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 Worldwide39.5 million4.3 million Sub-Saharan Africa24.7 million2.8 million Asia & Eastern Europe10.25 million1.23 million North America & Western/Central Europe2.14 million65,000 Other2.49 million242,100 Women are disproportionately affected by AIDS: In Sub-Saharan Africa, young women are 4 times more likely to be infected than young men.

5. 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

6. 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

7. 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 © Salam Dahbor, Courtesy Doubleshots Studio Possibly use of oral antiretroviral therapy, (tenofovir), for pre- exposure prophylaxis (PrEP) to prevent HIV infection.

8. 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

9. 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

10. 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.

11. MICROBICIDES IN CLINICAL TRIALS May ‘07 © Alliance for Microbicide Development

12. 3 Products Furthest Along Product Trial sponsor # women to be enrolledLocation Preliminary results expected in Buffer Gel HPTN035-NIH 3,100 womenSouth Africa, Malawi, Tanzania, Zambia, Zimbabwe and Philadelphia April 2009 Carraguard Population Council 6,299 womenSouth Africa – 3 locationsDecember 2007 PRO2000 (.5%) HPTN035-NIH 3,100 womenSouth Africa, Malawi, Zambia, Zimbabwe and Philadelphia April 2009 PRO2000 (.5 and 2%) DFID, MRC 9,673 womenSouth Africa, Uganda, Zambia, Tanzania December 2009

13. Planned Microbicide Trials There are 11 microbicide candidates in clinical development and over 30 in preclinical development

14. The Economics of Microbicide Development: A case for investment. THe Rockefeller Foundation. 2002 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.”

15. 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

16. 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 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

17. 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

18. 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

20. 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

21. Topics on BRC Scientific Agenda: Adherence & Acceptability TopicMeasurement ContextMeasurement approaches for contexts of microbicide use PartnersPartner types and relationship dynamics Microbicide AdministrationMethods BiomarkersUse of biomarkers for comparison with or validation of behavioral measures of adherence PregnancyPregnancy intentions at screening, affects of trial participation at individual and community level

25. 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

26. Handheld screen with 035 adherence question (n=400 in Malawi Courtesy of Barbara Mensch, Population Council

27. Malawi – Pop Council School Study Courtesy of Barbara Mensch, Population Council

28. 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 -

29. 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.orgwww.lifelube.org

30. 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.

31. 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

32. “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!

34. 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.

35. 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

36. Materials Developed (Video & Brochure) in LA in 2006 Community sites: Friends, APLA, UCLA-CARE

37. 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…

38. 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

39. Frank Herholdt, Courtesy of Microbicide Development Project 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