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Medical Forum / Diseases and Disorders / AIDS / December 2004CDC -Serious Adverse Events Attributed to Nevirapine Regimens
Serious Adverse Events Attributed to Nevirapine Regimens for Postexposure Prophylaxis After HIV Exposures --- Worldwide, 1997--2000 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. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4951a1.htm Nevirapine Misinformation: Will It Kill? by John S. James December 23, 2004: For a few days last week an Associated Press "exclusive" story touched off a firestorm of media by charging that side effects of single-dose nevirapine (to prevent mothers with HIV from infecting their babies during childbirth) had been covered up. Later the AP quoted responses -- one comparing nevirapine's distribution in Africa to the notorious Tuskegee Experiment, another charging that Africans were treated like guinea pigs. In fact there never was any evidence of a significant risk of side effects from only a single dose of nevirapine. There is a risk of HIV drug resistance from using even a single dose of the drug alone, but this is well known to all AIDS doctors and experts and has never been covered up. Every day about 1,800 babies are born with HIV, mostly to women who have no treatment options either for themselves or to prevent the infection of their child. There is no reason to doubt that single-dose nevirapine works, and could prevent about half of these infections. The brief media storm that still threatens the lives of thousands of unborn children grew out of a bitter dispute between two officials of the U.S. National Institutes of Health -- one of whom selectively released "thousands" of documents (according to news reports) to reporters and/or members of Congress. The danger now is that misleading stories published around the world will cause patients, doctors, or even some governments to reject single-dose nevirapine to prevent mother-to-child HIV transmission, even when no other treatment choice is possible. Background Nevirapine was approved in the U.S. in June 1996, for use in combination with other antiretrovirals for treating HIV. For this use it is taken twice a day for as long as the virus is under control. Later, a study in Uganda from 1997 to 1999 (the HIVNET 012 clinical trial) found that a single dose of nevirapine given to the mother and a single dose to the infant reduced HIV transmission to about half of what it was with a very short course of AZT. This study, conducted as a collaboration between researchers from Johns Hopkins University and Uganda and funded by the U.S. National Institutes of Health (NIH), was published in September 1999. It showed that HIV transmission at childbirth could be greatly reduced by a very inexpensive and easy regimen, even when the mother had little or no prenatal care. It is rightly considered one of the great successes in HIV prevention. Nevirapine alone is not the best regimen, however. Later it was learned from the same study that even the single dose sometimes selects for resistance mutations in the mother's HIV -- a serious problem because it could make her treatment more difficult in the future. This can be prevented by treating the mother's HIV if she needs antiretroviral treatment, which of course should be done anyway -- or by using a much more difficult regimen of AZT to prevent transmission -- or by adding other drugs (usually AZT plus 3TC) to suppress the virus while the nevirapine is slowly eliminated from the body. But still today the great majority of women with HIV do not have access to any antiretroviral treatment. Single-dose nevirapine is inexpensive and easy to deliver -- and many women will not use a longer course of medication, because they are afraid of the consequences if people around them learn or suspect that they have HIV. The recent controversy developed because after the Uganda study had been published, an NIH audit found that data on possible side effects had not been reported correctly by the Ugandan staff. This problem in one trial did not change the known safety of single-dose nevirapine -- which has been tested in many other clinical trials and widely used to prevent maternal transmission, without side effects. In continuous, long-term use in HIV treatment, serious or fatal side effects can occur, as with any antiretroviral. But these are rare, and they can be prevented with proper medical care, and they do not happen with one dose. Aside from the HIV resistance problem, there is no evidence of any significant safety risk from a single dose of nevirapine. The current dispute arose after NIAID/NIH hired a physician with clinical-trials monitoring experience, Jonathan M. Fishbein, M.D., in July, 2003, to help it correct the kinds of deficiencies that had been found in the study conducted several years earlier in Uganda. The key issue seems to be whether the reporting problems found in that study should invalidate the conclusion that single-dose nevirapine is safe and effective for preventing maternal-infant transmission. Recently Dr. Fishbein, still a Federal employee, claimed whistleblower status and used his Web site, http://www.honestdoctor.org, to release selected documents about problems with the nevirapine study. Comment We looked through all the documents on Honestdoctor.org as of December 22, 2004, and found nothing there that raised any new doubt on single-dose nevirapine -- now established by much more than the one trial in Uganda. Instead, the documents on that site show the extensive work that NIH and others were doing, both before and after Dr. Fishbein was hired, to correct universally acknowledged technical reporting problems. The goal was and is to re-analyze the Uganda trial in the light of all available information, both to re-check the conclusions, and also to improve clinical research in the future, particularly in developing countries, which often have a steep learning curve in applying standards created for pharmaceutical-company research in the West. I have no idea why Dr. Fishbein alleged "widespread scientific and professional misconduct at the NIH Division of AIDS (DAIDS)" (quote from Honestdoctor.org). There is no reason to doubt that single-dose nevirapine works and reduces HIV transmission to about half of what it would be without treatment. (It may do better than that, since the comparison group was not a placebo but a very short course of AZT, which may have had fewer HIV transmissions than a placebo would have.) The NIH Division of AIDS, like almost all other experts, wants to focus on public-health efforts to make preventive and other treatment available, and not derail these efforts because of technical problems in a trial that ended five years ago. This is not "scientific and professional misconduct." AIDS organizations did well last week in answering the misinformation about nevirapine. But the damage had already been done. The story went out on December 13, and was totally unexpected because it was tied to no medical or scientific development; it went around the world immediately and no answer could catch up. It is possible that children have already been born with HIV as a result, and that many more will be infected unnecessarily. What Can We Learn for the Future? This is not the last time the AIDS world will face mass-media storms that carry serious misinformation throughout the world. What can we do about it? AIDS needs a major organization dedicated to consensus development, and able to offer reporters a single entry point to learn what credible consensus exists on almost any AIDS issue. No position will speak for everybody, but the process should be open to hearing and understanding all dissenting views. Two or more incompatible consensus clusters could emerge, and they would have to be represented by different organizations. But reporters could immediately find broadly credible consensus statements, and talk with experts who have worked on an issue for years. They may still publish misinformation, but at least an answer could go out with it -- or be clearly missing from their story. Years ago AIDS had well-known broad policy organizations, like the AIDS Action Council in Washington DC. But they represented insiders with their own interests more than a national or world community. For example, treatment, research, and international issues were mostly locked out for years -- and usually the only way to have a voice was to be part of the scene in Washington. Still these organizations served an important purpose in providing a common policy base for reporters and others, and we miss that today. But now we need a new kind of organization that prides itself on listening and learning from different people (almost like social scientists exploring what is out there instead of imposing their own view) -- but then finds and suggests practical, creative ways these views and movements can work together in a larger whole. __________________________________________ Communication Note Ten days into this controversy Dr. Fishbein has a better Web site than most AIDS organizations do after many years -- immediately raising the communication standard. AIDS will face new media storms in the future, and must get its house in order. Honestdoctor.org is very well organized, allowing readers to see immediately what is available and navigate to what they want. The site has a extensive collection of the recent press articles, consistently and attractively laid out. Under "Definitions" it has a list of acronyms and a list of people with their titles -- and will have a glossary and organizational diagrams. When documents are photographed and displayed as images, they are processed correctly, so that they are entirely readable and yet download rapidly on any Internet connection. And last but not least this site has clearly legible type on its main pages, when most sites have text that is too small, too light, or without enough contrast between text and background. In the future, AIDS organizations should ask for volunteer or professional Web help that can do at least as well. Remember that our visitors have millions of other pages a few clicks away, and if a site is hard to read or hard to use, many will leave. ____________________________________________ For More Information Here are sources for more information on the recent nevirapine controversy. Except for the last one, they are December 2004 statements or articles in chronological order. * December 14, 2004, "Elizabeth Glaser Pediatric AIDS Foundation on issue of prevention of mother-to-child transmission of HIV/AIDS and single-dose nevirapine," http://www.pedaids.org/press_release_nevirapine_december_14_2004.htm * December 15, "Project Inform statement regarding the use of single-dose nevirapine to prevent mother-to-child transmission of HIV," http://www.projectinform.org/news/04_12nvppr.html * December 15, Treatment Action Campaign, South Africa, "Single-dose nevirapine is safe and effective: But public health facilities must switch to more effective regimens wherever possible." http://www.tac.org.za/newsletter/2004/ns15_12_2004a.html * December 17, the U.S. National Institute of Allergy and Infectious Diseases, "Questions and answers: The HIVNET 012 study and the safety and effectiveness of nevirapine in preventing mother-to-infant transmission of HIV," http://www2.niaid.nih.gov/newsroom/Releases/HIVNET012QA.htm * December 21 The New York Times, "Furor in Africa Over Drug for Women with HIV," http://www.nytimes.com/2004/12/21/international/africa/21aids.html * December 22, Nature, "Activists and Researchers Rally Behind AIDS Drug for Mothers,"Nature.December 23, 2004; volume 432, page 935. * December 25, Science, "Allegations Raise Fears of Backlash Against AIDS Prevention Strategy,"Science. December 25, 2004; volume 306, pages 2168-2169. * You can find more background on nevirapine for prevention of mother to child transmission at http://womenchildrenhiv.org/ -- John S James AIDS Treatment News www.aidsnews.org > Serious Adverse Events Attributed to Nevirapine Regimens > for Postexposure Prophylaxis After HIV Exposures --- Worldwide, [quoted text clipped - 267 lines] > > http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4951a1.htm |
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