Tnf Inhibitors to Reduce Mortality in HIV-1 Infected PAtients With Tuberculosis meNIngitis

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.

• 3-month incidence of severe/life threatening bacterial infections and opportunistic infections [Срок оценки: 3 months]
• 3-month incidence of grade 3 and 4 adverse reactions and those leading to ART or anti tuberculosis treatment (ATT) interruption [Срок оценки: 3 months]
• 3-month incidence of all grade 3 and 4 adverse events [Срок оценки: 3 months]
• 9-month and 12-month all-cause mortality [Срок оценки: 9 months and 12 months]
• 9-month disability free survival (using Rankin score) [Срок оценки: 9 months]
• 3-month and 9-month incidence of all grade infectious diseases and opportunistic infections [Срок оценки: 3 months and 9 months]
• 9-month neurological disability score (Rankin score) [Срок оценки: 9 months]
• Time to and severity of TB-associated paradoxical immune reconstitution inflammatory syndrome (IRIS) between D0 and 9 months [Срок оценки: up to 9 months]
• Time to discharge [Срок оценки: up to 9 months]
• Cerebrospinal fluid (CSF) pleocytosis/protein/glucose levels at W0, W1 and W4 [Срок оценки: week 0, week1 and week4]
• CSF mycobacterial cultures negativation (culture conversion), time to culture positivity and cycle threshold (GeneXpert Mycobacterium tuberculosis/Rifampicin Ultra) at W1, W4, [Срок оценки: week1 and week4]
• Proportion of patients with HIV-1 RNA<50 copies/mL at 9 months [Срок оценки: 9 months]