Nevirapine skin rash

Nevirapine is a non-nucleoside reverse transcriptase inhibitor used to treat HIV-infected patients that causes mild to severe skin rash and even Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) in a substantial proportion (16%) of patients. Nevirapine also induces hepatotoxicity. These adverse clinical symptoms may also occur in non-HIV subjects taking the drug as postoperative prophylaxis [15]. 

The development of nevirapine-induced disease is clearly immune-mediated as upon re-challenge with nevirapine the rash developed faster in previously exposed and fully recuperated rats. In addition, memory for skin reactions in response to nevirapine were transferable by splenocytes from treated to naive animals [15]. In summary, nevirapine-induced skin reactions in rat are immune-mediated and dependent on genetic background, including gender. 

Shenton, J.M. et al., Characterization of a potential animal model of an idiosyncratic drug reaction Nevirapine-induced skin rash in the rat. Chem. Res. Toxicol., 16, 1078, 2003... 

Adverse effects include drowsiness, insomnia, dizziness, agitation, confusion, depression, delusions, vomiting, diarrhoea, crystalluria, elevation in liver enzyme and total serum cholesterol. Serious side effect is skin rash including Stevens Johnson syndrome as in case of nevirapine. 

In four men aged 27, 41, 47, and 49 years, nevirapine was associated with a skin rash, malaise, and icteric hepatitis, 4-6 weeks after the start of therapy resolution occurred after withdrawal of nevirapine (13). 

Recently, nevirapine has been found to cause skin rash in 100% of high-exposed (150mg/kg by oral gavage) female BN rats (Shenton et al., 2003). Female Sprague-Dawley rats were less sensitive (21% of rats showed a rash), and male BN, Sprague-Dawley rats, and female Lewis rats were resistant. Nevirapine-induced disease was shown to be immune-mediated because upon rechallenge with nevirapine, the rash developed faster in previously exposed rats, and because skin reactions were transferable by splenocytes from nevirapine-treated to naive animals (Shenton et al., 2003). 

Normucleoside reverse transcriptase inhibitor (NNRTI) used in combination regimens for HIV. Tox skin rash, CNS effects. Other NNRTIs delavirdine, nevirapine. 

Nevirapine and its analogues exhibit antiretroviral effect against azothymidine-resistant HIV strains (87). Nevirapine in combination with ZDV and ddl produced approximately 18% higher CD4 cell counts and a decrease in viral load compared with patients who took ZDV and ddl. Nevirapine is recommended with nucleosides for patients infected with HIV-1 who have experienced clinical or immunologic deterioration. The significant side effects of nevirapine are liver dysfunction and skin rashes. 

Chat J, Maimaigudi BM, Xu L, Uetiecht J (2008) Demonstration of the metabolic pathway responsible for nevirapine-induced skin rash. Chem Res Toxicol 21 1862-1870 Claes P, Winizen M, Allard S et al (2004) Nevirapine-induced toxic epidermal necrolysis and toxic hepatitis treated successfully with a combination of intravenous immunoglobulins and N-acetylcysteine. Eur J Intern Med 15 255-258... 

Nevirapine-Induced Skin Rash in Brown Norway Rats... 

Animal Model of Nevirapine-Induced Skin Rash.441... 

In 2003, Shenton et al. reported a novel animal model of a drug-induced idiosyncratic reaction nevirapine-induced skin rash in the female Brown Norway rat. This animal model does not reproduce severe skin rashes such as TEN and SJS, nor does it reproduce the liver toxicity observed in some nevirapine-treated patients. However, the skin rash that develops in nevirapine-treated rats closely resembles the mild erythematous rash observed in patients (Shenton et al. 2003). 

At a nevirapine dose of 400 mg/day, 32—48% of patients develop skin rash versus 9% with a dose of 200 mg (Taiwo 2006). In female Brown Norway rats treated with nevirapine at a dose of 150 mg/kg/day, all developed a skin rash, while only half the rats developed the rash when dosed at 100 mg/kg/day. No rat developed a rash at doses of <75 mg/kg/day (Shenton et al. 2003). 

To decrease the incidence of skin rash in patients, a tolerance induction regime was established in patients 200 mg of nevirapine is administered daily for the first 2 weeks, followed by the full therapeutic dose of 200 mg twice daily. This regime successfully decreases the rash incidence by about 50% (Nevirapine product insert). In rats, daily treatment with 40 or 75 mg/kg/day of nevirapine for the first 2 weeks followed by 150 mg/kg/day (a dose that otherwise leads to a 100% incidence of rash) completely prevents the skin rash (Shenton et al. 2005). 

In the skin lesions of both patients and rats with nevirapine-induced skin rash, T cells have been observed. Furthermore, patients with low 04" T cell counts have a significantly lower incidence of rash than those with normal counts, and in rats, partial depletion of these cells also decreases the incidence of skin rash (Shenton et al. 2005). Most drug-induced skin rashes are believed to be immune-mediated and dependence of the rash on CD4 T cells in both humans and rats supports this hypothesis. 

Starting with the second week of nevirapine treatment, progressive infiltration of T cells into the rat skin dermis was observed. To assess the specific role of the T cell populations in triggering the onset of skin rash, Shenton et al. transferred splenocyte T cells from rechallenged rats into naive recipients. Spleen CD4 T and CD8 T cells were isolated from the nevirapine-rechallenged rats, purified, and intravenously injected into naive recipients, which were then started on a full (150 mg/kg/day) nevirapine dose (Shenton et al. 2005). Recipients of CD4 T cells developed skin rash 9 days later, while CDS" T cell recipients behaved as nevirapine naive rats, only developing red ears by day 7 and skin rash by day 21... 

Popovic M, Caswell JL, Mannargudi B, Shenton JM, Uetrecht JP (2006) Study of the sequence of events involved in nevirapine-induced skin rash in Brown Norway rats. Chem Res Toxicol 19(9) 1205-1214... 

Sanne I, Mommeja-Marin H, Hinkle J, Bartlett JA, Lederman MM, Maartens G, Wakeford C, Shaw A, Quinn J, Gish RG, Rousseau F (2005) Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 191 825-829 Shenton JM, Teranishi M, Abu-Asab MS, Yager JA, Uetrecht JP (2003) Characterization of a potential animal model of an idiosyncratic drug reaction nevirapine-induced skin rash in the rat. Chem Res Toxicol 16(9) 1078-1089... 

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