Definition of viroIogical endpoints improving the design of HIV cure strategies using analytical antiretroviral treatment interruption

BackgroundAnalytical treatment interruption (ATI) is the gold standard in HIV research to validate the ability of novel therapeutic strategies to long-term control viremia without antiretroviral treatment (ART). Viral setpoint is commonly used as endpoint to evaluate their efficacy. However, to mitigate higher viremia risk without ART, trials use short ATI phases and strict virological ART re-start criteria, compromising the observation of the setpoint. MethodsWe analyzed viral dynamics in 235 HIV-infected participants from three trials, examining various virological criteria during ATI phases. Time-related (e.g. time to rebound, peak and setpoint) and VL magnitude-related criteria (peak, setpoint and time-averaged AUC [nAUC]) were described. Spearman correlations were analyzed to identify surrogate endpoints for setpoints. Additional correlation analyzes were performed to identify optimal virological ART re-start criteria mitigating the risks of ART interruption and the evaluation of viral control. ResultsComparison of virological criteria between trials showed strong dependencies on ATI design. Similar correlations were found across trials, with nAUC identified as the criterion most strongly correlated with the setpoint, with correlations higher than 0.70. A threshold of at least 100,000 copies/mL for two consecutive VL measurements is requested as virological ART re-start criteria to keep strong correlations between the setpoint and nAUC. ConclusionsOur results emphasize the benefits of an ATI phase longer than 12 weeks, with regular monitoring, and a VL threshold of 100,000 copies/mL as virological ART re-start criteria to limit the risk for patients while capturing enough information to keep nAUC as an optimal proxy for the setpoint.