The Phase 3 Opti-DOR trial found doravirine, lamivudine, and TDF achieved noninferior HIV viral suppression with significantly less weight gain than dolutegravir plus TAF.
Written By: Anamika Koshti, PharmD
Reviewed By: Pharmacally Editorial Team
Adults initiating antiretroviral therapy (ART) with a regimen containing doravirine, lamivudine, and tenofovir disoproxil fumarate (TDF) achieved viral suppression comparable to those receiving dolutegravir, emtricitabine, and tenofovir alafenamide (TAF), while experiencing significantly less weight gain over 48 weeks, according to results from the Opti-DOR randomized clinical trial (NCT05924438) led by researchers at Wits Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, in collaboration with the Africa Health Research Institute (AHRI) and international investigators from Harvard Medical School, Massachusetts General Hospital, and the University of Liverpool. The findings were published in JAMA.
The investigator-initiated study enrolled 600 ART-naïve adults across two South African clinical sites and addressed a growing challenge in HIV treatment. Although integrase strand transfer inhibitor (INSTI)-based regimens remain the global standard of care, accumulating evidence has linked combinations containing dolutegravir and TAF with clinically meaningful weight gain that may increase long-term cardiometabolic risk.
Scientific and Clinical Context
Second-generation INSTIs have transformed HIV care by providing potent, durable viral suppression with a high barrier to resistance. However, weight gain associated with dolutegravir and TAF-containing regimens has emerged as an important clinical concern, particularly among women, Black individuals, and patients with advanced HIV infection.
Doravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with established antiviral activity and a favorable metabolic profile. Investigators evaluated whether replacing both the INSTI anchor and the TAF backbone with doravirine, lamivudine, and TDF could preserve antiviral efficacy while limiting treatment-associated weight gain.
Trial Design and Key Findings
Opti-DOR was an open-label, randomized, Phase 3 noninferiority trial conducted in Johannesburg and Somkhele, South Africa. Adults with HIV who had not previously received ART, had HIV RNA levels above 500 copies/mL, and had no high-level baseline doravirine resistance were randomly assigned to receive once-daily doravirine (100 mg), lamivudine (300 mg), and TDF (300 mg) (n=299) or dolutegravir (50 mg), emtricitabine (200 mg), and TAF (25 mg) (n=301). The study evaluated whether the doravirine regimen could maintain viral suppression within a prespecified noninferiority margin while improving metabolic outcomes.
At Week 48, 89.0% of participants receiving doravirine, lamivudine, and TDF achieved HIV RNA levels below 50 copies/mL compared with 90.7% of those receiving dolutegravir, emtricitabine, and TAF. The between-group difference of −1.7 percentage points (95% CI, −6.6 to 3.1) met the predefined noninferiority criterion.
The doravirine regimen also demonstrated a significant metabolic advantage. Median weight gain was 3.0 kg compared with 5.0 kg in the dolutegravir group, representing a between-group difference of −2.0 kg (95% CI, −3.0 to −1.0; P<0.001). Participants receiving doravirine also experienced smaller increases in total body fat, trunk fat, visceral adipose tissue, and body mass index. Lipid changes were likewise more favorable, with lower total cholesterol, LDL cholesterol, and triglyceride levels than those observed with the dolutegravir-based regimen.
Safety Profile and Important Trade-Offs
The metabolic benefits of the doravirine regimen were accompanied by greater reductions in bone mineral density, consistent with the established safety profile of TDF. Median hip bone mineral density declined by 2.1% compared with 0.5% in the dolutegravir group, while spine bone mineral density decreased by 3.2% versus 1.3% (P<0.001 for both comparisons). Conversely, clinically significant declines in creatinine clearance occurred more frequently in participants receiving dolutegravir, emtricitabine, and TAF (23.9% vs 10.7%).
Protocol-defined virologic failure occurred in nine participants receiving doravirine and six receiving the comparator regimen. Doravirine resistance emerged in seven participants, most of whom had advanced HIV disease at baseline. Following a switch to dolutegravir-based therapy, five of six patients subsequently achieved viral suppression. Overall safety profiles were comparable between treatment groups, and the two reported deaths in the doravirine arm were considered unrelated to study treatment.
Clinical Perspective
The findings suggest that selecting an initial ART regimen with doravirine, lamivudine, and TDF can reduce treatment-associated weight gain without compromising virologic efficacy. This may be particularly relevant for patients at increased risk of obesity, diabetes, or cardiovascular disease.
The investigators also emphasized that weight gain associated with contemporary INSTI-based regimens appears difficult to reverse once established, reinforcing the importance of considering metabolic outcomes when selecting first-line therapy rather than attempting to address excess weight after treatment has begun.
Future Development
Although Opti-DOR demonstrated a favorable balance between antiviral efficacy and metabolic outcomes, longer follow-up will be needed to determine whether reduced weight gain translates into lower rates of diabetes, cardiovascular disease, and other long-term complications. The authors also noted that the regimen-level comparison cannot fully distinguish the contributions of the anchor drug and the nucleoside backbone. An ongoing randomized trial (NCT06203132) comparing doravirine and dolutegravir on a shared TDF-based backbone is expected to further clarify the individual effects of these agents on treatment-associated weight gain.
Reference
About the Writer
Anamika Koshti (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, and evidence-based medicine. She has authored peer-reviewed publications on Alzheimer’s disease and PCOS, presented research at national conferences, and gained hands-on experience in medical content development and clinical data interpretation. She is committed to translating complex medical research into accurate, accessible content for healthcare professionals and patients.