Stevens–Johnson syndrome in HIV patients treated with nevirapine: two case reports

Abstract

We describe two cases of Stevens–Johnson syndrome (SJS) caused by nevirapine, a non-nucleoside reverse transcriptase inhibitor for HIV therapy. It frequently causes adverse cutaneous events: rash (32–48% within 2–6 weeks after starting therapy); severe cutaneous reactions (8% grade 3–4 of WHO scale); and SJS (0.3–1%) [1]. Case 1 A 37-year-old intravenous drug using white man, an HIV patient (Centers for Disease Control 1993 stage B3), with hepatitis C virus (HCV) chronic hepatitis, secondary mild thrombocytopenia and cryoglobulinaemia, chronic gasthritis, mild hypertension, had been receiving, since 1998, stavudine, lamivudine and methylprednisolone (25 mg a day, as maintenance therapy), ranitidine, enalapril and trimethoprim/sulphamethoxasole, for HIV-related opportunistic infection prophylaxis. In October 1999 he started nevirapine with a standard treatment schedule (a lower lead-in dose: 200 mg/day for 15 days, then 200 mg twice a day) for the suboptimal effect of previous antiretroviral therapy (CD4 cell count 109 cells/mm3 and HIV-RNA level 35 000 copies/ml). Twenty days later, the patient had malaise, a generalized skin rash, characterized by erythematoviolaceous targoid lesions of his trunk, arms, legs and painful oral erosions, sparing the anogenital mucosal membranes. He was taking no other medications and had no history of previous drug allergies. He was afebrile and his platelet count was 36 000 cells/mm3, his hepatic function was altered, but consistent with HCV mild chronic hepatitis (serum glutamic-oxaloacetic transaminase 60 UI/l, serum glutamate-pyruvate transaminase 85 UI/l), and cryoglobulinaemia was present, although at a low percentage of cryocritous. The patient did not accept a skin biopsy. We investigated all other related syndromes or HIV opportunistic infections but we excluded other diagnoses. Despite a high dosage of steroids (methylprednisolone 50 mg a day) and prompt discontinuation of nevirapine, the rash lasted for 20 days, then slowly faded. The patient continued steroids, stavudine and lamivudine, without rechallenge nevirapine. A complete resolution of the skin lesions, leaving a hyperpigmented halo, was obtained after 2 months, and a recurrence of the rash was not observed. Case 2 A 35-year-old, heterosexual white man, with HIV transmission risk, had already been diagnosed with AIDS as a result of neurotoxoplasmosis and HIV-related encephalopathy, and was also affected by oral thrush, lower limb neuropathy, HCV chronic hepatitis, and secondary mild thrombocytopenia. He was already receiving treatment with highly active antiretroviral therapy and secondary prophylaxis for toxoplasmosis with clindamycin and pyrimethamine as a result of allergy to sulphamidics. The patient was not taking steroid treatment. In August 2000 he needed a shift in his highly active antiretroviral therapy schedule, as a result of virological failure and antiretroviral genotypic resistance: stavudine, lamivudine, nelfinavir plus nevirapine at standard doses. At this time, his CD4 cell count was 195 cells/mm3 and his plasma HIV-RNA level was 32 000 copies/ml, his aspartate aminotransferase/alanine aminotransferase value was 84/85 UI/l and his platelet count was 42 000 cells/mm3. In spite of keeping the strict lead-in period of treatment with nevirapine (200 mg/day for 15 days, then 200 mg twice a day), after 29 days of therapy, the patient, in the absence of prodromal symptoms, showed low-grade fever, diffuse erythematoviolaceous maculopapular cutaneous rash with targoid lesions over the palms and foresurface of the legs. Considering the allergic diathesis of the patient, all clinical investigations for a differential diagnosis of the nevirapine cutaneous reaction were performed. The patient was not taking other drugs beside his therapeutic schedule. The IgE dosage was increased (110 UI/l) but was not clearly demonstrative for atropy. A skin biopsy was not performed. The skin lesions completely disappeared after the early discontinuation of nevirapine and 20 days of corticosteroid therapy (betamethasone 2 mg a day). After this the patient took regular antiretroviral therapy with zidovudine, lamivudine, nelfinavir and efavirenz. Patients infected with HIV are at increased risk of developing severe cutaneous or mucocutaneous drug reactions [1]. The identification of a single drug as the cause of a drug eruption is difficult because antiretroviral agents are not used in monotherapy, and are often associated with many other drugs, such as antibiotics [1]. SJS is defined as a hypersensitivity cutaneous drug reaction [2]. Its pathogenesis, during treatment with nevirapine, is unclear and has rarely been described [3]. In our observations, we point out the peculiar clinical aspects: rare incidence (1%), difficult differential diagnosis [4,5], risk of developing SJS notwithstanding long-term steroid therapy (0.5 mg/kg a day) [6,7], and the prolonged course of SJS in spite of early nevirapine withdrawal and high-dose steroid treatment. Clinical guidelines have been developed to reduce the frequency of cutaneous rash and to avoid further toxicity after a severe rash [8]. Ferdinando Dodi Anna Alessandrini Marco Camera Lorenzo Gaffuri Norberto Morandi Gabriella Pagano