Section 30.4: Infectious Disease, GI, and Pain-Management Pharmacogenomics

30.4.1 The “Why”: PGx as a Universal Tool for Medication Safety and Efficacy

Thus far in our exploration of pharmacogenomics, we have focused on the “big three” therapeutic areas where PGx has gained the most significant traction: cardiology, psychiatry, and oncology. These fields are characterized by high-risk medications and clear, devastating consequences of therapeutic failure or toxicity. However, the principles of genetically-guided medicine are not confined to these specialties. The same enzymes, transporters, and receptors that influence a patient’s response to an antidepressant or a chemotherapy agent are also intimately involved in the pharmacology of drugs used every single day in primary care, infectious disease, gastroenterology, and pain management. To become a true medication expert in the modern era, you must learn to see pharmacogenomics not as a niche specialty, but as a fundamental layer of patient information, as essential as renal function or a list of drug allergies.

This section will broaden your PGx horizons, demonstrating through practical, case-based examples how these genetic principles apply to a diverse range of common clinical scenarios. We will shift our focus to two distinct but equally critical applications of PGx. First, we will explore the world of HLA-mediated hypersensitivity reactions. This is a profound departure from the metabolic (`CYP450`) variations we have mostly discussed. Here, the risk is not a simple overdose or lack of efficacy, but a rare, catastrophic, and potentially fatal immune system meltdown triggered by a specific drug in a genetically-susceptible individual. For two common drugs—the HIV medication abacavir and the gout medication allopurinol—a simple, one-time genetic test can virtually eliminate the risk of these devastating reactions. As a pharmacist, you are the final checkpoint in a system designed to prevent this harm, and knowing when to demand these tests is a non-negotiable professional responsibility.

Second, we will revisit our “old friends,” the `CYP2C19` and `CYP2D6` enzymes, and see how they impact some of the most frequently prescribed drug classes in all of medicine. We will investigate why a significant portion of patients fail therapy with Proton Pump Inhibitors (PPIs) for GERD and how a `CYP2C19` test can guide us to a more effective choice. Finally, we will tackle the complex and highly charged topic of opioid pain management, focusing on the infamous “codeine conundrum.” You will learn why codeine can be both completely ineffective and dangerously toxic in different patients, and how understanding `CYP2D6` genetics is essential for the safe and rational selection of an appropriate analgesic. This section will empower you to apply your PGx skills across the full spectrum of your practice, transforming you from a specialist in a few areas to a truly universal, genetically-informed medication expert.

Masterclass 1: The HLA System and Catastrophic Hypersensitivity Reactions

We begin with a class of gene-drug interactions that are fundamentally different from the metabolic variations we’ve previously covered. These are not about pharmacokinetics; they are about immunology. These reactions are rare, but when they occur, they are medical emergencies with high rates of morbidity and mortality. Pre-emptive genetic testing for these variants is one of the most successful and impactful applications of pharmacogenomics in all of medicine.

30.4.2 Mechanism Deep Dive: An Introduction to the HLA System

The Human Leukocyte Antigen (HLA) system is a group of genes that code for proteins found on the surface of our cells. These proteins are an essential part of our immune system’s ability to recognize “self” from “non-self” (like viruses or bacteria). The Class I HLA proteins (HLA-A, HLA-B, HLA-C) are found on almost all cells and their job is to present small fragments of proteins from inside the cell (peptides) to the surface. Patrolling immune cells, like T-cells, constantly “check” these presented peptides. If they recognize a normal, “self” peptide, they move on. If they recognize a foreign peptide (e.g., from a virus), they trigger an immune response to kill the infected cell.

The `HLA` genes are the most polymorphic in the entire human genome, with thousands of known alleles. This diversity is what allows the human population as a whole to respond to a vast array of pathogens. However, specific HLA alleles have unique structural properties. Certain alleles have a binding groove on their surface that can, by unfortunate chance, interact with a specific drug molecule. This drug-HLA interaction can cause the HLA protein to present a normal “self” peptide in a way that makes it look foreign to T-cells. This is the “altered self” hypothesis. The T-cells are tricked into believing that millions of the body’s own healthy cells are foreign invaders, launching a massive, systemic, and catastrophic immune attack. This is the mechanism behind `HLA-B`-associated severe cutaneous adverse reactions (SCARs).

30.4.3 `HLA-B*57:01` and Abacavir: The Poster Child for PGx Safety

The Drug: Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) used as a key component in many combination antiretroviral therapy (ART) regimens for HIV.

The Risk: In about 5-8% of patients, abacavir triggers a multi-systemic and potentially fatal Abacavir Hypersensitivity Syndrome (AHS). The reaction typically occurs within the first 6 weeks of treatment and is characterized by a constellation of symptoms, including fever, rash, malaise, and GI and respiratory symptoms. Critically, if the drug is stopped and then re-challenged, the reaction can be much more rapid, severe, and can lead to hypotensive shock and death.

The Genetic Link: Landmark research discovered that this severe reaction occurs almost exclusively in patients who carry the `HLA-B*57:01` allele. The negative predictive value of this test is nearly 100% (if you don’t have the allele, you are at almost zero risk of AHS), and the positive predictive value is around 55% (if you have the allele, you have about a 1 in 2 chance of developing AHS). Given the severity of the reaction, this level of risk is considered unacceptable.

Masterclass Table: `HLA-B*57:01` and Abacavir Dosing

`HLA-B*57:01` Test Result	Clinical Implication	CPIC Recommended Therapeutic Action
Positive	High risk of a severe, potentially fatal hypersensitivity reaction.	Abacavir is contraindicated. Do not prescribe. The patient’s allergy profile must be updated to reflect a severe allergy to abacavir. An alternative, non-abacavir-containing ART regimen must be selected.
Negative	Very low risk of hypersensitivity reaction.	Abacavir may be initiated at the standard dose. Counsel the patient that while the risk of a true AHS is extremely low, any new symptoms (especially rash and fever) should still be reported.

Case Study: Initiating ART in a Newly Diagnosed Patient

Patient: A 28-year-old male is newly diagnosed with HIV. His provider wants to start him on Triumeq (dolutegravir/abacavir/lamivudine), a highly effective, single-tablet regimen.

The Pharmacist’s Role: You receive the electronic prescription for Triumeq. Your first action is not to fill it, but to check the patient’s record for an `HLA-B*57:01` test result. You see no result in the system.

• The Intervention: You immediately place the prescription on hold and contact the provider.
• The Script (SBAR): “(S) I’m calling about the new prescription for Triumeq for your patient. (B) Triumeq contains abacavir, which carries a black box warning for potentially fatal hypersensitivity reactions. The standard of care and DHHS guidelines require `HLA-B*57:01` screening before the first dose. (A) I do not see a test result in the patient’s chart. Dispensing this without a negative test result would place the patient at significant risk. (R) I recommend we hold the Triumeq, order the `HLA-B*57:01` test today, and in the meantime, we can consider starting a different single-tablet regimen that does not contain abacavir, such as Biktarvy, if immediate initiation is desired. Once the HLA result is back and confirmed negative, we could always switch to Triumeq.”

This intervention is a perfect example of the pharmacist’s role as a critical safety sentinel. You have enforced a national standard of care and prevented a potential iatrogenic disaster.

30.4.4 `HLA-B*58:01` and Allopurinol: Preventing SJS/TEN in Gout

The Drug: Allopurinol is a first-line urate-lowering therapy for the management of gout.

The Risk: While generally safe, allopurinol can cause one of the most feared adverse drug reactions: a severe cutaneous adverse reaction (SCAR), which includes Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). These are medical emergencies involving severe blistering and sloughing of the skin and mucous membranes, akin to a body-wide third-degree burn, with a mortality rate that can exceed 30%.

The Genetic Link: There is a very strong association between the `HLA-B*58:01` allele and the risk of allopurinol-induced SCAR. This association is particularly strong in certain ethnic populations. The allele is present in up to 15% of individuals of Han Chinese, Korean, and Thai descent, but is much less common (<1%) in Caucasians and Japanese populations.

Masterclass Table: `HLA-B*58:01` and Allopurinol Dosing

`HLA-B*58:01` Test Result	Clinical Implication	CPIC Recommended Therapeutic Action
Positive	Significantly increased risk of SJS/TEN. The odds ratio can be over 100 in some populations.	Allopurinol is contraindicated. Do not prescribe. An alternative urate-lowering agent, such as febuxostat or probenecid, must be used.
Negative	Low risk of allopurinol-induced SCAR.	Allopurinol may be initiated at the standard dose. Normal vigilance for any new rash, especially early in therapy, is still warranted for all patients.

Masterclass 2: Optimizing Common GI and Pain Medications

We now shift from preventing rare, catastrophic immune reactions to optimizing the safety and efficacy of some of the most commonly prescribed drugs in the world. Here, we revisit our key metabolic enzymes, `CYP2C19` and `CYP2D6`, to see how they influence everyday patient care.

30.4.5 Proton Pump Inhibitors (PPIs) and `CYP2C19`

The Drugs: Omeprazole, esomeprazole, lansoprazole, and pantoprazole are workhorse drugs for GERD, peptic ulcer disease, and *H. pylori* eradication.

The Efficacy Problem: A frustratingly large number of patients report incomplete symptom control despite adherence to standard PPI doses. This is particularly problematic in situations requiring profound acid suppression, such as healing erosive esophagitis or during triple therapy for *H. pylori*.

The Genetic Link: As we’ve learned, these four PPIs are extensively metabolized and inactivated by `CYP2C19`. A patient’s `CYP2C19` metabolizer status directly impacts the systemic exposure and duration of action of the PPI, and therefore, the degree of acid suppression.

Masterclass Table: `CYP2C19` and PPI Dosing

`CYP2C19` Phenotype	Impact on PPI Exposure	CPIC Recommended Therapeutic Action (for GERD / Erosive Esophagitis)
Ultra-rapid / Rapid Metabolizer	Decreased plasma concentrations and shorter duration of action.	High likelihood of therapeutic failure at standard doses. CPIC recommends increasing the standard daily dose by 100% (e.g., omeprazole 40 mg daily instead of 20 mg) or switching to a PPI that is not primarily metabolized by `CYP2C19` (e.g., dexlansoprazole, rabeprazole).
Normal Metabolizer	Expected plasma concentrations.	Standard dosing is appropriate. Start with the recommended dose for the indication.
Intermediate / Poor Metabolizer	Increased plasma concentrations and longer duration of action.	Standard dosing is likely to be effective. These patients often have excellent responses. No dose reduction is needed unless adverse effects occur. They may be at a higher risk for long-term complications associated with PPIs due to higher systemic exposure.

Case Study: Refractory GERD

Patient: A 45-year-old female complains of persistent heartburn and regurgitation despite taking pantoprazole 40 mg every morning for the past 3 months. She has a PGx test on file.

The PGx Report: `CYP2C19 *1/*17` (Rapid Metabolizer).

The Pharmacist’s Intervention: The PGx report immediately provides the reason for her treatment failure. She is clearing pantoprazole too quickly. The recommendation is straightforward: “Dr. Jones, your patient’s refractory GERD is likely due to her being a `CYP2C19` Rapid Metabolizer, which is causing therapeutic failure with pantoprazole. Per CPIC guidelines, I recommend we either increase the pantoprazole dose to 40 mg twice daily before meals, or we could switch her to rabeprazole 20 mg daily, which is less affected by her `CYP2C19` status.”

30.4.6 Opioids and `CYP2D6`: The Codeine Conundrum

The Drugs: Codeine and tramadol.

The Risk: These drugs represent the two extremes of PGx risk: complete lack of effect on one end of the spectrum, and life-threatening toxicity on the other.

The Genetic Link: Both codeine and tramadol are prodrugs that require bioactivation by `CYP2D6`.

• Codeine is metabolized by `CYP2D6` into morphine. Morphine provides the vast majority of the analgesic effect.
• Tramadol is metabolized by `CYP2D6` into its much more potent M1 metabolite, O-desmethyltramadol, which has a 200-fold higher affinity for the mu-opioid receptor.

Masterclass Table: `CYP2D6` and Codeine Therapy

`CYP2D6` Phenotype	Impact on Codeine Metabolism	CPIC Recommended Therapeutic Action
Poor Metabolizer (PM)	Inability to convert codeine to morphine.	High likelihood of therapeutic failure. The patient will experience little to no pain relief. RECOMMENDATION: Avoid codeine. Use an alternative analgesic that is not a prodrug (e.g., morphine, oxycodone, hydromorphone).
Intermediate Metabolizer (IM)	Reduced conversion to morphine.	Suboptimal analgesia is likely. If an alternative is not possible, titrate to effect with close monitoring for efficacy. However, an alternative is strongly preferred.
Normal Metabolizer (NM)	Expected conversion to morphine.	Standard dosing is appropriate, if codeine is indicated.
Ultra-rapid Metabolizer (UM)	Rapid, extensive conversion to morphine, leading to supratherapeutic morphine levels.	High risk of severe toxicity, including respiratory depression and death. RECOMMENDATION: Avoid codeine. Codeine is contraindicated in these patients due to the risk of overdose. Use an alternative analgesic.