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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,330
8 weeks of RHEZ with high dose of rifampicin (R) and isoniazid (H). Fixed dose combination (FDC) of RHZE with the addition of FDC of RH and single caps of R. 6 weeks of prednisone with tapering doses. 3 days of albendazole 400 mg.
8 weeks of RHEZ with FDC.
National Center for HIV/AIDS, Dermatology and STD (NCHADS)
Phnom Penh, Cambodia
Jamot Hospital
Yaoundé, Cameroon
Ignace Deen Hospital
Conakry, Guinea
MACHAVA Hospital
Maputo, Mozambique
Mbarara Regional Referral hospital
Mbarara, Uganda
University Teaching Hospital
Lusaka, Zambia
Rate of all causes death
Number of deaths between the inclusion visit and week 48, divided by the total person-years of follow-up until week 48
Time frame: Up to 48 weeks
Rate of all causes death
Death for any cause at week 8 will be calculated as the number of deaths between the inclusion visit and week 24, divided by the total person-years of follow-up during the same period
Time frame: Up to 8 weeks
Rate of all causes death
Death for any cause at week 24 will be calculated as the number of deaths between the inclusion visit and week 24, divided by the total person-years of follow-up during the same period
Time frame: Up to 24 weeks
Rate of adverse events
Number of serious adverse events, all grade 3-4 adverse events (using the DAIDS tables), and any grade 2 adverse events of interest (e.g., hepatotoxicity, rash, peripheral neuropathy, thrombocytopenia, neuropsychiatric disorders), between the inclusion visit and week 48, divided by the total person-years of follow-up during that period
Time frame: Up to 48 weeks
Rate of AIDS-defining illnesses
Number of AIDS-defining illnesses according to the WHO clinical staging table
Time frame: Up to 48 weeks
Rate of paradoxical TB-associated IRIS
Number of paradoxical TB-associated IRIS according to the definition of the international network for the study of HIV-associated (INSHI) consensus case definition
Time frame: Up to 14 weeks
Rate of TB treatment success
The percentage of patients with TB success will be calculated as the number of patients who are cured or who have completed TB treatment, as defined by WHO, divided by the total number of randomized patients
Time frame: Up to 24 weeks
Rate of TB recurrence
The number of patients with TB recurrence divided by the total number of randomized patients with TB treatment success at week 24
Time frame: Up to 48 weeks
Rate of virological success
The percentage will be calculated as the number of patients with HIV RNA \<50 copies/mL divided by the total number of randomized patients.
Time frame: Week 24
Rate of virological success
The percentage will be calculated as the number of patients with HIV RNA \<50 copies/mL divided by the total number of randomized patients.
Time frame: Week 48
Adherence to TB and ART treatment
The proportion of days with perfect adherence divided by the total number of days of treatment
Time frame: up to 24 weeks
Immunological response
The mean CD4 cell count gain (with 95% confidence interval) will be calculated as the difference of CD4 cell count between pre-inclusion and week 48
Time frame: Up to 48 weeks
Plasma concentrations of rifampicin and isoniazid
Determined 2 hours after the TB drugs intake at day 3, day 7 and week 2 in a subset of 20 patients per arm per country
Time frame: Up to 2 weeks
Plasma concentrations of efavirenz and dolutegravir
Determined 12 hours after the drugs intake at week 4 (i.e. 2 weeks after the onset of ART) in a subset of 60 patients per arm for efavirenz and 60 patients per arm for dolutegravir
Time frame: Week 4
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