Efavirenz-Based Antiretroviral Therapy Reduces Artemether-Lumefantrine Exposure for Malaria Treatment in HIV-Infected Pregnant Women

Abstract

Background: The choice of malaria treatment for HIV-infected pregnant women receiving efavirenz-based antiretroviral therapy must consider the potential impact of drug interactions on antimalarial exposure and clinical response. The aim of this study was to investigate the effects of efavirenz on artemether-lumefantrine (AL) because no studies have isolated the impact of efavirenz for HIV-infected pregnant women.

Methods: A prospective clinical pharmacokinetic (PK) study compared HIV-infected, efavirenz-treated pregnant women with HIV-uninfected pregnant women in Tororo, Uganda. All women received the standard 6-dose AL treatment regimen for Plasmodium falciparum malaria with intensive PK samples collected over 21 days and 42-days of clinical follow-up. PK exposure parameters were calculated for artemether, its active metabolite dihydroartemisinin (DHA), and lumefantrine to determine the impact of efavirenz.

Results: Nine HIV-infected and 30 HIV-uninfected pregnant women completed intensive PK evaluations. Relative to controls, concomitant efavirenz therapy lowered the 8-hour artemether concentration by 76% (P = 0.013), DHA peak concentration by 46% (P = 0.033), and day 7 and 14 lumefantrine concentration by 61% and 81% (P = 0.046 and 0.023), respectively. In addition, there were nonsignificant reductions in DHA area under the concentration-time curve0-8hr (35%, P = 0.057) and lumefantrine area under the concentration-time curve0-∞ (34%, P = 0.063) with efavirenz therapy.

Conclusions: Pregnant HIV-infected women receiving efavirenz-based antiretroviral therapy during malaria treatment with AL showed reduced exposure to both the artemisinin and lumefantrine. These data suggest that malaria and HIV coinfected pregnant women may require adjustments in AL dosage or treatment duration to achieve exposure comparable with HIV-uninfected pregnant women.

Figure 1.

Treatment and PK sampling schedule. Following malaria diagnosis on study day 0, six doses of AL were administered from study days 0 to 3 (green box). Plasma PK samples were collected on day 0 prior to treatment, before (0hr) and at 0.5, 1, 2, 3, 4, 8, 24, 120 (day 8*), 264 (day 14), and 432 (day 21) hr post sixth dose (blue arrows). Active follow up for malaria was performed on days 28 and 42 (pink arrows). The 120 hr sample occurred on day 8 in this study due to the elongated dosing schedule. Previously studies using the standard three day dosing report the 120 hr sampling point as day 7 values. Given that sampling occurred at the same post-dose time we will refer to day 8 as day 7 throughout. AR, artemether; DHA, dihydroartemisinin; LR, lumefantrine.

Figure 2.

Artemether (A), dihydroartemisinin (B) and lumefantrine (C) plasma concentration-time profiles in pregnant HIV-uninfected and infected women with malaria. The median concentrations are reported with the error bars indicating interquartile ranges.