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With approximately 8 million incident cases and 1.3 million deaths each year, increasing drug resistance, and exacerbating coexisting conditions such as the human immunodeficiency virus–acquired immunodeficiency syndrome and diabetes, tuberculosis continues to pose a massive threat to global health. In the absence of a vaccine to provide long-term protection, control of drug-susceptible tuberculosis is largely dependent on a standard 6-month chemotherapy regimen that has been in use for more than three decades. Any experimental therapy designed to modify this short-course regimen — which comprises a 2-month intensive phase with four drugs (rifampin, isoniazid, pyrazinamide, and ethambutol) followed by a 4-month continuation phase with two drugs (isoniazid and rifampin) — must not increase the rate of recurrence due to relapse.

Where the aim is to reduce the duration of treatment — a critical transformation to improve patient adherence and reduce costs — the challenge is significant: demonstration of noninferiority with fewer months of therapy. Three trials reported in this issue of the Journal offer a sobering reminder of the enormity of this task, while providing some insight into the factors that are likely to determine the success of new, treatment-shortening regimens.