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Therapeutic Efficacy of Artemether–Lumefantrine for Uncomplicated Falciparum Malaria in Northern Zambia

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  • 1 Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
  • 2 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland;
  • 3 The Johns Hopkins Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland;
  • 4 W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland;
  • 5 Ministry of Health, Government of the Republic of Zambia, Lusaka, Zambia;
  • 6 Macha Research Trust, Macha, Zambia;
  • 7 Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island;
  • 8 Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya;
  • 9 Department of Clinical Pharmacology, University of California San Francisco School of Pharmacy, San Francisco, California;
  • 10 Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina;
  • 11 Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina;
  • 12 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland

ABSTRACT

Artemether–lumefantrine (AL) is a first-line agent for uncomplicated malaria caused by Plasmodium falciparum. The WHO recommends periodic therapeutic efficacy studies of antimalarial drugs for the detection of malaria parasite drug resistance and to inform national malaria treatment policies. We conducted a therapeutic efficacy study of AL in a high malaria transmission region of northern Zambia from December 2014 to July 2015. One hundred children of ages 6 to 59 months presenting to a rural health clinic with uncomplicated falciparum malaria were admitted for treatment with AL (standard 6-dose regimen) and followed weekly for 5 weeks. Parasite counts were taken every 6 hours during treatment to assess parasite clearance. Recurrent episodes during follow-up (n = 14) were genotyped to distinguish recrudescence from reinfection and to identify drug resistance single nucleotide polymorphisms (SNPs) and multidrug resistance protein 1 (mdr1) copy number variation. Day 7 lumefantrine concentrations were measured for correspondence with posttreatment reinfection. All children who completed the parasite clearance portion of the study (n = 94) were microscopy-negative by 72 hours. The median parasite elimination half-life was 2.7 hours (interquartile range: 2.1–3.3). Genotype-corrected therapeutic efficacy was 98.8% (95% CI: 97.6–100). Purported artemisinin and lumefantrine drug resistance SNPs in atp6, 3D7_1451200, and mdr1 were detected but did not correlate with parasite recurrence, nor did day 7 lumefantrine concentrations. In summary, AL was highly effective for the treatment of uncomplicated falciparum malaria in northern Zambia during the study period. The high incidence of recurrent parasitemia was consistent with reinfection due to high, perennial malaria transmission.

Author Notes

Address correspondence to Matthew M. Ippolito, Johns Hopkins University School of Medicine, 725 North Wolfe St., Rm. 211, Baltimore, MD 21205. E-mail: mippolito@jhu.edu

Financial support: This work was supported by the Johns Hopkins Malaria Research Institute, the Bloomberg Philanthropies, and the National Institute of Allergy and Infectious Diseases at the NIH (U19AI089680). M. M. I. is supported by the National Institute of Allergy and Infectious Diseases at the NIH (K23AI139343), the Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases, and by the Burroughs Wellcome Fund-American Society of Tropical Medicine and Hygiene Postdoctoral Fellowship in Tropical Infectious Diseases. This work was also supported by additional grants from the NIH to O. A. and J. A. B. (R01AI139530), to L. H. and F. T. A. (R01HD068174), and to J. J. J. (K24AI13499 and R01AI121558).

Authors’ addresses: Matthew M. Ippolito, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, and The Johns Hopkins Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, E-mail: mippolito@jhu.edu. Julia C. Pringle, W. Harry Feinstone Department of Molecular Microbiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, E-mail: jpringl3@jhu.edu. Mwiche Siame, Ministry of Health, Government of the Republic of Zambia, Lusaka, Zambia, E-mail: siamemp@gmail.com. Ben Katowa, Macha Research Trust, Macha, Zambia, E-mail: ben.katowa@macharesearch.org. Ozkan Aydemir and Jeffrey A. Bailey, Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, E-mails: ozkan_aydemir@brown.edu and jeffrey_bailey@brown.edu. Peter O. Oluoch, Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, and Center for Global Health Research, Kenyan Medical Research Institute, Kisumu, Kenya, E-mail: peter_owuor_oluoch@brown.edu. Liusheng Huang and Francesca T. Aweeka, Drug Research Unit, University of California San Francisco School of Pharmacy, San Francisco, CA, E-mails: liusheng.huang@ucsf.edu and fran.aweeka@ucsf.edu. Jonathan J. Juliano, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, E-mail: jonathan_juliano@med.unc.edu. Steven R. Meshnick, Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, E-mail: meshnick@email.unc.edu. Theresa A. Shapiro, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, and The Johns Hopkins Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, E-mail: tshapiro@jhmi.edu. William J. Moss, The Johns Hopkins Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, and Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, E-mail: wmoss1@jhu.edu. Philip E. Thuma, The Johns Hopkins Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, and Macha Research Trust, Macha, Zambia, E-mail: phil.thuma@macharesearch.org.

Deceased.

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