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Microbicide Update: What’s New, What’s Next?

Microbicide Update: What’s New, What’s Next?. Christine Mauck, MD. Learning objectives. Describe what microbicides are and how they work List three benefits of microbicide in prevention of pregnancy and transmission of STIs

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Microbicide Update: What’s New, What’s Next?

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  1. Microbicide Update:What’s New, What’s Next? Christine Mauck, MD

  2. Learning objectives • Describe what microbicides are and how they work • List three benefits of microbicide in prevention of pregnancy and transmission of STIs • Describe where microbicides are in the research pipeline and how soon the pubic will have access to use in the United States and abroad • List two benefits of microbicides used with a diaphragm • Indicate how health care providers can play a role in expediting public access to microbicides • Describe in general terms the results of the CS contraceptive trial

  3. What is a Microbicide? • A topical product that reduces transmission of sexually transmitted infections (STIs) when applied either in the vagina or rectum • Includes many forms • Gels, creams, suppositories, films • Sponge or vaginal ring that slowly releases the active ingredient • Some of the microbicides being investigated prevent pregnancy and some do not

  4. Why are microbicides important? • Today's prevention options--condoms, mutual monogamy, and STI treatment--are not feasible for millions of people around the world, especially women. • Married women in developing countries are among those at highest risk of contracting HIV. • Many women do not have the social or economic power necessary to insist on condom use or to abandon partnerships that put them at risk. • Because microbicides would not require a partner's cooperation, they would put the power to protect into the women's hand. • Microbicides that are even 60 percent effective against HIV could avert at least 2.5 million infections over three years. From http://www.global-campaign.org/about_microbicides.htm

  5. What would a perfect microbicide look like? • Active against: • HIV • Other STIs • Could be used in a combination product • To have more than one mechanism of action against a specific STI • To target multiple STIs • Safe: • Not inflammatory • No deleterious effect on micro flora • Safe for use in pregnancy • No or little systemic absorption • Long effect window • Does not have to be used immediately before sex Adapted from: DHHS/NIH/NIAID/DAIDS

  6. The perfect microbicide (continued) • Compatible with • Condoms • Cervical barriers • Seminal fluid/vaginal secretions • Availability • Cost • Can be produced where needed • Accessible • Easy to use and acceptable

  7. Laboratory Testing 2-6 Years Phase 1 (safety) 1 to 6 Months Phase 2 (safety) Up to 2 Years Phase 3 (efficacy) 2 to 4 Years 200-400 people 3,000-10,000 people 25 – 40 people Simultaneous studies: HIV+, penile & rectal 10 or more years From identified need to marketplace:Drug development

  8. Microbicide pipeline • As of August 2006: • Over 30 microbicide candidates in preclinical development • 14 microbicide candidates in clinical trials • 5 in ongoing Phase 2/2b or Phase 3 trials

  9. How do microbicides work? Shattock RJ and Moore JP. Nature Reviews Microbiology, vol. 1 Oct/2003

  10. Microbicides in clinical trials and their mechanism of action Adapted from An Analytical Overview of the Microbicide Preclinical and Clinical Pipeline, Plescia, Finley, Harrison, des Vignes

  11. 5 Products Furthest Along

  12. Safety testing of microbicides • Vaginal application in women: • Once daily X 14 days then twice daily X 14 days • Sexually abstinent then sexually active • HIV-uninfected then HIV-infected • Penile application in men: • Once daily X 7 days • HIV-uninfected then HIV-infected • Rectal use – men and women • Issue: assessment of irritation • Colposcopy • Soluble and cellular markers of inflammation (e.g. cytokines, SLIPI)

  13. Efficacy testing of microbicides • Issues: • Lack of surrogate markers of protection • Use of condoms • Control arms: • Condom only (no gel) • Placebo (plus condom) • Local incidence of disease • P level needed • Assumed efficacy • Length of follow-up • Management of women who become pregnant • Development of resistance when using antiretroviral products • Studies end up enrolling thousands of women and following them for at least one year

  14. Microbicides and contraception • There is a need for microbides that prevent pregnancy and HIV/STIs and those that prevent only HIV/STIs • Cannot assess contraception and HIV/STI prevention in the same trial: • Contraceptive trial requires no use of condoms • HIV/STI trial requires condom counseling

  15. Contraceptive studies of microbicides • Cellulose sulfate used alone – completed • BufferGel used with Ortho All-Flex diaphragm - completed • Savvy used alone - underway

  16. Microbicides and physical barriers • Combining a physical barrier (e.g. diaphragm) with a microbicide has advantages: • Should increase overall efficacy • May “concentrate” formulation on target cells in cervix • Replacesapplicator • Issues: • Acceptability • Irritation • Cleaning & storage if barrier is reusable • Disposal, environmental concerns & cost if single-use • Examples: • BufferGel used with the Ortho All-Flex diaphragm – phase 3 done • Cellulose sulfate used with the new SILCS diaphragm – phase 3 about to start • Cellulose Sulfate used with the Ortho All-Flex diaphragm – phase 1 done • ACIDFORM used with the Ortho All-Flex diaphragm – phase 1 done • BufferGel Duet (BufferGel used with a new diaphragm) – phase 1 done

  17. Who is involved in microbicide development? • Clinical trials: • Phase 2/2b or 3 trials: • Population Council – Carraguard • Microbicide Trials Network – PRO 2000 & BufferGel • Medical Research Council – PRO 2000 • Global Microbicide Project (CONRAD) – Cellulose sulfate • FHI – Savvy • Others: • CDC • International Partnership for Microbicides

  18. Microbicides Trial Network • Funded by NIH • Replaces HPTN that began in October 2001 • Involves the University of Pittsburgh, University of Washington in Seattle, UCLA, and Family Health International • Total funding of $285 million for the first year. • Will conduct clinical trials to evaluate the safety and effectiveness of microbicides • New trials • Two ongoing trials (tenofovir and BufferGel)

  19. Who else is involved in microbicide development? • Funders • Bill and Melinda Gates Foundation • US Government • NIH • USAID • CDC • British government (Medical Research Council) • Advocates • Alliance for Microbicide Development • Global Campaign for Microbicides

  20. Alliance for Microbicide Development • Global coalition of representatives from biopharmaceutical companies, nonprofit research institutions, health advocacy groups • Authoritative source of information on microbicide research, development, funding • Neutral objective convener of dialogue on key policy issues • Educator about public health potential of microbicides • Advocate for resources needed to develop them • “Trouble-shooter” for the microbicide field www.microbicide.org

  21. Global Campaign for Microbicides • Broad-based, international effort to build support for increased investment into microbicides • Goals are to: • Raise awareness and mobilize political support for increased funding; • Create a supportive policy environment for the development of new prevention technologies; and • Ensure that the public interest and trial participants, users, and communities are protected. www.global-campaign.org/about.htm

  22. Microbicide Development Strategy (MDS) Available at www.microbicide.org. Initiated by the Microbicide Donors Committee Year-long consultative process with key players in microbicide R&D Purpose: To take stock of the current status of the field, identify gaps, and build consensus on current R&D priorities

  23. Laboratory Testing Phase 1 (safety) Phase 2 (safety) Up to $13 Million Phase 3 (efficacy) Up to $50 Million What does the development of a microbicide cost?

  24. Development will require significant public money • Why aren’t big pharmaceutical companies investing? • Perceived low profitability • Liability concerns • Lack of in-house expertise • Uncertain regulatory environment • For the last 20 years, almost all funding for contraceptive R & D has come from governments and foundations • Success with microbicides MUST depend on multidisciplinary, multisectoral partnerships & ADVOCACY • What can you do to help?

  25. Support the Microbicide Development Act • Barely 2% of the US budget for HIV/AIDS research is spent on microbicides. • Three federal agencies support and/or implement microbicide R&D – NIH, CDC, Agency for International Development (USAID). But no one entity is in charge of coordinating everything.  • The Act would achieve better coordination and expanded resources for microbicide research at NIH, CDC and USAID. • The Microbicide Development Act was introduced in the Senate in March 2005 and in the House in September 2005 • You can take action by asking your congress person to support the act. Go to http://www.global-campaign.org/legislativeadvocacy.htm

  26. ACKNOWLEDGMENTS • ♦ Alliance for Microbicide Development • ♦ Global Campaign for Microbicides • ♦ Certain slides courtesy of: • Sharon Hillier, PhD University of Pittsburgh • Jim Turpin, PhD, NIAID/DAIDS • Salim Abdool Karim, MBChB, PhD, University of KwaZulu-Natal

  27. Cellulose Sulfate Contraceptive Trial • Test product:CS gel – 3.5 ml used alone • Site:California Family Health Council, Inc. • Participants:200 couples who did not desire a pregnancy, were at low risk for STIs, and agreed to use the study product as their primary means of contraception for six months • Objectives: • 6-month typical and perfect use pregnancy probabilities • Consistency of use • Safety • Acceptability

  28. Results • Enrollment: • 2022 women screened • 200 enrolled • Disposition:

  29. Demographics

  30. Pregnancy Probabilities - CS

  31. How do these compare with N-9? • NIH/FHI N-9 study:* • Most recent N-9 contraceptive study • Done in U.S. • Five arms: • 3 gel arms • 1 suppository arm • 1 film arm • # of women per arm averaged 297 • 6-month follow-up * Raymond et al. Contraceptive effectiveness and safety of five nonoxynol-9 spermicides: a randomized trial. Obstet Gynecol. 2004 Mar;103(3):430-9

  32. Pregnancy Probabilities – N-9

  33. Pregnancy Probabilities CS & N-9

  34. Adverse events • 28.5% of women reported at least one gel-related adverse event during 6 months of use. • Adverse events (percent of women ever experiencing the 5 most common gel-related events): • 78% of these adverse events were mild. • Only one was severe (UTI requiring temporary interruption of gel). • Only 1 gel-related male AE: mild reaction to study gel.

  35. Acceptability

  36. Conclusions of CS contraceptive trial • CS gel is effective as a contraceptive: • The 6-month cumulative probabilities of pregnancy in both typical and “perfect” use compare well with nonoxynol-9, the only contraceptive vaginal gel still approved for marketing in the U.S. • CS gel is safe, with about three quarters of users reporting no gel-related adverse events during 6 months of use. • CS gel is acceptable, with about three quarters of both women and men reporting liking it and being willing to recommend it to a friend.

  37. The end

  38. Coital acts On average, there were 11.5 coital acts per cycle:

  39. Cycles

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