Ask A Pharmacist: The ART of Pharmacogenomics and Personalized Medicine
John, a man recently diagnosed with HIV, waits nervously in his doctor’s office while the doctor reviews his computer screen. The doctor turns to John and says, “At our last visit, you mentioned that you wanted to start HIV medicines right away.”
John nods, and reminds his doctor of all the reasons why he wanted to start treatment. John also discusses his concerns, particularly his worries around experiencing bad side effects.
The doctor listens carefully and smiles reassuringly. “I’m glad you want to start HIV medicines despite your fears of side effects. The good news is that the tests you took have already helped us choose the most effective HIV treatment regimen with the fewest side effects. Your blood tests suggest that you start taking…”
Is this a scene from the future? Not exactly! HIV treatments (and the way we select them) have advanced rapidly since the discovery of the virus in the 1980s. Even though regimens have gotten simpler and more powerful, adverse effects are still one of the primary reasons people discontinue antiretroviral therapy. In one U.S. cohort study, up to 18% of patients had stopped antiretroviral therapy (ART) due to adverse effects. In other cohort studies, the percentage of people stopping ART due to adverse effects is much higher. Approximately 51% of persons had discontinued or changed therapy due to adverse effects in a Swiss cohort, for example, while in UK and Italian cohorts, 51% and 58% respectively had changed stopped ART due to adverse effects—during the first year!
Enter the era of personalized medicine. The National Genome Project defines personalized medicine as a practice that “uses a person’s individual genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of disease.” “Pharmacogenomics” is a subset of personalized medicine that focuses on using genetic information to guide the selection of drug therapy, and pharmacogenomic testing may be helpful to identify HIV-positive individuals at risk for ART side effects, just as in the scenario above.
Testing for Abacavir Hypersensitivity
HLA-B*5701 testing, used to detect hypersensitivity to the antiretroviral drug abacavir, is an example of a pharmacogenomic test that has already been widely implemented in HIV clinical practice.
Abacavir, a nucleoside reverse transcriptase inhibitor contained in Ziagen, Epzicom, and Trizivir, is generally well tolerated. However, some people who take abacavir will experience a drug hypersensitivity reaction during the first six weeks of therapy. The symptoms are not specific and include fever, fatigue, nausea, and flu-like illness. In a few cases, patients with these symptoms died after they stopped abacavir and restarted it later. Diagnosis of the reaction is challenging because it is so non-specific, and once a person is thought to have abacavir hypersensitivity, they should never take abacavir again. The exact mechanism of the reaction is unknown, but it likely involves the (mistaken) activation of certain of the body’s defensive immune system cells.
In clinical trials, African-American and white participants experienced abacavir hypersensitivity at different rates, prompting researchers to look for a genetic link. For example, a case-control study found that having the HLA-B*5701 allele (one of the two copies of a gene received from each parent) was significantly associated with hypersensitivity.
Two key studies called PREDICT-1 and SHAPE helped to demonstrate the value of HLA-B*5701 screening for abacavir hypersensitivity.
PREDICT-1 was a double–blind, randomized, controlled trial of 1,956 primarily white individuals from Australia and Europe. It compared the frequency of abacavir hypersensitivity in those who received HLA-B*5701 screening prior to starting treatment versus people who were not screened. Participants received a skin patch test to confirm a diagnosis of abacavir hypersensitivity. When pharmacogenomic testing was available before starting abacavir, there were no hypersensitivity reactions. In the group that did not receive pharmacogenomic testing, abacavir hypersensitivity occurred in 2.7% of patients. In this study, HLA-B*5701 testing had a 100% negative predictive value and a 48% positive predictive value. This means that if an individual’s test is negative, it is nearly certain that he or she will not have abacavir hypersensitivity. (There have been a few cases, but the rate is extremely low.) If the test is positive, it is not certain that the screened individual will have the hypersensitivity reaction; it just means he or she is at high risk.
The SHAPE trial was a matched case-control study with 199 participants who were diagnosed with abacavir hypersensitivity by clinical symptoms alone or by diagnosis plus skin patch testing. In this study, all of the participants who had abacavir hypersensitivity confirmed with skin patch testing also had a positive HLA-B*5701 test. The genetic test was less sensitive for patients who were diagnosed based only on symptoms.
The Future of Pharmacogenomic Testing
Right now, the HLA-B*5701 test for abacavir hypersensitivity is the only commercially available pharmacogenomic test for HIV treatment. However, researchers are carefully examining other genes that could predict toxicity to other antiretroviral agents.
Nevirapine, a non-nucleoside reverse transcriptase inhibitor, is associated with a more serious hypersensitivity reaction that manifests with a very severe rash and liver toxicity, plus systemic symptoms such as fever. Studies have identified several candidate alleles that may be linked to nevirapine hypersensitivity, but promising candidates differ among ethnic groups. Having the allele HLA-DRB1*01 is associated with three-fold higher odds of having nevirapine sensitivity in whites. Having HLA-Cw*04 carries an almost 19-fold higher odds of having a nevirapine hypersensitivity reaction in African-Americans. Having an HLA-B*35 allele carries a 3.47-fold higher risk of nevirapine hypersensitivity in Asians. Just as for abacavir, in the future, pharmacogenomic testing could be useful for identifying people who should avoid nevirapine.
Treatment with efavirenz, a non-nucleoside reverse transcriptase inhibitor, can be hindered by side effects such as grogginess, feelings of “fuzzy thinking,” and abnormal dreams. Cytochrome P4502B6 is one of the enzymes responsible for the metabolism of efavirenz, and rates of metabolism vary between patients. Inefficient metabolism can result in higher concentrations of efavirenz in the blood, which in turn may lead to side effects.
Genetic polymorphisms (changes in amino acids) such as G516T in the CYP2B6*6 allele are associated with decreased CYP2B6 enzyme activity and increased efavirenz concentrations. Some studies have suggested that African-American and Latino populations have a higher prevalence of this G516T polymorphism, which may in turn lead to higher efavirenz concentrations and higher risk of side effects.
Although these pharmacogenomic tests for efavirenz are not ready for prime time, in the future, they may help clinicians determine a patient-specific dose of efavirenz that is both effective and less likely to cause side effects. A few studies have looked at this approach, using pharmacogenomics and therapeutic drug monitoring to guide efavirenz dose adjustments from the standard dose of 600 mg daily down to 400 mg or even 200 mg daily. These studies have demonstrated viral suppression, low rates of discontinuation, and improved toxicity profiles.
One factor that confuses the picture is that a study by David Haas of Vanderbilt University suggests the central nervous system side effects from efavirenz may wane after the first week of treatment, even without a dosing intervention. So it is not clear how much future pharmacogenomic testing will help if the side effects tend to decline fairly rapidly.
Candidate genes are also being studied for their ability to predict hyperbilirubinemia, a condition that causes jaundice, from atazanavir; kidney toxicity from tenofovir; and other adverse effects. As relationships between genetic alleles are discovered, pharmacogenomic tests to identify these alleles (or alterations in them) will also be developed.
In the future of personalized medicine, you may be able to walk in to your clinician’s office and learn which antiretroviral regimen will have the least chance of side effects given your own genetic makeup—all with a simple blood test.
Jennifer Cocohoba, PharmD, is an associate clinical professor in the School of Pharmacy at the University of California, San Francisco (UCSF). Since 2004, she has worked as the clinical pharmacist for the UCSF Women’s HIV Program, where she provides adherence support and medication information to patients and providers.
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