Lessons learned from HIV antiretroviral treatment interruption trials

Abstract

Clinical trials with an antiretroviral therapy (ART) interruption remains indispensable for assessing strategies for ART-free HIV remission. This review highlights the lessons learned from ART interruption studies so far, including the risks to the participants and implications for HIV remission. Historically, analytic HIV treatment interruption (ATI) studies were commonly designed with a prolonged duration of ART interruption and with viral load set point as the primary outcome. For a variety of reasons, including participant risk, recent treatment interruption trials have frequently used time to viral rebound as the primary endpoint and have restarted ART once a predetermined viral load threshold is reached. Through treatment interruption trials, investigators have tested the efficacy of therapeutic and curative strategies that showed promise in preclinical trials, including therapeutic vaccines, latency-reversing agents, and broadly neutralizing antibodies. In most populations, ATI trials have been well tolerated, with few adverse clinical events and no significant changes to the reservoir. Several reservoir predictors of HIV-rebound timing have been reported, with a subset of trials uncovering posttreatment controllers who can maintain HIV remission despite ART discontinuation. Treatment interruption trials are a vital tool, but their optimal design remain uncertain and must balance participant risks with scientific rigor. The ability to predict the timing or extent of HIV rebound and identify mechanisms of posttreatment control may accelerate the development of novel therapeutics for sustained HIV remission.