CONCEPTS HIV; zidovudine

Prophylaxis With Zidovudine (AZT) After Exposure to Human Immunodeficiency Virus: A Brief Discussion of the Issues for Emergency Physicians [Callaham ML: Prophylaxis with zidovudine (AZT) after exposure to human immunodeficiency virus: A brief discussion of the issues for emergency physicians. Ann Emerg Med December 1991;20:1351-1354.]

INTRODUCTION The AIDS epidemic has had a devastating effect on medical facilities in many cities, and urban emergency departments have been particularly hard hit. Because the HIV status of patients in the ED is usually unknown and could never be determined quickly enough to be of use to ED personnel, the risk of being infected with HIV is of particular concern to emergency medicine personnel. Studies have shown that as many as 18% of penetrating trauma patients in inner-city EDs may be HIV positive, although the incidence is much lower for patients presenting with other problems and in other socioeconomic environments.i, 2 The use of universal precautions has been widely recommended by the Centers for Disease Control and strongly endorsed by the American College of Emergency Physicians and the Society for Academic Emergency Medicine.3, 4 Although these precautions are effective, many health care workers do not observe them, and it will probably never be possible to observe precautions 100% of the time. Thus, potential exposure to HIV cannot be entirely eliminated from the ED work environment. Recently, HIV was transmitted by a dentist to five patients; this is the only documented transmission from a health care worker to a patient in a decade of AIDS health care. Despite the uniqueness and rarity of this event, it has evoked hysterical public reaction and led to the proposal of legislation that suggests the real possibility of mandatory HIV testing for health personnel, with subsequent barring of HIV-positive physicians from performing a variety of "exposure-prone procedures." The Centers for Disease Control has issued new guidelines that call for HIV-positive physicians to stop performing exposure-prone procedures or to obtain informed consent, s Although there are no data that would allow for a rational decision as to what is exposure prone, the Centers for Disease Control has called on physicians to define such procedures in their specialties. The misleading logic of this approach is well discussed in previous articles6, z and in the editorial by Schulman in this issue. There has been no similar outcry to provide counseling, economic support, or retraining for physicians thus deprived of their livelihood.8, 9 Because of these job-related risks and their profound negative impact on health personnel, considerable interest has focused on possible prevention of infection after exposure has occurred. The only potentially useful agent at this time is zidovudine, or AZT, but the data concerning its possible effectiveness are extremely scanty, lO There is not enough information for a truly scientific recommendation, but despite this, many hospitals have instituted zidovudine prophylaxis protocols, u The following discussion is a general overview for clinicians and is not meant to provide all of the information and background necessary for establishing a zidovudine prophylaxis protocol. Establishing such a protocol requires reading the original publications, understanding the pharmacology of zidovudine, and instituting a collaborative approach with infectious dis-

20:12 December 1991

Annals of Emergency Medicine

Michael L Callaham, MD San Francisco, California From the University of California, San Francisco; and the American College of Emergency Physicians Task Force on AIDS, Dallas, Texas. Received for publication June 24, 1991. Accepted for publication July 22, 1991. No reprints available.

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ease experts. Specific recommendations for such a protocol appear in the article by Go et al in this issue. The importance of participating in an organized program with immediate counseling available cannot be overemphasized. The decisions involved are extremely complex, and health care workers who have suffered an exposure often need emotional support as well as medical advice.

BACKGROUND Zidovudine prevents HIV replication by blocking the transcription of viral RNA into DNA, which can then be integrated into the host's DNA to subsequently produce more virions. Z i d o v u d i n e w o r k s o n l y within cells; it has no effect on cellfree virus, on viral attachment to cells, on inactive virus, or on viral uptake into cells. Once DNA corresponding to the viral genome has been formed, zidovudine has no subsequent effect. Zidovudine is effective in cell cultures in decreasing replication of the virus, but the results are very dependent on timing, the assays used, and the laboratory performing the test. In patients who are already HIV positive, zidovudine is effective in decreasing replication of the virus and thereby attenuating the disease, but it does not kill the virus, eliminate infection, cure the patient, or prevent ultimate progression to death.

ANIMAL STUDIES Two s t u d i e s in cats and m i c e showed that zidovudine administered within hours of HIV challenge altered the natural history of retrovirus infection by decreasing viremia, eliminating clinical signs of retrovirus infection, and delaying or preventing an antibody response.IZ,13 These two studies did not test the actual HIV virus, however, and they did not determine whether zidovudine prevents establishment of chronic latent retroviral infection. This is of considerable importance because it is this l a t e n t chronic infection that causes AIDS. The initial acute retrovirus infection and antibody response are of only transitory and minimal clinical significance, and the diagnostic tests used to determine virologic response in clinical studies may be q u i t e i n s e n s i t i v e to the a c t u a l amount of virus present. A study in eight monkeys found 102/1352

that ddC (a drug with a similar mechanism of action) failed to prevent establishment of simian retrovirus infection (an agent of simian AIDS) even when given two days before challenge.14 A one-week course of zidovudine begun eight hours before challenge with simian immunodeficiency virus did not prevent viremia but delayed its onset until after zidovudine was stopped.10 A recent study used immune-deficient mice into which human fetal liver, thymus, marrow, and lymph nodes have been implanted, thereby creating an animal model of the hu-

man h e m a t o l y m p h o i d system. 15 Dosages of 250 mg/kg/day of intraperitoneal zidovudine were given at varying times after challenge with a large inoculum of HIV. Acute infection of lymph nodes was prevented in 100% of mice if prophylaxis was given within two hours. If given at four hours, 80% were protected; at 24 hours, 40%; at 36 hours, 20%; and at 48 hours, none. However, the zidovudine was given parenterally in a dose almost ten times larger than that used in human beings; the test used for detecting HIV infection had limited sensitivity; and long-term effects were not studied. The researchers could thus not be sure that they had detected all infected cells, which have been observed in p r e v i o u s studies to begin the spread of virus after zidovudine was stopped. The authors state that "the suppression of viral infection cannot be equated with complete protection against HIV infection."

EXPERIENCE IN HUMAN BEINGS Zidovudine has been well demonstrated to help delay and ameliorate the clinical course of AIDS, 16 but there are no studies of its effectiveness in prophylaxis against HIV infection. A clinical trial to answer this question was begun in 1989, but it was abandoned due to lack of enrollment. It seems unlikely that any such study will ever be completed. The only evidence in human beings consists of a handful of anecdotal case reports, none of them encouraging. A women who inoculated herself with 3 mL of HIV-infected blood and had zidovudine prophylaxis {1 g/day) initiated w i t h i n two hours later seroconverted. 17 A better-studied case involved a patient who inadAnnals of Emergency Medicine

vertently received 100 to 200 p~L of infected blood IV and was started on z i d o v u d i n e p r o p h y l a x i s (2 g/day) within 45 minutes but seroconverted within 45 clays. 18 Although one may argue that the initial dose of zidovudine was too low, that the inocula were very large, and that perhaps IV rather than oral zidovudine should have been administered, neither of these cases suggests that prophylaxis is very effective. The largest case series of health care workers treated with zidovudine consists of 21 patients treated with 1 g/day, chiefly after needlesticks. 19

None has seroconverted, but since the incidence of seroconversion after needlestiek is thought to be less than 0.5%, this small series cannot be cited as proving any therapeutic effect. A similar size series of health care workers has been followed at the University of California San Francisco, with only fatigue and nausea exhibited as complications. Hundreds of proven high-risk exposures would have to be studied, however, to draw conclusions about efficacy.

RISI~BENEFIT RATIO OF ZIDOVUDINE In the near future, it is unlikely that there will be enough evidence in human beings with which to draw firm conclusions. Thus, decisions about using prophylactic zidovudine must be based on risk:benefit assessments. Because there are very little data on this subject, much of the following is also conjecture. The benefit of zidovudine is unproven. Clearly, any person would like to avoid the risk of HIV infection, with its attendant social, economic, and emotional costs and its virtual certainty of mortality. In the light of recent public and professional h y s t e r i a about the risk of health care workers transmitting HIV to p a t i e n t s , 4,2° a n e w r i s k h a s emerged. The p h y s i c i a n who ser o c o n v e r t s can a n t i c i p a t e b e i n g p r o m p t l y deprived of a livelihood through a combination of adverse publicity, legal action by patients, and job termination, s,9 (This has already occurred to an emergency physician, and the decision was implemented not by physicians or infectious disease experts but rather by the hospital administrator and attorneys.) This current public fear of HIV20:12 December 1991

ZI DOVU DIN E Callaham

positive physicians creates a new theoretically potential benefit for prophylactic zidovudine. Despite the risk of delayed diagnosis and treatment, some individuals may choose to take any prophylactic regimen that would obscure or delay a positive antibody response (regardless of its effects on the actual virus or on clinical infection). Such a strategy raises additional ethical concerns. Although the effects of zidovudine on the individual m a y be beneficial, models show that the effects on society are negative because delayed antibody development may expose more sexual partners to infection. 21 In regard to risks, oral zidovudine has few serious side effects when used to treat patients early in the course of HIV infection. 16 (IV zidovudine has a much higher incidence of hematologic complications; the drug is not available for intramuscular administration.) Approximately 6% of asymptomatic HIV-positive patients treated with oral zidovudine develop anemia, n e u t r o p e n i a , and, sometimes, t h r o m b o c y t o p e n i a . T h e s e complications increase with larger doses and usually occur only after more than a month of therapy. Headache, fatigue, myalgias, and nausea are common but relatively minor and reversible. Renal andhepatic insufficiency are relative contraindications for zidovudine prophylaxis. However, the longterm health consequences of administering zidovudine to healthy persons are unknown. The worst known side effect is fatal bone marrow failure, which has occurred once in an estimated 15,000 patients who have taken the drug. Zidovudine is potentially carcinogenic (but not teratogenic) in animals, causing vaginal cancers in large doses. Its use for prophylaxis in pregnancy is not advised regardless of possible HIV exposure. Sacks and Rose performed a useful decision analysis of the risk:benefit ratio of prophylactic zidovudine that should be read by all emergency physicians. 2~ The optimal strategy is to take zidovudine when exposed to blood known to be seropositive if one believes the efficacy of zidovudine in preventing HIV infection to be anything greater than 2.6%. The strategy is greatly altered by one's assumptions about the incidence of HIV infection in the patient population; the lower this incidence, the greater the 20:12 December 1991

number of persons who must take zidovudine for any of them to benefit. For example, if 20% of the patient population is HIV positive (probably a worst-case scenario for penetrating trauma patients in an inner-city ED), zidovudine would have to be about 10% effective in preventing infection to justify the risk. However, if only 5% of the population is HIV positive (which is probably higher than the incidence in the majority of EDs~), zidovudine would have to be 50% effective to justify the risk. Costs must also be considered. A typical six-week course of zidovudine costs about $1,150 (including costs of HIV testing, h e m a t o l o g i c monitoring, and so on). If zidovudine is only 10% effective, it would cost $2.8 million to prevent one seroconversion; if it is 90% effective, it would cost only $110,630 to prevent one seroconversion. 2~ Although these figures may seem intimidating, they must be balanced against the lifetime cost of a case of AIDS, which is estimated to be about $70,000 in direct medical costs and about $600,000 in lost earnings (for nonphysicians). For emergency physicians, typical lost earnings could easily exceed $3.5 million per case, m a k i n g zidovudine prophylaxis a very cost-effective practice, even at low efficacy rates. None of this, of course, addresses either the personal or emotional losses caused by HIV infection or the losses to society and patients of an emergency health care worker at a time when such workers are already in short supply.

SUMMARY Sound scientific information with which to determine the true efficacy of zidovudine for prophylaxis will probably not be available soon. Physicians should educate themselves thoroughly on the issues. It is highly recommended that thoughtful discussions of the issue of transmission of HIV from health personnel to patients 6-9 as well as the key articles cited in this discussion be read. The details of a prophylaxis program, including laboratory evaluation, are provided in an article by Henderson and Gerberding 11 and in greater detail in the article by Go et al. (Health care workers exposed to I/IV can be enrolled in the Centers for Disease Control surveillance program by calling 404/639-1644. To enroll persons Annals of Emergency Medicine

with large exposures to HW in the zid o v u d i n e prophylaxis study, call 800/537-9978.) ED directors should work closely with local infectious disease specialists to determine if such a program is needed and how to implement it. Further details regarding the implementation of a prophylaxis program should be obtained from the literature and the Centers for Disease Control. All of the details of such a program should be worked out well in advance so that knowledgeable and i m m e d i a t e counseling can be provided to h e a l t h care workers within one or two hours of exposure. Highly qualified individuals and institutions vary in their recommendations on prophylaxis, a l t h o u g h most provide them.l l, a3 Zidovudine probably does not provide very effective protection, if it provides any. However, the medical, social, and economic consequences of HIV infection of health care workers are very real, and the serious irreversible adverse effects of zidovudine are very rare. My personal interpretation is that the potential benefits outweigh the risks and that pending better data, health personnel with injection exposure to blood likely to be HIV positive should receive immediate zidovudine therapy.

REFERENCES 1. Kelen GD, J:ritz S, Qaquish B, et al: Substantial increase in human immunodeficiency virus (HIV-1} infection in critically ill emergency patients: 1986 and 1987 compared. Ann Ernerg Med 1989;18:378-382. 2. Rhee K, Albertson T, Kizer K, et aI: The H I V I seroprevalence rate of injured patients admitted through California emergency departments. Ann Emerg Med 1991;20:969-972. 3. ACEP: AIDS - Statement of principles and interim recommendations for emergency department personnel and prehospital care providers. Ann Emerg Med 1988; 17:1249-1251. 4. Knopp R, Adams J, Derse A, et al: The HIV-infected emergency health care professional. Ann Emerg Med 1991;20:1036-I040. 5. Recommendations for preventing transmission of human immunodeficiency virus and hepatitis B virus to patients during exposure-prone inv~sive procedures. MMWR 1991~40:1-9. 6. Jonsen A: Is individual responsibility a sufficient basis for public confidence? Arch Intern Med 1991; 151:660-662. 7. Landesman S: The HIV-positive health professional: Policy options for individuals, institutions, and states. Arch Intern Med 1991~151:655-657. 8. Gostin L: The HIV-infected health care professional: Public policy, discrimination, and patient safety. Arch Intern Med 1991;151:663-665. 9. Price D: What should we do about HIV-positive h e a l t h professionals? Arch Intern Med 1991;151: 658~659. 10. Public health service statement on management of occupational exposure to human immunodeficiency vi-

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ms, including considerations regarding zidovudine postexposure use. M M W R 1990;39:1-14. ll. Henderson D, Gerberding J: Prophylactic zidovudine after occupational exposure to the human immunodeficiency virus: An interim analysis. J Infect Dis 1989; 160:321-327.

15. Shih CC, Kaneshima H, Rabin L, et aI: Postexposure prophylaxis with zidovudine suppresses human immunodeficiency virus type 1 infection in SCID-hu mice in a time-dependent manner. J Infect Dis 1991; 163:625-627.

19. Puro V, Ippolito G: Zidovudine in post-exposure prophylaxis of health-care workers (letter}. Lancet 1990;1:1166-1167. 20. Barondess J, New York Academy of Medicine Working Group: The risk of contracting HIV infection in the course of health care. lAMA 1991;285:1872-1873.

12. T a v a r e s L, R o n e k e r C, J o h n s t o n K~ et ah 3'-Azido-g'-deoxythymidine in feline leukemia virus-infected cats: A model for therapy and prophylaxis of AIDS. Cancer Res 1987;47:3190-3194.

16. Volberding P, Lagakos S, Koch M: Zidovudine in asymptomatic human immunodeficiency virus infection: A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl ] Med 1990;3221:941-949.

13. Ruprecht R, O'Brien L, Rossoni L, et ah Suppression of mouse viraemia and retroviral disease by 3'-azido-3'deoxythymidine. Nature 1986;323:467-469.

17. Durand E, Le Jeunne C, Hugues F: Failure of prophylactic zidovudine after suicidal inoculation of HIVinfected blood. N Engl J Med 1991;324:1062.

14. Tsai C, Follis K, Yarnal M, et al: Toxicity and efficacy of 2',3'-dideoxycytidine in clinical trials of pigtailed macaques infected with simian retrovirus type 2. Antimicrob Agents Chemother 1989;33:1908-1914.

22. Sacks HS, Rose DN: Zidovudine prophylaxis for needlestick exposure to human immunodeficiency virus: A decision analysis. ] Gen Intern Med 1990;5: i32-137.

18. Lange JM, Boucher CA, Hollak CE, et al: Failure of zidovudine prophylaxis after accidental exposure to HIV-1. N Engl l Med 1990;322:1375-1377.

23. Henry K, Thurn J: HIV infection in healthcare workers: How great is the risk? What can be done before and after exposure? Postgrad Med 1991;89:30-38.

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21. Anderson RM, Gupta S, May RM: Potential of community-wide chemotherapy or immunotherapy to control the spread of HIV-1. Nature I991;350:356-359.

20:12 December 1991

Prophylaxis with zidovudine (AZT) after exposure to human immunodeficiency virus: a brief discussion of the issues for emergency physicians.

Sound scientific information with which to determine the true efficacy of zidovudine for prophylaxis will probably not be available soon. Physicians s...
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