Nevirapine (NVP), a non-nucleoside analogue reverse transcriptase inhibitor, is widely used as part of highly active anti-retroviral therapy (HAART) in the treatment of HIV disease. NVP is usually well tolerated, but in 5% of HIV infected patients, NVP therapy can result in idiosyncratic reactions such as rash and hepatotoxicity [1]. The underlying mechanisms of NVP hypersensitivity are unclear, although its onset within the first 6 weeks would suggest an immune aetiology. However, there is no laboratory evidence in humans to support this. Investigation of the immune basis is complicated by the fact that the immune system in HIV individuals is over-stimulated, the lymphocytes are relatively anergic, and display high levels of cell death [2]. The aim of this study was to provide laboratory evidence to determine whether NVP hypersensitivity is immune mediated.

PBMCs were isolated from an HIV-positive patient (male, 30 years of age) who developed hepatitis 4 weeks after starting NVP; improvement occurred after dechallenge. PBMCs were also obtained from six HIV-positive non-hypersensitive patients who acted as controls. Cells from all individuals were incubated with varying concentrations of NVP (1-100 µm) and three NVP metabolites (1-100  µm; 99% pure). The re-call antigen tetanus toxoid (1 µg ml^-1) and the non-specific mitogen PHA (5 µg ml^-1) were used as positive controls, while medium alone acted as the negative control . Proliferative responses to the presence of the drug antigen were calculated as the stimulation index (SI; counts min^-1 in drug-treated culture/counts min^-1 in cultures with medium alone) after 5 days incubation, with a positive response being defined as an SI  2. Where proliferation was observed, the cells were cloned using a previously published procedure [3].

A reproducible positive proliferative response to NVP with a SI > 2, was demonstrated in the HIV-positive patient with NVP hepatitis, while none of the control patients had a SI  2. Lymphocyte viability in the hypersensitive patient was shown by a good PHA response (average SI of 122), although the response to TT was low (average SI of 4). No response was detected with the NVP metabolites. T cells were cloned and 28 T cell lines generated, of which six remained sensitive to NVP with an average SI of 2.5. Prolonged culture (for 4 months) led to the development of anergy and loss of the T cell phenotype.

Lymphocytes isolated from an HIV-positive patient with NVP hepatitis proliferated following presentation of the drug in vitro. This study provides the first laboratory evidence that NVP hypersensitivity reactions are immune mediated. Further cloning work is on going to define the nature of this T cell-mediated response, with the aim of providing further insights into the pathogenesis of NVP-induced hypersensitivity.

1. Floridia M, et al.HIV Med 2004; 5: 1.
2. Lederman HM, et al. JID 2003; 188: 1794.
3. Schnyder B, et al. J Immunol 2000; 164: 6647.