Why PEP Now?
There is no cure for AIDS. And there is no proof that post-exposure prophylaxis (PEP) can actually work as a so-called "morning after" pill in humans exposed to HIV through sex or injection drug use (IDU). Avoiding internal exposure to HIV-infected blood, semen and vaginal fluids still remains the most effective way to remain HIV-negative. However, for HIV-uninfected persons who are exposed to HIV, there may be a window of opportunity in the first few hours or days after exposure in which antiretroviral combination therapy may be able to prevent established infection. The idea of providing potent anti-HIV drugs to prevent infection makes sense biologically, but some people believe the results from post-exposure studies to date (primarily using AZT in occupational exposures among healthcare workers) are far from definitive, and there have been no studies yet on the efficacy of PEP for sexual or injection exposure. The potency of the new anti-HIV drugs, however, is a compelling, if unproven, reason to offer PEP treatment after exposure to this life-threatening infection.
What is Known About PEP?
There is currently information from three different settings that suggests that PEP might be an effective strategy in reducing -- but not entirely preventing -- new HIV infections.
Most of the information regarding PEP comes from healthcare workers. Several years ago, a comprehensive strategy was developed to identify and reduce occupational risk behaviors among healthcare workers. Those who had been exposed to HIV through occupational hazards such as needle-stick injuries (occupational exposure) were offered AZT. Recent analysis of data comparing the rate of infection in those who took AZT with the rate of infection in those who did not receive treatment suggests that AZT is very effective in preventing HIV infection in this setting (79% reduction). The second set of information about PEP comes from studies of AZT in HIV-positive pregnant women and their newborns. Recent analysis of viral load data from the largest study to date suggests that AZT's usefulness in preventing HIV infection in the newborns of HIV-infected mothers (67% reduction) is due in part to prevention of the establishment of HIV infection in the exposed infant. Reduction in the mother's viral load, and thus the fetus' exposure to HIV, also plays some role.
Finally, studies in macaque (Simian) monkeys who were exposed to SIV (the simian immunodeficiency virus) intravenously and were then treated with an experimental antiretroviral agent called PMPA have demonstrated a reduction in the rate of SIV infection. Other animal studies suggest that it is important to treat as soon as possible after exposure to prevent infection.
What is Not Known About PEP?
These data suggest -- but do not prove -- that taking antiretroviral medications after a sexual or injection drug use exposure may reduce the rate of new HIV infections. It is important to generate data that demonstrate whether PEP is an effective strategy because there are potential risks associated with providing anti-HIV drugs to people after these types of exposures. All anti-HIV drugs have toxicities associated with them. There is also likely to be some emotional distress associated with taking powerful anti-HIV medications for a period of time after a high-risk exposure. Thus, careful counseling would need to be included in PEP programs. The costs of the medications and the necessary counseling would be significant, underscoring the need for research prior to providing PEP as a service.
We do not know what effect the availability of potentially effective medications will have on people's choices and behaviors. One overriding concern is that even the act of developing a study would convey to people that it is thought PEP will work -- and, consequently, that people will believe that they can engage in high-risk behaviors safely if PEP is available. Such a belief could undermine years of prevention work that have been crucial to reducing the rate of new infections in the communities at risk. We hope, but do not know, that a combination of medications and prevention techniques could result in a significant reduction in new HIV infections.
It is also not known how PEP might affect HIV drug resistance patterns. There may also be unexpected adverse effects such as birth defects, increased risk of tumors, and negative impact on the quality of life. Concerns about confidentiality and partner notification may present significant obstacles. These issues must be addressed before a study is initiated.
What Are Components of PEP?
Since July 1997, when a panel of experts convened by the U.S. Centers for Disease Control and Prevention (CDC) to discuss HIV prophylaxis for non-occupational exposures urged that "caution be used in future decision making until more data are available," many physicians and clinics across the country currently have been offering PEP in widely varying forms. Most forms of PEP involve providing one or several anti-HIV drugs -- most commonly either Combivir® (AZT and 3TC in one pill) or Combivir® plus Crixivan® -- within 72 hours of possible exposure. These drugs are then taken for a four- to six-week period. The average cost of PEP for a four-week treatment -- including AZT, 3TC, a protease inhibitor, medical care and tests -- ranges from $1,300 to $1,800.
Before PEP is implemented, a thorough risk assessment is usually conducted to determine an individual's level and frequency of risk-taking, as well as the HIV status of the partner. Individuals should be informed of the potential side effects and difficulty taking the drugs and should be assisted in developing strategies to successfully take the drugs as prescribed.
One of the potential benefits of PEP is the opportunity to reach and counsel people at high risk for HIV. PEP programs should include a counseling component to help patients deal with the fear of becoming infected and develop skills for avoiding future exposure to HIV. Referrals to HIV prevention, substance abuse, medical, mental health and housing programs can also be included to help high-risk individuals to address important risk factors. The best PEP programs will also offer testing and treatment for other STDs and testing for pregnancy.
Does PEP Work?
No one knows for sure. Researchers from the Centers for Disease Control and Prevention (CDC) reported at the 12th World AIDS Conference that over 30 percent of healthcare workers who received post-exposure prophylaxis (PEP) to lower the risk of HIV infection did not complete the recommended drug regimen. About three-quarters of those who did not complete the regimen said that the side effects associated with the drugs -- including fatigue and nausea -- caused them to stop the treatment. Dr. Helene Gayle, director of the CDC's National Center for HIV, STD, and TB Prevention, noted that the study shows that anti-HIV efforts must focus more on prevention. "The most effective way to protect healthcare workers is to prevent exposure in the first place," Gayle said. The researchers involved in the study analyzed information collected by the National Surveillance System for Hospital Healthcare Workers from June 1995 to December 1997. Of 114 healthcare workers who were occupationally exposed to HIV, 58 decided to start PEP. Seventy-one percent of these workers reported side effects and 36 percent stopped treatment.
Latest Data on Post-Exposure Prophylaxis
The latest word on PEP following sex and/or injection drug use was heard at the 12th World AIDS Conference. Researchers from UCSF presented preliminary data from the Post-Exposure Prevention Project, a collaborative effort between UCSF, San Francisco General Hospital and the San Francisco Department of Public Health. From October 1997 to May 1998, 151 individuals reporting unprotected sexual activity or needle-sharing within the previous 72 hours participated in the project. Of the participants, 127 (84%) were male, 71% white, 16% Latino and 10% African-American.
Ninety percent of the participants reported sexual exposure as the event leading to enrollment, with receptive anal intercourse the risk activity in almost half. The source individual was known to be HIV-positive in 48% of cases, and to have HIV risk factors in 44%. All participants were offered PEP and only six declined. Of those receiving PEP, 84% were prescribed Combivir®, 11% ddI + d4T, 2% Combivir® + nelfinavir and 1% ddI + d4T + nelfinavir. Remarkably, 80% of the participants completed the four-week course of therapy and only two of those who discontinued treatment early did so because of adverse effects. This is a fraction of the number of healthcare workers who stop PEP with AZT alone following exposure.
The researchers concluded that their preference for dual therapy was based on the better tolerability of two agents and that such combinations are sufficiently potent for PEP -- hardly a universal opinion. Dr. James Kahn of UCSF believes the high tolerance of antiretrovirals is due to the close follow-up of participants in the project and the dispensation of medication at weekly intervals for the first two weeks.
What are the Potential Disadvantages of PEP?
Two of the biggest fears are, as mentioned earlier, possibly encouraging a return to unsafe sex practices and the development of drug-resistant HIV strains due to misuse of PEP drug therapies. If PEP drug therapy is unsuccessful and a person does develop a drug-resistant virus, the new anti-HIV drugs may not be as effective for treating that person. This can occur not only with PEP, but with any combination therapy.
PEP regimens can be both complicated and prohibitively expensive to follow. PEP drugs need to be taken at specific times of the day on a regular schedule. About one-third of the healthcare workers who received PEP never finished the regimen because of difficulty taking the drugs. Side effects of the drugs can be severe, and long-term effects are still unknown.
Prescribing PEP can be a tough decision. Many clinicians believe that a person with a single case of exposure to an HIV-infected partner would be a good candidate for PEP. Others worry that providing PEP repeatedly to a person with ongoing high-risk behavior may promote unsafe sex and could also be toxic.
What Programs Exist?
San Francisco General Hospital has recently implemented a project to determine the safety and feasibility of PEP rather than its effectiveness. The study offers intensive behavioral counseling, HIV testing and anti-HIV medication to persons who have been exposed within the last 72 hours. In Boston, the Fenway Community Clinic has been offering PEP to walk-in clients for the past 12 months. And in New York, Dr. Gabriel Torres of the Bentley-Salick Medical Practice is currently in the final planning stages of a large 24-hour PEP clinic which is expected to give patients and their primary care providers a menu of experimental PEP combination therapies from which to choose. Internationally, many countries are moving ahead with PEP.
Mike Barr has been a clinical research assistant at St. Vincent's Hospital since 1990. He is also editor of the monthly newsletter of the Treatment Action Group (TAG) in New York.
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