Challenges in tuberculosis drug research and development (original) (raw)

Nature Medicine volume 13, pages 290–294 (2007)Cite this article

The present decade has seen a reawakening of tuberculosis (TB) drug research and development (R&D), spurred on by an urgent need to stem the tide of the disease globally and develop new, more effective treatments against drug-sensitive and resistant strains. As a result, there are now seven products in clinical development and the largest pipeline of early-stage projects and compounds in history. The primary goals of this resurgent activity are to shorten and simplify the treatment of active TB, provide safer and more efficacious treatments for drug-resistant TB, simplify treatment of TB-HIV coinfections by eliminating troublesome drug-drug interactions, and shorten treatment for latent TB infection. Successful development of new, safe and effective TB therapies faces a number of challenges, some unique to TB drug R&D, many with implications for other therapeutic indications.

In February 2000, TB and global health stakeholders gathered in Cape Town, South Africa and declared an urgent need for development of improved TB treatments[1](/articles/nm0307-290#ref-CR1 "Cape Town Declaration. < http://www.tballiance.org/pdf/CapeTownDecl.pdf

            &gt; (2000)."). The reasons were obvious. Two billion people worldwide are estimated to be infected with _Mycobacterium tuberculosis_, the bacterium that causes TB, although less than one percent of these have active tuberculosis at any given time. The rest are referred to as having latent TB infection (LTBI). Of the approximately nine million new cases of active TB each year, all but approximately 425,000 are estimated to be sensitive to current therapy, a regimen that routinely demonstrates greater than 95% efficacy in clinical trials. However, despite the potential effectiveness of standard therapy for drug-sensitive disease, there are close to two million deaths attributable to this disease each year. The urgency for improved treatments is driven by the fact that globally TB is not being controlled effectively with presently available treatment, particularly in parts of the world with limited public health infrastructure, high HIV incidence, or both[2](/articles/nm0307-290#ref-CR2 "Dye, C. Lancet 367, 938–940 (2006)."),[3](/articles/nm0307-290#ref-CR3 "Zignol, M. et al. J. Infect. Dis. 194, 479–485 (2006)."). The limited effectiveness of current therapy stems largely from the lengthy and complicated nature of first-line treatment for active TB: a six- to nine-month course of four drugs in combination (two months of isoniazid, rifampin, pyrazinamide and ethambutol, followed by four to seven months of isoniazid and rifampin). _M. tuberculosis_ shows a still poorly understood ability to persist in very low numbers for long periods in human and animal hosts despite treatment with drugs to which it is genetically sensitive. This phenomenon, called phenotypic resistance or tolerance, is also commonly referred to as 'persistence', and the bacilli that remain in the host for relatively long periods despite appropriate drug treatment are referred to as 'persistors'. Investigators have demonstrated that isoniazid alone at the standard dose kills over 90% of the infecting mycobacteria in the first two days of treatment[4](/articles/nm0307-290#ref-CR4 "Donald, P. et al. Am. J. Respir. Crit. Care Med. 156, 895–900 (1997)."). Yet, it takes months of isoniazid-containing combination drug therapy to eradicate the relatively few remaining persistors and ensure that patients won't relapse once therapy is stopped.

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  1. Global Alliance for TB Drug Development, New York, New York, USA
    Ann M Ginsberg & Melvin Spigelman

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  1. Ann M Ginsberg
  2. Melvin Spigelman

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Ginsberg, A., Spigelman, M. Challenges in tuberculosis drug research and development.Nat Med 13, 290–294 (2007). https://doi.org/10.1038/nm0307-290

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