Prevention of Early Mortality by Presumptive Tuberculosis (TB) Treatment

Study Overview
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Brief Summary
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This study investigates the prevention of early mortality in patients initiating antiretroviral therapy (ART) in sub-Saharan Africa where 79% of the co-infected cases of TB reside. Many published studies have shown a surprisingly high proportion of all patients initiated on ART dying within 6 months (8-26%) with increasing risk with decreasing CD4 T cell count. The majority (median 70%) occur in the first 3 months with the greatest proportion of deaths due to previously undiagnosed tuberculosis (TB). The investigators will enroll patients from 4 geographically diverse countries (Gabon, Mozambique, South Africa, and Uganda) in a randomized open label clinical trial targeting a population of people with high mortality risk; patients with CD4 T cell count < 50 cells/μl and body mass index (BMI) < 18 kg/m2. Severely immunocompromised patients with low BMI in the intervention arm will receive presumptive anti-TB 4-drug chemotherapy and subsequently initiate ART within 2 weeks compared to ART alone. The main objective is to measure and compare early mortality in the group presumptively treated for TB in addition to ART. Other sub-objectives are to determine the predictors of early mortality and the causes of death by autopsy (traditional and verbal), to determine if presumptive anti-TB treatment affects viral suppression with ART, and to assess incidence rates and characterize drug toxicity in patients dually treated. Because of the high rates of TB co-infection in sub-Saharan Africa in the HIV-infected, the investigators expect that patients presumptively treated for TB in addition to HIV will have a lower mortality rate than patients receiving ART only. This trial is expected to be of great public health benefit and generalisability.

Official Title
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Prevention of Early Mortality by Presumptive TB Treatment in HIV-infected Patients Initiating Antiretroviral Therapy

Conditions
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HIV Infection, Tuberculosis

Intervention / Treatment
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* Drug: Experimental: Empiric TB treatment
* Drug: ART only arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged > 18 years old HIV-1 positive Eligible for antiretroviral treatment with CD4 T cell count < 50 cells/μl BMI < 18 Exclusion Criteria: Patients with smear-positive pulmonary TB Patients who fulfill the diagnostic criteria for smear-negative pulmonary or extrapulmonary TB (http://www.who.int/tb/publications/2006/tbhiv_recommendations.pdf ). Previous TB treatment (history of TB medication for > 1 month History of using antiretroviral drugs Symptomatic known underlying liver disease or transaminases > 5x upper limit of normal Known or suspected drug resistance to more than one first-line TB drug according to WHO criteria but excluding HIV infection (e.g. household contacts of MDRTB patients) Pregnant or breast-feeding Patients with cryptococcal meningitis (CrAG positive with neurologic symptoms) Patients with other severe (opportunistic) disease such as disseminated KS, malignant lymphoma, toxoplasmosis who may not be able to tolerate anti-TB medication or require other specific therapy Patients with danger signs (respiratory rate > 30 per minute, heart rate > 120bpm, temperature > 39oC, and unable to ambulate) Taking other potentially life-saving medications (e.g. for other OIs, or immunosuppressants) that are incompatible with anti-TB chemotherapy or ART Unable to swallow TB medications Unable to follow-up at the clinic for regularly scheduled follow-up (e.g. too far from clinic)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empiric TB treatment<br>Empiric initiation of 4 drug TB treatment (8 weeks of 4 drug, 16 weeks of 2 drug therapy) followed by ART (efavirenz-based) within 2 weeks | Drug: Experimental: Empiric TB treatment<br>* Initiation of 4 drug TB treatment (8 weeks of 4 drug, 16 weeks of 2 drug therapy) followed by ART (efavirenz-based) within 2 weeks<br>|
| Active Comparator: ART only arm<br>ART (efavirenz-based) only (+ pyridoxine 50mg) given within 2 weeks after enrolment | Drug: ART only arm<br>* ART (efavirenz-based) only (+ pyridoxine 50mg) given within 2 weeks after enrolment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality in the first 24 weeks after initiation of ART |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD4 T cell absolute increase |  | 24 weeks | 
| Causes of death |  | 24 weeks | 
| Safety and tolerability of anti-tuberculous medications |  | 24 weeks | 
| HIV viral suppression |  | 24 weeks | 
| TB incidence rates after ART initiation |  | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TB