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To the Editor: Guidelines for HIV (human immunodeficiency virus) postexposure prophylaxis (PEP) recommend administration of zidovudine and lamivudine with inclusion of a protease inhibitor if there is an increased risk of HIV transmission or if resistance to zidovudine and lamivudine is suspected.¹ The guidelines do not recommend the routine use of nonnucleoside reverse transcriptase inhibitors (NNRTIs), but allow for their use with expert consultation. A severe hypersensitivity reaction is a known complication of nevirapine and can present as a fulminant hepatitis,² or as a systemic syndrome with predominant cutaneous manifestations referred to as hypersensitivity syndrome (HSS) or drug rash with eosinophilia and systemic symptoms.³ We report a case of a severe systemic reaction with rash in a health care worker shortly after administration of a nevirapine-containing PEP regimen.

Report of a Case
A 33-year-old female nurse sustained a hollow-bore needlestick injury after drawing blood from a patient with advanced HIV infection (CD4 cell count, 4 x 10⁶/L; viral load, <400 copies/mL). A PEP regimen of lamivudine/zidovudine, twice daily, and nevirapine, 200 mg once daily, was initiated after review of the source patient's antiretroviral treatment history and discussion with the nurse. Eight days later, the nurse complained of nausea, anorexia, and lightheadedness during the previous 24 hours, and fever and headache since the previous night. She was febrile (39.4°C [102.8°F]) and had tender cervical adenopathy and mild left lower quadrant abdominal tenderness. Her PEP regimen was switched to efavirenz, 600 mg once daily, lamivudine, 150 mg twice daily, and stavudine, 40 mg twice daily, because of concern about toxicity related to nevirapine.

Two days later (10 days after starting PEP) she was reevaluated because of continued fever with new onset of rash since the previous evening. The rash started bilaterally in the arms, then extended to the trunk and the whole body and was accompanied by generalized pruritus. On examination, she was nonicteric, but had a diffuse, blanching maculopapular rash that was confluent on the extensor surfaces of the arms, but involved the trunk, face, and lower extremities above the knees. Her white blood cell count was 2.7 x 10⁹/L with 66% neutrophils, 22% lymphocytes, 11% monocytes, and 1% basophils. Prednisone, 20 mg daily, was administered.

Her symptoms improved, but 2 days after finishing the course of prednisone (17 days after starting PEP) rash, pruritus, and low-grade fever (37.7°C [99.8°F]) returned. In addition, she noted facial and lip swelling. At this time her white blood cell count was 4.1 x 10⁹/L with 63% neutrophils, 22% lymphocytes, 6% monocytes, and 9% eosinophils. Her alanine aminotransferase and aspartate aminotransferase levels were 215 U/L and 117 U/L, respectively. The PEP regimen was again modified by discontinuation of efavirenz and institution of nelfinavir. Her temperature increased to 38.9°C (102.0°F) the following day and prednisone therapy was reinstituted. Her fever resolved and her rash eventually desquamated. The PEP regimen was discontinued 25 days after initiation and the prednisone was continued for another week. Two weeks later (38 days after initiation of PEP) her only remaining symptoms were soreness of her forearms and hands. HIV serology test results were negative at 31 and 64 days after exposure.

Comment
Although implication of nevirapine in this case of HSS was potentially confounded by continued antiretroviral treatment, including introduction of another NNRTI, the signs and symptoms of this patient are most consistent with nevirapine-induced HSS.³ Rash is a potential adverse effect for all NNRTIs, but there appears to be only minor cross-toxicity between nevirapine and efavirenz with respect to hypersensitivity reactions.⁴ Severe cutaneous reactions to nevirapine also include Stevens-Johnson syndrome and toxic epidermal necrolysis,⁵ which occurs at a rate of 0.3.⁶ The rate of severe hypersensitivity reactions in general to nevirapine may be even higher. The European Medicines Evaluation Agency (EMEA) recently issued a warning of increased reports of serious cutaneous and hepatic reactions, sometimes fatal, associated with nevirapine (EMEA/11260/00, London, April 12, 2000, public statement, http://www.eudra.org/humandocs/PDFs/PS/1126000EN.pdf). In light of the increased reports of severe hypersensitivity reactions to nevirapine, we suggest that this agent not be used for PEP until the incidence and full spectrum of nevirapine toxicity is clear, particularly if the risk of HIV seroconversion following a needlestick (0.3%)¹ is equal to or less than the risk of this life-threatening complication.

Stuart Johnson, MD; John G. Baraboutis, MD
Department of Medicine
Northwestern University Medical School and the Veterans Affairs Chicago Healthcare System, Lakeside Division
Chicago, Ill

1. Centers for Disease Control and Prevention. Public Health Service guidelines for the management of health-care worker exposures to HIV and recommendations for postexposure prophylaxis. MMWR Morb Mortal Wkly Rep. 1998;47(RR-7):1-33. PUBMED 2. Leitze Z, Nadeem A, Chodhay A, Saul Z, Roberts I, Manthous CA. Nevirapine-induced hepatitis treated with corticosteroids? AIDS. 1998;12:1115-1117. WEB OF SCIENCE | PUBMED 3. Bourezanne Y, Salard D, Hoen B, Vandel S, Drobasheff C, Laurent R. DRESS (Drug rash with eosinophilia and systemic symptoms) syndrome associated with nevirapine therapy. Clin Infect Dis. 1998;27:1321-1322. WEB OF SCIENCE | PUBMED 4. Soriano V, Dona C, Barreiro P, González-Lahoz J. Is there cross-toxicity between nevirapine and efavirenz in subjects developing rash? AIDS. 2000;14:1672-1673. PUBMED 5. Warren KJ, Boxwell DE, Kim NY, Drolet BA. Nevirapine-associated Stevens-Johnson syndrome [letter]. Lancet. 1998;351:567. FULL TEXT | PUBMED 6. Barner A, Myers M. Nevirapine and rashes [letter]. Lancet. 1998;351:1133. FULL TEXT | PUBMED

Report of a Case

To the Editor: Current guidelines from the US Centers for Disease Control and Prevention concerning PEP for HIV-exposed health care workers recommend the use of combination antiretroviral therapy with 2 to 3 medications, depending on the extent of exposure and source patient characteristics.¹ While the risk of transmission of HIV via a needlestick is approximately 0.3%, the risk of serious adverse effects of these preventive strategies remains undefined.¹ We report a case of a health care worker who experienced serious morbidity from PEP.

A 43-year-old female, African American phlebotomist sustained a needlestick injury after drawing blood from an HIV- and hepatitis C virus (HCV)–infected patient. She received PEP with zidovudine, lamivudine, and nevirapine. Triple therapy including nevirapine was selected based on the source patient's advanced disease, antiretroviral treatment history, and severity of the exposure. The health care worker's baseline serum transaminase, total bilirubin, alkaline phosphatase, and complete blood count test results were normal. Baseline hepatitis serology for hepatitis B and C viruses revealed positive test results for antibody to hepatitis B surface antigen only. HIV antibody test results were negative. Fourteen days after starting PEP, the patient developed malaise, fatigue, fever, and chills.

Laboratory evaluations showed aspartate transaminase levels of 34 U/L, alanine transaminase levels of 49 U/L, total bilirubin levels of 5.13 µmol/L (0.3 mg/dL), and alkaline phosphatase levels of 107 U/L. Blood culture results were negative. At day 20, laboratory evaluations showed the following levels: aspartate transaminase, 2370 U/L; alanine transaminase, 1080 U/L; total bilirubin, 22.2 µmol/L (1.3 mg/dL), and alkaline phosphatase, 150 U/L. The patient's medications were discontinued. Blood culture results remained negative. On day 27, the patient developed acute hepatic failure and coma. At hospitalization, repeat hepatitis serology results were unchanged. Quantitative plasma HIV RNA was less than 50 copies/mL. The results of both qualitative and quantitative HCV RNA polymerase chain reactions were negative.

The patient required an orthotopic liver transplant 35 days following initiation of PEP. Pathology of the native liver showed confluent hepatic necrosis. Six months after transplantation, her liver enzyme levels were normal, and she remained seronegative for HIV and HCV.

Comment
Nevirapine has been associated with severe and life-threatening cutaneous reactions. Asymptomatic hepatitis has been known to occur in 8% to 28% of patients receiving nevirapine.^2-3 More recently, severe hepatic reactions have been described and appear to represent hypersensitivity reactions within the first 2 months of treatment. Fever, rash, arthralgias, myalgias, hypereosinophilia, and/or acute renal failure are the hallmarks of this reaction^4-5 (EMEA/11260/00, London, April 12, 2000, public statement). We think that this patient had a severe hypersensitivity reaction to nevirapine that resulted in hepatic failure.

Current guidelines for health care worker–related PEP do not specifically exclude use of NNRTIs, but reserve their use for situations in which resistance to first-line drugs is suspected. This case raises the question of whether the safety profile of nevirapine warrants its use as a prophylactic medication in health care workers who are exposed to HIV when the risk of transmission is low.

Beverly E. Sha, MD; Laurie A. Proia, MD; Harold A. Kessler, MD
Department of Medicine
Rush-Presbyterian-St Luke's Medical Center
Chicago, Ill

1. Centers for Disease Control and Prevention. Public Health Service guidelines for the management of health-care worker exposures to HIV and recommendations for postexposure prophylaxis. MMWR Morb Mortal Wkly Rep. 1998;47(RR-7):1-33. PUBMED 2. Carr A, Vella S, deJong MA, Sorice F, et al. A controlled trial of nevirapine plus zidovudine versus zidovudine alone in p-24 antigenemic HIV-infected individuals. AIDS. 1996;10:635-641. WEB OF SCIENCE | PUBMED 3. Havlir D, Cheeseman SH, McLaughlin M, et al. High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. J Infect Dis. 1995;171:537-545. WEB OF SCIENCE | PUBMED 4. Cattelan AM, Erne E, Saltino A, et al. Severe hepatic failure related to nevirapine treatment. Clin Infect Dis. 1999;29:455-456. WEB OF SCIENCE | PUBMED 5. Leitze Z, Nadeem A, Chodhay A, Saul Z, Roberts I, Manthous CA. Nevirapine-induced hepatitis treated with corticosteroids? AIDS. 1998;12:1115-1117. WEB OF SCIENCE | PUBMED

Letters Section Editors: Stephen J. Lurie, MD, PhD, Senior Editor; Phil B. Fontanarosa, MD, Executive Deputy Editor.

JAMA. 2000;284:2722-2723.

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