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Clinical Testing of Microbicides

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. Overview. Need for a microbicide

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Clinical Testing of Microbicides

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  1. 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 • Status of current microbicide clinical trials • Challenges in undertaking microbicide clinical trials

  3. Global burden: Role of heterosexual transmission in 2004 *(conservative estimate) Source: Joint UNAIDS and WHO AIDS epidemic update December 2005

  4. Global burden: Modes of transmission in 2004 Eastern Europe & Central \Asia 1.6 milion IDU Western Europe 720 000 MSM, IDU North America 1.2 million HSex, MSM, IDU East Asia 870 000 HSex,IDU, MSM North Africa & Middle East 510 000 HSex, IDU Caribbean 300 000 HSex,MSM South & South-East Asia 7.4 million HSex, IDU Sub Saharan Africa 25.8 million HSex Latin America 1.8 million HSex,MSM, IDU Oceania 74 000 MSM 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

  5. 40 30 30 HIV prevalence (%) 20 20 HIV prevalence (%) 10 10 0 1988 1990 1992 1994 1996 1998 2000 2002 1998 1990 1992 1994 1996 1998 2000 2002 HIV Infection in ANC attendees in South Africa Source: Department of Health

  6. Age specific HIV prevalence in antenatal clinic attendees in Vulindlela: 2001-2004

  7. 350 300 250 200 PERCENTAGE OF 1985-1990 AVERAGE 150 100 50 0 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 Temporal changes in adult mortality rate for men in SA 1996-1998 1999-2000 AGE Source: Dorrington R, Bradshaw D, et al. Medical Research Council

  8. 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 Temporal changes in adult mortality rate for women in SA 350 300 250 1996-1998 1999-2000 200 PERCENTAGE OF 1985-1990 AVERAGE 150 100 50 0 AGE Source: Dorrington R, Bradshaw D, et al. Medical Research Council

  9. Estimated Date at which Events would Occur from 2 Acts of Unprotected Intercourse Per Week Chlamydia Pregnancy HIV (if cofactors) Syphilis Gonorrhea Jan. April July Oct. Dec. Ward Cates, JR FHI

  10. BufferGel SAVVY Pro2000 Cellulose Sulfate PMPA/ Tenofovir

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

  12. Current status of microbicide effectiveness trials Global Alliance for Microbicides update, April 2005

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

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

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

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

  18. Effectiveness vs Efficacy • Real world constraints • Poor adherence -suboptimal product usage • 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.

  19. Adherence to product useGel and Condom Use in HPTN 035 Among participants assigned to gel, number of last vaginal sex acts reported on = 393 (265 participants) • 69% of sex acts used a condom • 80% of sex acts with condom also had gel • 53% of sex acts without condom had 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 • 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 • RESULT: Lower usage of product leading to lowering of the effect size

  21. Ethical challenges • 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 • Post-trial agreements – not all trials pivotal

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

  23. Summary • Urgent need for a safe & effective microbicide • 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 • 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

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

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