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doi: 10.1097/QAD.0000000000000345
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HLA Class I restricted CD8+ and Class II restricted CD4+ T cells are implicated in the pathogenesis of nevirapine hypersensitivity.

Keane, Niamh M.; Pavlos, Rebecca K.; McKinnon, Elizabeth; Lucas, Andrew; Rive, Craig; Blyth, Christopher C.; Dunn, David; Lucas, Michaela; Mallal, Simon; Phillips, Elizabeth

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Objectives: This study sought to examine nevirapine hypersensitivity (NVP HSR) phenotypes and their relationship with differing major histocompatibility complex (MHC) Class I and Class II alleles and the associated CD4+ and CD8+ T cell NVP-specific responses and their durability over time.

Methods: A retrospective cohort study compared HIV-positive patients with NVP HSR, defined by fever and hepatitis and/or rash, with those tolerant of NVP more than 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 by interferon-gamma (IFN[gamma]) ELISpot assay and intracellular cytokine staining (ICS).

Results: NVP HSR occurred in 19 out of 451 (4%) NVP-exposed individuals between March 1993 and December 2011. HLA associations were phenotype dependent with HLA-DRB1*01 : 01 associated with hepatitis (P = 0.02); HLA-B*35 : 01 and HLA-Cw4 were associated with cutaneous NVP HSR (P = 0.001, P = 0.01), and HLA-Cw*08 was associated with NVP HSR with eosinophilia (P = 0.04) and multisystemic NVP HSR (P = 0.02). NVP-specific INF[gamma] responses waned significantly more than 3 months from the original reaction and were diminished or completely abrogated when either CD4+ or CD8+ T cells were depleted from the PBMC culture.

Conclusion: The association of specific class I and II allele pairings with specific phenotypes of 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 contribute to the immunopathogenesis of NVP HSR.

(C) 2014 Lippincott Williams & Wilkins, Inc.


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