Immunotherapy with a JAK1/JAK2 inhibitor (baricitinib) and an mTORC1 inhibitor (sirolimus), alone and in combination, for the control of HIV-1 replication after antiretroviral treatment interruption: a phase II multicenter, multi-arm, multi-stage, randomized, double-blind, placebo-controlled, adaptative trial

HIV-1 Infection

Time from treatment interruption to ART resumption, either because of a viral rebound or because of a clinical decision to restart ART because of a CD4 T cell decline, a clinical adverse event, or for any other reason, evaluated at W26 visit.

Time to treatment resumption due to CD4 T-cell decline or immunotherapy-related adverse events., Adverse events related to baricitinib and sirolimus (clinical and biological grade 3 or higher AEs according to DAIDS, serious adverse events); Treatment discontinuation rate; Time to immunotherapy discontinuation., Changes in CD4 and CD8 T-cell counts between W0 and W10, between W10 and W26, and between W26 and W50;Incidence of confirmed CD4 decline <300 cells/µL or <15%., Post hoc analysis of sirolimus concentrations and their relationship with safety and efficacy endpoints., Time to treatment resumption due to virological rebound., Time between treatment interruption and first occurrence of VL ≥1000 copies/mL, Proportion of participants with VL <50 or <400 copies/mL at W10, W26, and W50; Viral load AUC during ART interruption until treatment resumption., Proportion of participants with VL <50 or <400 copies/mL at W10, W26, and W50 after transient rebound., Proportion of participants with VL <50 or <400 copies/mL at W10, W26, and W50 among those who discontinued immunotherapy before W10 (due to intolerance) but did not resume ART., Changes in total and intact HIV-1 DNA levels, cell-associated HIV-1 RNA in PBMCs, and residual plasma viral load between W0 and W10 and between W10 and W26., Susceptibility of CD4 T cells to ex vivo HIV infection and sensitivity to latency reversal agents between W0 and W10 and between W10 and W26., Time to ART resumption due to virological rebound according to biological sex., Time to ART resumption due to virological rebound according to the third agent used before ATI (INSTI vs NNRTI)., Changes in frequency, phenotype, and function of blood T lymphocytes between W0 and W10 and between W10 and W26., Changes in frequency, phenotype, and function of NK cells in blood between W0 and W10 and between W10 and W26., Changes in frequency, phenotype, and function of myeloid cells (monocytes, dendritic cells) in blood between W0 and W10 and between W10 and W26., Quantitative and qualitative indicators regarding perceptions of cure trials, motivations, fears (rebound, transmission, placebo), and their evolution between W-4, W2, W26, treatment resumption, and W50/W24 after resumption., Reported reasons for participation, refusal, or withdrawal (expectations, fears, constraints, relationship to HIV, healthcare, personal context); Elements of the decision-making process (information, hesitations, discussions); Descriptive comparisons between groups; Typologies derived from qualitative interview analyses and open-ended responses., Changes in WHO-5, GAD-2, PHQ-2, and perceived health scores across protocol time points (pre-inclusion, W2, W26, treatment resumption, end of trial) and associated factors; Participation satisfaction level and associated factors., Self-reported assessments of ATI experience (fears, constraints, anxiety), modalities and understanding of treatment resumption, associated emotions; Evolution of prevention behaviors from start to end of follow-up., Quantitative and qualitative analyses of changes in trial perceptions, benefit/risk assessment, ethical issues, and decision-making processes.

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