Concomitant Efavirenz Reduces Pharmacokinetic Exposure to the Antimalarial Drug Artemether–Lumefantrine in Healthy Volunteers

Huang, Liusheng; Parikh, Sunil; Rosenthal, Philip J.; Lizak, Patricia; Marzan, Florence; Dorsey, Grant; Havlir, Diane V.; Aweeka, Francesca

doi:10.1097/qai.0b013e31826ebb5c

Cited by 46 publications

(42 citation statements)

References 40 publications

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“…(iii) Concomitant NVP-based ART has no significant influence on plasma lumefantrine concentration. To date, only two studies have investigated the influence of EFV-based ART on lumefantrine disposition in healthy volunteers 39 and HIV-infected patients without malaria coinfection. 32 To the best of our knowledge, this is the first casecontrol study to investigate pharmacogenetic, pharmacokinetic and pharmacodynamic interactions between antiretroviral drugs and AL in HIV-malaria-coinfected patients.…”

Section: Discussionmentioning

confidence: 99%

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

et al. 2015

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We investigated the influence of efavirenz (EFV)- or nevirapine (NVP)-based antiretroviral therapy (ART) on lumefantrine plasma exposure in HIV-malaria-coinfected patients and implication of pharmacogenetic variations. A total of 269 HIV patients with uncomplicated falciparum malaria on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) or not receiving ART (control-arm) were enrolled and treated with artemether-lumefantrine. Day-7 lumefantrine, baseline EFV and NVP plasma concentrations, and CYP2B6*6,*18, CYP3A4*1B, CYP3A5*3,*6,*7, ABCB1 c.3435C>T and ABCB1 c.4036A>G genotypes were determined. The median day-7 lumefantrine plasma concentration was significantly lower in the EFV-arm compared with that in NVP- and control-arm. High EFV plasma concentrations and CYP2B6*6/*6 genotype significantly correlated with low lumefantrine plasma concentrations and high rate of recurrent parasitemia. No significant effect of NVP-based ART on lumefantrine exposure was observed. In conclusion, owing to long-term CYP3A induction, EFV-based ART cotreatment significantly reduces lumefantrine plasma exposure leading to poor malaria treatment response, which is more pronounced in CYP2B6 slow metabolizers.

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Section: Discussionmentioning

confidence: 99%

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

et al. 2015

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“…However, emerging data suggest that protease inhibitor-based HAART may have additional benefits on malaria, including activity against gametocytes and transmission-blocking activity [42,43]. In addition, in contrast to the extension of prophylactic activity seen with lopinavir-ritonavir, the use of artemether-lumefantrine in the setting of efavirenz-based HAART is associated with a significant reduction in lumefantrine exposure [44,45]. A further benefit of switching from NNRTIs to protease inhibitors is that protease inhibitors have been found to provide a higher barrier to the development of drug-resistance in HIV [8].…”

Section: Discussionmentioning

confidence: 99%

The epidemiological impact of HIV antiretroviral therapy on malaria in children

Greenhalgh¹,

Ndeffo²,

Galvani³

et al. 2015

Aids

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Objective The objective of this study is to determine the epidemiological effectiveness of a first-line antiretroviral regimen with HIV protease inhibitor for preventing recurrent malaria in children under the range of HIV prevalence levels and malaria transmission intensities encountered in sub-Saharan Africa. Design A dynamic model of malaria transmission was developed using clinical data on the protease inhibitor extended posttreatment prophylactic effect of the antimalarial treatment, artemether-lumefantrine, in addition to parameter estimates from the literature. Methods To evaluate the benefits of HIV protease inhibitors on the health burden of recurrent malaria among children, we constructed a dynamic model of malaria transmission to both HIV-positive and HIV-negative children, parameterized by data from a recent clinical trial. The model was then evaluated under varying malaria transmission and HIV prevalence settings to determine the health benefits of HIV protease inhibitors in the context of artemether-lumefantrine treatment of malaria in children. Results Comparing scenarios of low, intermediate and high newborn HIV prevalence, in a range of malaria transmission settings, our dynamic model predicts that artemether-lumefantrine with HIV protease inhibitor based regimens prevents 0.03–0.10, 5.2–13.0 and 25.5–65.8 annual incidences of malaria per 1000 children, respectively. In addition, HIV protease inhibitors save 0.002–0.006, 0.22–0.8, 1.04–4.3 disability-adjusted life-years per 1000 children annually. Considering only HIV-infected children, HIV protease inhibitors avert between 278 and 1043 annual incidences of malaria per 1000 children. Conclusion The use of HIV protease inhibitor based regimens as first-line antiretroviral therapy for HIV is an effective measure for reducing recurrent malaria among HIV-infected children in areas where HIV and malaria are coendemic, and artemether-lumefantrine is a first-line antimalarial.

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“…While the sampling protocols were nearly identical and assays were conducted in the same laboratory, differences in demographic features, ethnicity, and HIV status between subjects enrolled in the control and nevirapine-based ART groups are important (16,18,25). In addition, the shorter follow-up time for the nevirapine-based ART group versus the control group (96 h versus 296 h) may underestimate the t 1/2 and AUC 0 -ϱ .…”

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confidence: 99%

“…The historical control group included healthy adults (n ϭ 16). The same laboratory analyzed all plasma drug concentrations (16). The University College Hospital Ethics Committee approved this study (protocol NHREC/05/01/2008a).…”

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confidence: 99%

“…Participants received a standard Nigerian meal 30 to 60 min postdose. The control group received artemether-lumefantrine alone, following the same schedule but with food provided immediately postdose (16). Blood samples for quantification of artemether, DHA, lumefantrine, and nevirapine were collected around the sixth (last) dose on day 3, predose and 0.5, 1, 1.5, 2, 3, 4,6,8,10,12,24,48,72, and 96 h postdose.…”

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Artemether-Lumefantrine Exposure in HIV-Infected Nigerian Subjects on Nevirapine-Containing Antiretroviral Therapy

Parikh

Fehintola

Huang

et al. 2015

Antimicrob Agents Chemother

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i Coadministration of nevirapine-based antiretroviral therapy (ART) and artemether-lumefantrine is reported to result in variable changes in lumefantrine exposure. We conducted an intensive pharmacokinetic study with 11 HIV-infected adults who were receiving artemether-lumefantrine plus nevirapine-based ART, and we compared the results with those for 16 HIV-negative adult historical controls. Exposure to artemether and lumefantrine was significantly lower and dihydroartemisinin exposure was unchanged in subjects receiving nevirapine-based ART, compared with controls. Nevirapine exposure was unchanged before and after artemether-lumefantrine administration. Malaria and HIV affect millions of children and adults in subSaharan Africa, and drug-drug interactions between antiretroviral therapy (ART) and antimalarial agents are clinically important to characterize. Nevirapine-based ART represents 50% of first-line ART in regions where malaria coinfection occurs (1). Artemether-lumefantrine, an artemisinin derivative combined with a longer-acting partner drug, represents the most common antimalarial therapy (2, 3). Metabolism of these HIV and antimalarial agents occurs primarily via cytochrome P450 (CYP) enzymes. Artemether is metabolized to an active metabolite, dihydroartemisinin (DHA), predominately by CYP3A4/5 and to a lesser extent by CYP2B6, CYP2C9, and CYP2C19 (4). DHA undergoes glucuronidation by uridine diphosphoglucuronosyltransferases. Lumefantrine is metabolized by CYP3A4 into active desbutyl-lumefantrine (2, 4, 5). Nevirapine is metabolized by CYP3A4 and CYP2B6 while inducing CYP3A4 (6, 7). Studies report reduced artemisinin exposure in the presence of nevirapinebased ART, but the effects on lumefantrine concentrations are variable, with studies showing increased, decreased, or unchanged concentrations (8)(9)(10)(11)(12)(13)(14). Importantly, reduced antimalarial levels have been associated with therapeutic failure (12,13,15). The primary objective of this study was to evaluate the pharmacokinetics of artemether, DHA, and lumefantrine in HIV-infected Nigerian adults without clinical malaria who were receiving nevirapine-based ART.(Data were presented at the 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Washington, DC, 19 May 2014.) HIV-infected subjects (Ն18 years of age) who had been receiving nevirapine-based ART for Ն4 weeks (nevirapine-based ART group) were eligible after informed consent was obtained. Exclusion criteria were current pregnancy; intolerance to study drugs; use of antimalarials or CYP substrates, inducers, or inhibitors within 4 weeks; and clinical symptoms of malaria. The historical control group included healthy adults (n ϭ 16). The same laboratory analyzed all plasma drug concentrations (16). The University College Hospital Ethics Committee approved this study (protocol NHREC/05/01/2008a).Participants received coformulated nevirapine-zidovudinelamivudine (200/300/150 mg; Aurobindo Pharma, India) twice daily. On day 0, participants underwent venou...

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Concomitant Efavirenz Reduces Pharmacokinetic Exposure to the Antimalarial Drug Artemether–Lumefantrine in Healthy Volunteers

Cited by 46 publications

References 40 publications

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

The epidemiological impact of HIV antiretroviral therapy on malaria in children

Artemether-Lumefantrine Exposure in HIV-Infected Nigerian Subjects on Nevirapine-Containing Antiretroviral Therapy

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