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

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 for 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 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 peripheral blood mononuclear cells 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 Wolters Kluwer Health | Lippincott Williams & Wilkins