Microbicides: A New Hope for HIV/STIs. Global and Local Perspectives
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  • [Please start off by introducing yourself and your organization. Say why you are making this presentation and why this issue is important to you. You may want to say that you are doing this presentation on behalf of the Global Campaign for Microbicides which is a coalition of 250 non-profit organizations that advocate for new HIV prevention options. The Global Campaign does not sponsor trials or do the research. Then you could say something like:] Microbicides are products that have the potential to transform the HIV prevention landscape by giving us a new method of protection that is user-initiated, instead of partner initiated. I think it is clear to all of us that not everyone has the power in their relationships to insist on condom use during every act of intercourse. So we need to start talking about what IS possible for women and men in this situation -- what can be developed that would enable both partners to protect themselves when a condom isn’t being used and add to the effectiveness when condoms are used. Today, I would like to talk about three things: 1) First, I will introduce you to the concept of microbicides and how they might fit into an overall program of HIV prevention; 2) Then, I will talk a little bit about how microbicides are being developed, how they would work and where the research is at right now; Finally, I will talk about why we have to develop a vocal and active constituency for microbicides to make sure that this vital new technology reaches the market as soon as possible. [Note to speaker: References are on the final page of the script for this presentation; You are welcome to add your group’s logo to the home page, and your website to the bottom of each slide]
  • Even if you don’t work in HIV/AIDS or women’s health, you can tell by reading the newspaper or listening to the news how urgently we need more prevention options to fight the spread of the pandemic around the world and right here at home. The statistics are mind-numbing. 1 AIDS has killed more than 25 million people since it was first recognised in 1981, making it one of the most destructive epidemics in recorded history. 2 More than 14,000 people are newly infected every day, and almost 40 million people are living with HIV today. Sub-Saharan Africa has been the hardest hit region, with rates soaring in other parts of the world as well, particularly in China and India. It is women who are bearing the brunt of the pandemic in Africa, especially young women. In Sub-Saharan Africa, young women are three times more likely to be infected than young men (aged 15-24). 1
  • Women are at higher risk of HIV infection than men partly because of biology, partly because of economics, and partly because of culture. Women are more vulnerable to HIV because they are exposed to more virus for a longer period of time during sex. 3 Young girls are especially at risk because their reproductive tracts are not fully mature. Economically, in many places, women have less access than men to education, job opportunities, property, or credit, making them financially dependent on their partners. 4 As a result, women often cannot afford to leave relationships that put them at risk of HIV and other STDs. Culture also plays a role. Here and abroad, women are expected to be faithful but men are not. A male partner’s infidelity is one of the greatest HIV risks women face. In addition, gender based violence is a big factor in women’s risk. 5 The current prevention methods (abstinence, fidelity, and condom use) often require active acceptance, participation, consent and cooperation by both partners. But women don’t always have control over when and how they have sex. Although we are making important progress on getting treatment to people, we still need to do everything we can to give people more prevention options especially those that they themselves can control . [Note for some audiences: In this presentation, I am talking mainly in terms of the risk women experience when their male partners won’t use condoms. I realize that all people need tools to protect themselves. For the sake of simplicity, I’m going to just say “women’s risk” here – and ask you to bear in mind that both men and women need more prevention options.]
  • A little recognized truth is that more women get infected with HIV from their boyfriends and husbands, than from casual or commercial sex. Throughout the world, once trust enters a relationship –- condoms usually exit the scene. With proper condom promotion programs, we can help people use condoms in the context of casual or commercial sex. But few people continue to use condoms once they establish a regular partnership. Even with intense condom promotion efforts, consistent condom use among regular partners is difficult to achieve, unless of course the couple knows that one is infected and one is not. 9 “In representative surveys of women in 13 African countries found that fewer than 7% report condom use in the last sex act with their regular partner.” 9,10 Microbicides could potentially help to fill the gap by offering couples a more intimate option in long-term relationships.
  • So what is a microbicide? A microbicide is any substance that can substantially reduce the risk of acquiring or transmitting sexually transmitted diseases, including HIV, when it is applied in the vagina or rectum. It’s important to understand that no proven microbicides exist yet on the market. What we’re talking about here are products that are still being researched. The first generation of microbicides could be available on the market in as little as five to seven years. They will probably look a lot like the over-the-counter yeast infection treatments and birth control products we already know -- the gel, foam, cream and suppository-type products that have been on the shelves for years. They won’t contain the same chemicals as these birth control products but they will come in some of the same formulations. But scientists are also working on developing new formulations that may make the second generation of microbicides even more user-friendly than today’s spermicides. For example, they’re working to make formulations that women can use several hours or even days before intercourse, if necessary. One possibility is a vaginal ring or sponge-- something that could slowly release the protective substance over time, providing round the clock protection. Another possibility is combining a physical barrier -- such as a diaphragm or cervical cap -- with a microbicide. Since the cervix is more vulnerable to infection than the vaginal walls, this combination might provide highly effective protection.
  • Some of the microbicides being developed will also be contraceptive. And that’s great because many women would like to have a product that can protect them from disease and pregnancy at the same time. But scientists are also working on non-contraceptive microbicides that would be helpful to women and men who want to conceive a child while still protecting themselves from possible infection --- something that is impossible with condoms. Some microbicides are also being tested for efficacy against other sexually transmitted infections (STIs), and several of them appear to reduce risk of at least one or two other STIs . Eventually, scientists may be able to combine active ingredients so that one product can serve several purposes. Obviously, we need products that are safe and don’t irritate any tissue or organs. Irritation, inflammation or allergic reaction to any product can actually increase HIV and STI transmission risk because it makes it easier for pathogens (germs) to enter the bloodstream. So it’s critical to have products that are safe, even when they are used several times a day. The issue of access is one of the fundamental goals of the Global Campaign. Advocates around the world are already working to make sure that microbicides are affordable and easily accessible and made available without a prescription. Finally, when using a microbicide, a woman wouldn’t need to gain her partner’s active cooperation at each act of intercourse – the way she has to with male or female condoms. Many women probably will choose to discuss microbicide use with their partners. But this could be a one time conversation -- and it wouldn’t have to happen right before sex. After that, the woman could manage her own protection without need to “negotiate” or interrupt sexual spontaneity every time.
  • Vaginal and rectal microbicides could work in similar ways. The first approach they’re using is pretty obvious -- coming up with products that just kill or disable HIV and other pathogens that come into the body. The trick here, of course, is to make something that kills pathogens but doesn’t irritate the epithelial lining of the vagina or rectum. Some products in this category are in vaginal trials but none are in rectal trials yet. Since the rectum is more fragile than the vagina, it may be difficult to create a product with this mechanism of action for the rectum. The second approach involves trying to enhance the body’s own ability to protect itself. One product in this category, called BufferGel, is designed primarily to keep the vaginal pH low even after ejaculation -- since low pH is one of the vagina’s defense mechanisms. A low pH can inactivate a substantial amount of HIV entering the body, as well as some other pathogens. Although rectal pH is naturally higher than vaginal pH, the creators of BufferGel feel that their product might still have some efficacy in reducing HIV risk in the rectum. Research is needed to see if the rectum can tolerate BufferGel without problems. In the test tube, BufferGel appears to inactivate not only HIV but also chlamydia and Human Papilloma Virus (HPV). The third approach involves creating products that make a barrier to keep pathogens, like HIV, from attaching to epithelial cells. We know that HIV has to attach to a cell in order to infect it. If it can’t attach, it can’t infect A fourth approach is to take some of the anti-retroviral drugs that many people with HIV take to reduce viral load and re-formulate them for topical use in the vagina or rectum. Products in this category are just going into vaginal trials but none are in rectal trials yet. In the end, we will ideally be able to combine these mechanisms for greatest effectiveness. (More details available from the Alliance for Microbicide Development – www.microbicide.org)
  • So how do microbicides work? The products now in the research pipeline fall into four basic categories -- defined by how they work. These are also known as ”mechanisms of action”. This slide is a picture of the vaginal wall and illustrates the different ways that candidate products might work to reduce infection. 12 1. The first approach is to build or improve upon what the body already does to protect itself. For example a healthy vagina is normally acidic, which makes it inhospitable to invading pathogens like HIV. But semen counteracts this acidity, creating an environment where HIV can survive. Some candidate microbicides build on the simple principle of maintaining the vagina’s natural acidic even in the presence of semen. 2. Surfactants disable the virus by breaking up its surface membrane or envelope. They can also disable sperm in the same way so they are also effective contraceptives. The trick is to make sure that surfactants are strong enough to disrupt the invading pathogen, but without damaging the healthy cells that line the vagina’s walls. 3. Entry inhibitors work by interfering with the virus getting into the body’s white blood cells—the target cells of HIV. There are two categories of entry inhibitors: attachment inhibitors that prevent attachment of the virus to the white blood cell and fusion inhibitors that prevent HIV from actually entering the cell. 4. Finally, some microbicides are being created by reformulating the same anti-retroviral drugs developed to treat people with HIV. These drugs are designed to stop HIV from replicating. So what happens if you make them into products that can be applied in the vagina? Could you stop the replication of any HIV that enters a vaginal cell so that the virus does not have a chance to disseminate and enter the blood stream? That’s what some researchers are trying to find out. The first microbicides to become available may operate with just one mechanism of action. It is very likely, however, that later generation microbicides will be combination products -- using two or more mechanisms of action to enhance their effectiveness.
  • As you saw earlier, there are currently three products in large scale effectiveness trials around the world. This slide shows the names of these products and the group running the trial in the first column, how many people the trials aim to recruit, where they are taking place, and when we can expect results assuming everything goes according to plan. 14 I like to show this slide not only so that you can become familiar with the names of the products but also to recognise the thousands of women who are involved in this endeavor. On average a woman in a current effectiveness trial will attend 29 study visits, including monthly visits for HIV and pregnancy tests, and have 11 pelvic exams and over 2 years. It is so important to recognise and honour their commitment. 16 Without their participation, it would be impossible to find out which, if any of these candidate microbicides, actually works. [Expected preliminary results. 15] [For a more technical audience, you can hand out a copy of the Global Campaign’s Factsheet #13 Clinical Trial Watch that describes these products in more detail – www.global-campaign.org/download.htm] [For a more information on the January 2007 Cellulose Sulfate trials closure, please see www.global-campaign.org/cellulose-sulfate.htm]
  • Microbicides will help people reduce risk of infection -- but we need to be clear about the fact that they aren’t going to eliminate risk. Microbicides will probably never be as effective as condoms. 7 It’s safer to keep a virus out of your body than it is to try to kill or disable it once it’s there. That’s common sense. But remember, we’re talking about microbicides as an option for people who can’t or don’t use condoms. The first microbicides are only likely to be 40-60% protective against HIV. The second generation microbicides may be 60-80% effective against HIV. 7 A condom with 80 to 95% effectiveness 8 is definitely the most effective disease prevention option, but it has ZERO effectiveness if a couple is not using it. It is our hope that although microbicides may be less effective, couples may be able to use them more consistently than they currently use condoms. So we should talk about microbicides as part of a risk reduction approach . We need to encourage people to continue to use condoms if they possibly can. Many folks may want to use microbicides with their condoms for back-up protection and added pleasure. Microbicides would give us something to suggest when a woman says “I just can’t make him use a condom. Isn’t there something else I can do to protect myself?” Once microbicides become available, we’ll be able to answer by explaining clearly that these new products aren’t as effective as condoms -- but they are much better than nothing. And, as we all know, a lot of women are getting infected because “nothing” is all they have.
  • Even if we are talking about partially effective microbicides that complement other interventions, they could still have a big impact. Computer modelling conducted at the London School of Hygiene and Tropical Medicine estimates that: 7 if a 60% effective microbicide is introduced in 73 low income countries with high HIV rates and gets used by only 20% of the people with access to existing health services and those people use it only half of the time when they’re not using condoms it could prevent 2.5 million new HIV infections among women, men & children over 3 years. 4 I’m not saying that this impact would be immediate. But we’re still talking about millions of lives potentially saved. And, as you see, these calculations are on relatively modest estimates of effectiveness, uptake and use. A more effective microbicide, used by a larger number of people, would have an even greater effect. Microbicides are not a panacea. But they could save a lot of lives and make an enormous difference in the spread of the pandemic. Now before I tell you more bout how microbicides work and where we are at in the research, are there any questions before we move on?
  • As you can see, drug development is a long and complicated process…taking more than a decade to develop and test a new drug for use. Before any new drug candidate can be tested in human beings, the developers have to show that (a) it’s not likely to be harmful to humans and (b) it may be beneficial. The research is done in laboratory testing and in animals and can take anywhere from 2 to 6 years. Currently there are over 30 candidates in pre-clinical testing (i.e. that is, that have not yet entered human testing). If a product is approved for human trials, it goes first through a series of Phase I safety trials, where small numbers of people who are at low risk of infection use the product and are carefully monitored for signs of problems. Next come one or more Phase II trials to gather extended safety data and establish safety among different groups of people–-for example, those who may already be HIV positive or have another sexually transmitted disease. If a product is shown to be safe in these first two phases, a product can then be tested for effectiveness. The Phase III trials can take several years because they need to enroll thousands of women who use the product for many months up to several years to see if it reduces their risk of HIV infection. It may be necessary to do two Phase III trials before a product can be licensed for use. While clinical trials are going on in women, researchers also need to undertake separate trials to look at whether the product is irritating to the penis or rectum. [ Products in Phase I/II are counted as Phase II and products from Phase II/IIB are counted as Phase III products. 13 ]
  • This slide is to give you a sense of where these trials are taking place. 14 As you see, Phase I and II safety trials are going on all over the world, but especially concentrated in the U.S. and Africa. To study effectiveness, a microbicide has to be tested by large numbers of women at high risk of sexually transmitted HIV. This means that the countries in which Phase III trials are carried out must have: ·  A high incidence of HIV · A stable population so that participants can be followed up easily ·  Almost no injecting drug use or other sources of HIV risk among women These conditions are found across sub-Saharan Africa and in India and parts of Southeast Asia. Places where HIV is prevalent among women in the North America and Europe also tend to have high rates of injecting drug use. This factor could confuse the trial results by introducing other sources of HIV risk. In part due to this reason, the majority of effectiveness trials are taking place in Africa as indicated here. [Map 21 ]
  • Results from the trials furthest along could become available in 2008, but it will take additional time for the products to be reviewed and approved for licensure – at least 1-2 years. Thus, we could be ready to introduce a product by 2010, but that would only happen in a few countries, and most likely through smaller scale introductory programmes. If the current set of products in effectiveness trials does not prove effective, the time horizon will be longer. There are several second-generation leads already in human testing, so we need to ensure that the entire pipeline continues to advance. Due to advocates work around the world and the recent attention on microbicides at the 2006 International AIDS Conference in Toronto, millions of people have heard about microbicides. The challenge that the microbicide field faces now is to find the correct balance between building enthusiasm and political support for microbicides, while avoiding raising unrealistic expectations in the media or our outreach work.
  • Every woman who is recruited for an effectiveness trial goes through a careful informed consent process in their own language and is tested for HIV and other STIs. Women who test positive for HIV can’t enroll in these first effectiveness trials because women have to be negative at the start of the trial to see how well the product helps them to remain negative. Women who test positive are connected to local providers of HIV-related care, treatment and support. Everyone in a Phase III trial receives state-of-the-art HIV prevention services. Right now, this means participants receive intensive risk reduction counseling, including condom counseling, large supplies of condoms and treatment for sexually transmitted infections if needed. All the women are encouraged to use condoms, whether they are given the active microbicide or not. In order to actually find out if the experimental microbicide works, the trial participants are randomly divided into two groups: Those who receive the condoms and prevention services plus the experimental microbicide gel. Those who receive the condoms and preventions services plus a placebo gel that looks just like the drug being studied but does not contain the active ingredient. An independent data safety monitoring board (DSMB) monitors the trials for any concerns that suggest the trial should be stopped. At the end of the trial researchers compare the two groups to see if the HIV rate is lower among those who received the microbicide versus those who received the placebo. If it is, that difference is the measure of the microbicide’s effectiveness. Trials can also bring increased health care, prevention services and treatment access into highly-impacted communities. How those services are provided and how well they are continued after the trial is a subject of intense ethical debate among researchers and communities. One of the Global Campaign’s functions is to help trial communities prepare to advocate effectively for their communities during this process.
  • Formulating a microbicide for rectal use is more challenging than making one for vaginal use just because the rectum is a very different environment. First of all, it’s an open ended cavity. The vagina is a closed pouch. You can coat the inside of the vagina with about 3-5 milliliters of product. Since the rectal cavity isn’t closed, it could require significantly more product to protect the rectal walls where they need protection. One of the key questions scientists are trying to answer now is exactly how much product it will take and what areas have to be covered to get a good protective effect. Rectal tissue is also more fragile than the tissue lining most of the vagina. It is is thinner and populated with cells that are especially vulnerable to HIV infection. 6 Research has begun to develop rectal microbicides. They are urgently needed -- not only by gay men but also by the many women who engage in anal intercourse. The International Rectal Microbicide Working Group brings together advocates and researchers, and now has over 200 members. You can find out more through the Global Campaign website. But until we have an effective rectal microbicide, we have to insist that all vaginal microbicides nonetheless be tested for safety in the rectum, even if not designed for that use. And products designed for vaginal use must be carefully labeled to alert users that they should not be used rectally, until proven safe and effective for rectal use. [Note: if the audience is particularly interested in rectal microbicides, visit www.global-campaign.org/download.htm for a factsheet and complete presentation on rectal microbicides. Also visit www.lifelube.org]
  • We need to work towards an expanded toolkit of HIV prevention and treatment to combat this epidemic. Right now, we have many tools that people can use before exposure, right at he point of HIV transmission, and also after being infected. Admittedly we need to improve people’s access to these existing tools—we need to make sure that male and female condoms are available to those who need them at an affordable price, and that women can access prevention of mother to child transmission services when they need them. [Speaker can indicate existing interventions in blue] Advocates and researchers around the world are also working to see if there are new options that we can add to this spectrum in the near future. [Speaker can indicate new interventions in pink] [Speaker may choose to use this slide only with audiences who are familiar with the field of HIV/AIDS.] VCT is voluntary counseling and testing for HIV PREP is pre-exposure prophylaxis PMTCT is prevention of mother to child transmission PEP is post-exposure prophylaxis
  • 1. 2006 Report on the Global AIDS Epidemic . UNAIDS. World Health Organization. Geneva, Switzerland. June 2006. 2. World Health Organization, AIDS Epidemic Update. December 2005. 3. European Study Group on Heterosexual Transmission of HIV. Comparison of female to male and male to female transmission of HIV in 563 stable couples. British Medical Journal. 1992; 304:809-813. 4. Economic Security for Women Fights AIDS. Global Coalition on Women and AIDS Report, Issue #3. UNAIDS Initiative. Geneva, Switzerland. 2005. Kelley Hallman, “Gendered socioeconomic conditions and HIV risk behaviors among young people in South Africa,” African Journal of AIDS Research, 2005, 4(1):37-50. Richard Strickland, “To Have and To Hold: Women’s Property and Inheritance Rights in the Context of HIV/AIDS in Sub-Saharan Africa,” ICRW Working Paper, June 2004. 5. Garcia-Moreno C and Watts C (2000) ‘Violence against women: its importance for HIV/AIDS’, in AIDS, 14, Geneva. 6. Royce, R.A.; Sena, A.; Cates, W. Sexual transmission of HIV. New England Journal of Medicine. 1997; 336:1072-1078. Abreu, M.; Anton, P.; Coombs, R. Anatomy, physiology, immunology of the anorectal mucosa. From: Rectal Microbicides Workshop: Baltimore, MD, June 7-8, 2001; Rectal microbicides that protect against HIV infection:8. American Foundation for AIDS Research. 7. Foss, A.; Vickerman, P.; Heise, L. Shifts in condom use following microbicide introduction: should we be concerned? AIDS 2003, 17:1227-1237 8. Studies show that consistent use of latex condoms reduces the likelihood of HIV infection by 80 to 90 percent. “ USAID: HIV/STI Prevention and Condoms. May 2005” :   http://www.usaid.gov/our_work/global_health/aids/TechAreas/prevention/condomfactsheet.html Pinkerton, S.D.; Abramson, P.R. Effectiveness of condoms in preventing HIV transmission . Social Sciences & Medicine 44(9):1, 303-312. From Condom Promotion for AIDS Prevention in the Developing World: Is it Working? By Norman Hearst and Sanny Chen. Davis KR and Weller SC. The effectiveness of condoms in reducing heterosexual transmission of HIV. Fam Plann Perspect 1999;31:272-279. Weller S, Davis K. Condom effectiveness in reducing heterosexual HIV transmission (Cochrane Review). In: The Cochrane Library, Issue 2, 2004. Chichester, UK, John Wiley & Sons, Ltd. HIV Tools Research Group: Department of Public Health and Policy, London School of Hygiene and Tropical Medicine. Are people using condoms? Current evidence from Sub-Saharan Africa and Asia and the implications for microbicides. November 2003. available from GCM website: http://www.global-campaign.org/clientfiles/LSHTM-Condom.pdf 10. Foss, A.; Watts, C. Condoms and prevention of HIV are essential and effective, but additional methods are also needed. British Medical Journal. Vol 329. 24 July 2004. pp. 185-186. Jenkins, R. A.; Manopaiboon, C.; Samuel, A. P. Condom use among vocational school students in Chiang Rai, Thailand. AIDS Educ Prev 2002; 14(3): 228-245. 11. Brady, Martha. Population Council, Conceptual Framework. 2005. 12. Shattock, R.; Moore, J. Inhibiting Sexual Transmission of HIV-1 Infection . Nature Reviews Microbiology. Vol 1, October 2003. 13. Alliance for Microbicide Development News Digest. Vol. 7, No. 33. September 2006 Pipeline Update. www.microbicide.org/publications. 14. Alliance for Microbicide Development, Microbicides Research and Development Database. www.microbicide.org 15. Ramjee, G. Microbicides and other prevention technologies. XVI International AIDS Conference, Toronto: 15 August, 2006. Plenary session: Proven approaches and new technologies. 16. Microbicide Clinical Trials: Needs and Challenges, Salim Abdool Karim, MBChB, PhD, Director, Centre for the AIDS Programme of Research in South Africa (CAPRISA), Presented at US Congressional briefing, 18 July 2006. 17. Financing the expanded response to AIDS: HIV vaccine and microbicides research and development. U NAIDS, 2005. http://hivresourcetracking.org 18. Lamphear, T. Determining the Costs: Getting to proof-of-concept. Microbicides 2004 Conference. London, UK, 30 March, 2004. 19. Harrison, P.; Lamourelle, G.; Rowley, J. Warren, M. Tracking funding for Microbicide Research and Development: Estimates of annual investments 2000 to 2005. HIV Vaccines and Microbicides Resource Tracking Working Group Report. June 2005. 20. African Microbicides Advocacy Group, Alliance for Microbicide Development, Global Campaign for Microbicides, International Partnership for Microbicides. (8 July 2005). “Global Health Leaders React to G8’s First –Ever Call for More Investment in Microbicides to Protect Women from HIV”. Press release. 21. Graphic Maps. http://graphicmaps.com/aatlas/worldant.htm 22. Quote from last slide: Quote found in UNICEF, Facing the Future Together: Report of the Secretary-General's Task Force on Women, Girls and HIV/AIDS in Southern Africa, July 2004. http://www.unicef.org/publications/SGs_report_final.pdf – Quote from UNICEF’s Voices of Youth, www.unicef.org/voy References: Remember! Updates of this presentation are available at www.global-campaign.org/download.htm

Transcript

  • 1. Microbicides: New Hope for Prevention of HIV and other STIs Pamina M. Gorbach UCLA- SPH & Medicine
  • 2. The Global Impact of HIV People living with HIV in 2006 New infections in 2006 Worldwide 39.5 million 4.3 million Sub-Saharan Africa 24.7 million 2.8 million Asia & Eastern Europe 10.25 million 1.23 million North America & Western/Central Europe 2.14 million 65,000 Other 2.49 million 242,100 Women are disproportionately affected by AIDS: In Sub-Saharan Africa, young women are 4 times more likely to be infected than young men.
  • 3. Why We Need Female Controlled Methods Biology –Women are 2-4 times more likely than men to get HIV from unprotected sex Economics –Economic need or dependency –Less able to assert their rights Social & Cultural –Gender norms about sexuality –Gender based violence Current methods (abstinence, fidelity, and condom use) often require male consent, participation & cooperation
  • 4. Protection in Primary Partnerships: Difficult to Achieve • People generally are willing to to use condoms with new partners, or during casual or commercial sex • But once “trust” enters the equation the condom comes off • Sex with a primary partner is the biggest source of HIV infection among women globally
  • 5. What is a Microbicide? A substance that can reduce the transmission of HIV and other STI pathogens when applied topically to genital mucosal surfaces - vaginally and, possibly, rectally. They are not yet available. First Generation: • Gels and creams In the future: • Sponges, vaginal rings • Gels with barrier devices ©SalamDahbor,CourtesyDoubleshotsStudio •Possibly use of oral antiretroviral therapy, (tenofovir), for pre- exposure prophylaxis (PrEP) to prevent HIV infection.
  • 6. What Do We Need from Microbicides? •To be contraceptive and non-contraceptive •To reduce risk of other STIs •To be safe and non-irritating •To be inexpensive and available over the counter •To be possibly used without partner’s cooperation or even awareness
  • 7. How could microbicides work? • Kill/inactivate/immobilize the virus • Boost body’s natural defenses • Prohibit viral entry by blocking fusion • Inhibit viral replication • Create a physical barrier or some combination of these approaches
  • 8. 2. surfactants 3. entry inhibitors = CS, Carraguard, Pro2000 4. anti-retrovirals =Tenofovir, UC781, TMC120 1. boosts vagina’s natural defenses - Buffergel Source: Shattock, R.; Moore, J. Inhibiting Sexual Transmission of HIV-1 Infection. Nature Reviews Microbiology. Vol 1, October 2003.
  • 9. MICROBICIDES IN CLINICAL TRIALS May ‘07 © Alliance for Microbicide Development
  • 10. 3 Products Furthest Along Product Trial sponsor # women to be enrolled Location Preliminary results expected in Buffer Gel HPTN035-NIH 3,100 women South Africa, Malawi, Tanzania, Zambia, Zimbabwe and Philadelphia April 2009 Carraguard Population Council 6,299 women South Africa – 3 locations December 2007 PRO2000 (.5%) HPTN035-NIH 3,100 women South Africa, Malawi, Zambia, Zimbabwe and Philadelphia April 2009 PRO2000 (.5 and 2%) DFID, MRC 9,673 women South Africa, Uganda, Zambia, Tanzania December 2009
  • 11. Planned Microbicide Trials There are 11 microbicide candidates in clinical development and over 30 in preclinical development
  • 12. How Effective Will Microbicides Be? First microbicides may be 40-60% protective Second generation may be 60-80% Promoted as a back-up to condoms, not as a replacement. “Use a microbicide with your condom for added pleasure and protection.” “Use a male or female condom every time you have sex; if you absolutely can’t use a condom, use a microbicide.”
  • 13. Potential Public Health Impact If a 60% effective product Offered to 73 lower income countries Is used by 20% people reached by health care during 50% of unprotected sex acts = 2.5 million HIV infections averted in 3 years including women, men and children
  • 14. Laboratory Testing 2-6 Years Phase III (efficacy) 2 to 4 Years Simultaneous studies in some cases: HIV+, penile & rectal safety 10 or more years 3 products 3 products 4 products 30+ products Phase I (safety) 1 to 6 Months Phase II (safety) Up to 2 Years 25 – 40 people 200-400 people 3,000-10,000 people The Product Pipeline in 2007 Source: Alliance Pipeline Update, first week of every month - http://www.microbicide.org/publications
  • 15. Clinical Trial Sites in 2007 AUSTRALIA - Phase 1 WEST AFRICA: -Cameroon: Phase I, II THE AMERICAS: -United States: Phase I, II, IIB -Brazil: Phase II SUB-SAHARAN AFRICA: -Botswana: -Kenya: planned -Madagascar: Phase -Malawi: Phase II, IIB -Rwanda: Phase I/II -South Africa: Phase I, IIB, III -Tanzania: Phase III -Uganda: Phase III -Zambia: Phase IIB, III -Zimbabwe: Phase I, II, IIB ASIA -India: Phase II -Thailand: Phase I Source: Alliance for Microbicide Development EUROPE - Belgium: Phase I/II
  • 16. When can we expect a microbicide? •Earliest results from current Phase 3 trials in 2008-2009 •If shown to be effective, a microbicide may be available in a few countries via introductory studies in the next 5 years • If not, we will have to wait for results from second generation products
  • 17. The Microbicide Trials Network (MTN) is a worldwide collaborative clinical trials network that evaluates the safety and efficacy of microbicides designed to prevent HIV transmission and will support licensure of topical microbicide products. The MTN plans to develop and/or execute 15 separate clinical trials of microbicides between 2006 and 2013. Network led by Sharon Hillier at Magee Women’s Health Foundation/U Pitts: Dr. Ian McGowan is a Co-principal investigator. PMG – Chair of Behavioral Research Committee
  • 18. Topics on BRC Scientific Agenda: Adherence & Acceptability Topic Measurement Context Measurement approaches for contexts of microbicide use Partners Partner types and relationship dynamics Microbicide Administration Methods Biomarkers Use of biomarkers for comparison with or validation of behavioral measures of adherence Pregnancy Pregnancy intentions at screening, affects of trial participation at individual and community level
  • 19. Experience of a Phase III Participant Recruitment: Participant receives information about the trial in their own language Screening Visit 1: Education about the trial, HIV and pregnancy test, STI tests and treatment, baseline data collected Screening Visit 2: Results of tests, counselling, reinforce education about trial Randomisation : Participant assigned by chance to a group. Family Planning Informed consent for screening Informed consent to enroll. Condoms + placebo Condoms + experimental gel
  • 20. Handheld screen with 035 adherence question (n=400 in Malawi Courtesy of Barbara Mensch, Population Council
  • 21. Malawi – Pop Council School Study Courtesy of Barbara Mensch, Population Council
  • 22. Microbicide Research in LA • Focus on rectal microbicide development • Principle research effort led by UCLA: – Microbicide Development Program (MDP) – U19 funded by NIAID • Preparedness: – NARLA: Project 2 -
  • 23. Rectal Microbicides • Many people (women and men) need microbicides for anal intercourse • Creating an effective rectal microbicide is scientifically more complicated • Vaginal microbicides must be accurately labeled Photo courtesy of www.lifelube.org
  • 24. •PI: Peter Anton & Ian McGowan. Collaborative effort with NIH and industry to initiate multidisciplinary research on rectal microbicides through multiple projects including:  Preclinical Evaluation of HIV Rectal Microbicides Rectal Health, Behaviors and Product Acceptability Phase I trial of a rectal microbicide UC-781 a reverse transcriptase (RT) microbicide •These studies are designed to help develop a product that people will find acceptable and actually use. Findings will help guide the selection of the formulation used in human trials.
  • 25. Two Components: (1) Integrated behavioral and clinical study of receptive anal intercourse (2) Applicator method acceptability (preference) study • 2 sites: LA, Baltimore Rectal Health, Behaviors and Microbicide Acceptability – U19 Project 3 - Gorbach
  • 26. “AMP” Ano-rectal Microbicide Project 896 participants ½ in LA ½ men & ½ women ½ HIV positive ½ report recent RAI All complete: STI/HIV testing HRA Clinical exam Behavioral Questionnaire Already ~ 219 studied!
  • 27. Why This Study? Preparedness… • Rectal microbicides are in development. • The public knows little about rectal microbicides. • There will soon be clinical trials of rectal microbicides that will need participation from those who need and will use them. A Phase I trial started in LA (U19). • There is a need for specially designed materials to introduce the public to rectal microbicides (both within clinical trials and beyond) to optimize their value as a method of HIV prevention. • Preliminary work with communities is necessary to prevent misinformation and enhance acceptability.
  • 28. Study Goals 1. Assess the best format to deliver educational materials about rectal microbicides to potential participants in clinical trials, and 2. Consider potential barriers to microbicide trial participation by analyzing factors that facilitate enrollment and retention in a microbicide trial registry in a cohort of men in Los Angeles N=>106 already! Total cohort 450 men
  • 29. Materials Developed (Video & Brochure) in LA in 2006 Community sites: Friends, APLA, UCLA-CARE
  • 30. What if microbicides don’t work? • Build on the lessons in development of new technologies – process is iterative. • But….keep perspective. Failure of one product that utilizes one mechanism of action in microbicide does not mean all microbicides are doomed. Many other products and other mechanisms in the pipeline • Future microbicide will likely use combination mechanisms and will likely include coitally & non- coitally dependent methods • Setbacks may happen but science must move forward – there is an epidemic…
  • 31. Imagine a Full Spectrum of Interventions Prior to exposure Point of transmission Treatment •Male and female condoms and lube •PMTCT •Clean injecting equipment •Vaginal and rectal microbicides •Cervical barriers •PEP •Anti-retroviral treatment •Treatment for opportunistic infections •Basic care/nutrition •Prevention for positives •Education and behavior change •Therapeutic vaccines •Rights-focused behaviour change •VCT •STI screening and treatment •Preventative Vaccines •PREP •Male circumcision
  • 32. FrankHerholdt,CourtesyofMicrobicideDevelopmentProject •The global and local need for microbicides is urgent as women and men continue to become infected and suffer from HIV •There are vaginal & rectal microbicides in clinical trials now •Microbicides offer great potential to impact HIV epidemics –one more prevention tool - self not partner controlled