Efficacy of Dolutegravir Plus Lamivudine Without Resistance Testing

In an open-label, non-inferiority, single-center, phase 4 randomized controlled trial, researchers demonstrated that dolutegravir plus lamivudine is non-inferior to a three-drug regimen consisting of dolutegravir, tenofovir disoproxil fumarate, and either emtricitabine or lamivudine in treatment-naive individuals with HIV, even in the absence of baseline resistance testing.

“Dolutegravir plus lamivudine has emerged as a preferred treatment for HIV; however, initiating this regimen without baseline resistance testing raises concerns about the potential presence of pretreatment lamivudine resistance,” Cordova and colleagues wrote.

To fill this gap, the researchers evaluated the safety and efficacy of dolutegravir plus lamivudine in treatment-naive individuals with HIV, specifically in the absence of baseline resistance testing, addressing a key clinical question regarding its use in real-world settings.

For their trial, known as D2ARLING, Cordova and colleagues enrolled 214 treatment-naive individuals with HIV-1 infection between November 17, 2020, and August 31, 2022. Participants were randomly assigned in a 1:1 ratio to receive either dolutegravir plus lamivudine (n = 106) or the three-drug regimen (n = 108). Randomization was stratified by baseline HIV-1 RNA levels (≤ 100,000 vs > 100,000 copies/mL) and CD4 cell count (< 200 vs ≥ 200 cells/μL). Baseline characteristics were comparable between groups, with a median participant age of 31 years (IQR, 26–39), and 23% were female. At enrollment, 31% had an HIV-1 RNA viral load >100,000 copies/mL, and 21% had a CD4 T-cell count <200 cells/μL.

The primary endpoint was the proportion of participants achieving HIV-1 RNA suppression at 48 weeks, analyzed via the intention-to-treat exposed Snapshot algorithm with a non-inferiority margin of 10%.

At 48 weeks, 92% of participants receiving dolutegravir plus lamivudine achieved plasma HIV-1 RNA suppression to less than 50 copies/mL compared with 89% in the control group, with a treatment difference of 2.62% (95% CI, –5.3 to 10.6), confirming non-inferiority. No participants in the dolutegravir plus lamivudine group experienced virologic failure, and none developed treatment-emergent resistance mutations. Adverse event rates were similar between arms, with fewer than 1% of participants in both groups discontinuing treatment due to adverse events.

A key limitation of the study is its single-center design, which may limit generalizability. Additionally, the trial did not assess long-term resistance emergence beyond the 48-week period.

"These findings suggest that baseline resistance testing might not be a requirement for initiating treatment with dolutegravir plus lamivudine in settings with low frequency or suspicion of transmitted drug resistance to these drugs," the authors concluded.

Reference
Cordova E, Hernandez Rendon J, Mingrone V, et al. Efficacy of dolutegravir plus lamivudine in treatment-naive people living with HIV without baseline drug-resistance testing available (D2ARLING): 48-week results of a phase 4, randomised, open-label, non-inferiority trial. Lancet HIV. 2025;12(2):e95-e104. doi:10.1016/S2352-3018(24)00294-7