Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study.

TitlePharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study.
Publication TypeJournal Article
Year of Publication2006
AuthorsRibaudo HJ, Haas DW, Tierney C, Kim RB, Wilkinson GR, Gulick RM, Clifford DB, Marzolini C, Fletcher CV, Tashima KT, Kuritzkes DR, Acosta EP
Corporate AuthorsAdult AIDS Clinical Trials Group Study
JournalClin Infect Dis
Volume42
Issue3
Pagination401-7
Date Published2006 Feb 1
ISSN1537-6591
KeywordsAcquired Immunodeficiency Syndrome, Adult, African Americans, Anti-HIV Agents, Aryl Hydrocarbon Hydroxylases, Asian Continental Ancestry Group, Benzoxazines, Cytochrome P-450 CYP2B6, European Continental Ancestry Group, Female, Genotype, Half-Life, Hispanic Americans, Humans, Male, Oceanic Ancestry Group, Oxazines, Oxidoreductases, N-Demethylating, Polymorphism, Genetic, Viral Load
Abstract

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.

DOI10.1086/499364
Alternate JournalClin. Infect. Dis.
PubMed ID16392089
Grant ListAI046381 / AI / NIAID NIH HHS / United States
AI25903 / AI / NIAID NIH HHS / United States
AI27659 / AI / NIAID NIH HHS / United States
AI32775 / AI / NIAID NIH HHS / United States
AI33835 / AI / NIAID NIH HHS / United States
AI38855 / AI / NIAID NIH HHS / United States
AI38858 / AI / NIAID NIH HHS / United States
AI46339 / AI / NIAID NIH HHS / United States
AI46386 / AI / NIAID NIH HHS / United States
AI51966 / AI / NIAID NIH HHS / United States
AI54999 / AI / NIAID NIH HHS / United States
GM31304 / GM / NIGMS NIH HHS / United States
HL65962 / HL / NHLBI NIH HHS / United States
NS32228 / NS / NINDS NIH HHS / United States
RR00047 / RR / NCRR NIH HHS / United States