Correspondence
disease attributable to either tobacco smoking or tuberculosis2,4 and their potential combined effect, it is crucial that smoking cessation interventions form part of national tuberculosis control and prevention programmes, and countries with a high burden of tuberculosis need to develop clinical and public health strategies to manage patients with COPD. GBM reports grants from AstraZeneca and has served on an advisory board for Novartis. All other authors declare no competing interests.
*Anthony L Byrne, Ben J Marais, Carole D Mitnick, Leonid Lecca, Guy B Marks [email protected] The University of Sydney, Sydney, NSW, Australia (ALB, BJM, GBM); Socios En Salud Sucursal (Partners In Health), Lima, Perú (ALB, CDM, LL); Centre for Research Excellence in, Sydney, NSW, Australia (ALB, BJM, CDM, LL); Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia (BJM); and Harvard Medical School, Boston, MA, USA (CDM) 1
2 3
4
5
Postma DS, Bush A, Van Den Berge M. Risk factors and early origins of chronic obstructive pulmonary disease. Lancet 2015; 385: 899–909. WHO. Global tuberculosis report 2014. Geneva: World Health Organization, 2014. Byrne AL, Marais BJ, Mitnick CD, Lecca L, Marks GB. Tuberculosis and chronic respiratory disease: a systematic review. Int J Infect Dis 2015; 32: 138–46. Lopez AD, Mathews CD, Ezzati M, Jamison DT, Murray CJL. Global burden of disease and risk factors. Washington: The World Bank, 2006. Van Zyl Smit RN, Pai M, Yew WW, et al. Global lung health: the colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD. Eur Respir J 2010; 35: 27–33.
Informed use of bedaquiline for tuberculosis
the scarcity of data, increased mortality in the bedaquiline group of one phase 2 trial, and public health importance of the drug, the FDA’s accelerated approval required that a patient registry be set up to assess serious adverse events, including death.2 In view of the small number of American patients receiving bedaquiline and to avoid selection bias, the inclusion of all recipients of bedaquiline in this registry is essential.2 Yet bedaquiline’s prospective registry opened in March, 2014, missing all the patients who started on the drug since the approval in December, 2012. The registry was developed without consulting end users and little has been done to inform prescribers about its existence. Clinicians who attempt to report in to the registry find the forms onerous and unclear. Importantly, consent forms are only available in English, despite the documented frequency of tuberculosis cases in foreign-born people.3 A simple, clear, and widely accessible process is urgently needed to gather crucial safety information from patients and providers. Results must be shared with FDA and with researchers and the public. We declare no competing interests.
*Erica M Lessem, John Bernardo, Caitlin Reed, Donna H Wegener [email protected] Treatment Action Group, New York, NY 10016-7701, USA (EML); Boston University School of Medicine, Boston, MA, USA (JB); Olive View-UCLA Medical Center Inpatient Tuberculosis Unit, Division of Infectious Diseases, Department of Medicine and David Geffen School of Medicine, UCLA, Los Angeles, CA, USA (CR); and National Tuberculosis Controllers Association, Smyrna, GA, USA (JB, DHW) 1
In their Viewpoint (Jan 31, p 477),1 Laia Ruiz Mingote and colleagues highlight the urgent need for additional safety data on bedaquiline, the first new tuberculosis drug to receive US Food and Drug Administration (FDA) approval in more than 40 years. Because the drug received accelerated approval based solely on phase 2 studies, critical safety data for bedaquiline are incomplete. In view of 1724
2
3
Ruiz Mingote L, Namutamba D, Apina F, et al. The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosisaffected communities. Lancet 2015; 385: 477–79. US Food and Drug Administration. Postmarketing requirements and commitments: Sirturo. August 2013. http:// www.accessdata.fda.gov/scripts/cder/pmc/ index.cfm (accessed July 18, 2014). Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2012. Atlanta, USA: 2013. http://www.cdc. gov/tb/statistics/reports/2012/pdf/ report2012.pdf (accessed July 18, 2014).
The Viewpoint by Laia Ruiz Mingote and colleagues1 raises safety concerns regarding bedaquiline in treatment shortening trials for pan-resistant tuberculosis (tuberculosis that is susceptible to all first-line antituberculosis treatments). A trial with similar issues is STAND TB, by the Global Alliance for TB Drug Development (TBA), which is testing the nitroimidazole PA-824 (pretomanid) in combination with pyrazinamide and moxifloxacin (PaMZ).2 There are little safety data on the use of PA-824 longer than 8 weeks, and both PA-824 and moxifloxacin have significant toxic effects.3 TBA have also decided to test the PaMZ regimen in a 4-month treatment-shortening trial. Few data support the use of this combination for treatment-shortening and this regimen might not be robust enough, in view of the results of other treatment-shortening trials.4 Another concern in STAND TB is the proposed use of PaMZ for patients with multidrug-resistant tuberculosis. Three-drug combinations have never been shown to be successful for the treatment of multidrug-resistant tuberculosis in any setting. In view of the high likelihood of developing resistance to the nitroimidazoles, there are also concerns about resistance amplification.5 Better treatment for multidrug-resistant tuberculosis is urgently needed, but safety and resistance amplification cannot be overlooked. Unfortunately, TBA is waiting to test the drug in more robust combinations for multidrug-resistant tuberculosis until it has been used for six months in the STAND-TB regimens. Much work is needed to improve care for patients with tuberculosis and multidrug resistant tuberculosis. The need for such radical changes, however, should not ignore the risks for patients inherent in such trials. I declare no competing interests.
Jennifer Furin [email protected]
www.thelancet.com Vol 385 May 2, 2015
Correspondence
1
2
3
4
5
Ruiz Mingote L, Namutamba D, Apina F, et al. The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosis affected communities. Lancet 2015; 385: 477–79. TB Alliance. New tuberculosis drug regimen will move to landmark phase 3 clinical trial. http://www.tballiance.org/newscenter/ viewbrief.php?id=1096 (accessed July 15, 2014). Dawson R, Diacon A, Everitt D, et al. Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drugsusceptible or drug-resistant pulmonary tuberculosis. Lancet 2015; published online March 17. http://dx.doi.org/10.1016/S01406736(14)62002-X. Merle CS, Sisimanadis C, Sow OB, et al. A pivotal registration phase III multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project. Trials 2012; 13: 61. Manjunatha U, Boshoff H, Dowd C, et al. Identification of a nitroimidazo-oxazinespecific protein involved in PA-824 resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2006; 103: 431–36.
Authors’ reply We thank Erica Lessem and colleagues for commenting on our Viewpoint1 regarding the challenges surrounding the bedaquiline patient registry in the USA. For drugs like bedaquiline that receive accelerated approval, patient registries are a critical mechanism for collecting safety data on new drugs. Recent data from the US Centers for Disease Control and Prevention indicate that the tuberculosis epidemic in the USA is marked by increasing racial and ethnic disparities, and concentrated among foreign-born people. 2 It is essential that patient registries be made inclusive by facilitating the enrolment of non-native English speakers and susceptible populations. The inconsistencies that characterise tuberculosis epidemics should not be mirrored in the collection of drug safety data. Collecting important safety data on bedaquiline should also be facilitated globally. Global health institutions should support www.thelancet.com Vol 385 May 2, 2015
tuberculosis programmes with technical assistance, and create a multinational programme of data collection, analysis, and dissemination to facilitate WHO– recommended pharmacovigilance of new tuberculosis drugs. 3 The National Bedaquiline Clinical Access Program in South Africa offers one example of a successful monitoring programme.4 Importantly, it collects data on bedaquiline’s safety when given to patients with drug-resistant tuberculosis, or patients with HIV who are taking antiretrovirals—a patient population excluded from the phase 2 trials supporting bedaquiline’s approval. Although data from observational cohort studies are not as useful as evaluation of bedaquiline’s safety and efficacy in phase 3 clinical trials, interim analysis of 91 patients receiving bedaquiline in South Africa’s clinical access programme, presented in October, 2014, provide encouraging information on bedaquiline’s safety in the absence of further trials data.5 Further clinical trials for new tuberculosis drugs, including a phase 3 trial of bedaquiline, are still necessary. Jennifer Furin raises concerns about the evaluation of PA-824 (pretomanid) in combination with pyrazinamide and moxifloxacin in the Global Alliance for TB Drug Development’s STAND trial. Our community advisory board, the Community Research Advisors Group, does not advise the Global Alliance for TB Drug Development and cannot comment on the specifics of pretomanid’s development. Furin also notes the Global Alliance for TB Drug Development’s decision not to provide pretomanid to a proposed AIDS Clinical Trials Group study. Investigators have reported similar difficulties in acquiring bedaquiline for further studies. Increasingly, access to new compounds is a challenge not only for communities affected by tuberculosis, but also for researchers. New tuberculosis drugs
such as bedaquiline and delamanid must be available for researchers to study in different combinations to arrive at optimum treatment options. We call on tuberculosis drug developers to work together in the best interests of patients and communities.
GUSTOIMAGES/Science Photo Library
Case Western Reserve University, TB Research Unit, Cleveland, OH 44106, USA
MWF has received grants from the Global Alliance for TB Drug Development and the Stop TB Partnership for projects outside the submitted work. All other authors declare no competing interests.
Laia Ruiz Mingote, Dorothy Namutamba, Barbara Seaworth, Cynthia Lee, *Mike Watson Frick [email protected] Community Research Advisors Group, New York, NY, USA (LRM, DN, BS, CL); and Treatment Action Group, New York, NY 10016, USA (MWF) 1
2
3
4
5
Ruiz Mingote L, Namutamba D, Apina F, et al. The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosisaffected communities. Lancet 2015; 385: 477–79. Scott C, Kirking H, Jeffries C, Price S, Pratt R. Tuberculosis trends—United States, 2014. MMWR Morb Mortal Wkly Rep 2015; 64: 265–69. WHO. The use of bedaquiline in the treatment of multidrug resistant tuberculosis: expert group meeting report. Geneva: January 29–30, 2013. http://www.who.int/tb/challenges/ mdr/Report_EGM_BDQ_2013.pdf (accessed March 25, 2015). Conradie F, Meintjes G, Hughes J, et al. Clinical access to bedaquiline programme for the treatment of drug-resistant tuberculosis. S Afr Med J 2014; 104: 164–66. Ndjeka N, Conradie F, Hughes J, et al. Safe and effective bedaquiline treatment of drug resistant tuberculosis (DR-TB) within the National Bedaquiline Clinical Access Programme in South Africa. 45th Union World Conference on Lung Health, Oct 28–Nov 1, 2014, Barcelona.
Dengue vaccine—time to act now Maria Rosario Capeding and colleagues (Oct 11, p 1358) 1 have demonstrated the efficacy and safety of a dengue vaccine in a study conducted in five Asian countries where more than 1 in 25 unvaccinated children suffered a symptomatic dengue episode each year. With 56·5% (95% CI 43·8–66·4) overall 1725
disease attributable to either tobacco smoking or tuberculosis2,4 and their potential combined effect, it is crucial that smoking cessation interventions form part of national tuberculosis control and prevention programmes, and countries with a high burden of tuberculosis need to develop clinical and public health strategies to manage patients with COPD. GBM reports grants from AstraZeneca and has served on an advisory board for Novartis. All other authors declare no competing interests.
*Anthony L Byrne, Ben J Marais, Carole D Mitnick, Leonid Lecca, Guy B Marks [email protected] The University of Sydney, Sydney, NSW, Australia (ALB, BJM, GBM); Socios En Salud Sucursal (Partners In Health), Lima, Perú (ALB, CDM, LL); Centre for Research Excellence in, Sydney, NSW, Australia (ALB, BJM, CDM, LL); Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia (BJM); and Harvard Medical School, Boston, MA, USA (CDM) 1
2 3
4
5
Postma DS, Bush A, Van Den Berge M. Risk factors and early origins of chronic obstructive pulmonary disease. Lancet 2015; 385: 899–909. WHO. Global tuberculosis report 2014. Geneva: World Health Organization, 2014. Byrne AL, Marais BJ, Mitnick CD, Lecca L, Marks GB. Tuberculosis and chronic respiratory disease: a systematic review. Int J Infect Dis 2015; 32: 138–46. Lopez AD, Mathews CD, Ezzati M, Jamison DT, Murray CJL. Global burden of disease and risk factors. Washington: The World Bank, 2006. Van Zyl Smit RN, Pai M, Yew WW, et al. Global lung health: the colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD. Eur Respir J 2010; 35: 27–33.
Informed use of bedaquiline for tuberculosis
the scarcity of data, increased mortality in the bedaquiline group of one phase 2 trial, and public health importance of the drug, the FDA’s accelerated approval required that a patient registry be set up to assess serious adverse events, including death.2 In view of the small number of American patients receiving bedaquiline and to avoid selection bias, the inclusion of all recipients of bedaquiline in this registry is essential.2 Yet bedaquiline’s prospective registry opened in March, 2014, missing all the patients who started on the drug since the approval in December, 2012. The registry was developed without consulting end users and little has been done to inform prescribers about its existence. Clinicians who attempt to report in to the registry find the forms onerous and unclear. Importantly, consent forms are only available in English, despite the documented frequency of tuberculosis cases in foreign-born people.3 A simple, clear, and widely accessible process is urgently needed to gather crucial safety information from patients and providers. Results must be shared with FDA and with researchers and the public. We declare no competing interests.
*Erica M Lessem, John Bernardo, Caitlin Reed, Donna H Wegener [email protected] Treatment Action Group, New York, NY 10016-7701, USA (EML); Boston University School of Medicine, Boston, MA, USA (JB); Olive View-UCLA Medical Center Inpatient Tuberculosis Unit, Division of Infectious Diseases, Department of Medicine and David Geffen School of Medicine, UCLA, Los Angeles, CA, USA (CR); and National Tuberculosis Controllers Association, Smyrna, GA, USA (JB, DHW) 1
In their Viewpoint (Jan 31, p 477),1 Laia Ruiz Mingote and colleagues highlight the urgent need for additional safety data on bedaquiline, the first new tuberculosis drug to receive US Food and Drug Administration (FDA) approval in more than 40 years. Because the drug received accelerated approval based solely on phase 2 studies, critical safety data for bedaquiline are incomplete. In view of 1724
2
3
Ruiz Mingote L, Namutamba D, Apina F, et al. The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosisaffected communities. Lancet 2015; 385: 477–79. US Food and Drug Administration. Postmarketing requirements and commitments: Sirturo. August 2013. http:// www.accessdata.fda.gov/scripts/cder/pmc/ index.cfm (accessed July 18, 2014). Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2012. Atlanta, USA: 2013. http://www.cdc. gov/tb/statistics/reports/2012/pdf/ report2012.pdf (accessed July 18, 2014).
The Viewpoint by Laia Ruiz Mingote and colleagues1 raises safety concerns regarding bedaquiline in treatment shortening trials for pan-resistant tuberculosis (tuberculosis that is susceptible to all first-line antituberculosis treatments). A trial with similar issues is STAND TB, by the Global Alliance for TB Drug Development (TBA), which is testing the nitroimidazole PA-824 (pretomanid) in combination with pyrazinamide and moxifloxacin (PaMZ).2 There are little safety data on the use of PA-824 longer than 8 weeks, and both PA-824 and moxifloxacin have significant toxic effects.3 TBA have also decided to test the PaMZ regimen in a 4-month treatment-shortening trial. Few data support the use of this combination for treatment-shortening and this regimen might not be robust enough, in view of the results of other treatment-shortening trials.4 Another concern in STAND TB is the proposed use of PaMZ for patients with multidrug-resistant tuberculosis. Three-drug combinations have never been shown to be successful for the treatment of multidrug-resistant tuberculosis in any setting. In view of the high likelihood of developing resistance to the nitroimidazoles, there are also concerns about resistance amplification.5 Better treatment for multidrug-resistant tuberculosis is urgently needed, but safety and resistance amplification cannot be overlooked. Unfortunately, TBA is waiting to test the drug in more robust combinations for multidrug-resistant tuberculosis until it has been used for six months in the STAND-TB regimens. Much work is needed to improve care for patients with tuberculosis and multidrug resistant tuberculosis. The need for such radical changes, however, should not ignore the risks for patients inherent in such trials. I declare no competing interests.
Jennifer Furin [email protected]
www.thelancet.com Vol 385 May 2, 2015
Correspondence
1
2
3
4
5
Ruiz Mingote L, Namutamba D, Apina F, et al. The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosis affected communities. Lancet 2015; 385: 477–79. TB Alliance. New tuberculosis drug regimen will move to landmark phase 3 clinical trial. http://www.tballiance.org/newscenter/ viewbrief.php?id=1096 (accessed July 15, 2014). Dawson R, Diacon A, Everitt D, et al. Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drugsusceptible or drug-resistant pulmonary tuberculosis. Lancet 2015; published online March 17. http://dx.doi.org/10.1016/S01406736(14)62002-X. Merle CS, Sisimanadis C, Sow OB, et al. A pivotal registration phase III multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the Gatifloxacin for TB (OFLOTUB) project. Trials 2012; 13: 61. Manjunatha U, Boshoff H, Dowd C, et al. Identification of a nitroimidazo-oxazinespecific protein involved in PA-824 resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2006; 103: 431–36.
Authors’ reply We thank Erica Lessem and colleagues for commenting on our Viewpoint1 regarding the challenges surrounding the bedaquiline patient registry in the USA. For drugs like bedaquiline that receive accelerated approval, patient registries are a critical mechanism for collecting safety data on new drugs. Recent data from the US Centers for Disease Control and Prevention indicate that the tuberculosis epidemic in the USA is marked by increasing racial and ethnic disparities, and concentrated among foreign-born people. 2 It is essential that patient registries be made inclusive by facilitating the enrolment of non-native English speakers and susceptible populations. The inconsistencies that characterise tuberculosis epidemics should not be mirrored in the collection of drug safety data. Collecting important safety data on bedaquiline should also be facilitated globally. Global health institutions should support www.thelancet.com Vol 385 May 2, 2015
tuberculosis programmes with technical assistance, and create a multinational programme of data collection, analysis, and dissemination to facilitate WHO– recommended pharmacovigilance of new tuberculosis drugs. 3 The National Bedaquiline Clinical Access Program in South Africa offers one example of a successful monitoring programme.4 Importantly, it collects data on bedaquiline’s safety when given to patients with drug-resistant tuberculosis, or patients with HIV who are taking antiretrovirals—a patient population excluded from the phase 2 trials supporting bedaquiline’s approval. Although data from observational cohort studies are not as useful as evaluation of bedaquiline’s safety and efficacy in phase 3 clinical trials, interim analysis of 91 patients receiving bedaquiline in South Africa’s clinical access programme, presented in October, 2014, provide encouraging information on bedaquiline’s safety in the absence of further trials data.5 Further clinical trials for new tuberculosis drugs, including a phase 3 trial of bedaquiline, are still necessary. Jennifer Furin raises concerns about the evaluation of PA-824 (pretomanid) in combination with pyrazinamide and moxifloxacin in the Global Alliance for TB Drug Development’s STAND trial. Our community advisory board, the Community Research Advisors Group, does not advise the Global Alliance for TB Drug Development and cannot comment on the specifics of pretomanid’s development. Furin also notes the Global Alliance for TB Drug Development’s decision not to provide pretomanid to a proposed AIDS Clinical Trials Group study. Investigators have reported similar difficulties in acquiring bedaquiline for further studies. Increasingly, access to new compounds is a challenge not only for communities affected by tuberculosis, but also for researchers. New tuberculosis drugs
such as bedaquiline and delamanid must be available for researchers to study in different combinations to arrive at optimum treatment options. We call on tuberculosis drug developers to work together in the best interests of patients and communities.
GUSTOIMAGES/Science Photo Library
Case Western Reserve University, TB Research Unit, Cleveland, OH 44106, USA
MWF has received grants from the Global Alliance for TB Drug Development and the Stop TB Partnership for projects outside the submitted work. All other authors declare no competing interests.
Laia Ruiz Mingote, Dorothy Namutamba, Barbara Seaworth, Cynthia Lee, *Mike Watson Frick [email protected] Community Research Advisors Group, New York, NY, USA (LRM, DN, BS, CL); and Treatment Action Group, New York, NY 10016, USA (MWF) 1
2
3
4
5
Ruiz Mingote L, Namutamba D, Apina F, et al. The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosisaffected communities. Lancet 2015; 385: 477–79. Scott C, Kirking H, Jeffries C, Price S, Pratt R. Tuberculosis trends—United States, 2014. MMWR Morb Mortal Wkly Rep 2015; 64: 265–69. WHO. The use of bedaquiline in the treatment of multidrug resistant tuberculosis: expert group meeting report. Geneva: January 29–30, 2013. http://www.who.int/tb/challenges/ mdr/Report_EGM_BDQ_2013.pdf (accessed March 25, 2015). Conradie F, Meintjes G, Hughes J, et al. Clinical access to bedaquiline programme for the treatment of drug-resistant tuberculosis. S Afr Med J 2014; 104: 164–66. Ndjeka N, Conradie F, Hughes J, et al. Safe and effective bedaquiline treatment of drug resistant tuberculosis (DR-TB) within the National Bedaquiline Clinical Access Programme in South Africa. 45th Union World Conference on Lung Health, Oct 28–Nov 1, 2014, Barcelona.
Dengue vaccine—time to act now Maria Rosario Capeding and colleagues (Oct 11, p 1358) 1 have demonstrated the efficacy and safety of a dengue vaccine in a study conducted in five Asian countries where more than 1 in 25 unvaccinated children suffered a symptomatic dengue episode each year. With 56·5% (95% CI 43·8–66·4) overall 1725
