Impact of efavirenz, ritonavir-boosted lopinavir and nevirapine based antiretroviral regimens on the pharmacokinetics of lumefantrine and safety of artemether-lumefantrine in falciparum-negative HIV-infected Malawian adults stabilized on antiretroviral therapy

There is conflicting evidence of the impact of commonly used antiretroviral therapies (ARTs) on the pharmacokinetics of lumefantrine and safety profile of artemether-lumefantrine. We compared the area under the concentration-time curve (AUC0-14 days) of lumefantrine and safety profile of artemether-lumefantrine in malaria-negative human immunodeficiency virus (HIV) infected adults in two steps. In step 1, a half-dose adult course of artemether-lumefantrine was administered as a safety check in four groups (n = 6/group): (i) antiretroviral-naïve, (ii) on nevirapine-based ART, (iii) on efavirenz-based ART and (iv) on ritonavir-boosted lopinavir-based ART. In step 2, a standard-dose adult course of artemether-lumefantrine was administered to a different cohort in three groups (n = 10–15/group): (i) antiretroviral-naïve, (ii) on efavirenz-based ART and (iii) on ritonavir-boosted lopinavir-based ART. In step 1, lumefantrine’s AUC0-14 days was 53% [95% CI: 0.27-0.82] lower in the efavirenz-based ART group than the ART-naïve group and was 2.4 [95% CI: 1.58-3.62] and 2.9 [95% CI: 1.75-4.72] times higher in the nevirapine and ritonavir-boosted lopinavir groups, respectively. In step 2, lumefantrine’s AUC0-14 days was 1.9 [95% CI: 1.26-3.00] times higher in the ritonavir-boosted lopinavir group and not significantly different between the efavirenz-and ART-naïve groups (0.99 [95% CI: 0.63-1.57]). Frequent cases of haematological abnormalities (thrombocytopenia and neutropenia) were observed in the nevirapine group in step 1, leading to a recommendation from the data and safety monitoring board not to include a nevirapine group in step 2. Artemether-lumefantrine was well tolerated in the other groups. The therapeutic implications of these findings need to be evaluated among HIV-malaria co-infected adults.

4 To further characterize the impact of nevirapine-, efavirenz-, or ritonavir-boosted lopinavir -75 based ART on the PK of lumefantrine and safety profile of AL, we conducted an intensive PK 76 study to compare secondary PK parameters of lumefantrine and the incidence of treatment-77 emergent adverse events in malaria-negative HIV-infected adults taking AL plus NVP-, EFV-, or 78 LPV/r -based ART or AL only.

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We excluded subjects who had a body mass index of <18.5kg/m 2 , haemoglobin concentration of 116 <10 g/dL (subsequently changed to <8.5 g/dL based on DSMB recommendation), reported use 117 of any antimalarial drugs within the preceding 4 weeks, reported hypersensitivity to any of the 118 ACTs , receipt of other drugs which are known inhibitors or inducers of P450 enzymes or P- The sample size in step 1 was 6 in each of the AL/ART and control (ART-naive) and this was 131 based on standard practice in early PK studies of antimalarial drugs which aim to safeguard the 132 safety of study subjects and minimize the number of subjects who may be potentially exposed 133 to harmful drug levels. In step 2, the sample size was 15 per group which had at least 90%

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In step 1, 26 participants were enrolled in the study; 24 participants were successfully followed 220 up for 28 days. Two participants taking NVP-based ART were discontinued from the study due

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There were no major differences between baseline characteristics in step 1 or step 2.

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Pharmacokinetics of lumefantrine and interactions with antiretroviral therapy in step 1 232 Table 1 summarizes the PK parameters in the study groups in step 1. Compared with the ART-233 naïve group, the geometric mean AUC 0-14 days of lumefantrine was 53% lower in the EFV-ART

Pharmacokinetics of lumefantrine and interactions with antiretroviral therapy in step 2
255 Table 2 summarizes the PK parameters in the study groups in step 2. The geometric mean 256 lumefantrine AUC 0-14 days was similar in the EFV-based ART group and the ART-naïve group.

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Participants in the LPV/r-based ART group had an approximately 1.9 times higher geometric 258 mean AUC 0-14 days than those in the ART naïve group. There were no significant differences in 259 C max , t 1/2 and median t max in the EFV-and LPV/r-based ART groups compared to the ART-naïve

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Unlike in step 1, where lumefantrine exposure in the EFV-based ART group was significantly 306 lower in comparison to the ART-naïve group, overall lumefantrine exposure (AUC 0-14 days ) in step 307 2 was surprisingly not significantly different between the two groups. Lumefantrine 308 concentrations in the terminal elimination phase however, were consistently lower in the EFV-309 based ART group compared to the ART-naïve group in both steps (Figures 1a and 1b). Since

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(parasitaemia <135,000/μL) (46). In step 2 of this study, although participants on EFV-ART had lower day 7 lumefantrine concentrations than ART-naïve participants and those on LPV/r-based 357 ART had higher concentrations, the proportion achieving lumefantrine concentration ≥0.2 μg/mL 358 was only slightly lower in the EFV-ART group but was not significantly different from the ART-359 naïve group. This suggests that AL is still likely to be highly efficacious in those on EFV-based 360 ART, despite the PK interaction.

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In this study, we did not assess impact of ART on plasma concentrations of the artemisinin