Evidence for Nevirapine Bioactivation in Man: Searching for the First Step in the Mechanism of Nevirapine Toxicity

Despite its efficacy, including in the prevention of vertical transmission, the antiretroviral nevirapine is associated with severe idiosyncratic hepatotoxicity and skin rash. The mechanisms underlying nevirapine toxicity are not fully understood, but drug bioactivation to reactive metabolites capable of forming stable protein adducts is thought to be involved. This hypothesis is based on the paradigm that drug reactive metabolites have the potential to bind to self-proteins, which results in drug-modified proteins being perceived as foreign by the immune system. The aim of the present work was to identify hemoglobin adducts in HIV patients as biomarkers of nevirapine haptenation upon bioactivation. The ultimate goal is to develop diagnostic methods for predicting the onset of nevirapine-induced toxic reactions. All included subjects were adults on nevirapine-containing antiretroviral therapy for at least 1month. The protocol received prior approval from the Hospital Ethics Committees and patients gave their written informed consent. Nevirapine-derived adducts with the N-terminal valine of hemoglobin were analyzed by an established liquid chromatography-electrospray ionization-tandem mass spectrometry method and characterized on the basis of retention time and mass spectrometric fragmentation pattern by comparison with adduct standards prepared synthetically. The nevirapine adducts were detected in 12/13 patient samples, and quantified in 11/12 samples (2.58±0.8 fmol/g of hemoglobin). This work represents the first evidence of nevirapine-protein adduct formation in man and confirms the ability of nevirapine to modify self-proteins, thus providing clues to the molecular mechanisms underlying nevirapine toxicity. Moreover, the possibility of assessing nevirapine-protein adduct levels has the potential to become useful for predicting the onset of nevirapine-induced adverse reactions.

The Management of the Allergic Child at School: EAACI/GA2LEN Task Force on the Allergic Child at School

Allergy affects at least one-quarter of European schoolchildren, it reduces quality of life and may impair school performance; there is a risk of severe reactions and, in rare cases, death. Allergy is a multi-system disorder, and children often have several co-existing diseases, i.e. allergic rhinitis, asthma, eczema and food allergy. Severe food allergy reactions may occur for the first time at school, and overall 20% of food allergy reactions occur in schools. Up to two-thirds of schools have at least one child at risk of anaphylaxis but many are poorly prepared. A cooperative partnership between doctors, community and school nurses, school staff, parents and the child is necessary to ensure allergic children are protected. Schools and doctors should adopt a comprehensive approach to allergy training, ensuring that all staff can prevent, recognize and initiate treatment of allergic reactions.