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Combining the investigational drug delamanid with standard tuberculosis treatment significantly increased sputum-culture conversion rates in MDR tuberculosis, an international study demonstrated.
The results could be particularly good news for China, which now has one-quarter of the world’s cases of MDR TB, according to a second study.
In the delamanid study, the conversion proportion was 45% after 2 months of treatment among those who received the new drug plus standard therapy, compared with a 30% rate for standard therapy alone, Dr. Maria T. Gler and her coauthors reported in the June 7 issue of the New England Journal of Medicine.
"It is important to learn more about the use of delamanid in combination with other new and existing antimycobacterial agents to develop better regimens for multidrug-resistant tuberculosis," wrote Dr. Gler, of Makati Medical Center and the Tropical Disease Foundation, Makati City, Philippines, and her colleagues (N. Engl. J. Med. 2012;366:2151-60).
Delamanid, which inhibits mycolic acid synthesis, has shown effectiveness against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis in preclinical tests.
The team investigated the drug’s effect at 200 mg/day and 400 mg/day, plus a background treatment regimen approved by the World Health Organization for multidrug-resistant (MDR) tuberculosis. A placebo group received only the background treatment – the current standard of care. The 2-month study was carried out in nine countries: China, Egypt, Estonia, Japan, Korea, Latvia, Peru, the Philippines, and the United States.
The study group included 481 patients with sputum culture–proven MDR tuberculosis infections. The patients’ mean age was 35 years. More than 90% of the group had received prior treatment for tuberculosis, including 50% who had already taken only first-line antitubercular agents and 40% who had received a second- or third-line agent. Only four of the patients were coinfected with HIV.
By the end of 2 months, both groups receiving delamanid had significantly higher proportions of sputum-culture conversion than the placebo groups. Similar conversion proportions occurred in both active groups: 45% of the 200-mg/day delamanid group, and 42% of the 400-mg/day group. Conversion in the placebo group (30%) was significantly less than in both of the active groups.
Time to conversion also differed significantly between the active and placebo groups, with conversion proportions beginning to separate by 30 days of treatment.
There were more adverse events in the delamanid groups, although the investigators found that only the incidence of QT prolongation was significantly less in the placebo group (4%) than in the 200- and 400-mg/day delamanid groups (10% and 13%, respectively). None of the arrhythmias were clinically significant, they noted.
There were no between-group differences in the rate of hepatotoxicity. One patient died from tuberculosis during the trial.
A longer trial is underway to more closely examine delamanid’s effect on the hard-to-treat disease in patients taking antiretroviral drugs for HIV infections.
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.
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.
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.
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.
Combining the investigational drug delamanid with standard tuberculosis treatment significantly increased sputum-culture conversion rates in MDR tuberculosis, an international study demonstrated.
The results could be particularly good news for China, which now has one-quarter of the world’s cases of MDR TB, according to a second study.
In the delamanid study, the conversion proportion was 45% after 2 months of treatment among those who received the new drug plus standard therapy, compared with a 30% rate for standard therapy alone, Dr. Maria T. Gler and her coauthors reported in the June 7 issue of the New England Journal of Medicine.
"It is important to learn more about the use of delamanid in combination with other new and existing antimycobacterial agents to develop better regimens for multidrug-resistant tuberculosis," wrote Dr. Gler, of Makati Medical Center and the Tropical Disease Foundation, Makati City, Philippines, and her colleagues (N. Engl. J. Med. 2012;366:2151-60).
Delamanid, which inhibits mycolic acid synthesis, has shown effectiveness against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis in preclinical tests.
The team investigated the drug’s effect at 200 mg/day and 400 mg/day, plus a background treatment regimen approved by the World Health Organization for multidrug-resistant (MDR) tuberculosis. A placebo group received only the background treatment – the current standard of care. The 2-month study was carried out in nine countries: China, Egypt, Estonia, Japan, Korea, Latvia, Peru, the Philippines, and the United States.
The study group included 481 patients with sputum culture–proven MDR tuberculosis infections. The patients’ mean age was 35 years. More than 90% of the group had received prior treatment for tuberculosis, including 50% who had already taken only first-line antitubercular agents and 40% who had received a second- or third-line agent. Only four of the patients were coinfected with HIV.
By the end of 2 months, both groups receiving delamanid had significantly higher proportions of sputum-culture conversion than the placebo groups. Similar conversion proportions occurred in both active groups: 45% of the 200-mg/day delamanid group, and 42% of the 400-mg/day group. Conversion in the placebo group (30%) was significantly less than in both of the active groups.
Time to conversion also differed significantly between the active and placebo groups, with conversion proportions beginning to separate by 30 days of treatment.
There were more adverse events in the delamanid groups, although the investigators found that only the incidence of QT prolongation was significantly less in the placebo group (4%) than in the 200- and 400-mg/day delamanid groups (10% and 13%, respectively). None of the arrhythmias were clinically significant, they noted.
There were no between-group differences in the rate of hepatotoxicity. One patient died from tuberculosis during the trial.
A longer trial is underway to more closely examine delamanid’s effect on the hard-to-treat disease in patients taking antiretroviral drugs for HIV infections.
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.
Combining the investigational drug delamanid with standard tuberculosis treatment significantly increased sputum-culture conversion rates in MDR tuberculosis, an international study demonstrated.
The results could be particularly good news for China, which now has one-quarter of the world’s cases of MDR TB, according to a second study.
In the delamanid study, the conversion proportion was 45% after 2 months of treatment among those who received the new drug plus standard therapy, compared with a 30% rate for standard therapy alone, Dr. Maria T. Gler and her coauthors reported in the June 7 issue of the New England Journal of Medicine.
"It is important to learn more about the use of delamanid in combination with other new and existing antimycobacterial agents to develop better regimens for multidrug-resistant tuberculosis," wrote Dr. Gler, of Makati Medical Center and the Tropical Disease Foundation, Makati City, Philippines, and her colleagues (N. Engl. J. Med. 2012;366:2151-60).
Delamanid, which inhibits mycolic acid synthesis, has shown effectiveness against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis in preclinical tests.
The team investigated the drug’s effect at 200 mg/day and 400 mg/day, plus a background treatment regimen approved by the World Health Organization for multidrug-resistant (MDR) tuberculosis. A placebo group received only the background treatment – the current standard of care. The 2-month study was carried out in nine countries: China, Egypt, Estonia, Japan, Korea, Latvia, Peru, the Philippines, and the United States.
The study group included 481 patients with sputum culture–proven MDR tuberculosis infections. The patients’ mean age was 35 years. More than 90% of the group had received prior treatment for tuberculosis, including 50% who had already taken only first-line antitubercular agents and 40% who had received a second- or third-line agent. Only four of the patients were coinfected with HIV.
By the end of 2 months, both groups receiving delamanid had significantly higher proportions of sputum-culture conversion than the placebo groups. Similar conversion proportions occurred in both active groups: 45% of the 200-mg/day delamanid group, and 42% of the 400-mg/day group. Conversion in the placebo group (30%) was significantly less than in both of the active groups.
Time to conversion also differed significantly between the active and placebo groups, with conversion proportions beginning to separate by 30 days of treatment.
There were more adverse events in the delamanid groups, although the investigators found that only the incidence of QT prolongation was significantly less in the placebo group (4%) than in the 200- and 400-mg/day delamanid groups (10% and 13%, respectively). None of the arrhythmias were clinically significant, they noted.
There were no between-group differences in the rate of hepatotoxicity. One patient died from tuberculosis during the trial.
A longer trial is underway to more closely examine delamanid’s effect on the hard-to-treat disease in patients taking antiretroviral drugs for HIV infections.
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.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE