A Prospective Study of Shortening the Duration of Standard Short Course Chemotherapy from 6 Months to 4 Months in HIV-non-infected Patients with Fully Drug-Susceptible, Non-cavitary Pulmonary Tuberculosis with Negative Sputum Cultures after 2 Months of Anti-TB Treatment
Information:
DMID Protocol Number: 01-009
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Type of Study |
Phase III Clinical Trial |
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Design |
Prospective randomized, open-label, Phase III clinical trial |
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Project Site |
Kampala, Uganda |
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Sample Size |
394 subjects |
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Population |
HIV-uninfected 18 to 60 year old adults with suspected or newly diagnosed pulmonary tuberculosis at participating sites in Uganda, Brazil, or the Philippines |
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Study Period |
2002-2008 |
Goal of Study:
This phase III two-sided equivalence trial compares 4 and 6 months of TB treatment (2 months of daily treatment with INH, rifampicin, ethambutol and pyrazinamide followed by either 2 or 4 months of daily INH and rifampicin) in HIV-non-infected adults with non-cavitary pulmonary tuberculosis who become sputum culture negative after the initial 2 months of anti-TB treatment.
Objectives of Study:
Primary Objectives:
- To assess the efficacy of shortening anti-TB treatment to 4 months in HIV-non-infected adults with drug-susceptible, non-cavitary pulmonary tuberculosis who convert their sputum culture to negative after 2 months of treatment.
Secondary Objectives:
- Compare pre-treatment sputum bacillary load in patients with and without cavitary disease.
- Compare time after inoculation of BACTEC or MGIT liquid culture media until positive with semi-quantitative sputum AFB smear and culture on solid media as measures of pre-treatment sputum bacillary load.
- Determine the influence of immunologic characteristics of subjects pre-treatment, during treatment and at the end of therapy on rate of bacillary clearance and risk for relapse.
Patients meeting initial eligibility criteria were enrolled and started on standard chemotherapy (2EHRZ/4HR). Drug susceptibility testing to INH, streptomycin, rifampicin, pyrazinamide and ethambutol was performed on initial isolates from all patients. Sputum smear and culture were performed monthly during treatment. Treatment was administered by directly observed therapy. Patients with drug-susceptible TB who were sputum culture negative after 2 months of treatment were randomly assigned at 4 months (when the final results of 2 month cultures are available) to stop treatment or to receive an additional 2 months of daily INH and rifampicin. The primary study endpoint was bacteriologic or clinical relapse at 30 months after the onset of anti-TB treatment.
Thirteen patients in the 4 month arm relapsed compared to 3 subjects enrolled in the 6 month arm (7.0% vs. 1.6% risk difference (RD) 0.054, 95% CI with Hauck-Anderson correction 0.010, 0.098). All patients who relapsed had drug-susceptible TB. Shortening treatment from 6 to 4 months in HIV-uninfected adults with non-cavitary disease and culture conversion after the intensive phase using current first line anti-TB drugs resulted in a greater relapse rate.
The results of this completed study can be found in:
Johnson JL, Hadad DJ, Dietze R, Maciel ELN, Sewali B, Gitta P, Okwera A, Mugerwa RD, Alcaneses MR, Quelapio M, Tupasi T, Horter L, Debanne S, Eisenach KD, Boom WH. Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am J Respir Crit Care Med. 2009; 180:558-563. PMCID: PMC2742745.