1. Microbicides for HIV Prevention Pamina M. Gorbach, Epidemiology & Infectious Diseases UCLA

2. What is a microbicide? ….a product applied inside the vagina or rectum that are intended to protect against HIV though sex. Microbicides that incorporate antiretroviral (ARV) drugs are showing particular promise.

3. Microbicides  First generation:  Gels & creams for rectum or vagina  Inserted daily or before and after sex  Current generation:  Vaginal rings: Inserted and remain in place for > 1 month  Pills: PrEP (Pre-exposure prophylaxis)  Future: Injectables, film?

4. What Do Participants Need from HIV Prevention Methods?  To reduce risk of HIV and other STIs  To prevent pregnancy and not prevent pregnancy!  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 Photo courtesy of http://www.mtnstopshiv.org/

5. If microbicides work… 1. Only taken if you KNOW you are HIV negative.  So regular HIV testing is necessary. 2. May be available by prescription only.  So access to a qualified health care provider is necessary. 3. Different dosing is being tested in trials.  These include application daily or before and after sex.

6. Why would HIV+ people want microbicides? Reduce risk of:  Infection with multiple strains of HIV  Infection with other STIs, yeast or bladder infections Women can get pregnant while still protecting their partner from HIV.

7. Findings from Recent Microbicide Trials: Effectiveness – Do they work?

8. Who is doing the research? Research entityExamplesFunding sources Not-for-profit health groups and academic institutions MTN, CONRAD, FHI, CAPRISA Governments (South Africa DST, US NIH, UK DFID), philanthropic foundations Public-private partnerships IPMEuropean/US/Canadian governments, philanthropic foundations, UNFPA, World Bank Smaller pharmaceutical companies Endo StarPharma Venture capital, some government grants

9. Outcomes of first trials – not good Signs of efficacyNo efficacy Safe Carraguard® BufferGel® PRO 2000 0.5% Trend toward harm Nonoxynol-9 Savvy Cellulose sulphate

13. FACTS 001: Follow-on African Consortium for Tenofovir Studies  Compared HIV infection rates between 2 groups of sexually active HIV-women aged 18– 30 in nine sites in South Africa (n=2,059):  those assigned a vaginal gel containing tenofovir for use before and after sex  those who received a placebo gel  New HIV infections occurred at the same rate in both groups: The HIV incidence was 4% in both groups  Showed that the results of CAPRISA 004 could not be replicated in a large study population comprising diverse women across South Africa.  In this trial, overall use of the gel by participants was low.

15. VOICE 2.0 (MTN 003) 5,000 Women Tablet (3,000) Vaginal Gel (2,000) Truvada (1,000) Tenofovir (1,000) Placebo Tablet (1,000) Tenofovir Gel (1,000) Placebo Gel (1,000)

16. VOICE: Primary Efficacy Results. Marrazzo JM et al. N Engl J Med 2015;372:509-518

17. Marrazzo, J. et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections. Atlanta. March 3­–6, 2013. Abstract #26LB. Abstract #26LB

18. Conclusions: VOICE  Incidence of HIV substantially higher than anticipated  No study drug significantly reduced risk of HIV  Adherence to study products was low, especially among younger, unmarried women  Results consistent with FEM-PrEP  Consider PrEP agents/delivery systems that are long acting and require minimal daily adherence  Understanding HIV risk perception and biomedical, social and cultural determinants of adherence in this high-risk population urgently needed Marrazzo, J. et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections. Atlanta. March 3­–6, 2013. Abstract #26LB. Abstract #26LB

20. Rectal Microbicides

21. MSM Throughout the World Need HIV Prevention

22. Chandra A, Mosher WD et al. Sexual Behavior, Sexual Attraction, and Sexual Identity in the United States: Data From the 2006–2008 National Survey of Family Growth. National Health Statistics Reports n Number 36 n March 3, 2011 Anal Intercourse: Lifetime (ever) NSFG US General Population

23. Lubricants are Popular for AI

24. Peri-sexual behaviors: Rectal Douching Common

25. Rectal and Vaginal Mucosa Are Very Different  Histology  Immunology  Microbiology  Differential susceptibility to candidate microbicides

26.  MTN 017  A Phase 2 Randomized Sequence Open Label Expanded Safety and Acceptability Study of Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet and Rectally- Applied Tenofovir Reduced-Glycerin 1% Gel.

28. So Where Now?

29. MTN -017 Progress – Enrolled!

30. ASPIRE – Enrolled!  Multi-site randomized controlled Phase III trial of Dapivirine vaginal ring for HIV prevention  3,476 women enrolled in South Africa  Phase I Safety Study of Post-Menopausal women in US completed  Phase I Safety Study of Adolescent girls in US (done with ATN) in process 59/96 enrolled.

31. Coming Up

32. Issues with Microbicides  Many provide only partial protection : How will people interpret this?  What will be best medication schedules (daily, weekly, activity-based, long-acting (30-90 days)?  How often & who will track:  Adherence/consistent use  Drug resistance  New HIV infections by users (seroconversion)

33. Other Issues  Who will get the products? Should adolescents? Pregnant women? Transgender?  For how long should/could they be used?  Who will pay for them?  Will there be an increase in risk behavior?

34. Drug resistance from microbicides?  Most likely when using only one drug or one type of ARV.  Can become HIV+ while using microbicide.  Continued use (you don’t know you’re HIV+) may lead to resistance.  Options for treatment may be more limited—you might pass on resistant virus.  There are unanswered questions at this point.

35. In a nutshell: Acceptability  The Good News  Rectal Microbicides looking promising  Rings seem to have high adherence  The Bad News  Some participants may not satisfied with current product characteristics and dosing  Adherence vastly under-reported & products not used in trails enough to detect effectiveness  The “Ugly” news  Not everyone (dis)likes the same things, and there will need to be product choices

36. Creating Desire for Microbicides To enjoy (the gel) first you need to use it

38. Summary: State of the Science  Vaginal gel---unclear effectiveness in preventing HIV in women due to low adherence – not moving forward  Vaginal rings and injectables seem to show promise for women – under “Microbicides” umbrella  Rectal gel---shown to prevent HIV in Phase I trial in men and women  Cultural differences:  African women may prefer a vaginal gel  U.S. women may prefer a pill Bottom Line: People may have choices!