Hypersensitivity Related to Abacavir in Two Members of a Family

TO THE EDITOR: The principal adverse effect of abacavir, a potent reverse transcriptase inhibitor, is a hypersensitivity reaction, which is seen in approximately 5% of patients, usually within the first six weeks of therapy.1 This is characterized by fever, nausea/vomiting, malaise, and/or rash, and respiratory symptoms.2,3 We report cases occurring in a father and his daughter. Case Reports. A 39-year-old white HIV-infected man with no known drug allergy received zidovudine, lamivudine, saquinavir, and cotrimoxazole for several years. His CD4+ count was 180/mm3 and plasma HIV-1-RNA 16 000 copies/mL. Fifteen days after abacavir 300 mg twice daily was added to the preexisting treatment regimen, the patient developed nausea, vomiting, and fever. Three days later, he was admitted to the hospital with high fever and a circulatory collapse (BP 70/40 mm Hg). Other complications included headache, diarrhea, generalized erythema, neutropenia (441 cells/mm3), cytolytic hepatitis, and increase in serum creatinine concentration (169 μmol/L) and C-reactive protein (18.8 mg/L). All treatments were stopped. The duration of abacavir therapy was 17 days. Within seven days, the clinical and biological status of the patient improved. The eosinophil count had always been normal. When the patient was discharged, co-trimoxazole, saquinavir, nelfinavir, zidovudine, and lamivudine were resumed with no adverse event. For years, the patient had complained of chronic rhinitis: in this context, total immunoglobulin (Ig) was within the normal range. The daughter of this patient, a nine-year-old girl (140 cm/35 kg), without known atopy or drug allergy, had been treated for mother-to-child HIV transmission since she was 18 months old. She had been treated with lamivudine and efavirenz for several months. Nine days after the start of abacavir 300 mg twice daily, she developed headache, fatigue, and fever (39 ̊C). In the following days, the fever increased, and erythema of the face, trunk, and limbs appeared. Abacavir was discontinued, and all symptoms resolved within one day without treatment. Biological tests were not performed. Her new treatment regimen comprises efavirenz, stavudine, and lamivudine. Use of the Naranjo ADR probability scale4 indicated a possible relationship between adverse effects reported and abacavir in these patients. Discussion. Abacavir-related hypersensitivity reaction may limit the use of this drug in a small number of patients. The management of this adverse effect is now well documented, and rechallenge with abacavir is unnecessary.5 This is the first report of a familial hypersensitivity reaction to abacavir. The genetic predisposition of drug allergy is known with antibiotics: children of parents who are allergic to an antibiotic have been reported6 to have a 15-fold greater relative risk for allergic reactions to antibiotics than children without such family histories. Hypersensitivity reactions to drugs can be explained by immunologic and/or metabolic pathways involving cytochrome P450. Abacavir is not metabolized by cytochrome P450, and the reactivity of the formed metabolites is unknown. Immunologic factors may also be involved. In cases previously reported,2,3 the rapid onset of hypotension after rechallenge with abacavir may point to an IgE-mediated reaction, although there is no direct evidence of this type of reaction. A recent study7 suggests that epidermal cytokines and activated CD8+ lymphocytes are involved in abacavir-induced hypersensitivity. All infiltrating lymphocytes expressed HLA-DR, with no evidence of B cells, eosinophils, or CD23 expression (suggesting the absence of type 2 cytokines such as interleukin 4). The conclusions of this study suggest that the immune response in the skin does not involve antibody responses and type 2 cytokines, but may be primarily a type 1 cytokine response. The absence of CD4+ cells in the epidermis distinguishes this rash from more severe cutaneous adverse events, such as Stevens–Johnson syndrome. At this time, the pathogenesis (metabolic, immunologic, or genetic) of this reaction is undefined. Thus, our cases suggest that the genetic predisposition may play a role in abacavir hypersensitivity. The research of the precise mechanisms underlying this hypersensitivity reaction should allow to propose predictive factors to this reaction and to improve the risk/benefit ratio of this essential drug. Although confirmation is needed, abacavir should be administered with caution in children of parents who have developed a hypersensitivity reaction.