The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients

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dc.contributor.authorKredo, T
dc.contributor.authorMauff, K
dc.contributor.authorWorkman, L
dc.contributor.authorVan der Walt, J S
dc.contributor.authorWiesner, L
dc.contributor.authorSmith, P J
dc.contributor.authorMaartens, G
dc.contributor.authorCohen, K
dc.contributor.authorBarnes, K I
dc.date.accessioned2016-06-07T09:46:35Z
dc.date.available2016-06-07T09:46:35Z
dc.date.issued2016-01-27
dc.date.updated2016-05-18T15:44:04Z
dc.description.abstractBackground: 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 Cmaxincreased 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. Conclusion: 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.en_ZA
dc.identifier.apacitationKredo, T., Mauff, K., Workman, L., Van der Walt, J. S., Wiesner, L., Smith, P. J., ... Barnes, K. I. (2016). The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients. <i>BMC Infectious Diseases</i>, http://hdl.handle.net/11427/19931en_ZA
dc.identifier.chicagocitationKredo, T, K Mauff, L Workman, J S Van der Walt, L Wiesner, P J Smith, G Maartens, K Cohen, and K I Barnes "The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients." <i>BMC Infectious Diseases</i> (2016) http://hdl.handle.net/11427/19931en_ZA
dc.identifier.citationKredo, T., Mauff, K., Workman, L., Van der Walt, J. S., Wiesner, L., Smith, P. J., ... & Barnes, K. I. (2016). The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients. BMC infectious diseases, 16(1), 30.en_ZA
dc.identifier.issn1471-2334en_ZA
dc.identifier.ris TY - Journal Article AU - Kredo, T AU - Mauff, K AU - Workman, L AU - Van der Walt, J S AU - Wiesner, L AU - Smith, P J AU - Maartens, G AU - Cohen, K AU - Barnes, K I AB - 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 Cmaxincreased 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. Conclusion: 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. DA - 2016-01-27 DB - OpenUCT DO - 10.1186/s12879-016-1345-1 DP - University of Cape Town J1 - BMC Infectious Diseases KW - HIV KW - Malaria KW - Artemether KW - Lumefantrine KW - Lopinavir KW - Ritonavir KW - Drug interaction KW - Safety Pharmacokinetic KW - Dose-related exposure LK - https://open.uct.ac.za PB - University of Cape Town PY - 2016 SM - 1471-2334 T1 - The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients TI - The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients UR - http://hdl.handle.net/11427/19931 ER - en_ZA
dc.identifier.urihttp://dx.doi.org/10.1186/s12879-016-1345-1
dc.identifier.urihttp://hdl.handle.net/11427/19931
dc.identifier.vancouvercitationKredo T, Mauff K, Workman L, Van der Walt JS, Wiesner L, Smith PJ, et al. The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients. BMC Infectious Diseases. 2016; http://hdl.handle.net/11427/19931.en_ZA
dc.languageengen_ZA
dc.language.rfc3066en
dc.publisherBioMed Centralen_ZA
dc.publisher.departmentDivision of Clinical Pharmacologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsCreative Commons Attribution 4.0 International (CC BY 4.0)*
dc.rights.holderKredo et al.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_ZA
dc.sourceBMC Infectious Diseasesen_ZA
dc.source.urihttp://bmcinfectdis.biomedcentral.com/
dc.subjectHIV
dc.subjectMalaria
dc.subjectArtemether
dc.subjectLumefantrine
dc.subjectLopinavir
dc.subjectRitonavir
dc.subjectDrug interaction
dc.subjectSafety Pharmacokinetic
dc.subjectDose-related exposure
dc.titleThe interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patientsen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetype
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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