Randomized Trials to Optimize Treatment of Multidrug-Resistant Tuberculosis: The time for action is now

Policy Forum Randomized Trials to Optimize Treatment of Multidrug-Resistant Tuberculosis The time for action is now Carole D. Mitnick*, Kenneth G. Castro, Mark Harrington, Leonard V. Sacks, William Burman This is the third of three articles in the November 2007 issue on developing new drug treatments for tuberculosis. The Pressing Need for MDR-TB Clinical Trials 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 The Policy Forum allows health policy makers around the world to discuss challenges and opportunities for improving health care in their societies. PLoS Medicine | www.plosmedicine.org Summary Points The Past The time is now right for randomized trials of MDR-TB: u The burden of multidrug-resistant tuberculosis (MDR-TB) is growing, and the standard-of-care treatment is long, toxic, and frequently unsuccessful. The history of the development of current, short-course standardized treatment for drug-susceptible TB is instructive for developing regimens to treat MDR-TB. Identified through a series of randomized clinical trials, the short-course approach offered dramatic benefits over earlier standards of care—treatment duration decreased from 24 to six months while outcomes improved [21]. In contrast, guidelines for management of MDR-TB [22] are based on expert opinion and results of cohort and case series analyses, since no large-scale randomized trials of treatment have been conducted. As in the case of drug-susceptible TB, randomized controlled trials u The need for additional research is clearly illustrated by suboptimal treatment outcomes and limited estimates of the burden of MDR-TB and extensively drug-resistant TB. u The expansion of MDR-TB treatment programs provides the settings in which trials can be implemented. u For the first time in 30 years, several new drug classes that hold promise for MDR-TB treatment are under development; these new agents should be evaluated in parallel for drug-resistant and drug-susceptible TB. u Concerns about MDR-TB can help mobilize additional funding for TB drug development, while clinical trials for MDR-TB will likely allow accelerated regulatory approval for new agents. 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. 1730 Funding: The authors received no specific funding for this article. Competing Interests: The authors have declared that no competing interests exist. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the United States Department of Health and Human Services. Citation: Mitnick CD, Castro KG, Harrington M, Sacks LV, Burman W (2007) Randomized trials to optimize treatment of multidrug-resistant tuberculosis. PLoS Med 4(11): e292. doi:10.1371/journal.pmed.0040292 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Abbreviations: MDR-TB, multidrug-resistant tuberculosis; TB, tuberculosis; XDR-TB, extensively drug-resistant tuberculosis Carole D. Mitnick is with Harvard Medical School, Boston, Massachusetts, United States of America. Kenneth G. Castro is with the Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America. Mark Harrington is with the Treatment Action Group, New York, New York, United States of America. Leonard V. Sacks is with the Food and Drug Administration, Rockville, Maryland, United States of America. William Burman is with Denver Public Health and the University of Colorado Health Sciences Center, Denver, Colorado, United States of America. * To whom correspondence should be addressed. E-mail: November 2007 | Volume 4 | Issue 11 | e292 Recent developments in MDR-TB epidemiology, treatment programs, clinical trials methodology, and TB drug development suggest an end to the present impasse. First, the magnitude of the MDR-TB problem is now understood to be much greater than previously thought. Half a million new cases and an additional 1–1.5 million prevalent cases of MDR-TB were estimated to have occurred globally in 2004 [23]. We also now know that fitness costs are not an inevitable consequence of mutations that confer resistance [24]. And models have illustrated the potential epidemiologic importance of even a few highly fit, drug-resistant strains of M. tuberculosis [25]. There is growing consensus that universal access to high-quality treatment for all patients with TB, including those infected with drug-resistant isolates, is the right of every patient and is sound public health practice [20,26]. Second, MDR-TB treatment programs have expanded dramatically: 40 programs in resource-limited settings are managing treatment for nearly 30,000 patients. These programs receive quality-assured second-line drugs through a pooled-procurement mechanism suppo (...truncated)