determination of adequate tuberculosis regimen in patients hospitalized with hiv-associated severe immune suppression

Conditions: Tuberculosis; HIV-1-infection; Immuno-Deficiency

Summary: datura trial is a phase iii, multicenter, two-arm, open-label, randomized superiority trial to compare the efficacy and the safety of an intensified tuberculosis (tb) regimen versus standard tb treatment in hiv-infected adults and adolescents hospitalized for tb with cd4 ≤ 100 cells/μl over 48 weeks: * intensified tb treatment regimen: increased doses of rifampicin and isoniazid together with standard-dose of pyrazinamide and ethambutol for 8 weeks in addition to prednisone for 6 weeks and albendazole for 3 days * who standard tb treatment regimen. the continuation phase of tb treatment will be identical in the two arms: 4 months of rifampicin and isoniazid at standard doses.

settings: 5 african (cameroon, guinea, uganda, zambia, mozambique) and 1 south-east asian (cambodia) countries. sample size : 1330 patients (665 in each arm). follow-up : 48 weeks after entry in the trial (tb treatment initiation). all participants will initiate antiretroviral therapy (art) 2 weeks after starting tb treatment. in each country, the chosen art regimen will be the same in both arms. according to the first-line regimen recommended in each country, the art combination will be tdf/3tc/efv 600 mg, or tdf/3tc + double-dose dtg. the primary objective is to estimate the impact of an intensified initial phase of tb treatment on mortality at 48 weeks among hiv-infected adults and adolescents hospitalized for tb with cd4 ≤ 100 cells/μl in comparison with standard tb treatment. the secondary objectives are to estimate the impact of an intensified initial phase of tb treatment, in comparison with the standard tb regimen, on: * mortality at weeks 8 and 24 * adverse events, including * all grade 3 and 4 events * selected grade 2 events of interest * drug-related adverse events * aids-defining illnesses * paradoxical tb-associated immune reconstitution inflammatory syndrome (iris) * tb treatment success * tb recurrence * art response in terms of virological success and immunological response * adherence to tb treatment and art * peak plasma concentrations of rifampicin and isoniazid (and its n-acetyl-metabolite) at day 3, day 7 and week 2 * plasma concentrations of efavirenz and dolutegravir at week 4 (i.e. 2 weeks after the onset of art). a pharmacokinetic sub-study of rifampicin and isoniazid will be carried out in 72 voluntary patients (6 patients/arm/country) at the second week of the main study.

Eligibility criteria:
inclusion criteria * patient (and legally designed representative of minor patient) able to correctly understand the trial and to sign the informed consent * aged ≥ 15 years * confirmed hiv-1 infection as documented at any time prior to trial entry per national hiv testing procedures * cd4 count ≤ 100 cells/μl * hospitalized for a newly diagnosed tb, defined by: * any positive xpert® mtb/rif specimen (sputum, urine, pus, other), * or a positive urine lipoarabinomannan (lam) test, * or an abnormal chest x-ray compatible with active tb exclusion critera * initiation of tb drugs for more than 7 days * history of tb treatment during the last 6 months * central neurological symptoms, including but not restrictive to tb meningitis * suspected tb pericarditis * documented mycobacterium tuberculosis strain resistant to rifampicin using rapid molecular testing (xpert® mtb/rif) * any concomitant medication or known hypersensitivity contraindicating any component of the tb treatment * hiv-2 co-infection * current treatment with art containing protease inhibitors * any contraindication to efavirenz and dolutegravir * severe associated diseases requiring corticosteroids or for which corticosteroids are contra-indicated * impaired hepatic function with alt (sgpt) \> 5 times the upper limit of normal (uln) value * creatinine clearance \< 30 ml/min/1.73m2 (according to either the mdrd or the ckd-epi formula) * pregnancy or breastfeeding

Keywords: tuberculosis hiv-1 mortality immuno-deficiency isoniazid rifampicin