title: Neither the HIV protease inhibitor lopinavir-ritonavir nor the antimicrobial trimethoprim-sulfamethoxazole prevent malaria relapse in plasmodium cynomolgi-infected non-human primates.
abstract: Plasmodium vivax malaria causes significant morbidity and mortality worldwide, and only one drug is in clinical use that can kill the hypnozoites that cause P. vivax relapses. HIV and P. vivax malaria geographically overlap in many areas of the world, including South America and Asia. Despite the increasing body of knowledge regarding HIV protease inhibitors (HIV PIs) on P. falciparum malaria, there are no data regarding the effects of these treatments on P. vivax's hypnozoite form and clinical relapses of malaria. We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium actively dividing liver stages in rodent malarias and in vitro in P. falciparum, but effect against Plasmodium dormant hypnozoite forms remains untested. Separately, although other antifolates have been tested against hypnozoites, the antibiotic trimethoprim sulfamethoxazole, commonly used in HIV infection and exposure management, has not been evaluated for hypnozoite-killing activity. Since Plasmodium cynomolgi is an established animal model for the study of liver stages of malaria as a surrogate for P. vivax infection, we investigated the antimalarial activity of these drugs on Plasmodium cynomolgi relapsing malaria in rhesus macaques. Herein, we demonstrate that neither TMP-SMX nor LPV-RTV kills hypnozoite parasite liver stage forms at the doses tested. Because HIV and malaria geographically overlap, and more patients are being managed for HIV infection and exposure, understanding HIV drug impact on malaria infection is important.
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 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 Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Dixit
authors.affiliation: Department of Pharmacotherapy, University of North Texas System College of Pharmacy, Fort Worth, Texas, 76107, United States of America.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Penzak
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Tejram
authors.initials: T
authors.lastname: Sahu
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 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 Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Lynn
authors.initials: L
authors.lastname: Lambert
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Katie
authors.initials: K
authors.lastname: Zeleski
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Jingyang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Jillian
authors.initials: J
authors.lastname: Neal
authors.affiliation: Department of Pediatrics, Division of Infectious Disease and Immunology, 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: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Duffy
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D005260:Female; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D061466:Lopinavir / Q000627:therapeutic use*; D008253:Macaca mulatta; D008288:Malaria / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D016789:Plasmodium cynomolgi; D019438:Ritonavir / Q000627:therapeutic use*; D013420:Sulfamethoxazole / Q000627:therapeutic use*; D014295:Trimethoprim / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; D017320:HIV Protease Inhibitors; D061466:Lopinavir; D014295:Trimethoprim; D013420:Sulfamethoxazole; D019438:Ritonavir