Starting treatment with a regimen containing doravirine and tenofovir disoproxil (TDF) resulted in less weight gain than starting treatment with a regimen containing dolutegravir and tenofovir alafenamide (TAF), according to findings from the OptiDOR trial presented at the 26th International AIDS Conference in Rio de Janeiro, Brazil. While both regimens achieve high levels of viral suppression, researchers noted distinct clinical trade-offs regarding weight, metabolic profiles, and drug resistance risks when comparing the two first-line options.
OptiDOR Trial Design and Patient Demographics
The OptiDOR trial investigated whether starting HIV treatment with a regimen omitting TAF or an integrase inhibitor would maintain viral suppression while curbing side effects. According to the study data, researchers in South Africa enrolled 600 previously untreated adults. Eligible participants weighed more than 35kg and lacked high-level resistance to doravirine. Pregnant or breastfeeding women, individuals with active tuberculosis, and people with impaired kidney function or liver disease were excluded from the trial.
The study population had a median age of 34 years, and 69% of participants were female. The median CD4 count stood at 322 cells, with more than 25% of participants presenting with CD4 counts below 200—a clinical threshold defining advanced HIV. A low CD4 count at treatment initiation is known to increase a patient’s risk of subsequent weight gain. Furthermore, the median weight among participants was 75kg, and roughly one in three met the criteria for clinical obesity, defined as a body mass index greater than 30kg/m2.
Viral Suppression and Resistance Outcomes
Participants were randomized into one of two treatment arms. One arm received doravirine, TDF, and lamivudine, while the comparator arm received dolutegravir, TAF, and emtricitabine. The primary study endpoint measured the proportion of participants maintaining a viral load below 50 copies/ml at week 48, utilizing a non-inferiority margin of -10%.
According to the trial results, virologic suppression in the doravirine, TDF, and lamivudine arm was non-inferior to the dolutegravir and TAF arm, achieving 89% versus 90.7% suppression respectively, with a difference of -1.7% and a 95% confidence interval ranging from -6.6% to 3.1%. Across the study, 15 participants experienced virologic failure. Nine of these cases occurred in the doravirine arm, where high-level resistance to doravirine emerged due to non-adherence. In six of the seven cases, virologic resuppression was achieved after switching to dolutegravir, TDF, and lamivudine, while one participant was lost to follow-up. All cases of virologic failure in the doravirine group occurred in individuals with advanced HIV and high baseline viral loads, featuring a median CD4 count of 34 cells and a median viral load of 4.9 log10 copies/ml. Conversely, none of the participants in the dolutegravir arm who experienced virologic failure developed resistance to their regimen.
Did you know? Weight gain can occur after starting antiretroviral therapy regardless of the specific drugs used in the regimen, though studies consistently show that increases are greater among women and Black populations, particularly when regimens combine TAF with an integrase inhibitor like dolutegravir or bictegravir.
Weight Gain and Metabolic Differences
Secondary outcomes tracked changes in weight, body composition via DEXA scans, lipid levels, bone mass, and kidney function. The doravirine-containing regimen was associated with significantly less weight gain at week 48, showing a difference of -1.92kg compared to the comparator arm. Additionally, fewer participants in the doravirine group experienced a weight gain of at least 5% of their total body weight, at 41.1% versus 56.8%.
Modest yet statistically significant differences also emerged in lipid profiles, favoring the doravirine arm regarding total cholesterol, LDL cholesterol, triglycerides, and the total cholesterol-to-HDL cholesterol ratio. Regarding renal markers, significantly fewer participants in the doravirine arm experienced reductions in creatinine clearance of 25% or greater. However, researchers observed no corresponding difference in cystatin increases exceeding 25%. Investigators concluded that the creatinine clearance discrepancy stemmed from greater tubular secretion inhibition caused by dolutegravir rather than actual kidney damage.
Bone Density and Clinical Trade-Offs
Total bone mineral density changes showed no significant difference between the two study arms. However, reductions in spinal bone mineral density were significantly greater in the doravirine group, dropping by 3.2% compared to 1.3% in the dolutegravir group. No bone fractures were reported during the follow-up period.
Drug-related serious adverse events were uncommon, with five reported in the dolutegravir arm and three in the doravirine arm. Only one participant discontinued treatment due to a serious adverse event. Dr. Joana Woods of Wits Ezintsha at the University of the Witwatersrand highlighted the clinical trade-offs between the two options. According to Dr. Woods, while dolutegravir-based treatment minimizes the risk of drug resistance, doravirine-based treatment offers a more favorable impact on weight and lipid levels. She concluded that while doravirine, TDF, and lamivudine does not serve as a universal replacement for dolutegravir regimens, it provides a valuable targeted first-line choice for patients where preventing obesity and cardiometabolic risk is a priority.
Pro Tip: Past attempts to reverse established antiretroviral-induced weight gain by switching medications have largely proved unsuccessful. Clinical data indicates that preventing significant weight gain at the time of treatment initiation is considerably more achievable than reversing it later.
Frequently Asked Questions
What causes weight gain after starting HIV treatment?
Weight gain can happen with any antiretroviral regimen, but it is often more pronounced in women and Black populations, especially when regimens include tenofovir alafenamide (TAF) combined with an integrase inhibitor like dolutegravir or bictegravir.
Can weight gain from HIV drugs be reversed by switching medications?
Clinical attempts to reverse established weight gain by switching away from these drugs have generally been unsuccessful, making initial regimen selection a critical factor for weight management.
Is doravirine as effective as dolutegravir for suppressing the virus?
According to the OptiDOR trial data, a doravirine, TDF, and lamivudine regimen demonstrated non-inferior viral suppression rates at week 48 compared to a dolutegravir, TAF, and emtricitabine regimen (89% versus 90.7%).
Did patients taking doravirine develop drug resistance?
Nine cases of virologic failure occurred in the doravirine arm, with high-level resistance emerging due to non-adherence, primarily among individuals who began treatment with advanced HIV and high viral loads.
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