DEFINE: A Prospective, Randomized, Phase 4 Trial to Assess a Protease Inhibitor-Based Regimen Switch Strategy to...

Area of Science:

• Infectious Diseases
• Virology
• Pharmacology

Background:

• Integrase strand transfer inhibitor (INSTI)-based antiretroviral (ARV) therapies are linked to increased weight gain in people with human immunodeficiency virus (HIV).
• Protease inhibitor (PI)-based regimens have been associated with less weight gain compared to INSTI-based therapies.

Purpose of the Study:

• To investigate if switching from an INSTI-based to a PI-based ARV regimen can mitigate or reverse weight gain in adults with HIV.
• To evaluate the impact of switching ARV therapy on body weight and metabolic parameters.

Main Methods:

• A 48-week, randomized, open-label, phase 4 study (DEFINE; NCT04442737) involving virologically suppressed adults with HIV-1 experiencing weight gain.
• Participants either switched immediately to darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) or continued INSTI + emtricitabine/tenofovir alafenamide (FTC/TAF) before switching at week 24.
• Primary endpoint: percent weight change from baseline to week 24.

Main Results:

• No significant difference in weight change was observed at week 24 between the immediate switch (0.63%) and continued INSTI groups (-0.24%).
• A trend toward weight loss was observed from baseline to week 48 after switching to D/C/F/TAF (-0.36%), particularly in female and Black/African American participants.
• Metabolic endpoints mirrored weight changes; D/C/F/TAF was well-tolerated with comparable virologic efficacy.

Conclusions:

• Switching to a PI-based regimen (D/C/F/TAF) did not result in significant weight change at 24 weeks.
• A trend toward weight loss emerged with longer duration post-switch, suggesting ARV selection may play a role in weight management for people with HIV.
• Further investigation into ARV selection and switching strategies for weight management is warranted.