Efavirenz, Poor Metabolism Of

A number sign (#) is used with this entry because poor metabolism of efavirenz and susceptibility to efavirenz central nervous system (CNS) toxicity are associated with variation in the CYP2B6 gene (123930) on chromosome 19q13.2.

Description

Highly active antiretroviral therapy (HAART) has reduced mortality associated with acquired immunodeficiency syndrome (AIDS; see 609423) by at least 70%. Efavirenz is a non-nucleoside reverse transcriptase inhibitor that is frequently prescribed with 2 nucleoside reverse transcriptase inhibitors as initial therapy for human immunodeficiency virus (HIV) infection. However, during the first weeks of therapy, up to half of patients who receive efavirenz experience CNS side effects, including dizziness, insomnia, impaired concentration, somnolence, and abnormal dreams. Severe depression, aggressive behavior, and paranoid or manic reactions may also occur, and such side effects may reflect varying efavirenz plasma concentrations. Plasma clearance of efavirenz appears slower in African Americans than in European Americans, and studies have suggested earlier virologic failure on efavirenz for both African Americans and Hispanics compared with European Americans. Efavirenz is metabolized primarily by hepatic CYP2B6, with some involvement of CYP3A (CYP3A4; 124010) (summary by Haas et al., 2004).

Mapping

Poor metabolism of efavirenz and susceptibility to efavirenz CNS toxicity are associated with variation in the CYPB2B6 gene, which Trask et al. (1993) mapped to chromosome 19q13.2.

Molecular Genetics

Haas et al. (2004) examined associations between CNS side effects and efavirenz plasma concentration-time profiles and polymorphisms in the CYP2B6, CYP3A4 (124010), CYP3A5 (605325), and MDR1 (ABCB1; 171050) genes in 157 American HIV-infected patients. They found that homozygosity for a nonsynonymous CYP2B6 SNP, 516G-T (rs3745274; 123930.0001), was present in 20% of African Americans compared with only 3% of European Americans and was associated with higher efavirenz exposure in plasma (p less than 0.0001). The median 24-hour area under the curve of efavirenz was about 3-fold higher in 516T homozygotes than in 516G homozygotes, and was intermediate in 516GT heterozygotes, regardless of ethnicity, suggesting a gene dosage effect. Among all patients, CNS side effects at week 1 were associated with 516T (p = 0.036). There were no significant immunologic or virologic differences for polymorphisms in any of the genes studied. Haas et al. (2004) concluded that interindividual differences in drug metabolism may, in part, explain susceptibility to efavirenz CNS side effects.

Carr et al. (2010) determined plasma efavirenz concentrations in 219 HIV-positive Chilean patients and identified 11 CYP2B6 SNPs that were significantly associated with drug concentrations. Of these, only 516G-T (p = 5.6 x 10(-20)) was exonic. However, a composite model in which 516G-T was combined with 2 other SNPs was more strongly associated with efavirenz plasma concentrations than 516G-T alone.

Elens et al. (2010) studied 50 HIV-infected patients from Belgium and confirmed that minimum trough plasma level concentrations of efavirenz were associated with CYP2B6 allelic status. They also found that cell-associated concentrations of efavirenz were associated with CYP2B6 516G-T. Elens et al. (2010) concluded that knowledge of CYP2B6 genetic status should be taken into account for efavirenz treatment.

The Q172H (123930.0001) and K262R (123930.0002) substitutions define the CYP2B6*6 allele. In a study of 35 Japanese patients taking efavirenz, Tsuchiya et al. (2004) found that 2 patients who were homozygous for the *6 allele had significantly higher plasma efavirenz levels compared to those who were heterozygous for the *6 allele or those without the *6 allele.