Microbicides: research and clinical trials globally and in India

1. Microbicides: research and clinical trials globally and in India Dr. Badri N. Saxena, M.D., F.A.M.S. Professor, Centre for Policy Research, New Delhi Advisor, Indian Council of Medical Research, New Delhi January 2007

2. Healthy vagina Alan Stone

3. How might microbicides work prior to viral/tissue contact Viral disruption/inactivation Prevention of other STDs HIV Lactobacillus physical barrier lubrication Vaginal epithelium Maintenance of normal microflora and epithelial health

4. How might microbicides work after viral contact Lumen Epithelium Stroma

5. Pros and cons of ARV-based microbicides Pros • Higher potency against HIV • Could be delivered through a vaginal ring • Potentially longer acting Cons • No efficacy against other STIs • More complicated safety profile • Could promote resistance if used by HIV positive people • Long term efficacy could be undermined by spread of resistant virus

6. Evaluating safety and effectiveness • Pre-clinical testing • Uses cell cultures, explant models, animal studies • Does is work? Does it harm? • Clinical testing • Enrolls and follows people • Does it harm? (phase 1 & 2) • Does it work? (phase 2b & 3)

7. Predicting harm and evaluating safety - Phase 1 & 2 trials • Increasing circles of safety evaluation • Healthy sexually active (or abstinent) • Higher risk/poorer health (other STIs; malaria, etc) • HIV positive women • Pregnant women • Adolescent girls (less mature cervix) • Safe for use on male penis • HIV negative then HIV positive men

8. Testing microbicides effectiveness - Phase 3 trials • Trial site criteria • Thousands of people needed • HIV incidence must be high and non-IDU related • Research infrastructure must exist • Currently designed to measure the reduction of HIV transmission from HIV pos. men to HIV neg. women • HIV transmission that is more likely from HIV pos. men to HIV neg. women than from an pos. woman to neg. man • This is the fastest way of determining a “proof of concept”

9. Experience of an effectiveness (phase 3) trial participant Family Planning Condoms + experimental gel Informed consent for screening Informed consent to enroll. Condoms + placebo Recruitment: Participant receives information about the trial Screening Visit 1: Education about the trial, HIV and pregnancy test, STI tests and treatment, baseline data collected Screening Visit 2: Results of tests, counseling, reinforce education about trial Randomization: Participant assigned by chance to a group.

10. Are participants in trials at greater risk of getting HIV? No It will be lower or the same as it was before they joined the trial Condoms only Condoms + control gel RISK Condoms + microbicide (if it works) Before trial During trial

11. How are microbicides developed at a glance Participants Length Purpose Phase 1 10-100 several mos. safety Phase 1/2 several 100 several mos. safety/ dose ranging Phase 2 ~200 (couples?) 6 mos.- 1 yr. expanded safety Phase 2/2B several 1,000 ~3 yrs. safety/ direct estimate effectiveness Phase 3 300-30,000 1-4 yrs. effectiveness

12. Microbicides research pipeline in 2005 5 products 2 products 9 products 10-20 products Phase 2 (safety) 2 Years Phase 3 (efficacy) 3.5 Years Phase 1 (safety) 1 Year Laboratory Testing 2-6 Years Phase 1 and 2 HIV+ penile & rectal studies 10 + Years Source: Tufts Center for the Study of Drug Development

13. Microbicides clinical trial sites in 2006 EUROPE - Belgium: Phase I/II THE AMERICAS: -United States: Phase I, II, IIB -Brazil: Phase II ASIA -India: Phase II, III -Thailand: Phase I WEST AFRICA: -Benin: Phase III -Nigeria: Phase III -Cameroon: Phase I, II AUSTRALIA - Phase 1 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 Source: Alliance for Microbicide Development

14. Five products furthest along

15. HIV positive women in microbicides effectiveness trials (Phase 3) To test if microbicides prevents transmission from HIV pos. woman to HIV neg. man trials would probably enroll sero-discordant couples • Both HIV neg. man& HIV pos. woman must be counseled and consent must be given before using the trial product • Require a different trial design, is more challenging, would take longer • An important question that needs to be answered • We know little about vaginal health and HIV transmission from pos. women to neg. man. Background research is greatly needed

16. Microbicides research in India

17. Microbicides research in India

18. Vaginal microbicide studies ongoing in India • CONRAD • Phase III Randomized controlled Trial of 6% Cellulose Sulphate Gel and the Effect on Vaginal HIV Transmission • 2574 HIV negative women • Sites: Benin, Burkina Faso, India (YRG CARE and St. Johns Institute, Bangalore), Kenya, South Africa, Uganda • HPTN 059 • Phase II Expanded Safety and Acceptability Study of the Vaginal Microbicide 1% Tenofovir Gel • NARI, Pune • NY, USA • UAB, USA

19. How effective will they be? • First microbicides will be 40-60% protective • Second generation will be 60-80% • Should be promoted as a“back-up”to condoms, not as a replacement • Use with risk reduction messages, like: • 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

20. Potential public health impact of microbicides: model projections 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 microbicides 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 (Watts et al, 2002)

21. When can we expect a microbicide? • Earliest results from current Phase 3 trials expected between 2008-2009 • Positive results ≠ immediate availability of a product • 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

22. Thank you