PrEP Work
If effective, pre-exposure prophylaxis for HIV will offer many opportunities, but also numerous challenges
By Regina McEnery
More than a decade ago, highly active antiretroviral therapy (HAART) began rescuing HIV-infected individuals from the brink of death by aggressively suppressing viral replication. Yet this is only part of the critical role antiretrovirals (ARVs) have played in the battle against HIV. These drugs, alone or in combination, have also been effective soldiers in HIV prevention.
In 1994, a landmark study showed that administration of AZT to pregnant women and newborns could reduce the risk of mother-to-child HIV transmission from 25% to 8% (1). Since then routine and timely delivery of ARV therapy to pregnant women and their babies has nearly eliminated perinatal transmission in developed countries. While curbing mother-to-child HIV transmission in developing nations continues to be a major battle, use of antiviral prophylaxis in low- and middle-income countries has grown from just 9% in 2004 to 33% in 2007, according to the latest figures from the Joint United Nations Programme on HIV/AIDS (UNAIDS).
ARVs are also thought to possibly block infection following known exposure to HIV in adults, a concept called post-exposure prophylaxis (PEP). Current recommendations call for a short course, typically one month, of ARVs to be given to health care workers within 72 hours following exposure to HIV from contaminated blood, medical supplies, or equipment, as a way to prevent the establishment of an HIV infection. PEP is also sometimes administered following known sexual exposure to the virus. While clinical evidence linking PEP with reduced rates of HIV transmission is sparse, one study found that a month-long course of AZT reduced the risk of HIV infection by approximately 81% (2).
Considering all this, it’s not surprising that researchers are now investigating whether delivering ARVs prior to HIV exposure, an idea known as pre-exposure prophylaxis (PrEP), can also be turned into an effective prevention tool. The first evidence that this strategy might work came from nonhuman primate studies conducted in 1995. Now, after some delay, there is a sudden surge of attention and money directed toward studying PrEP. Several large clinical trials are testing whether the ARV drug tenofovir disoproxil fumarate (Viread), or a combination pill of two ARVs—tenofovir and emtricitabine—known as Truvada, will be effective at preventing HIV transmission in high-risk adults.
If these trials yield promising results, there could finally be another biomedical weapon added to the stockpile of existing HIV prevention strategies that despite years of research still largely revolve around condom use, sexual abstinence, and syringe exchange (3). Male circumcision, the latest biomedical intervention against HIV, was found to reduce HIV acquisition by as much as 65% in heterosexual men in randomized controlled clinical trials, but because of logistical, cultural, and religious considerations, only a handful of countries so far have adopted policies recommending this surgical procedure for HIV prevention. “The challenge is really at the local level and getting national governments to understand the potential of large-scale prevention,” says Robert Bailey, an epidemiologist at the University of Illinois, who has been studying circumcision for more than a decade. “That is what PrEP is going to go through. You have to do lots of consultations, get people engaged, and set up committees. You have to get the community behind it.”
To ensure that PrEP, if found effective, doesn’t face a similar fate as circumcision, HIV prevention researchers and advocates are now starting to consider some of the weighty challenges, both logistical and medical, that will need to be overcome to successfully introduce this new prevention tool. Governments and public health agencies, like the World Health Organization (WHO), will have to tackle numerous questions should PrEP work, including identifying who should be the recipients, determining the best systems for distributing the drugs, and monitoring any long-term effects they may cause. Massive public education campaigns will also be required to explain PrEP and counter any behavior change that might occur as a result of its use. Countries will also need a mechanism to track the development of HIV resistance in individuals who become infected despite taking PrEP. Other considerations include the cost of this intervention and its impact on the design and conduct of future HIV prevention trials.
All of this could add considerably to the already staggering costs of HIV/AIDS prevention, treatment, and care in many of the hardest-hit countries. But if it works, PrEP will also bring unprecedented opportunities. Despite achievements in treating HIV/AIDS, last year alone 2.7 million people were newly infected with the virus.
“In the absence of data, it is way too premature to frame the response dramatically because we don’t know how good PrEP will be or in what settings it will work,” says Kenneth Mayer, a professor of medicine at Brown University, who has surveyed PrEP awareness. “But you still need to be intellectually prepared to deal with the different scenarios based on how the trials come out.”
Animal evidence
Studies in nonhuman primates already offer strong evidence that ARVs administered systemically prior to exposure to simian immunodeficiency virus (SIV) can prevent infection, although the success of the intervention seems to vary with the challenge model and the ARVs used (4). Pioneering studies published more than a decade ago first documented that injections of tenofovir, then still an experimental ARV, prevented SIV infection when administered either two days before, four hours after, or 24 hours following SIV challenge, with treatment continuing for four weeks (5).
In 2001, California-based pharmaceutical company Gilead Sciences obtained regulatory approval and licensure from the US Food and Drug Administration (FDA) for tenofovir. Truvada, also developed and licensed by Gilead, received FDA approval in 2004. Both are considered attractive ARVs for PrEP because they are potent, require only a single daily dose, and cause low rates of adverse effects. These criteria opened the door to PrEP research (3).
Since then, some of the most significant data has emerged from the US Centers for Disease Control and Prevention (CDC), where researchers have focused on testing PrEP in a low-dose mucosal challenge model against a hybrid SIV/HIV known as SHIV. Their earliest studies showed that tenofovir, given orally, delayed the establishment of SHIV infection after repeated exposure and even prevented infection altogether in one of four rhesus macaques. It took a median of six challenges to infect animals treated daily with tenofovir and seven for those treated weekly, compared to a median of 1.5 challenges for the control animals to become infected (6).
At the 13th Conference on Retroviruses and Opportunistic Infections in 2006, the CDC reported that daily subcutaneous dosing of emtricitabine and tenofovir for nine days—with a higher dose of tenofovir than is approved for treatment—fully protected all six rhesus macaques following repeat rectal exposure to SHIV. And in a study published this year comparing daily and intermittent doses of this same regimen, the CDC found that all treated animals were completely protected against repeat mucosal SHIV challenge over a 14-week period, whether emtricitabine/tenofovir was given daily or intermittently—two hours before and 24 hours after challenge (7).
Findings published this year also found Truvada effective in preventing vaginal transmission of HIV in a humanized mouse model developed by J. Victor Garcia-Martinez, an immunologist at the University of Texas Southwestern Medical Center (see Mighty mice, IAVI Report, Sept.-Oct. 2008). None of the humanized mice that received Truvada became infected after receiving inoculations of HIV, while 88% of the untreated control mice were infected (8).
Although Truvada has become the drug of choice for PrEP studies—five of seven clinical trials are using this two-drug combination pill—other ARVs might also be effective at preventing HIV infection. The Tulane National Primate Research Center in Louisiana found that oral delivery of an experimental CCR5 inhibitor known as CMPD167 in rhesus macaques on the day of SHIV challenge and for 10 days following provided considerable protection (9).
Seeking human data
There are now seven planned or ongoing clinical trials of PrEP that will enroll upwards of 18,000 individuals. These trials involve men who have sex with men (MSM) and injection drug users (IDUs) in Asia, the US, Latin America, and Africa, and heterosexual men and women from Africa (see Figure 1). The first round of data—a safety study being conducted in 400 HIV-uninfected MSM in the US—is expected to be released next year and results of the first efficacy trial involving 2,400 IDUs in Thailand will closely follow.
Figure 1. The Status of PrEP Research
There is anecdotal evidence suggesting that some high-risk individuals may already be using PrEP as a way to stay HIV free, but although there have been isolated reports of MSM taking antiviral drugs in advance of unsafe sex, the notion that there is widespread use of PrEP in this population has so far not been born out by the data. A survey of 1,819 MSM in San Francisco found that PrEP use and awareness was rare (10). “I wasn’t totally surprised that not that many people had heard of it,” says Albert Liu, director of HIV prevention and intervention studies for the San Francisco Department of Public Health, who conducted the survey and is also involved in an ongoing PrEP clinical trial. “It’s still a relatively new concept and the PrEP trials are still getting underway.”
There is anecdotal evidence suggesting that some high-risk individuals may already be using PrEP as a way to stay HIV free, but although there have been isolated reports of MSM taking antiviral drugs in advance of unsafe sex, the notion that there is widespread use of PrEP in this population has so far not been born out by the data. A survey of 1,819 MSM in San Francisco found that PrEP use and awareness was rare (10). “I wasn’t totally surprised that not that many people had heard of it,” says Albert Liu, director of HIV prevention and intervention studies for the San Francisco Department of Public Health, who conducted the survey and is also involved in an ongoing PrEP clinical trial. “It’s still a relatively new concept and the PrEP trials are still getting underway.”
Mayer conducted a survey on PrEP among 250 MSM in Boston and found that fewer than 20% had ever heard of it. “When we explained what PrEP was, we found a lot of enthusiasm,” he says, but people also raised some concerns, including potential side effects and cost.
The challenges
The rapid escalation in the number and breadth of large-scale clinical trials that has occurred recently has generated excitement about PrEP—it was one of the hot topics at the XVII International AIDS Conference in Mexico City in August. This has motivated advocates, governments, and public health organizations to start considering the process of implementing PrEP should it prove safe and effective. Researchers most closely involved in the study of PrEP agree that it is productive to start conversations now, particularly with key stakeholders in the PrEP debate, including organizations such as the WHO that often set policies that developing countries adopt. But some researchers also stress caution on moving too quickly before the studies are completed.
“Countries hardest hit by the epidemic have a lot of other things going on,” says Lynn Paxton, the coordinator of PrEP studies with the CDC. “They don’t have much money and to ask them to start intensive preparation for something that might not have been shown to work yet is difficult.”
The AIDS Vaccine Advocacy Coalition (AVAC) has spearheaded many of the discussions about PrEP so far, even though its central mission has historically centered around AIDS vaccines. AVAC’s executive director Mitchell Warren says the group diversified its message for two reasons. “First, we are many years from vaccine efficacy,” says Warren. “We will also begin to get answers about PrEP over the next two years and there has been pitifully little said about what we will do if it works.” Warren says response plans that are adequately funded and which correctly identify the high-risk uninfected individuals most likely to benefit from this intervention should be developed sooner rather than later.
Adherence and access
As conversations about PrEP implementation get underway, researchers and advocates are just beginning to address the challenges associated with this potential HIV prevention measure. One key challenge will be identifying possible strategies for implementing PrEP, if effective. It is likely that PrEP programs will, at least initially, target high-risk individuals in communities in which the HIV infection rates are highest. But many stakeholders say it is premature to determine now who should receive PrEP or what the obligations of government and industries should be in providing it.
“If a study shows it is highly effective then recommendations will be made on how best to use it and in what populations,” says James Rooney, vice president of medical affairs for Gilead. “In conjunction, there will also be discussions on whether the current infrastructure would allow for PrEP to be provided or whether there needs to be further discussions on how the drugs could be made available.”
With the exception of AZT, which is used to prevent mother-to-child HIV transmission, there are no indications for ARVs around prevention, and even if PrEP performs well in clinical trials Gilead does not plan to seek regulatory approval to market tenofovir or Truvada as preventive drugs against HIV. “Gilead does not view prevention of HIV as a commercial opportunity that they would actively promote,” says Rooney. “We do view PrEP as a potentially important public health intervention and we would want to provide appropriate education to physicians about PrEP use and the fact that it is not a substitute for other well demonstrated means of preventing HIV infection.”
Another key obstacle will be adherence. There are studies from both developed and developing countries that have documented adherence to ARVs in HIV-infected individuals, but the data are variable. At the 15th Conference on Retroviruses and Opportunistic Infections in Boston earlier this year, researchers from the CDC estimated adherence to HAART among a cohort of 926 men and women from rural Uganda to be around 95% during three years of treatment.
There are clear-cut medical reasons for HIV-infected individuals to stick to treatment. Failure to do so could make them more susceptible to drug resistance and accelerate progression to AIDS. In contrast, motivating high-risk but uninfected individuals to take a daily dose of ARVs could prove difficult, much like convincing men and women to use a condom every time they have sex or IDUs to use clean needles every time they inject drugs. Though PrEP is hardly as intrusive to sexual spontaneity as stopping intercourse to apply a condom, some advocates see adherence as potentially the biggest barrier to PrEP effectiveness.
To avoid issues with daily adherence, some researchers are eyeing the possibility of testing intermittent PrEP use—such as before and after high-risk activity. “It will be important to understand if intermittent PrEP is feasible and effective,” says Timothy Mastro, senior director of research at Family Health International. “Taking the drug intermittently around the time one might be exposed is probably more feasible for many people in the world.” IAVI is considering utilizing excess clinical trial capacity to evaluate the feasibility of intermittent PrEP use. Such a study could also provide insight into immunological questions that may be important for AIDS vaccine research.
Another concern among researchers and advocates is that even though PrEP will unlikely be 100% effective at protecting against HIV, PrEP users may feel protected and therefore increase their risk behaviors, a phenomenon social scientists refer to as behavioral disinhibition. Ume Abbas, formerly an assistant professor in the Department of Infectious Diseases at the University of Pittsburgh School of Medicine and now with the infectious disease division at the Cleveland Clinic, used mathematical modeling to measure the potential impact of PrEP in sub-Saharan Africa, home to about 66% of the 33 million people living with HIV. The model determined that about 2.7 million to 3.2 million new HIV infections in southern Africa could be prevented over 10 years, factoring into the model a 90% effectiveness of the PrEP regimen targeting individuals at high risk for HIV with no behavioral disinhibition (11).
Even with a 100% increase in high-risk behavior, a PrEP regimen carrying 90% effectiveness predicted a reduction of HIV infections between 23% and 63%. It is only when the effectiveness of PrEP hovers around 50% that the model shows that sexual disinhibition could actually increase the number of new HIV infections. ”We found that effectiveness of PrEP is key to determining the impact on HIV prevention. If PrEP has a high level of efficacy and adherence, it would be possible to withstand a greater degree of sexual disinhibition,” says Abbas.
While the mathematical models are used as just that, models to predict “real life” outcomes, their forecasts can be instructive. In this case, they underscore the need for counseling and education. “If the public feels that they can take a pill and now have more sex, the effect of PrEP will go way down,” says John Mellors, a professor of medicine at the University of Pittsburgh who directs clinical research activities in HIV/AIDS.
Mastro agrees and says that communicating accurate information about PrEP will be essential to achieving its goal of reducing the number of new HIV infections. “Once you give someone a biomedical intervention, if they think they have been given a get-out-of-jail-free card they may think, why be safe?” says Mastro, who is also involved in a large clinical trial of PrEP in multiple African countries. “To me that is one of the major challenges of PrEP. They are only partially effective interventions. You will still need to be careful.”
The threat of resistance
Another big concern is the possibility that people will become unknowingly HIV infected despite taking PrEP, either because it is partially effective or due to poor adherence, and continue to take the drugs. This could spur the development of drug-resistant strains of HIV and could compromise an individual’s treatment options over the long term.
For now, researchers can mostly only speculate about the likelihood that HIV drug resistance will develop when a person taking PrEP becomes HIV infected. The only clinical data available comes from a randomized controlled PrEP trial with tenofovir conducted in Ghana, Nigeria, and Cameroon that was never fully completed. Two seroconversions occurred in individuals receiving tenofovir and standard genotypic analysis found no evidence of drug-resistant mutations (12). Aside from that study, the only other evidence comes from a recent case report of a man who had been taking Truvada intermittently to prevent HIV during high-risk sexual encounters with other men and became HIV infected (13). In this case there was also no evidence of HIV resistance.
The development of HIV resistance, along with safety and efficacy, is being investigated in ongoing PrEP trials. Researchers conducting one trial involving 3,900 serodiscordant couples in Uganda and Kenya will look for evidence of drug-resistant HIV being transmitted or acquired among the seroconverters in the study.
Mellors said HIV drug resistance and its impact on ARV efficacy is the question he is asked about most often. But there are no clear-cut answers. “It is reasonable to assume that individuals will become infected on PrEP and will likely develop resistance unless PrEP is stopped,” he said during a talk at the XVII International AIDS Conference. Mellors used a computer model to predict how drug resistance might evolve in these large-scale PrEP prevention trials and how severe the impact will be if it isn’t properly addressed. Mellors said if only a handful of people enrolled in the trial are unknowingly infected with HIV, the impact in the general population will likely be minimal. But if the number of HIV-infected people taking PrEP is large, according to Mellors, the potential benefits of PrEP could be nullified by the amount of drug-resistant virus circulating throughout the population.
Mellors says this shows routine testing will be required. “Any rollout program needs to identify who is infected and who is not and not make the mistake of giving PrEP to people who are already infected,” he says. While monitoring thousands of people in a three-year clinical trial is a manageable exercise, repeatedly testing PrEP users in the general population will be more challenging. And HIV resistance testing, which is used extensively in developed countries to optimize ARV treatment, is still an expensive luxury in many poor countries where second-line treatment regimens are often limited and unaffordable.
In addition to tracking HIV drug resistance, PrEP programs will also need to monitor individuals for adverse effects from the drugs. Though studies have found the drugs to be well tolerated, tenofovir and emtricitabine have been known to cause nausea and diarrhea, and tenofovir has also been associated with renal toxicity, says Rooney. There is also some evidence in animal models that tenofovir causes reduction in bone density, although long-term follow up in clinical trials found no increased incidence of fractures in HIV-infected individuals (14).
Another concern will be planning for and conducting other HIV prevention trials. If PrEP’s efficacy is established in more than one randomized controlled clinical trial and government policies endorse the strategy, organizations conducting AIDS vaccine trials would likely be asked to provide PrEP or refer volunteers to a clinic where it is available. Including enough volunteers in a trial to determine a vaccine’s benefit, in addition to PrEP and circumcision, would add significantly to the complexity and cost of conducting AIDS vaccine trials. There are also possible safety and biological complications that would need to be evaluated during clinical trials in which vaccine candidates were tested in combination with PrEP, according to Fran Priddy, director of medical affairs at IAVI.
| Weighing the Costs |
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Just as pricing is one of the biggest points of contention for HIV treatment, it is also one of the key questions surrounding possible implementation of PrEP. The cost of HIV treatment has grown astronomically since the advent of HAART. To meet the goal of universal access, UNAIDS estimates it will cost approximately US$54 billion each year to provide ARVs to those in need in low- and middle-income countries by 2015. The price tag for tenofovir or Truvada used for PrEP will be the same as for treatment, says James Rooney, vice president of medical affairs at Gilead. The company now charges developing countries about $17 and $26 a month respectively for tenofovir and Truvada. As treatment costs soar, it will be difficult for cash-strapped countries with the highest HIV/AIDS burdens to take on the additional cost of providing drugs for HIV prevention. “I think many of these questions will be worked out once the trials are completed and if the trials demonstrate PrEP is safe and effective,” says Rooney. “There are a variety of discussions already surrounding regulatory and commercial issues, and of course reimbursement. Those discussions are in the preliminary stages at this point in time.” The US government is now the biggest financial backer of AIDS treatment in developing countries—it will be funneling nearly $50 billion in aid over the next five years through its US President’s Emergency Plan for AIDS Relief (PEPFAR) to expand existing HIV/AIDS prevention, treatment, and care efforts worldwide (seeVaccine Briefs IAVI Report, July-August 2008). In its report, “Anticipating the Results of PrEP Trials,” the AIDS Vaccine Advocacy Coalition (AVAC) noted that PEPFAR, the Global Fund, and other major funders of AIDS services should have plans in place to make PrEP available rapidly should it work. “Almost all prevention and treatment services in developing countries are dependent on development assistance—providing male and female condoms, male circumcisions, ARVs, voluntary counseling and testing etc.,” says Mitchell Warren, AVAC’s executive director. In the developed world, where public and private insurance programs pay for the bulk of ARV treatment, cost could also be an issue. It remains to be seen whether public or private insurance programs will be willing to pay the $6,000 to $9,000 a year it now costs for tenofovir or Truvada in order to fend off HIV. |
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