TY - JOUR
T1 - Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation
T2 - An adult AIDS clinical trials group study
AU - Ribaudo, Heather J.
AU - Haas, David W.
AU - Tierney, Camlin
AU - Kim, Richard B.
AU - Wilkinson, Grant R.
AU - Gulick, Roy M.
AU - Clifford, David B.
AU - Marzolini, Catia
AU - Fletcher, Courtney V.
AU - Tashima, Karen T.
AU - Kuritzkes, Daniel R.
AU - Acosta, Edward P.
N1 - Funding Information:
Financial support. This work was supported in part by the Adult AIDS Clinical Trials Group (grant AI38858) funded by the National Institute of Allergy and Infectious Diseases. Grant support included AI46339 (to D.W.H., R.B.K., and G.R.W.), AI38855 (to H.J.R. and C.T.), AI32775 (to E.P.A.), NS32228 and AI25903 (to D.B.C.), AI46386 (to R.M.G.), AI33835 (to C.V.F.), AI046381 (to K.T.T.), AI27659 (to D.R.K.), RR00047 (to R.M.G.), AI51966 (to R.M.G.), GM31304 (to R.B.K. and G.R.W.), HL65962 (to R.B.K.), and AI54999 (to D.W.H.). Boehringer-Ingelheim,Bristol-Myers Squibb, and GlaxoSmithKline provided study medications for ACTG protocol A5095.
Funding Information:
Potential conflicts of interest. D.W.H. has received research grants from Bristol Myers Squibb, Boehringer-Ingelheim, Tanox, GlaxoSmith-Kline, and Gilead Sciences and is a consultant for Boehringer-Ingelheim; R.B.K. has received research grants from Bristol Myers Squibb, Pfizer, Abbott, and Merck and is a consultant for Boehringer-Ingelheim; R.M.G. has received research grants from Abbott, Boehringer-Ingelheim, Merck, and Tibotec, has served as an ad-hoc consultant for Abbott, Bristol-Myers, Boehringer-Ingelheim, Gilead, GlaxoSmithkline, and Tibotec, and has received speaker honoraria from Bristol-Myers, Gilead, Merck, and Roche; D.B.C. has received research grants from Pfizer, Neurogesix, Glaxo-SmithKline, and Savient, has been a consultant for Pfizer, Biogen, and Boehringer Ingelheim, and has received an honorarium for speaking from Bristol Myers Squibb; C.V.F. has served on ad hoc advisory boards for GlaxoSmithKline, Bristol Myers Squibb, and Roche; K.T.T. has received research grants from Bristol Myers Squibb, GlaxoSmithKline, and Merck and is a consultant for Bristol Myers Squibb; D.R.K. is a consultant for and has received honoraria from Bristol-Myers Squibb, GlaxoSmithKline, Gilead Sciences, and Boehringer-Ingleheim and has also received research grant support from GlaxoSmithKline and Boehringer-Ingleheim. All other authors: no conflicts.
PY - 2006/2/1
Y1 - 2006/2/1
N2 - 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 I. 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.
AB - 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 I. 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.
UR - http://www.scopus.com/inward/record.url?scp=31044456584&partnerID=8YFLogxK
U2 - 10.1086/499364
DO - 10.1086/499364
M3 - Article
C2 - 16392089
AN - SCOPUS:31044456584
VL - 42
SP - 401
EP - 407
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
SN - 1058-4838
IS - 3
ER -