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Delamanid Boosts Treatment Punch in Resistant TB

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More Drugs Needed Faster

More – and faster – research is critical to controlling the epidemic of multidrug-resistant tuberculosis.

Globally, there were an estimated 9.27 million incident cases of TB in 2007 – 500,000 of which were resistant to multiple drugs. Regimens containing two or more agents that are known to be effective offer the greatest hope for "turning back the clock" on MDR tuberculosis. But despite the obvious need, most sponsors are (understandably) reluctant to combine novel agents, citing proprietary, safety, and regulatory concerns.

An 8-week study of another investigational drug, bedaquiline, showed response rates similar to those among patients receiving delamanid, although response rates in the placebo group were substantially lower in the bedaquiline trial than in the delamanid trial (Antimicrob. Agents Chemother. 2012;56:3271-6).

Both delamanid and bedaquiline enhance the activity of second-line regimens, but how should we use these drugs going forward? Unfortunately, neither study provides an answer.

The drug development process requires companies to show the independent effects of their candidate agents. However, to treat tuberculosis, clinicians need to know what combination regimens to use, in what configuration, and for what duration. Delamanid and bedaquiline may receive regulatory approval soon, yet we don’t know whether they can be used together safely and effectively.

It is important to accelerate research to identify the best regimens of new and existing drugs and guide clinicians in the most effective application of these drugs. Regulatory agencies should consider this imperative in their guidance to prospective sponsors and in their review of applications for the registration of new agents.

MDR and extensively drug-resistant tuberculosis are now widespread throughout the world, with the increase driven largely by transmission. In this new world of drug resistance, directing tuberculosis control programs to drug-resistant high-risk cases is no longer enough. Such efforts must be incorporated into basic control programs in order to accurately diagnose and effectively treat patients with MDR cases. This is a monumental task but one that cannot be avoided if tuberculosis is to be contained.

Dr. Richard E. Chaisson and Dr. Eric L. Nuermberger are associated with the Center for Tuberculosis Research at Johns Hopkins University in Baltimore. Their remarks are drawn from an accompanying editorial (N. Engl. J. Med. 2012;366:2223-4). Dr. Chaisson reported no relevant financial conflicts; Dr. Nuermberger reported receiving grant funding from Otsuka, Pfizer, and the Global Alliance for TB Drug Development.


 

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

MDR Need Greatest in China

Finding an effective treatment for MDR tuberculosis is especially important in China, which has the greatest number of cases in the world, Yanlin Zhao, Ph.D., reported in an accompanying study (N. Engl. J. Med. 2012;366:2161-70).

Dr. Zhao, of the Chinese Center for Disease Control and Prevention, and colleagues reported on a national disease survey conducted in 2007. The survey showed that about 110,000 MDR cases were reported that year, and that 8,200 showed extensive drug resistance (XDR) – defined as resistance to isoniazid, rifampin, ofloxacin, and kanamycin.

China’s prevalence rate of multidrug resistance among new cases of tuberculosis was 3.5 times greater than the global median, and nearly twice the global average.

"With the use of the World Health Organization estimate of multidrug-resistant tuberculosis in various countries as a reference, China has the highest annual number of cases of MDR tuberculosis in the world – a quarter of the cases worldwide," the authors wrote.

A numbers of factors were linked to drug-resistant disease. Patients with multiple previous treatments – with the most recent taken in a tuberculosis hospital – were at the highest risk.

Poor compliance also influenced drug resistance. In a subanalysis of 226 patients who had received prior treatment, 44% had not completed their prior regimen. Among the 127 patients who had completed treatment, 115 had relapsed TB, and 62% had received that last treatment in the Chinese Center for Disease Control (CDC) system.

"This finding points to the need for interventions that will increase the continuity of treatment and reduce the rate of treatment default, especially among patients treated within the hospital system," the authors noted.

Because national facilities provide limited follow-up, the Chinese Ministry of Health has strengthened the hospitals’ follow-up capabilities, the investigators added.

More needs to be done, however, they noted. China’s CDC system, which is responsible for monitoring patients with tuberculosis in the community, could test new approaches to improving adherence to treatment, such as mobile-phone text messaging, and expand such approaches if they prove to be effective.

Improvements are imperative, the study authors cautioned, as the future does not bode well. About 11% of new cases and 16% of previously treated cases are already resistant to either isoniazid or rifampin, "placing them one step away from having MDR tuberculosis."

In addition, in patients with MDR but not XDR tuberculosis, more than one-third of cases were resistant to either ofloxacin or kanamycin – leaving those patients also just one step away from XDR tuberculosis.

Dr. Gler has received consulting fees from Otsuka Novel Products, the company that sponsored the trial. Neither Dr. Zhao nor any of the coauthors had any financial disclosures.

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