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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.a,*; Pavlos, Rebecca K.a,*; McKinnon, Elizabetha; Lucas, Andrewa; Rive, Craiga; Blyth, Christopher C.b,c; Dunn, Davida; Lucas, Michaelad; Mallal, Simona,e; Phillips, Elizabetha,e

doi: 10.1097/QAD.0000000000000345
Clinical Science

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 (IFNγ) 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 INFγ 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.

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aInstitute for Immunology and Infectious Diseases, Murdoch University

bDepartment of Paediatrics and Adolescent Medicine, Princess Margaret Hospital for Children

cSchool of Paediatrics & Child Health

dSchool of Medicine & Pharmacology and School of Pathology & Laboratory Medicine, The University of Western Australia, Perth, Western Australia, Australia

eVanderbilt University School of Medicine, Nashville, Tennessee, USA.

*Niamh M. Keane and Rebecca K. Parlos contributed equally to this study.

Correspondence to Elizabeth Phillips, MD, Division of Infectious Diseases, Vanderbilt University School of Medicine, 1161 21st Avenue South, A-2200 Medical Centre North, Nashville, TN 37232-2582, USA. E-mail:

Received 13 March, 2014

Revised 6 May, 2014

Accepted 6 May, 2014

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© 2014 Lippincott Williams & Wilkins, Inc.