Treatment as Prevention
Researchers are studying the use of licensed antiretrovirals to prevent—rather than treat—HIV infection
By Kristen Jill Kresge
When HIV began spreading rapidly mostly among gay men in the US there were no therapies available. As scores of people started dying from AIDS, members of these affected communities staged protests and organized die-ins, demanding that the government and the nation's massive pharmaceutical industry put its weighty scientific resources into developing treatments for this lethal virus and that community members have a say in the process.
This became the model for patient advocacy and changed the way companies and licensing agencies approach the development of new therapies for many diseases. Now 25 years after the first AIDS cases in the US were described, there are more than 20 licensed drugs for the treatment of HIV infection.
A similar story does not exist for HIV prevention, where activism is a much harder sell. Instead of fighting to keep infected people alive, prevention activists are lobbying for healthy people to alter their behaviors. Almost five million new HIV infections occurred last year alone, yet still there are no newly demonstrated options for stopping transmission of the virus. Speaking recently at the closing ceremony of the Microbicides 2006 conference in Cape Town, renowned activist Zackie Achmat of South Africa's Treatment Action Campaign said, "Everyone present realizes that there is a local and global crisis of HIV prevention."
Many novel approaches to HIV prevention are currently in testing but to some, research seems to be crawling along. "Prevention studies are always a tough sell," says Kenneth Mayer, a prevention researcher at Brown University, who points to the lack of funding and interest from many of the pharmaceutical companies that successfully developed antiretrovirals (ARVs).
One novel idea that is gaining momentum is to give these effective ARVs to non-infected, healthy individuals who are considered at high risk of exposure to HIV. Much like travelers headed to endemic countries who swallow anti-malarials, it is hoped that taking ARVs could prevent the establishment of HIV infection. This idea is known as pre-exposure prophylaxis, or PrEP, and is being tested in five ongoing clinical trials (Table 1). "We urgently need new types of prevention tools and PrEP is one of many promising strategies, like microbicides and vaccines," says Albert Liu, director of one of the PrEP trials at the San Francisco Department of Health.
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Several animal studies provided the preliminary evidence that PrEP might be an effective approach but the complexities of conducting clinical trials to test the idea has put them at the forefront of debate. Some researchers harbor concerns that giving drugs that are known to be effective for treating the disease will encourage people to increase their risk behaviors, a phenomenon known as behavioral disinhibition, but others insist that these placebo-controlled trials are designed to prevent this from happening. And PrEP may have the greatest benefit for people who can't negotiate the use of traditional barrier methods, leaving them with 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 (PLoS Med. 2, e248, 2005).
If the idea of healthy people popping pills to stay HIV free is borne out in clinical trials, many other questions may arise about implementing this strategy on a global basis. Researchers will confront issues of drug toxicity, selection of drug-resistant virus in people on PrEP drugs who become HIV infected anyway, drug pricing, and the need to link PrEP availability to community outreach and educational campaigns to ensure compliance with daily dosing and to minimize disinhibition. "PrEP is not a universal panacea," says Lange, who calls an AIDS vaccine an "an absolute priority" since its impact will be far greater.
Birth of PrEP
The idea behind 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, a company that manufactures both of the 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 while following birth (see New strides in protecting infants from HIV, IAVI Report 9, 2, 2005).
Administering ARVs to laboratory or healthcare workers immediately after accidental exposure to HIV is also a common practice, known as post-exposure prophylaxis (PEP). But in both of these situations the potentially infectious event is known and healthy individuals are only exposed to 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 potential of multiple exposures to the virus either through sexual activity or injection drug use. Since the drugs are only licensed by the US Food and Drug Administration for the treatment of HIV infection, providing them to healthy people is considered off-label use. Such use has been reported anecdotally and in informal surveys among gay men in the US, but there are clear safety concerns when giving drugs to otherwise healthy people, especially long term.
The choice of drug is therefore paramount. Tenofovir, a once-daily drug licensed by Gilead for the treatment of HIV infection, was the first drug that researchers considered for PrEP. It is a nucleoside reverse transcriptase inhibitor (NRTI) that has been on the market since 2001 and, apart from some reported cases of renal toxicity or bone mineral loss in HIV-infected individuals, has a relatively good safety profile. Additionally, viral resistance mutations are not formed in response to selective pressure put on the virus by the drug as readily as they are to some other ARVs. The development of drug-resistant virus is an important concern for PrEP because no intervention is failsafe and in practice volunteers could still become HIV infected. Until their infection is discovered they would be taking a suboptimal therapy that could encourage the development of viral resistance and compromise their future response to treatment.
Recent evidence also offers a pharmacological rationale for choosing tenofovir to try to prevent sexual transmission of HIV. Researchers from Myron Cohen's group at the University of North Carolina at Chapel Hill, along with Gilead, conducted pharmacokinetic studies in HIV-infected individuals and found that tenofovir concentrations are significantly greater in the genital tract than in blood for both men and women. This data, presented in a poster at this year's Conference on Retroviruses and Opportunistic Infections (CROI; Ab# 569), shows that both the extra- and intracellular concentrations of tenofovir in the genital tract are the highest, compared to blood, of any ARV observed so far.
Monkeying around
The initial non-human primate study by Gilead looked at the efficacy of tenofovir at preventing infection when given either just before or just after exposure to simian immunodeficiency virus (SIV) (Science 270, 1197, 1995). The macaques were given subcutaneous injections of tenofovir (then known as PMPA) once daily for 4 weeks starting either 48 hours before, 4 hours after, or 48 hours after intravenous challenge with SIV.
All 10 control animals had established viremia within 3 weeks, while the 15 macaques that received tenofovir prior to viral challenge remained SIV-uninfected for 56 weeks. No clinical signs of drug toxicity were observed in animals that received the treatment regimen for one month.
A subsequent study looked at the efficacy of tenofovir in preventing SIV infection in newborn macaques with a viral isolate (SIVmac055) known to have a five-fold reduced susceptibility to the drug in vitro (J.Virol. 74, 1767, 2000). Five macaques were treated with tenofovir once daily for 4 weeks starting 24 hours prior to an oral viral challenge. Of these infant macaques, 2 had no evidence of infection and the other 3 had delayed onset of viremia, slower disease progression (immunodeficiency in 5-15 months), and enhanced antiviral antibody responses. The three untreated control monkeys developed fatal immunodeficiency within three months after viral challenge.
But these studies only tested tenofovir against a single viral challenge. At last year's CROI Tom Folks and colleagues at the US Centers for Disease Control and Prevention (CDC) presented some less encouraging data on PrEP when evaluated with a repeat-challenge model (CROI 2005; Ab# 136 LB). His group looked at tenofovir's ability to prevent the establishment of infection in 12 rhesus macaques that received weekly inoculations of SHIV (an HIV/SIV hybrid) administered rectally at a dose similar to the level of HIV found in human semen during acute infection. This low-dose, repeat-challenge model is considered by many researchers to more closely mimic human infection.
Four macaques received tenofovir daily, four received a weekly dose, and four were untreated controls. Two of the control animals were infected after a single SHIV inoculation, while the other two were infected after 2 and 11 viral challenges each. In the weekly and daily tenofovir groups, half of the animals in each group were infected after six SHIV inoculations, with all of the remaining animals becoming infected after 14 doses. Although daily or weekly treatment with tenofovir increased the median time to infection in macaques, it failed to completely protect any animals and disease progression was similar to that seen in the untreated controls.
Trials and tribulations
Although these findings raised concerns among researchers, 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 of daily tenofovir in 400 men who have sex with men (MSM) in the US, 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 protests from activists over the lack of a lifetime guarantee to treatment for volunteers who happen to become infected during the trial. Others were halted due to ethical or biological questions about these trials or the sites (Lancet366, 1499, 2005; Science 309, 2170, 2005; PloS Med. 2, e234, 2005). In Malawi the government closed the trial due to concerns that it could foster HIV resistance to tenofovir, a drug 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 researchers at the University of California, San Francisco (UCSF), with support from the US National Institutes of Health (NIH), 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.
But even now some question why it has taken more than a decade, since the original study in macaques showed promise, to finally test PrEP in humans. "The process is incredibly frustrating. For some reason PrEP is controversial," says Lange who doesn't see why studying this intervention should be any more complicated than microbicide trials.
Some researchers hesitated to dive into such studies because of fear that PrEP could actually encourage behavioral disinhibition in volunteers, who feel a false sense of protection from the intervention being tested and so increase their risk of HIV infection by abandoning other proven methods of prevention like condoms. "It did take a while to think about how to best design these trials," says Liu.
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.
Trial volunteers may be further discouraged from risky behavior since all of the trials are placebo controlled-counseling sessions throughout the trial will remind volunteers that they may not be receiving active study drug. The trial Liu is coordinating in San Francisco is attempting to further evaluate the extent of disinhibition by providing only half of the volunteers with either tenofovir or placebo for the first nine months of the study so that researchers can compare the reported behaviors of volunteers who are taking pills with those who aren't.
Several studies have analyzed the behaviors of volunteers during prevention trials and while some indicate a reduction in HIV incidence among trial volunteers, others found evidence of disinhibition. During the Phase III AIDS vaccine trial run by VAXGEN, the risk behaviors among injection drug users did not increase (AIDS 18, 295, 2004). 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 chemoprophylaxis." Volunteers in vaccine trials may receive at most three inoculations. "It's very different taking a pill every day," he adds.
Combo-PrEP
Researchers have long speculated that a combination of ARVs for PrEP may be even better at stopping the virus in its tracks, just as for treatment, and data has recently emerged supporting this hypothesis (seeCROI covers advancements from start to finish, IAVI Report 10, 1, 2006). The idea for combo-PrEP relies on the drug Truvada, also manufactured by Gilead, which is a single pill containing tenofovir and another NRTI called FTC. In studies conducted at the CDC with this PrEP regimen, macaques were able to fend off 24 viral challenges in the low-dose SHIV, repeat-challenge model.
These impressive results sparked great interest among PrEP researchers and in response the NIH/UCSF trial protocol has been altered to include combo-PrEP instead of tenofovir alone. The CDC trial in Botswana has also switched to Truvada, although the 70 volunteers that are already receiving just tenofovir will continue on this regimen. Both of these trials with Truvada are expected to start around August. The CDC also has plans to add an additional site to the US safety trial where volunteers will receive Truvada rather than tenofovir.
But there are additional concerns about individuals developing FTC-resistant HIV, which occurs more rapidly than to tenofovir, in some cases occurring overnight. FTC also has activity against hepatitis B virus so intermittent use could have implications for those who are HIV/hepatitis B virus co-infected.
Non-viral challenges
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 ARV doses but the next round of studies will evaluate more sporadic use. "If it works when taken daily, then you back up and look to see if you can just take it closer to the exposure time," says 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 an average of 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 around a dollar a day it is expensive for governments struggling to treat those already HIV infected and Gilead seems to recognize this. "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.
Giving 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."
Researchers who conduct AIDS vaccine trials are also considering how PrEP could affect their work. If PrEP is found to be effective or partially effective and is adopted as the standard of care in the community where the vaccine trial will occur, then investigators may be obligated to offer PrEP drugs to volunteers in vaccine trials, says Lange. The same may happen with male circumcision, if additional clinical trials show its protective effect. Offering these interventions in large-scale vaccine trials could drastically increase costs and may make it more difficult to tease out the efficacy of the vaccine candidate.
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.