Treatment of HIV-1
infections with
nevirapine is associated with skin and liver toxicity. These two organ toxicities range from mild to severe, in rare cases resulting in life-threatening
liver failure or
toxic epidermal necrolysis. The study of the mechanistic steps leading to
nevirapine-induced
skin rash has been facilitated by the discovery of an animal model in which
nevirapine causes a
skin rash in rats that closely mimics the
rash reported in patients. The similarity in characteristics of the
rash between humans and rats strongly suggests that the basic mechanism is the same in both. The
rash is clearly immune-mediated in rats, and partial depletion of CD4(+) T cells, but not CD8(+) T cells, is protective. We have demonstrated that the
rash is related to the 12-hydroxylation of
nevirapine rather than to the parent
drug. This is presumably because the 12-hydroxy metabolite can be converted to a reactive
quinone methide in skin, but that remains to be demonstrated. Although the
rash is clearly related to the 12-hydroxy metabolite rather than the parent
drug, cells from rechallenged animals respond ex vivo to the parent
drug by producing
cytokines such as
interferon-gamma with little response to the 12-hydroxy metabolite, even when the
rash was induced by treatment with the metabolite rather than the parent
drug. This indicates that the response of T cells in vitro cannot be used to determine what caused an immune response. We are now studying the detailed steps by which the 12-hydroxy metabolite induces an immune response and
skin rash. This animal model provides a unique tool to study the mechanistic details of an idiosyncratic
drug reaction; however, it is likely that there are significant differences in the mechanisms of different idiosyncratic
drug reactions, and therefore the results of these studies cannot safely be generalized to all idiosyncratic
drug reactions.