Post-exposure prophylaxis (PEP) is sometimes referred to as the "morning-after pill" for individuals with unanticipated sexual or injection drug related exposures to HIV. This is misleading, as PEP is not as simple as swallowing a single pill. It is, nonetheless, a compelling prevention intervention because it may stop an exposure to HIV from becoming an established infection.
The theory underlying the use of PEP is that antiviral treatment instituted immediately after exposure may abort the infection by inhibiting local HIV replication and by allowing the host's immune system to eradicate virus from the inoculum. Information about early HIV infection suggests that it can take several days for HIV to become established in the lymphoid and other tissues. This allows a window of opportunity during the immediate 24 to 72 hours post-exposure when antiviral treatment may possibly head-off HIV infection.
The Centers for Disease Control and Prevention (CDC) currently recommends the use of antiviral drugs to reduce the risk of HIV transmission from mother to child (vertical transmission)(1) and in healthcare workers who have been exposed to HIV in the workplace (occupational exposure).(2) The CDC recommendations are based upon the results of several studies. These include a retrospective case-control study of health care workers that demonstrated that PEP treatment with AZT reduced the risk of HIV acquisition by 81%.(3) In addition, a placebo-controlled trial of AZT administered to HIV-positive women during pregnancy and continuing in their newborns for six weeks postpartum reported a 67% reduction in vertical transmission in the treatment group.(4)
More recent data from the New York State Department of Health further support the role of AZT as post-exposure prophylactic treatment. A chart review of 939 HIV-exposed infants found that the rate of vertical transmission was significantly reduced when AZT was administered only to the infants, beginning within 48 hours postpartum. (This effect was not seen in infants who started AZT therapy more than 48 hours after birth.) When treatment was begun in the prenatal period, the rate of vertical transmission was 6.1% and when begun within the first 48 hours of life, the rate was 9.3%. In the absence of AZT treatment, the rate of vertical transmission was 26.6%.(5)
Questions have arisen about whether antiviral treatment should be offered to individuals who have been exposed to HIV through sex or sharing injection drug use equipment (nonoccupational exposure). The issue of PEP after nonoccupational exposure is important because these routes of HIV transmission are far more frequent than occupational transmission. However, there are no formal efficacy trials in the nonoccupational setting. Although the above-referenced studies suggest that antiviral agents are potentially valuable for treating HIV exposures in cases of occupational and vertical transmission, the data may not be directly relevant to nonoccupational exposures where the circumstances are typically more complicated.
With healthcare workers, the exact time of the exposure can usually be pinpointed. The HIV status of the source of the exposure is often known or can be readily determined and, most importantly, the PEP medications can usually be initiated within a few hours of the incident. With nonoccupational exposures, there may be multiple or on-going high-risk incidents. Potentially-exposed individuals may not present for treatment immediately and the HIV status of the source may not be known.
The CDC convened a scientific committee to review the issue of nonoccupational exposures and released a statement in September of 1998.(6) While stopping short of making definitive recommendations for or against the use of antiviral therapy, the Public Health Service Statement stresses that nonoccupational PEP should be considered a clinical intervention of unknown efficacy that poses risks including possible drug toxicity and reduced effectiveness of behavioral HIV prevention measures. However, the CDC acknowledges that there are certain situations where PEP may be beneficial when the risk for infection is high, the therapy can be initiated promptly and adherence to the regimen is likely. Yet even under "ideal" circumstances, PEP should only be regarded as a last effort to prevent HIV infection in patients for whom primary prevention methods have failed.
In order to gather more information, the CDC has established a National Nonoccupational HIV Post-exposure Prophylaxis Registry. The registry is a prospective surveillance program designed to collect data on utilization, safety and outcome about the use of antiviral agents in persons who are considered for or receive PEP for nonoccupational HIV exposures. No names or other personal identifiers of patients will be collected. Health care providers may call 877/448-1737 to register and report anonymous patient data.
While the CDC remains reluctant to offer definitive recommendations, a panel of AIDS prevention experts has developed some basic guidelines for the implementation of nonoccupational PEP. Peter Lurie, M.D., of Public Citizen's Health Research Group, and colleagues, published an article on this topic in November of 1998 in JAMA.(7) The authors of the article acknowledge the lack of efficacy data on PEP in nonoccupational settings and point out that definitive studies are unlikely because of both the large sample sizes required and the ethical obstacles to a placebo-controlled trial. However, Dr. Lurie and colleagues state: "By using the best available epidemiologic information, clinicians can estimate the risk of HIV transmission for any given exposure and compare it with the risk for which the CDC recommends occupational PEP. If the risk of HIV transmission through certain sexual practices or injection drug practices is of the same order of magnitude as those occupational exposures, PEP would seem to be indicated in these circumstances as well. The ethical principal of fairness requires that clinically similar patients be treated similarly, regardless of the route of HIV transmission."
The CDC recommends occupational PEP for needle stick injuries (percutaneous exposures) involving bodily fluid from an HIV-infected source. The average risk for HIV transmission after a percutaneous exposure to HIV-infected blood is approximately 0.3% (range 0.2%-0.5%).(8) The risk after nonoccupational exposure is less certain and figures vary from study to study. Basically, there is a hierarchy of risk after a single unprotected act with an HIV-positive partner (see Table I, below). The highest risk is through receptive anal intercourse (i.e., as the bottom). Following is the risk from injection needle exposure and receptive vaginal exposure. Insertive anal (i.e., as the top) and vaginal sex appear to be associated with moderate risk and while oral sex can transmit HIV, the risk appears to be too low to quantify with precision (although a recent study from the San Francisco Department of Public Health found the risk of transmission following receptive oral sex was 0.04%, which is similar to the risk from insertive sex).(9) Other factors associated with greater risk include a high viral load and more advanced disease stage in the source individual and the presence of a sexually transmitted disease (STD), mucosal trauma or blood in the exposed individual.
The authors of the JAMA article also differentiate between an isolated incident (sporadic) and on-going exposures (continuing). While repeated exposures are infrequent in the occupational setting, they are more common with sexual contact or drug injection. An individual who is exposed to HIV on frequent basis (e.g., weekly or monthly) would, in effect, require continuous prophylaxis. The authors do not recommend PEP be employed in this manner. Instead, such individuals should receive HIV testing and counseling and be referred to state-of-the-art risk-reduction programs that may more effectively deter future exposures.
In essence, receptive anal intercourse and sharing injection drug equipment with an HIV-infected partner probably carry a risk of HIV infection at least as great as, or greater than, the risk of those receiving a needle stick injury. Similar to the CDC occupational recommendations, Dr. Lurie and colleagues recommend PEP in cases of sporadic exposure where the risk of infection is about 0.3% or higher. If the risk of infection is in the range of 0.1%-0.3%, they believe PEP should be considered based on the individual circumstances and in lower risk situations, clinicians should inform patients about PEP but not recommend it.
|Table I: Estimated Likelihood of HIV Transmission Following Unprotected Sex or Contaminated Needle Exposure when the Source is HIV Infected(10)|
|Exposure||Likelihood of Transmission|
|Receptive anal intercourse||0.1%-0.3% (1/1,000-3/1,000)|
|Receptive vaginal intercourse||0.08%-0.2% (0.8/1,000-2/1,000)|
|Injection-needle sharing||0.67% (6.7/1,000)|
|Insertive anal sex||0.03% (3/10,000)|
|Insertive vaginal sex||0.03%-0.09% (3/10,000-9/10,000)|
Animal studies indicate the importance of initiating PEP as soon as possible after the exposure, ideally within 24 to 36 hours. Treatment started in primates after 72 hours had no effect.(11) As AZT is the only drug with human data to suggest that it has a prophylactic effect, it is a strong candidate for inclusion in any PEP regimen. The CDC guidelines for occupational PEP suggest a 28-day course of treatment using a combination of AZT and 3TC for most exposures for which PEP is indicated and adding the protease inhibitors indinavir or nelfinavir for the highest-risk exposures. All patients should be informed of possible drug toxicities and provided adherence counseling.
The average cost for four weeks of the two-drug regimen is about $500. This increases to over $1,000 for a protease inhibitor-containing regimen. In addition, the office visits and associated lab tests can cost another $500-$1,000. Although some studies have shown PEP to be cost effective in certain instances,(12) insurance companies may refuse to cover all of the costs.
Potential PEP patients should receive a baseline HIV test to establish pre-existing HIV infection. As sexual activities associated with a risk for HIV transmission are also associated with risk for pregnancy and STDs, all individuals should be screened, and if necessary, treated for STDs. Women should also be tested for unintended pregnancy and offered emergency contraception if appropriate.
Concerns have been raised that the availability of PEP may increase high-risk behaviors. If PEP is viewed as a "morning-after pill" that prevents infection, individuals may believe it is no longer necessary to practice safer sex or use clean needles. PEP is not a replacement strategy for avoiding HIV exposure. Even if PEP prevents some HIV transmission, a modest increase in the number of unprotected sexual acts could actually lead to an increase in HIV transmission.(13) For this reason, HIV prevention and risk-reduction counseling need to be integrated into the PEP treatment program. Antiviral medication should be provided in conjunction with individualized behavioral counseling and referrals for on-going psychosocial support and substance-use treatment in order to minimize the risk of future exposures.
Adherence counseling is also necessary to assist individuals who may have little or no previous treatment experience comply with an extended and possibly difficult medication regimen. Nonadherence to the prescribed treatment raises the theoretical risk that, should PEP fail, the patient could become infected with a drug-resistant strain of HIV. Since resistance usually develops when HIV is exposed to suboptimal levels of antiviral medication, maintaining strict adherence maximizes the efficacy of the PEP treatment and minimizes the likelihood of developing drug-resistance strains should infection occur.
In October of 1997, the University of California, San Francisco (UCSF) AIDS Program at San Francisco General Hospital (SFGH), the Center for AIDS Prevention Studies and the San Francisco Department of Public Health (SFDOPH) launched the first large-scale nonoccupational PEP feasibility study in the U.S. Funding was provided by the City of San Francisco and a National Institute of Health grant. The investigators designed a comprehensive protocol that provided intensive counseling (risk-reduction and adherence) and a 28-day course of antiviral medication at no cost to approximately 500 individuals who experienced a high-risk HIV exposure with a high-risk partner within the past 72 hours. A high-risk exposure was defined as unprotected (no condom or condom breakage) receptive or insertive anal or vaginal sex, receptive oral intercourse with ejaculation or sharing of drug use equipment. A high-risk partner was defined as known HIV-positive, unknown HIV serostatus with HIV risk factors (man who has sex with men, injection drug user or commercial sex worker) or an anonymous partner.
The standard drug regimen selected included AZT and 3TC administered in one co-formulated tablet (Combivir). The protease inhibitor nelfinavir was offered to study subjects only if the source patient reported a detectable viral load while on therapy, indicating nucleoside resistance. The investigators chose a two-drug combination because they believed it would be effective as a PEP treatment, less expensive and easier to adhere to than a protease inhibitor-containing regimen.
As of April 1, 1999, the trial completed enrollment with over 400 participants. Preliminary data on 328 study subjects were presented at the 6th Conference on Retroviruses and Opportunistic Infections held in Chicago early this year (Abstract 215). The majority of the participants were white (72%), male (89%) and between the ages of 20 and 40 (75%). The most common risk factor was receptive anal intercourse (38%), followed by insertive anal intercourse (24%). Receptive and insertive vaginal intercourse were less frequently reported (9% and 6% respectively). The least common risk behaviors triggering enrollment were oral sex and sharing needles (3% and 2% respectively). Combivir alone was used in 86% of participants and while about half the participants reported fatigue and nausea, only 6% discontinued treatment due to toxicity. Retention was extremely high -- more than 80% of the subjects completed the recommended four weeks of medication with higher than 95% adherence rates to medication. (This compares favorably to PEP in the occupational setting where a surveillance study reported that as many as 36% of health care workers prematurely discontinued antiviral therapy.)(15)
There have been no seroconversions within six months of exposure. As this was not an efficacy study, no conclusions on the effectiveness of the antiviral treatment can be drawn. However, the investigators have concluded that providing PEP within 72 hours of a nonoccupational exposure is feasible and that the PEP regimen used is safe.
Since the study phase of the program has completed, the SFDOPH has added PEP to the services provided through the city STD clinic, effectively incorporating PEP into the standard of care. New PEP patients are seen free of charge and continue to receive the same comprehensive counseling as was provided through the study. However, patients now receive a prescription instead of a supply of free medication. To date, about 120 PEP patients have been treated at the STD clinic and most have experienced no problems with insurance coverage for the medication. Patients without coverage may use the SFGH pharmacy, which has a sliding scale for payment. (The lowest cost for Combivir is about $330).
Now that PEP is being provided through the SFDOPH, the eligibility requirements have tightened (see Table II, below). Sex workers and anonymous partners are no longer considered high-risk partners and receptive oral sex is no longer considered a behavior that warrants post-exposure prophylactic treatment (although, as noted above, the department has now concluded that unprotected oral sex carries approximately the same risk as insertive anal intercourse without a condom -- which remains classified as high risk). For more information, individuals may call 415/487-5538 during the day and 415/514-4PEP in the evening.
Outside of San Francisco, there are few formal PEP programs in existence. Perhaps the only other government-sponsored project is at the Fenway Community Health Center in Boston. Funding from the Massachusetts Department of Health supports this small pilot program that provides comprehensive services and PEP medication free of charge to eligible participants. Since September of 1997, 59 patients have received PEP treatment. Interested individuals may call Jeffrey Kwong at 617/927-6450.
The lack of access to widely-available PEP programs leaves many individuals who have been exposed to HIV through sex or sharing needles roughly 72 hours to embark on an often frantic, hit or miss search for a physician willing and able to assess the exposure and, if appropriate, prescribe PEP. Some clinicians may be reluctant to provide treatment due to a lack of experience or a judgement that the patient has acted irresponsibly. Even in the event that a potentially-exposed individual receives treatment in time, appropriate counseling may not be available.
In areas with high HIV seroprevalence, well-designed and adequately-funded programs would address an unmet need. A survey conducted by Gabriel Torres, M.D., of the Bentley-Salick Medical Practice, P.C. (BSMP), set out to determine the demand for PEP in New York City and found that 15 of 23 local health care providers had received at least one request in the last year. A total of 65 individuals requested PEP and 40 were treated. The most common reason for refusing treatment was a low-risk exposure.
|Table II: San Francisco DOPH Recommendations for Treatment(14)|
|Offer||Unprotected receptive anal intercourse
Unprotected receptive vaginal intercourse
Blood to blood contact
Other needle stick
|Consider||Unprotected insertive anal intercourse
Unprotected insertive vaginal intercourse
|Don't Offer*||Unprotected receptive oral intercourse with ejaculation
Blood or semen splash on mucosal surface or open wound
Sharing cookers, cotton or other drug paraphernalia
|Insertive oral intercourse
Semen or blood on intact skin
Unprotected receptive oral intercourse without ejaculation
|The source patient must have a high level of suspicion for one or more of the following HIV risk factors: HIV positive, MSM or IDU.
*If other outstanding historical details are present such as gingivitis, mucosal trauma, obvious blood contamination, etc. clinician may offer medications following "low-risk" exposures.
In response to reluctance on the part of the New York City Department of Health to provide PEP for nonoccupational exposures, Dr. Torres is initiating a pilot PEP program in the Fall of 1999 for 120 participants at BSMP, a private physicians' practice and outpatient medical practice specializing in serious diseases, such as HIV/AIDS. In the absence of government support, Dr. Torres has received funding and medication through the pharmaceutical industry to establish a 24-hour hotline and provide participants with free PEP drugs and comprehensive counseling. Accompanying medical care and lab tests are provided on a fee-for-service basis.
Persons who report a high-risk exposure with a high-risk partner within 72 hours will receive an individualized antiviral regimen including two nucleoside analogs and an NNRTI. The advantage of drugs in the NNRTI class is that they do not require an intracellular activation step and can begin to work immediately. If the source partner has previously been treated, a three-drug combination is selected employing antiviral agents that are unlikely to manifest cross resistance. Nelfinavir will be utilized when an individual presents for treatment 48 to 72 hours after exposure, since the protease inhibitors are effective during the latter stages of viral replication. Experimental models for HIV infection propose that the virus does not reach this stage until approximately 2.1 days after exposure.
Dr. Torres is planning several novel strategies for the program. Instead of the traditional HIV ELISA antibody test, the rapid antibody test will be used for baseline HIV screening. The rapid test is performed in the office and potential PEP patients will receive the results in about 10 to 15 minutes. According to CDC fact sheets, the rapid test is as accurate as the traditional test.(16)
An ultrasensitive viral load assay will be performed after one week of PEP treatment in an attempt to detect early viremia. If there is an undetectable viral load and a negative rapid antibody test, participants may elect to discontinue PEP after two weeks. Factors such as adherence, degree of risk of initial exposure and circumstances of the source subject will be considered. The effective length of treatment to prevent HIV infection after exposure is unknown. A four-week course of treatment has been used for occupational exposures despite the absence of controlled data. Dr. Torres believes that two weeks of treatment may be sufficient to prevent infection. He states: "Our program will require two weeks of treatment. Patients will be informed that an additional two weeks are available but, as their significance is questionable, the last two weeks will be optional."
If viral load is detectable, the PEP regimen is modified with the assumption that the original combination has not been maximally suppressive of viral replication. Participants whose PCR assays continue to detect viremia are discontinued from the PEP program and begin receiving HIV primary care. All participants who seroconvert despite PEP treatment will also receive phenotypic testing and subsequent HAART regimens will be determined based upon the results of the resistance assay results.
Additionally, Dr. Torres will conduct an observational database study through the PEP Registry. The Registry will gather information prospectively on the participants in the PEP program and track trends in this high-risk patient population. Data collected will be used to assess risk factors associated with nonoccupational HIV exposures; patterns of PEP drug prescription; doses and duration of therapy; levels of patient adherence when therapy is prescribed; rates of toxicity to drug prescribed and feasibility of implementing such a program within a high-risk community without government funding. Interested individuals may call 212/358-2400 for more information, or go to the Bentley-Salick website at http://www.bentley-salick.com.
The most effective ways to prevent HIV infection remain abstinence, the proper and consistent use of condoms and the avoidance of high-risk behaviors. PEP is not intended to replace adopting and maintaining behaviors that guard against exposure to HIV. However, a person with a recent exposure has already failed primary prevention. In addition, many persons diligently practice safer sex but are accidentally exposed to HIV when a condom breaks, slips off or is omitted inadvertently under the influence of drugs or alcohol.
If properly implemented, PEP can act as a prevention strategy that works on two levels: the first is to block the immediate HIV infection through the use of antivirals, the second is to minimize the risk of future exposures by providing health care, STD treatment and risk-reduction counseling to those at high risk for HIV infection.
Back to the GMHC Treatment Issues July/August 1999 contents page.