Pharmacogenetics is the study of the extent to which genetic differences influence the response of individuals to drug therapy. Individuals vary in their response to the same medicine and a drug can fail to be effective or an adverse event can occur.
Delphic is developing a panel of HIV pharmacogenetic assays designed to address known relationships between a patient’s genetic make-up and individual HIV antiretroviral drugs.
The assays are developed, and testing is carried out, in our ISO 9001:2000 certified laboratory.
PHARMACOGENETIC TESTING
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| Adverse drug reactions are multifactorial in origin, but for some drugs 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, but this is at best incomplete since there may be other markers within that gene, or other genes as yet uncharacterised, in addition to a host of environmental factors which are important determinants of toxicity.
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 who carry susceptibility genotypes, and to maintain pharmacovigilance in those who do not. In particular, prescribing according to the manufacturer’s SPC should be adhered to and is not circumvented by the use of genetic testing. |
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ADDITIONAL PHARMACOGENETICS TESTS
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Unconjugated bilirubin is conjugated with glucuronic acid in the liver to be excreted in bile. This step is mediated by the UDP glucuronosyltransferase enzyme UGT1A1. Individuals with the UGT1A1*28 allele may develop jaundice when exposed to atazanavir, since this protease inhibitor is also an inhibitor of this particular UGT enzyme. Genotyping for UGT1A1*28 before initiation of antiretroviral therapy containing atazanavir may aid in identifying individuals 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.1
1 Rotger M, Taffe P, Bleiber G et al. Gilbert syndrome and the development of antiretroviral therapy associated hyperbilirubinaemia. JID 2005; 192:1381-1386
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Efavirenz is mainly metabolised by the cytochrome P450 2B6 (CYP2B6) enzyme. One variant in exon 4 (516G>T), a marker of haplotypes CYP2B6*6 and *7, is associated with significant loss of enzyme function.1 Higher efavirenz concentrations are seen more frequently in carriers of 516G>T. This polymorphism could be important for identifying individuals at risk of high concentrations of efavirenz (i.e. TT > GT > GG). 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.
1 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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