title: Sulfadoxine-pyrimethamine, chlorproguanil-dapsone, or chloroquine for the treatment of Plasmodium vivax malaria in Afghanistan and Pakistan: a randomized controlled trial.
abstract: BACKGROUND
  In areas where Plasmodium falciparum and Plasmodium vivax coexist and treatments for the 2 species differ, misdiagnosis can lead to poor outcomes in either disease. A unified therapy effective against both species would reduce reliance on species-specific diagnosis, which in many areas is difficult to maintain. The antifolates are an important and affordable antimalarial class to which it is often assumed P vivax malaria is intrinsically resistant.
  
  
  OBJECTIVE
  To test the relative efficacy and safety of 2 antifolate drugs against P vivax malaria and compare each with chloroquine.
  
  
  METHODS
  An open-label randomized controlled trial comparing chloroquine, sulfadoxine-pyrimethamine, and chlorproguanil-dapsone for the treatment of P vivax malaria was conducted in eastern Afghanistan and northwestern Pakistan, areas in which P vivax malaria predominates. A total of 20,410 patients older than 3 years were screened; 767 patients (315 in Pakistan and 452 in Afghanistan) with confirmed P vivax malaria were enrolled and followed up daily for 4 days, then weekly for 28 days, between March 2004 and June 2006.
  
  
  METHODS
  Complete clearance of parasites with no recrudescence by day 14. Secondary outcomes included being parasite-free by day 28, clinical failure, and anemia.
  
  
  RESULTS
  By day 14, only 1 patient in the sulfadoxine-pyrimethamine group had parasites. By day 28, failure rates were found in 2 of 153 patients (1.3%) in the chloroquine group, 5 of 290 patients (1.7%) in the sulfadoxine-pyrimethamine group, and 27 of 272 patients (9.9%) in the chlorproguanil-dapsone group. Chlorproguanil-dapsone was less effective than sulfadoxine-pyrimethamine (adjusted odds ratio [OR], 6.4; 95% confidence interval [CI], 2.4-17.0; P<.001) and chloroquine (adjusted OR, 8.4; 95% CI, 2.0-36.5; P = .004). Chloroquine and sulfadoxine-pyrimethamine were equivalent in efficacy at day 28 (adjusted OR, 1.3; 95% CI, 0.3-7.0; P = .73). Chloroquine cleared gametocytes and asexual parasites more rapidly than sulfadoxine-pyrimethamine or chlorproguanil-dapsone did. All drugs were well tolerated.
  
  
  CONCLUSIONS
  Although chloroquine remains the drug of choice, antifolates are effective against P vivax malaria in South Asia. These drugs may be appropriate for unified treatment where species-specific diagnosis is unavailable, most likely in combination with other drugs.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00158561.
authors.affiliation: HealthNet TPO Malaria and Leishmaniasis Control Programme, Peshawar, Northwest Frontier Province, Pakistan. toby.leslie@lshtm.ac.uk
authors.forename: Toby
authors.initials: T
authors.lastname: Leslie
authors.forename: M Ismail
authors.initials: MI
authors.lastname: Mayan
authors.forename: M Anwar
authors.initials: MA
authors.lastname: Hasan
authors.forename: M Hanif
authors.initials: MH
authors.lastname: Safi
authors.forename: Eveline
authors.initials: E
authors.lastname: Klinkenberg
authors.forename: Christopher J M
authors.initials: CJ
authors.lastname: Whitty
authors.forename: Mark
authors.initials: M
authors.lastname: Rowland
mesh_terms: D000293:Adolescent; D000328:Adult; D000346:Afghanistan; D000368:Aged; D000962:Antimalarials / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000627:therapeutic use; D003622:Dapsone / Q000627:therapeutic use; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D005493:Folic Acid Antagonists / Q000627:therapeutic use*; D006801:Humans; D016780:Malaria, Vivax / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010154:Pakistan; D002727:Proguanil / Q000031:analogs & derivatives / Q000627:therapeutic use; D011739:Pyrimethamine / Q000627:therapeutic use; D013413:Sulfadoxine / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D005493:Folic Acid Antagonists; C519882:chloroguanil, dapsone drug combination; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D002738:Chloroquine; C007030:chlorproguanil; D003622:Dapsone; D002727:Proguanil; D011739:Pyrimethamine