Research on postexposure prophylaxis for HIV.

Antiretroviral treatment of rape victims definitely or probably exposed to HIV during their assaults can be cost-effective in countries with high HIV prevalence. It also may be affordable in a middle-income country like South Africa, a recent modeling study conducted there shows. (1)

Such treatment, called postexposure prophylaxis (PEP), has been available through the South African public health system since 2002. "In one year between April 2002 and March 2003, nearly 53,000 rapes and attempted rapes were reported in South Africa, although the actual rate may be up to nine times greater," says Nicola Christofides, the study's principal author and a senior scientist with the Medical Research Council of South Africa. With 14 percent to 28 percent of rapists in South Africa estimated to be HIV-infected, their victims face considerable infection risks. Providing all rape victims with PEP may be substantially less costly than later treating only those who become infected. In South Africa, the difference could be as great as U.S. $2,000 per person.

In the modeling exercise, researchers made several assumptions. First, they assumed that the use of PEP after rape would be at least 80 percent effective. This reflects results from a retrospective case-control study indicating that the odds of HIV infection were reduced by about 81 percent among health care workers who took PEP after exposure to HIV via needlestick injuries. (2) A substantial body of other research also supports the effectiveness of PEP after occupational exposures to HIV in health care settings. PEP has become the standard of care in such settings, and the United States has national guidelines for occupational PEP. Nevertheless, the efficacy of occupational PEP has not been proven, and failure of PEP to prevent HIV infection has been reported. (3)

Limited data exist about PEP's effectiveness when given after sexual exposure to HIV. A small Brazilian study among homosexual men exposed to HIV found that PEP reduced seroconversion by 83 percent. (4) Otherwise, efficacy has been largely assumed on the basis of animal and human data including occupational, perinatal, and nonoccupational exposures to HIV. Several European nations, Australia, and some U.S. states--New York, Rhode Island, Massachusetts, and California--have issued guidelines for the use of PEP after sexual or other forms of nonoccupational exposure to HIV. (5) The U.S. Centers for Disease Control and Prevention (CDC) had not recommended for or against the use of PEP after nonoccupational exposure to HIV because it lacked information on PEP's effectiveness at curbing infection. (6) But in January 2005, after considering recent animal and lab studies, the CDC began recommending a 28-day course of antiretroviral therapy for persons seeking care within 72 hours after nonoccupational exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be HIV-infected, when that exposure represents a substantial risk of infection. (7)

Nevertheless, the question of how to determine whether the risks of HIV infection justify use of PEP remains. Most exposures to HIV will not result in infection. In the case of sexual assault, considerations include the infectiousness of the rapist (e.g., viral loads are higher in recently seroconverted individuals) and the risk of infection based on the victim's age. For biological reasons, younger women are more susceptible. (Notably, the South African researchers estimated that women under age 18 years had twice the risk of infection than did adult women.) Also to be considered is the degree of vaginal trauma and abrasions caused by rape. Risk of HIV infection after unforced vaginal intercourse with an infected man has been estimated to be 0.1 percent to 0.2 percent per act, (8) but traumatic, forced sex could quadruple that risk, the South African researchers estimated. This heightened risk approximates that associated with occupational needlestick exposure, which may be as high as 0.36 percent. (9)

Even when HIV risk is clearly high and thus use of PEP seems most appropriate, type of treatment and compliance to treatment regimens need to be considered.

PEP involves taking a brief course (usually 28 days) of antiretroviral medications as soon as possible after exposure, preferably beginning within 36 hours. Usually, a regimen of two nucleoside reverse transcriptase inhibitors--ideally, zidovudine and lamivudine (otherwise, lamivudine and stavudine, or stavudine and didanosine)--is recommended. This approach is especially advised if the source is of unknown HIV status but presumed to be at low risk of infection. A regimen that includes a third drug--usually a protease inhibitor such as indinavir or nelfinavir--may be warranted for exposures that pose an especially high risk of HIV transmission (for example, when the source is definitely HIV-positive or at very high risk of infection). (10)

The potential benefits of PEP must be carefully weighed against its potential dangers. All approved antiretroviral drugs have substantial drug interactions and adverse side effects that are occasionally serious; thus, PEP is not justified for exposures posing a negligible risk for HIV infection. (11) (Regardless of HIV risk, nevirapine is not recommended for PEP for safety reasons. (12)) The health risks associated with PEP are of particular concern when treatment is considered for adolescents or children, and great care must be taken in its administration. (13)

Among the factors that the South African researchers considered in their PEP cost-effectiveness model was that of treatment compliance, which can be poor. Analysis of a registry of some 450 U.S. health care workers who received PEP (often consisting of at least three antiretroviral drugs) after exposure to HIV found that nearly half of the workers discontinued all drugs and another 13 percent modified their drug regimen, commonly in response to adverse side effects. (14) Even with support and counseling of patients, discontinuation of PEP can be high. (15)

In the South African cost-effectiveness study, a two-drug regimen of zidovudine and lamivudine was modeled. Whether to use a two- or three-drug regimen is debated. (16) Because a two-drug regimen is likely to be less costly, less toxic, have fewer side effects, and be better tolerated than a three-drug regimen, it may be less frequently discontinued and may actually result in lower HIV transmission rates. (17) In a study of PEP that primarily involved two reverse transcriptase inhibitors, 78 percent of some 400 individuals treated for four weeks completed treatment. (18)

A multidisciplinary team approach to PEP provision for rape victims may increase adherence even to the three-drug regimen, a small study in London suggests. (19) Although evidence-based guidelines are needed, essential services suggested for rape victims receiving PEP include HIV testing for at least six months after exposure; counseling about the importance of completing the drug regimen, possible drug interactions and side effects, and how to minimize side effects and recognize serious side effects; and medical evaluation for toxicity at baseline and again two weeks after starting PEP.

In middle- and low-income countries, particularly those with generalized HIV epidemics, research is urgently needed on how PEP can be included in patient care. (20) But, in South Africa, the researchers who found PEP for rape victims to be cost-effective have conducted additional research to explore how women themselves want PEP to be delivered. (21) Interviews with 292 women, 159 of whom had accessed sexual assault services, revealed that they preferred PEP to be offered with other related sexual assault services. Such services included provision of HIV testing before PEP begins, increased availability of counseling, easily remembered information about side effects, and medications to alleviate the common side effect of nausea. Finally, the interviewed women preferred delivery of all PEP drugs at an initial visit. Although not current practice, this approach appears to increase compliance, which was only 44 percent, says study coauthor Christofides.

References

(1) Christofides N. Postexposure prophylaxis after rape. XV International AIDS Conference, Bangkok, Thailand, July 11-16, 2004.

(2) Cardo DM, Culver DH, Ciesielski CA, et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Surveillance Group. N Engl J Med 1997;337(21): 1485-90.

(3) U.S. Centers for Disease Control and Prevention (CDC). Updated U.S. Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR 2001;50(RR-11):1-42; Fournier S, Maillard A, Molina J-M. Failure of postexposure prophylaxis after sexual exposure to HIV. AIDS 2001;15(3):430.

(4) Schechter M, Lago RF, Ismerio R, et al. Acceptability, behavioral impact, and possible efficacy of post-sexual exposure chemoprophylaxis (PEP) for HIV. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, February 24-28, 2002.

(5) New York State Department of Health AIDS Institute. HIV Prophylaxis Following Non-occupational Exposure Including Sexual Assault. New York State Department of Health AIDS Institute, 2004. Available: http://www.hivguidelines.org; Mayer KH, Merchant RC, Browning CA. Nonoccupational Human Immunodeficiency Virus Postexposure Prophylaxis Guidelines for Rhode Island Healthcare Practitioners. Brown University AIDS Program and the Rhode Island Department of Health, 2004. Available: http://www.health.ri.gov/disease/ NPEPFinalDraftJuly26.pdf; Massachusetts Department of Public Health. HIV Prophylaxis Following Non-Occupational Exposures Recommended Protocol Components. Massachusetts Department of Public Health, 2002. Available: http://www.mass.gov/dph/aids/guidelines/exposure_ nonwork.htm; Myles JE, Bamberger J. Offering HIV Prophylaxis Following Sexual Assault: Recommendations for the State of California. San Francisco Department of Public Health, California HIV PEP after Sexual Assault Task Force, California State Office of AIDS, 2001. Available: http://www. dhs.ca.gov/ps/ooa/Reports/PDF/HIVProphylaxisFoll owingSexualAssault.pdf; Stephenson J. PEP talk: treating nonoccupational HIV exposure. JAMA 2003;289(3):287-88.

(6) U.S. Centers for Disease Control and Prevention (CDC). Management of possible sexual, injecting-drug-use, or other nonoccupational exposure to HIV, including considerations related to antiretroviral therapy. MMWR 1998;47(RR-17):1-14.

(7) U.S. Centers for Disease Control and Prevention (CDC). Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States. MMWR 2005;54(RR-02):1-20; Health officials hail government's decision to extend emergency AIDS treatment to rape victims, drug users. Associated Press, January 21, 2005.

(8) Mastro TD, de Vincenzi I. Probabilities of sexual HIV-1 transmission. AIDS 1996;10(Suppl A):75-82.

(9) Tokars JI, Marcus R, Culver DH, et al. Surveillance of HIV infection and zidovudine use among health care workers after occupational exposure to HIV-infected blood. Ann Intern Med 1993;118(12):913-19.

(10) CDC, 2001; Olshen E, Samples CL. Postexposure prophylaxis: an intervention to prevent human immunodeficiency virus infection in adolescents. Curr Opin Pediatr 2003;15(4):379-84; Sarrazin U, Brodt R, Sarrazin C, et al. Postexposure prophylaxis after occupational exposure to HBV, MCV and HIV. Radiologe 2004;44(2):181-94; Alvarado-Ramy F, Beltrami E. New guidelines for occupational exposure to blood-borne viruses. Cleveland Clin J Med 2003;70(5):457-65. Available: http://www.ccjm. org/pdffiles/Alvarado-Ramy503.pdf.

(11) CDC, 2001.

(12) Patel SM, Johnson S, Belknap SM, et al. Serious adverse cutaneous and hepatic toxicities associated with nevirapine use by non-HIV-infected individuals. J Acquir Immune Defic Syndr 2004;35(2):120-25.

(13) Havens PL, American Academy of Pediatrics Committee on Pediatric AIDS. Postexposure prophylaxis in children and adolescents for nonoccupational exposure to human immunodeficiency virus. Pediatrics 2003;111(6 Pt 1):1475-87.

(14) 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(12):780-85.

(15) Rabaud C, Bevilacqua S, Beguinot I, et al. Tolerability of postexposure prophylaxis with zidovudine, lamivudine, and nelfinavir for human immunodeficiency virus infection. Clin Infect Dis 2001;32(10):1494-95.

(16) Kim JC, Martin LJ, Denny L. Rape and HIV postexposure prophylaxis: addressing the dual epidemics in South Africa. Reprod Health Matters 2003;11(22):101-12.

(17) Bassett IV, Freedberg KA, Walensky RP. Two drugs or three? Balancing efficacy, toxicity, and resistance in postexposure prophylaxis for occupational exposure to HIV. Clin Infect Dis 2004;39(3):395-401; Katz MH, 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(15):1097-100.

(18) Kahn JO, Martin JN, Roland ME, et al. Feasibility of postexposure prophylaxis (PEP) against human immunodeficiency virus infection after sexual or injection drug exposure: the San Francisco PEP Study. J Infect Dis 2001;183(5):707-14.

(19) Limb S, Kawsar M, Forster GE. HIV post-exposure prophylaxis after sexual assault: the experience of a sexual assault service in London. Int J STD AIDS 2002;13(9):602-5.

(20) Krug EG, Dahlberg LL, Mercy JA, et al., eds. World Report on Violence and Health. Geneva, Switzerland: World Health Organization, 2002.

(21) Muirhead D, Christofides N, Jewkes R, et al. Including the provision of post exposure prophylaxis for the prevention of HIV after rape into sexual assault services in South Africa: how do women want services delivered? XV International AIDS Conference, Bangkok, Thailand, July 11-16, 2004.