Pharmacogenetics of hypersensitivity to abacavir: from PGx hypothesis to confirmation to clinical utility.
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.
Hughes
A R
AR
GlaxoSmithKline Pharmacogenetics, Research Triangle Park, NC 27709, USA. arlene.r.hughes@gsk.com
Spreen
W R
WR
Mosteller
M
M
Warren
L L
LL
Lai
E H
EH
Brothers
C H
CH
Cox
C
C
Nelsen
A J
AJ
Hughes
S
S
Thorborn
D E
DE
Stancil
B
B
Hetherington
S V
SV
Burns
D K
DK
Roses
A D
AD
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
D015224:Dideoxynucleosides; D015235:HLA-B Antigens; D018894:Reverse Transcriptase Inhibitors; D000099227:Abacavir