Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study.
BACKGROUND
Efavirenz has a long plasma half-life and a low genetic barrier to resistance. Simultaneously stopping treatment with all agents in efavirenz-containing regimens may result in functional efavirenz monotherapy that selects for drug-resistant human immunodeficiency virus type 1. Lower plasma efavirenz clearance is associated with a cytochrome P450 2B6 gene (CYP2B6) polymorphism (516G-->T) that is more frequent among African American individuals than among European American individuals.


METHODS
We characterized relationships between this polymorphism and predicted plasma efavirenz concentration-time profiles after discontinuation of therapy with use of data obtained from subjects receiving therapy. Pharmacokinetic parameters were estimated using population-based methods. Concentrations after discontinuation of therapy were predicted from subject-specific estimates. RESULTS. Median estimated efavirenz half-lives were 23, 27, and 48 h for patients with CYP2B6 position 516 GG (78 patients), GT (60), and TT (14) genotypes, respectively (P<.001). After therapy was stopped, plasma efavirenz concentrations in patients with GG, GT, and TT genotypes were predicted to exceed 46.7 ng/mL (the estimated protein-adjusted 95% inhibitory concentration for wild-type virus) for a median of 5.8 days (interquartile range [IQR], 4.4-8.3 days), 7.0 days (IQR, 5.0-8.0 days), and 14 days (IQR, 11.1-21.2 days), respectively (P<.001). Plasma efavirenz levels were predicted to exceed 46.7 ng/mL for >21 days in 5% of subjects with GG genotype, 5% of subjects with GT genotype, and 29% of subjects with TT genotype.


CONCLUSIONS
The CYP2B6 position 516 TT genotype or a prolonged measured elimination half-life may predict increased risk of developing drug resistance among patients who discontinue efavirenz-containing regimens. This has implications for strategies to safely discontinue antiretroviral regimens while avoiding the emergence of drug resistance.
Ribaudo
Heather J
HJ
Statistical Data Analysis Center, Harvard School of Public Health, Harvard Medical School, Boston, MA, USA.
Haas
David W
DW
Tierney
Camlin
C
Kim
Richard B
RB
Wilkinson
Grant R
GR
Gulick
Roy M
RM
Clifford
David B
DB
Marzolini
Catia
C
Fletcher
Courtney V
CV
Tashima
Karen T
KT
Kuritzkes
Daniel R
DR
Acosta
Edward P
EP
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000328:Adult; D001741:Black or African American; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People; D048588:Benzoxazines; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005838:Genotype; D006207:Half-Life; D006630:Hispanic or Latino; D006801:Humans; D008297:Male; D044468:Native Hawaiian or Pacific Islander; D010078:Oxazines / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011110:Polymorphism, Genetic; D019562:Viral Load; D044465:White People
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz