR trial recruited adults with HIV and no prior ART exposure from two South African sites from October 2023 to March 2025. Participants had HIV RNA levels greater than 500 copies/mL and no detectable baseline, high-level doravirine resistance. The primary outcome was viral suppression at 48 weeks, with secondary outcomes including mean change from baseline in body weight.
Nearly all patients (99.5%) were Black African, median age was 34 years, and 68.8% were assigned female at birth. Median baseline body weight was 74.9 kg, and median body mass index (BMI) was 27.7. Median baseline CD4 cell count was 324 cells/µL, and 27.3% of patients had a count below 200 cells/µL.
By week 48, CD4 cell counts increased by a mean of 180 cells/µL in the doravirine group and 185 cells/µL in the dolutegravir group (P=0.72).
Median increases in total body fat percentages were significantly lower in the doravirine group versus the dolutegravir group (1.5% vs 2.2%, respectively, P<0.001). Visceral adipose tissue area increased by a median of 8.4 cm2 versus 11.6 cm2 (P=0.04).
Both groups had minimal changes to their fasting glucose and insulin levels, HbA1c levels, and cholesterol and triglyceride levels. The doravirine group had a significantly greater median decline in bone mineral density at week 48, with a drop of -1.2% compared with -0.1% in the dolutegravir group (P<0.001).
Serious adverse events occurred in 3.7% of patients taking the doravirine-based regimen and 2.3% of those taking the dolutegravir-based regimen. Treatment discontinuation due to adverse events was rare, occurring in only one patient in the dolutegravir group.
During follow-up, seven patients developed high-level doravirine resistance. Six of those patients switched to the dolutegravir regimen, and five reached viral suppression by week 48.
Limitations included the study’s open-label design, and its 48-week follow-up, which prevented the investigators from studying potential links between early weight gain and longer-term cardiovascular and metabolic effects. The study also couldn’t link weight and metabolic differences directly to the doravirine and dolutegravir anchor drugs or the tenofovir backbone drugs.
