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

Background. Analytical 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. Methods. We 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. Results. Comparison 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. Conclusions. Our 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Investissements d Avenir program managed by the ANR under reference ANR-10-LABX-77-01 (VRI - Vaccine Research Institute) and by the European Unions Horizon 2020 research and innovation program under grant agreement No. 681032 (EHVA). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The paper included data from three distinct clinical trials. The protocol of VRI02 ANRS 149 LIGHT trial ([NCT01492985][1]) was approved by the ethics committee of Ile de France 5 (Paris-Saint-Antoine) and authorized by the French regulatory authority (ANSM). The ANRS/VRI DALIA trial ([NCT00796770][2]) was sponsored by the Baylor Institute for Immunology Research and the Agence Nationale de Recherches sur le SIDA et les hepatites (INSERM ANRS), and the protocol was approved by the IRB of Baylor Research Institute (BRI). The protocol of the ANRS 118 ILIADE trial ([NCT00071890][3]) was approved by the ethics committee of the Hospital Henri Mondor and the National Institute of Allergy and Infectious Diseases (NIAID). All participants provided written informed consent before participation. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding author (Pr Rodolphe Thiebaut, rodolphe.thiebaut@u-bordeaux.fr), upon reasonable request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01492985&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F26%2F2024.01.26.24301813.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00796770&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F26%2F2024.01.26.24301813.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00071890&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F26%2F2024.01.26.24301813.atom