Analytical treatment interruption as a tool in the evaluation of immune-mediated interventions for long-term antiretroviral-free control of HIV-1 among people with HIV

Abstract

Background: Immune-mediated interventions have the potential to induce long-term antiretroviral treatment (ART)-free viral suppression in people with HIV. However, in the absence of biomarkers of viral control, studies looking at immune interventions require a planned long term analytical treatment interruption (ATI) that may bring risks to participants and challenges for data interpretation. Herein, we describe an ongoing, global, proof-of-concept, randomized, placebo-controlled, phase-2 clinical trial with a planned ATI and illustrate how those risks have been mitigated to safely evaluate the long-term durability of ART-free viral control.

Methods: The trial evaluates an immunologic combination of low-dose budigalimab and trosunilimab administered during ATI. Adults aged 18-70 with confirmed HIV-1 on stable ART with viremia below the limit of detection and CD4+ counts >500 cells/mL willing to undergo ATI are randomized to receive budigalimab, trosunilimab, both (at 2 different trosunilimab doses), or neither. The primary efficacy endpoint is the proportion of participants achieving viral control (HIV-1 RNA <1000 copies/mL) without restarting ART at week 24. The planned ATI duration (≤112 weeks) evaluates the durability of off-ART viral control, long-term safety, and biomarkers. Key ATI elements align with published consensus recommendations [1] while incorporating feedback from members of the global HIV community.

Conclusions: By sharing this study design, we hope to inform on the lessons learned from operationalizing a global study evaluating durable ART-free viral control, including the critical role of engaging members of the HIV community during clinical trial design to ensure the success of an ATI-inclusive study.

Keywords: Analytical treatment interruption; Antiretroviral treatment; Budigalimab; HIV community; HIV-1; People with HIV; Protocol; Trosunilimab.