Correspondence in the July 16th issue ofThe New England Journal of Medicine (NEJM) ^1,2 suggests significant progress in the development of 2 drugs to fight extremely, or extensively, drug-resistant tuberculosis (XDR-TB). These scientific advances may be just the tip of the iceberg in an innovative global effort to eradicate all forms of TB—including multidrug-resistant TB (MDR-TB), which is resistant to isoniazid and rifampin, and XDR-TB, which is also resistant to any fluoroquinolone and at least 1 of 3 injectable second-line drugs (capreomycin, kanamycin, and amikacin).³

NEJM Updates and Commentary

The NEJM letters provide updates on linezolid, an agent currently approved in the U.S. for treatment of certain bacterial infections, and delamanid, a drug conditionally approved by the European Medicines Agency for MDR-TB. Following up on their previously published 4-month study results,⁴ Lee and colleagues reported that at 1 year, 71% (27 of 38) of patients who had linezolid added to their background regimen were cured of XDR-TB infection.⁴

In another letter, Gupta and researchers reported a post-hoc analysis of cases of XDR-TB culled from 3 trials that tested delamanid for MDR-TB. In their analysis, 65% (11 of 17) of patients with delamanid added to their background treatment regimen for 6 months or more were cured.²

What impact will these reports have on the management of XDR-TB?

Commenting on behalf of the World Health Organization (WHO), Karin Weyer, MD, coordinator of WHO’s Global TB Programme Unit for Laboratories, Diagnostics, & Drug Resistance, says, “The paper on linezolid suggests potential in using a lower dose of the drug to reduce its well-described serious adverse effects; however, given the limited data (as acknowledged by the authors), the findings are not sufficient to indicate a change in clinical practice, and more controlled trials are necessary.” She points out that delamanid is one of the drugs that the WHO recommends for MDR-TB, giving the clinician more options to design an effective treatment regimen.

Building a Global Armamentarium

Another expert in this field, C. Robert Horsburgh, Jr., MD, Professor of Epidemiology, Biostatistics, and Infectious Diseases at Boston University, also stresses the need for drugs. He says, however, that, “The advantage for patients with XDR-TB is that it’s unlikely that they would have encountered these drugs before, so resistant isolates are unlikely.”

Dr. Horsburgh adds that Lee and colleagues reported that cases of linezolid resistance developed in patients treated with linezolid.⁴

Albert A. Rizzo, MD, Senior Medical Advisor, American Lung Association, and Chief, Pulmonary and Critical Care Medicine Section, Christiana Care Health System, in Newark, Delaware, says, “The updates on linezolid and delamanid are encouraging in supporting the efficacy of these drugs when used in combination with WHO-recommended background regimens of medications for treating MDR- and XDR-TB. These 2 drugs have the ability to increase the sputum conversion rate more quickly, which can be an indication of more likely cure. This is particularly important in the MDR and XDR strains.”

But even if large-scale prospective clinical trials support the efficacy of these drugs against XDR-TB, they don’t solve the global problem. The 3 experts cited above referred to the potentially game-changing work of the TB Alliance, an organization charged with creating global solutions to TB drug development.

A Completely New Strategy

Mel Spigelman, MD, President and Chief Executive Officer of the TB Alliance, compared the research described above with the approach of the Alliance: “The work coming out now is excellent science and will lay the groundwork for things down the road. The challenge is, we need treatments for drug-resistant TB that can be translated into dramatic effects around the world. In most parts of the world, current treatment regimens are too expensive, take too long, and require too much sophisticated medical supervision. Adding a drug to the current MDR- or XDR-TB therapy will just make the regimen more expensive, complex, and less feasible in different parts of the world.”

But these very same drugs, and others currently under investigation, can be used in a new way that may radically alter TB treatment.

“One of our Phase 2 clinical trials, Nix-TB,5 uses new drugs in a different way,” Dr. Spigelman says. “The 3-drug regimen we’re testing—linezolid, bedaquiline, and pretomanid—is designed to be administered orally once a day. In the mouse model it cured TB in 3 to 4 months. If it works in man, it could reduce the cost of treatment for drug-resistant TB by 95% or more.”

All TB treatment—for TB, MDR-TB, and XDR-TB—here and in developing countries will shift dramatically if a well-tolerated, simple, short “universal regimen” is developed. “Our goal is to provide a new regimen, like the one above, to which no one is resistant,” says Dr. Spigelman. To lessen the likelihood of resistance to the new regimen, the Alliance will seek to develop a fixed-dose combination.

Problem solved?

Dr. Weyer is very encouraged by the progress so far. “The novel drug regimen being developed by the TB Alliance could be one of the few game-changers in TB treatment, should the trials prove its efficacy and safety, and feasibility is later confirmed in the field.”

But implementation of the universal regimen is at least 10 years off, predicts Dr. Horsburgh. In the meantime, he stresses the importance of susceptibility testing to identify the right regimen, and patient support to ensure compliance with it.

For now, says Dr. Rizzo, “The best advice is to use the most effective agents and have them administered in a correct, compliant manner for the needed duration to achieve cure.”

Published: 08/20/2015

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