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Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*01 and higher CD4+ T cell counts

Martin, A., Cameron, P., Nolan, D., James, I., Keller, J., Phillips, E. and Mallal, S. (2004) Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*01 and higher CD4+ T cell counts. In: XV International AIDS Conference, 11 - 16 July 2004, Bangkok, Thailand.


Introduction: The major treatment-limiting toxicities associated with nevirapine (NVP) include varying combinations of rash, fever and hepatitis occurring within the first 6 weeks of therapy. Predisposing factors include pre-treatment CD4+ count suggesting an immunologic component, although genetic associations have not been described.

Aims and Methods: Genetic (HLA), disease-related and demographic risk factors for NVP reactions within the first six weeks were examined among 230 patients exposed to NVP. HLA typing was carried out by routine serological or DNA sequence-based assays.

Results: A retrospective review by a clinician blinded to HLA typing identified 24 cases of NVP reactions, characterised according to presence of rash (n=20), hepatitis (n=10) or fever (n=11), with 6 cases of rash + hepatitis + fever. Taken together all NVP reactions were associated with the presence of HLA-DRB1*01 (P=0.014). In logistic regressions an interaction between HLA-DRB1*01 and %CD4+ cells was strongly associated with NVP reactions (P=0.00006), whilst neither HLA-DRB1*01 nor %CD4+ remained individually significant after adjustment for this effect (P = 0.1). Similar results were obtained when considering rash + hepatitis, hepatitis, or fever (HLA-DRB1*01 by %CD4 interaction P<0.001). In contrast, risk of NVP-associated rash alone (n=9) was associated with HLA-DRB1*07 (P=0.04), and in this case no significant associations with HLA-DRB1*01 (P = 0.24) and/or %CD4 T cells were detected (P>0.1).

Conclusion: This retrospective study suggests that HLA-DRB1*01 may determine susceptibility to hepatitis-associated NVP HSR, and that this effect is may be abrogated by low %CD4+ count, as could be expected for a Class II-restricted, CD4+ T cell-dependent immune response to NVP-specific antigens. These data also argue that isolated NVP-associated rash without other features of NVP HSR may be a distinct clinical and pathophysiologic entity with unique HLA associations.

Publication Type: Conference Item
Murdoch Affiliation: Centre for Clinical Immunology and Biomedical Statistics
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