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Summary of a Panel Discussion at the Centers for Disease Control and Prevention
Executive Summary
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EXECUTIVE SUMMARY:
On April 15, 1996, representatives of CDC's Office of Women’s Health; the National Center for HIV, STD, and TB Prevention (NCHSTP); the National Center for Chronic Disease Prevention and Health Promotion; and the National Center for Infectious Diseases convened a one-day panel discussion on female-controlled chemical methods for HIV/STD prevention. The goals of this meeting were:
1) To have experts from governmental and nongovernmental organizations brief CDC staff on accomplishments, work in progress, and future directions in biomedical and behavioral research on and development and marketing of topical microbicides, and development and implementation of policy concerning their use (See attached agenda).
2) To have CDC staff brief panelists and guests on ongoing research at CDC.
3) To discuss ways to foster collaboration between CDC and other governmental and nongovernmental organizations.
4) To seek guidance on developing a CDC research agenda that would establish a science base for developing and implementing policy about use of female-controlled HIV/STD prevention methods.
Panelists recommended several future actions for CDC, including:
1) Continuing behavioral research on determinants of acceptability and use and on attitudes of consumers and providers toward vaginal and rectal microbicides.
2) Conducting research on how complex, hierarchical prevention messages are understood and whether recommending other, less effective HIV/STD prevention methods causes “drifting” away from male condom use.
3) Increasing support of Phase III human effectiveness trials of nonoxynol-9 (N-9) and other candidate compounds against HIV through collaboration with other agencies and development of CDC-sponsored high- and moderate-risk cohorts.
4) Developing population-based research on vaginal products with both contraceptive and antiinfective action and rectal microbicides.
5) Publishing and distributing a document for providers, consumers, and HIV/STD prevention specialists on the effectiveness and acceptability of female-controlled methods for HIV/STD prevention, current gaps in knowledge, and recommendations for future research.
6) Deferring development of a policy to promote N-9 as a topical microbicide until more data are available. Meeting highlights are summarized below.
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Introduction
Helene Gayle, MD, NCHSTP Director, reviewed the reasons for CDC’s growing interest in this topic; these include the growing number of women with HIV/AIDS; the fact that women are disproportionately affected by STDs; NCHSTP's increased emphasis on prevention programs; the limited progress with other preventive strategies, such as vaccine development and male condom promotion; and the growing recognition that women who are at risk for HIV/STD infection through heterosexual contact need methods other than the male latex condom to protect themselves.
Clinical efficacy studies of N-9: status
and
future directions.
David Sokal, MD, Family Health International (FHI),
reviewed
results of in vitro, animal, and human testing of nonoxynol-9 (N-9), a
candidate microbicide found in spermicides commercially available
worldwide.
Although N-9 kills HIV in vitro, the effects of N-9 on HIV/STD
acquisition
in humans are uncertain. The results of three randomized, controlled
field
trials of the effectiveness of various forms of N-9 indicate that N-9
reduces
the risk of acquiring gonorrhea and/or chlamydia by 20% to 70%, but
these
trials did not evaluate HIV and other bacterial STD. In the only
randomized
controlled trial of N-9 against HIV, high-dose N-9 in a vaginal sponge
showed no protective effect against HIV acquisition among
commercial
sex
workers (CSWs). Two multicenter, randomized controlled clinical
trials,
including one sponsored by FHI, are underway. Recruitment for the
FHI
study
of the effects of N-9 film on HIV infection among CSWs in Cameroon
is
complete,
and the final analysis is expected in December 1996.
Jos Perriens, MD, UNAIDS,
reviewed
the status of UNAIDS-sponsored microbicide trials. A study of
menfegol,
a spermicidal surfactant similar to N-9 that is found in foaming
tablets
used in many developing countries, was stopped in early stages
because
of dose-dependent toxicity to the genital mucosa that appeared to be
partly
due to the toxicity of the vehicle. This finding suggests that foaming
tablets containing N-9 may also cause toxicity. He then reported on
safety
studies with an N-9-containing gel (COL-1492 or Advantage 24).
Healthy
volunteers in Europe and Thailand were randomly assigned to one of
three
groups: once-daily use of gel, once-daily use of placebo, or no
treatment.
The incidence of genital ulcers and abrasions was very low in all
three
groups, but the incidence of erythema was higher in the COL-1492
group
than in the other two groups. In a subsequent study investigating the
safety
of COL-1492 used four times a day by healthy volunteers in
Thailand,
the
incidence of lesions was still very low but was slightly higher than
with
once-daily use. However, because of the overall low incidence of
lesions,
COL-1492 was considered safe for phase III studies. A phase III
study
is
starting in June 1996 in South Africa and Thailand; Projet Retro CI in
Cote d’Ivoire will also participate if they receive IRB approval. Dr.
Perriens
also described the accomplishments of the Interagency Working
Group
on
Vaginal Microbicides, a group of representatives from public-sector
agencies
supporting vaginal microbicide research. At the group’s meeting in
April
1996, guidance on the preclinical and clinical development of vaginal
microbicides
was approved and will be published by July 1996. The ensuing
discussion
concluded that important issues to address in ongoing and future
research
include:
1) The generalizability of results of trials among CSWs to the general population of women at lower risk of bacterial STDs.
2) Potential problems with recruiting sufficient numbers of participants to account for inadequate statistical power and confounding due to high frequency of concurrent male condom use.
3) The importance of product formulation in determining effectiveness, toxicity, and acceptability.
4) The correlation of self-reported symptoms and colposcopic, histologic, and immunohistochemical findings in the lower genital tract and the impact of these factors on HIV transmission.
5) The role of pharmacokinetics (e.g., half-life, duration of effect) in determining effectiveness and adverse effects.
6) The need to define the "minimum threshold" of effectiveness that would be necessary to support various messages for use of N-9 for HIV/STD prevention (e.g., as a stand- alone product, as a back-up if condoms are not available, or as an adjunct to condom use).
Role of in vitro testing in developing
and
evaluating female-controlled chemical methods:
Michael Norcross, PhD, Food and Drug
Administration,
emphasized that in vitro testing is an important first step in
evaluating
toxicity and efficacy of candidate compounds, especially for
determining
the diverse types and mechanisms of HIV entry and replication in
cells.
However, he cautioned that in vitro test results cannot predict results
in animal or human studies because of the complex microbiologic and
immunologic
environment of the lower genital tract. He reviewed the two broad
categories
of HIV-1 isolates: T-cell line trophic and macrophage trophic. Testing
algorithms for N-9 are largely T-cell trophic, but because N-9 has
nonspecific
cytotoxic properties, algorithms using either cell type are
appropriate.
Lee Claypool, PhD, Program for
Contraceptive
Research and Development (CONRAD), outlined CONRAD
objectives
and activities in the development of topical vaginal microbicides,
including:
1) Collaboration with Federal agencies.
2) The testing of experimental compounds and existing products for spermicidal activity.
3) The evaluation and decision tree used to direct and focus preclinical development of new candidatae compounds.
4) The testing algorithm and assay methods for evaluating the in vitro anti-HIV activity of test compounds and existing spermicides against cell-free HIV, cell-associated HIV, and viral binding of target cells
5) Research on vaginal physiology and virus-cell interactions.
He also reviewed the current leading candidate compounds, the pending evaluations for toxicity, and the additional research needed to support product development regarding safety, efficacy, and acceptability.
Role of animal testing in developing
and
evaluating
female-controlled chemical methods:
Nancy Alexander, PhD, National Institute for Child Health and
Development,
described the theoretical advantages of using animal models in
developing
and evaluating microbicides, including the ability to perform toxicity
tests and do necropsies. She reviewed the common animal models
used
for
reproductive and toxicity studies (rabbits) and retroviral
transmission
studies (cats and macaques).
Christopher Miller, DVM, University of
California
at Davis, summarized studies showing that N-9 can
prevent
vaginal
transmission of FIV in cats and SIV in macaques. He concluded that,
although
animal models are useful in developing and evaluating chemical
methods
to prevent HIV transmission, they cannot predict the outcome of
clinical
trials. He emphasized that research is needed on the clinical
implications
of self-reported vaginal irritation associated with microbicide use
because
data are lacking on the "background" irritation associated
with
vaginal sex without microbicide use.
New candidate compounds: status and
future
directions for in vitro and in vivo testing:
Lourens Zaneveld, DVM, PhD, Program for Topical Prevention of
Conception
and Disease (TOPCAD), explained that his program is
focusing
on developing and testing noncytotoxic antimicrobial contraceptives
because
nonspecific, cytotoxic compounds such as N-9 have a high potential
for
disrupting vaginal epithelium and adversely altering vaginal flora. In
addition, it is unlikely that another nonspecific cytotoxic agent could
be found that would be so much better than N-9 that it would
warrant
the
high cost of drug development. TOPCAD is currently evaluating five
noncytoxic
contraceptive antimicrobials, two of which are entering preclinical
development,
as well as two N-9 releasing formulations. He emphasized that
formulations
are critical in determining the efficacy and acceptability of a product
and that several formulations of the same active ingredient may be
needed
to meet individual preferences. However, clinical trials evaluate a
single
formulation of a single active ingredient. If this formulation is not
acceptable
in clinical testing, research and development must return to
preclinical
testing with another formulation for FDA licensure requirements,
slowing
the progress of an acceptable product to market.
Zeda Rosenberg, PhD, National
Institute of
Allergy and Infectious Diseases, described the categories
of
new candidate compounds under development at NIAID and
elsewhere,
including:
1) Broad-spectrum microbicides:
surfactants
(N-9), acid buffers, natural products (lactobacilli, magainins,
protegrins).
2) Inhibitors of viral entry:
monoclonal
antibodies, soluble CD4, sulfated polysaccharides, naphthalene
sulfated
polymers, n-docosanol.
3) Inhibitors of HIV replication:
postbinding
fusion inhibitors, reverse transcriptase inhibitors.
In vitro, many such products vary widely in their activity against wild versus lab HIV strains, suggesting that testing against various strains is valuable. She emphasized three factors that will be key to successful product development:
1) the development of
"combination
products" that may act through more than one mechanism,
2) the ability to economically
synthesize
compounds in bulk
3) the use of a formulation that
adequately
covers the vagina and is acceptable to women and their partners.
HIV/STD prevention methods with
contraceptive
action: advantages and disadvantages: Penelope Hitchcock, DVM,
National
Institute of Allergy and Infectious Diseases, noted that
outstanding
contraceptive methods are available, but no methods (other than
Hepatitis
B vaccine) are available that prevent STD/HIV infection but allow
conception.
Currently, couples must risk infection to have children. In addition,
the
best methods for preventing pregnancy (e.g., hormones, intrauterine
devices)
are least effective against STD/HIV and may lower consistent
condom
use.
She raised three questions about promoting N-9 as a microbicide:
1) If N-9 lyses cells, will N-9
trigger
the release of cell-bound virus into the vagina as free virus and thus
possibly promote infection of other vaginal cells or make women
more
infectious
to partners?
2) Will reducing the dosage or
frequency
of N-9 to minimize irritation also reduce N-9's contraceptive
efficacy?
3) If the results of clinical trials of
N-9 do not answer questions about N-9's effectiveness against HIV, is
this
effectiveness best evaluated through postmarket surveillance?
Willard Cates, MD, Family Health International, noted that national surveys indicate that US women desire contraception during 85% of their reproductive years, whereas women in developing countries may desire contraception for shorter durations, albeit still a large part of their reproductive years. These findings suggest the need to develop microbicides with and without contraceptive action and to study the relative value of recommending dual methods of contraceptive/microbicide regimens. He described an FHI-sponsored study of condom use in Colombia in which female CSWs were counseled to use male condoms and/or spermicides as HIV/STD prevention methods. While CSWs were more likely to report ever using condoms than spermicides, they were more likely to report consistent use of spermicides than consistent use of condoms, suggesting "drift" away from consistent condom use. Because studies among CSWs may not be generalizable to populations at lower risk, he encouraged CDC to study the comparative effectiveness of promoting a single method vs. two methods for HIV/STD prevention in population-based cohorts of women at moderate risk for HIV/STD. He also called for CDC studies of the role of microbicides in postexposure prophylaxis for HIV/STD.
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Characteristics of the ideal method:
what do women need?
Muriel Harris, Society of Women and AIDS in Africa and the
Microbicide
Research Advocacy Project, reviewed several
characteristics
of the ideal method: it must be safe, easy to use, available,
affordable,
nonirritating, and effective in preventing infection. She emphasized
that
research indicates that the majority of STD and HIV transmission to
women
can be prevented if women are given the means to protect
themselves;
that
research, especially behavioral research, on female-controlled
microbicides
is needed; and that advocates are needed to promote the
development
of
methods that meet the most important needs of women.
Chris Elias, MD, of The Population
Council,
emphasized that research on the acceptability of various
formulations
is important in determining user preferences and user dynamics and
in
documenting
adverse effects during typical use. He reviewed an N-9 formulation
preference
study being conducted at five sites in several different countries.
Women
are instructed to use a different formulation (gel, film, or
suppository)
each month for 3 months. Preliminary results from four countries
indicate
that preferences are highly variable within and between countries;
are
not well correlated with expectations before use; and are strongly
influenced
by perceptions of “wet” vs. “dry” sex, partner’s perceptions, and the
product’s
ability to enhance sexual pleasure or frequency. No significant
irritation
was found with any of the three formulations. Film was the most
preferred,
suppositories the least. This study suggests that:
1) influencing the way a product is
introduced
and supported among users may be easier than changing the product
itself,
2) more focus on partner
preferences is needed,
3) "trade-offs"
between promoting a product for disease prevention vs. enhancing sexual pleasure or
vaginal health need to be explored.
Sheila Murphy, PhD, University of
Southern
California, reviewed preliminary data from a CDC-
sponsored
study
of the most desirable features of HIV/STD prevention methods
among
African-American
and Latina women attending STD clinics in Los Angeles. The study is
evaluating
several dimensions, including availability, reliability, female control,
interruption of the sexual sequence, and ease of use. In a preliminary
subset of African-American women, the most desired characteristics
were
that the method:
1) did not cause vaginal or urinary
tract
infection
2) did not cause physical
discomfort
3) worked immediately
4) was reliable
Women who desired a female-controlled method were at lower
risk
for
HIV/STD infection as measured by age at onset of sexual activity and
number
of lifetime sexual partners. Focus group analysis suggest that the
features
that women find important may differ by cultural background and
beliefs;
this issue is being evaluated in a larger quantitative survey. The
study
is also evaluating how women process single vs. multiple prevention
messages
(e.g., male condom alone vs. male condom, female condom, and/or
spermicide).
Questions being asked include
1) Does offering a second option
such
as spermicides undercut the perceived efficacy of the primary option
of
the male condom?
2) Does offering multiple options,
especially
specific hierarchies, create confusion?
She emphasized the need for community-level trials to supply
data
for
policy making but pointed out that data on the effectiveness of
products
are needed before community-level studies can be done.
Licensing, labeling, regulatory, and
marketing
issues for female-controlled methods in the United States:
Sheryl Lard, PhD, Food and Drug Administration,
explained
that unlike toxicity testing requirements the type and extent of
studies
that the FDA requires for approval of new topical antiviral
compounds
or
new labeling claims for existing topical compounds are not defined
by
law.
Rather, preclinical research needs are determined on a case-by-case
basis,
depending on the amount and quality of existing data, the design of
the
initial clinical trial, and the mechanisms of drug action (e.g.,
nonspecific
lysis, biochemical barrier, immune-based mechanisms). Relevant
characteristics
of drug activity in vitro include the dose/response curve against
clinically
relevant virus types, the results of cytotoxicity testing, and the
kinetics
of drug action. She encouraged new product sponsors to contact the
FDA
early in the development stages before bringing products to the most
expensive
clinical trial phase.
Deborah Birnkrant, MD, Food and Drug
Administration,
reviewed requirements for clinical testing for new products, for
submitting
claims for change in dosage or route of administration, and for
supporting
a new labeling claim for an existing product for use in different
patient
populations. These include safety studies (Phase I) and efficacy
studies
(Phases II and III). She encouraged using formulations with
demonstrated
acceptability in clinical trials.
Lorna Totman, PhD, Nonprescription
Drug
Manufacturer's
Association, explained that over-the-counter (OTC) vaginal
spermicides
are a small, shrinking, non-profitable market: only about 2-3% of
married
US women use spermicides with or without mechanical barriers.
Manufacturers
are reluctant to pursue new product development or submit FDA
labeling
claims of HIV/STD prevention for existing products for many
reasons,
including
liability concerns, especially when OTC products are used in ways not
recommended
by the label and manufacturers may still be found liable for such
"off-label"
use. A major current focus of manufacturers is responding to the
1993
FDA-proposed
rule that recommends collecting data to support claims of
contraceptive
effectiveness of specific formulations of OTC N-9-containing
spermicides.
She emphasized that market surveys indicate that there is virtually
no
US market for HIV/STD prevention methods without contraceptive
action and
that adding a labeling claim for HIV/STD prevention to spermicides
would
at best double a very small market.
CDC’s current behavioral and
biomedical
research
on female-controlled HIV/STD prevention methods:
Rebecca Cabral, PhD, Division of Reproductive Health, CDC,
reviewed
the CDC-sponsored study of psychosocial predictors of female condom
use
among women in STD clinics in Alabama. Preliminary data from first-
month
follow-up interviews indicate that 17% of women reported using the
female
condom as their only barrier method during intercourse, 15% only
the
male
condom, and 54% both the female and male condoms (on different
occasions).
Other findings from baseline data indicate that, although most
women
expressed
favorable opinions about the properties of female-controlled
barriers,
only 4% currently use spermicides, and that women who have
experience with
diverse methods like spermicides least. Dr. Cabral concluded that the
determinants
of barrier use are complex; we need to know more than what women
say they
like or dislike about product formulation properties. Comprehensive
behavioral
research is needed.
Katherine Stone, MD, Division of
Sexually
Transmitted Disease Prevention, CDC, reviewed other CDC-
sponsored
behavioral and biomedical research on female-controlled HIV/STD
prevention
methods (See attachment). She reviewed preliminary data from a
study
in
Philadelphia STD clinics evaluating the effect of counseling women
about
the New York State Department of Health hierarchical prevention
message
for HIV/STD prevention, which recommends both male and female
condoms;
if neither are used, spermicides are recommended. Among women
exposed to
the hierarchical message, the number of acts of intercourse in which
at
least one recommended method was used dramatically increased.
Development and implementation of
policy on
HIV/STD preventive methods:
Zena Stein, MBBS, Columbia University, reviewed the
development
of the New York State Department of Health AIDS Institute
hierarchical
prevention message of “Don’t do nothing.” She emphasized that, if CDC
continues
to advocate a policy of preventing HIV/STD through male condom
use
only,
it will be "walking away from the problem." The condom-
only policy
is not working, especially among women at low to moderate risk,
who,
unlike
CSWs with paying partners, tend to be ineffective condom users.
Spermicides
were included in the hierarchy for several reasons: male condoms
are
not
an “exciting” HIV/STD prevention option for most women, the
efficacy of
N-9 in reducing the risk of gonorrhea and chlamydia has been
demonstrated,
HIV transmission may be reduced indirectly by reducing risk of
these
bacterial
STD, and there is no convincing evidence that N-9 enhances HIV
transmission.
However, she cautioned that the efficacy of N-9 in reducing HIV has
not
yet been demonstrated and the extent to which N-9 guards the
cervix,
which
may be an important target organ for HIV, remains unclear. She
emphasized
that women need client-centered counseling about options that are
appropriate
for their specific circumstances. She recommended that CDC play an
active
role in determining if women offered options other than male
condoms
"drift"
away from condom use and in training providers to counsel women
about appropriate
prevention methods.
Martha Rogers, Division of HIV/AIDS
Prevention,
CDC, reviewed the long and arduous process CDC typically
goes
through to develop and implement health recommendations and
policy
in collaboration
with other governmental and nongovernmental agencies. Factors that
are
weighted heavily in guideline development are science (as available),
expert
opinion, cost, and practicality. In considering guidelines for
microbicide
use, CDC is faced with incomplete data and a dearth of scientific
evidence.
Questions that need to be answered include
1) How should results expected
from
the
Cameroon study in June and December 1996 be incorporated into
guidelines?
2) If microbicides are
recommended
for
HIV prevention, how will they fit with other prevention modes?
3) How will the guidelines be
implemented?
4) How will the potential impact of
policy
be determined?
5) What is CDC's role in this
process?
Finally, she solicited recommendations about CDC's role in the development of topical microbicides.
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