Successful translation of pharmacogenetics into the clinic: the abacavir example.
Abacavir hypersensitivity syndrome (AHS) is a potentially life-threatening illness occurring in 4-8% of those initiating the drug. Early studies identified a strong association between the MHC class I allele HLA-B*5701 and AHS. These studies suggested that HLA-B*5701 holds promise as a screening test to prevent AHS, but concern arose from HLA-B*5701-negative cases with a clinical diagnosis of AHS, and particularly from early reports of apparently low sensitivities of HLA-B*5701 for AHS in patients of non-White race. However, open screening studies suggested that HLA-B*5701 screening can largely eliminate AHS. Furthermore, skin-patch testing was used in later-generation studies to separate those patients with true immunologically mediated AHS from those with false-positive clinical diagnoses. Currently, high-level evidence suggests that HLA-B*5701 has a negative predictive value of 100% for patch-test-confirmed AHS, which is generalizable across White and Black populations. Current HIV treatment guidelines have been revised to reflect the recommendation that HLA-B*5701 screening be incorporated into routine care for patients who may require abacavir. New laboratory techniques such as PCR and flow cytometric methods, as well as an international quality assurance program, have evolved to ensure the availability of cost-effective screening methods whose consistency and standard can be maintained over time. An elegant body of basic science has evolved, which supports and complements the clinical research in suggesting that AHS is specifically and exquisitely restricted by HLA-B*5701 and mediated by CD8+ lymphocytes. Abrogating factors explaining why 45% of those carrying HLA-B*5701 can tolerate abacavir remain to be defined. The research approach applied to AHS has led to a genetic screening test being successfully implemented globally in primary HIV clinical practice. The abacavir 'example' can be applied to other drugs to facilitate the development and operationalization of genetic tests that may be useful to predict and prevent otherwise unpredictable drug reactions.
Phillips
Elizabeth
E
Institute for Immunology and Infectious Diseases, Murdoch University and Department of Clinical Immunology & Immunogenetics, Royal Perth Hospital, Perth, Western Australia, Australia. e.phillips@iiid.com.au
Mallal
Simon
S
D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015224:Dideoxynucleosides / Q000009:adverse effects / Q000627:therapeutic use*; D004342:Drug Hypersensitivity / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D010328:Patch Tests; D010597:Pharmacogenetics; D013577:Syndrome; D000099227:Abacavir
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D015235:HLA-B Antigens; D000099227:Abacavir; C484830:HLA-B*57:01 antigen