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Postexposure Prophylaxis for HIV

Public health measures for HIV prevention have focused on limiting exposure through condom use, needle-exchange programs, education, and safety protocols. Still, HIV transmission continues at epidemic levels and additional strategies are needed. Prophylaxis with antiretrovirals after occupational exposure to HIV is demonstrably efficacious in reducing transmission, but efficacy of prophylaxis after sexual exposure is completely unknown. Postexposure prophylaxis regimens are toxic and expensive and protect incompletely; moreover, they have not yet been shown to protect from exposure of mucosal tissue to HIV. Routine use of postsexual exposure prophylaxis may lead to decreased use of effective measures, such as condoms, and result in increased HIV transmission. Postexposure prophylaxis is an exciting advance in the management of percutaneous exposure in the workplace, but its efficacy in other settings awaits further study.

Occupational Exposure

The mainstays of risk reduction for health care workers have been universal precautions and safety devices on sharps that are designed to prevent percutaneous exposure. These measures have been partially effective, but percutaneous exposures continue to occur even when safety protocols are observed.

Table 1 lists cases of health care workers with documented or possible occupationally acquired HIV infection reported to the CDC between 1978 and 1996. The vast majority of documented occupational transmissions were a result of percutaneous exposure: 47 to blood, 1 to visibly bloody fluid, and 3 to concentrated virus in a laboratory.

Of the various body fluid compartments, serum carries the highest viral titer, correlating with risk of acquisition. The average risk for acquisition of HIV through percutaneous exposure to infected blood is approximately 0.3%. Analysis reveals that the risk is increased by:

1. Deep injury to the exposed health care worker

2. Visible blood on the injuring device

3. Exposure of the device to source patient's vein or artery

4. Source patient's death from AIDS within 60 days of the incident (impending death is a marker for a high viral titer)

These markers of increased risk suggest that likelihood of transmission is related to viral inoculum and that exposure to a large volume of blood and/or a source patient with a high viral titer are the greatest risks to health care workers.

Highest risk, as used in Table 2, is defined as the presence of all four factors named above. Increased risk is defined by the presence of factor one or four. No increased risk is defined as exposure to neither a large volume of blood nor blood with a high viral titer. In counseling an individual exposed worker, these factors are important determinants of risk and need for prophylaxis. Viral strain, transmission cofactors, and host immune factors may further alter the risk equation, but their role is unknown. Source patients not known to be HIV positive should be counseled and offered voluntary HIV testing; approved rapid diagnostic techniques should be considered. Generalized assumptions about a source patient's serostatus -- based on the patient's age, demographics, ethnicity, or any other factor -- are not valid. The source patient's serostatus is obviously an important determinant of whether postexposure prophylaxis can be discontinued or altered in the face of side effects.

Prophylaxis for percutaneous exposure, if indicated, should be initiated within one to two hours to be effective. Postexposure counseling, risk stratification, and prophylactic medications must be available around the clock. The interval after which prophylaxis is no longer beneficial is unknown, though studies in animals suggest a delay of more than 24 to 36 hours renders therapy ineffective. The CDC's position is that, particularly for the highest risk exposures, initiation of therapy even after an interval of one to two weeks may be beneficial, at which time it becomes "early treatment" of HIV infection.

A case - control study of health care workers found that postexposure prophylaxis with AZT alone was associated with a 79% decrease in risk of acquisition of HIV after percutaneous exposure to HIV-infected blood. The success of this postexposure strategy, as well as case reports of postexposure prophylaxis failure and the expanding understanding of viral dynamics, led the CDC to recommend more aggressive, multidrug antiviral prophylactic regimens, detailed in Table 2. Clearly, exposed workers in the highest-risk category should receive triple therapy. Exposed workers at lower risk could consider the less toxic, two-drug regimen. Each case should be evaluated individually and the risks and benefits of all alternatives should be reviewed with the exposed worker.

In case of occupational exposure, HIV antibody titers should be measured immediately and at six weeks, twelve weeks, and six months after exposure. To date, only AZT has been demonstrated efficacious for postexposure prophylaxis, so it should be included in any regimen. There are no guidelines regarding adjustment of postexposure prophylaxis based on the source patient's antiviral history except to favor the three-drug regimen. As for side effects, AZT can produce nausea, headache, and gastrointestinal symptoms; the use of certain antihistamines and other contraindicated drugs should be reviewed with patients on protease inhibitors; and indinavir can cause renal stones, so oral hydration should be emphasized. All patients on postexposure prophylaxis should be enrolled in an anonymous toxicity-monitoring register that has been jointly developed by drug manufacturers and the CDC (888-737-4448). Discontinuation of therapy for disagreeable side effects should be weighed against degree of risk; in high-risk cases, changing the regimen is preferable to discontinuation. Updated guidelines from the CDC are expected to be released this year.

Mucous membrane exposure carries an estimated transmission rate of 0.1%. HIV is infrequently recovered from saliva, which may contain intrinsic factors that inactivate HIV. Dentists, who use sharp objects in a small operative field on patients who may move suddenly, may be prone to mucocutaneous exposure. Over the past decade safety improvements have significantly reduced the number of percutaneous injuries sustained by dental workers. Occupational acquisition of HIV by a dental care worker has not been documented, though seven seroconversions possibly following workplace exposure have been reported to the CDC. The extremely low risk of occupationally related HIV transmission to dental professionals has been confirmed in various studies. If a dental worker sustains an exposure, risk should be stratified in the manner described previously; the source patient's serostatus and viral load should be assessed. The Web site www.hivdent.org is an excellent reference for dental workers.

HIV is rarely isolated from tears and there is no evidence for transmissibility of HIV to health care workers during ophthalmologic procedures. Sharing of contact lenses is discouraged, though no transmission by this route has been reported.

HIV is rarely isolated from urine, which is not thought to be infectious. Of 15 health care workers who have experienced parenteral, mucous-membrane, or open-wound exposure to the urine of HIV-infected persons and 61 others performing or assisting in procedures on HIV patients that involved direct exposure to urine, none developed HIV. The CDC does not recommend prophylaxis after exposure to infected urine.

HIV contact with intact skin carries a very low risk of transmission, estimated at less than 0.1%. Prophylaxis after skin exposure is recommended if additional risk factors, as noted in Table 2, are present.

Sexual Exposure

HIV is transmitted most frequently, by far, through penile/vaginal or penile/ anal sexual contact. It is not known whether postexposure prophylaxis is effective after sexual mucosal exposure. It's unclear if antivirals reach sufficiently high levels in these compartments to clear the virus before infection irretrievably occurs or the virus is sequestered. The effect of antiretrovirals on vertical transmission may offer insight. Data on vertical transmission suggest that transmission occurs via either the blood-borne route (intrauterine) or mucosal route (intrapartum). AZT decreases transmission perinatally, but the route affected is unclear. In some studies AZT has been shown to reduce viral shedding in the semen, although other studies have not borne this out. The effect of antiviral therapy on virus in cervical and vaginal lavage fluid is under investigation. The risk of male-to-female vaginal transmission is estimated at 0.3%. Studies suggest a per-contact infectivity rate for receptive anal intercourse ranging from 5 to 30 transmissions per 1000 exposures to 2 per 100 exposures. The higher incidence of transmission in receptive anal intercourse compared with vaginal intercourse may be related to trauma or the presence of CD4 receptors on colorectal epithelium. There have been reports, both human and simian, of transmission resulting from oropharyngeal exposure to infected ejaculate. Finally, cervical and vaginal fluid could theoretically infect the oropharynx.

For sexual as well as occupational risk, reducing exposure should continue to be the mainstay of public health efforts. Condoms are effective and their use should continue to be emphasized. Prophylaxis after sexual exposure as a primary method of preventing sexual transmission is an unproved strategy that could be harmful. Public misperceptions about the effectiveness of postexposure prophylaxis may encourage risk-taking and actually increase HIV transmission. Drug toxicity, drug resistance, and costs are also important considerations. The consequences of routine prophylaxis (i.e., repeated courses of prophylaxis in the same individual) after sexual exposure require careful consideration. However, prophylaxis may be appropriate after unforeseeable events such as sexual assault or condom breakage.

The same type of risk stratification and evaluation of transmission cofactors should theoretically be applicable here. The rate of sexual transmission of HIV is quite low compared with other sexually transmitted diseases. For example, in one study the risk of transmission of Neisseria gonorrhea in a single sexual exposure has been estimated at 20% to 25%. Clearly, HIV is capable of being transmitted in a single exposure, but some patients may not become infected after hundreds of exposures. Host and viral factors may affect mucosal transmission and acquisition of the virus. Factors that may increase the risk include:

• Advanced disease in the source partner (low CD4 count, high viral load, p24 antigenemia)
  
• Primary HIV infection in the source partner
  
• Active menstrual flow in a female source partner during sex
  
• A history of genital ulcers, sexually transmitted diseases, or disrupted mucosal barrier in either the source case or the partner
  
• Absence of male circumcision, which enhances risk of both acquisition and transmission
  
• Receptive anal intercourse
  
• Specific viral properties that alter tropism for mucosal cells
  
• Specific features of the exposed individual's immune system, which may enhance or deter infection
  

Risk assessment after sexual assault requires special consideration. The assault, often violent, may disrupt the mucosa and cause bleeding, which may enhance viral transmission. As with all exposures, the assailant's clinical status, and other factors outlined above, determine the victim's degree of risk of contracting HIV. Prison rape may present a high-risk exposure since the prevalence of AIDS is approximately 14 times as high in state and federal corrections systems than in the general U.S. population. If the assailant is apprehended, it is important to know if preconviction testing and disclosure to the victim is sanctioned, since the law varies from state to state. Risk stratification and prophylaxis are particularly difficult in the setting of sexual assault, but prophylaxis, if indicated, should be instituted as soon as possible.

Conclusion

AZT prophylaxis following percutaneous occupational exposure has dramatically decreased transmission in this setting and multiple drug regimens have become the standard of care to further increase efficacy. Prophylaxis after non-occupational exposures such as sexual intercourse or sharing needles could potentially decrease transmission, though no efficacy has yet been demonstrated. Routine prophylaxis after sexual exposure may be an ineffective strategy. Physicians, scientists, public health officials, and the community need to develop consensus guidelines. Postexposure prophylaxis issues that need further study include determination of maximally effective regimens, minimal side effects, duration and timing of therapy, identification of other transmission cofactors, and the impact of the patient's antiviral history.

— Johanna P. Daily, MD

Johanna P. Daily, MD, is Instructor in Medicine, Harvard Medical School; Director of Women's HIV Clinic and Associate Physician at Brigham and Women's Hospital; and InfectiousDisease Consultant to Harvard Pilgrim Health Care.

Published in Journal Watch HIV/AIDS Clinical Care August 1, 1997

Citation(s):

Update: Provisional Public Health Service recommendations for chemoprophylaxis after occupational exposure to HIV. MMWR Morb Mortal Wkly Rep 1996 June 7 45 468-472.

• Medline abstract (Free)

Kats MH and Gerberding JL. Postexposure treatment of people exposed to the human immunodeficiency virus through sexual contact or injection drug use. N Engl J Med 1997 336 1097-1100.

• Original article (Subscription may be required)
• Medline abstract (Free)

Henderson D et al. Risk for occupational transmission of human immunodeficiency virus type 1 (HIV-1) associated with clinical exposures. A prospective evaluation. Ann Intern Med 1990 113 740-746.

Royce R et al. Sexual transmission of HIV. N Engl J Med 1997 336 1072-1078.

• Original article (Subscription may be required)
• Medline abstract (Free)

Gostin L et al. HIV testing, counseling and prophylaxis after sexual assault. JAMA 1994 271 1436-1444.

• Medline abstract (Free)