What second-line ART regimens are optimal for HIV if first-line treatment fails?

Dolutegravir (DTG) plus ritonavir-boosted darunavir (DRV/r) and DTG with tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC) or emtricitabine (FTC) are both noninferior to DRV/r plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) for HIV virologic suppression in patients who experience treatment failure on non-NRTI (NNRTI)-based first-line antiretroviral therapy (ART), according to study results published in The Lancet HIV.

Researchers conducted an international, randomized, open-label, noninferiority phase 3b/4 trial (ClinicalTrials.gov Identifier: NCT03017872) at 28 sites in 14 countries between 2017 and 2022 to assess optimal second-line ART regimens for patients with HIV infection. Adult patients who had experienced treatment failure after at least 24 weeks on NNRTI-based first-line ART were eligible for enrollment. In stage 1, patients were randomly assigned 1:1 to receive either DRV/r plus DTG or DRV/r plus 2 NRTIs (standard care). In stage 2, a third study arm of patients assigned to receive DTG with fixed TDF plus either 3TC or FTC was added within the first year of the analysis. The primary outcome was 48-week virologic suppression, defined as an HIV RNA load of fewer than 50 copies/mL.

A total of 826 patients (mean age, 39.4 years; mean BMI, 24.2 kg/m²; women, 54%; Black, 69%) commenced their randomly assigned treatment regimen and comprised the primary analysis population. At baseline, the mean CD4⁺ count was 252.5 cells/µL and the median HIV RNA viral load was 15,400 copies/mL.

In first stage of the study, 52 patients received standard care and 55 received DRV/r plus DTG. In the second stage of the study, 209 patients received standard care, 216 received DRV/r plus DTG, and 294 received DTG/TDF plus 3TC or FTC.

At week 48, virologic suppression was observed among 75% of patients in the standard care group, 84% of those in the DRV/r plus DTG group, and 78% of those in the DTG/TDF plus 3TC or FTC group.

In the noninferiority analysis, both DRV/r plus DTG and DTG/TDF plus 3TC or FTC were favored over standard care for virologic suppression, with efficacy differences of 8.6% (95% CI, 1.7-15.5; P =.016) and 6.7% (95% CI, -1.2 to 14.4; P =.093), respectively. The researchers noted that both intervention groups met noninferiority criteria, with superiority to standard care observed among patients who received DRV/r plus DTG.

A total of 6 deaths (infection, n=3; progressive multifocal leukoencephalopathy, n=1; sudden cardiac death, n=1; trauma-related death, n=1) occurred during the study, none of which were considered related to the study drugs. There were also 19 pregnancies by week 48, of which 11 resulted in livebirth; no birth defects were documented during the study period.

Study limitations include the addition of a third treatment arm, as well as the decision to halt enrollment prior to the target sample size being reached.According to the researchers, “These global data support the most recent WHO [World Health Organization] treatment guidelines.”

By Jessica Nye, PhD

References:

D²EFT Study Group. Dolutegravir plus boosted darunavir versus recommended standard-of-care antiretroviral regimens in people with HIV-1 for whom recommended first-line non-nucleoside reverse transcriptase inhibitor therapy has failed (D²EFT): an open-label, randomised, phase 3b/4 trial. Lancet HIV. Published online May 21, 2024. doi:10.1016/S2352-3018(24)00089-4