To the editor—Limited data exist on pharmacokinetic interactions between antiretroviral and antimalarial drugs, with both classes of drugs being metabolized through cytochrome P450 pathways. To evaluate interactions between the widely adopted antimalarial drug combination of amodiaquine plus artesunate (AQ/AS) and the commonly used antiretroviral drug efavirenz (EFV), we administered AQ/AS alone (days 1–3) and then AQ/AS (days 18–20) combined with EFV (days 7–23) to healthy volunteers. Five healthy volunteers were enrolled, but the study was prematurely discontinued after the first 2 subjects developed significant increases in hepatic transaminase levels (figure 1). Subject 1, a 51-year-old African American man, was noted to have increased transaminase levels 34 days after study completion; the levels peaked 3 days later, with an alanine aminotransferase (ALT) level of 206 U/L and an aspartate aminotransferase (AST) level of 78 U/L. The patient was found to be asymptomatic, with a normal physical examination. Other laboratory values were normal, including the serological test results for hepatitis virus A, B, and C; Epstein-Barr virus; and cytomegalovirus. The subject denied ingestion of potentially hepatotoxic substances. His transaminase levels slowly decreased and returned to normal 102 days after study completion. Time course for abnormalities in liver-associated enzyme levels. Bars, duration of study drug administration. ALT, alanine aminotransferase; AQ/AS, amodiaquine plus artesunate; AST, aspartate aminotransferase; EFV, efavirenz; ULN, upper limit of normal for ALT and AST level. Subject 2, a 26-year-old white woman, experienced a similar course, with a peak ALT level of 868 U/L and a peak AST level of 559 U/L 42 days after study completion; normalization occurred 154 days after study completion. Of note, subject 2 had ingested ∼9 alcoholic beverages per week after completing the study and was taking an oral contraceptive containing ethinyl estradiol and drospirenone during the study. Subject 3 withdrew from the study after day 3 because of nausea. Subjects 4 and 5 were removed from the study prior to receiving the second course of AQ/AS therapy and had no laboratory abnormalities. Plasma levels of AQ, desethylamodiaquine (DEAQ)–active metabolite, and EFV were analyzed by high-performance liquid chromatography, using previously published methods [1, 2]. The addition of EFV therapy resulted in increases in AQ area under the plasma concentration-versus-time curve (AUC0–96 h) of 114.7% and 302.3% in subjects 1 and 2, respectively, and increases in the maximum concentration (Cmax) and half-life for AQ. For DEAQ, a 23.7% decrease in AUC0–96 h and increases in Cmax and half-life were observed in subject 1; an 8.5% decrease in AUC0–96 h, a decrease in Cmax, and a minimal increase in half-life were noted in subject 2. EFV AUC0–24 h was noted to be within the reported range for healthy volunteers in subject 1 and higher than the reported values in subject 2 [3]. The administration of EFV therapy in the context of AQ/AS therapy increased AQ exposure and decreased DEAQ exposure in both subjects. Both subjects had normal transaminase levels throughout the period of study drug administration but developed substantial asymptomatic increases in their transaminase levels several weeks following study completion. Changes in AQ/DEAQ exposure and hepatotoxicity were surprising and could not be explained by available data on AQ/DEAQ metabolism [4]. Hepatitis induced by EFV therapy is uncommon and has not been associated with AS therapy [5]. AQ therapy has resulted in hepatitis when used for chronic malaria chemoprophylaxis [6–8], but 3-day treatment courses of AQ/AS therapy have not been linked to hepatotoxicity. Optimal malaria treatment regimens for HIV-infected persons receiving antiretroviral therapy are not clear. The dramatic, delayed onset of hepatitis we observed in 2 subjects suggests that patients treated with a regimen containing AQ or AS while receiving EFV-based antiretroviral regimens should be monitored for liver toxicity. Continued research is needed to establish the safety and efficacy of antimalarial regimens in patients receiving antiretroviral therapy. Financial support. National Institutes of Health, University of California San Francisco-Gladstone Institute of Virology … Immunology Center for AIDS Research (P30 AI27763) and the General Clinical Research Center at San Francisco General Hospital, funded by the National Center for Research Resources, National Institutes of Health (MO1-RR00083-43). N.L. is supported by The Wellcome Trust of Great Britain as part of the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme. Potential conflicts of interest. All authors: no conflicts.
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German et al. (2007) studied this question.