title: HIV treatments reduce malaria liver stage burden in a non-human primate model of malaria infection at clinically relevant concentrations in vivo.
abstract: We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium liver stages in rodent malarias and in vitro in P. falciparum. Since clinically relevant levels are better achieved in the non-human-primate model, and since Plasmodium knowlesi is an accepted animal model for the study of liver stages of malaria as a surrogate for P. falciparum infection, we investigated the antimalarial activity of these drugs on Plasmodium knowlesi liver stages in rhesus macaques. We demonstrate that TMP-SMX and TMP-SMX+LPV-RTV (in combination), but not LPV-RTV alone, inhibit liver stage parasite development. Because drugs that inhibit the clinically silent liver stages target parasites when they are present in lower numbers, these results may have implications for eradication efforts.
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rockville, Maryland, United States of America.
authors.forename: Charlotte V
authors.initials: CV
authors.lastname: Hobbs
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rockville, Maryland, United States of America.
authors.forename: Jillian
authors.initials: J
authors.lastname: Neal
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rockville, Maryland, United States of America.
authors.forename: Solomon
authors.initials: S
authors.lastname: Conteh
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rockville, Maryland, United States of America.
authors.forename: Liam
authors.initials: L
authors.lastname: Donnelly
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rockville, Maryland, United States of America.
authors.forename: Jingyang
authors.initials: J
authors.lastname: Chen
authors.affiliation: AbbVie Inc., North Chicago, Illinois, United States of America.
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rockville, Maryland, United States of America.
authors.forename: Lynn
authors.initials: L
authors.lastname: Lambert
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rockville, Maryland, United States of America.
authors.forename: Sachy
authors.initials: S
authors.lastname: Orr-Gonzalez
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rockville, Maryland, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hinderer
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rockville, Maryland, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Healy
authors.affiliation: Division of Infectious Disease and Immunology, Department of Pediatrics, New York University School of Medicine, New York, New York, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Borkowsky
authors.affiliation: Clinical Center Pharmacy Department, Clinical Pharmacokinetics Research Laboratory, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Penzak
authors.affiliation: Sanaria, Inc. Rockville, Maryland, United States of America.
authors.forename: Sumana
authors.initials: S
authors.lastname: Chakravarty
authors.affiliation: Sanaria, Inc. Rockville, Maryland, United States of America.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hoffman
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Rockville, Maryland, United States of America.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Duffy
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D061466:Lopinavir / Q000494:pharmacology*; D008253:Macaca mulatta; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010963:Plasmodium falciparum; D019438:Ritonavir / Q000494:pharmacology*; D013413:Sulfadoxine / Q000494:pharmacology*; D014295:Trimethoprim / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; C000301:trimethoprim, sulfadoxine drug combination; D013413:Sulfadoxine; D014295:Trimethoprim; D019438:Ritonavir