One of the more surprising discoveries of the last decade was that HIV meds could not only treat HIV infection, but also prevent it. Using these drugs soon after exposure to HIV has become an accepted practice, but using them before exposure remains controversial. Here's what we know about both of these approaches.
PEP, short for post-exposure prophylaxis, was first shown to be effective in preventing occupational exposure to HIV (needlesticks and blood splashes, etc.). This led researchers to study whether giving HIV meds shortly after sexual exposure might also work. But since the drugs used are all FDA-approved and available by prescription, it was not considered ethical to conduct controlled studies (in which half the participants get drug and half get a placebo, or dummy pill). So the only studies done have given meds to everyone in the study -- a useful source of data, but not a method that can conclusively prove whether this approach works. Still, results have been impressive: of 401 people treated in a PEP study in San Francisco in the late '90s, none seroconverted.
Timing is critical when it comes to PEP. HIV meds must be started as soon as possible (recommendations vary from 36 to 72 hours after exposure), and continued for 28 days. The effectiveness decreases the longer treatment is delayed, so starting quickly is important. In many states, every organization working with people with HIV is required to have a policy in place to deal with occupational exposures so that employees don't have to scramble to find out what to do after an exposure occurs. People should know where to go for care before an exposure happens. If you're exposed in the middle of the night, don't wait until morning to call your doctor -- go to the nearest ER as soon as possible and take that first dose!
Before starting PEP, a provider must determine that:
If it's possible to interview the source individual, a regimen will be chosen based on that person's treatment history and any known drug resistance. For women, interactions with birth control meds and the possibility of pregnancy will be taken into account. Generally, triple combination therapy (the same kind used to treat HIV infection) is used.
PEP is not a picnic. Side effects to HIV meds are often strongest in the first few weeks, and for PEP to be effective, it must be taken for at least 28 days. Choosing a regimen that will lead to the fewest missed doses and preparing for side effects (including what to do if they occur) is important. It's also necessary to check for any interactions with other drugs, including over-the-counter and street drugs.
The final step is to follow up with another HIV antibody test in four to six weeks. If that's negative, another test should be taken three months after the exposure to confirm that infection did not occur.
PEP is intended for rare, one-time exposures -- not for repeated use. For people who are exposed to HIV on a regular basis, a more controversial approach is being studied: the use of HIV meds to prevent infection before exposure. Called PrEP, for pre-exposure prophylaxis, it is based on the common practice of using antiretrovirals to prevent HIV transmission in pregnancy.
Current PrEP studies are using either Viread (tenofovir) or Truvada (tenofovir plus emtricitabine). These products were chosen because they are taken once daily, can be taken without food, and have strong safety records, limited side effects, and favorable resistance profiles. In addition, animal studies have shown that Viread and Truvada can reduce the risk of transmission of simian immunodeficiency virus (SIV) in monkeys. SIV is a virus commonly used in animal research in the hopes that it mirrors HIV infection in humans. But results have been mixed: some studies have found that PrEP in monkeys prevented transmission of SIV, while others found that PrEP only delayed transmission. And, of course, humans may not respond in the same way.
A study presented last month at the 16th International HIV Drug Resistance Workshop found that infusions of Truvada given 2 hours before and 24 hours after exposure prevented SIV infection in all of the six monkeys tested. Once again, we don't know if this will translate to HIV exposure in humans. (All PrEP trials to date have studied the drugs taken as pills once a day, not as infusions just before and after exposure.)
Four PrEP trials have been stopped before completion for very different reasons. Studies in Cambodia and Cameroon were stopped when activists protested that adequate safer sex counseling was not being provided and that little or no planning was in place to provide healthcare for those who seroconverted during the trial. The Malawi Ministry of Health ended a trial because of concerns that widespread use of tenofovir could complicate its use as an HIV treatment, and a trial in Nigeria was shut down due to questions about trial sites' capacity to conduct the study.
Questions have also been raised about the populations being studied. We know from experience in countries like Thailand that government enforcement of condom use in brothels can dramatically lower HIV infection rates. So is it ethical to conduct studies in sex workers when we already have a method proven to work? In particular, is it ethical to conduct studies in injection drug users in countries where clean needles are not provided by the government? These concerns and others have been the subject of heated debate.
After years of waiting, the first results of a PrEP study were presented at the International AIDS Conference in Toronto in 2006. A study in Ghana enrolled 936 HIV-negative women, half of whom took Viread and half placebo. The results showed that two of the women taking Viread and six of the women taking placebo seroconverted. But these results were not statistically significant because the rigorous safer sex education done by the trial sites led to a decrease in the number of new partners and an impressive increase in self-reported condom use during the last reported sexual encounter -- from 52% to 94%! It may be that trials that are conducted ethically (that is, with proper counseling) will lead to too few seroconversions to yield useful results.
In Thailand, the CDC is conducting a study of once-daily Viread in 2,000 HIV-negative injection drug users. The trial is being conducted in collaboration with the Thailand Ministry of Public Health at 17 drug-treatment clinics in Bangkok. But the Thai government, like that in the U.S., does not provide clean needles for drug users, and concerns have been raised about the ethics of testing an unproven prevention method when a proven intervention is not also made available.
The CDC is also conducting a trial with the Botswana Ministry of Health of once-daily Truvada. 1,200 HIV-negative heterosexual men and women aged 18 to 29 are being recruited at HIV counseling and testing centers, sexually transmitted disease and family planning clinics, youth organizations, and community events. The trial had originally been planned to study Viread alone, and had already enrolled 71 people before there was evidence to support trials of Truvada. Researchers therefore will continue to follow those participants to obtain data on the safety of Viread alone.
In the U.S., the CDC is studying once-daily Viread in collaboration with the San Francisco Department of Public Health, the AIDS Research Consortium of Atlanta, and Fenway Community Health in Boston. A variety of recruitment techniques, including outreach and referrals through clinicians and community-based service organizations, are being used to enroll 400 HIV-negative men who have sex with men (MSM) who have had anal intercourse during the past year. To reflect the demographics of the U.S. HIV epidemic, a substantial number of the participants will be MSM of color.
Two groups in the U.S. study will take either Viread or placebo, and two other groups will do the same but after waiting nine months after enrollment. This design will allow researchers to compare risk behaviors among persons who are taking a daily pill and those who are not. This analysis will be critical to understanding the potential impact of a daily drug regimen on HIV risk behavior. Because the number of people in the trial is comparatively small, it will study only the safety of this approach, not its effectiveness.
The National Institutes of Health is preparing a safety and efficacy trial of Truvada PrEP in 1,400 MSM in Peru and Ecuador, and the CDC is in the planning stages for a U.S. study of the safety of Truvada PrEP. (For details on current PrEP studies, visit prepwatch.org.)
There have been concerns that people may use PrEP before studies are complete, thinking they are protecting themselves from HIV. Rumors abound that some gay men are already using PrEP, including a "new cocktail" at sex parties called "MTV" (Meth, Tenofovir, and Viagra). But a CDC survey given at gay pride events in 2005 showed that out of 397 HIV-negative gay men, only one person had used PrEP, while five had used PEP. Almost 19% said they had heard of PrEP, indicating that though the concept is somewhat known, its use is not widespread.
If PrEP is proven effective, understanding its impact on HIV risk behaviors will be critical. One of the greatest risks is that people will reduce their use of proven prevention strategies. Because no single strategy will likely be 100% effective, reducing transmission will require integrating all available methods -- both biomedical and behavioral. During trials, all participants must receive state-of-the-art HIV risk-reduction counseling and other proven HIV prevention interventions.
Even if these trials demonstrate that PrEP can reduce HIV transmission, it is equally important to understand whether persons at risk will be willing and able to maintain consistent use of a daily drug. These trials will therefore closely examine participants' adherence to, and acceptance of, daily drug use.
Drug resistance will also need to be addressed during trials. Unlike PEP, which has been so effective that developing resistance has not appeared to be a problem, it is unclear how often resistance will develop if PrEP fails and a person becomes infected while taking Viread alone. Similarly, while the risk of drug-resistant virus will likely be lower in trials of Truvada, which contains two drugs, it will be important to assess any resistance that emerges to either drug.
Several study procedures have been designed to minimize the risk of resistance among any individuals who become infected despite receiving PrEP. It is hoped that regular HIV testing with a rapid HIV test and immediate discontinuation of study pills if participants become infected will lower any risk of a resistant virus emerging. In addition, HIV resistance testing will be provided to all persons infected during the trial. These data will provide important information on the degree to which resistance occurs and will help guide treatment decisions as infected persons are referred to treatment and care.
Community activists are balancing two contradictory needs. Advocacy is needed to ensure these new prevention ideas are funded appropriately and tested ethically. But it's important not to raise expectations for interventions that may not work, that may prove no more popular than condoms, or that may do harm if used inappropriately.
And PrEP raises some particularly challenging issues of access. Health care providers will need to ensure that PrEP is used before exposure, not after infection, or it could lead to drug-resistant HIV. And exactly who would be prescribed PrEP? Would people be required to prove they're "high risk," and will that lead to their being stigmatized? Will it be available through questionable websites, like Viagra? If it is found to be effective, will ineffective quick fixes like "MTV" become rampant?
It's important to remember that if PrEP is found to be effective, it will need to be a part of a comprehensive HIV prevention program that includes education, empowerment, and proven risk-reduction behaviors. At the same time, after 25 years of HIV, many people are clearly hoping for something other than a lifetime of rubber-insulated sex.
Luis Scaccabarrozzi and Mark Milano are editors of ACRIA Update.