HIV Integrase Inhibitor Pharmacogenetics: An Exploratory Study
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Background and Objectives
Integrase strand transfer inhibitors (INSTIs), dolutegravir, elvitegravir, and raltegravir, have become integral in the treatment of HIV, with close monitoring of continued efficacy and tolerability. As side effect occurrence varies among subjects receiving these drugs, we sought to perform an exploratory analysis examining the role of several single-nucleotide polymorphisms (SNPs) on drug concentration changes, selected clinical outcomes, and the occurrence of subject-reported adverse events.
Adults (aged ≥ 18 years) receiving INSTI-based regimens for treatment of HIV were recruited and genotyped with an iPLEX ADME PGx Pro v1.0 Panel. Multiple linear or logistic regression with covariates [age, sex, BMI, regimen (in the across-regimen group), regimen duration, and baseline variables (for continuous parameters)] was used to detect significant (p < 0.05) association of selected clinical data with genetic variants within the study population.
In a sample (n = 88) with a median age of 52.5 years (IQR 45.7–57.2) being predominately Caucasian (88.6%) and male (86.4%), this exploratory study discovered several associations between variables and SNPs, when using INSTIs. Abnormal dream occurrence was statistically different (p = 0.028) between regimens. Additionally, several SNPs were found to be associated with adverse event profiles primarily when all regimens were grouped together.
The associations found in this study point to a need for further assessment, within the population living with HIV, of factors contributing to unfavorable subject outcomes. These exploratory findings require confirmation in larger studies, which then may investigate pharmacogenetic mechanisms.
Portions of this article were published in dissertation form in fulfillment of the requirements for the Ph.D. Program for Derek E. Murrell. The Vanderbilt VANTAGE Core provided technical assistance for this work. VANTAGE is supported in part by CTSA Grant (5UL1 RR024975-03), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), and NIH/NCRR (G20 R030956). We would like to thank Angela Hanley for her help with recruitment and sample handling; everyone involved at the ETSU Center of Excellence in HIV/AIDS care, especially Susan Dotson for initiating patient contact; and the Eastman Chemical Company and Dr. Rainey Garland for their assistance with drug analysis. Finally, we would like to thank the numerous people involved in the completion of this study and the volunteers who participated.
DM: Designed research, performed research, analyzed data, and wrote manuscript; DC: Designed research, performed research, and wrote manuscript; JM: Designed research, performed research, and wrote manuscript; SB: Performed research, analyzed data, and wrote manuscript; KW: Designed research, analyzed data, and wrote manuscript; MD: Designed research and wrote manuscript; SH: Designed research, performed research, analyzed data, and wrote manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest.
This study was funded in part by a Research and Development Committee Interdisciplinary Grant and a Graduate Studies Student Research Grant from East Tennessee State University.
All study procedures were conducted in accordance with the 1964 Helsinki Declaration (and its amendments). The study was approved by the East Tennessee State University/Veterans Affairs Medical Campus Institutional Review Board (IRB#: 1214.4sw).
Informed consent was obtained from study participants in the presence of at least one investigator and witness.
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