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Testing PrEP on a Global Scale

February 28, 2009

In her opening plenary at CROI 2009 in Montreal, Canada, Dr. Sharon Hillier from the University of Pittsburgh School of Medicine highlighted the possible dramatic impact that using PrEP (Pre-Exposure Prevention), if effective, could have on the world's HIV epidemic, along with some of its possible disadvantages. PrEP is using HIV drugs (either as a pill or as a gel or cream, vaginally or rectally) to prevent HIV infection in non-infected individuals.

The potential promise of PrEP

Given the breadth of global resources being used to treat HIV disease today, it's becoming clearer that alternative solutions to the AIDS crisis must be found. So far, potent HIV therapy has extended the lives of millions of people, but with it comes challenges, such as the need for lifelong therapy or the swelling costs of global health care, to name just a couple. Medical prevention strategies such as PrEP (as opposed to behavioral strategies such as negotiating safer sex) could be one avenue to curbing escalating infection rates and reducing the consequent burden of HIV disease on health care settings around the world.

This year, CROI 2009 presented data on many PrEP-related research projects, in both humans and animals. The buzz surrounding this topic, especially from the animal data, reflects the hope that this area or at least its investigation may one day lead to advances that turn the escalating rates of infection around. But what is PrEP and why is it getting so much attention? The following is an overview of the current PrEP landscape.

What is PrEP?

PrEP is using HIV therapies, before an exposure to HIV, in hopes of preventing HIV infection. It might be taken as a pill or applied topically in a gel or other substance. These products could be applied to the vagina or rectum as a lubricant or spermicidal jelly. The intent for using PrEP is to reduce HIV infection by taking medicine daily or intermittently, before a sexual event. So far, one or two HIV drugs have been used in studies. In these studies, PrEP is given to people along with targeted prevention counseling, encouraging them to continue using other forms of prevention such as condoms and other risk reduction practices.

Current studies of PrEP

Animal studies and one early study in women have provided the groundwork for eight major ongoing PrEP studies in humans. One notable animal study (rectal transmission in macaques), compared four regimens in 18 animals with various doses of Viread (tenofovir) with and without Emtriva (emtricitabine) to 18 control animals. One of the regimens with Truvada (tenofovir + emtricitabine) given by injection showed 100% protection against sHIV infection, which satisfied a proof of concept leading to human study.

A West African PrEP study (2004-06) involved 936 women who took 300mg tenofovir or placebo daily. Although this study could not show Viread's effectiveness, it did provide information on its side effects in uninfected people and on risk compensation, which is when a person adjusts his/her behavior in response to a perceived change in risk. At least in this study, using PrEP did not increase a woman's risk for HIV infection.

Eight human studies are ongoing or planned where PrEP is given orally. In total, they're studying nearly 21,000 people in various settings. More than half the study volunteers will be high- and low-risk women, as the need for proven woman-controlled prevention methods like PrEP is well past due. The PrEP study landscape also includes researching other primary areas of transmission such as in men who have sex with men (MSM), heterosexual men, injection drug users, and couples with mixed HIV status.

The eight studies include:

  • US tenofovir extended safety study
    This study includes 400 HIV-negative MSM in three US cities. In addition to collecting information on PrEP side effects, other data such as access to HIV care, drug resistance and health outcomes are being examined among those who become infected in the study. It started in early 2005 and will end later in 2009.
  • Bangkok tenofovir study
    This study is includes 2,400 HIV-negative injection drug users. It's a randomized, double-blind study comparing tenofovir to placebo.
  • Botswana Truvada (tenofovir + emtricitabine) study
    This phase II/III study is comparing the use of Truvada to placebo in about 2,000 heterosexual men and women aged 18-39. Endpoints include documented cases HIV infection, adverse events, risk behaviors and adherence issues. The study started in early 2007.
  • iPrEX
    This global study will enroll about 3,000 high-risk MSM and compares daily PrEP of Truvada to placebo. Endpoints include documented cases of HIV infection, adverse events, metabolic changes to bone and blood fats, risk behaviors and adherence, or a person's ability to take the therapy daily as prescribed.
  • Partners PrEP
    This African study will compare once a day Viread, Truvada and placebo in 3,900 heterosexual couples with mixed HIV status. Endpoints include documented cases of HIV infection and safety.
  • FemPrEP
    This phase III African study will follow 3,900 women at high risk for HIV infection and will compare daily Truvada and placebo.
    This study is planned to start in early 2009 and will enroll 4,200 women. Four study groups include: 1) taking a tenofovir gel, 2) taking oral Viread, 3) taking oral Truvada and 4) taking either a placebo gel or tablet.
    This fully enrolled study is following about 1,000 women taking either tenofovir or placebo gel in a vaginal application. The gel is applied both before and after having sex.

The drugs used in PrEP

In the studies mentioned earlier, two HIV drugs are being evaluated: Viread (tenofovir) with or without Emtriva (emtricitabine). Taken together as a pill, it's marketed as Truvada and is given as one pill once a day. Viread was chosen as a PrEP drug because it has a long half-life, which means it takes at least 17 hours for half of the drug to clear from the blood. Thus, it exerts anti-HIV activity in the blood for a long time. It also has high concentrations within cells (active up to 60 hours), hopefully improving its ability in block HIV infection when using PrEP. Both qualities are desirable for PrEP regimens since HIV is most vulnerable to antiviral affects during early infection.

Viread has side effects, ones that affect kidney function and bone density in those who take it. These effects are fairly well studied in HIV-positive people taking tenofovir. What's not known is how much of an impact these side effects will have in uninfected individuals, and whether this may deter people from taking PrEP as prescribed. Although Viread is the most studied HIV drug for PrEP, another drug called Selzentry (maraviroc) is also being researched as a possible PrEP drug. Data on its use as PrEP will be forthcoming.

The downsides of using PrEP as prevention

This medical approach to prevention doesn't come without possible downsides. One main concern is a person developing resistant HIV while using PrEP, which impacts not only the individual but others in the community who may become exposed to the drug-resistant virus. Once a person develops resistance to a drug like Viread or Emtriva, he or she may not fully benefit from HIV therapy, or the resistant virus could be more aggressive. Though data from animal models have not shown this to be a significant concern, it's data from the full spectrum of these human studies that will need to be pooled in order to clarify the rate of resistant HIV transmission and what, if any, consequence it may have for people.

Another concern is that PrEP may fuel, rather than curb, the epidemic through more infections. Some individuals will likely see PrEP as a "magic bullet" of sorts and rely upon it as their only form of HIV prevention - and it may fail. Believing one is protected when using PrEP, a person may engage in risky (or riskier) behavior and actually increase his or her chance for getting HIV. Further, a person who becomes infected while on PrEP may believe they're HIV-negative and may engage in risky behavior that puts others at risk. These factors, among others, could fuel the epidemic. However, in large preventive vaccine studies where this is also a concern, this was not a major issue. It's almost certain that anyone wanting a PrEP prescription will have an HIV antibody test done. In studies, PrEP is given to people in tandem with prevention messaging and encouragement to use other forms of risk reduction while using PrEP.

Yet another concern is the people who are not included in current PrEP studies. These projects are mostly studying PrEP in 18 to 40-year-olds. Many others are excluded from these studies, including people with chronic diseases such as TB or evidence of liver or kidney disease. Women who were recently or are currently pregnant or breastfeeding have been excluded. How PrEP impacts these populations will need bridging studies done to assess its effectiveness.

Final thoughts

A great deal of data has accumulated since 2004 in animal studies of PrEP. This has given way to the voluminous study in human that's currently being researched or scheduled to begin. Although many are anticipating what these data could mean to prevention efforts worldwide, study results answering the question about the effectiveness of PrEP in humans won't be available until 2011 or 2012.

PrEP could be given either in a topical or oral product. Through a gel, PrEP can provide higher concentrations of the HIV drug(s) in genital tissues, which could provide more durable preventive effects. Topical PrEP tends to have fewer side effects than its oral counterpart. Women may also have an easier time using it during pregnancy. Long-acting types of gels as well as possible combination products could also be developed.

In pill form, PrEP may provide possible longer-acting protection from HIV infection. However, it also brings with it more issues for side effects, which may impact a person's ability to use or adhere to it as prescribed. It is, however, slightly easier for a person to control or conceal using a pill to using a gel - which is an important factor for those who have a difficult time negotiating sex.

This type of prevention brings up many issues for health care programs, governments, pharmaceutical companies, and for the individuals who may be the future consumers of the product. A greater collaboration between HIV prevention and treatment programs will need to be developed, along with better access to HIV screening programs. Groups who will most benefit from this intervention will need to be identified. How and who will pay for the products will also need to be addressed.

So is PrEP a magic bullet, as Dr. Hillier remarked, or can it live up to its potential? Simply, will it stop HIV infection in people? Will it replace condoms? Or will it become another instrument in our growing toolbox of ways to prevent and treat HIV? Will it be used only in certain populations or will the data direct scientists to develop products that work for everyone?

Project Inform has been involved in many of these issues through its work in national conversations on PrEP. The National PrEP Working Group is one such collaboration of dozens of entities working to lay the groundwork for implementing PrEP in the US should it be shown to work.

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This article was provided by Project Inform. Visit Project Inform's website to find out more about their activities, publications and services.
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CROI 2009 Newsroom

Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.