Correspondence
1
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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
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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
Correspondence
efficacy, more than 80% of dengue haemorrhagic fever episodes were avoided, and hospitalisation was reduced by two-thirds. Therefore, this vaccine should have a substantial public health impact in the Asia Pacific region, which hosts more than 75% of the 2·5 billion people at risk of dengue worldwide, constituting a so-called silent disaster. 2 Similar findings were reported from a sister study in five countries in Latin America.3 In her Comment, 4 Annelies Wilder-Smith recognises the dawn of a new era, as the potential use of this vaccine could be a major turning point for global dengue control. While waiting for additional data from Latin America, 3 it is important that Asian countries start considering how best this vaccine could be introduced along with the preventive measures already used, including vector control and public awareness. To reach a reduction in dengue morbidity of 25% and mortality of 50% by 2020, 5 a vaccination programme covering both routine target populations and several catch-up cohorts is required. Therefore, mobilisation of the international community is needed to support countries of limited resource in the implementation of an effective and sustainable dengue prevention programme based on social mobilisation, vector control, and evidence-based vaccination programmes. The vaccine has a reassuring safety profile. Let’s ensure the vaccine is rationally deployed in countries that need it most to help end this silent disaster once and for all. We declare no competing interests.
*Tikki Pang, Daniel Goh Yam Thiam, Terapong Tantawichien, Zulkifli Ismail, Sutee Yoksan [email protected] Lee Kuan Yew School of Public Policy, National University of Singapore, Singapore 259772, Singapore (TP); Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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(DGYT); Department of Medicine, Chulalongkorn University, Bangkok, Thailand (TT); KPJ Selangor Specialist Hospital, Kuala Lumpur, Malaysia (ZI); and Centre of Vaccine Development, Institute of Molecular Biosciences, Mahidol University, Bangkok, Thailand (SY) 1
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Capeding MR, Tran NH, Hadinegoro SR, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observermasked, placebo-controlled trial. Lancet 2014; 384: 1358–65. International Federation of Red Cross and Red Crescent Societies. Dengue. Turning up the volume on a silent disaster. 03/2014 E200. http://www.ifrc.org/dengue (accessed July 18, 2014). Villar L, Dayan GH, Arredondo-Garcia JL, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 2015; 373: 113–23. Wilder-Smith A. Dengue vaccines: dawning at last? Lancet 2014; 384: 1327–29. WHO Global strategy for dengue prevention and control, 2012. http://www.who.int/ denguecontrol/9789241504034/en/ (accessed April 10, 2015).
Differential efficacy of dengue vaccine by immune status Maria Rosario Capeding and colleagues1 report the first phase 3 trial results assessing Sanofi-Pasteur’s dengue vaccine candidate. Perprotocol analysis showed overall efficacy of 56·5% (95% CI 43·8–66·4), meeting the study’s primary endpoint. Post-hoc analyses showed high efficacy against dengue haemorrhagic fever (80%) and markedly different efficacy by baseline immune status (74·3% in previously exposed patients vs 35·5% in naive patients). The reduced risk of dengue haemorrhagic fever in vaccine recipients is encouraging, and suggests that the vaccine might have substantial public health impact. The differential efficacy by baseline immune status, however, might have implications for vaccine introduction. First, although efficacies were similar across study sites, all five trial settings are hyperendemic. Potential effectiveness in lower transmission
settings, or in places where only subsets of serotypes circulate, will probably be a function of the level of seropositivity and serotype distribution in the vaccinated population.2 Second, a vaccine that shows reduced efficacy in unexposed individuals will inevitably show dynamic efficacy when applied at the population level. Vaccineinduced reductions in transmission intensity will lead to lower levels of population immunity that will result in reduced vaccine efficacy. Targeted vaccination programmes will be fundamental to maximise public health effect. Careful subgroup analyses of this study and a Latin American phase 3 trial (NCT01374516)3 will be crucial for anticipation of vaccine efficacies in specific settings. Additionally, transmission modelling could have a particularly important role in the assessment of the short-term and medium-term effect of potential immunisation strategies, given the complex efficacy profile of this vaccine. DSB serves as an unpaid scientific adviser to Sanofi Pasteur on dengue vaccines. We declare no other competing interests.
*Isabel Rodriguez-Barraquer, Luis Mier-y-Teran-Romero, Neil Ferguson, Donald S Burke, Derek A T Cummings [email protected] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA (IR-B, LM-y-T-R, DATC); Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, London, UK (NF); and University of Pittsburgh Graduate School of Public Health (DSB) 1
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3
Capeding MR, Tran NH, Hadinegoro SR, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet 2014; 384: 1358–65. Rodriguez-Barraquer I, Mier-y-Teran-Romero L, Burke DS, Cummings DAT. Challenges in the interpretation of dengue vaccine trial results. PLoS Negl Trop Dis 2013; 7: e2126. Villar L, Dayan GH, Arredondo-Garcia JL, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 2015; 373: 113–23.
www.thelancet.com Vol 385 May 2, 2015
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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
Correspondence
efficacy, more than 80% of dengue haemorrhagic fever episodes were avoided, and hospitalisation was reduced by two-thirds. Therefore, this vaccine should have a substantial public health impact in the Asia Pacific region, which hosts more than 75% of the 2·5 billion people at risk of dengue worldwide, constituting a so-called silent disaster. 2 Similar findings were reported from a sister study in five countries in Latin America.3 In her Comment, 4 Annelies Wilder-Smith recognises the dawn of a new era, as the potential use of this vaccine could be a major turning point for global dengue control. While waiting for additional data from Latin America, 3 it is important that Asian countries start considering how best this vaccine could be introduced along with the preventive measures already used, including vector control and public awareness. To reach a reduction in dengue morbidity of 25% and mortality of 50% by 2020, 5 a vaccination programme covering both routine target populations and several catch-up cohorts is required. Therefore, mobilisation of the international community is needed to support countries of limited resource in the implementation of an effective and sustainable dengue prevention programme based on social mobilisation, vector control, and evidence-based vaccination programmes. The vaccine has a reassuring safety profile. Let’s ensure the vaccine is rationally deployed in countries that need it most to help end this silent disaster once and for all. We declare no competing interests.
*Tikki Pang, Daniel Goh Yam Thiam, Terapong Tantawichien, Zulkifli Ismail, Sutee Yoksan [email protected] Lee Kuan Yew School of Public Policy, National University of Singapore, Singapore 259772, Singapore (TP); Yong Loo Lin School of Medicine, National University of Singapore, Singapore
1726
(DGYT); Department of Medicine, Chulalongkorn University, Bangkok, Thailand (TT); KPJ Selangor Specialist Hospital, Kuala Lumpur, Malaysia (ZI); and Centre of Vaccine Development, Institute of Molecular Biosciences, Mahidol University, Bangkok, Thailand (SY) 1
2
3
4 5
Capeding MR, Tran NH, Hadinegoro SR, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observermasked, placebo-controlled trial. Lancet 2014; 384: 1358–65. International Federation of Red Cross and Red Crescent Societies. Dengue. Turning up the volume on a silent disaster. 03/2014 E200. http://www.ifrc.org/dengue (accessed July 18, 2014). Villar L, Dayan GH, Arredondo-Garcia JL, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 2015; 373: 113–23. Wilder-Smith A. Dengue vaccines: dawning at last? Lancet 2014; 384: 1327–29. WHO Global strategy for dengue prevention and control, 2012. http://www.who.int/ denguecontrol/9789241504034/en/ (accessed April 10, 2015).
Differential efficacy of dengue vaccine by immune status Maria Rosario Capeding and colleagues1 report the first phase 3 trial results assessing Sanofi-Pasteur’s dengue vaccine candidate. Perprotocol analysis showed overall efficacy of 56·5% (95% CI 43·8–66·4), meeting the study’s primary endpoint. Post-hoc analyses showed high efficacy against dengue haemorrhagic fever (80%) and markedly different efficacy by baseline immune status (74·3% in previously exposed patients vs 35·5% in naive patients). The reduced risk of dengue haemorrhagic fever in vaccine recipients is encouraging, and suggests that the vaccine might have substantial public health impact. The differential efficacy by baseline immune status, however, might have implications for vaccine introduction. First, although efficacies were similar across study sites, all five trial settings are hyperendemic. Potential effectiveness in lower transmission
settings, or in places where only subsets of serotypes circulate, will probably be a function of the level of seropositivity and serotype distribution in the vaccinated population.2 Second, a vaccine that shows reduced efficacy in unexposed individuals will inevitably show dynamic efficacy when applied at the population level. Vaccineinduced reductions in transmission intensity will lead to lower levels of population immunity that will result in reduced vaccine efficacy. Targeted vaccination programmes will be fundamental to maximise public health effect. Careful subgroup analyses of this study and a Latin American phase 3 trial (NCT01374516)3 will be crucial for anticipation of vaccine efficacies in specific settings. Additionally, transmission modelling could have a particularly important role in the assessment of the short-term and medium-term effect of potential immunisation strategies, given the complex efficacy profile of this vaccine. DSB serves as an unpaid scientific adviser to Sanofi Pasteur on dengue vaccines. We declare no other competing interests.
*Isabel Rodriguez-Barraquer, Luis Mier-y-Teran-Romero, Neil Ferguson, Donald S Burke, Derek A T Cummings [email protected] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA (IR-B, LM-y-T-R, DATC); Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, London, UK (NF); and University of Pittsburgh Graduate School of Public Health (DSB) 1
2
3
Capeding MR, Tran NH, Hadinegoro SR, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet 2014; 384: 1358–65. Rodriguez-Barraquer I, Mier-y-Teran-Romero L, Burke DS, Cummings DAT. Challenges in the interpretation of dengue vaccine trial results. PLoS Negl Trop Dis 2013; 7: e2126. Villar L, Dayan GH, Arredondo-Garcia JL, et al. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 2015; 373: 113–23.
www.thelancet.com Vol 385 May 2, 2015
