Randomized Trials to Optimize Treatment of Multidrug-Resistant Tuberculosis

Drug-resistant strains of Mycobacterium tuberculosis may account for 10% of the 8 million new cases of tuberculosis (TB) that occur annually. Systematic surveys have been undertaken in at least 90 countries. Drug-resistant isolates were found in every site, and multidrug-resistant tuberculosis (MDR-TB; resistant to at least isoniazid and rifampin) in all but eight [1]. Extensively drug-resistant tuberculosis (XDR-TB)—disease caused by MDR strains that are also resistant to at least one fluoroquinolone and one or more injectable agents [2]—has been reported in at least 37 countries, with very poor treatment outcomes [3–5]. Increasing concern about resistance has redoubled interest in strategies to control drug-resistant TB, especially in settings of high HIV prevalence [6]. There is, therefore, increased urgency for clinical trials that will identify safe and effective regimens for patients who have no treatment options. Furthermore, although the feasibility and cost-effectiveness of treating patients with MDR-TB in resource-constrained countries is well established [7–13], outcomes of MDR-TB treatment remain suboptimal. MDR-TB can be lethal; 5%–20% of HIV-uninfected patients [7,9–11,14] and 66% of HIV-infected patients die during treatment [15]. MDR-TB treatment lasts between 18 and 24 months, and adverse events are common [16]. As a result, the combined frequency of cure and completion often remains below 50% [7,17,18]. Even when therapy is designed with access to the full complement of antituberculosis agents presently available, outcomes rarely approach the target for TB treatment success (cure among at least 85% of patients initiating therapy) [14,19]. The long duration and toxicity of current MDR-TB regimens will impede achievement of the goal of treating nearly 1.6 million MDR-TB patients by 2015, set out in the Global Plan to Stop TB [20]. In addition, the poor outcomes of current regimens mean that many of those treated will develop chronic, highly resistant forms of TB that have a high mortality rate and can be transmitted to others. The Past