title: The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients.
abstract: BACKGROUND
  Artemether-lumefantrine is currently the most widely recommended treatment of uncomplicated malaria. Lopinavir-based antiretroviral therapy is the commonly recommended second-line HIV treatment. Artemether and lumefantrine are metabolised by cytochrome P450 isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions.
  
  
  METHODS
  An adaptive, parallel-design safety and pharmacokinetic study was conducted in HIV-infected (malaria-negative) patients: antiretroviral-naïve and those stable on lopinavir/ritonavir-based antiretrovirals. Both groups received the recommended six-dose artemether-lumefantrine treatment. The primary outcome was day-7 lumefantrine concentrations, as these correlate with antimalarial efficacy. Adverse events were solicited throughout the study, recording the onset, duration, severity, and relationship to artemether-lumefantrine.
  
  
  RESULTS
  We enrolled 34 patients. Median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naïve group [3170 versus 336 ng/mL; p = 0.0001], with AUC(0-inf) and Cmax increased five-fold [2478 versus 445 μg.h/mL; p = 0.0001], and three-fold [28.2 versus 8.8 μg/mL; p < 0.0001], respectively. Lumefantrine Cmax, and AUC(0-inf) increased significantly with mg/kg dose in the lopinavir, but not the antiretroviral-naïve group. While artemether exposure was similar between groups, Cmax and AUC(0-8h) of its active metabolite dihydroartemisinin were initially two-fold higher in the lopinavir group [p = 0.004 and p = 0.0013, respectively]. However, this difference was no longer apparent after the last artemether-lumefantrine dose. Within 21 days of starting artemether-lumefantrine there were similar numbers of treatment emergent adverse events (42 vs. 35) and adverse reactions (12 vs. 15, p = 0.21) in the lopinavir and antiretroviral-naïve groups, respectively. There were no serious adverse events and no difference in electrocardiographic QTcF- and PR-intervals, at the predicted lumefantrine Tmax.
  
  
  CONCLUSIONS
  Despite substantially higher lumefantrine exposure, intensive monitoring in our relatively small study raised no safety concerns in HIV-infected patients stable on lopinavir-based antiretroviral therapy given the recommended artemether-lumefantrine dosage. Increased day-7 lumefantrine concentrations have been shown previously to reduce the risk of malaria treatment failure, but further evidence in adult patients co-infected with malaria and HIV is needed to assess the artemether-lumefantrine risk : benefit profile in this vulnerable population fully. Our antiretroviral-naïve patients confirmed previous findings that lumefantrine absorption is almost saturated at currently recommended doses, but this dose-limited absorption was overcome in the lopinavir group.
  
  
  BACKGROUND
  Clinical Trial Registration number NCT00869700. Registered on clinicaltrials.gov 25 March 2009.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. Tamara.kredo@mrc.ac.za.|Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa. Tamara.kredo@mrc.ac.za.
authors.forename: T
authors.initials: T
authors.lastname: Kredo
authors.affiliation: Department of Statistical Sciences, University of Cape Town, Cape Town, South Africa. katya.mauff@gmail.com.
authors.forename: K
authors.initials: K
authors.lastname: Mauff
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. lesley.workman@uct.ac.za.
authors.forename: L
authors.initials: L
authors.lastname: Workman
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. janstefan.vanderwalt@gmail.com.
authors.forename: J S
authors.initials: JS
authors.lastname: Van der Walt
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. lubbe.wiesner@uct.ac.za.
authors.forename: L
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. peter.smith@uct.ac.za.
authors.forename: P J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. gary.maartens@uct.ac.za.
authors.forename: G
authors.initials: G
authors.lastname: Maartens
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. karen.cohen@uct.ac.za.
authors.forename: K
authors.initials: K
authors.lastname: Cohen
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. karen.barnes@uct.ac.za.|WorlldWide Antimalarial Resistance Network (WWARN), Oxford, UK. karen.barnes@uct.ac.za.
authors.forename: K I
authors.initials: KI
authors.lastname: Barnes
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077549:Artemether; D037621:Artemisinins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004347:Drug Interactions; D004983:Ethanolamines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005449:Fluorenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D061466:Lopinavir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000078102:Lumefantrine; D008297:Male; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D061466:Lopinavir; C039060:artenimol; D000077549:Artemether; D000078102:Lumefantrine; D019438:Ritonavir
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