676 VOLUME 88 NUMBER 5 | NOVEMBER 2010 | www.nature.com/cpt ARTICLES nature publishing group herapeutic management of HIV/AIDS has enabled critically ill patients to achieve good clinical recovery and viral suppression in a median time of 16 weeks. 1 However, a substantial propor- tion of patients experience viral rebound and clinical progres- sion to AIDS even ater initial recovery because of the emergence of drug-resistant HIV. 1–5 Diiculties in maintaining long-term adherence to treatment regimens lead to decreases in plasma concentrations of the drugs to subtherapeutic levels; this has been reported as one of the major reasons for treatment failure. 1,4,5 However, failure of highly active antiretroviral therapy (HAART) has been reported even in patients with good adherence to treat- ment regimens, 6 and it is likely that prolonged autoinduction of efavirenz metabolism, leading to subtherapeutic plasma levels, may explain treatment failure in some of these patients. Plasma levels of efavirenz, a non-nucleoside reverse-transcriptase inhibi- tor, predict treatment outcome in patients on HAART. 7,8 he majority of patients with trough efavirenz plasma levels <1 µg/ml experience treatment failure, whereas those with levels >4 µg/ml are associated with central nervous system toxicity. 9–11 Patients who failed treatment were later found to harbor HIV strains that were resistant to coadministered nucleotide reverse-transcriptase inhibitors as well as non-nucleotide reverse-transcriptase inhibitors. 2,7,12 his indicates that maintaining adequate levels of efavirenz plasma concentration may be important in prevent- ing the emergence of resistant HIV-1 strains. Ater oral administration, efavirenz undergoes rapid absorp- tion, and maximum plasma concentration is reached in 3–6 h. Efavirenz is 99% bound to plasma protein and distributes well to sanctuary sites including cerebrospinal luid and testicles, reaching therapeutic levels in just a few days ater commenc- ing treatment. 13–15 Efavirenz has been reported to accumulate in cells, reaching intracellular concentrations well above its 90% inhibitory concentration. 16 However, efavirenz induces its own metabolism, thereby decreasing the plasma exposure ater 1 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital-Huddinge, Karolinska Institute, Stockholm, Sweden; 2 Department of Pharmacognosy, Unit of Pharmacology and Therapeutics, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania; 3 Department of Internal Medicine, Muhimbili National Hospital, Dar es Salaam, Tanzania; 4 Department of Infectious Diseases, Karolinska University Hospital at Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; 5 Department of Clinical Pharmacology, School of Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania; 6 Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany; 7 Department of Internal Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania. Correspondence: E Aklillu (Eleni.Aklillu@ki.se) Received 19 April 2010; accepted 22 June 2010; advance online publication 29 September 2010. doi:10.1038/clpt.2010.172 Long-Term Efavirenz Autoinduction and Its Effect on Plasma Exposure in HIV Patients E Ngaimisi 1,2 , S Mugusi 3,4 , OM Minzi 2 , P Sasi 5 , K-D Riedel 6 , A Suda 1 , N Ueda 1 , M Janabi 3 , F Mugusi 7 , WE Haefeli 6 , J Burhenne 6 and E Aklillu 1 We investigated the influence of gender and pharmacogenetic variations on long-term efavirenz autoinduction and disposition among patients with HIV in Tanzania (N = 129). Plasma concentrations (at 16 h) of efavirenz and 8-hydroxyefavirenz were quantified at weeks 4 and 16 of therapy. Genotyping was performed to identify cytochrome P450 (CYP) 2B6*6, CYP3A5*3, *6, and *7, and ABCB1-3435 C/T genotypes. There were reductions in the median efavirenz concentration (Wilcoxon matched-pair test P < 0.001) and efavirenz/8-hydroxyefavirenz ratio (P < 0.001) by 19 and 32%, respectively, at week 16 as compared with week 4. The proportion of patients with efavirenz concentration <1 µg/ml at week 16 was higher by 67, 25, and 5% in CYP2B6*1/*1, *1/*6, and *6/*6 genotypes, respectively. The defined therapeutic range based on observed plasma concentrations is affected by the time point of sampling and the CYP2B6 genotype. The effect of efavirenz autoinduction on reducing plasma exposure continues up to week 16 and predominantly affects CYP2B6 extensive metabolizers. Among CYP2B6 slow metabolizers, the presence of a CYP3A5 genotype allele is associated with greater effects of efavirenz autoinduction on plasma concentrations of the drug. The cumulative induction may influence the long-term antiretroviral therapy outcome, particularly in CYP2B6*1 carriers.