The Experts for Comprehensive, Convenient Personalized Health!
The Experts for Comprehensive, Convenient Personalized Health!
UGT1A1
UDP-glucuronosyltransferases (UGTs) are a family of enzymes involved in catalyzing conjugation reactions during in phase II metabolism (Gonzalez, et al. 2022). Specifically, UGTs form glucuronide metabolites via the addition of the glucuronic acid functional group, which increases the associated water solubility of lipophilic drugs, xenobiotics, and endogenous compounds, targeting them for urinary or biliary excretion (Gonzalez, 2022; Gammal, 2015). UGTs are further classified into subfamilies based on similarities in genetic sequencing: UGT1A, UGT2A, UGT2B. Enzymes included in the UGT1A subfamily are encoded by a single gene located on chromosome 2q37.1 via differential exon splicing (Gammal, 2015; UGT_OMIM, 2022). UGT1A1, a major enzyme of the UGT1A subfamily, catalyzes glucuronidation reactions essential for the elimination of bilirubin, a primary byproduct of heme metabolism (Gammal, 2015; Bosma, 1994). Impaired or reduced UGT1A1 activity results in the accumulation of unconjugated bilirubin, which is often characterized by a yellowing of the skin and eyes (jaundice) but can lead to severe neurological effects and death in extreme cases. Genetic polymorphisms in UGT1A1 according to functional status, including normal function (*1), decreased function (*6, *27, *28, *37), and increased function (*36) (Gammal, et al. 2015; supp allele functionality).
UGT1A1 and Atazanavir
Studies have demonstrated CYP2B6 genotypes, characterized as poor metabolizer (PM), to be associated with the decreased clearance of efavirenz and a subsequent increased risk for efavirenz-associated toxicity, including CNS toxicity, drug-induced hepatic injury, and QT prolongation (Desta, 2019; Csajka, 2003; Yimer, 2012; Abdelhady, 2016). Moreover, clinical studies have shown pharmacogenomic-guided efavirenz dosing to be associated with therapeutic drug plasma concentrations and decreased CNS toxicity (Desta, et al. 2019). Therefore, CYP2B6genotyping in certain individuals, particularly those of African descent, may be beneficial in reducing the risk of AEs associated with efavirenz (Lee, et al. 2013).
Summary: Patients with the HLA-B*5701 allele are at a higher risk of abacavir-induced
hypersensitivity reaction (HSR), characterized by fever, rash, gastrointestinal, respiratory, and flu-like, symptoms. Onset of symptoms typically occurs in the first 6-8 weeks of therapy and increase with continued dosing. The recommendation for HLA-B*5701 screening prior to initiation of abacavir therapy has been issued by the U.S. Department of Health and Human Services and with a black box warning within the prescribing information from the manufacturer.
HLA Pharmacogenomics
A specific group of cell surface proteins, known as major histocompatibility complex (MHC), function by binding foreign molecules, thereby enabling T-cell recognition and a subsequent immune system response (Fan, et al. 2017). Since its discovery, MHC has been established as a genomic region linked to the greatest number of human diseases, the majority of which involve an immunological component (Dendrou, 2018; Trowsdale, 2013). Among humans, MHC is more commonly known as human leukocyte antigen (HLA) complex and consists of over 200 different genes on chromosome 6p21.3, which are categorized into 3 main subcategories: class I, class II, and class III. Of these, the highly polymorphic class I and II genes, with over 15,000 identified alleles, are most frequently implicated in disease. Within class I, the three main genes include HLA-A, HLA-B, and HLA-C(Fan, et al. 2017).
HLA-B and HLA-A
HLA-B and HLA-A encode cell surface proteins that present immune cells with intracellular antigens or peptides produced in the normal breakdown of cellular proteins (Phillips, et al. 2018). Under normal physiological conditions, presented antigens are recognized as “self”; however, antigens derived from pathogens and transplanted tissues can be identified as “non-self” and activate a subsequent immune response. assist in recognition of foreign molecules and pathogens (Martin, et al. 2012). Specific HLA-B and HLA-A gene variants are shown to be associated with immunologically mediated severe cutaneous adverse drug reactions (SCAR), including Steven-Johnson Syndrome (SJS), toxic epidermal necrosis (TEN), and drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) (Chung, et al. 2016). Although the prevalence of SCAR is low (occurring at a rate of approximately 2%), associated mortality rates can be as high as 50% (SJS, 5-10%; SJS-TEN overlap, 30%; TEN, 50%, and DIHS, 10%). Allele variants of interested with published CPIC guidelines include: HLA-B*57:01, HLA-B*58:01, HLA-B*15:02, and HLA-A*31:01(Hershfield, 2013; Phillips, 2018; Martin, 2012; Karnes, 2021).
HLA-B*57:01 and Abacavir Abacavir is a nucleoside reverse transcriptase inhibitor with FDA approved indications for the treatment of HIV infection in combination with other antiretroviral agents (Ziagen_PI, 2020). Although HLA gene allele status does not affect abacavir associated pharmacokinetics or pharmacodynamics, it can increase the likelihood of hypersensitivity reactions (HSRs) (Martin, et al. 2012). Specifically, the HLA-B*57:01 variant is shown to be associated with abacavir hypersensitivity reactions and is known to exhibit codominant expression. Therefore, genotyping is classified as either positive (presence of 1-2 copies of HLA-B*57:01) with an associated high risk of HSR or negative (no copies of HLA-B*57:01) with a low risk of HSR. Prevalence of the *57:01 allele is shown to vary across geographically, racially, and ethnically diverse groups, with the highest frequency in Southwest Asian populations (20% are carriers), followed by European populations (6-7%), and lowest among African and Asian populations (completely absent in some subpopulations). Results from the PREDICT-1 study led to the FDA implementing a black box warning in 2008 (Mallal, et al. 2008). HLA-A*57:01genotyping is now considered the standard of care with testing recommended in all abacavir-naïve patients prior to treatment initiation; alternative therapeutic agents are recommended for patients with the presence of this variant (Martin, et al. 2012).
CYP2B6
The CYP2B6 gene is considered a highly polymorphic gene with approximately 38 known allele variants and significant differences in allele frequencies demonstrated across various ethnic groups (Klein, 2005; Hoffman,2001; Desta, 2019). CYP2B6 is located within the CYP2 gene cluster on chromosome 19 and encodes the CYP2B6 enzyme, which serves a primary role in the metabolism of several important therapeutic drugs including the chemotherapeutic agents, cyclophosphamide and ifosphamide; the antidepressant, bupropion; and the non-nucleoside reverse transcriptase inhibitors, efavirenz and nevirapine (Lee, 2013; Klein, 2005; Owen, 2006; Viramune, 2019; Sustiva, 2017).
CYP2B6 and Efavirenz
Studies have demonstrated CYP2B6 genotypes, characterized as poor metabolizer (PM), to be associated with the decreased clearance of efavirenz and a subsequent increased risk for efavirenz-associated toxicity, including CNS toxicity, drug-induced hepatic injury, and QT prolongation (Desta, 2019; Csajka, 2003; Yimer, 2012; Abdelhady, 2016). Moreover, clinical studies have shown pharmacogenomic-guided efavirenz dosing to be associated with therapeutic drug plasma concentrations and decreased CNS toxicity (Desta, et al. 2019). Therefore, CYP2B6genotyping in certain individuals, particularly those of African descent, may be beneficial in reducing the risk of AEs associated with efavirenz (Lee, et al. 2013).