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HLA-B*5701 screening reduces abacavir hypersensitivity reactions (ABC HSR); multiple lines of evidence to establish a new standard of care
P. Wannamaker1, S. Mallal2, E. Phillips2, B. Young3, C. Brothers1, D. Sutherland-Phillips1, D. Thorborn4, M. Shaefer1
1GlaxoSmithKline, Research Triangle Park, United States, 2Royal Perth Hospital and Murdoch University, Perth, Australia, 3Denver Infectious Disease Consultants, Denver, United States, 4GlaxoSmithKline, Brentford, United Kingdom
Background: ABC HSR has been associated with the pharmacogenetic marker HLA-B*5701 in several studies. However, evidence of the clinical utility of screening is required from controlled clinical trials, open screening programs and from different target populations to justify uptake into clinical practice.
Methods: PREDICT-1 was a prospective, randomized, controlled, double-blinded study enrolling European and Australian subjects to compare the incidence of ABC HSR with or without prospective HLA-B*5701 screening. SHAPE was a retrospective case-control study to estimate the sensitivity of HLA-B*5701 in Black and White subjects in the United States with ABC HSR. ARIES is a prospective treatment simplification study of ABC/3TC + atazanavir/ritonavir in HLA-B*5701 negative ART-naïve subjects across the United States and Canada. Skin patch testing (SPT) was used to provide immunologic confirmation of suspected ABC HSR in all studies.
Results: In the predominantly white population enrolled in PREDICT-1, 5.6% of subjects carried HLA-B*5701. SPT-positive cases of ABC HSR were reduced from 2.7% to 0% in the screening arm (7.8% to 3.4%, all cases) (p<0.001). SHAPE demonstrated a 100% sensitivity of HLA-B*5701 for SPT-positive ABC HSR in both White (n=42) and Black (n=5) subjects. In ARIES, which employed prospective HLA-B*5701 screening, 725 ART-naïve subjects were screened of which 32 (7.2%) of Whites and 7 (2.8%) Blacks were positive for HLA-B*5701 and excluded. After open screening and initiation of ABC, suspected HSR was reported in 4 subjects (0.8%) through 18 weeks, none were SPT-positive.
Conclusions: Results from PREDICT-1, SHAPE and ARIES provide conclusive evidence of the validity, generalizability and effectiveness of HLA-B*5701 screening as a standard of care approach before starting an abacavir containing regimen. Although screening dramatically reduces the risk of ABC HSR, appropriate clinical management of suspected HSR remains paramount.