Update on the CNS Adverse Effects of Sustiva® (Efavirenz)
Special Feature
By Kiron Punwani, Shannon Suedkamp, Diem Nguyen, and Jessica C. Song, Kiron Punwani, Shannon Suedkamp, and Diem Nguyen are PharmD Candidates at the University of the Pacific School of Pharmacy. Jessica C. Song, MA, PharmD, is Pharmacy Residency Coordinator, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.
Kiron Punwani, Shannon Suedkamp, Diem Nguyen, and Jessica C. Song report no financial relationships relevant to this field of study.
Introduction
The US Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents recommends efavirenz (EFV) as part of the preferred non-nucleoside reverse transcriptase inhibitor-based regimen for HIV patients.1 EFV represents a frequently used component of several antiretroviral combination regimens, even though many patients report CNS (central nervous system) side effects.
Studies, to date, have limited data on non-Caucasian patients, despite the fact that according to the DHHS, the AIDS rate for Hispanic adults and adolescents was 25 per 100,000, compared to 7.1 for Whites and 72.1 for Blacks.2 Hence, there is a compelling need to study this population segment. Of note, post-marketing surveillance of EFV revealed numerous cases of CNS adverse effects associated with elevated plasma concentrations of this drug, especially in the non-Caucasian patient population.3-6
This article will present a review of: 1) case reports of EFV-associated CNS effects observed in patients with elevated concentrations of this drug; 2) differences in pharmacokinetic profiles between Caucasian and non-Caucasian populations; and 3) monitoring recommendations for patients receiving this drug.
Published Reports of CNS Toxicity
Previous studies have evaluated CNS side effects associated with EFV plasma levels.3-6 A study conducted by Marzolini and colleagues showed that EFV plasma concentration levels help predict treatment failure and CNS side effects. Virologic failure occurred in 22% of patients with EFV levels of 1000-4000 ug/L, and CNS toxicity was 3 times more frequent in patients with EFV levels greater than 4000ug/L compared with patients whose levels ranged from 1000 to 4000ug/L. This study also confirmed the presence of marked inter-patient and low intra-patient variability, suggesting that therapeutic drug monitoring may be useful for individualizing treatment.3
Various patient populations have been studied, but Hispanic patients were often under-represented. For example, Gutierrez and colleagues demonstrated that a predominantly Caucasian patient population (94.1%) with EFV plasma concentrations greater than 2.74ug/mL were 5.68 times more likely to experience CNS toxicity.4 Findings from a study performed by Ribaudo and colleagues supported the strong association of race with the clearance of EFV. The clearance increased by 32% in White non-Hispanic subjects, compared with Black and Hispanic subjects; possibly due to differences in metabolism. Of note, patients in this study consisted of 53% Caucasian, 32% Black, and only 15% Hispanic.5
A report published by Hasse and colleagues described the case of a 33-year-old, HIV-infected Taiwanese woman who exhibited symptoms of acute psychosis, resulting from her EFV- based antiretroviral (ARV) regimen. About a week after treatment cessation, all psychiatric symptoms disappeared. Since the patient's symptoms were attributed to an interaction between EFV and fluconazole, interventions included a lowering of her fluconazole dose from 400 mg to 200mg once daily and re-initiation of her EFV-based ARV regimen. Her psychiatric symptoms reappeared, and her EFV level was discovered to be 30-fold higher than the upper normal limit. EFZ is metabolized by cytochrome (CYP) 2B6, and the inter-individual differences in CYP2B6 activity may be responsible for the differences in susceptibility to EFV associated CNS side effects.6
Differences Between Caucasian and Non-Caucasian PATIENTS
EFV undergoes metabolism by cytochrome p450 (CYP) 2B6 to form inactive hydroxylated metabolites that include 8- and 7-hydroxy efavirenz.7 Genetic polymorphisms of the CYP2B6 isoenzyme have been shown to increase plasma concentrations of EFV in susceptible individuals exposed to this drug.
Single nucleotide polymorphisms of CYP2B6 arise from the 2B6*6 allele (15631G > T (Q172H); 18053A > G (K262R)), with the highest frequencies seen in African-Americans.8-9 Less is known about the incidence of CYP2B6 polymorphisms in the Hispanic population. One study conducted by Ribaudo et al demonstrated that Caucasians exhibited a 32% higher clearance of EFV compared with the clearances observed in African-Americans and Hispanics.5
Monitoring Recommendations
Several studies have documented the effects of various drugs on CYP2B6 activity. Table 1 summarizes the drug-interaction profile of EFV, as shown by the list of CYP2B6 substrates, inhibitors, and inducers.7,10-17
In order to anticipate EFV-associated CNS effects, physicians should monitor for drug interactions of this drug with CYP2B6 inhibitors. Furthermore, plasma concentration level monitoring may be warranted in patients with intolerable CNS adverse effects, with levels being drawn 12 hours post-dose.3-4
Conclusion
To date, numerous studies have demonstrated that high plasma levels of EFV are associated with CNS side effects, and some have shown inter-patient variability that may be due to race and/or genetic polymorphisms involved in the metabolism of EFV. Although the populations studied have included Hispanic patients, they have represented only a small percentage, and the focus has been primarily on Caucasian populations. In light of the fact that Hispanics account for an estimated 19% of total AIDS diagnoses in the United States,2 physicians should be particularly alert for signs of EFV-induced toxicity in this under-studied population.
References
- Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents Developed by the Panel on Clinical Practices for Treatment of HIV Infection Convened by the Department of Health and Human Services. May 4, 2006. Available at: http://AIDSinfo.nih.gov. Accessed: 30 August 2006.
- Centers for Disease Control and Prevention, HIV/AIDS Surveillance Report 2004, Vol. 16. Available at: www.cdc.gov/hiv/stats/2004surveillancereport.pdf.
- Marzolini C, et al. Efavirenz Plasma Levels Can Predict Treatment Failure and Central Nervous System Side Effects in HIV-1 Infected Patients. AIDS. 2001;15:71-75.
- Gutierrez F, et al. Prediction of Neuropsychiatric Adverse Events Associated with Long-Term Efavirenz Therapy, Using Plasma Drug Level Monitoring. Clin Infect Dis. 2005;41:1648-1653.
- Ribaudo H, et al. Relationships Between Efavirenz Pharmacokinetics, Side Effects, Drug Discontinuation, Virologic Response, and Race: Results from ACTG A5095/A5097s. 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, CA. Abstract 132.
- Hasse B, et al. Efavirenz Intoxication Due to Slow Hepatic Metabolism. Clin Infect Dis. 2005;40:e22-e23.
- Ward BA, et al. The Cytochrome p450 2B6 (CYP2B6) is the Main Catalyst of Efavirenz Primary and Secondary Metabolism: Implication for HIV/AIDS Therapy and Utility of Efavirenz as a Substrate Marker of CYP2B6 Catalytic Activity. J Pharmacol Exp Ther. 2003;306:287-300.
- Klein K, et al. Genetic Variability of CYP2B6 in Populations of African and Asian Origin: Allele Frequencies, Novel Functional Variants, and Possible Implications for Anti-HIV Therapy with Efavirenz. Pharmacogenet Genomics. 2005;15:861-873.
- Ribaudo HJ, et al. Pharmacogenetics of Plasma Efavirenz Exposure after Treatment Discontinuation: An Adult AIDS Clinical Trials Group Study. Clin Infect Dis. 2006;42:401-407.
- Faucette SR, et al. Validation of Bupropion Hydroxylation as a Selective Marker of Human Cytochrome p450 2B6 Catalytic Activity. Drug Metab Dispos. 2000;28:1222-1230.
- Chang TK, et al. Differential Activation of Cyclophosphamide and Ifosphamide by Cytochromes p-450 2B and 3A in Human Liver Microsomes. Cancer Res. 1993;53:5629-5637.
- Rae JM, et al. Triethylenethiophosphoramide is a Specific Inhibitor of Cytochrome p450 2B6: Implications for Cyclophosphamide Metabolism. Drug Metab Dispos. 2002;30:525-530.
- Turpeinen M, et al. Effect of Clopidogrel and Ticlopidine on Cytochrome p450 2B6 Activity as Marked by Bupropion Hydroxylation. Clin Pharmacol Ther. 2005;77:553-559.
- Palovaara S, et al. Inhibition of Cytochrome p450 2B6 Activity by Hormone Replacement Therapy and Oral Contraceptives as Measured by Bupropion Hydroxylation. Clin Pharmacol Ther. 2003;74:326-333.
- Loboz KK, et al. Cytochrome p450 2B6 Activity as Measured by Bupropion Hydroxylation: Effect of Induction by Rifampin and Ethnicity. Clin Pharmacol Ther. 2006;80:75-84.
- Chang TK, et al. Enhanced Cyclophosphamide and Ifosphamide Activation in Primary Human Hepatocyte Cultures: Response to Cytochrome p450 Inducers and Autoinduction by Oxazaphosphorines. Cancer Res. 1997;57:1946-1954.
- Ducharme MP, et al. Phenytoin-Induced Alteration in the N-Dechloroethylation of Ifosfamide Stereoisomers. Cancer Chemother Pharmacol. 1997;40:531-533.
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