Abacavir hypersensitivity syndrome: Results of clinical, immunological and genetic screening

BACKGROUND: Cutaneous patch testing has been previously described as a potential diagnostic modality for patients having experienced abacavir (ABC) hypersensitivity reaction (HSR). However, the duration of positivity, correlation with in vitro lymphocyte responses to ABC and strength of association of these tests with genetic markers is currently unknown. OBJECTIVE: To explore associations between cutaneous patch testing, lymphocyte proliferation, cytokine response and genetic testing in previously patch test positive patients clinically characterized as ABC HSR. METHODS: Seven patients previously found to be positive on ABC patch testing with histories consistent with ABC HSR between July 2000 and June 2003 were re-consented for repeat 24-h patch testing, genetic testing (HLA-typing) and in vitro PBMC assays to measure drug-specific T-lymphocyte proliferation and cytokine [interferon-γ (IFNγ) and tumour necrosis factor alpha (TNFα)] production in response to ABC 0.1 µg/ml and 1 µg/ml. HLA-typing, proliferation and cytokine assays were also conducted on 11 abacavir tolerant controls. Immunological and genetic tests were performed by laboratory staff blinded to clinical status. RESULTS: Seven out of seven patients who had experienced ABC HSR a median of 25 months (range 10–45) previously and who were patch test positive a median of 23 months (range 7–42) previously were strongly positive at 24 h on repeat testing. There were no significant differences in CD4+ T cell cytokine production or proliferation between patch test positive HSR cases and ABC-tolerant controls. However, five out of seven (71%) cases showed significant CD8+ proliferation in response to ABC versus one out of 11 (9%) of the controls tolerating ABC (P=0.005), and CD8+ IFNγ production was seen in two out of seven (29%) cases and no controls (P=0.04). HLAB* 5701 was present in seven out of seven patch test positive patients versus one out of 11 controls who was taking and tolerating ABC (P<0.001). CONCLUSIONS: Patch testing appears to be consistently positive even remote from the original ABC HSR and showed good correlation with ABC-specific CD8+ T lymphocyte responses and presence of HLA-B*5701. This strongly suggests that ABC HSR is mediated by HLA-B*5701 restricted CD8+ T lymphocytes, and suggests that clinical, genetic and immunological tests may have complementary application in the prevention, diagnosis and management of ABC HSR.