title: Antiretroviral agents and prevention of malaria in HIV-infected Ugandan children.
abstract: BACKGROUND
  Human immunodeficiency virus (HIV) protease inhibitors show activity against Plasmodium falciparum in vitro. We hypothesized that the incidence of malaria in HIV-infected children would be lower among children receiving lopinavir-ritonavir-based antiretroviral therapy (ART) than among those receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART.
  
  
  METHODS
  We conducted an open-label trial in which HIV-infected children 2 months to 5 years of age who were eligible for ART or were currently receiving NNRTI-based ART were randomly assigned to either lopinavir-ritonavir-based ART or NNRTI-based ART and were followed for 6 months to 2 years. Cases of uncomplicated malaria were treated with artemether-lumefantrine. The primary end point was the incidence of malaria.
  
  
  RESULTS
  We enrolled 176 children, of whom 170 received the study regimen: 86 received NNRTI-based ART, and 84 lopinavir-ritonavir-based ART. The incidence of malaria was lower among children receiving the lopinavir-ritonavir-based regimen than among those receiving the NNRTI-based regimen (1.32 vs. 2.25 episodes per person-year; incidence-rate ratio, 0.59; 95% confidence interval [CI], 0.36 to 0.97; P=0.04), as was the risk of a recurrence of malaria after treatment with artemether-lumefantrine (28.1% vs. 54.2%; hazard ratio, 0.41; 95% CI, 0.22 to 0.76; P=0.004). The median lumefantrine level on day 7 after treatment for malaria was significantly higher in the lopinavir-ritonavir group than in the NNRTI group. In the lopinavir-ritonavir group, lumefantrine levels exceeding 300 ng per milliliter on day 7 were associated with a reduction of more than 85% in the 63-day risk of recurrent malaria. A greater number of serious adverse events occurred in the lopinavir-ritonavir group than in the NNRTI group (5.6% vs. 2.3%, P=0.16). Pruritus occurred significantly more frequently in the lopinavir-ritonavir group, and elevated alanine aminotransferase levels significantly more frequently in the NNRTI group.
  
  
  CONCLUSIONS
  Lopinavir-ritonavir-based ART as compared with NNRTI-based ART reduced the incidence of malaria by 41%, with the lower incidence attributable largely to a significant reduction in the recurrence of malaria after treatment with artemether-lumefantrine. Lopinavir-ritonavir-based ART was accompanied by an increase in serious adverse events. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT00978068.).
authors.affiliation: Department of Pediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda. achanj@yahoo.co.uk
authors.forename: Jane
authors.initials: J
authors.lastname: Achan
authors.forename: Abel
authors.initials: A
authors.lastname: Kakuru
authors.forename: Gloria
authors.initials: G
authors.lastname: Ikilezi
authors.forename: Theodore
authors.initials: T
authors.lastname: Ruel
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Clark
authors.forename: Christian
authors.initials: C
authors.lastname: Nsanzabana
authors.forename: Edwin
authors.initials: E
authors.lastname: Charlebois
authors.forename: Francesca
authors.initials: F
authors.lastname: Aweeka
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Diane
authors.initials: D
authors.lastname: Havlir
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
mesh_terms: D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D000962:Antimalarials / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000493:pharmacokinetics / Q000627:therapeutic use; D002675:Child, Preschool; D004338:Drug Combinations; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005449:Fluorenes / Q000493:pharmacokinetics / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D006801:Humans; D015994:Incidence; D007223:Infant; D053208:Kaplan-Meier Estimate; D061466:Lopinavir / Q000627:therapeutic use*; D008288:Malaria / Q000188:drug therapy / Q000453:epidemiology / Q000517:prevention & control*; D008297:Male; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use*; D055502:Secondary Prevention; D014454:Uganda
chemical_list: D044966:Anti-Retroviral Agents; D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D061466:Lopinavir; D019438:Ritonavir