Dolutegravir-based ART regimens may be effective second-line option in HIV

In the setting of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART), dolutegravir (DTG)-based ART regimens may be an appropriate option for second-line therapy in patients with HIV infection. These findings were published in Clinical Infectious Diseases.

The World Health Organization recommends dolutegravir-based regimens after first-line ART failure. However, backbone agents are an important component of ART regimens but there are limited comparative data to guide clinical decision making about these agents.

Researchers conducted a prospective, multicenter, phase 3B/4 randomized, open-label trial (D²EFT; ClinicalTrials.gov Identifier: NCT03017872) at 28 sites across 14 low- and middle-income countries in Latin America, Africa, and Asia. Adults (N=826) with HIV infection who had 2 consecutive viral loads greater than 500 copies/mL after at least 24 weeks of continuous treatment with first-line NNRTI plus 2NRTIs were included in this 2-stage analysis.

In stage 1, patients were randomly assigned 1:1 to receive either ritonavir-boosted darunavir (DRV/r) plus 2 NRTIs (n=55) or DTG+DRV/r (n=52). In stage 2, patients were randomly assigned 1:1:1 to receive either DRV/r+2NRTIs (n=210), DTG+DRV/r (n=216), or DTG combined with tenofovir disoproxil fumarate plus lamivudine or emtricitabine (TDF/XTC; n=295). The follow-up period was 96 weeks.

The primary outcome was the rate of virologic suppression at 48 weeks, defined as HIV RNA levels below 50 copies/mL. Virologic failure was defined as HIV RNA levels at or above 1000 copies/mL. Multivariable logistic regression was used to investigate factors associated with virologic failure in a modified intention-to-treat population, and a noninferiority analysis of efficacy was used to compare virologic suppression outcomes across treatment arms.

Among the patient population, the median age was 39 (IQR, 33-46) years, 54.0% were women, 69.0% were Black, the median BMI was 23.0 (IQR, 20.3-26.8) kg/m², and 65.6% had a viral load between 500 and 49,000 copies/mL. Data captured from 726 patients showed 51% had intermediate or high-level TDF resistance and 92% had high-level NRTI resistance.

The rate of virologic suppression at 96 weeks was 76.1% in patients who received DRV/r+2NRTIs, 85.7% in those who received DTG+DRV/r, and 81.6% in those who received DTG+TDF/XTC. Compared with patients who received DRV/r+2NRTIs, the rate of virologic suppression was significantly higher in those who received DTG+DRV/r (difference, 9.6%; 95% CI, 2.7-16.4; P =.01) and those who received DTG+TDF/XTC (difference, 9.0%; 95% CI, 1.4-16.6; P =.02).

In a subset of patients (n=139) with baseline viral loads above 100,000 copies/mL, virologic suppression was achieved by 80.5% of those who received DRV/r+2NRTIs, 76.9% of those who received DTG+DRV/r, and 63.0% of those who received DTG+TDF/XTC. Overall, there were no significant differences across treatment arms (stage 1+2, P =.89; stage 2, P =.23) and the findings met prespecified noninferiority criteria.

The multivariable analysis indicated virologic failure was less likely to occur with DTG+DRV/r than with DRV/r+2NRTIs (adjusted odds ratio [aOR], 0.3; 95% CI, 0.1-0.6; P =.001), including in patients with intermediate or high-level baseline TDF resistance (aOR, 0.5; 95% CI, 0.3-0.8; P =.006).

In regard to safety, the researchers noted 40, 24, and 30 serious adverse events across the DRV/r+2NRTIs, DTG+DRV/r, and DTG+TDF/XTC treatment arms, respectively. They also noted 11 total deaths across these arms (6, 2, and 3, respectively), though none were considered related to treatment. Moreover, 2 DRV/r+2NRTI recipients, 2 DTG+DRV/r recipients, and 5 DTG+TDF/XTC recipients showed DTG resistance.

Study limitations include the addition of a third treatment arm after enrollment began, the reliance on self-reported outcomes, and the inability to detect low-level emergent resistance.

The researchers concluded, “[W]eek-96 findings from D²EFT demonstrated sustained virological efficacy, immunological recovery, safety and tolerability of two DTG-based second-line regimens, DTG+DRV/r and DTG+TDF/XTC, following NNRTI-based first-line failure.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

By Jessica Nye, PhD

References:

Nyein PP, Borok M, Eriobu N, et al; on behalf of the DEFT Study Team. A randomised trial to compare dolutegravir plus boosted darunavir versus recommended standard of care antiretroviral regimens in people with HIV-1, whose first-line non-nucleoside reverse transcriptase inhibitor therapy has failed: final 96-week results of the D²EFT study. Clin Infect Dis. Published online June 27, 2025. doi:10.1093/cid/ciaf346