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BMJ No 7108 Volume 315 Editorial Saturday 6 September 1997
Prophylaxis after occupational exposure to HIVRecent guidelines should promote good practice and data collectionHealth care workers have a low but measurable risk of HIV infection after accidental exposure to infected blood or body fluids. Based on over 3,000 incidents, the average risk of HIV infection after a single percutaneous exposure is 0.3% (95% confidence interval 0.18% to 0.46%).(1,2) Contamination of mucous membranes and non-intact skin carries an even lower risk, while conjunctival contamination with blood carries a slightly higher risk.(2) As a result HIV attributable to occupational exposure is uncommon: only 92 cases have been reported worldwide (J Heptonstall and G Ippolito, personal communication). Although compliance with infection control recommendations in handling sharps is the mainstay of prevention,(3,4) additional prevention strategies now include post-exposure prophylaxis with antiretroviral therapy. This has become widely used since the early 1990s, despite lack of clear evidence of benefit. Importantly, there has been no randomised controlled trial of the efficacy of such treatment, and nor are such trials likely to be practicable given the low risk of transmission. Indirect evidence for antiretroviral therapy after occupational exposure to HIV comes from four main sources: biological plausability of benefit; a retrospective case-control study(5); its efficacy in some animal models(6); and zidovudine's effectiveness in reducing the risk of vertical transmission.(7) The biological rationale is that initial virus uptake and antigen processing after inoculation may take several hours or even days. This presents a window for therapeutic intervention before virus propagation occurs. In theory, even if infection is not prevented, antiretroviral therapy may modify the clinical course through attenuating the initial viraemia during acute seroconversion.(8) In a case-control study of 31 health care workers infected after percutaneous exposure zidovudine (1 g/day for 3-4 weeks) given soon after exposure reduced the odds of seroconversion by 79% (adjusted odds ratio 0.21 ( 0.06 to 0.57).(5) Animal studies have yielded inconclusive results (showing protection in some species but not in others(6)), and their results are difficult to extrapolate to humans. Although most of the evidence for prophylaxis is based on zidovudine monotherapy, this approach has been rendered obsolete by the superior efficacy of combination therapy in established infection and the potent antiviral efficacy of the new protease inhibitors.(9) There are increasing reports of resistance to zidovudine and at least 11 cases where postexposure zidovudine failed to prevent HIV infection.(10) Recommendations for the use of postexposure prophylaxis were issued by the US Public Health Service,(11) the International AIDS Society,(12) and the Italian Ministry of Health(13) in 1996 and the UK Department of Health last month.(14) These guidelines differ substantially from the position held in 1990 - that the data were insufficient to support or reject prophylaxis(15) - to now recommending treatment for four weeks with zidovudine in combination with lamivudine for most parenteral exposures. But while the International AIDS Society and the British guidelines suggest adding a protease inhibitor for all significant exposures, the American guidelines advocate it only for particularly high risk exposures or when drug resistance is suspected. The choice of lamivudine and the protease inhibitor indinavir as the companion drugs to zidovudine is to some extent arbitrary, and newer drugs such as the non-nucleoside reverse transcriptase inhibitors may soon provide more choices. Lamivudine proved safe in early treatment trials and combined with zidovudine acts against zidovudine resistant virus; indinavir is similarly active and appears to be the most active protease inhibitor available.(9) Nevertheless, studies have not been performed with these drugs combined to see whether they provide incremental prophylactic benefit. Nor are there definitive data on which to base optimal dosages or route of administration. Little is also known about the long term safety of these combinations in uninfected individuals, although lifethreatening side effects have not been reported. Serious short term toxicity is rare with high dose zidovudine alone after occupational exposure, though one third of patients discontinued prophylaxis because of intolerance.(16) Deciding when to recommend prophylaxis after occupational exposure remains problematic. Given the limited toxicity data and low risk of infection, it should be targeted at the subset of exposed workers at high risk of infection. Factors that increase the risk of seroconversion include exposures to a large inoculum of infected blood (indicated by a deep injury, visible blood on the device, and procedures entailing needles placed directly in arteries or veins) and a source patient with terminal HIV infection.(5) Therefore, initial risk assessment should include details of the exposure as well as information about the CD4 count, viral load, and antiretroviral history of the source patient. Risk assessment is inexact, however, especially in exposures outside hospital and involving patients with unknown HIV status. In general, an assessment of the source patient's likelihood of infection can avoid unnecessary testing, especially when the probability of infection is low. In Britain the General Medical Council is preparing guidance on ethical procedures for HIV, hepatitis B, and C testing in the source patient.(17) If the source patient is unavailable or refuses to be tested, then follow up care should generally be based on the best estimate of risk. Implementing these guidelines presents other challenges. Occupational exposures are notoriously under-reported. Institutions therefore need to publicise the importance of reporting all exposures and provide a user friendly and confidential mechanism for doing so. Since most studies show a time limited response with prophylaxis, if a decision is made to use it, it should be started promptly. Hospitals should ensure they can provide timely prophylaxis, with three or five day starter treatment packs available in accident and emergency departments. Exposed health workers need to be fully informed of the risks, the rationale for treatment, and the lack of data, so that when possible the decision about prophylaxis rests in their hands. Referral to centres experienced in the use of antiretroviral drugs is advisable, especially when the exposed worker is pregnant or breast feeding, has concurrent medical conditions or drug therapy, or has developed adverse events or when drug resistance is suspected. Finally, since many health workers prematurely discontinue prophylaxis,(18) optimal compliance requires counselling about the importance of drug dosing in relation to meals, the dietary restrictions with indinavir, and contraindicated medications. Exposed staff should be followed for at least six months. The lack of clinical follow up data on the effectiveness, tolerability, and safety of different forms of prophylaxis requires a systematic approach to data collection. In America the Centers for Disease Control have recently established a national registry for cases of occupational exposure. A similar UK or European network would be useful. These recommendations will require updating as new drugs are licensed and further data emerge on the prevalence of drug resistant strains and on the efficacy and toxicity of prophylaxis from three studies in the US and Italy. The use of prophylaxis for high risk sexual exposures is another area of concern, and such cases should be managed on a case by case basis.(18) Recommendations from the Centers for Disease Control should soon be available. Philippa Easterbrook
Imperial College School of Medicine, Giuseppe Ippolito
Centro di Riferimento AIDS, References 1 Tokars J I, Marcus R, Culver D H, Schahle C A, McKibben P S, Bonden C I, et al. Surveillance of HIV infection and zidovudine use among health care workers after occupational exposure to HIV-infected blood: the CDC Cooperative Needlestick Surveillance Group. Ann Intern Med 1993;118:913-9. 2 Ippolito G, Puro V, De Carli G, and the Italian Study Group on Occupational Risk of HIV infection. The risk of occupational human immunodeficiency virus infection in health care workers. Arch Intern Med 1993;153:1451-8. 3 Centers for Disease Control. Update: universal precautions for prevention of human immunodeficiency virus, hepatitis B virus, and other blood borne pathogens in health care settings. MMWR 1988;37:377-82, 387-8. 4 Ippolito G, De Carli G, Puro V, Petrosillo N, Aria O, Bertucci R, et al. Device-specific risk of needlestick injury in Italian health care workers. JAMA 1994;272:607-10. 5 Case-control study of HIV seroconversion in health-care workers after percutaneous exposures to HIV-infected blood: France, United Kingdom, and United States, January 1988-August 1994. MMWR 1995;44:929-33. 6 Black R J. Animal studies of prophylaxis. Am J Med 1997;102:39-44. 7 Connor E M, Sperling R S, Gerber R, Kiseler P, Scott G, O'Sullivan M J, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994;331:1173-80. 8 Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995;333:4450-1. 9 Hirsch M S, D'Aquila R T. Therapy for human immunodeficiency virus infection. N Engl J Med 1993;328:1686-95. 10 Jochimsen E M. Failures of zidovudine postexposure prophylaxis in human immunodeficiency virus post-exposure management of health care workers. Am J Med 1997;1-2:52-5. 11 Update: provisional Public Health Service recommendations for chemoprophylaxis after occupational exposure to HIV. MMWR 1996;45:468-80. 12 Antiretroviral therapy for HIV infection in 1996. Recommendations of an International Panel. JAMA 1996;276:146-54. 13 Commissione Nazionale per al lotta contro l'AIDS. Aggiornamenta della lineguida paer la chemioprofilassi con antiretroviral depo esposizione occupazionale ad HIV negli aperatori sanitori. Rome: Ministaro della Sanita, 1996. 14 Expert Advisory Group on AIDS. Post-exposure prophylaxis for health care workers exposed occupationally to HIV. London: Department of Health, 1997. 15 Public Health Service statement on management of occupational exposure to human immunodeficiency virus, including considerations regarding zidovudine postexposure use. MMWR 1990;39:1-14. 16 Ippolito C, Puro V. Zidovudine toxicity in uninfected health careworkers. Human immunodeficiency virus post-exposure management of health care workers. AM J Med 1997;102:58-62. 17 General Medical Council. Serious communicable diseases. Guidance for doctors on the ethical issues raised by HIV and other serious communicable conditions. London: General Medical Council, 1997 (draft). 18 Katz M H, Geberding J L. Postexposure treatment of people exposed to the human immunodeficiency virus through sexual contact or injection drug use. N Engl J Med 1997;366:1097-1100.
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