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
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
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
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
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
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
Laboratory Testing
2-6 Years
Phase 3(efficacy)
2 to 4 Years
Simultaneous studies:HIV+, penile & rectal
10 or more years
Phase 1(safety)
1 to 6 Months
Phase 2(safety)
Up to 2 Years
25 – 40 people
200-400 people
3,000-10,000 people
From identified need to marketplace:Drug development
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
How do microbicides work?
Shattock RJ and Moore JP. Nature Reviews Microbiology, vol. 1 Oct/2003
Microbicides in clinical trials and their mechanism of action
MECHANISM OF ACTION CANDIDATE PHASE
Surfactant (viral disruption)
Savvy™ (C31G) 3
Entry/fusion inhibitors Carraguard® 3
Cellulose sulfate/CS (Ushercell) 3
PRO 2000 3
Invisible Condom™ 1/2
Cellulose acetate 1,2-benzenedicarboxylate (cellacefate/CAP)
1
VivaGel™/SPL7013 1
Vaginal defense enhancers
BufferGel® 2/2B
ACIDFORM™/Amphora™ 1
Replication inhibitors Tenofovir/PMPA gel 2
TMC120 1/2
UC-781 1
Uncharacterized Praneem polyherbal vaginal tablet 2
Combinations PC 815 (Carraguard® and MIV-150) 1Adapted from An Analytical Overview of the Microbicide Preclinical and Clinical Pipeline, Plescia, Finley, Harrison, des Vignes
5 Products Furthest AlongProduct/Developer
# to be enrolled
Location of trial Estimated end of follow-up
Carraguard®
Population Council
6,299 South Africa March 2007
BufferGel®
ReProtect, Inc.
3,220 Malawi, South Africa, United States, Zambia, and Zimbabwe
July 2008
PRO 2000Indevus Pharmaceuticals
.5% formulation
PRO 2000.5% & 2% formulations
9,673 S Africa, Tanzania, Uganda, Zambia March 2009
Cellulose sulfate Global Microbicide Project
2,574 Benin, Zimbabwe, India, South Africa, Uganda
February 2009
Family Health International
2,160 Nigeria February 2009
Savvy™Family Health International
2,142 Nigeria Stopped August 06
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)
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
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
Contraceptive studies of microbicides
Cellulose sulfate used alone – completed BufferGel used with Ortho All-Flex
diaphragm - completed Savvy used alone - underway
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 Replaces applicator
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
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
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)
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
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
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
Microbicide Development Strategy (MDS)
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
Available at www.microbicide.org.Available at www.microbicide.org.
What does the development of a microbicide cost?
Laboratory Testing
Phase 1(safety)
Phase 2(safety)
Up to $13 Million
Phase 3(efficacy)
Up to $50 Million
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?
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
ACKNOWLEDGMENTSACKNOWLEDGMENTS
♦ Alliance for Microbicide Development♦ Global Campaign for Microbicides♦ Certain slides courtesy of:
Sharon Hillier, PhD University of PittsburghJim Turpin, PhD, NIAID/DAIDSSalim Abdool Karim, MBChB, PhD, University of KwaZulu-Natal
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
Results Enrollment:
2022 women screened 200 enrolled
Disposition:
Completed study without becoming pregnant
82 (41%)
Became pregnant 18 (10%)
Discontinued early for gel-related reason: 14 ( 7%)
Discontinued early for other reasons 66 (33%)
Never used gel 18 ( 9%)
Lost to follow-up 2 ( 1%)
Females
Male partners
Age (mean) 26.6 yrs
29.0 yrs
Race (percent)
White, non-Hispanic 46% 48%
Hispanic 29% 25%
African American 21% 21%
Other 4% 6%
Education (% who attended college)
82% 74%
Ever used spermicide 27.5% NA
Demographics
Pregnancy Probabilities - CS
13.4
3.9
0
5
10
15
20
25
Typical use (6 months) Perfect use (6 cycles)
Cellulose sulfate
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
Pregnancy Probabilities – N-9
22.2
15.715.5
8.5
14
9.5
0
5
10
15
20
25
Typical use (6 months) Perfect use (6 cycles)
Advantage S (52.5 mg N-9)
Ortho Options Gel B (100 mg N-9)
Ortho Options Gel C (150 mg N-9)
Pregnancy Probabilities CS & N-9
22.2
15.715.5
8.5
14
9.5
13.4
3.9
0
5
10
15
20
25
Typical use (6 months) Perfect use (6 cycles)
Advantage S (52.5 mg N-9)
Ortho Options Gel B (100 mg N-9)
Ortho Options Gel C (150 mg N-9)
Cellulose sulfate
►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):
Vulvovaginitis, unspecified 9.5%Urinary tract infection 7%Gel reaction 7%Spotting 5%Yeast infection 3.5%
►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.
Adverse events
Females
Male partners
% who liked the gel “OK” or “very much”
82% 84%
% who would either “recommend” or “strongly recommend” the gel to a friend or relative
73% 73%
% who said the gel is “the same,” “better,” or “much better” than other spermicides (of those who ever used spermicide)
89% 94%
Acceptability
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.
The end
On average, there were 11.5 coital acts per cycle:
Study gel used alone as instructed (“perfect use”)
78%
Study gel used with an additional method
5%
Study gel used alone but incorrectly
4%
Use of an alternative method alone 10%
Unprotected intercourse 4%
Coital acts
Cycles
Correct and consistent (“perfect”) gel use
343 (45%)
Incorrect use of CS, use of an additional contraceptive method, or use of an alternative contraceptive method
290 (38%)
Unprotected intercourse 125 (17%)
TOTAL 758 cycles
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