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Both HLA Class I restricted CD8+ and Class II restricted CD4+T Cells are implicated in the pathogenesis of nevirapine hypersensitivity

Phillips, E., Keane, N., Blyth, C., Lucas, A., Pavlos, R., Lucas, M., McKinnon, E. and Mallal, S. (2011) Both HLA Class I restricted CD8+ and Class II restricted CD4+T Cells are implicated in the pathogenesis of nevirapine hypersensitivity. In: 51st Interscience Conference of Antimicrobial Agents and Chemotherapy, 17 - 20 September 2011, Chicago, IL.


Background: Nevirapine hypersensitivity (NVP HSR) has been characterized as CD4+ T cell dependent, however associations between HLA class I alleles and NVP HSR implicate the role of CD8+ T cells. Methods: A prospective cohort study compared HIV+ patients with NVP HSR, defined by fever and hepatitis and/or rash, with those tolerant of NVP >3 months. Covariates included class I (HLA-A,B,C) and class II (HLA-DR) alleles. Cellular studies examined NVP specific CD4+ and CD8+ T cell responses. Results: NVP HSR occurred in 18/450(4%) of those NVP exposed between March 1993 and June 2011. Compared to NVP tolerant controls, NVP HSR was significantly associated with DRB1*0101-CD4>25% (OR 8.9,p=0.0002); HLA-B*3501 (OR 5.4, p=0.0021) and HLA-B15/DR15 (OR = 8.9, p=0.0010) in a multivariate model. HLA-DRB1*0101-CD4 >25% associated with hepatitis(OR=10.5, p=0.0001); HLA-B*3501 associated with rash (OR = 3.9, p=0.005) and HLA-B*15/DR15 associated with hepatitis(OR=10.6, p=0.005) and eosinophilia (OR=16.7, p=0.0006). NVP specific CD8+ and CD4+ T cell responses were seen on ICS in an HLA-B15/DR15 positive, 5 month old Southeast Asian infant with fever, rash, eosinophilia and hepatitis on day 7 of NVP/abacavir/3TC. NVP specific γ-interferon responses were abrogated in an HLA-B*35 positive patient when either CD4+ or CD8+ T cells were depleted from PBMC culture. Conclusions: Class I and II HLA associations with NVP HSR are phenotype specific. The association of specific class I and II allele pairings with NVP HSR, and cellular studies showing both CD4+ and CD8+ T cell NVP specific responses suggest that specific combinations of NVP reactive class I restricted CD8+ and class II restricted CD4+ T cells are necessary for NVP HSR.

Item Type: Conference Item
Murdoch Affiliation(s): Institute for Immunology and Infectious Diseases
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