Determination of Adequate Tuberculosis Regimen in Patients Hospitalized With HIV-associated Severe Immune Suppression
Determination of Adequate Tuberculosis Regimen in Patients Hospitalized With HIV-associated Severe Immune Suppression
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: 4 African (Cameroon, Guinea, Uganda, Zambia) and 2 South-East Asian (Cambodia,
 Vietnam) 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.
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 3 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

 -  History of ART, unless if stopped for more than 1 year

 -  Current treatment with ART for more than 1 week

 -  Any contraindication to efavirenz and dolutegravir

 -  Severe associated diseases requiring specific treatment (including all specific AIDS
 defining illnesses other than TB and any severe sepsis)

 -  Impaired hepatic function with ALT (SGPT) > 5 times the upper limit of normal (ULN)
 value

 -  Creatinine clearance < 50 mL/min (according to the Cockcroft-Gault formula)

 -  Pregnancy or breastfeeding