tnf inhibitors to reduce mortality in hiv-1 infected patients with tuberculosis meningitis

Conditions: Tuberculous Meningitis; HIV I Infection

Summary: randomized phase ii clinical trial which aims to assess the impact on 3-month mortality and safety of adding adalimumab to standard treatment (anti-tuberculosis drugs and corticosteroids) in hiv patients with tuberculosis meningitis in 3 countries (brazil, mozambique, and zambia).

phase ii multicenter, open-label, randomized, proof of concept, comparative trial with a large alpha (type 1 error rate) to evaluate the impact on 3-month mortality of adding the tumor necrosis factor inhibitor adalimumab to the standard treatment with antituberculosis drugs and high-dose steroids in hiv-infected adults diagnosed with tuberculosis meningitis (tbm) in 3 countries (brazil, mozambique, and zambia). all hiv1-infected patients diagnosed with tbm will be started on standard tb therapy for the duration recommended by national guidelines (2 months intensive phase and 7 months maintenance phase) and high-dose dexamethasone up to 4 weeks. as soon as possible during the first 3 days of the standard tbm treatment that includes antituberculosis treatment and high-dose steroids, consenting patients will be randomized to standard treatment alone or standard treatment + adalimumab. randomization will be stratified on country and initial severity using the british medical research council (mrc) score. adalimumab arm: * standard tbm treatment as described above * adalimumab 40 mg: one sub-cutaneous injection, every 2 weeks for 10 weeks (total 6 injections), started as soon as possible during the first 3 days of antituberculosis treatment and high-dose steroids as world health organization and national guidelines for early antiretroviral therapy (art) introduction in patients with tbm advise caution, art will be started after 4 weeks of tb treatment in both arms if patients are clinically improved (but no later than 8 weeks of anti-tb treatment). an interim analysis will be performed after 20 patients have been followed up for 3 months in adalimumab arm. this interim analysis will monitor the safety of adding tnf-inhibitor adalimumab.

Eligibility criteria:
inclusion criteria: * age ≥18 years * hiv-1 infection * art-naïve or art discontinued for at least 6 months * definite or probable tuberculosis meningitis * standard tuberculosis meningitis treatment ≤3 days: anti tb drugs at standard doses and high-dose dexamethasone as per who guidelines * signed informed consent form by patient or relative. exclusion criteria: * other concomitant neurological infection, i.e. toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, bacterial meningitis, neuro-syphilis * asymptomatic positive cryptococcal antigen in serum * hiv-2 infection (single or dual) * hbsag positive or anti hepatitis c virus antibodies positive * alanine transaminase (alt)\>5 uln * rifampicin-resistant tb detected by genexpert mtb/rif ultra * history of previous tb treatment in patients with genexpert mtb/rif ultra negative or unavailable * current use of drugs contraindicated with study drugs and that cannot be safely stopped * allergy to study drugs or any of their components * uncontrolled opportunistic infection * moderate to severe cardiac insufficiency (nyha classes iii / iv) * any condition which might, in the investigator's opinion, compromise the safety of treatment and/or patient's adherence to study procedures * for women of childbearing age: 1) pregnancy or breastfeeding; 2) refusal to use effective contraception to be discussed with the investigator * subjects participating in another clinical trial evaluating therapies and including an exclusion period that is still in force during the screening phase * person under guardianship, or deprived of freedom by a judicial or administrative decision * positive sars cov-2 test (according to hospital procedures at the time of inclusion)