HIV treatment switch trial offers new insights into options after first-line ART failure

Important new findings from a head-to-head antiretroviral therapy (ART) switch study challenge some of our assumptions regarding the optimal approach to second-line HIV treatment. They also offer us a more expansive view of the options we (and our patients) may have at our disposal when deciding how to move forward from viral nonsuppression on first-line therapy, especially in scenarios where genotypic resistance test results are unavailable.

Highlighted Study Population and Methods

D²EFT was a multicenter, open-label, randomized noninferiority trial, initially two‑armed and later expanded to three arms. The study was conducted across 14 low- and middle-income countries in Africa, Asia, and Latin America.

The study enrolled 826 people living with HIV who were experiencing confirmed virological failure on first-line NNRTI-based ART (HIV‑RNA >1,000 copies/mL), with no prior exposure to protease or integrase inhibitors.

Participants were randomized to three groups:

• Standard of care (SOC): Ritonavir‑boosted darunavir + 2 NRTIs (guided by genotyping or WHO algorithm).

• Dual ART regimen: Darunavir/r (DRV/r) + dolutegravir (DTG).

• Dolutegravir + recycled NRTIs (tenofovir + lamivudine/emtricitabine; this arm was added after initial enrollment).

The primary endpoint was the proportion achieving HIV‑RNA < 50 copies/mL at 48 weeks; follow-up data extended to 96 weeks.

Key Findings

There were many noteworthy data points within the 96-week results:

• Viral Suppression (<50 copies/mL):

  • SOC: 76.1%

  • DRV/r + DTG: 85.7% (+9.6%, 95% CI 2.7–16.4)

  • DTG + recycled NRTIs: 81.6% (+9.0%, 95% CI 1.4–16.6)

• Resistance Profile:

  • No darunavir resistance detected.

  • DTG resistance emerged in 3/27 failures on the DTG + recycled NRTI arm, none in DRV/r + DTG arm.

• Immunological Response:

  • CD4 cell increase significantly larger in both DTG arms compared to SOC. For example: median +174 cells/mm³ for DRV/r versus +130 cells/mm³ for SOC (p<0.001).

• Weight Gain:

  • Greater mean weight/BMI increase in DTG‑based arms (~5–6 kg vs 3.2 kg in SOC).

• Safety:

  • 11 deaths (5 in the DTG arms; none of the 11 were deemed drug-related).

  • Few grade 3/4 lab abnormalities were attributed to the study drugs.

  • Comparable discontinuation rates across arms.

  • 33 pregnancies occurred (26 in the DTG arms), all of which had no congenital anomalies.

Read an expert analysis from Benjamin Young, M.D., Ph.D. at TheBodyPro.