Background: A WHO-recommended 8-month regimen based on ethambutol and isoniazid was evaluated in a randomised clinical trial against a 6-month standard regimen.
Methods: 1355 patients with newly diagnosed smear-positive pulmonary tuberculosis were randomly assigned one of three regimens: daily ethambutol, isoniazid, rifampicin, and pyrazinamide for 2 months, followed by ethambutol and isoniazid for 6 months (2EHRZ/6HE); the same drugs but given three times weekly in the initial intensive phase (2[EHRZ]3/6HE); or the same initial intensive phase as the first regimen, followed by 4 months of daily rifampicin and isoniazid (2EHRZ/4HR). Follow-up was to 30 months after the start of chemotherapy. Sputum was regularly examined by microscopy and culture. Unfavourable outcome was defined as failure during treatment or relapse afterwards. Analyses were by intention to treat.
Findings: At 2 months, a significantly higher proportion of patients assigned the daily intensive phase than of those assigned the three-times-weekly regimen were culture negative (700/828 [85%] vs 333/433 [77%], p=0.001). 12 months after the end of chemotherapy, the proportions of unfavourable outcomes were 36 of 346 (10%) with 2EHRZ/6HE, 48 of 351 (14%) with 2(EHRZ)3/6HE, and 17 of 347 (5%) with 2EHRZ/4HR. Both 8-month regimens were significantly inferior to the control 6-month standard regimen (difference between control and 2EHRZ/6HE 5.5% [95% CI 1.6 to 9.4]; between control and 2(EHRZ)3/6HE 8.8% [4.5 to 13.0]). Adverse effects leading to interruption of treatment for 7 days or longer occurred in 28 patients (12 2EHRZ/6HE, five 2[EHRZ]3/6HE, 11 2EHRZ/4HR).
Interpretation: The results of this study must be taken into account in recommendations on management of new cases of smear-positive tuberculosis.