1. HIV Prevention Options for Women: Microbicides Martin Methot August 10, 2006 International Partnership for Microbicides

2. Outline of Presentation n The Face of HIV Globally n What is a Microbicide? n International Partnership for Microbicides (IPM) n Quotes from leaders in the HIV/AIDS field

3. The Face of HIV Globally Increasingly female Increasingly female In Sub-Saharan Africa, 74% of young people (aged 15-24 years) living with HIV are female In Asia, 30% of all adults living with HIV are female (and new cases are occurring faster in women) Female HIV infections are also on the rise in Eastern Europe and Latin America In South Africa – 1 in 4 women infected by age 22 Married, monogamous Married, monogamous In India – 22% of cases in housewives with single partner Mothers Mothers World Bank Photos

4. Current HIV Prevention Strategies n Abstinence n Delay first sexual act n Be faithful n Male and female condoms n Behavior change n Treatment of sexually transmitted infections

5. Other Prevention Strategies Under Research n Male circumcision n Cervical barriers (diaphragm) n Pre-exposure prophylaxis with ARVs n Herpes suppression n HIV Vaccines

6. Marriage and Motherhood as Risk Factors n Marriage and women’s own fidelity not enough to protect them against HIV infection n Many women infected, despite staying faithful to one partner: 66% of women surveyed in Zimbabwe and South Africa reported one lifetime partner – and 40% were HIV positive n According to the UN: 56% of pregnant women between 25 and 29 in Swaziland HIV positive – the highest prevalence in 5 years

7. Women’s Vulnerability n Women's susceptibility to HIV infection  results from a combination of biological, social and cultural factors n Young women are at highest risk of HIV infection due to:  an immature physiology  inequitable gender norms – climate that accepts exploitation and violence towards girls  prevalence of transactional sex, coupled with liaisons and marriages between girls and older, more sexually experienced men

8. The Need for HIV Prevention Initiated by Women n Most HIV infections are spread by unprotected sex n Most current methods are male-initiated and contraceptive n Women have no means to protect themselves if their partners do not use male condoms or allow female condoms n Abstinence and being faithful are not likely to protect married women or those who are sexually abused

9. What is a Microbicide?  Substance that can prevent transmission of HIV when applied to the vagina  Could be made in many forms:  gel or cream  sponge  film  suppository  vaginal ring or diaphragm

10. The Ideal Microbicide n Safe - must have no localized toxicity n Effective - must have a significant degree of efficacy in routine use n Cheap - pricing strategy must optimize distribution and availability n User-friendly - must be compatible with use during sex, and acceptable to women and their partners Robin Shattock, St George’s, University of London

11. Delivery Methods Vaginal applicator (right) and applicators being filled (above) Vaginal ring (above)

12. Comprehensive Approaches to HIV/AIDS Vaccines Pre-exposure prophylaxis STI treatment Male and female condoms Anti-retroviral therapies (mother-to-child) Microbicides Anti-retroviral therapies Opportunistic infection therapies Basic care Microbicides offer a woman-initiated method to reduce HIV transmission Behavior change Prior to ExposurePoint of Transmission Prevention Time of Exposure Prior to Exposure Treatment and Care

13. First Generation Microbicides  Products that form physical barriers to HIV or change the chemistry of the vagina to boost up defenses against HIV  In most advanced stage of clinical trials  But likely to be only partially effective

14. Candidate Microbicide Mechanism of Action Sponsor/FunderTrial Location CarraguardEntry InhibitorPopulation Council/Gates, USAID South Africa – Gugulethu, Isipingo, Durban, Gorankuwa, Shoshanguve Cellulose Sulfate Trial 1 Entry InhibitorGlobal Microbicide Program/Gates, USAID Nigeria – Port Harcourt, Lagos Cellulose Sulfate Trial 2 Entry InhibitorGlobal Microbicide Program/Gates, USAID Burkina Faso, Uganda India, Kenya South Africa PRO 2000Entry InhibitorUK Medical Research Council/DFID South Africa – Mtubatuba, Durban, Johannesburg Uganda – Masaka Tanzania – Mwanza PRO 2000 Buffer Gel Entry Inhibitor Vaginal Defense Enhancer NIH/NIAIDZimbabwe – Harare, Chitungwiza Zambia – Lusaka Malawi – Blantyre, Lilongwe South Africa – Durban, Hlabisa SAVVY (C31G)Membrane Disruptive Agent (Surfactant) CONRAD/FHI/USAIDNigeria – Lagos, Ibadan Current Clinical Efficacy Trials

15. Next Generation Microbicides n Next generation microbicides  Specifically active against HIV  Include microbicides that use antiretroviral drugs  Examples: Tenofovir/PMPA gel, Dapivirine/TMC120 gel, UC-781  In safety trials in humans  Highly active, can be formulated for slow release n Future of microbicides is likely in combinations  Two or more mechanisms of action included in one product to increase effectiveness

16. AIDS Therapy Timeline YearEventDescription 1981First documented AIDS case reported in the US Within 4 years, at least one case of HIV has been reported in each region of the world 1983HIV virus identifiedAIDS caused by a retrovirus: Human Immunodeficiency Virus 1987AZT mono-therapy approved for use A nucleoside reverse transcriptase (RT) inhibitor, AZT is the first drug to slow the progression of the disease; but not a cure or an easy solution (strict every-4-hour regimen, serious side effects, only offered in advanced stages of the disease) 1995Two-drug therapy becomes available FDA approves Invirase, the first protease inhibitor (PI), for use in combination with other nucleoside analogue medications 1997Three-drug therapy: HAART Triple-drug combinations proved to be the most effective in suppressing HIV and preventing resistance; Within one year, this highly active antiretroviral therapy (HAART) reduced new AIDS conditions, hospitalizations, and deaths by 80%. First NNRTI type drug, Nevirapine, also becomes available for use 2003Focus on combinations & reducing pill burden FDA approves a fourth class of drugs known as fusion inhibitors (FI), in addition to other 1 st and 2 nd class drugs; Dosing regimen is simplified from 5 to 2 pills a day, then further to 1 pill daily 200626 FDA-approved drugs & research continues Current research works to develop more potent therapies that have fewer toxic effects and are easier to administer (e.g. cellular metabolism modulators, gene therapy, coreceptors, etc.)

17. Source: Alliance for Microbicide Development Microbicide Trial Sites

18. Ethics of HIV Prevention Trials n Informed consent n Family planning counseling n Pre/Post HIV-testing counseling n Referrals for those screening positive n Treatment of STIs n Treatment of those who become HIV-infected during the trial n Treatment of adverse reactions n Resistance

19. Urgency and Access Historically, it can take decades for scientific innovation to reach the developing world The microbicide field is committed to speeding up availability of effective products - reaching those who are most in need first Microbicides must be widely available and affordable

20. Key Challenges n Expand pipeline of promising compounds n Promote community engagement at trial sites to ensure community and national ownership n Significantly increase funding for microbicide research and development n Encourage international leaders to support microbicides as part of a comprehensive response to HIV/AIDS

21. Funding for Microbicide Field

22. Cost and Financial Gap  In 2005 the global community spent just over $160 million for microbicide research and development.  Funding for the microbicide field needs to double to nearly $300 million annually to accelerate product development.

23. IPM Mission IPM’s mission is to prevent HIV transmission by accelerating the development and availability of safe and effective microbicides for use by women in developing countries.

24. Opportunities For Action 1. Assess and fund across the microbicide portfolio 4. Optimize clinical trial capacity 2. Help develop the “next generation” of microbicides 3. Provide common capabilities or supports for the field Coordinate effort to ensure widespread availability and adoption Discovery Basic research Pre- clinical Clinical trials Launch Multiple mechanisms/ targets/products Formulation capacity In vitro and in vivo models Regulatory Manufacturing

25. Pharmaceutical Partners n IPM in-licensed compounds from three large pharmaceutical companies:  TMC120 or Dapivirine - from Tibotec Pharmaceuticals/ Johnson & Johnson  M167 - from Merck & Co.  BMS793 - from Bristol-Myers Squibb n Royalty-free rights to develop, manufacture and distribute microbicides in developing countries

26. IPM Clinical Trials: TMC120 Safety n First use in Africa n Expanded safety (42 days use, 112 women) n Sites:  Kigali, Rwanda (with Project Ubuzima)  Moshi, Tanzania (with KCMC & Harvard)  Johannesburg, S. Africa (with Univ. of Witwatersrand)  Bloemfontein, S. Africa (with FARMVOS-Parexel)

27. Delivery Systems n The delivery vehicle for an active drug is just as critical as the active itself. n Semisolids: gels (including once-a-day gels), creams, lotions, emulsions n Develop “non-coitally dependent” microbicides and vehicles allowing for slow release: vaginal rings

28. Leaders Speak “Quite frankly, I find it extraordinary that the search for an effective and safe vaginal microbicide has been progressing so slowly. Particularly as we know that microbicides are a real possibility.” Dr. Peter Piot, Executive Director, UNAIDS “The women of Africa need new prevention options. They are at tremendous risk for HIV, so they should be empowered with an option to reverse the pandemic. Microbicides will put HIV- prevention into their hands”. Mrs. Graça Machel, President, Foundation for Community Development, Mozambique

29. Leaders Speak (cont.) “Making microbicides available, accessible and affordable for women is one of the greatest and most significant contributions the world can make for women to protect themselves from HIV infection”. Ms. Anandi Yuvaraj, India HIV/AIDS Alliance “ Gender inequality is driving the virus, and that is why the microbicide potential is perhaps in the immediate future the most significant potential of all”. Mr. Stephen Lewis, U.N. Special Envoy for HIV/AIDS in Africa

30. Leaders Speak (cont.) “If we’re going to end AIDS, we have to keep working on vaccines, microbicides and other prevention strategies”. Mr. Bill Clinton, The Clinton Foundation “If I had a magic bullet to accelerate something, it would be the microbicides”. Mr. Bill Gates, Bill & Melinda Gates Foundation

31. ConclusionConclusion Microbicides are scientifically achievable, as exemplified by AIDS therapeutics. With leadership, sufficient financial resources, collaborative efforts and product development expertise, women in developing countries could have access to effective microbicides within the next 5 to 7 years.

32. For More Information Martin Methot Executive Director, Resource Development and Communications International Partnership for Microbicides Phone: +1-301-608-2221 Email: mmethot@ipm-microbicides.org www.ipm-microbicides.org