Clinical trial NCT01417988: Prevention of Early Mortality by Presumptive Tuberculosis (TB) Treatment
Official title: Prevention of Early Mortality by Presumptive TB Treatment in HIV-infected Patients Initiating Antiretroviral Therapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: HIV Infection
Tuberculosis
Keywords: TB
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: European and Developing Countries Clinical Trials Partnership (EDCTP)
First posted: 2011-08-16
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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)

Primary outcomes:
measure: All-cause mortality in the first 24 weeks after initiation of ART
timeFrame: 24 weeks
Secondary outcomes:
measure: CD4 T cell absolute increase
timeFrame: 24 weeks
measure: Causes of death
timeFrame: 24 weeks
measure: Safety and tolerability of anti-tuberculous medications
timeFrame: 24 weeks
measure: HIV viral suppression
timeFrame: 24 weeks
measure: TB incidence rates after ART initiation
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Lambaréné
country: Gabon
facility: Medical Research Unit, Albert Schweitzer Hospital
city: Beira
country: Mozambique
facility: Ministry of Health -Provincial Heatlh Directorate of the Sofala Province (Direcção Provincial de Saúde de Sofala DPSS)
city: Kampala
country: Uganda
facility: Infectious Diseases Institute University Makarere
Study officials:
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Frank Cobelens
role: STUDY_DIRECTOR
affiliation: Infectious Diseases Institute at Makerere University
name: Yuka Manabe
role: PRINCIPAL_INVESTIGATOR
References: