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

Prior treatment

• Current or recent (<12 weeks before randomization) systemic corticosteroids, immunosuppressants, immunomodulators, or continuous NSAID treatment; history of anti-CD20 antibody treatment at any time;
• Vaccination within the previous 30 days or planned during immunotherapy;
• Previous experimental HIV vaccination ;
• Treatment with CYP3A4 and/or P-gp inducer or inhibitor or any medication affecting hepatic metabolism of investigational treatments within 2 weeks before randomization;
• Ongoing treatment at W0 with: o Gastrointestinal motility stimulants such as metoclopramide; o Potent OAT3 inhibitors (e.g., probenecid); o Cimetidine (interaction risk with valaciclovir); o Cannabidiol (interaction risk with sirolimus);
• Virological failure (VL >200 copies/mL confirmed on second sample) in treatment history. One isolated blip between 50 and 200 copies/mL is allowed within 6 months before pre-inclusion if controlled within 15 days with follow-up VL <50 copies/mL;

Other illness

• Participant unlikely, in the investigator’s opinion, to comply with study procedures or whose health condition is incompatible with participation;
• History of coronary artery disease, stroke, venous or arterial thrombosis, thrombophilia, or other venous thromboembolic risk factors (combined estrogen-progestin contraception allowed);
• Active opportunistic infection ;
• History of HIV-associated dementia or progressive multifocal leukoencephalopathy;
• Active or latent tuberculosis (except participants treated for latent TB); latent TB screening required at pre-inclusion;
• Chronic hepatitis B (HBsAg+) or past HBV infection (isolated anti-HBc+ without anti-HBs) or chronic hepatitis C (HCV RNA+); cirrhosis of any cause;
• HIV-2 infection ;
• History of solid organ transplantation or bone marrow transplantation;
• History of macrolide allergy;
• Hypersensitivity to sirolimus, baricitinib, valaciclovir, acyclovir, or any excipient;
• History of ART interruption ;
• History of CD4 nadir <200 cells/µL;

Lab values

• Rare hereditary problems of fructose or galactose intolerance, glucose-galactose malabsorption, sucrase-isomaltase deficiency, or Lapp lactase deficiency;
• Pre-inclusion laboratory abnormalities: o Neutrophils <1 G/L; hemoglobin <10 g/dL; platelets <100 G/L; o eGFR <30 mL/min/1.73m² ; o Prothrombin time <50%; ALT/AST >5× ULN; bilirubin >3× ULN.

Age

• High cardiovascular risk (SCORE2 >7.5% if <50 years or >10% between 50 and 65 years);
• Active cancer or history of cancer (except carcinoma in situ, basal cell or squamous cell skin cancer, or localized cancer cured by surgery alone >5 years previously); history of chemotherapy or radiotherapy;

Other

• Pregnant or breastfeeding woman;
• Woman planning pregnancy during the trial period;
• History or comorbidity contraindicating ART interruption;
• Persons benefiting from State Medical Aid (AME);
• Persons under guardianship or deprived of liberty by judicial or administrative decision (unless justified);
• Participation in another interventional study during participation period (observational study without blood sampling allowed);
• Long-acting ART with CAB/RPV, lenacapavir, islatravir, or ibalizumab;
• Intermittent ART (4–5 days/week);
• ART regimen including PI, EVG/c, NVP, EFV, ETR, or DOR after W-8;
• No alternative antiretroviral treatment option other than current regimen;

• Participant able to understand and sign consent;
• Current ART regimen based on DTG, BIC, RAL, or RPV combined with one or more NRTIs, or DTG/RPV dual therapy. Regimens including PI, EVG/c, NVP, EFV, ETR, or DOR must have been switched to DTG, BIC, RAL, or RPV by W-8;
• Blood CD4 T-cell count ≥500 cells/mm³ (on the two most recent measurements including pre-inclusion);
• Willing to undergo analytical treatment interruption and, if necessary, ART modification before immunotherapy to avoid drug interactions;
• Willing to take one tablet daily of valaciclovir 500 mg from W0 to W10 for prevention of herpes or shingles recurrence;
• Willing to use a reliable HIV transmission risk reduction method with sexual partners (condoms or partner PrEP) during ATI and until HIV-1 VL becomes undetectable again;
• For participants assigned female at birth and of childbearing potential*: willing to β-HCG testing at pre-inclusion, W0, then at least monthly until the last visit: o If heterosexually active: willing to use highly effective contraception from W0 until 12 weeks after stopping immunotherapy and during ATI; o Willing not to seek pregnancy, including via assisted reproductive technologies, until 12 weeks after stopping immunotherapy;*Persons assigned female at birth and of childbearing potential are defined as cisgender women and transgender men with a uterus and functioning ovaries.
• For participants assigned male at birth, if heterosexually active: willing to use condoms or ensure partners use effective contraception (and PrEP to prevent HIV transmission in case of viral rebound) from W0 until 12 weeks after stopping immunotherapy. Male participants also agree not to donate sperm during this period;
• Willing to comply with the visit schedule and blood sampling procedures;
• Covered by social security insurance.
• Written informed consent signed by participant and investigator before any study-related procedure;
• Age ≥18 and ≤65 years;
• Weight ≥50 kg and ≤100 kg ;
• HIV-1 infection diagnosed during primary infection with HIV-1 VL >1000 copies/mL and negative or incomplete WB or IB (WB [0–5] bands or IB [0–3] bands) and/or negative HIV-1 ELISA serology within the previous 3 months;
• ART initiated within 2 months following diagnosis of primary HIV-1 infection;
• Continuous ART without interruption ;
• ART for ≥1 year before pre-inclusion (treatment changes allowed except for virological failure);
• HIV-1 VL <50 copies/mL for ≥6 months before pre-inclusion (with at least two measurements <50 copies/mL, including pre-inclusion). One blip between 50 and 200 copies/mL is allowed, including at pre-inclusion, if controlled within 15 days with follow-up VL <50 copies/mL;