Hypersensitivity Syndrome Associated with Efavirenz Therapy

Hypersensitivity syndrome, also called DRESS (drug rash with eosinophilia and systemic symptoms) syndrome, is a life-threatening reaction that typically includes skin rash, fever, multivisceral involvement (lymphadenopathy, hepatitis, interstitial nephritis, pneumonia, and myocarditis), and hematologic abnormalities, especially eosinophilia and mononucleosis-like atypical lymphocytosis [1]. Recently, cases have been associated with nevirapine, a nonnucleoside HIV reverse transcriptase inhibitor [2, 3]. We describe a case of hypersensitivity syndrome in an HIV type 1-infected patient treated with efavirenz. A 44-year-old woman from the Ivory Coast was admitted to the hospital in March 1999 because of fever, diffuse maculopapular rash, abdominal pain, diarrhea, dry cough, and jaundice. She was diagnosed as HIV positive in 1991 but was not followed up until December 1998. At that time, she was admitted to the hospital because of toxoplasmic encephalitis, which was treated with pyrimethamine/sulfadiazine. By February 1999, antiretroviral treatment with stavudine (40 mg b.i.d.), lamivudine (150 mg b.i.d.), and efavirenz (600 mg q.d.) was started. Twenty days later, the patient presented with a maculopapular rash on the upper limbs. Sulfadiazine was switched to clindamycin. Ten days later, she was admitted to the hospital for a worsening condition. At admission, her temperature was 40°C, pulse rate was 137, and respiration rate was 26. The blood pressure was 130/85 mm Hg. Physical examination revealed a generalized maculopapular rash without mucosal involvement, moderate abdominal tenderness, hepatosplenomegaly, small cervical lymph nodes, jaundice, and bilateral crackles. Laboratory tests revealed the following: WBC count, 16×109/L (with 9% eosinophils [1.44×109/L] and 51% lymphocytes [8.16×109/L]); hemoglobin level, 9.2 mg/dL; platelet count, 203,000/mm3; aspartate aminotransferase level, 1228 IU/L (normal value, 0–40 IU/L); alanine aminotransferase level, 458 IU/L (normal value, 0–65 IU/L); lactate dehydrogenase level, 1920 U/L (normal value, 240–480 U/L); total bilirubin level, 282 mmol/L (normal value, 2–17 mmol/L); and partial prothrombin time, 27.2 s (control value, 14 s). Determination of arterial blood gas levels showed the following: partial pressure of oxygen, 79 mm Hg; partial pressure of carbon dioxide, 29 mm Hg; and pH, 7.44. Abdominal ultrasound examination revealed hepatosplenomegaly with-out lymph node involvement. Chest radiography showed moderate bilateral interstitial pneumonitis. No infectious agent was found. Cultures of specimens of blood, stool, urines, and sputum (comprising acid-fast bacilli) were negative. Serologic tests for syphilis, C pneumoniae, M pneumoniae, legionella, and cytomegalovirus were also negative. Only PCR of HHV-6 was positive, which is known to be associated with hypersensitivity syndrome. Results of histopathologic evaluation of a skin biopsy specimen were compatible with hypersensitivity syndrome. Administration of all drugs was discontinued, and treatment with iv methylprednisolone (360 mg daily for 3 days and 180 mg daily thereafter) was started. Results of liver function tests and anemia decreased within 2 days. One week later, skin rash and systemic manifestations resolved completely. The patient was treated again with lamivudine and stavudine, and nelfinavir was added to the therapeutic regimen without recurrence of biological or clinical manifestations. The patient was discharged, and her prednisone dose was tapered starting at 60 mg daily. We report a case of hypersensitivity syndrome associated with efavirenz. Our patient was treated again with lamivudine and stavudine without recurrence of the syndrome. This syndrome has been described in association with sulfonamides; however, the lag time between the administration of sulfadiazine and the occurrence of clinical signs was 3 months, whereas it was 3 weeks between efavirenz treatment and the occurrence of clinical symptoms. Because hypersensitivity syndrome usually develops 2–6 weeks after a drug is first used, this case points more toward efavirenz than to sulfadiazine. In addition, our patient's condition worsened after sulfadiazine treatment was with-drawn. Cases of hypersensitivity syndrome associated with anti-retroviral agents such as nevirapine, abacavir, and zalcitabine have been reported elsewhere [2–5]. Efavirenz should now be added to the list of antiretroviral agents associated with this syndrome.