title: Plasmodium vivax recurrence following falciparum and mixed species malaria: risk factors and effect of antimalarial kinetics.
abstract: BACKGROUND
  Plasmodium vivax malaria commonly follows treatment of falciparum malaria in regions of co-endemicity. This is an important cause of preventable morbidity.
  
  
  METHODS
  We examined the factors contributing to the risk of recurrence of P. vivax infection after treatment of acute falciparum malaria in a series of clinical trials conducted on the Thai-Myanmar border from 1991 through 2005.
  
  
  RESULTS
  Overall, 10,549 patients (4960 children aged <15 years and 5589 adults) were treated for falciparum malaria; of these patients, 9385 (89.0%) had Plasmodium falciparum monoinfection and 1164 (11.0%) had mixed P. falciparum/P. vivax infections according to microscopic examinations performed at screening. The cumulative proportion of patients with P. falciparum infection recurrence by day 63 was 21.5% (95% confidence interval [CI], 20.3%-22.8%), and the cumulative proportion with P. vivax infection recurrence was 31.5% (95% CI, 30.1%-33.0%). Significant risk factors for P. vivax infection recurrence were mixed infection at enrollment, male sex, younger age, lower hematocrit, higher asexual P. falciparum parasite density (P < .001 for all factors), and P. falciparum gametocytemia at enrollment (P = .001). By day 63, the cumulative risk of vivax malaria after P. falciparum monoinfection was 51.1% (95% CI, 46.1%-56.2%) after treatment with rapidly eliminated drugs (t(1/2) <1 day), 35.3% (95% CI, 31.8%-39.0%) after treatment with intermediate half-life drugs (t(1/2) 1-7 days), and 19.6% (95% CI, 18.1%-21.3%) after treatment with slowly eliminated drugs (t(1/2) > 7 days) (P < .001, by test for trend). Artemisinin-based combinations containing mefloquine or piperaquine, compared with the artemether-lumefantrine and artesunate-atovaquone-proguanil combinations, were associated with a 3.6-fold to 4.2-fold lower adjusted hazard ratio for P. vivax infection recurrence within 63 days after pure or mixed P. falciparum infections (P < .001, for comparisons with artesunate-mefloquine).
  
  
  CONCLUSIONS
  On the Thai-Myanmar border, P. vivax is the most common cause of parasitological failure after treatment for falciparum malaria. Slowly eliminated antimalarials reduce the risk of early P. vivax infection recurrence.
authors.affiliation: Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Douglas
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ashley
authors.forename: Lucy
authors.initials: L
authors.lastname: Phaiphun
authors.forename: Michèle
authors.initials: M
authors.lastname: van Vugt
authors.forename: Pratap
authors.initials: P
authors.lastname: Singhasivanon
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D016780:Malaria, Vivax / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D002052:Myanmar; D010963:Plasmodium falciparum / Q000302:isolation & purification*; D010966:Plasmodium vivax / Q000302:isolation & purification*; D012008:Recurrence; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000962:Antimalarials