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Genetic Mutations Affecting Response to Drugs Are Common in Veterans

by Annette Boyle

September 13, 2019

VA Debates Who Should Receive Pharmacogenetic Testing

SALT LAKE CITY—A massive VA study revealed that 99% of veterans have at least one genetic mutation known to affect response to specific drugs, including some commonly prescribed antidepressants, anticoagulants, antivirals, oncology medications and statins. That raises the question of who should be tested for which variants and when, which has stirred lively debate within the VA.1

Nearly 55% of the 7,769,356 veterans in the study took one of the drugs with strong evidence of interaction with a specific gene mutation over the six year period analyzed. More than one-third of veterans received a new prescription for one of these drug and, of those, 38% were prescribed more than one drug for which genetic information could guide use, dosage, and expected response within one year.

“Based on those key findings, if broad pharmacogenetic testing (PGx) were implemented, incorporating this information into prescribing decisions would impact a large proportion of veterans,” said the study’s lead author Catherine Chanfreau-Coffinier, PhD, research health scientist at VA Informatics Computing Infrastructure at Salt Lake City Health Care System.

In the categorization developed by the Clinical Pharmacogenetics Implementation Consortium, medications with known gene/drug interactions that affect prescribing are classified as level A drugs. The category includes nearly 60 drugs such as simvastatin, tramadol, warfarin, clopidogrel, codeine, citalopram, abacavir and amitriptyline.

The VA study focused on use of 30 level A drugs for which CPIC recommended prescribing an alternative medication or adjusting the dose based on genetic findings.

For some of the drugs, knowing if a veteran has a specific genetic mutation could be life altering.

“The right timing depends on the outcome you’re trying to prevent or enhance,” said study co-author Sony Tuteja, PharmD, of the Corporal Michael Crescenz VAMC in Philadelphia. “To avoid life-threatening reactions, you need to test before the first dose.”

The VA already conducts human leukocyte antigen testing prior to prescribing abacavir to avoid a potentially fatal reaction. HLA type also impacts response to pegylated interferon, carbamazepine, oxcarbazepine, phenytoin and allopurinol, with adverse effects ranging from hypersensitivity reaction to severe cutaneous adverse reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis.

“Similarly, if a variant influences the dose—a perfect example is warfarin—testing up front can minimize the time spent finding a proper dose and making adjustments,” Tuteja told U.S. Medicine.

The study found that two-thirds of veterans with European ancestry were likely to have actionable genetic variants for warfarin dosing. The authors noted that “veterans of African ancestry also are likely to have variants that could guide dosing, although different variants are likely to influence warfarin response in this population.”

Common mutations can reduce the effectiveness of medications or increase the risk of side effects of medications frequently prescribed to veterans. The researchers estimated that 8.9% of the nearly one million veterans prescribed tramadol for analgesia would have an inadequate response to therapy. Of the 533,928 veterans newly prescribed simvastatin, 25.6% were projected to have a variant in SLC01B1 that put them at risk of myopathy at any dose, and 1 in 4 of those were prescribed an 80 mg initial dose that would further increase their risk.

A genetic mutation that affects processing of a particular drug only matters for veterans prescribed that drug, though, which makes determining who should be tested and when more challenging.

Test Everyone?

“If you were to test everyone, it would be more efficient up front,” said Deepak Voora, MD, director of VA’s Pharmacogenomics Action for Cancer Survivorship, or PHASeR, program. “The challenge is knowing who would be getting those medications and not testing people who would never take the drug. An intermediate approach might be, when testing for one drug that will be prescribed in the next week or so, testing for all drugs to avoid reincurring the testing costs.”

The VA has started to take this approach with certain patient groups. Through a partnership announced in March with Sanford Health Care of Sioux Falls, South Dakota, the PHASeR program provides pharmacogenetic testing for veterans who are cancer survivors. Research shows cancer survivors have a high risk of chronic mental health, metabolic disease and chronic pain. The program will preemptively test for mutations in genes associated with drugs used to treat these conditions, explained Voora.

The PRecision medicine In MEntal health Care, or PRIME Care, study is evaluating the utility of pharmacogenetic testing in veterans with major depressive disorder. Six of the top level A drugs are antidepressants. Using genetic information to guide selection and dosing could dramatically reduce the time spent trying to find an effective medication, as antidepressants are typically given a trial of about six weeks and many patients must try several.

For wider use, Chanfreau-Coffinier recommended more research to determine when to conduct testing. “The optimal timing of testing is still unknown, and more data is needed to evaluate whether a reactive approach (e.g., testing at the time the drug is ordered) or a preemptive approach is preferable,” she said.

Complicating the issue, both the number of genetic variants known to impact drug safety and efficacy  and the number of drugs affected by those variants continues to grow.

“While the genetic information provided by pharmacogenomic (PGx) testing does not change over time, its interpretation regarding the list of drugs impacted and the clinical actions recommended is a domain evolving rapidly,” Chanfreau-Coffinier told U.S. Medicine.

Keeping test results accessible over a veteran’s lifetime creates another potential sticking point.

“Pharmacogenetic testing is very different from most tests physicians use,” Oslin said. “Most tests have a very, very short half-life of utility, while these are relevant for a long period of time. To make them relevant to me as a prescriber, I need the information when I am prescribing. We need to marry the data to prescribing behavior.”

Michael Icardi, MD, VA national director of pathology and laboratory medicine and chairman of the VA’s Molecular Genetics Pathology Workgroup, agreed. “For pharmacogenetic data to be useful, healthcare systems need to capture results of laboratory testing as machine readable data of sufficient detail that it can be returned to patients and incorporated into the electronic health record data, clinical decision support tools and pharmacy informatics systems.”

The VA has started to tackle the challenge of capturing and using genetic data. “If results of PGx tests are available for the Level A drugs, the results should be considered to guide therapy,” Chanfreau-Coffinier said. “VA Pathology, Pharmacy, and Genomic Medicine Services are collaborating to integrate veterans’ pharmacogenetic information in the electronic health record. This is an essential step to generate an evidence base for evaluating drug/gene interactions and guide which pharmacogenetic tests should be performed by VA labs.”

Pharmacogenetic data gathered by the VA could have a significant impact beyond veterans.

“Understanding pharmacogenetics across a racially diverse population is a priority of ours,” said Rachel Ramoni, chief research and development officer in the VA’s Office of Research and Development. “Minority populations have been underrepresented in most genetic studies. The VA’s contribution to pharmacogenetics research is particularly important because our veterans come from racially diverse backgrounds. What is learned from these studies will help us improve the health of the veteran population, while generating information that can be translated to the overall U.S. population.”

While the details remain to be worked out, the direction of the VA in terms of pharmacogenetic testing is clear.

“We’re still in the infancy or adolescent phase for all this,” said David Oslin, MD, director the VISN 4 Mental Illness Research, Education, and Clinical Center, leader of the PRIME Care initiative, and associate chief of staff for Behavioral Health at the Corporal Michael J. Crescenz VAMC in Philadelphia. “I can see in five to 10 years, assuming PGx testing continues to show benefit or shows greater benefit, we’ll do more testing. We’re just getting this area of medicine ramped up in a lot of ways.”

  1. Chanfreau-Coffinier C, Hull LE, Lynch JA, DuVall SL, Damrauer SM, Cunningham FE, Voight BF, Matheny ME, Oslin DW, Icardi MS, Tuteja S. Projected Prevalence of Actionable Pharmacogenetic Variants and Level A Drugs Prescribed Among US Veterans Health Administration Pharmacy Users. JAMA Netw Open. 2019 Jun 5;2(6):e195345.
Projected Numbers of New Drug Recipients With Actionable and Nonactionable Phenotypes for the Top 10 Level A Drugs
Projected Numbers of New Drug Recipients With Actionable and Nonactionable Phenotypes for the Top 10 Level A Drugs Projections based on the numbers of Veterans Health Administration pharmacy users receiving a new prescription for each drug from October 1, 2011, to September 30, 2017. Numbers are presented for all patients receiving clopidogrel and for patients receiving clopidogrel after a percutaneous coronary intervention (PCI) because of the larger clinical impact of the pharmacogenetic variant for this indication.


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