1. CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICA C APRISA CAPRISA is a UNAIDS Collaborating Centre for HIV Prevention Research Clinical Testing of Microbicides Quarraisha Abdool Karim, PhD) Head: CAPRISA Women and AIDS Programme Columbia University and University of KwaZulu-Natal AMAG/GCM Pre-Conference Workshop, Microbicides 2006, Cape Town, South Africa

2. Overview Need for a microbicide Need for a microbicide Status of current microbicide clinical trials Status of current microbicide clinical trials Challenges in undertaking microbicide clinical trials Challenges in undertaking microbicide clinical trials

3. Number HIV infected* Estimated % due to heterosexual transmission** Persons living with HIV 40.3 million 87% New infections 4.9 million 86% Estimated deaths 3.1 million 88% Global burden: Role of heterosexual transmission in 2004 Source: Joint UNAIDS and WHO AIDS epidemic update December 2005 *(conservative estimate)

4. HSex= heterosexual transmission IDU = transmission through injecting drug use MSM = sexual transmission among men who have sex with men Source: Joint UNAIDS and WHO AIDS epidemic update December 2005 Latin America 1.8 million HSex, MSM, IDU East Asia 870 000 HSex, IDU, MSM Eastern Europe & Central \Asia 1.6 milion IDU Sub Saharan Africa 25.8 million HSex Oceania 74 000 MSM Caribbean 300 000 HSex, MSM North America 1.2 million HSex, MSM, IDU North Africa & Middle East 510 000 HSex, IDU Western Europe 720 000 MSM, IDU South & South-East Asia 7.4 million HSex, IDU Global burden: Modes of transmission in 2004

5. HIV Infection in ANC attendees in South Africa Source: Department of Health 0 10 20 30 40 19881990199219941996199820002002 HIV prevalence (%) 1998 1990 1992 1994 1996 1998 2000 2002 HIV prevalence (%) 30 20 10

6. Age group Prevalence 2001(n=349)2002(n=409)2003(n=225)2004(n=550) <2015%26%19%27% 20-2444%46%45%55% 25-2931%43%66%66% 30-3414%22%43%54% >3516%16%36%10% Total32%34%41%43% Age specific HIV prevalence in antenatal clinic attendees in Vulindlela: 2001-2004

7. Temporal changes in adult mortality rate for men in SA 15-1920-2425-2930-3435-3940-4445-4950-5455-5960-6465-69 1996-1998 1999-2000 AGE 0 50 100 150 200 250 300 350 PERCENTAGE OF 1985-1990 AVERAGE Source: Dorrington R, Bradshaw D, et al. Medical Research Council

8. Temporal changes in adult mortality rate for women in SA 0 50 100 150 200 250 300 350 15-1920-2425-2930-3435-3940-4445-4950-5455-5960-6465-69 AGE PERCENTAGE OF 1985-1990 AVERAGE Source: Dorrington R, Bradshaw D, et al. Medical Research Council 1996-1998 1999-2000

9. Ward Cates, JR FHI Estimated Date at which Events would Occur from 2 Acts of Unprotected Intercourse Per Week Jan.AprilJulyOct.Dec. SyphilisGonorrhea ChlamydiaPregnancy HIV (if cofactors)

10. CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICA C APRISA CAPRISA is a UNAIDS Collaborating Centre for HIV Prevention Research BufferGel SAVVY Pro2000 Cellulose Sulfate PMPA/ Tenofovir

11. History of microbicide development Zena Stein publishes seminal article “HIV prevention: the need for methods women can use” N-9 sponge trial N-9 film trial COL-1492 trial CS trial SAVVY trial Carraguard trial HPTN trial 1 st generation: surfactants 2 nd generation: polymers 3 rd generation: ARVs 4 th generation: Co-receptor blockers CAPRISA trial IPM UC781 trial MDP trial ‘90 ‘92 ’98 ’00 ‘03 ‘04 ’04 ’05 ’05 ’06 ’07 ’08 / ’09 Abdool Karim SS. Update on Microbicides, 2 nd SA AIDS Conference, 2005

12. Current status of microbicide effectiveness trials Phase IIIIbIII  Cellulose sulfate  BufferGel™ & PRO 2000 (0.5%)  Carraguard®  Praneem Polyherbal Vaginal Tablet  Tenofovir gel (1%) & Savvy™(C31G)  Cellulose sulfate  Protected lactobacilli combined with BZK  PRO 2000 (0.5%;2%)  1% Tenofovir gel  Savvy™(C31G) Global Alliance for Microbicides update, April 2005

13. Dominican Republic Los Angeles, USA Norfolk, USA Providence, USA Philadelphia, USA Côte d’Ivoire Brazil South Africa Zimbabwe Malawi Tanzania Uganda India Chiang Rai, Thailand Nigeria New York, USA Yaoundé, Cameroon Cincinnati, USA Miami, USA Baltimore, USA London, UK Antwerp, Belgium Birmingham, USA Washington, USA Houston, USA Botswana Zambia Source: Alliance for Microbicide Development Ghana Trials Worldwide

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

15. Challenges in undertaking microbicide trials Lack of surrogate marker(s) of protection Lack of surrogate marker(s) of protection Efficacy vs effectiveness trials Efficacy vs effectiveness trials Adherence to product use during trial Adherence to product use during trial Product use during pregnancy Product use during pregnancy Ethical issues Ethical issues

16. Legacy of N-9 Phase 2/3 trial in 892 sex workers from 4 countries 32% women used >3.5 applicators per working day HIV outcome Lessons:- Potential for harm – obligations of researchers - Lack of a true placebo - Effectiveness trial possible with <1000 women RR=1.5 (CI:1.0-2.2; p=0.047) Source: Van Damme L, Ramjee G, Alary M, Vuylsteke B, Chandeying V, Rees H, Sirivongrangson P, Mukenge-Tshibaka L, Ettiegne-Traore V, Uaheowitchai C, Abdool Karim SS, Masse B, Perriens J, Laga M, on behalf of the COL-1492 study group. Lancet 2002, 360: 971-7. N-9Placebo N (women years) 376 (403) 389 (435) cumulative incidence 59/376 (16%) 45/389(12%) Incidence rate 14.710.3

17. Lack of surrogate markers of protection Lack of surrogate markers of protection Lack of a surrogate marker or correlate of protection: Lack of a surrogate marker or correlate of protection: lab assays lab assays clinical parameter clinical parameter animal model animal model No measure of biological activity of product No measure of biological activity of product Hence: The only meaningful effectiveness studies are those with HIV infection as the endpoint Hence: The only meaningful effectiveness studies are those with HIV infection as the endpoint

18. Effectiveness vs Efficacy Real world constraints Real world constraints Poor adherence -suboptimal product usage Poor adherence -suboptimal product usage RESULT: lower levels of product use - lowers effect size RESULT: lower levels of product use - lowers effect size Source: Roddy RE, Zekeng L, Ryan KA, Tamoufe U, Weir SS, Wong EL. A controlled trial of nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted diseases. N Engl J Med 1998;339(8):504-10.PlaceboN-9Client Non client Client Total no. coital acts 94,09252,85096,86151,135 % with film only 4%18%3%15% % with film and condom 83%63%86%69%

19. Adherence to product use Gel and Condom Use in HPTN 035 Adherence to product use Gel and Condom Use in HPTN 035 With Gel Without Gel Total With Condom 21853271 Without Condom 6557122 Total283110393 Among participants assigned to gel, number of last vaginal sex acts reported on = 393 (265 participants) 69% of sex acts used a condom 69% of sex acts used a condom 80% of sex acts with condom also had gel 80% of sex acts with condom also had gel 53% of sex acts without condom had gel 53% of sex acts without condom had gel 72% of all sex acts used gel 72% of all sex acts used gel

20. Product use during pregnancy Lack of reproductive toxicity data means products have to be withheld during pregnancy Lack of reproductive toxicity data means products have to be withheld during pregnancy High pregnancy rates in current microbicide trials High pregnancy rates in current microbicide trials A pregnancy rate of 40 per 100 women years (mean = 6 months pregnant) means that 20% of women years on study are without product A pregnancy rate of 40 per 100 women years (mean = 6 months pregnant) means that 20% of women years on study are without product RESULT: Lower usage of product leading to lowering of the effect size RESULT: Lower usage of product leading to lowering of the effect size

21. Ethical challenges Current standards of care require: Current standards of care require:  Intensive counselling on risk reduction  condom promotion  STD treatment  Adequate communication of equipoise to study participants  These combine to reduce risk of HIV infection in a study where the study is designed on HIV infection as the endpoint – and hence directly undermine the trial Pressure to provide ART to sero-convertors – need infrastructure to provide care long after study completion Pressure to provide ART to sero-convertors – need infrastructure to provide care long after study completion Post-trial agreements – not all trials pivotal Post-trial agreements – not all trials pivotal

22. Study Procedures Screen for HIV Site Enrollment Visit for HIV- Placebo Gel Product 2 Product 1 Monthly Monthly: HIV pregnancy test; medical hx, product use, sexual behaviour assessments, AEs, SAEs Quarterly Quarterly: Pelvic exams, Behav Assessments Other: DSMB, CAT, AI

23. Summary Urgent need for a safe & effective microbicide Urgent need for a safe & effective microbicide Ability to show effectiveness is undermined by: Ability to show effectiveness is undermined by:  Sub-optimal adherence in real world conditions  With-holding product during pregnancy  Ethical requirements to reduce risk  Condom promotion reduces coital acts with product only Microbicide trials are onerous on participants Microbicide trials are onerous on participants The field needs many more trials with HIV endpoints due to the lack of surrogate markers The field needs many more trials with HIV endpoints due to the lack of surrogate markers A major challenge for current trials is to contribute to understanding surrogate markers & not only to assess products for licensure A major challenge for current trials is to contribute to understanding surrogate markers & not only to assess products for licensure

24. Acknowledgements SS Abdool Karim, CAPRISA Ward Cates, FHI Global Alliance for Microbicides Rockefeller Foundation Microbicide Reports