HIV Pharmacogenetics
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Pharmacogenetic testing in HIV

Adverse drug reactions are multifactorial in origin, but for some drugs in HIV, an underlying genetic component may contribute to the risk of developing toxicity. Screening for genetic markers associated with a particular side-effect may identify some individuals predisposed to toxicity. These genetic markers include HLA-B*5701 for abacavir, UGT1A1*28 for Atazanavir and CYP2B6 516 G>T for Efavirenz.

HLA-B*5701 polymorphism for Abacavir

HLA-B*5701 testing is recommended to help identify patients with a lower risk of developing Abacavir hypersensitivity. For more information, please see the references and our HLA-B*5701 FAQ.

UGT1A1*28 polymorphism for atazanavir

UGT1A1*28 testing before initiation of antiretroviral therapy containing Atazanavir may aid in identifying individuals at risk of hyperbilirubinaemia.

The UGT1A1 gene codes for the UDP glucuronosyltransferase enzyme (UGT1A1). UGT1A1 mediates conjugation of bilirubin with glucuronic acid in the liver, which is then excreted in bile. Atazanavir inhibits UGT1A1, which may lead to hyperbilirubinaemia and jaundice in certain individuals. The UGT1A1*28 gene allele is associated with increased risk of hyperbilirubinaemia during Atazanavir treatment, and genotyping for UGT1A1*28 before initiation of antiretroviral therapy containing Atazanavir may therefore aid in identifying individuals most at risk of hyperbilirubinaemia. Individuals who carried two copies of the gene variant (UGT1A1*28 homozygotes) have been reported to have the highest risk, and UGT 1A1*28 heterozygotes an intermediate risk of developing hyperbilirubinaemia when commencing Atazanavir.

Cytochrome P450 2B6 (CYP2B6) 516 G>T polymorphism for Efavirenz

CYP2B6 516 G>T testing may be able to identify patients at higher risk of central nervous system side effects following standard dosing of Efavirenz.

The CYP2B6 gene codes for the CYP2B6 enzyme, which is mainly responsible for Efavirenz metabolism. One variant in exon 4 (516G>T), a marker of haplotypes CYP2B6*6 and *7, is associated with significant loss of enzyme function and higher Efavirenz concentrations are seen more frequently in carriers of 516G>T4. This polymorphism could therefore be important for identifying individuals at risk of high concentrations of Efavirenz. However, not all individuals with this variant will have high Efavirenz concentrations, and not all individuals with high concentrations will have this variant. The clinical utility of genetic testing for CYP2B6 is the subject of ongoing academic and clinical discussion.

Notes on Pharmacogenetic testing in HIV

Pharmacogenetic testing (PGx) in HIV may identify some individuals predisposed to toxicity and is well established especially for HLA-B*5701 and Abacavir. However, also other factors can be important determinants of toxicity, including different environmental factors and potentially other genetic mutations.

Thus, absence of a susceptibility genotype does not rule out the development of toxicity, and clinical judgment must be exercised when considering risks vs benefit of a drug in individuals with or without these genotypes. Prescribing according to the manufacturer’s instructions should be adhered to and is not circumvented by the use of genetic testing.

Lab21 is committed to providing the highest quality services to our customers, and test turnaround time is only 5 to 7 working days.

References
  1. British HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008. HIV Med, 2008; 9: 563–608.
  2. Guidelines for the Clinical Management and Treatment of HIV Infected Adults in Europe. European AIDS Clinical Society (EACS), Madrid, 2007.
  3. Rotger M, Taffe P, Bleiber G et al. Gilbert syndrome and the development of antiretroviral therapy associated hyperbilirubinaemia. JID, 2005; 192:1381-1386.
  4. Haas DW, Ribaudo HJ, Kim RB et al. Pharmacogenetics of Efavirenz and central nervous system side effects: an adult AIDS Clinical Trials Group Study. AIDS, 2004; 18:2391-2400.  
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