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EXTENSIVE EFAVIRENZ METABOLISM IS ASSOCIATED WITH GREATER CNS TOXICITY
Marijana Vujkovic1, Scarlett Bellamy2, Athena Zuppa1, Marc Gastonguay3, Xiaoyan Han4, Mosepele Mosepele5, Gregory Bisson4, Richard Aplenc1, Robert Gross4
1Children's Hosp of Philadelphia, Philadelphia, PA, USA,2Drexel Univ, Philadelphia, PA, USA,3Metrum Rsr Group, Tariffville, CT, USA,4Univ of Pennsylvania, Philadelphia, PA, USA,5Univ of Botswana, Gaborone, Botswana
Efavirenz causes central nervous system adverse effects (CNS AEs) including sleep disturbance, somnolence, vivid dreams and others. The relation between efavirenz clearance and CNS AEs has been unclear, particularly when stratified by race. P450 (CYP) isoenzyme 2B6 G516T confers slower metabolism and is more common with African origin. We hypothesized that this allele and additional CYP polymorphisms that affect efavirenz clearance mediate CNS AEs.
We included 842 HIV infected adults initiating efavirenz + 2 nucleoside analog reverse transcriptase inhibitors in a cohort study in Botswana. DNA was genotyped for 21 variants in CYP 2B6, 2A6, 3A4, and 3A5 genes and mid-dose EFV plasma samples were collected at 1 month of therapy. AEs were measured using 21 CNS symptoms in the ACTG Subject Experience Questionnaire. We used a one-compartment population PK model with nonlinear mixed effect modeling in NONMEM 7 to estimate EFV clearance, including the fixed covariates of allometrically scaled weight, G516T genotype, and visit number. SNPs that resulted in the greatest statistically significant decrease in the minimum objective function value (MOFV) were regarded as either extensive or slow metabolizers. Associations between metabolizer groups and CNS AEs were evaluated using negative binomials in a generalized linear regression model including the covariates: plasma EFV concentration, CYP2B6 G516T genotype, age, gender, alcohol intake, baseline CD4 count and viral load.
The initial covariate model showed a MOFV of 2075. Two SNPs showed a reduced apparent oral EFV clearance: rs28399499 (8.0, 4.7, and 1.4 L/hr/70kg for TT, CT, CC, MOFV=1768) and rs28399433 (7.6, 5.9, and 4.9 L/hr/70kg for TT, GT, GG, MOFV=2015). Four SNPs showed extensive apparent clearance: rs2279345 (6.5, 8.0, and 8.4 L/hr/70kg for TT, CT, CC, MOFV=1995), rs4803417 (6.8, 8.3, and 9.4 L/hr/70kg for AA, AC, CC, MOFV=2015), rs4802101 (7.3 and, 8.6 L/hr/70kg for AA, AG, MOFV=2037), and rs61663607 (7.2, 7.2, and 8.7 L/hr/70kg for TT, CT, CC, MOFV=2021). Faster efavirenz clearance was associated with greater reported CNS AEs (β=0.42, p=0.01, see Figure).
In a model including multiple fast and slow clearance polymorphisms, faster clearance was associated with more CNS AEs. These findings implicate metabolites rather than parent drug as the cause of efavirenz-related CNS AEs. Assays for extensive CYP polymorphisms may permit avoidance of EFV in HIV-infected Africans at high risk of CNS AEs.