- Email: [email protected]
Artemisinin resistance in Myanmar
Correspondence
A
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100
Proportion of correct responses (%)
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Proportion of correct responses (%)
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GS BA HS
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Morrill HJ, LaPlante KL. Overconsumption of antibiotics. Lancet Infect Dis 2015; 15: 377–78. National Science Foundation. Science and Engineering Indicators 2014. NSF, 2014. http:// www.nsf.gov/statistics/seind14/ (accessed April 12, 2015). Huttner B, Goossens H, Verheij T, et al. Characteristics and outcomes of public campaigns aimed at improving the use of antibiotics in outpatients in high-income countries. Lancet Infect Dis 2010; 10: 17–31. Podolsky SH. The antibiotic era: reform, resistance, and the pursuit of a rational therapeutics. Baltimore, MD, USA: Johns Hopkins University Press, 2014. Mangione-Smith R, Elliott MN, Stivers T, McDonald LL, Heritage J. Ruling out the need for antibiotics: are we sending the right message? Arch Pediatr Adolesc Med 2006; 160: 945–52. Mangione-Smith R, Elliott MN, Stivers T, McDonald LL, Heritage J. McGlynn EA. Racial/ ethnic variation in parent expectations for antibiotics: implications for public health campaigns. Pediatrics 2004; 113: e385–94. Little P, Moore M, Kelly J, et al. Delayed antibiotic prescribing strategies for respiratory tract infections in primary care: pragmatic, factorial, randomised controlled trial. BMJ 2014; 348: g1606.
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Artemisinin resistance in Myanmar
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Figure: Public knowledge of antibiotics in the USA, 1990–2012 (A) Proportion of correct responses for all respondents to the survey question “Antibiotics kill viruses as well as bacteria” (false; p<0·001 for trend). (B) Proportion of correct responses to the survey question “Antibiotics kill viruses as well as bacteria” by sex and highest level of educational attainment. HS=high school or less. BA=college. GS=graduate school or higher.
practicing in predominately low socioeconomic status regions might have a dis proportionate effect on overall antibiotic use. Deferral or no antibiotic prescribing has been associated with a softening of beliefs among patients in the necessity of antibiotics,7 suggesting that coordinated efforts to reduce antibiotic prescribing could have a virtuous downstream effect on patient knowledge and outcomes. Public health officials and clinicians must better assess the state of knowledge of the public as a precursor to the design and implementation of more effective interventions to promote understanding, and encourage the judicious use of antibiotics.
This study was supported by grants from the Interfaculty Initiative in Health Policy (Cordeiro Research Fellowship to Mr Hwang), Center for American Political Studies, and Dunwalke Fund, all at Harvard University. Dr. Gibbs is supported by a grant from the David and Lucile Packard Foundation. Dr Linder was supported by grants from the National Institutes of Health (RC4 AG039115), the National Institute of Allergy and Infectious Diseases (R21 AI097759), and the Agency for Healthcare Research and Quality (R18 HS018419).
*Thomas J Hwang, Karine A Gibbs, Scott H Podolsky, Jeffrey A Linder [email protected] Faculty of Arts and Sciences (TJH), and Department of Molecular and Cellular Biology (KAG) , Harvard University, Cambridge, MA, USA; Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA (SHP); Center for the History of Medicine, Francis Countway Library of Medicine, Boston, MA, USA (SHP); and Division of General Medicine and Primary Care, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA (JAL)
www.thelancet.com/infection Vol 15 September 2015
We were surprised to read in Kyaw Tun and colleagues’ report1 in The Lancet Infectious Diseases that artemisinin resistance is spreading in Myanmar. In 2014, we reported no evidence of spread of artemisinin resistance from Cambodia to Myanmar.2 Genotyping of the adjacent region of Plasmodium falciparum chromosome 13 showed that some of the same K13 mutants in Cambodia and Vietnam arose on the same genetic background, whereas those in Myanmar and Cambodia emerged on different backgrounds, suggesting spread between Cambodia and Vietnam but independent emergence of artemisinin resistance in Myanmar.2 Another report confirmed this finding.3 The possibility was also raised of a spread in the past of a resistance-prone (but not resistant) strain upon which K13 mutations arose, but this scenario is hard to reconcile with the evidence of K13 mutations arising on different extended haplotypes surrounding K13. Both papers2,3 showing independent emergence of artemisinin resistance 1001
Correspondence
in southeast Asia were co-authored by several investigators who wrote the Article by Tun and colleagues.1 We were further surprised to read, in reference to artemisinin resistance in central Myanmar, that “Before this study, the prevalence of artemisininresistant parasites in other parts of Myanmar had not been reported.”1 Our 2014 paper reported that the prevalence of K13 mutations in southern Myanmar in 2011 was 37%.2 Many K13 mutations are of unknown importance, and the efficacy of artemisinin-based com bination therapies has been shown to remain high throughout Myanmar, Laos, Vietnam, and China, despite high prevalence of delayed clearance.4 However, artemisinin-based combination therapies are failing in Cambodia, probably because resistance to the partner drug had already been present when such therapies were implemented. The role of artemisinin resistance in the development of partner-drug resistance needs to be further studied. Malaria elimination demands rigorous evidence and an accurate interpretation of that evidence. Although the story of a westward spread of artemisinin resistance from Cambodia through Myanmar to India and Africa is compelling to news organisations, this story is not supported by the available data. The evidence is clear: artemisinin resistance is both spreading and emerging independently in the Greater Mekong subregion. On the basis of independent emergence of artemisinin resistance, the existence of multidrug resistance in western Cambodia, and the lowest burden of disease ever seen in southeast Asia, WHO has recommended that containment of artemisinin resistance be abandoned in favour of elimination of P falciparum malaria from the entire Greater Mekong subregion. WHO and regional governments are now gearing up for a regional malaria elimination campaign. We declare no competing interests.
1002
*Christopher V Plowe, Pascal Ringwald [email protected] Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA (CVP); and Global Malaria Programme, World Health Organization, Geneva, Switzerland (PR) © 2015. World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. 1
2
3
4
Tun KM, Imwong M, Lwin KM, et al. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis 2015; 15: 415–21. Takala-Harrison S, Jacob CG, Arze C, et al. Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in southeast Asia. J Infect Dis 2015; 211: 670–79. Miotto O, Amato R, Ashley EA, et al. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat Genet 2015; 47: 226–34. Ashley EA, Dhorda M, Fairhurst RM, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2014; 371: 411–23.
Authors’ reply We thank Christopher Plowe and Pascal Ringwald for their comments on our Article about the spread of artemisinin-resistant Plasmodium falciparum in Myanmar.1 8 years ago when artemisinin resistance was first recognised, there was hope that it might be confined to western Cambodia and contained there. Since then, artemisinin resistance has appeared in northwest Thailand2,3 and intensified in western Cambodia and other parts of Thailand.3,4 Resistance has spread throughout southeast Asia in the face of intensified control measures; in other words, containment has failed. We stand by our conclusion that artemisinin resistance is spreading faster than the rate at which control and elimination measures are being developed and instituted. We have heard that “WHO and regional governments are now gearing up for a regional malaria elimination campaign”, but in the meantime people, and presumably malaria parasites, are travelling to south Asia and Africa. So far we do not have evidence for either spread to, or independent emergence in, these regions that harbour most of
the world’s malaria. Clearly more can be learned about the genetic changes that allow multiple single point mutations in the P falciparum K13 protein to be selected. Plowe and Ringwald suggest that “many K13 mutations are of unknown significance”, but of 371 parasites with K13 propeller mutations reported in our Myanmar study, 326 (88%) carried mutations known to be associated with phenotypic resistance, including the F446I mutation prevalent across much of Upper Myanmar.5 From an operational perspective the key message is that artemisinin resistance is associated with partner drug resistance. We think it unwise to rely on the continued efficacy of relatively unprotected single partner drugs in artemisinin-based combination therapy. The malaria burden has declined in most of the southeast Asian region where partner drugs still retain high efficacy, but failure rates of artemisinin-based combination therapy have risen at the Thai–Myanmar border6 (not just in Cambodia), and the increase in malaria in provinces in Cambodia where piperaquine resistance is widespread should be a warning to us all. We declare no competing interests.
*Mallika Imwong, Kyaw Myo Tun, Tin Maung Hlaing, Eric P Grist, Philippe Guerin, Frank Smithuis, Arjen M Dondorp, Nicholas P Day, Francois Nosten, Nicholas White, Charles J Woodrow [email protected] Mahidol University, Molecular Tropical Medicine, 420/6 Bangkok,Thailand (MI); Myanmar-Oxford Clinical Research Unit, Yangon, Myanmar (KMT, FS); Defence Services Medical Research Centre, Naypyitaw, Myanmar (TMH); WorldWide Antimalarial Resistance Network, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK (EPG, PG); Shoklo Malaria Research Unit, Mae Sot, Thailand (FN); and Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (AMD, NPD, NW, CJW) 1
Tun KM, Imwong M, Lwin KM, et al. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis 2015; 15: 415–421.
www.thelancet.com/infection Vol 15 September 2015
A
1
100
Proportion of correct responses (%)
2 75
3 50
4 25
5 2011
2012
2010
2009
2007
2008
2005
2006
2003
2004
2001
2002
2000
1999
1997
1998
1995
1996
1993
1994
1991
1992
1990
0
6
Year
B Female Male
Proportion of correct responses (%)
100
GS BA HS
75
7
Morrill HJ, LaPlante KL. Overconsumption of antibiotics. Lancet Infect Dis 2015; 15: 377–78. National Science Foundation. Science and Engineering Indicators 2014. NSF, 2014. http:// www.nsf.gov/statistics/seind14/ (accessed April 12, 2015). Huttner B, Goossens H, Verheij T, et al. Characteristics and outcomes of public campaigns aimed at improving the use of antibiotics in outpatients in high-income countries. Lancet Infect Dis 2010; 10: 17–31. Podolsky SH. The antibiotic era: reform, resistance, and the pursuit of a rational therapeutics. Baltimore, MD, USA: Johns Hopkins University Press, 2014. Mangione-Smith R, Elliott MN, Stivers T, McDonald LL, Heritage J. Ruling out the need for antibiotics: are we sending the right message? Arch Pediatr Adolesc Med 2006; 160: 945–52. Mangione-Smith R, Elliott MN, Stivers T, McDonald LL, Heritage J. McGlynn EA. Racial/ ethnic variation in parent expectations for antibiotics: implications for public health campaigns. Pediatrics 2004; 113: e385–94. Little P, Moore M, Kelly J, et al. Delayed antibiotic prescribing strategies for respiratory tract infections in primary care: pragmatic, factorial, randomised controlled trial. BMJ 2014; 348: g1606.
50
Artemisinin resistance in Myanmar
25
Year
2012
2010
2006
2008
2004
2002
2000
1998
1996
1992
1994
1990
2012
2010
2008
2006
2004
2002
2000
1998
1996
1994
1992
1990
0
Year
Figure: Public knowledge of antibiotics in the USA, 1990–2012 (A) Proportion of correct responses for all respondents to the survey question “Antibiotics kill viruses as well as bacteria” (false; p<0·001 for trend). (B) Proportion of correct responses to the survey question “Antibiotics kill viruses as well as bacteria” by sex and highest level of educational attainment. HS=high school or less. BA=college. GS=graduate school or higher.
practicing in predominately low socioeconomic status regions might have a dis proportionate effect on overall antibiotic use. Deferral or no antibiotic prescribing has been associated with a softening of beliefs among patients in the necessity of antibiotics,7 suggesting that coordinated efforts to reduce antibiotic prescribing could have a virtuous downstream effect on patient knowledge and outcomes. Public health officials and clinicians must better assess the state of knowledge of the public as a precursor to the design and implementation of more effective interventions to promote understanding, and encourage the judicious use of antibiotics.
This study was supported by grants from the Interfaculty Initiative in Health Policy (Cordeiro Research Fellowship to Mr Hwang), Center for American Political Studies, and Dunwalke Fund, all at Harvard University. Dr. Gibbs is supported by a grant from the David and Lucile Packard Foundation. Dr Linder was supported by grants from the National Institutes of Health (RC4 AG039115), the National Institute of Allergy and Infectious Diseases (R21 AI097759), and the Agency for Healthcare Research and Quality (R18 HS018419).
*Thomas J Hwang, Karine A Gibbs, Scott H Podolsky, Jeffrey A Linder [email protected] Faculty of Arts and Sciences (TJH), and Department of Molecular and Cellular Biology (KAG) , Harvard University, Cambridge, MA, USA; Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA (SHP); Center for the History of Medicine, Francis Countway Library of Medicine, Boston, MA, USA (SHP); and Division of General Medicine and Primary Care, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA (JAL)
www.thelancet.com/infection Vol 15 September 2015
We were surprised to read in Kyaw Tun and colleagues’ report1 in The Lancet Infectious Diseases that artemisinin resistance is spreading in Myanmar. In 2014, we reported no evidence of spread of artemisinin resistance from Cambodia to Myanmar.2 Genotyping of the adjacent region of Plasmodium falciparum chromosome 13 showed that some of the same K13 mutants in Cambodia and Vietnam arose on the same genetic background, whereas those in Myanmar and Cambodia emerged on different backgrounds, suggesting spread between Cambodia and Vietnam but independent emergence of artemisinin resistance in Myanmar.2 Another report confirmed this finding.3 The possibility was also raised of a spread in the past of a resistance-prone (but not resistant) strain upon which K13 mutations arose, but this scenario is hard to reconcile with the evidence of K13 mutations arising on different extended haplotypes surrounding K13. Both papers2,3 showing independent emergence of artemisinin resistance 1001
Correspondence
in southeast Asia were co-authored by several investigators who wrote the Article by Tun and colleagues.1 We were further surprised to read, in reference to artemisinin resistance in central Myanmar, that “Before this study, the prevalence of artemisininresistant parasites in other parts of Myanmar had not been reported.”1 Our 2014 paper reported that the prevalence of K13 mutations in southern Myanmar in 2011 was 37%.2 Many K13 mutations are of unknown importance, and the efficacy of artemisinin-based com bination therapies has been shown to remain high throughout Myanmar, Laos, Vietnam, and China, despite high prevalence of delayed clearance.4 However, artemisinin-based combination therapies are failing in Cambodia, probably because resistance to the partner drug had already been present when such therapies were implemented. The role of artemisinin resistance in the development of partner-drug resistance needs to be further studied. Malaria elimination demands rigorous evidence and an accurate interpretation of that evidence. Although the story of a westward spread of artemisinin resistance from Cambodia through Myanmar to India and Africa is compelling to news organisations, this story is not supported by the available data. The evidence is clear: artemisinin resistance is both spreading and emerging independently in the Greater Mekong subregion. On the basis of independent emergence of artemisinin resistance, the existence of multidrug resistance in western Cambodia, and the lowest burden of disease ever seen in southeast Asia, WHO has recommended that containment of artemisinin resistance be abandoned in favour of elimination of P falciparum malaria from the entire Greater Mekong subregion. WHO and regional governments are now gearing up for a regional malaria elimination campaign. We declare no competing interests.
1002
*Christopher V Plowe, Pascal Ringwald [email protected] Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA (CVP); and Global Malaria Programme, World Health Organization, Geneva, Switzerland (PR) © 2015. World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. 1
2
3
4
Tun KM, Imwong M, Lwin KM, et al. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis 2015; 15: 415–21. Takala-Harrison S, Jacob CG, Arze C, et al. Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in southeast Asia. J Infect Dis 2015; 211: 670–79. Miotto O, Amato R, Ashley EA, et al. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat Genet 2015; 47: 226–34. Ashley EA, Dhorda M, Fairhurst RM, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2014; 371: 411–23.
Authors’ reply We thank Christopher Plowe and Pascal Ringwald for their comments on our Article about the spread of artemisinin-resistant Plasmodium falciparum in Myanmar.1 8 years ago when artemisinin resistance was first recognised, there was hope that it might be confined to western Cambodia and contained there. Since then, artemisinin resistance has appeared in northwest Thailand2,3 and intensified in western Cambodia and other parts of Thailand.3,4 Resistance has spread throughout southeast Asia in the face of intensified control measures; in other words, containment has failed. We stand by our conclusion that artemisinin resistance is spreading faster than the rate at which control and elimination measures are being developed and instituted. We have heard that “WHO and regional governments are now gearing up for a regional malaria elimination campaign”, but in the meantime people, and presumably malaria parasites, are travelling to south Asia and Africa. So far we do not have evidence for either spread to, or independent emergence in, these regions that harbour most of
the world’s malaria. Clearly more can be learned about the genetic changes that allow multiple single point mutations in the P falciparum K13 protein to be selected. Plowe and Ringwald suggest that “many K13 mutations are of unknown significance”, but of 371 parasites with K13 propeller mutations reported in our Myanmar study, 326 (88%) carried mutations known to be associated with phenotypic resistance, including the F446I mutation prevalent across much of Upper Myanmar.5 From an operational perspective the key message is that artemisinin resistance is associated with partner drug resistance. We think it unwise to rely on the continued efficacy of relatively unprotected single partner drugs in artemisinin-based combination therapy. The malaria burden has declined in most of the southeast Asian region where partner drugs still retain high efficacy, but failure rates of artemisinin-based combination therapy have risen at the Thai–Myanmar border6 (not just in Cambodia), and the increase in malaria in provinces in Cambodia where piperaquine resistance is widespread should be a warning to us all. We declare no competing interests.
*Mallika Imwong, Kyaw Myo Tun, Tin Maung Hlaing, Eric P Grist, Philippe Guerin, Frank Smithuis, Arjen M Dondorp, Nicholas P Day, Francois Nosten, Nicholas White, Charles J Woodrow [email protected] Mahidol University, Molecular Tropical Medicine, 420/6 Bangkok,Thailand (MI); Myanmar-Oxford Clinical Research Unit, Yangon, Myanmar (KMT, FS); Defence Services Medical Research Centre, Naypyitaw, Myanmar (TMH); WorldWide Antimalarial Resistance Network, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK (EPG, PG); Shoklo Malaria Research Unit, Mae Sot, Thailand (FN); and Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (AMD, NPD, NW, CJW) 1
Tun KM, Imwong M, Lwin KM, et al. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis 2015; 15: 415–421.
www.thelancet.com/infection Vol 15 September 2015