title: HIV nonnucleoside reverse transcriptase inhibitors and trimethoprim-sulfamethoxazole inhibit plasmodium liver stages.
abstract: BACKGROUND
  Although nonnucleoside reverse transcriptase inhibitors (NNRTIs) are usually part of first-line treatment regimens for human immunodeficiency virus (HIV), their activity on Plasmodium liver stages remains unexplored. Additionally, trimethoprim-sulfamethoxazole (TMP-SMX), used for opportunistic infection prophylaxis in HIV-exposed infants and HIV-infected patients, reduces clinical episodes of malaria; however, TMP-SMX effect on Plasmodium liver stages requires further study.
  
  
  METHODS
  We characterized NNRTI and TMP-SMX effects on Plasmodium liver stages in vivo using Plasmodium yoelii. On the basis of these results, we conducted in vitro studies assessing TMP-SMX effects on the rodent parasites P. yoelii and Plasmodium berghei and on the human malaria parasite Plasmodium falciparum.
  
  
  RESULTS
  Our data showed NNRTI treatment modestly reduced P. yoelii liver stage parasite burden and minimally extended prepatent period. TMP-SMX administration significantly reduced liver stage parasite burden, preventing development of patent parasitemia in vivo. TMP-SMX inhibited development of rodent and P. falciparum liver stage parasites in vitro.
  
  
  CONCLUSIONS
  NNRTIs modestly affect liver stage Plasmodium parasites, whereas TMP-SMX prevents patent parasitemia. Because drugs that inhibit liver stages target parasites when they are present in lower numbers, these results may have implications for eradication efforts. Understanding HIV drug effects on Plasmodium liver stages will aid in optimizing treatment regimens for HIV-exposed and HIV-infected infected patients in malaria-endemic areas.
authors.affiliation: NIH/NIAID/Laboratory of Malaria Immunology and Vaccinology, Rockville, Maryland 20852, USA.
authors.forename: Charlotte V
authors.initials: CV
authors.lastname: Hobbs
authors.forename: Tatiana
authors.initials: T
authors.lastname: Voza
authors.forename: Patricia
authors.initials: P
authors.lastname: De La Vega
authors.forename: Jillian
authors.initials: J
authors.lastname: Vanvliet
authors.forename: Solomon
authors.initials: S
authors.lastname: Conteh
authors.forename: Scott R
authors.initials: SR
authors.lastname: Penzak
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fay
authors.forename: Nicole
authors.initials: N
authors.lastname: Anders
authors.forename: Tiina
authors.initials: T
authors.lastname: Ilmet
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Li
authors.forename: William
authors.initials: W
authors.lastname: Borkowsky
authors.forename: Urszula
authors.initials: U
authors.lastname: Krzych
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Duffy
authors.forename: Photini
authors.initials: P
authors.lastname: Sinnis
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology*; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy; D010961:Plasmodium / Q000187:drug effects*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013045:Species Specificity; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D018894:Reverse Transcriptase Inhibitors; D015662:Trimethoprim, Sulfamethoxazole Drug Combination