Related Experiment Video
Updated: May 18, 2026

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and
Melissa A Frasco1, Wendy J Mack, David Van Den Berg
1Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Objective:
CYP2B6 variation predicts pharmacokinetic characteristics of its substrates. Consideration for underlying genetic structure is critical to protect against spurious associations with the highly polymorphic CYP2B6 gene.
Design:
The effect of CYP2B6 variation on response to its substrates, nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored in the Women's Interagency HIV Study.
Methods:
Five putative functional polymorphisms were tested for associations with virologic suppression within 1 year after NNRTI initiation in women naive to antiretroviral agents (n = 91). Principal components were generated to control for population substructure. Logistic regression was used to test the joint effect of rs3745274 and rs28399499, which together indicate slow, intermediate, and extensive metabolizers.
Results:
Rs3745274 was significantly associated with virologic suppression [odds ratio = 3.61, 95% confidence interval (CI) 1.16-11.22, P trend = 0.03]; the remaining polymorphisms tested were not significantly associated with response. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66 to infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for principal components (P trend = 0.005). Failure to control for genetic ancestry resulted in substantial confounding of the relationship between the metabolizer phenotype and treatment response.
Conclusion:
The CYP2B6 metabolizer phenotype was significantly associated with virologic response to NNRTIs; this relationship would have been masked by simple adjustment for self-reported ethnicity. Given the appreciable genetic heterogeneity that exists within self-reported ethnicity, these results exemplify the importance of characterizing underlying genetic structure in pharmacogenetic studies. Further follow-up of the CYP2B6 metabolizer phenotype is warranted, given the potential clinical importance of this finding.
Related Concept Videos
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes
Pharmacogenetics of Drug Metabolism: Overview
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
Principles of Pharmacogenetics: Types of Genetic Variants
Drug toxicity: Idiosyncratic Reactions