Investigation of Efavirenz Discontinuation in Multi-ethnic Populations of HIV-positive Individuals by Genetic Analysis.
BACKGROUND
Efavirenz (EFV) based antiretroviral therapy is expanding worldwide. However discontinuation of EFV containing regimens is common in some patients, particularly black patients, due most often to neuropsychiatric side effects. These adverse drug effects often result in premature drug discontinuation, as well as considerable morbidity.


METHODS
We genotyped CYP2A6, CYP2B6 and CYP3A4, which encode enzymes principally involved in EFV metabolism, from patients enrolled in the multinational SMART, FIRST and ESPRIT studies, for whom outcome data of treatment adherence was available. Patients with loss or decrease of function single nucleotide polymorphisms (SNPs) in the above genes were assigned a risk score based upon the number of SNPs present weighted relative to whether CYP2B6 (main metabolism pathway) and/or CYP2A6 and CYP3A4 (accessory pathways) were involved. Cox regression models were used to study the association between high genetic risk and time from initiation to EFV discontinuation. Failure was defined as discontinuation of an antiretroviral regimen other than for virologic failure or protocol determined discontinuation.


RESULTS
Patients with highest pharmacogenetic risk, as defined by cumulative SNPs in CYP2A6, CYP2B6 and CYP3A4, have an increased risk of discontinuation of EFV containing therapy compared to patients with lower genetic risk scores (adjusted HR 1.9, 95% CI 1.2, 3.1, P = 0.009). High genetic risk score was not associated with an increased risk of discontinuing atazanavir or nevirapine. High genetic risk was present more often in blacks compared to non-blacks (Adjusted OR 4.5, 95% CI: 1.9,10.5), and treatment discontinuation was also increased in blacks overall (Adjusted HR 1.4, 95% CI 1.0, 1.9). However, high genetic risk was more associated with treatment discontinuation than race alone for both blacks (Adjusted OR 1.9, 95% CI 0.8, 4.8) and non-blacks (Adjusted OR 5.3, 95% CI 1.5, 18.0).


CONCLUSIONS
Premature discontinuation of ART delays the time to effective long term viral suppression, and is associated with significant morbidity. Pharmacogenetic testing may predict those with a high risk of EFV discontinuation, and therefore should be considered in patients in whom initiation of EFV based ART is being considered.


BACKGROUND
Funded by NIH.
Mayo Clinic, Rochester, MN, United States.
Nathan W
NW
Cummins
University of Minnesota, Minneapolis, MN, United States.
Jacqueline
J
Neuhaus
University of Minnesota, Minneapolis, MN, United States.
Haitao
H
Chu
University of Minnesota, Minneapolis, MN, United States.
James
J
Neaton
University of Cologne, Germany.
Christoph
C
Wyen
Department of Medicine I, University of Bonn, Germany.
Jürgen K
JK
Rockstroh
Baystate Medical Center, Springfield, MA, United States.
Daniel J
DJ
Skiest
The Kirby Institute, UNSW Medicine, University of New South Wales-Australia, NSW 2052, Australia.
Mark A
MA
Boyd
University of Liverpool, United Kingdom.
Saye
S
Khoo
University of Lausanne, Switzerland.
Margalida
M
Rotger
University of Lausanne, Switzerland.
Amalio
A
Telenti
Mayo Clinic, Rochester, MN, United States.
Richard
R
Weinshilboum
Mayo Clinic, Rochester, MN, United States.
Andrew D
AD
Badley
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines / Q000627:therapeutic use*; D003521:Cyclopropanes; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006679:HIV Seropositivity / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013557:Switzerland; D016896:Treatment Outcome; D028761:Withholding Treatment
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C098320:efavirenz
Efavirenz; HIV; Pharmacogenetics; Premature discontinuation