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.accessioned2021-10-08T06:20:27Z
dc.date.available2021-10-08T06:20:27Z
dc.date.issued2015
dc.description.abstractBackgroundArtemether-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 P450isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions.MethodsAn 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.ResultsWe enrolled 34 patients. Median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naïve group [3170 versus 336ng/mL; p = 0.0001], with AUC(0-inf) and Cmax increased five-fold [2478 versus 445μg.h/mL; p = 0.0001], and three-fold [28.2 versus 8.8μg/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 21days 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.ConclusionDespite 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.Trial registrationClinical Trial Registration number NCT00869700. Registered on clinicaltrials.gov 25 March 2009Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1345-1) contains supplementary material, which is available to authorized users.
dc.identifier.apacitationKredo, T., Mauff, K., Workman, L., Van Der Walt, J., Wiesner, L., Smith, P. J., ... Barnes, K. I. (2015). The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients. <i>BMC Infectious Diseases</i>, 16(1), 174 - 177. http://hdl.handle.net/11427/34280en_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> 16, 1. (2015): 174 - 177. http://hdl.handle.net/11427/34280en_ZA
dc.identifier.citationKredo, T., Mauff, K., Workman, L., Van Der Walt, J., Wiesner, L., Smith, P.J., Maartens, G. & Cohen, K. et al. 2015. The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients. <i>BMC Infectious Diseases.</i> 16(1):174 - 177. http://hdl.handle.net/11427/34280en_ZA
dc.identifier.issn1471-2334
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 - BackgroundArtemether-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 P450isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions.MethodsAn 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.ResultsWe enrolled 34 patients. Median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naïve group [3170 versus 336ng/mL; p = 0.0001], with AUC(0-inf) and Cmax increased five-fold [2478 versus 445μg.h/mL; p = 0.0001], and three-fold [28.2 versus 8.8μg/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 21days 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.ConclusionDespite 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.Trial registrationClinical Trial Registration number NCT00869700. Registered on clinicaltrials.gov 25 March 2009Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1345-1) contains supplementary material, which is available to authorized users. DA - 2015 DB - OpenUCT DP - University of Cape Town IS - 1 J1 - BMC Infectious Diseases LK - https://open.uct.ac.za PY - 2015 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/11427/34280 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/34280
dc.identifier.vancouvercitationKredo T, Mauff K, Workman L, Van Der Walt J, 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. 2015;16(1):174 - 177. http://hdl.handle.net/11427/34280.en_ZA
dc.language.isoeng
dc.publisher.departmentDepartment of Medicine
dc.publisher.facultyFaculty of Health Sciences
dc.sourceBMC Infectious Diseases
dc.source.journalissue1
dc.source.journalvolume16
dc.source.pagination174 - 177
dc.source.urihttps://dx.doi.org/10.1186/s12879-016-1345-1
dc.subject.otherAdult
dc.subject.otherAnti-HIV Agents
dc.subject.otherArtemisinins
dc.subject.otherDrug Interactions
dc.subject.otherEthanolamines
dc.subject.otherFemale
dc.subject.otherFluorenes
dc.subject.otherHIV Infections
dc.subject.otherHIV-1
dc.subject.otherHumans
dc.subject.otherLopinavir
dc.subject.otherMale
dc.subject.otherRitonavir
dc.subject.otherAnti-HIV Agents
dc.subject.otherArtemisinins
dc.subject.otherEthanolamines
dc.subject.otherFluorenes
dc.subject.otherLopinavir
dc.subject.otherdihydroartemisinin
dc.subject.otherartemether
dc.subject.otherlumefantrine
dc.subject.otherRitonavir
dc.titleThe interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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