HIV treatments reduce malaria liver stage burden in a non-human primate model of malaria infection at clinically relevant concentrations in vivo

• Published in: PloS one 2014-07, Vol.9 (7), p.e100138
• Main Authors: Hobbs, Charlotte V, Neal, Jillian, Conteh, Solomon, Donnelly, Liam, Chen, Jingyang, Marsh, Kennan, Lambert, Lynn, Orr-Gonzalez, Sachy, Hinderer, Jessica, Healy, Sara, Borkowsky, William, Penzak, Scott R, Chakravarty, Sumana, Hoffman, Stephen L, Duffy, Patrick E
• Format: Article
• Language: English
• Subjects: AIDS treatment; Analysis; Animals; Antibacterial agents; Antibiotics; Antimalarial activity; Antimalarial agents; Antimalarials - pharmacology; Culicidae; Developmental stages; Disease Models, Animal; Drug Combinations; Drug development; Drugs; HIV; HIV infections; HIV Protease Inhibitors - pharmacology; Human immunodeficiency virus; Immunology; Infection; Infections; Infectious diseases; Laboratories; Liver; Liver - metabolism; Liver - parasitology; Liver - pathology; Lopinavir; Lopinavir - pharmacology; Macaca mulatta; Malaria; Malaria, Falciparum - drug therapy; Malaria, Falciparum - metabolism; Malaria, Falciparum - pathology; Medicine and Health Sciences; Mosquitoes; Parasites; Pharmacy; Plasmodium; Plasmodium cynomolgi; Plasmodium falciparum; Plasmodium knowlesi; Primates; Protease inhibitors; Proteases; Proteinase inhibitors; Ritonavir; Ritonavir - pharmacology; Sulfadoxine - pharmacology; Sulfamethoxazole; Trimethoprim; Trimethoprim - pharmacology; Vector-borne diseases
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0100138

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.