Atazanavir and UGT1A1

Atazanavir (generic for Reyataz®) belongs to a class of antiretroviral medications known as protease inhibitors. It is often used in combination with other antiretroviral agents to treat human immunodeficiency virus type 1 (HIV-1) infection in patients who are at least 3 months old and weigh at least 5 kg. A protease inhibitor blocks the action of a viral enzyme known as protease. The HIV virus needs protease in order to properly process proteins during the creation of new viral particles. By interfering with this process, atazanavir produces immature viral particles that are no longer infectious. It is important to take this medication with food to increase its absorption. Atazanavir should be taken separately from some medications such as antacids (e.g. milk of magnesia, Tums®, Rolaids®, Alka-seltzer®), H2 receptor antagonists (e.g. ranitidine, famotidine), and proton pump inhibitors (e.g. omeprazole, lansoprazole) which can interfere with its absorption.

The UGT1A1 gene belongs to a family of genes that provide instructions for making enzymes called uridine diphosphate glucuronosyltransferases (UGT). These enzymes perform a chemical reaction called glucuronidation, which increases water solubility and efficient elimination of a variety of substances in both bile and urine. One of these substances is bilirubin, a waste product from the breakdown of red blood cells. There are three main UGT subfamilies: UGT1A, UGT2A, and UGT2B. UGT1A1 is the major enzyme in the UGT1A subfamily and is responsible for eliminating bilirubin efficiently in the liver and gastrointestinal tract.

Atazanavir reduces the activity of UGT1A1 in the liver, which inhibits glucuronidation and ultimately prevents bilirubin from being eliminated. As a result there is a buildup of bilirubin which causes jaunice, a noticeable yellow discoloration of the eyes and skin. The risk of this occurring is highest if an individual has two alleles that reduce the activity of UGT1A1, specifically UGT1A1*28, UGT1A1*37, or UGT1A1*6. UGT1A1*28 is most prevalent among African Americans and least prevalent among those of Asian descent. UGT1A1*37 occurs almost exclusively among individuals of African descent while UGT1A1*6 is most common among Japanese, Korean, and Chinese populations. The development of jaundice often leads to stopping the treatment course of atazanavir early, which affects adherence. As a result, it is recommended that individuals who have two alleles that decrease the function of UGT1A1 consider alternative medications to atazanavir. On the other hand, individuals who carry one or no alleles that decrease the function of UGT1A1 may take atazanavir as the risk of developing jaundice and discontinuing the treatment course is very low.

Amy is a 32-year-old Asian female that has recently been diagnosed with human immunodeficiency virus (HIV). The doctor considered prescribing atazanavir and conducted a thorough literature review of the drug. He found that some patients developed hyperbilirubinemia (high bilirubin levels in the blood) in response to therapy with atazanavir. The likelihood of this was associated with a combination of UGT1A1 gene baseline bilirubin level and baseline hemoglobin level. He explained to Amy the risks of taking this medication and offered to have genetic testing done to help determine the best treatment option for her; however, she declined the genetic testing and the doctor prescribed atazanavir for the treatment of HIV. A couple weeks later, Amy noticed that her skin and the whites of her eyes were turning yellow. She was admitted into the hospital with grade III hyperbilirubinemia and clinical jaundice. Her doctor ordered genetic testing and found that she is a carrier for two decreased function alleles for the UGT1A1 gene (UGT1A1*28/*28). This polymorphism is associated with a high risk of hyperbilirubinemia in patients taking atazanavir. Her doctor discontinued the atazanavir and started her on a different course of therapy that takes her genotypes into account.

Eugene is a 48-year-old African American male that is being treated by the same doctor as Amy three months later. Following a diagnosis of HIV, he believed atazanavir would be the appropriate drug of choice. After the risks were explained to him, Eugene agreed to have the genetic tests performed. Using his judgment after his experience with Amy, the doctor ordered a genetic test of the UGT1A1 gene and lab tests of baseline bilirubin and hemoglobin levels, all to which Eugene agreed to do. The results revealed that Eugene was a heterozygous carrier of the UGT1A1 gene, (UGT1A1*28/*37) and his baseline bilirubin and hemoglobin were normal. The doctor explained to Eugene that he carried two decreased function alleles which overall had markedly decreased the function of UGT1A1. Had he taken the medication, Eugene would have been placed at high risk of experiencing a bilirubin-associated adverse event. Due to his doctor’s proactive approach to pharmacogenomics-based therapy, Eugene was able to start a course of therapy that was suitable for his genome and avoid potential adverse events.

Atazanavir genetic testing does not completely eliminate the risk of bilirubin-associated adverse events, nor does it guarantee the medication will work. Genetic testing serves as a guide to personalize therapeutic regimens and improve clinical outcomes.

The links below provide access to important articles and information relative to glimepiride. The links are to external websites and will be checked regularly for consistency.

• Atazanavir Prescribing Information
• Atazanavir Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Atazanavir

Bissio E and Lopardo G. Incidence of hyperbilirubinemia and jaundice due to atazanavir in a cohort of Hispanic patients. AIDS Res Hum Retroviruses. 2013 Mar;29(3): 415-17.

Gammal RS, Court MH, Haidar CE, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for UGT1A1 and atazanavir prescribing. Clin Pharmacol Ther. 2016 Apr [cited 2018 Feb 1];99(4):363-9.

Johnson DH, Venuto C, Ritchie MD, et al. Genome-wide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202. Pharmacogenet Genomics. 2014 Apr;24(4):195-203.

Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer Clinical Drug Information Inc. c1978-2018 [cited 2018 Feb 1]. Available from: http://online.lexi.com.onu.ohionet.org/lco/action/home.

Park W, Choe P, Song K, et al. Genetic factors influencing severe atazanavir-associated hyperbilirubinemia in a population with low UDP-glucuronosyltransferase 1A1*28 allele frequency. Cain Infect Dis. 2010 July;51(1): 101-6.

Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012 Oct;92(4):414-7.