1. On behalf of the Global Campaign for Microbicides laurie.sylla@yale.edu Microbicides Research: An Overview

2. The Need The Need Define microbicides/methods of action Define microbicides/methods of action Research overview Research overview Potential impact of microbicides Potential impact of microbicides How microbicides fit into HIV prevention How microbicides fit into HIV prevention Need for advocacy Need for advocacy Overview

3. “All too often, HIV prevention is failing women and girls” - Dr. Peter Piot Executive Director, Joint United Executive Director, Joint United Nations Programme on HIV/AIDS Nations Programme on HIV/AIDS

4. The Global Challenge HIV is rapidly becoming a “women’s epidemic” HIV is rapidly becoming a “women’s epidemic” –Worldwide, 6 out of every 10 people newly infected with HIV are women -In 2005 17.5 million women were living with HIV; 1 million more than in 2003. -In Sub-Saharan Africa, 67% of the almost 9 million HIV  youth (15-25 years) are female -In the US, women have gone from less than 10% to nearly a quarter of new cases (more than a third of new HIV cases in CT) -Young girls are three to six times more likely than their male counterparts to be infected.

5. Women’s Risk is… Biological Biological –Cervical vulnerability; untreated STD Social Social –Couplings with older men and younger women; rape Cultural Cultural –Sanctioned polygamy; institutionalized ignorance of sex; lack of women’s rights, economic inequity

6. Young Women Are Especially Vulnerable Numerous physiologic and cognitive changes in youth strongly influence STI rates and HIV acquisition among young women Cognitive vulnerabilityCognitive vulnerability Structural vulnerability of the mucosaStructural vulnerability of the mucosa Immunologic vulnerabilityImmunologic vulnerability Cultural VulnerabilityCultural Vulnerability

7. Current Prevention Options for Women Abstinence Abstinence Trusting Partner to be Uninfected and Monogamous Trusting Partner to be Uninfected and Monogamous Persuading Partners to Use Male Condoms Persuading Partners to Use Male Condoms Female Condoms Female Condoms

8. How can we address women’s disproportionate risk? Empower women Empower women -Education, economic opportunities, legal reform Change gender dynamics Change gender dynamics -Work with men, promote non-violence, egalitarian family relationships Get women tools to protect themselves Get women tools to protect themselves -female condoms; topical microbicides

9. Why non-condom prevention? Existing methods -- condoms and mutual monogamy -- depend upon the cooperation of a male partner. Existing methods -- condoms and mutual monogamy -- depend upon the cooperation of a male partner. Violence, coercion, and economic dependency in relationships make it hard to “negotiate” condom use or to leave a partnership that puts a woman at risk. Violence, coercion, and economic dependency in relationships make it hard to “negotiate” condom use or to leave a partnership that puts a woman at risk. Condoms interfere with conception Condoms interfere with conception

10. So, What is a Microbicide?

11. Microbicides Products that reduce the probability of mucosal transmission of HIV and possibly other STDs. Products that reduce the probability of mucosal transmission of HIV and possibly other STDs. –The first generation of microbicides will likely be topical agents applied in the vagina, and possibly the rectum. –Other “delivery devices”, such as slow release rings are being explored

12. Microbicides Must Be… Safe for all potential users: Safe for all potential users: –Sexually active women and men –Pregnant women –HIV positive women –Adolescents Compatible with condoms and other barriers Compatible with condoms and other barriers

13. Microbicides Must Work: In normal situations In normal situations Where there is cervical ectopy Where there is cervical ectopy In the presence of inflammatory and ulcerative STDs In the presence of inflammatory and ulcerative STDs In the face of micro trauma due to intercourse. In the face of micro trauma due to intercourse.

14. either inactivate the virus in the vaginal lumen or prevent the virus from attaching to and/or fusing with its cellular targets or accumulate inside the target cells and prevent viral replication if the virus manages to enter or a combination of some or all of these Microbicides must NOT:  damage the protective mucosal barrier  interfere with the vaginal lactobacilli ALAN STONE ~ LONDON ~ To prevent HIV transmission a microbicide MUST …

15. Shattock CROI 04

16. POTENTIAL PROTECTIVE EFFECTS OF A MICROBICIDAL GEL Physicochemical effect of microbicidal ingredient (inactivates the pathogen or prevents its interaction with target cell/tissue or blocks its replication) Anti-infective effect of polymeric gelling agent or preservative Low pH formulation hostile to pathogens Gel forms a physical barrier between pathogen and target cell/tissue Gel acts as a lubricant during sex and thus minimises trauma to mucosa Ideally all of these ALAN STONE ~ LONDON ~

17. bi-directional bi-directional available over the counter available over the counter active against a range of sexually- transmitted pathogens active against a range of sexually- transmitted pathogens long duration of effect long duration of effect available in spermicidal & non- spermicidal formulations available in spermicidal & non- spermicidal formulations sustain or enhance normal vaginal ecology sustain or enhance normal vaginal ecology the ideal microbicide … Alliance for Microbicide Development

18. Attributes Considered Breadth of activity (phenotype and clade) Therapeutic index Activity in physiological fluids (semen, mucus, blood) Ease of Manufacture Ease of Formulation Time to Develop Regulatory Hurdles Stability (40C for 6 months) Cost “Best in class/better than existing” Acceptability Resistance Profile Safety / Efficacy Shattock CROI 04

19. Effectiveness Will Be Determined By: Formulation Formulation Acceptability Acceptability Distribution Distribution Stability Stability

20. Laboratory Testing 2-6 Years Phase 3 (efficacy) 2 to 4 Years Simultaneous studies: HIV+, penile & rectal 10 or more years 5 products 2 products 10 products 10-20 products Phase 1 (safety) 1 to 6 Months Phase 2 (safety) Up to 2 Years 25 – 40 people 200-400 people 3,000-10,000 people The Product Pipeline

21. Clinical trial sites in 2005 Source: Alliance for Microbicide Development

22. Context of Microbicide Clinical Trials Enroll large numbers of healthy women Enroll large numbers of healthy women Partner exposure to product Partner exposure to product Infections will occur among some participants Infections will occur among some participants Participants receive “gold standard” prevention Participants receive “gold standard” prevention Products primarily developed in “western” countries and tested in “resource-constrained” settings Products primarily developed in “western” countries and tested in “resource-constrained” settings Limited resources for microbicide trials Limited resources for microbicide trials Access to treatment may be limited Access to treatment may be limited

23. Prevention Counseling is a Routine Part of Microbicide Trials

24. If Providing Prevention Counseling and Condoms Means it Will Take More Time and Resources to Discover a Microbicide, Is it More Ethical to Provide the Prevention Intervention or to Hasten Discovery ???

25. Blah Blah Placebo Blah Blah Randomize Blah Blah Blah Informed Consent

26. That gel is doing wonders for my complexion! I’m sure that gel is protecting me. It is even giving me more energy ! I know that nice nurse must be giving me the real gel! Therapeutic Misconception

28. Partner Exposure Should male partners consent? Should male partners consent? –Women could have multiple partners during trial –What is disempowering effect on women if partners have to consent? –Are women placed at increased risk of violence if partners don’t consent? –Is it feasible to require partner consent? Penile safety studies being conducted in earlier safety phases of testing Penile safety studies being conducted in earlier safety phases of testing

29. Vulnerable Individuals- Adolescents Treated by law as “children” needing special protection; unable to give fully informed consent Treated by law as “children” needing special protection; unable to give fully informed consent At high risk of acquiring HIV At high risk of acquiring HIV Biologically different than adult females Biologically different than adult females Unique potential benefits and harms Unique potential benefits and harms Need to assess safety and efficacy in this population as they are likely to be signicant users Need to assess safety and efficacy in this population as they are likely to be signicant users How to enroll and protect confidentiality? How to enroll and protect confidentiality?

30. Responsibility to Sero- Converters Women in microbicide trials are likely at less risk than those not in trials Women in microbicide trials are likely at less risk than those not in trials ` Before trial During Trial Condoms + placebo gel Condoms + microbicide (if it works) Risk Condom only Source: Heise, L.

31. ARVS for HIV+ Repro Health Care STD Care New Labs/Clinics Improving Local Care Capacity Budget Constraints Treatment Needs After Study Completion Lack of Country Infrastructure Ethical Obligations Competing Community Interests Balancing Responsibilities to Sero-Converters

32. 5 Products Furthest Along Buffer Gel ReProtect LLC Feb 2005 - 3,220 women South Africa, Malawi, Tanzania, Zambia, and Philadelphia Carraguard Population Council Mar. 2004 - 6,270 women South Africa – 3 locations Cellulose sulfate Global Microbicide Project Oct. 2004 - 2160 women Mar. 2005 - 2,574 women Nigeria Benin, Burkina Faso, India, Kenya, South Africa, Uganda PRO 2000 (.5%) Indevus Pharmaceutical, Inc. Feb 2005 - 3,220 women South Africa, Malawi, Tanzania, Zambia, and Philadelphia PRO 2000 (.5% and 2%) Indevus Pharmaceutical, Inc. 2005 - 11,920 women South Africa, Uganda, Zambia, Tanzania Savvy Biosyn, Inc Mar. 2004 - 2,142 women Ghana and Nigeria

33. How will microbicides and condoms compare? Early generation products will probably be less effective than condoms… Early generation products will probably be less effective than condoms… But they will more effective than condoms that aren’t used correctly or at all. But they will more effective than condoms that aren’t used correctly or at all.

34. Watts Prevention Trade-Off A low efficacy method used consistently can achieve the same protection as a high- efficacy method used less consistently A low efficacy method used consistently can achieve the same protection as a high- efficacy method used less consistently A 90% efficacious method (like condoms) used in 20% of sex acts, provides less protection than a: A 90% efficacious method (like condoms) used in 20% of sex acts, provides less protection than a: 70% efficacy used> 30% of the time 70% efficacy used> 30% of the time 50% efficacy used> 40% of the time 50% efficacy used> 40% of the time 30% efficacy used> 60% of the time 30% efficacy used> 60% of the time

35. How Effective Will Microbicides Be? First microbicides may be 40-60% protective First microbicides may be 40-60% protective Second generation products may be 60-80% Second generation products may be 60-80% Should be promoted as an adjunct or “back- up” to condoms, not as a replacement Should be promoted as an adjunct or “back- up” to condoms, not as a replacement use with harm reduction messages, such as: use with harm reduction messages, such as: –Use a male or female condom every time you have sex; if you absolutely can’t use a condom, use a microbicide –Use a microbicide with your condom for added pleasure and protection

36. Watts Women newly infected with HIV (2002) 2.0 million Adult women dying of AIDS (2002) 2.0 million Potential public health Impact (Watts et al, 2002) Introduction of a 60% efficacious microbicide in 73 lower income countries would avert 2.5 million HIV infections over 3 years (in men, women & infants) Introduction of a 60% efficacious microbicide in 73 lower income countries would avert 2.5 million HIV infections over 3 years (in men, women & infants) –assumes microbicide is used by 20% of those individuals likely to be reached by existing services –microbicides used in 50% of sex acts where condoms are not –assumes 10% migration away from condom

37. Watts Impact is driven by coverage

38. Watts Take Home Messages Even a relatively low efficacy microbicide could have a large impact on the epidemic Even a relatively low efficacy microbicide could have a large impact on the epidemic The magnitude of impact is strongly influenced by coverage and use The magnitude of impact is strongly influenced by coverage and use CoverageInfections averted* 10% 1.4 million 20% 2.5 million 30% 3.6 million * over 3 years

39. Microbicides as Harm Reduction Microbicides fit within a harm reduction model of disease prevention Microbicides fit within a harm reduction model of disease prevention If you are going to be sexual: If you are going to be sexual: –Use male/female condoms + microbicides- if not; –Use male/female condoms alone, if not; –Use a microbicide

40. What About “Condom Migration” ?

41. What About “Condom Migration”? Data from contraception studies shows more methods are better than fewer Data from contraception studies shows more methods are better than fewer Addition of each new method Addition of each new method – increases overall number of protected acts – decreases unintended pregnancies For HIV risk: modeling suggests that substantial migration can occur without increasing rates infection For HIV risk: modeling suggests that substantial migration can occur without increasing rates infection

42. Foss, Vickerman, Heise, Watts Changes in condom use and impact on HIV/STD risk IF: a microbicide of 50% efficacy were used in 50% of acts when condoms aren’t used IF: a microbicide of 50% efficacy were used in 50% of acts when condoms aren’t used Condom consistency could decrease from: Condom consistency could decrease from: BEFORE AFTER BEFORE AFTER 30% 5% 30% 5% 50% 32% 50% 32% 70% 59% 70% 59% 90% 86% 90% 86% without increasing individual risk without increasing individual risk

43. Foss, Vickerman, Heise, Watts Condom Consistency Condom Consistency BEFORE AFTER BEFORE AFTER 30% 0% 30% 0% 50% 0% 50% 0% 70% 37% 70% 37% 90% 79% 90% 79% Reductions in Condom Consistency That Could be Tolerated Without Increasing Risk Microbicide HIV/STI efficacy = 50%; Used in 100% of acts not protected by condoms

44. Will Women Use Microbicides? 21.3 million women in the US would be interested in using a microbicide (Darroch & Frost, 1999) 21.3 million women in the US would be interested in using a microbicide (Darroch & Frost, 1999) Even in resource-poor countries, women at risk are willing to pay twice as much (or more) than the local price of a condom (EU study, 1998; Hardy, et al 1998) Even in resource-poor countries, women at risk are willing to pay twice as much (or more) than the local price of a condom (EU study, 1998; Hardy, et al 1998) Women have widely different needs and formulation preferences so multiple products will be the key to widespread acceptability and use Women have widely different needs and formulation preferences so multiple products will be the key to widespread acceptability and use

45. What About Rectal Microbicides? Needed by BOTH men and women BUT Needed by BOTH men and women BUT Science of developing a rectal microbicide is challenging Science of developing a rectal microbicide is challenging –Long, open tunnel, fragile epithelium Money for rectal research not abundant in current political climate Money for rectal research not abundant in current political climate Research hampered by stigma, homophobia Research hampered by stigma, homophobia Some argue to wait for proof of Some argue to wait for proof of concept of vaginal microbicide concept of vaginal microbicide

46. MSMs Likely to Use a Rectal Microbicide If Available Reports indicate that 80% of MSMs use lubricants 80% of the time. Condoms only 59%. Reports indicate that 80% of MSMs use lubricants 80% of the time. Condoms only 59%. 41% of MSMs look for products containing N-9, which we now know is harmful. This is indicative that MSMs are likely to use a microbicide if one were available

47. So, Where Are We?

48. biopharmaceutical companies (~25) biopharmaceutical companies (~25) non-profit research entities (~38) non-profit research entities (~38) public-sector entities worldwide (~5) public-sector entities worldwide (~5) institutions conducting supportive research (~36) institutions conducting supportive research (~36) Who is Doing the Work? Alliance for Microbicide Development

49. Development will require significant public money Why aren’t the big pharmaceuticals investing? -perceived low profitability -liability concerns -lack of in-house expertise -uncertain regulatory environment For the last 20 years, almost all funding for contraceptive development and related research has come from governments and foundations.

50. What do these trials cost? Laboratory Testing Phase 1 (safety) Phase 2 (safety) Up to $13 Million Phase 3 (efficacy) Up to $50 Million

51. Preliminary annual funding needs Annual funding needs to double! All combined: Need $246M

52. The Advocates’ Message There is a broad-based, demonstrable demand for user-controlled prevention methods There is a broad-based, demonstrable demand for user-controlled prevention methods North American and European Union investment in microbicide research and development should be North American and European Union investment in microbicide research and development should be -substantially increased and -raised annually until first products available Without this investment, we may not see user- controlled HIV prevention tools available within this decade. Without this investment, we may not see user- controlled HIV prevention tools available within this decade.

53. Hastening the Day…… The Global Campaign for Microbicides is working to Raise Awareness Raise Awareness Accelerate Product Development Accelerate Product Development Assure Access by Those Most in Need Assure Access by Those Most in Need Hold Developers, Researchers Accountable to High Ethical Standards Hold Developers, Researchers Accountable to High Ethical Standards

54. Goals of the Global Campaign Mobilize resources and political will for increased investment in microbicide research and worldwide access to the female condom and other cervical barrier methods; Mobilize resources and political will for increased investment in microbicide research and worldwide access to the female condom and other cervical barrier methods; Create a supportive policy environment for the timely development, introduction and use of new prevention technologies; and Create a supportive policy environment for the timely development, introduction and use of new prevention technologies; and Ensure that as science proceeds, the public interest is protected and the rights and interests of trial participants, users, and communities are fully represented and respected Ensure that as science proceeds, the public interest is protected and the rights and interests of trial participants, users, and communities are fully represented and respected

55. public awareness political support public demand increased resources for R&D ($$$) safe and effective microbicides on the market all people know about & have access to affordable microbicides

56. You Can Help in Many Ways Visit www.global-campaign.org

57. There Are Many Ways You Can Help 1) Learn more about microbicides. Visit the campaign website at www.global-campaign.org 2) Talk to everyone you know about microbicides 3) Sign up to get on the GC News and Alliance email lists. 4) Get any organizations, community groups, or networks you are involved with to host a program on microbicides. 5) Host a microbicides film night/discussion 6) Sign the Global Campaign petition and help collect signatures. 7) Get your organization to endorse the Global Campaign. 8) Contact your policy makers 9) Write letters to the editor, articles, etc., for local media 10)Add microbicides to your group’s advocacy agenda

58. Impact of Microbicide Positioning on Acceptance and Use

59. Possible Positioning of Microbicide Introduction For use in primary partnerships For use in primary partnerships For use by discordant couples For use by discordant couples When couples seek to increase intimacy When couples seek to increase intimacy When conception is desired (some products) When conception is desired (some products) When partners refuse to use condoms When partners refuse to use condoms When it is too great a risk to ask partners to use condoms When it is too great a risk to ask partners to use condoms As a back-up for condoms already being used As a back-up for condoms already being used

60. Put the Power to Protect in YOUR Hands…

61. When You’re Ready to Move a Little Closer…..

62. When he refuses and you can’t…..

63. When you desire a baby, but not HIV….

64. When you don’t want anything to come between you…..

65. When You Want to Be Extra Sure…..

67. Acknowledgements –Anna Forbes –Lori Heise –Polly Harrison –Anna Foss –Peter Vickerman –Charlotte Watts –Alan Stone –Michael Gross –Anna-Barbara Moscicki –Peg Weeks –Maryann Abbott –Katherine Mosack –Robin Shattock –Global Campaign for Microbicides –Alliance for Microbicide Development