Background In Uganda, isoniazid plus ethambutol is used for 6 months (6HE) during the continuation treatment phase of new tuberculosis (TB) cases. However, the World Health Organization (WHO) recommends using isoniazid plus rifampicin for 4 months (4HR) instead of 6HE. We compared the impact of a continuation phase using 6HE or 4HR on total cost and expected mortality from the perspective of the Ugandan national health system. Methodology/Principal Findings Treatment costs and outcomes were determined by decision analysis. Median daily drug price was US$0.115 for HR and US$0.069 for HE. TB treatment failure or relapse and mortality rates associated with 6HE vs. 4HR were obtained from randomized trials and systematic reviews for HIV-negative (46% of TB cases; failure/relapse –6HE: 10.4% vs. 4HR: 5.2%; mortality –6HE: 5.6% vs. 4HR: 3.5%) and HIV-positive patients (54% of TB cases; failure or relapse –6HE: 13.7% vs. 4HR: 12.4%; mortality –6HE: 16.6% vs. 4HR: 10.5%). When the initial treatment is not successful, retreatment involves an additional 8-month drug-regimen at a cost of $110.70. The model predicted a mortality rate of 13.3% for patients treated with 6HE and 8.8% for 4HR; average treatment cost per patient was predicted at $26.07 for 6HE and $23.64 for 4HR. These results were robust to the inclusion of MDR-TB as an additional outcome after treatment failure or relapse. Conclusions/Significance Combination therapy with 4HR in the continuation phase dominates 6HE as it is associated with both lower expected costs and lower expected mortality. These data support the WHO recommendation to transition to a continuation phase comprising 4HR.
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