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. Findings: 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). Interpretation: 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. Funding: Funded by NIH.
Bibliographical noteFunding Information:
JKR has received honoraria for speaking at educational events or consulting from AbbVie, Bionor, Boehringer-Ingelheim, BMS, Gilead, Janssen, Merck, Tibotec, and ViiV. MB has received honoraria from AbbVie, Boehringer-Ingelheim, Bristol Myers Squibb, Gilead, Janssen-Cilag and Merck and grant funding from Gilead and Merck. All other authors declare no conflict of interests.
This publication was made possible in part by through the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health through grants U01AI042170 , U01AI46957 , U01AI046362 , U01AI068641 , R01AI110173 and R56AI102959 ; CTSA Grant Number UL1 TR000135 and 8KL2TR000136-08 from the National Center for Advancing Translational Sciences (NCATS) , a component of the NIH; as well as NIH grants R01 GM28157 and U19GM61388 (Pharmacogenomics Research Network); and the Swiss National Science Foundation (no. 141234 ). It was also supported by the Pharmacogenomics Translational Program of the Mayo Center for Individualized Medicine. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. We thank the staff of the Medical Genome Facility Genotyping Core (GTC) at the Mayo Clinic for carrying out the genotyping analyses for this study. The GTC is supported in part by the NCI Cancer Center Support Grant P30 CA 15083.
- Premature discontinuation