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[Dr. Shapiro] This is Dr. Samantha Shapiro, executive editor of Harrison's Principles of Internal Medicine. Harrison's Podclass is brought to you by McGraw Hill's AccessMedicine, the online medical resource that delivers the latest trusted content from the best minds in medicine. And now, onto the episode.
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[Dr. Handy] Hi, everyone. Welcome back to Harrison's Podclass. We're your co-hosts. I'm Dr. Cathy Handy.
[Dr. Wiener] And I'm Dr. Charlie Wiener, and we're joining you from the Johns Hopkins School of Medicine. Welcome to episode 104, a 35-year-old with HIV. Hey, Cathy. Today's patient is a 35-year-old woman who's newly diagnosed with HIV after a high-risk heterosexual contact six weeks ago. Currently, she's clinically asymptomatic. Her physical examination is normal and her CD4 count is 1,100/mm3. She has no significant past medical history and her tuberculosis screening is negative. You're planning on starting a highly active antiretroviral treatment that includes abacavir. Prior to initiating therapy, you should obtain genetic testing for which of the following? Okay, so I'm going to list about five different genes that you're going to test for, Cathy, or think about testing for.
[Dr. Handy] Okay.
[Dr. Wiener] The first one is CYP2C19; B. is delta F508; C. is G6PD; D. is HLA-B*57.01; and E. is RYR1.
[Dr. Handy] Interesting. So this is really a question about pharmacogenomics and the field is changing rapidly as new technology allows more accurate and less expensive genetic testing. Now, it's still a nascent field, but every year we're getting new insights into the power and the limitations of how this testing can enhance efficacy or limit complications in individuals. So it's a hot topic in precision medicine.
[Dr. Wiener] And you know I love precision medicine.
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[Dr. Wiener] So how about this patient?
[Dr. Handy] Abacavir is a nucleoside reverse transcriptase inhibitor and it's used for the treatment of HIV so it would be appropriate to talk about in the setting of this patient. Now, the answer for the question is that what you need to test for prior to starting is option D. So that's HLA-B*57.01. The FDA has a black box warning that screening for the HLA-B*57.01 allele is recommended prior to initiating therapy with abacavir. And it's because this approach has been found to decrease the risk of hypersensitivity reactions. In fact, a randomized clinical trial demonstrated that HLA-B*57.01 testing eliminates Stevens-Johnson syndrome or toxic epidermal necrolysis syndrome due to abacavir.
[Dr. Wiener] Wow, that's pretty impressive. What about the other options? They're also associated with specific disorders, too. Right?
[Dr. Handy] Yeah, so let's review those quickly. So G6PD deficiency, which I think we've talked about on prior podcasts, it occurs most often in men of African, Mediterranean, or South Asian descent, and it increases the risk of hemolytic anemia in response to infections, also in response to some foods such as fava beans and a variety of medications.
[Dr. Wiener] Just to remind us, which are the most common medications that predispose you to hemolytic anemia if you have G6PD deficiency?
[Dr. Handy] Well, among the common precipitators are anti-malarial and sulfa drugs. Hemolytic anemia has also been seen with the uric acid-lowering agent, rasburicase, which doesn't cause hemolysis in patients with normal amounts of G6PD. Now rasburicase, the agent that I mentioned, can cause hemolytic anemia because hydrogen peroxide byproducts of uric acid break down and can cause severe hemolysis in the setting of G6PD deficiency.
[Dr. Wiener] Wow. What about the other genes mentioned in the question?
[Dr. Handy] CYP2C19 is a member of the cytochrome P450 system and is responsible for the metabolism of a large number of drugs. It's a key component in the bioactivation of the antiplatelet drug, clopidogrel, and several large retrospective and more recently even prospective studies have documented decreased efficacy. So that means that patients who have this and are taking these medicines will have an increased risk of myocardial infarction after placement of coronary stents or an increased risk of stroke or transient ischemic attacks. And that happens among subjects with one or two reductions of functional alleles. So that means that patients who have this and are on clopidogrel are not protected from thrombotic events to the same degree as those without this. These data haven't been translated yet into clinical recommendations.
[Dr. Wiener] So we really need to keep track of that because this sounds like it could be an important next step in the advancing of precision medicine. How about delta F508 and RYR1?
[Dr. Handy] Well, delta F508 is the most common genetic mutation in cystic fibrosis. And RYR1 is also known as the type 1 ryanodine receptor, it encodes the protein that's involved with skeletal muscle intracellular release calcium. Patients with this genetic defect are asymptomatic but can develop malignant hyperthermia if exposed to general anesthetics such as halothane. Interestingly, genetic defects in other members of the ryanodine receptor in cardiac muscle may be associated with QT prolongation and torsades de pointes. Again, these genetic defects are under active research but have not translated into common clinical utility yet.
[Dr. Wiener] Okay, so, great. I mean, the teaching points here are really that pharmacogenomics is a remarkably dynamic field where the clinical utility will evolve with more time and research. And I think we all need to stay tuned for all of these important advances in our understanding of individual or precision medicine. For this patient, it is recommended that patients who are initiating therapy with abacavir be screened for the presence of HLA-B*57.01 and it should not be used in those patients because of the risk of serious side effects, notably Stevens-Johnson syndrome and toxic epidermal necrolysis.
[Dr. Handy] And you can read more about this in Harrison's chapter on pharmacogenomics.
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[Dr. Shapiro] Thanks for listening to Harrison's Podclass. You can listen to this episode and more on AccessMedicine.com, which includes the complete Harrison's Principles of Internal Medicine text, Harrison's review questions, which complement and expand upon the questions in this episode, and much more. AccessMedicine.com may already be available to you via your academic institution. Check it out.
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