Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion

Abstract

Rationale: Cavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients.

Objectives: To assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months.

Methods: This study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment.

Measurements and main results: Enrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10).

Conclusion: Shortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.

Figure 1.

Study profile. *Reasons for exclusion during screening (n): Cavitary disease (596), signs and symptoms not consistent with TB (410), HIV infected (344), extrapulmonary tuberculosis (TB) (82), serum aspartate aminotransferase over 1.5 upper limit of normal (82), refused directly observed treatment (DOT) (75), alcoholism, drug use or sex work (54), serum bilirubin over 1.3 mg/dl (51), hemoglobin less than 8 g/dl (37), random serum glucose more than 150 mg/dl (35), silicosis or chronic comorbidity (27), prior TB or TB treatment (22), serum creatinine more than 2 mg/dl (17), pregnant or breastfeeding (11), not ambulatory (7), exposure to MDR TB (5), receiving steroids (5). Categories not exclusive. ^†DOT. ^‡Reasons for exclusion before randomization (n): TB not culture confirmed (277), drug-resistant TB (54), unwilling to continue on DOT (50), nonadherence to study schedule (76), positive 2-month culture (29), incomplete DOT or incomplete treatment (6), pregnant (6), HIV seropositive (2), serious illness contraindicating enrollment (1), eligibility criteria not confirmed (1), enrollment suspended by DSMB before randomization (64). Categories not exclusive.

Figure 2.

Kaplan Meier curve showing the cumulative percentage of patients who relapsed after completing anti-tuberculosis (TB) treatment. The chi-square test for a difference in the percentage of patients who relapsed by treatment arm was significant (P < 0.01). Error bars represent the standard error of the mean percentage of patients who relapsed at 6, 12, and 24 months of follow-up after completing treatment.