In September 2000, two instances of life-threatening hepatotoxicity were reported in health-care workers taking nevirapine (NVP) for postexposure prophylaxis (PEP) after occupational human immunodeficiency virus (HIV) exposure. In one case, a 43-year-old female health-care worker required liver transplantation after developing fulminant hepatitis and end-stage hepatic failure while taking NVP, zidovudine, and lamivudine as PEP following a needlestick injury. In the second case, a 38-year-old male physician was hospitalized with life-threatening fulminant hepatitis while taking NVP,
zidovudine, and lamivudine as PEP following a mucous membrane exposure. To characterize NVP-associated PEP toxicity, CDC and the Food and Drug Administration (FDA) reviewed MedWatch reports of serious adverse events in persons taking NVP for PEP received by FDA.
This report summarizes the results of that analysis and indicates that healthy persons taking abbreviated 4-week NVP regimens for PEP are at risk for serious adverse events. Clinicians should use recommended PEP guidelines and dosing instructions to reduce the risk for serious adverse events.
MedWatch is a voluntary reporting system for adverse events and problems
with drugs, medical devices, biologics, and special nutritional products. For this analysis,
a serious adverse event was defined as any event that was life-threatening,
permanently disabling, required or prolonged hospitalization, required intervention to prevent
permanent impairment or damage, or any other event that required medical attention.
Including the two case reports of fulminant hepatitis, FDA received reports of
22 cases of serious adverse events related to NVP taken for PEP from March 1997
through September 2000. These 22 events included hepatotoxicity (12), skin reaction (14),
and rhabdomyolysis (one); four cases involved both hepatotoxicity and skin reaction,
and one case involved both rhabdomyolysis and skin reaction. The median age of
affected persons was 36.5 years (range: 12--50 years; age was not reported for four cases);
12 were female, and 12 occurred in the United States. Reasons for administration of
PEP were occupational needlestick or other sharps injury (12), other occupational
exposure (four), sexual exposure (three), nonoccupational (pediatric) needlestick injury (one),
other nonoccupational exposure (one), and unknown (one).
Nine persons took a maximum NVP dose of 200 mg per day, and 12 persons took
a maximum dose of 200 mg twice per day (the dose of NVP was not recorded for
one person). Among the 12 persons taking a maximum dose of 200 mg twice daily, six
were first given a lead-in dose of 200 mg per day for 3--14 days. Concomitant
antiretroviral agents used with NVP for PEP included zidovudine and lamivudine (10); stavudine
and lamivudine (three); zidovudine and didanosine (two); stavudine and didanosine
(one); stavudine and indinavir (one); didanosine and indinavir (one); stavudine, didanosine,
and ritonavir (one); lamivudine, didanosine, and nelfinavir (one); stavudine,
lamivudine, nelfinavir, and saquinavir (one); and none (one). Among the 12 persons with
hepatotoxic reactions, one developed liver failure (requiring liver transplantation), seven had
clinical hepatitis (e.g., jaundice, fever, nausea, vomiting, abdominal pain, and/or
hepatomegaly), and four had elevations in serum liver enzymes (i.e., alanine aminotransferase [ALT]
and aspartate aminotransferase [AST]) without reports of clinical hepatitis.
Baseline liver function tests were reported for six patients and were within
normal limits. Abnormal liver function tests were reported during PEP for 10 patients;
peak ALT was 215 U/L (range: 182--2790 U/L; normal: 10--34 U/L), median peak AST
was 375 U/L (range: 96--2370 U/L; normal: 10--34 U/L), and median peak total bilirubin was
7.5 mg/dL (range: 2.0--33.7 mg/dL; normal: 0.2--1.0 mg/dL). The median time from
initiation of NVP use to first abnormal liver function tests was 21 days (range: 13--36 days). In
six cases, hepatitis A, B, and C serologies were reported; all were negative. Eleven
persons reported symptoms, including fever, malaise, and abdominal pain. The median onset
of these symptoms was 14 days after beginning NVP for PEP (range: 3--36 days). The
14 reports of skin rash included one documented and two possible cases of
Stevens-Johnson syndrome. The median onset of rash occurred 9 days after beginning PEP (range:
Reported by: D Boxwell, Pharm D, Office of Postmarketing Drug Risk Assessment; H
Haverkos, MD, S Kukich, MD, K Struble, Pharm D, H Jolson, MD, Div of Anti-Viral Drug Products, Center
for Drug Evaluation and Research, Food and Drug Administration. Prevention and Evaluation
Br, Div of Healthcare Quality Promotion [proposed], National Center for Infectious Diseases, CDC.
Severe, life-threatening, and fatal cases of hepatotoxicity and
skin reactions have occurred among HIV-infected patients treated with NVP
(2,3) and are described in a box warning on the NVP label (Viramune [package
insert], Boehringer Ingelheim/Roxane Laboratories, Inc., Ridgefield, Connecticut, 1998). This report
suggests that persons taking NVP regimens for PEP after HIV exposures also are at risk
for serious adverse events.
In 1996, the U.S. Public Health Service (PHS) first recommended PEP after
certain occupational exposures to HIV (4). These recommendations, updated in 1998
(5), are being revised to include other antiretroviral agents that have been approved by FDA
for use in HIV-infected persons. NVP is not recommended for basic or expanded PEP
regimens. However, data on the safe and effective use of single-dose NVP to prevent
perinatal HIV transmission (6,7) and a theoretical advantage of more rapid activity (i.e.,
NVP does not require phosphorylation for activation) have prompted clinicians to include
NVP in PEP regimens following HIV exposures. In the HIV PEP registry, which collected data
on occupational HIV PEP use from October 1995 through March 1999, six cases of
serious adverse events related to PEP were reported among 492 registered participants; a
severe skin reaction occurred in one of 11 health-care workers taking a regimen
that included NVP (8).
Because most occupational HIV exposures do not result in transmission of HIV
(9), clinicians considering prescribing PEP for exposed persons must balance the risk for
HIV transmission represented by the exposure and the exposure source against the
potential toxicity of the specific agent(s) used
(4). In many circumstances, the risks
associated with NVP as part of a PEP regimen outweigh the anticipated benefits. When PEP is
prescribed, the manufacturer's package insert should be consulted for dosing
instructions, possible side effects, and potential drug interactions.
The findings in this report are subject to at least three limitations. First, MedWatch
is a voluntary, passive reporting system, and it is unlikely that all serious adverse events
in persons taking NVP for PEP have been reported. Second, data about administration of
a lead-in dose and results of baseline liver function tests and hepatitis serologies were
not included in all reports. In six cases, the initial dose of NVP was 200 mg twice daily
without the recommended 2-week dose escalation, which may have increased the likelihood
of adverse events (10). Third, available denominator data about the use of NVP for
PEP were insufficient to calculate accurate rates of adverse events.
The findings in this report do not apply to NVP use in other settings. Single-dose
NVP is one of the regimens recommended by PHS for prevention of perinatal HIV
transmission (7). No serious toxicity has been reported among mother-infant pairs using
this regimen. Combination antiretroviral regimens containing NVP may be used in HIV-
infected persons after weighing the risks and benefits and monitoring adverse
Health-care providers and the public can assist in monitoring the safety
of antiretrovirals and other agents by reporting adverse reactions to the FDA
MedWatch program: telephone, (800) 332-1088, fax, (800) 332-0178, World-Wide Web,
http://www.FDA.gov/medwatch, or mail, MedWatch, HF-2, FDA, 5600 Fishers Lane,
Rockville, MD 20857.
- Johnson S, Baraboutis JG, Sha BE, Proia LA, Kessler HA. Adverse effects associated
with use of nevirapine in HIV postexposure for 2 health care workers [Letters].
- Cattelan AM, Erne E, Slatino A, et al. Severe hepatic failure related to nevirapine
treatment. Clin Infect Dis 1999;29:455--6.
- Sidley P. South Africa to tighten control on drug trials after five deaths. Br Med
- CDC. Update: provisional Public Health Service recommendations for
chemoprophylaxis after occupational exposure to HIV. MMWR 1996;45:468--72.
- CDC. Public Health Service guidelines for the management of health-care worker
exposures to HIV and recommendations for postexposure prophylaxis. MMWR
- Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose
nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1
in Kampala, Uganda: HIVNET 012 randomized trial. Lancet 1999;354:795--802.
- US Public Health Service. Public Health Service Task Force recommendations for use
of antiretroviral drugs in pregnant HIV-1 infected women for maternal health and
interventions to reduce perinatal HIV-1 transmission in the United States. Available at
http://hivatis.org/guidelines/perinatal/Nov_00/text/index.html. Accessed January 2001.
- Wang SA, Panlilio AL, Doi PA, et al. Experience of healthcare workers taking
postexposure prophylaxis after occupational HIV exposures: findings of the HIV Postexposure
Prophylaxis Registry. Infect Control Hosp Epidemiol 2000;21:780--5.
- Bell DM. Occupational risk of human immunodeficiency virus infection in
healthcare workers: an overview. Am J Med 1997;102:9--15.
- Soriano AP, Jiménez-Nácher I, Rodriguez-Rosado R, Dona MC, Barreiro PM,
González-Lahoz J. Incidence of rash and discontinuation of nevirapine using two different
escalating initial doses [Letter]. AIDS 1999;13:524.