title: Persistence of Plasmodium falciparum parasitemia after artemisinin combination therapy: evidence from a randomized trial in Uganda.
abstract: Artemisinin resistance is rapidly spreading in Southeast Asia. The efficacy of artemisinin-combination therapy (ACT) continues to be excellent across Africa. We performed parasite transcriptional profiling and genotyping on samples from an antimalarial treatment trial in Uganda. We used qRT-PCR and genotyping to characterize residual circulating parasite populations after treatment with either ACT or ACT-primaquine. Transcripts suggestive of circulating ring stage parasites were present after treatment at a prevalence of >25% until at least 14 days post initiation of treatment. Greater than 98% of all ring stage parasites were cleared within the first 3 days, but subsequently persisted at low concentrations until day 14 after treatment. Genotyping demonstrated a significant decrease in multiplicity of infection within the first 2 days in both ACT and ACT-primaquine arms. However, multiple clone infections persisted until day 14 post treatment. Our data suggest the presence of genetically diverse persisting parasite populations after ACT treatment. Although we did not demonstrate clinical treatment failures after ACT and the viability and transmissibility of persisting ring stage parasites remain to be shown, these findings are of relevance for the interpretation of parasite clearance transmission dynamics and for monitoring drug effects in Plasmodium falciparum parasites.
authors.affiliation: Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
authors.forename: Hsiao-Han
authors.initials: HH
authors.lastname: Chang
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
authors.forename: Elamaran
authors.initials: E
authors.lastname: Meibalan
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Zelin
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.|Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Daniels
authors.affiliation: Immunology and Infection Department, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Alice C
authors.initials: AC
authors.lastname: Eziefula
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
authors.forename: Evan C
authors.initials: EC
authors.lastname: Meyer
authors.affiliation: Immunology and Infection Department, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Fitsum
authors.initials: F
authors.lastname: Tadesse
authors.affiliation: Immunology and Infection Department, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Lynn
authors.initials: L
authors.lastname: Grignard
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
authors.forename: Regina C
authors.initials: RC
authors.lastname: Joice
authors.affiliation: Immunology and Infection Department, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Drakeley
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.|Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.|Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.|Simmons College, 300 Fenway, Boston, MA 02115, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Volkman
authors.affiliation: Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Buckee
authors.affiliation: Immunology and Infection Department, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.|Institute for Molecular Life Sciences, Radboud University, Geert Grooteplain Zuid 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Teun
authors.initials: T
authors.lastname: Bousema
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Marti
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage / Q000627:therapeutic use*; D037621:Artemisinins / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D016054:DNA, Protozoan / Q000032:analysis; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005838:Genotype; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000469:parasitology; D011319:Primaquine / Q000008:administration & dosage / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D014454:Uganda
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D016054:DNA, Protozoan; D011319:Primaquine