title: Pharmacogenetics of hypersensitivity to abacavir: from PGx hypothesis to confirmation to clinical utility.
abstract: The hypersensitivity (HSR) to abacavir (ABC) pharmacogenetics (PGx) program represents the progression from an exploratory discovery to a validated biomarker. Within the program, two retrospective PGx studies were conducted to identify HIV-1 patients at increased risk for ABC HSR, a treatment-limiting and potentially life-threatening adverse event. A strong statistical association between the major histocompatibility complex allele, HLA-B*5701, and clinically diagnosed ABC HSR was identified but varied between racial populations. Subsequently, ABC skin patch testing was introduced as a research tool to supplement clinical case ascertainment. In a randomized, prospective study evaluating the clinical utility of HLA-B*5701 screening, avoidance of ABC in HLA-B*5701-positive patients significantly reduced clinically diagnosed ABC HSR and eliminated patch test-positive ABC HSR. Finally, a retrospective PGx study supports the generalizability of the association across races. Prospective HLA-B*5701 screening should greatly reduce the incidence of ABC HSR by identifying patients at high risk for ABC HSR before they are treated.
authors.affiliation: GlaxoSmithKline Pharmacogenetics, Research Triangle Park, NC 27709, USA. arlene.r.hughes@gsk.com
authors.forename: A R
authors.initials: AR
authors.lastname: Hughes
authors.forename: W R
authors.initials: WR
authors.lastname: Spreen
authors.forename: M
authors.initials: M
authors.lastname: Mosteller
authors.forename: L L
authors.initials: LL
authors.lastname: Warren
authors.forename: E H
authors.initials: EH
authors.lastname: Lai
authors.forename: C H
authors.initials: CH
authors.lastname: Brothers
authors.forename: C
authors.initials: C
authors.lastname: Cox
authors.forename: A J
authors.initials: AJ
authors.lastname: Nelsen
authors.forename: S
authors.initials: S
authors.lastname: Hughes
authors.forename: D E
authors.initials: DE
authors.lastname: Thorborn
authors.forename: B
authors.initials: B
authors.lastname: Stancil
authors.forename: S V
authors.initials: SV
authors.lastname: Hetherington
authors.forename: D K
authors.initials: DK
authors.lastname: Burns
authors.forename: A D
authors.initials: AD
authors.lastname: Roses
mesh_terms: D015224:Dideoxynucleosides / Q000009:adverse effects*; D004342:Drug Hypersensitivity / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics; D006801:Humans; D010328:Patch Tests; D010597:Pharmacogenetics; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D000099227:Abacavir
chemical_list: D015224:Dideoxynucleosides; D015235:HLA-B Antigens; D018894:Reverse Transcriptase Inhibitors; D000099227:Abacavir