Gametocyte Carriage, Antimalarial Use, and Drug Resistance in Cambodia, 2008–2014

Jessica T. Lin Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina;

Search for other papers by Jessica T. Lin in
Current site
Google Scholar
PubMed Close
,
Jaymin C. Patel Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina;

Search for other papers by Jaymin C. Patel in
Current site
Google Scholar
PubMed Close
,
Lauren Levitz Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina;

Search for other papers by Lauren Levitz in
Current site
Google Scholar
PubMed Close
,
Mariusz Wojnarski Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand;

Search for other papers by Mariusz Wojnarski in
Current site
Google Scholar
PubMed Close
,
Suwanna Chaorattanakawee Department of Parasitology and Entomology, Faculty of Public Health, Mahidol University, Bangkok, Thailand;

Search for other papers by Suwanna Chaorattanakawee in
Current site
Google Scholar
PubMed Close
,
Panita Gosi Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand;

Search for other papers by Panita Gosi in
Current site
Google Scholar
PubMed Close
,
Nillawan Buathong Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand;

Search for other papers by Nillawan Buathong in
Current site
Google Scholar
PubMed Close
,
Soklyda Chann Armed Forces Research Institute of Medical Sciences, Phnom Penh, Cambodia;

Search for other papers by Soklyda Chann in
Current site
Google Scholar
PubMed Close
,
Rekol Huy National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia;

Search for other papers by Rekol Huy in
Current site
Google Scholar
PubMed Close
,
Khengheng Thay National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia;

Search for other papers by Khengheng Thay in
Current site
Google Scholar
PubMed Close
,
Darapiseth Sea Armed Forces Research Institute of Medical Sciences, Phnom Penh, Cambodia;

Search for other papers by Darapiseth Sea in
Current site
Google Scholar
PubMed Close
,
Nou Samon Armed Forces Research Institute of Medical Sciences, Phnom Penh, Cambodia;

Search for other papers by Nou Samon in
Current site
Google Scholar
PubMed Close
,
Shannon Takala-Harrison Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland;

Search for other papers by Shannon Takala-Harrison in
Current site
Google Scholar
PubMed Close
,
Mark Fukuda Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand;

Search for other papers by Mark Fukuda in
Current site
Google Scholar
PubMed Close
,
Philip Smith Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand;

Search for other papers by Philip Smith in
Current site
Google Scholar
PubMed Close
,
Michele Spring Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand;

Search for other papers by Michele Spring in
Current site
Google Scholar
PubMed Close
,
David Saunders U.S. Army Medical Materiel Development Activity, Fort Detrick, Maryland

Search for other papers by David Saunders in
Current site
Google Scholar
PubMed Close
, and
Chanthap Lon Armed Forces Research Institute of Medical Sciences, Phnom Penh, Cambodia;

Search for other papers by Chanthap Lon in
Current site
Google Scholar
PubMed Close
DOI:
https://doi.org/10.4269/ajtmh.18-0509
Volume/Issue:
Volume 99: Issue 5
Page(s):
1145–1149
Restricted access
Get Permissions

Gametocytes are the malaria parasite stages responsible for transmission from humans to mosquitoes. Gametocytemia often follows drug treatment, especially as therapies start to fail. We examined Plasmodium falciparum gametocyte carriage and drug resistance profiles among 824 persons with uncomplicated malaria in Cambodia to determine whether prevalent drug resistance and antimalarial use has led to a concentration of drug-resistant parasites among gametocyte carriers. Although report of prior antimalarial use increased from 2008 to 2014, the prevalence of study participants presenting with microscopic gametocyte carriage declined. Gametocytemia was more common in those reporting antimalarial use within the past year, and prior antimalarial use was correlated with higher IC50s to piperaquine and mefloquine, as well as to increased pfmdr1 copy number. However, there was no association between microscopic gametocyte carriage and parasite drug resistance. Thus, we found no evidence that the infectious reservoir, marked by those carrying gametocytes, is enriched with drug-resistant parasites.

    • Supplemental Materials (PDF 32 KB)
    • Supplemental Materials (JPG 1854 KB)
    • Supplemental Materials (TIFF 757 KB)
    • Supplemental Materials (PDF 124 KB)

Author Notes

Address correspondence to Jessica T. Lin, Division of Infectious Diseases, University of North Carolina School of Medicine, 130 Mason Farm Rd., CB 7030, Chapel Hill, NC 27599. E-mail: jessica_lin@med.unc.edu

Financial support: Funding was provided by the Global Emerging Infections Surveillance (GEIS) Program, the Armed Forces Health Surveillance Center, the U.S. Department of Defense, and the National Institute of Allergy and Infectious Diseases (K08 AI110651 to J. T. L.).

Authors’ addresses: Jessica T. Lin, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, NC, E-mail: jessica_lin@med.unc.edu. Jaymin C. Patel and Lauren Levitz, Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, E-mails: jaymin86@gmail.com and lauren.levitz@gmail.com. Mariusz Wojnarski, Panita Gosi, Nillawan Buathong, Mark Fukuda, Philip Smith, and Michele Spring, Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, E-mails: mariusz.wojnarski.mil@afrims.org, panitag.fsn@afrims.org, nillawanb.fsn@afrims.org, mark.fukuda.mil@afrims.org, philip.smith.mil@afrims.org, and michele.spring.ctr@afrims.org. Suwanna Chaorattanakawee, Department of Parasitology and Public Health, Mahidol University, Bangkok, Thailand, E-mail: suwann67@yahoo.com. Soklyda Chann, Chanthap Lon, Sea Darapiseth, and Samon Nou, Armed Forces Research Institute of Medical Sciences, AFRIMS Cambodia, Phnom Penh, Cambodia, E-mails: channs.ctr@afrims.org, darapiseths.ca@afrims.org, chanthapl.ca@afrims.org, and samon.nu.ctr@afrims.org. Huy Rekol and Khengheng Thay, National Malaria Center, Malaria Phnom Penh, Ministry of Health, Phnom Penh, Cambodia, E-mails: kolhuy@gmail.com and thaykhengheng@yahoo.com. Shannon Takala-Harrison, Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, E-mail: stakala@som.umaryland.edu. David Saunders, Immunology, Armed Forces Research Institute of Medical Sciences, Fort Detrick, MD, E-mail: david.l.saunders.mil@mail.mil.

Copyright:
© The American Society of Tropical Medicine and Hygiene 2018
Received:
16 Jun 2018
|
Accepted:
10 Aug 2018
|
Published Online:
17 Sep 2018
Cover The American Journal of Tropical Medicine and Hygiene
The American Journal of Tropical Medicine and Hygiene
Print ISSN:
0002-9637
Online ISSN:
1476-1645
  • 1.

    WHO, 2013. Emergency Response to Artemisinin Resistance in the Greater Mekong Subregion. Regional framework for action 2013–2015. World Health Organization Archived publication. Available at: http://www.who.int/malaria/publications/atoz/9789241505321/en/. Accessed February 4, 2018.

  • 2.

    Chaorattanakawee S et al. 2015. Ex vivo drug susceptibility testing and molecular profiling of clinical Plasmodium falciparum isolates from Cambodia from 2008 to 2013 suggest emerging piperaquine resistance. Antimicrob Agents Chemother 59: 4631–4643.

    • Search Google Scholar
    • Export Citation
  • 3.

    Spring MD et al. 2015. Dihydroartemisinin-piperaquine failure associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study. Lancet Infect Dis 15: 683–691.

    • Search Google Scholar
    • Export Citation
  • 4.

    Lon CT, Tsuyuoka R, Phanouvong S, Nivanna N, Socheat D, Sokhan C, Blum N, Christophel EM, Smine A, 2006. Counterfeit and substandard antimalarial drugs in Cambodia. Trans R Soc Trop Med Hyg 100: 1019–1024.

    • Search Google Scholar
    • Export Citation
  • 5.

    Bousema T, Drakeley C, 2011. Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination. Clin Microbiol Rev 24: 377–410.

    • Search Google Scholar
    • Export Citation
  • 6.

    Ashley EA et al. 2014. Tracking resistance to artemisinin collaboration (TRAC). Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 371: 411–423.

    • Search Google Scholar
    • Export Citation
  • 7.

    Price R, Nosten F, Simpson JA, Luxemburger C, Phaipun L, ter Kuile F, van Vugt M, Chongsuphajaisiddhi T, White NJ, 1999. Risk factors for gametocyte carriage in uncomplicated falciparum malaria. Am J Trop Med Hyg 60: 1019–1023.

    • Search Google Scholar
    • Export Citation
  • 8.

    WWARN Gametocyte Study Group, 2016. Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data. BMC Med 14: 79.

    • Search Google Scholar
    • Export Citation
  • 9.

    Bell AS, Huijben S, Paaijmans KP, Sim DG, Chan BHK, Nelson WA, Read AF, 2012. Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria. PLoS One 7: e37172.

    • Search Google Scholar
    • Export Citation
  • 10.

    Lin JT et al. 2011. Plasmodium falciparum gametocyte carriage is associated with subsequent Plasmodium vivax relapse after treatment. PLoS One 6: e18716.

    • Search Google Scholar
    • Export Citation
  • 11.

    Lin JT et al. 2016. Microscopic Plasmodium falciparum gametocytemia and infectivity to mosquitoes in Cambodia. J Infect Dis 213: 1491–1494.

  • 12.

    Chaorattanakawee S et al. 2016. Ex vivo piperaquine resistance developed rapidly in Plasmodium falciparum isolates in northern Cambodia compared to Thailand. Malar J 15: 519.

    • Search Google Scholar
    • Export Citation
  • 13.

    Lim P et al. 2009. Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia. Malar J 8: 11.

  • 14.

    Ariey F et al. 2014. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505: 50–55.

  • 15.

    Maude RJ et al. 2014. Spatial and temporal epidemiology of clinical malaria in Cambodia 2004–2013. Malar J 13: 385.

  • 16.

    Parobek CM et al. 2017. Partner-drug resistance and population substructuring of artemisinin-resistant Plasmodium falciparum in Cambodia. Genome Biol Evol 9: 1673–1686.

    • Search Google Scholar
    • Export Citation
  • 17.

    Leang R et al. 2015. Evidence of Plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in western Cambodia: dihydroartemisinin-piperaquine open-label multicenter clinical assessment. Antimicrob Agents Chemother 59: 4719–4726.

    • Search Google Scholar
    • Export Citation
  • 18.

    Witkowski B et al. 2017. A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study. Lancet Infect Dis 17: 174–183.

    • Search Google Scholar
    • Export Citation
  • 19.

    Amato R et al. 2017. Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study. Lancet Infect Dis 17: 164–173.

    • Search Google Scholar
    • Export Citation
  • 20.

    Price RN et al. 1996. Effects of artemisinin derivatives on malaria transmissibility. Lancet 347: 1654–1658.

Past two years Past Year Past 30 Days
Abstract Views 78 78 7
Full Text Views 776 122 1
PDF Downloads 151 34 0
 
Membership Banner
 
 
 
Affiliate Membership Banner
 
 
Research for Health Information Banner
 
 
CLOCKSS
 
 
 
Society Publishers Coalition Banner
Save