1. Advancing HIV-Prevention Options for Women
4/21/2017
Advancing HIV-Prevention Options for Women
Parliamentary Seminar on New HIV-Prevention Technologies
Dr. Zeda Rosenberg
Helsinki, 24 October 2007

2. The Face of HIV is Increasingly…
4/21/2017
The Face of HIV is Increasingly…
Female
Young
Married and monogamous
A mother
NEW PHOTO
HIV infections are increasing among women and girls in Eastern Europe, Asia, Sub-Saharan Africa and Latin America and the Caribbean. Women are vulnerable to HIV for biological, economic and socio-cultural reasons.
Biologically, male-to-female transmission is easier than male-to-female transition.
Economically, women are often financially dependent on male partners. Women’s inequality can also result in sexual exploitation and violence.
Cultural practices such as early marriage, intergenerational sex and marital infidelity also place women at risk of infection.
Young women are at even higher risk. In Sub-Saharan Africa, 3 out of year-olds living with HIV are female. In South Africa, 1 in 4 women are infected by age 22.
Marriage is no protection for many women. In India, 80% of women who are HIV-positive are married and have never had sex with anyone but their husbands.
And the impact of HIV on women goes beyond the individual to affect entire families. Many women living with HIV are mothers. In Swaziland, more than half of pregnant women between 25 and 29 are HIV positive.
Clearly, we need to do more to help women protect themselves against this virus.

3. What is a Microbicide? Vaginal products to prevent or reduce HIV
4/21/2017
What is a Microbicide?
Vaginal products to prevent or reduce HIV
Could be delivered in many forms:
transmission
gel
intravaginal ring
softgel capsule
vaginal film
vaginal tablet
sponge
Microbicides are vaginal products being developed to prevent or reduce the transmission of HIV. Because they are used vaginally, a woman could decide for herself to use a microbicide, instead of being forced to rely on her partner’s actions for protection.
Microbicides could potentially take many forms, for example:
Gel (photo shows an applicator that could be used to apply the gel)
vaginal ring (second photo)
vaginal tablet
Film
Sponge
diaphragm
Vaginal applicator
Vaginal ring

4. Microbicides in Product Development
4/21/2017
Microbicides in Product Development
Lactin-V
Invisible Condom
Free virus
BufferGel
Carraguard
PRO2000
SPL7013 (VivaGel)
Monoclonal antibodies
DS003 (BMS)
DS001 (Merck)
DS006 (Maraviroc)
SCHs (Schering-Plough)
Attachment
Locus small molecules
Fusion
S-DABO
Dapivirine (TMC120)
UC781
Tenofovir (PMPA)
PC815 (MIV150 + Carraguard)
Pyrimidinediones (Samjin)
Replication
(RT)
Integration
*Note the science on this is not vetted and may need revision!*
Microbicides are currently being developed. They could potentially block HIV infection by interfering at several stages of the HIV lifecycle. They could:
Prevent the virus from interacting with [Keeping the virus away from?] the cell, by binding electrostatically to [surrounding?] the virus or by making the vagina inhospitable to HIV. This is how the compounds in the upper left, including all the candidates currently in efficacy trials, would work.
They could also prevent the virus from attaching to the cell by interfering with certain proteins on the surface of the virus that are necessary to binding with the cell. The compounds on the upper right do this by blocking gp120, while the compounds on the left do so by blocking gp41, which is involved in fusing together the membranes of the virus and the cell.
Or, they could instead block the receptors on the human cell where HIV needs to attach. The second set of candidates on the right block the CCR5 receptor.
Once the virus has entered the cell, it makes many copies of itself which eventually move out of the cell to infect the rest of the body. A microbicide could also work by preventing HIV from replicating in the cell. The set of candidates associated with “replication” work in this way.
Protein synthesis and assembly
Budding
IPM compounds
IPM-supported compounds
Maturation

5. Microbicide Development Process
4/21/2017
Microbicide Development Process
Research & Development
Site Development
Clinical Trials
Regulatory Approval
Launch & Access
Pipeline
Basic research
Pre-clinical studies
Lead selection
Community engagement
Site selection
Site preparation
Site monitoring
Incidence studies
Pharmacokinetic
Safety
Efficacy
Acceptability
Clinical Trials
Licensure
Post-licensure
studies
Manufacturing
Service delivery
Marketing
*Slide is changed to Donor Presentation Slide Title
The reason you see so many different candidates in development is that drug development is a long and complex process and most candidates will not make it all the way to becoming a safe, effective, approved product. Each product has to be worked on in the laboratory through the research and development phase. Clinical trial sites have to be selected, prepared, established and monitored. Then a whole series of clinical trials needs to be carried out for each candidate, from pharmacokinetic studies that measure how the drug is absorbed into a woman’s body, through trials to test safety and acceptability, through to efficacy trials to determine how well the product works at its ultimate goal—in this case, preventing HIV infection.
Once a microbicide candidate has been shown to be safe, acceptable and effective, it still needs to be approved by regulatory authorities, and marketing and distribution plans need to be in place to get it into the hands of the women who need it.

6. Early Generation Microbicides
4/21/2017
Early Generation Microbicides
Products that non-specifically block HIV from interacting with target cells
In efficacy trials
Partial, low or no effectiveness
Short-acting (used near time of sex)

7. Early Generation Efficacy Trials Candidate Microbicide
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Early Generation Efficacy Trials
Candidate Microbicide
Phase
Mechanism of Action
Sponsor/Developer
Trial Location
Carraguard 3
Entry Inhibitor
Gates, USAID /
Population Council
South Africa – Cape Town, Durban, Medunsa
PRO 2000
UK Medical Research Council, DFID / MDP
South Africa – Mtubatuba, Durban, Johannesburg
Uganda – Masaka
Tanzania – Mwanza
Zambia – Mazabuka
PRO 2000 &
Buffer Gel
2/2B
Entry Inhibitor &
Vaginal Defense Enhancer
NIAID / HPTN (MTN)
Zimbabwe – Harare, Chitungwiza
Zambia – Lusaka
Malawi – Blantyre, Lilongwe
South Africa – Durban, Hlabisa
United States – Philadelphia

8. Next Generation Microbicides
4/21/2017
Next Generation Microbicides
Based on antiretroviral drugs used to treat HIV
IPM’s microbicide candidates fall in this category
Highly potent and HIV-specific
Delivery mechanism for sustained protection
Once a day or less
Gels, intravaginal rings, vaginal tablets and others
Developed as single drugs and in combination
Trial of tenofovir gel initiated May 2007
South Africa (CAPRISA, CONRAD, USAID)
Coitally dependent
*Note these points may need refining, are they the correct key points defining “next generation”?*
The next generation of microbicide candidates is based on the antiretroviral drugs that have been shown to work against HIV, as they are already being used successfully in treatment. Unlike earlier types of microbicide candidates, they block HIV specifically and are highly potent.
While the first generation candidates have all been tested as gels that women must apply shortly before having sex, the next-generation candidates lend themselves to alternative formulations. They offer longer-term protection and could be used as long-acting gels (for example, once-a-day application), vaginal rings, or vaginal tablets.
In order to take advantage of multiple mechanisms of action , the future of microbicides may be in combinations of two or more active ingredients.
Phase 2B trial of tenofovir gel (South Africa)
Initiated May 2007 (CAPRISA, CONRAD, USAID)
All of IPM’s microbicide candidates fall into this next generation.

9. 4/21/2017
IPM Mission & Donors
Established in 2002 as a non-profit product development partnership (PDP).
IPM’s mission is to prevent HIV transmission by accelerating the development and availability of safe and effective microbicides for use by women in developing countries.
Donors
Belgium, Canada, Denmark, France, Germany, Ireland,
Norway, Netherlands, Sweden, United Kingdom, United
States, European Commission, World Bank, UNFPA, Bill &
Melinda Gates Foundation, Rockefeller Foundation
PDP = functioning like a small pharmaceutical enterprise (R&D of the product and clinical trials)

10. Partnerships with Industry
4/21/2017
Partnerships with Industry
IPM Licenses with Industry
Year
Company
Compound
Type
2004
Tibotec (J&J)
Dapivirine (TMC120)
NNRTI
2005
Merck
M167, M872, M882
CCR5 blockers
Bristol- Myers Squibb
BMS793
gp120 binder
2006
Gilead
Tenofovir (PMPA gel)
NRTI
IPM Material Transfer Agreements with Industry
Year
Company
Compound
Type
2007
Pfizer
Maraviroc
CCR5 blocker
Schering-Plough
Anti-HIV Compounds
CCR5 blockers

11. Research and Development
4/21/2017
Research and Development
GMP Manufacture
Pennsylvania, US
Applicator Filling Line

12. IPM Clinical Studies of Dapivirine
4/21/2017 PK
PK/Feasibility
Safety/
Feasibility
Safety
2007
2008
2009
So far, Dapivirine has been tested both as a gel (once-daily) and vaginal ring
Studies above the time line have been completed (the last PK/Feasibility study is IPM 018, currently ongoing in Belgium – data analysis stage)
Studies below the line represent planned studies (IPM 013 is the first gel PK study below the line, planned for Oct 2007)
Missing from this slide: IPM 011 (Placebo ring safety & acceptability study), currently ongoing in South Africa, Kenya, Tanzania (this is a placebo, not dapivirine study)
Safety
Safety
Male
tolerance PK
Seroconverter protocol PK
Efficacy trial
Studies in Belgium, Kenya, Rwanda, South Africa, Tanzania

13. IPM Site Development in Africa
4/21/2017
IPM Site Development in Africa
IPM is conducting epidemiological studies of HIV incidence in approximately 20 sites across sub-Saharan Africa. These findings will help us determine the most appropriate sites for conducting a phase III efficacy trial.
Note: Not all sites will progress to efficacy trials.
Early stage site development
(cross-sectional incidence studies)
Advanced stage site development
(cohort incidence studies)

14. Why Test Microbicides in Developing Countries?
4/21/2017
Why Test Microbicides in Developing Countries?
Countries in greatest need of new HIV prevention options
Communities with high HIV incidence
Test microbicides in contexts in which they will be used
Clinical and regulatory implications
Building understanding and support

15. IPM Research Center Partners
4/21/2017
IPM Research Center Partners
Stanza Bopape Community Trust
Ladysmith Hospice Association
Afrimesh Research and Care

16. Ethical Guidelines for Clinical Trials
Community engagement
Informed consent process
Counseling
Pre- and post-HIV testing
Condom education and provision
Family planning
Referrals
Those who initially screen HIV-positive
Pregnancy
Social harms
Treatment
Sexually transmitted infections
Adverse reactions
Antiretrovirals for HIV infections

17. Product Acceptability Studies
4/21/2017
Product Acceptability Studies
Placebo gel formulations
Market research in Kenya, Zambia, South Africa (500 volunteers), 2006
Assess women’s preferences
Supported acceptability of a daily product
Placebo vaginal ring
Study launched February 2007 (200 volunteers)
Four sites in South Africa, Tanzania, Kenya
Collect early safety and acceptability data
Vaginal tablet and film: initiated Q4 2007

18. IPM Access Principles Availability Accessibility Acceptability
4/21/2017
IPM Access Principles
Availability
Accessibility
Acceptability
Affordability

19. Sample Access Activities
4/21/2017
Sample Access Activities
Intellectual property agreements
Community mobilisation for trials
Market research
Mapping regulatory pathways
Surveying manufacturing capacity
Modelling introduction scenarios
Assessing health system capacity
Lessons learned from other health technologies

20. European Activities
Europrise: European Vaccines & Microbicides Initiative
Int’l research network of 33 partners from 10 countries
Chair of IPM’s SAB is coordinator & IPM Belgium is affiliate member
EMPRO: European Microbicides Project
Int’l research network of 25 partners in Europe & Africa
IPM has advisory role & is planning a joint Phase IIVR trial
EDCTP: European and Developing Countries Clinical Trials Partnership
Partnership of 14 EU countries, Norway & Switzerland to develop clinical interventions in cooperation with 18 African countries
IPM provides proposal review and expertise and supports bridge funding for sites, as requested

21. IPM Support of Global Development Efforts
4/21/2017
IPM Support of Global Development Efforts
Improvement in health
Reduction in new HIV infections
Increased community education and mobilization
Regulatory path for new prevention technologies
Capacity building
Infrastructure and equipment
Income and skills generation (jobs and training)
Access to medical care and support
Women’s rights

22. 4/21/2017
Contribution to MDGs
“Microbicides are a development priority. I can think of no other technology that has the potential to dramatically improve the health of women in developing countries. Moreover, I do not see how we can meet the MDGs without safe and effective microbicides.”
STEPHEN LEWIS, 2005
Former UN Special Envoy for HIV/AIDS in Africa