Immunotherapy With Baricitinib and Sirolimus, Alone and in Combination, for the Control of HIV-1 Replication After Antiretroviral Treatment Interruption

This phase II multicenter, multi-stage, randomized, double-blind, placebo-controlled, adaptive clinical trial will evaluate the effect of baricitinib and sirolimus, alone and in combination, on viral control following an analytical treatment intervention (ATI).

The trial will follow an adaptive multi-arm multi-stage (MAMS) design. It will be divided into three stages, two interim stages and one final stage. Recruitment in any arm may be stopped early if, in the opinion of the Independent Data Monitoring Committee (IDMC), an experimental arm is considered to have insufficient efficacy or for safety reasons. The final sample size and study duration will depend on how many arms are continued beyond the interim analyses

Participants will be randomized 1:1:1:1 to either one of 4 arms:

• Arm 1: baricitinib + placebo of sirolimus
• Arm 2: sirolimus + placebo of baricitinib
• Arm 3: baricitinib + sirolimus
• Arm 4: placebo of baricitinib + placebo of sirolimus

Inclusion criteria

• Age ≤ 18 years and ≥ 65 years,
• Weight ≥ 50 kg and ≤ 100 kg,
• HIV-1 infection having been diagnosed at primary infection stage with an HIV-1 RNA VL > 1,000 copies/mL and either a negative or incomplete WB [0-5] bands or IB [0-3] bands and/or a previous negative HIV-1 ELISA within the past 3 months,
• Having initiated ART within 2 months of primary HIV-1 infection diagnosis,
• Having received ART continuously without interruption,
• Receiving ART for at least 1 year prior to enrollment,
• Receiving DTG-, BIC-, RAL-, or RPV-based ART (PI-, EVG/c-, NVP-, EFV-, ETR- or DOR-based ART must have been switched to DTG-, BIC-, RAL-, or RPV-based ART at W-8).
• Sustained HIV-1 plasma viral load ≤ 50 copies/mL for ≥ 6 months prior to enrollment (with at least two measurements, including the screening value),
• Blood CD4 T-cell count ≥ 500 cells/µL (on the last two measurements, including screening),
• Willing to interrupt ART for ATI and change ART regimen before if required to avoid drug-drug interactions,
• Willing to take valaciclovir 500 mg QD from W0 to W10 to prevent recurrence of herpes or herpes zoster,
• If sexually active, willing to use a reliable method of reducing the risk of transmission to their sexual partners during treatment interruption (condoms or PrEP for their sexual partners).
• If able to have children, willing to use a highly effective method of contraception (combined oral contraceptive pill; implanted contraceptive device, IUD/IUS; physiological or anatomical sterility for self of partner); willing to undergo blood bHCG at screening and before ATI.
• Willing to comply with visit schedule and provide blood samples according to the protocol.
• Written informed consent (at the latest on the day of the enrollment visit and before any exams to be performed in the context of the trial) (article L1122-1-1 of the French CSP).
• Participant covered by Health Insurance (article L1121-11 of the French CSP).

Exclusion criteria

• HIV-2 infection,
• Previous interruption of ART,
• Loss of virologic suppression (VL > 200 c/mL) at any time while on effective ART; previous blips of VL between 50 and 200 c/mL allowed, except in the 6 months prior to screening,
• Long-acting ART based on CAB/RPV, lenacapavir, islatravir, or ibalizumab,
• Receiving PI-, EVG/c-, NVP-, EFV-, ETR- or DOR-based ART beyond W-8,
• No other active ARV regimen in addition to the current one,
• Pregnant or lactating woman,
• Woman expecting to conceive during the trial period,
• Any medical condition that will contraindicate an interruption of ARV treatment,
• History of coronary artery disease, stroke, or blood clots; thrombophilia,
• High cardiovascular risk (SCORE2 ≥ 7.5% if < 50 years, or ≥ 10% if 50-65 years),
• Active cancer or history of cancer,
• Active opportunistic infection,
• Active or latent tuberculosis (unless prophylaxis has been received in the past); participant must be screened for latent tuberculosis according to routine practice prior to initiation of immunotherapeutic interventions,
• Chronic hepatitis B (positive HBs antigen and/or positive HBV DNA) or past-hepatitis B infection (positive anti-HBc antibodies) or hepatitis C (positive HCV RNA); cirrhosis,
• Treatment with systemic corticosteroids or immunosuppressants currently or within 12 weeks prior to study randomization,
• History of experimental vaccination against HIV,
• Ongoing treatment with strong CYP3A4 inducers or inhibitors,
• History of hypersensitivity to macrolides.

Laboratory parameters at screening:

• Polynuclear neutrophils <1 G/L; Hemoglobin <10 g/dL; Platelets <100 G/L
• GFR <30 ml/min/1.73m2
• TP <50%; ALAT/ASAT >5x ULN; Bilirubin >3x ULN