Science China Life Sciences

, Volume 56, Issue 2, pp 119–124 | Cite as

Studies on abacavir-induced hypersensitivity reaction: a successful example of translation of pharmacogenetics to personalized medicine

  • YongLi Guo
  • LeMing Shi
  • HuiXiao Hong
  • ZhenQiang Su
  • James Fuscoe
  • BaiTang Ning
Open Access
Review Special Topic

Abstract

Abacavir is an effective nucleoside analog reverse transcriptase inhibitor used to treat human immunodeficiency virus (HIV) infected patients. Its main side effect is hypersensitivity reaction (HSR). The incidence of the HSR is associated with ethnicity among patients exposed to abacavir, and retrospective and prospective studies show a significantly increased risk of abacavir-induced HSR in human leukocyte antigen (HLA)-B*57:01-carrying patients. Immunological studies indicated that abacavir interacts specifically with HLA-B*57:01 and changed the binding specificity between the HLA molecule and the HLA-presented endogenous peptide repertoire, leading to a systemic autoimmune reaction. HLA-B*57:01 screening, combined with patch testing, had clinically predictive value and cost-effective impact in reducing the incidence of abacavir-induced HSR regardless of the HLA-B*57:01 prevalence in the population. Therefore, the US Food and Drug Administration (FDA) and international HIV treatment guidelines recommend a routine HLA-B*57:01 screening prior to abacavir treatment to decrease false positive diagnosis and prevent abacavir-induced HSR. The studies of abacavir-induced HSR and the implementation of the HLA-B*57:01 screening in the clinic represent a successful example of the use of pharmacogenetics for personalized diagnosis and therapy.

Keywords

personalized medicine pharmacogenetics drug safety abacavir hypersensitivity reaction (HSR) HLA-B*57:01 HLA-B*57:01 screening 

References

  1. 1.
    Foster R H, Faulds D. Abacavir. Drugs, 1998, 55: 729–736PubMedCrossRefGoogle Scholar
  2. 2.
    Hervey P S, Perry C M. Abacavir: a review of its clinical potential in patients with HIV infection. Drugs, 2000, 60: 447–479PubMedCrossRefGoogle Scholar
  3. 3.
    Hughes A R, Spreen WR, Mosteller M, et al. Pharmacogenetics of hypersensitivity to abacavir: from PGx hypothesis to confirmation to clinical utility. Pharmacogenomics J, 2008, 8: 365–374PubMedCrossRefGoogle Scholar
  4. 4.
    Chaponda M, Pirmohamed M. Hypersensitivity reactions to HIV therapy. Br J Clin Pharmacol, 2011, 71: 659–671PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Hughes C A, Foisy M M, Dewhurst N, et al. Abacavir hypersensitivity reaction: an update. Ann Pharmacother, 2008, 42: 387–396PubMedCrossRefGoogle Scholar
  6. 6.
    Clay P G. The abacavir hypersensitivity reaction: a review. Clin Ther, 2002, 24: 1502–1514PubMedCrossRefGoogle Scholar
  7. 7.
    Hetherington S, McGuirk S, Powell G, et al. Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther, 2001, 23: 1603–1614PubMedCrossRefGoogle Scholar
  8. 8.
    Rodriguez-Novoa S, Soriano V. Current trends in screening across ethnicities for hypersensitivity to abacavir. Pharmacogenomics, 2008, 9: 1531–1541PubMedCrossRefGoogle Scholar
  9. 9.
    Symonds W, Cutrell A, Edwards M, et al. Risk factor analysis of hypersensitivity reactions to abacavir. Clin Ther, 2002, 24: 565–573PubMedCrossRefGoogle Scholar
  10. 10.
    Cutrell A G, Hernandez J E, Fleming J W, et al. Updated clinical risk factor analysis of suspected hypersensitivity reactions to abacavir. Ann Pharmacother, 2004, 38: 2171–2172PubMedCrossRefGoogle Scholar
  11. 11.
    Peyrieere H, Nicolas J, Siffert M, et al. Hypersensitivity related to abacavir in two members of a family. Ann Pharmacother, 2001, 35: 1291–1292PubMedCrossRefGoogle Scholar
  12. 12.
    Hetherington S, Hughes A R, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet, 2002, 359: 1121–1122PubMedCrossRefGoogle Scholar
  13. 13.
    Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet, 2002, 359: 727–732PubMedCrossRefGoogle Scholar
  14. 14.
    Arrizabalaga J, Rodriguez-Alcantara F, Castaner J L, et al. Prevalence of HLA-B*5701 in HIV-infected patients in Spain (results of the EPI Study). HIV Clin Trials, 2009, 10: 48–51PubMedCrossRefGoogle Scholar
  15. 15.
    Berka N, Gill J M, Liacini A, et al. Human leukocyte antigen (HLA) and pharmacogenetics: screening for HLA-B*57:01 among human immunodeficiency virus-positive patients from southern Alberta. Hum Immunol, 2012, 73: 164–167PubMedCrossRefGoogle Scholar
  16. 16.
    Cao K, Hollenbach J, Shi X, et al. Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations. Hum Immunol, 2001, 62: 1009–1030PubMedCrossRefGoogle Scholar
  17. 17.
    Hughes A R, Mosteller M, Bansal A T, et al. Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations. Pharmacogenomics, 2004, 5: 203–211PubMedCrossRefGoogle Scholar
  18. 18.
    Hughes D A, Vilar F J, Ward C C, et al. Pirmohamed M, Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics, 2004, 14: 335–342PubMedCrossRefGoogle Scholar
  19. 19.
    Lee K W, Oh D H, Lee C, et al. Allelic and haplotypic diversity of HLA-A, -B, -C, -DRB1, and -DQB1 genes in the Korean population. Tissue Antigens, 2005, 65: 437–447PubMedCrossRefGoogle Scholar
  20. 20.
    Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med, 2008, 358: 568–579PubMedCrossRefGoogle Scholar
  21. 21.
    Martin A M, Nolan D, Gaudieri S, et al. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci USA, 2004, 101: 4180–4185PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Middleton D, Hawkins B R, Williams F, et al. HLA class I allele distribution of a Hong Kong Chinese population based on high-resolution PCR-SSOP typing. Tissue Antigens, 2004, 63: 555–561PubMedCrossRefGoogle Scholar
  23. 23.
    Middleton D, Menchaca L, Rood H, et al. New allele frequency database: http://www.allelefrequencies.net. Tissue Antigens, 2003, 61: 403–407PubMedCrossRefGoogle Scholar
  24. 24.
    Moore C B, John M, James I R, et al. Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science, 2002, 296: 1439–1443PubMedCrossRefGoogle Scholar
  25. 25.
    Munderi P, Snowden W B, Walker A S, et al. Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART. Trop Med Int Health, 2011, 16: 200–204PubMedCrossRefGoogle Scholar
  26. 26.
    Nolan D, Gaudieri S, Mallal S. Pharmacogenetics: a practical role in predicting antiretroviral drug toxicity? J HIV Ther, 2003, 8: 36–41PubMedGoogle Scholar
  27. 27.
    Park W B, Choe P G, Song K H, et al. Should HLA-B*5701 screening be performed in every ethnic group before starting abacavir? Clin Infect Dis, 2009, 48: 365–367PubMedCrossRefGoogle Scholar
  28. 28.
    Phillips E, Mallal S. Successful translation of pharmacogenetics into the clinic: the abacavir example. Mol Diagn Ther, 2009, 13: 1–9PubMedCrossRefGoogle Scholar
  29. 29.
    Phillips E J. Genetic screening to prevent abacavir hypersensitivity reaction: are we there yet? Clin Infect Dis, 2006, 43: 103–105PubMedCrossRefGoogle Scholar
  30. 30.
    Rauch A, Nolan D, Martin A, et al. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis, 2006, 43: 99–102PubMedCrossRefGoogle Scholar
  31. 31.
    Saito S, Ota S, Yamada E, et al. Allele frequencies and haplotypic associations defined by allelic DNA typing at HLA class I and class II loci in the Japanese population. Tissue Antigens, 2000, 56: 522–529PubMedCrossRefGoogle Scholar
  32. 32.
    Sun H Y, Hung C C, Lin P H, et al. Incidence of abacavir hypersensitivity and its relationship with HLA-B*5701 in HIV-infected patients in Taiwan. J Antimicrob Chemother, 2007, 60: 599–604PubMedCrossRefGoogle Scholar
  33. 33.
    Saag M, Balu R, Phillips E, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis, 2008, 46: 1111–1118PubMedCrossRefGoogle Scholar
  34. 34.
    Martin S, Weltzien H U. T cell recognition of haptens, a molecular view. Int Arch Allergy Immunol, 1994, 104: 10–16PubMedCrossRefGoogle Scholar
  35. 35.
    Lavergne S N, Park B K, Naisbitt D J. The roles of drug metabolism in the pathogenesis of T-cell-mediated drug hypersensitivity. Curr Opin Allergy Clin Immunol, 2008, 8: 299–307PubMedCrossRefGoogle Scholar
  36. 36.
    Pichler W J. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol, 2002, 2: 301–305PubMedCrossRefGoogle Scholar
  37. 37.
    Pichler W J, Beeler A, Keller M, et al. Pharmacological interaction of drugs with immune receptors: the p-i concept. Allergol Int, 2006, 55: 17–25PubMedCrossRefGoogle Scholar
  38. 38.
    Pirmohamed M, Naisbitt D J, Gordon F, et al. The danger hypothesis—potential role in idiosyncratic drug reactions. Toxicology, 2002, 181–182: 55–63PubMedCrossRefGoogle Scholar
  39. 39.
    Li J, Uetrecht J P. The danger hypothesis applied to idiosyncratic drug reactions. Handb Exp Pharmacol, 2010, 196: 493–509PubMedCrossRefGoogle Scholar
  40. 40.
    Chessman D, Kostenko L, Lethborg T, et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity, 2008, 28: 822–832PubMedCrossRefGoogle Scholar
  41. 41.
    Yang L, Chen J, He L. Harvesting candidate genes responsible for serious adverse drug reactions from a chemical-protein interactome. PLoS Comput Biol, 2009, 5: e1000441PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Illing P, Vivian J, Dudek N, et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature, 2012, 486: 554–558PubMedGoogle Scholar
  43. 43.
    Ostrov D, Grant B, Pompeu Y, et al. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire. Proc Natl Acad Sci USA, 2012Google Scholar
  44. 44.
    Zucman D, Truchis P, Majerholc C, et al. Prospective screening for human leukocyte antigen-B*5701 avoids abacavir hypersensitivity reaction in the ethnically mixed French HIV population. J Acquir Immune Defic Syndr, 2007, 45: 1–3PubMedCrossRefGoogle Scholar
  45. 45.
    Nolan D. HLA-B*5701 screening prior to abacavir prescription: clinical and laboratory aspects. Crit Rev Clin Lab Sci, 2009, 46: 153–165PubMedCrossRefGoogle Scholar
  46. 46.
    Dervieux T, Bala M V. Overview of the pharmacoeconomics of pharmacogenetics. Pharmacogenomics, 2006, 7: 1175–1184PubMedCrossRefGoogle Scholar
  47. 47.
    Rodriguez-Novoa S, Garcia-Gasco P, Blanco F, et al. Value of the HLA-B*5701 allele to predict abacavir hypersensitivity in Spaniards. AIDS Res Hum Retroviruses, 2007, 23: 1374–1376PubMedCrossRefGoogle Scholar
  48. 48.
    Schackman B R, Scott C A, Walensky R P, et al. The cost-effectiveness of HLA-B*5701 genetic screening to guide initial antiretroviral therapy for HIV. AIDS, 2008, 22: 2025–2033PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Lalonde R G, Thomas R, Rachlis A, et al. Successful implementation of a national HLA-B*5701 genetic testing service in Canada. Tissue Antigens, 2010, 75: 12–18PubMedCrossRefGoogle Scholar
  50. 50.
    Nieves Calatrava D, Calle-Martin Ode L, Iribarren-Loyarte J A, et al. Cost-effectiveness analysis of HLA-B*5701 typing in the prevention of hypersensitivity to abacavir in HIV+ patients in Spain. Enferm Infecc Microbiol Clin, 2010, 28: 590–595PubMedCrossRefGoogle Scholar
  51. 51.
    Phillips E J, Wong G A, Kaul R, et al. Clinical and immunogenetic correlates of abacavir hypersensitivity. AIDS, 2005, 19: 979–981PubMedCrossRefGoogle Scholar
  52. 52.
    Shear N H, Milpied B, Bruynzeel D P, et al. A review of drug patch testing and implications for HIV clinicians. AIDS, 2008, 22: 999–1007PubMedCrossRefGoogle Scholar
  53. 53.
    Phillips E J, Sullivan J R, Knowles S R, et al. Utility of patch testing in patients with hypersensitivity syndromes associated with abacavir. AIDS, 2002, 16: 2223–2225PubMedCrossRefGoogle Scholar
  54. 54.
    Su Z, Ning B, Fang H, et al. Next-generation sequencing and its applications in molecular diagnostics. Expert Rev Mol Diagn, 2011, 11: 333–343PubMedGoogle Scholar
  55. 55.
    ten Bosch J R, Grody W W. Keeping up with the next generation: massively parallel sequencing in clinical diagnostics. J Mol Diagn, 2008, 10: 484–492PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© The Author(s) 2013

Authors and Affiliations

  • YongLi Guo
    • 1
  • LeMing Shi
    • 2
  • HuiXiao Hong
    • 2
  • ZhenQiang Su
    • 2
  • James Fuscoe
    • 1
  • BaiTang Ning
    • 1
  1. 1.Division of Systems Biology, National Center for Toxicological Researchthe US Food and Drug AdministrationJeffersonUSA
  2. 2.Division of Bioinformatics and BiostatisticsNational Center for Toxicological Research, the US Food and Drug AdministrationJeffersonUSA

Personalised recommendations