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Genetic Factors Predicting Abacavir Hypersensitivity and Tolerance in HLA-B*5701+ Individuals: Combined Analysis from PREDICT-1, SHAPE, and a Multinational Study
D Nolan1, D Thorborn2, M Schaefer3, R Laird1, A Rauch4, J Montaner5, A Hughes3, I James1, S Mallal1, Elizabeth Phillips*6, and PREDICT-1(CNA106030) & SHAPE(ABC107442) Study Teams
1Ctr for Clinical Immunology and Biomed Statistics, Murdoch Univ, Royal Perth Hosp, Australia; 2GlaxoSmithKline, Brentford, UK; 3GlaxoSmithKline, Research Triangle Park, NC, US; 4Inselspital Bern, Switzerland; 5BC Ctr for Excellence in HIV/AIDS, Vancouver, Canada; and 6Ctr for Clinical Pharma and Infectious Diseases, Murdoch Univ, Western Australia
Background: Although multiple studies have confirmed
that HLA-B*5701 is highly associated with abacavir (ABC) hypersensitivity
syndrome (HSR), genetic factors predicting ABC tolerance in patients positive
for HLA-B*5701 have not been defined.
Methods: HLA-B*5701+ patients were
identified from 3 multi-centre studies: PREDICT-1 (CNA106030), SHAPE
(ABC107442), and a collaborative Australian-Swiss-Canadian retrospective study.
Genetic characteristics of patients with patch test confirmed (PTC) ABC HSR were
compared with patients who tolerated ABC for >6 weeks with no symptoms (AT).
MHC markers associated with the HLA-B*5701 allele and genetic markers
related to abacavir metabolism and immune response were examined. Sequence
based typing was used for TNF-238,-376, and PCR-SSP assays were
used to detect a nonsynonymous SNP in the HCP5 gene (rs 2395029), BAT1-223,
HSP70Hom 493T, C4A6, MICA*017, KIR3DS1/KIR3DL1 and
type 1 alcohol dehydrogenase (ADH) isoforms 1B (rs 1229984) and 1C (rs 698), and
a RFLP approach was used to identify a functional polymorphism in the promoter
region of the CD14 gene [-159 C/T].
Results: Pooled analysis from the 3 studies
identified 95 PTC ABC HSR cases, all of whom carried HLA-B*5701 and 40 HLA-B*5701+
AT patients. Analysis of 78 patients with complete genotyping across the HLA-B*5701-associated
MHC markers HCP5 (rs 2395029), BAT1-223, TNF-238/376, HSP70Hom
493T, and C4A6 showed no significant differences between PTC ABC HSR
(n = 48) and AT (n = 30) (Pc = NS, Fisher's exact test).
Furthermore, recombination events were identified at multiple sites within the
MHC, revealing incomplete linkage dysequilibrium between HLA-B*5701 and
each of the MHC markers examined. Importantly, these included one HLA-B*5701+
PTP ABC HSR case with a negative result for the HCP5 allele, an MHC haplotype marker
close to HLA-B, previously reported to show complete concordance with HLA-B*5701.
Conclusions: HLA-B*5701 is necessary, but not
sufficient for the development of ABC HSR and genetic factors outside of the
MHC may be responsible for explaining ABC tolerance among a subset of HLA-B*5701+
individuals. The presence of multiple recombination events within the 57.1 MHC
haplotype indicate that haplospecific markers are incomplete surrogates for HLA-B*5701
that cannot be safely used as screening tests for ABC HSR, and HLA-B*5701
remains the gold standard in this regard.
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