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Now that the spermicide nonoxynol-9 (N-9) has been ruled out as a
microbicide1 (see N-9 Not for Women at
High Risk of HIV Infection), attention has shifted to other
substances that might be used topically as a protective barrier against
HIV and other sexually transmitted infections (STIs). An effective
vaginal microbicide would offer a desperately needed option for women at
risk of HIV who cannot persuade their partners to use condoms.
More than 50 agents are being studied for their microbicide
potential, and about one-third are in clinical (human) trials.2
While a microbicide is unlikely to reach the market until after 2010,
six microbicide products are expected to enter effectiveness trials —
the most advanced stages of testing in humans — in 2003 and 2004, says
Dr. Zeda Rosenberg, chief executive officer of the International
Partnership for Microbicides (IPM) and former FHI scientific director
for the HIV Prevention Trials Network (HPTN), a worldwide collaborative
research program that evaluates HIV prevention interventions. The IPM
was founded in 2002 to accelerate microbicide research, development, and
access and has attracted nearly $100 million in support, including a $60
million grant from the Bill and Melinda Gates Foundation.
Those products nearing effectiveness trials act in different ways to
prevent HIV and other STI pathogens from infecting cells. Four of them
— Carraguard (carageenan, derived from red seaweed),
dextrin-2-sulfate, cellulose sulfate, and PRO 2000 — are sulfated or
sulphonated polymers with large, negatively charged molecules that bind
to pathogens or to potential host target cells, forming a protective
coating (see table
for information on how the different microbicides work).
The other two microbicide candidates poised to enter effectiveness
trials kill or inactivate pathogens. C31G, like N-9, damages bacterial
membranes and viral envelopes. BufferGel destroys pathogens by
maintaining the natural acidity of the vagina in the presence of
alkaline semen.
All six compounds have shown some ability to block HIV and other
sexually transmitted pathogens in test tubes or in animals.3
Four of them may also offer protection against pregnancy. The two that
do not appear to be contraceptive are Carraguard and dextrin-2-sulfate.
The six candidates have performed well in safety trials designed to
detect systemic toxicity or disruption of the epithelial cells that line
the vagina.4 Such trials usually begin by studying the safety
and acceptability of the compound among healthy women. Subsequent study
populations represent the range of people who might use a microbicide,
including HIV-positive individuals. Recognizing that anal sexual
intercourse greatly increases the risk of HIV infection for both men and
women, researchers are also beginning to assess the safety of rectal
microbicide use.
Two of the compounds, Carraguard and dextrin-2-sulfate, have
completed expanded safety trials. Results of the Carraguard trials,
involving 565 women in South Africa and Thailand, are expected in May of
2003. Preliminary results of those trials and from the first 35
HIV-negative, sexually active women enrolled in an expanded safety trial
of dextrin-2-sulfate at St. Francis Hospital in Kampala, Uganda, showed
no adverse effects.5 If the final results of the Uganda trial
are equally positive, an effectiveness trial of dextrin-2-sulfate could
begin in South Africa, Tanzania, Zambia, and Uganda in 2004. The
Population Council hopes to begin an effectiveness trial of Carraguard,
involving about 6,000 women in South Africa and Botswana, in 2003.
FHI and the U.S.-based CONRAD Program are also awaiting completion of
data analysis — from a recent safety trial involving 54 Cameroonian
women — before deciding whether to proceed to an effectiveness trial
of cellulose sulfate. CONRAD plans to test the effectiveness of
cellulose sulfate in a second trial in Benin, Uganda, and India, and FHI
researchers are designing effectiveness trials of another compound,
C31G.
HPTN plans to conduct a combined expanded safety and effectiveness
trial of BufferGel and PRO 2000. The proposed study design calls for
enrollment of more than 3,100 sexually active, HIV-negative women in
India, Malawi, South Africa, Tanzania, the United States, Zambia, and
Zimbabwe. If this design is approved by a review committee of the U.S.
National Institutes of Health (NIH), which is HPTN's sponsor, the trial
could begin in 2004. (FHI works with NIH, FHI's Protection of Human
Subjects Committee, and local ethical review boards and community groups
to ensure that its research is always conducted in compliance with U.S.
regulatory requirements and international guidelines designed to protect
human research participants and to ensure that study participation is
equitable and free of coercion.)
In October 2002, a contraceptive effectiveness trial sponsored by the
U.S. National Institute of Child Health and Human Development began
enrolling 975 U.S. women who will use a diaphragm with either BufferGel
or a conventional spermicide. (Contraceptives do not need to be tested
for effectiveness in as many women as do microbicides because the risk
of becoming pregnant when one is not using a family planning method is
so much greater than the risk of acquiring HIV during each act of
unprotected intercourse.) If the results show that BufferGel offers
contraceptive protection equivalent to that of the spermicide, it could
be sold as a contraceptive in the United States within two years.
Bringing a substance to market as a microbicide is expected to take
much longer, even if any of the first-generation candidates are shown to
protect against HIV in humans. Most likely, first-generation
microbicides will, at best, be only partially effective.
Other candidates
The six leading microbicide candidates act before HIV invades a host
cell. Others are being developed that will interrupt the HIV life cycle
after it enters a target cell in the vagina or cervix, by inhibiting
either initial replication of HIV or further spread of the infection.
One of these postinfection challengers, a topical formulation of the
HIV drug tenofovir disoproxil fumarate (tenofovir DF) called PMPA, is
being evaluated in an HPTN safety and acceptability study in the United
States. FHI is designing a multinational effectiveness trial to test
whether taking a daily tenofovir DF tablet can reduce the risk of HIV
infection.
Other promising compounds for second- and third-generation
microbicides include monoclonal antibodies and large, artificial
molecules called dendrimers. Both inhibit fusion of HIV with targeted
cells by binding specific proteins on the surface of the virus.6
Research is also under way to test microbicide delivery devices,
including the diaphragm (see Will Diaphragms
Protect against STIs?), a vaginal cap, and an intravaginal silicone
ring.
The most effective microbicides are likely to be those that combine
different or complementary mechanisms of action against HIV, "just
as antiretrovirals are much more effective when used in combination than
when used alone against HIV," says Dr. Rosenberg.
— Kathleen Henry Shears
References
- World Health Organization (WHO), CONRAD Program. Safety of
Nonoxynol-9 When Used for Contraception: Report from WHO/CONRAD
Technical Consultation, October 2001. Geneva, Switzerland: WHO
and CONRAD, 2002. Available online.
- Harrison PF, Rosenberg Z, Bowcut JC. HIV/AIDS: topical
microbicides for disease prevention — status and challenges.
Unpublished paper. Alliance for Microbicide Development and
International Partnership for Microbicides, 2003.
- McCormack S, Hughes R, Lacey CJN, et al. Microbicides in HIV
prevention. BMJ 2001;322(7283):410-13.
- Mauck C, Creinin M, Barnhart K, et al. A Phase I comparative
post-coital testing and safety study of three concentrations of
C31G. Microbicides 2002, Antwerp, Belgium, May 12-15, 2002;
Coggins C, Blanchard K, Alvarez F, et al. Preliminary safety and
acceptability of a carrageenan gel for possible use as a vaginal
microbicide. Sex Transm Infect 2000;76(6):480-83; Elias CJ,
Coggins C, Alvarez F, et al. Colposcopic evaluation of a vaginal gel
formulation of iota-carrageenan. Contraception
1997;56(6):387-89; Mauck D, Frezieres R, Walsh T, et al. Single and
multiple exposure tolerance study of cellulose sulfate gel: a Phase
I safety and colposcopy study. Contraception
2001;64(6):383-91; Stafford MK, Cain D, Rosenstein I, et al. A
placebo-controlled double-blind prospective study in healthy female
volunteers of dextrin sulphate gel: a novel potential intravaginal
virucide. J Acquir Immune Defic Syndr Hum Retrovirol
1997;14(3):213-18; Low-Beer N, Jespers V, McCormack S, et al. A
safety study of dextrin sulphate gel as a novel vaginal microbicide:
data from HIV negative and positive women. XIV International AIDS
Conference, Barcelona, Spain, July 7-12, 2002; Van Damme L,
Wright A, Depraetere K, et al. A phase I study of a novel potential
intravaginal microbicide, PRO 2000, in healthy sexually inactive
women. Sex Transm Infect 2000;76(2):126-30; Mayer K, Abdool
Karim S, Kelly C, et al. Safety and tolerability of vaginal PRO 2000
gel in sexually active HIV-uninfected and abstinent HIV-infected
women. AIDS 2003;17(3):321-29; Mayer KH, Peipert J,
Fleming T, et al. Safety and tolerability of BufferGel, a novel
vaginal microbicide, in women in the United States. Clin Infect
Dis 2001;32(3):476-82; van de Wijgert J, Fullem A, Kelly C, et
al. Phase I trial of the topical microbicide BufferGel: safety
results from four international sites. J Acq Immune Defic Syndr
2001;26(1):21-27.
- Johnston R. Microbicides 2002: an update. AIDS Patient Care and
STDs 2002;16(9):419-30; Bukenya M, Pickering J, Lacey C, et al.
A phase II study of the safety of dextrin sulphate gel in sexually
active females in Kampala. Microbicides 2002, Antwerp,
Belgium, May 12-15, 2002.
- Harrison; Watanabe M. Topical care of HIV transmission possible. The
Scientist 2002;16(22):34; Veazey RS, Shattock RJ, Pope M, et al.
Prevention of virus transmission to macaque monkeys by a vaginally
applied monoclonal antibody to HIV-1 gp120. Nature Medicine
2003;16(22):34.
N-9 Not for Women at
High Risk of HIV Infection
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Spermicides containing nonoxynol-9 (N-9) increase the risk
of HIV infection when used frequently by women at high risk of
infection, but they remain a moderately effective
contraceptive option for women at low risk of infection,
technical experts convened by the World Health Organization
(WHO) and the U.S.-based CONRAD Program have concluded.1
After reviewing research results about N-9's safety and
effectiveness against HIV and other sexually transmitted
infections (STIs), the group also agreed that:
- N-9 offers no protection against STIs such as gonorrhea
and chlamydial infection.
- Condoms lubricated with N-9 should no longer be promoted
because there is no evidence that they are more effective
in preventing pregnancy or infection than condoms
lubricated with silicone. However, it is better to use a
condom lubricated with N-9 than none at all.
- N-9 should not be used rectally.2
In May 2002, the U.S. Centers for Disease Control and
Prevention (CDC) published similar recommendations, advising
family planning providers to inform women at risk of HIV and
other STIs that N-9 spermicides do not protect against these
infections.3
The WHO and CDC recommendations are based, in part, on an
analysis of 10 randomized clinical trials of the effectiveness
of N-9 against HIV or other STIs, involving almost 5,000
women, that included trials conducted by the Joint United
Nations Programme on HIV/AIDS (UNAIDS) and FHI.4
The analysis, recently published in two parts in the Cochrane
Library, confirmed that there was no evidence that N-9
protects against STIs. (The Cochrane Library publishes
evidenced-based systematic reviews to provide high-quality
information on medical topics.)
Whether N-9 adds contraceptive protection to barrier
methods other than condoms is still unknown, although
spermicide use with the diaphragm is recommended. Researchers
from FHI and Christchurch School of Medicine in New Zealand
recently published a Cochrane Review of randomized controlled
trials comparing the contraceptive effectiveness, safety, and
acceptability of diaphragms with and without spermicide. They
were unable to draw any conclusions because they identified
only one eligible study, and even that study lacked
statistical power. Calling for further research, the review
authors wrote that their analysis "provides no evidence
to change the commonly recommended practice of using the
diaphragm with spermicide."5
— Kathleen Henry Shears
References
- World Health Organization(WHO), CONRAD. Safety of
Nonoxynol-9 When Used for Contraception: Report from
WHO/CONRAD Technical Consultation, October 2001.
Geneva, Switzerland: WHO and CONRAD, 2002. Available online.
- World Health Organization.
- U.S. Centers for Disease Control and Prevention.
Sexually transmitted diseases treatment guidelines, 2002. MMWR
2002;51(RR-6):1-77. Available online;
Nonoxynol-9 spermicide use — United States 1999. MMWR
2002;51(18):389-92. Available online.
- Wilkinson D, Ramjee G, Tholandi M, et al. Nonoxynol-9
for preventing vaginal acquisition of HIV infection by
women from men (Cochrane Review). In The Cochrane
Library, Issue 1. Oxford, UK: Update Software, 2003;
Wilkinson D, Ramjee G, Tholandi M, et al. Nonoxynol-9 for
preventing vaginal acquisition of sexually transmitted
infections by women from men (Cochrane Review). In The
Cochrane Library, Issue 1. Oxford, UK: Update
Software, 2003.
- Cook L, Nanda K, Grimes D. Diaphragm versus diaphragm
with spermicides for contraception (Cochrane Review). In The
Cochrane Library, Issue 1. Oxford, UK: Update
Software, 2003.
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