Treatment as prevention
Researchers are studying the use of licensed drugs to prevent—rather than treat—HIV infection
When AIDS was first described in the medical literature 25 years ago, there was not a single medicine to treat people infected with this new human virus. Since then more than 20 antiretrovirals (ARVs) have been licensed by the US Food and Drug Administration for the treatment of HIV/AIDS. These drugs have dramatically improved the health of millions of HIV-infected people around the globe and are now becoming increasingly available in developing countries where the need is still the greatest.
But with 4.9 million new HIV infections last year alone, new ways to stem the spread of HIV are more urgent than ever. In response researchers have turned their attention to novel approaches to HIV prevention. One of these involves giving the ARVs usually used to treat HIV infection to try to protect people from contracting the virus in the first place. The idea of healthy people popping pills to stay HIV free may seem strange, but it isn't without precedent. Travelers headed to countries where malaria is endemic will often take drugs to protect them from becoming infected with this parasitic disease. Researchers hope that giving ARVs to individuals at high risk of HIV infection could have the same effect. This idea is known as pre-exposure prophylaxis, or PrEP, and is being tested in five ongoing clinical trials. "We urgently need new types of prevention tools and PrEP is one of many promising strategies, like microbicides and vaccines," says Albert Liu, an investigator for one of the PrEP trials in the US.
Researchers first thought that PrEP might be an effective approach more than a decade ago but the complexities of conducting clinical trials to test the idea has placed them at the forefront of debate. Many researchers harbor concerns that giving drugs that are known to be effective for treating the disease could encourage people to participate in more risk behavior, an idea known as behavioral disinhibition, which could lead to a higher risk of infection. But investigators involved in clinical trials insist that measures are in place to limit this effect. And if found effective PrEP may have the greatest benefit for people who are unable to negotiate use of traditional barrier methods and therefore have few options when it comes to HIV prevention. "We desperately need PrEP to protect women in resource-poor settings," says Joep Lange of the University of Amsterdam.
If the idea of PrEP is borne out in clinical trials, many other questions may arise about implementing this strategy on a global basis. Researchers will confront issues of long-term drug toxicity when ARVs are taken outside the controlled environment of a clinical trial. Other issues like drug pricing and the community outreach and educational campaigns needed to introduce this concept to communities may present further obstacles. "PrEP is not a universal panacea," says Lange, who emphasizes that an AIDS vaccine is "still an absolute priority" since its impact will be far greater.
Preparing for PrEP
The concept of PrEP is not altogether new. "The concept of using an antiretroviral as a preventive has been tested and proven successful in preventing mother-to-child transmission of HIV," says Jim Rooney of Gilead Sciences, the company that manufactures both drugs currently being tested in PrEP trials. Over the last 12 years countless children have been spared from HIV infection because mothers and babies received ARVs during labor or for a short time following birth (see VAX February 2005 Spotlight article, Preventing mother-to-child transmission).
Administering ARVs to laboratory or healthcare workers after accidental needle-stick exposure to HIV is also a common practice, known as post-exposure prophylaxis (PEP). But in both of these situations the window of exposure to the virus is known and healthy individuals only need to take ARVs for a limited time. The premise of PrEP is that ARVs could be taken on a daily (possibly less frequent) basis for years in order to protect against the possibility of multiple exposures to the virus either through sexual activity or injection drug use. Giving ARVs, even if their toxic effects are minimal, to otherwise healthy people over a long period raises safety concerns.
The choice of ARV is therefore paramount. Tenofovir, licensed for the treatment of HIV infection, was the first drug that researchers considered for PrEP. Tenofovir has been on the market since 2001 and has a relatively good safety profile. It also has several other characteristics that make it favorable for PrEP, including once-daily dosing.
An initial study by Gilead showed that tenofovir was able to protect macaques from infection with simian immunodeficiency virus (SIV) when given just before or after exposure to the virus. However in subsequent studies when animals were treated with tenofovir and exposed repeatedly to a similar virus, the results weren't as promising.
Trials and tribulations
Still, researchers knew the ultimate answers on the efficacy of this approach will come from studying tenofovir PrEP in humans and clinical trials are now underway. The CDC started a Phase II safety study in February last year in the US with tenofovir in 400 men who have sex with men (MSM) and two larger Phase IIb/III trials with tenofovir PrEP with 1600 injection drug users (IDUs) in Thailand and 1200 heterosexual volunteers in Botswana.
Family Health International, a US-based nonprofit public health organization, also launched a series of tenofovir PrEP trials in Malawi, Nigeria, Cameroon, Cambodia, and Ghana, with funding from the Bill & Melinda Gates Foundation, but only the Ghana trial is still ongoing. Some of the trials were stopped or suspended after activist protests regarding the lifetime provision of ARV treatment for volunteers who become infected during the trial. Others were halted for concerns about the ethical or biological parameters of these trials. In Malawi the government halted the trial due to concerns that it would foster HIV resistance to tenofovir, which they are now using in treatment. In response to these events the International AIDS Society held a global consultation on PrEP research last year where researchers and activists discussed the issues regarding these trials (Building Collaboration To Advance HIV Prevention).
Another PrEP trial, conducted by the US National Institutes of Health (NIH) and the University of California, San Francisco (UCSF) is in the process of getting approval from local institutional review boards to begin recruiting 1400 MSM in Peru. This study is expected to start later this year, according to IMPACTA, a Peruvian non-governmental organization.
Questions linger about why PrEP is just now entering clinical trials, but disinhibition was one concern that kept researchers away from these studies. Many hesitated to dive into PrEP research because of fear it could actually encourage volunteers to abandon other proven methods of HIV prevention like condoms or increase their number of sexual partners.
Others like Lange are not as concerned about disinhibition. As in any clinical trial, volunteers in PrEP trials will be tested frequently for HIV infection and counseled on how they can reduce their risk. "Usually people are better off in a clinical trial than on the outside," he says. Volunteers will also have easy access to condoms. "We want to test the efficacy of PrEP on top of what we know already works," Liu adds.
Several studies have analyzed the behaviors of volunteers during prevention trials and the results have been mixed. During the Phase III AIDS vaccine trial run by VAXGEN, researchers found that injection drug users did not increase their risk behavior during the trial. But Mayer warns that this may not be a fair comparison. "We can't say that what happened in a vaccine trial will happen with PrEP." Volunteers in vaccine trials may receive at most three inoculations. "It's very different taking a pill every day," he adds, which researchers fear could reinforce a false sense of protection among volunteers on a regular basis.
All of the ongoing clinical trials are placebo controlled so that researchers can be sure to detect any protective effect the drug may offer. The trial Liu is coordinating in San Francisco is also attempting to evaluate the effects of disinhibition by staggering when volunteers start receiving pills. Only half of the volunteers will receive a daily pill of either tenofovir or placebo for the first nine months of the study, while the others receive nothing. This will allow the study investigators to compare the reported behaviors of volunteers who are taking pills and those who aren't. This information will be valuable to researchers, but the true impact of disinhibition isn't likely to be realized until PrEP is administered widely. Then educational campaigns will be critical in describing both the promise and limitations of this approach.
One is the loneliest number
Researchers have always speculated that a combination of ARVs, like that used for HIV treatment, may work even better for PrEP. At a major scientific meeting in the US earlier this year, researchers from the CDC presented results from an animal study with the drug Truvada, a single pill containing tenofovir and another drug called FTC, which supports this hypothesis. This idea, now being called combo-PrEP, may be even better at fending off infection than tenofovir alone and sparked great interest among prevention researchers. In response, some of the ongoing or planned PrEP trials have been modified to test Truvada.
The NIH/UCSF trial that will start later this year has been altered to include combo-PrEP instead of tenofovir alone and the CDC plans to add an additional site to the US safety trial where volunteers will receive Truvada rather than tenofovir. New volunteers in the CDC trial in Botswana will also receive Truvada, while the 70 who were already enrolled will continue on tenofovir.
Results from these trials are still several years away but some investigators are already considering the next steps. All of the current trials are testing daily doses of drug but the next round of studies will evaluate more sporadic use of PrEP drugs, according to Lynn Paxton who is running the PrEP trials at the CDC.
Others are considering how this approach could be implemented if found effective and one of the first considerations on everyone's mind is cost. "The access question is very important to start thinking about now," says Liu. Both drugs are only available from Gilead and a year's supply costs on average US$4800 for tenofovir and $7800 for Truvada. Gilead has provided free drugs for all of the trials but otherwise has stayed out of PrEP research altogether.
The company does have an access program for treatment, offering the drug at no-profit pricing in 97 developing countries. But even at this drastically reduced price of about a dollar a day it is expensive for governments struggling to treat those already HIV infected. The company does seem willing to negotiate. "If data suggest that tenofovir or Truvada is safe and effective in preventing transmission of HIV, we would continue to work to ensure access at the lowest feasible cost," says Rooney.
Distributing drugs to those most in need would be another challenge for PrEP programs. In developing countries it may be more difficult to educate communities on PrEP and to give out drugs to healthy individuals who are at high-risk for HIV infection if they aren't accustomed to seeking medical care. "This is going to have to be a team effort," says Paxton, "but there's no reason to think that it couldn't be done with proper planning."
Regardless of these questions, researchers and activists alike eagerly await the results of the ongoing PrEP trials and the public health opportunities this prevention strategy may hold.