Serious Adverse Events Attributed to Nevirapine Regimens for Postexposure
Prophylaxis After HIV Exposures --- Worldwide, 1997--2000

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4951a1.htm
   

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 (1). 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 (Figure 1). 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; median 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: 6--36 days).

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.

Editorial Note:

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 reactions.

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.

References

1.    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]. JAMA 2000;284:2722--3.
2.    Cattelan AM, Erne E, Slatino A, et al. Severe hepatic failure related
to nevirapine treatment. Clin Infect Dis 1999;29:455--6.
3.    Sidley P. South Africa to tighten control on drug trials after five
deaths. Br Med J 2000;320:1028.
4.    CDC. Update: provisional Public Health Service recommendations for
chemoprophylaxis after occupational exposure to HIV. MMWR
1996;45:468--72.
5.    CDC. Public Health Service guidelines for the management of health-care
worker exposures to HIV and recommendations for postexposure prophylaxis.
MMWR 1998;47(no. RR-7).
6.    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.
7.    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.
8.    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.
9.    Bell DM. Occupational risk of human immunodeficiency virus infection in
healthcare workers: an overview. Am J Med 1997;102:9--15.
10.    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.

* Information included in this report does not represent Food and Drug
Administration approval or approved labeling for the particular product or
indications in question.

† Use of trade names and commercial sources is for identification only and
does not constitute endorsement by CDC or the U.S. Department of Health
and Human Services.