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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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learning objectives
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
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
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
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
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
from identified need to marketplace drug development

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
microbicide pipeline
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
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
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

safety testing of microbicides
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
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
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
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
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
who is involved in microbicide development
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
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
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
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
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
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

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

What does the development of a microbicide cost?
development will require significant public money
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
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
slide26

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
cellulose sulfate contraceptive trial
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
Results
  • Enrollment:
    • 2022 women screened
    • 200 enrolled
  • Disposition:
how do these compare with n 9
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

slide34

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.
conclusions of cs contraceptive trial
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.
slide38

Coital acts

On average, there were 11.5 coital acts per cycle: