HIV infects 6,000 women every day because their men won't wear condoms. But a solution could be at and on their fingertips. It's odorless, kills HIV -- and, best of all, he doesn't have to know.
Sara and Paul are like countless married couples in the developing
world. While she raises children and looks after livestock on a farm in
rural Zimbabwe, he works a subsistence-wage job in a distant town. They
see each other, at best, once a month. The last time Paul came home,
Sara noticed a vaginal discharge just days after he left. A local
clinic confirmed her suspicion -- Paul had given her a sexually
transmitted infection. But when she tried to get him to wear a condom,
she received a severe beating.
If 20 years of AIDS have taught us anything, it's that men, straight
or gay, rich or poor, would sooner chuck a condom than slip it on. In
sub-Saharan African countries, condom use falls as low as 7 percent.
Nearly half of gay American men in their 20s report that they recently
had unprotected anal sex. "I don't think it's hard to ask someone to
wear a condom, but guys hate them," says Dyanne Stempel, a single white
female living in Los Angeles. "They don't say anything and then they
either can't perform or they get uncomfortable."
But what if Sara and Dyanne had a stealth method of protection?
Something called, let's say, Coochie Cream or Booty Butter -- an
odorless gel, lotion, foam or suppository that could help protect them
from STDs, but that would also ensure the seamless intimacy cherished
in those passionate moments? "It would be a dream," Stempel says.
For 15 years, certain scientists -- gravely underfunded and mostly
dismissed by the AIDS research mainstream -- have toiled to make this
dream a reality. Now the fruit of their labor is ripening, just as the
cause of women enters the vanguard of AIDS consciousness. Their
inventions are called microbicides -- and while the unfortunate name
sounds like a fungus-eradication product, if all goes well, these
woman-controlled "chemical condoms" could reach the over-the-counter
market in five years and become the biggest reproductive-health
innovation since the birth-control pill.
No longer the fantasy of womanist policy wonks and heated activists,
microbicides have become a cause célèbre, splashed onto the pages of
publications like Vogue and The Wall Street Journal.
Their credibility comes not only from the most promising candidates'
recent clinical trial advances but also from the stepped-up efforts of
billionaire philanthropists Bill and Melinda Gates, who have donated a
total of $50 million to microbicide research. In February, they made
their most recent contribution, $20 million to fund a Phase III trial
-- the final, FDA-required test of efficacy in humans -- of a promising
seaweed-based product called Carraguard.
The need for such a revolutionary product has become alarmingly
clear: Worldwide, 17.6 million women have HIV. A single unprotected sex
act is eight times more likely to infect a woman than a man. Across
Africa and Asia, women in ostensibly monogamous marriages are at great
risk of contracting HIV and STDs. In Thailand, a study in the Journal of Acquired Immune Deficiency Syndromes reported, 76 percent of HIV positive women said that their only sexual
contact was with their husbands.
"The issue of women has come front and center in the AIDS epidemic,"
says Helene Gayle, MD, who championed women's prevention programs as a
top official at the Centers for Disease Control and Prevention and now
oversees the Gates Foundation's AIDS giving. "The reality is, we're
still many years from having a vaccine, and that's made people realize
we need to diversify research and development. We can't just focus on
treatments and vaccines -- we need to find intermediary technologies."
Carraguard is just one of nearly 60 microbicides in development in
the United States, India, Brazil, Belgium and Britain. These products
come in a wide variety of formulations. Some are contraceptive as well
as antimicrobial; others would allow for conception while nixing HIV.
Because of the prevalence of anal sex, many researchers insist that
microbicides must work rectally as well as vaginally. This has the
added bonus of making them valuable to gay men as well as straight
women. But each prototype aspires to a common goal: skin-to-skin
contact, the ideal of intimacy across all cultures.
David Phillips, PhD, a senior scientist at the Population Council,
wishes that he could say he's the genius who discovered that a simple
red, seaweed-based product called carrageenan prevents viral infections
such as HIV. But in fact, carrageenan, a food thickener used in
Campbell's soups, ice cream and baby food, has been known for its
antiviral properties since the '60s. In the '80s, scientists began
looking at carrageenan's potential for herpes prevention. That was when
Phillips began the research that led to the formulation of Carraguard
in the late '90s. "We've shown that Carraguard is effective against HIV
in the test tube and against several sexually transmitted pathogens in
animals," he says. "But there's still a lot we don't know about how HIV
gets into the body. [See "Enemy at the Gate"]. Now it's our job to
prove it will work with people."
Carraguard is one of five microbicides set to enter advanced-stage
clinical trials this year. With so much riding on the results of the
research, scientists such as Zeda Rosenberg, the interim executive
director of the International Partnership on Microbicides at Family
Health International, has a barrage of urgent questions to answer.
Overseeing the Phase III tests of two other top contenders, PRO 2000
and BufferGel, Rosenberg is helping to design studies with upward of
8,000 women. As far as the sheer scale and ambition go, Rosenberg
maintains an upbeat attitude. "Every challenge can be overcome with
creative design and lots of resources," she says.
But the investigations are starting with a financial straitjacket.
Carraguard, for instance, has only about $20 million in its research
coffer, although conservative estimates put the cost of a trial closer
to $50 million. Beyond the money, there are logistical and ethical
problems. Scientists can't be in bed with participants when they
actually use the gel, so they must rely on self-reporting rather than
the data-gathering methods used in laboratory-controlled settings. Then
there's the moral dilemma that arises when Western scientists give,
say, an African woman -- whose chances of contracting HIV are 20 to 30
percent -- a placebo gel rather than the real thing. It's true that the
researchers will give all volunteers condoms and encourage the use of
both latex and microbicide (or placebo gel). But even the best
intentions could result in women being -- or ultimately feeling --
exploited when their risk of infection is frighteningly high. Rosenberg
acknowledges the ethical implications but still defends the
proceedings, arguing that the women will receive prevention and care at
standards comparable to those in the U.S. "That means condom promotion
and counseling and treatment of STDs," she says.
Rosenberg and her colleagues believe that a microbicide will have
demonstrated efficacy if, over three years, there are at least 30
percent fewer infections among users than in the control group. That
may sound far from ideal. But researchers at the London School of
Hygiene and Tropical Medicine estimate that a microbicide with 60
percent effectiveness could avert 2.5 million new HIV infections over
three years worldwide. On top of the obvious human benefits, that
translates into a $2.7 billion savings in health-care costs (not
including HIV meds) and $1 billion in productivity for developing
countries.
"This has been discussed by many experts in the field, and there is
some consensus, at least for the first clinical study, that 30 percent
could potentially lead to approval," says Debra Birnkrant, MD, director
of the FDA's division of antiviral drugs, who has reviewed every
microbicide that has entered trials. "This is being developed globally
-- not just for the U.S. -- and if we could prevent 30 percent of
infections in Africa, that would be tremendous." Still, she envisions
the FDA recommending the products for use with condoms. "The trials are
being conducted with them, and the labels have to reflect that," she
says.
Even with all the drum-rolling about the promise of the "fab five"
microbicides, researchers have great cause for caution. Two years ago,
four microbicide finalists had made it to Phase III trials, but all
ultimately failed because they contained Nonoxynol-9. In studies, the
spermicide was found to cause vaginal abrasions, making women even more
susceptible to HIV.
The current crop works differently. Carraguard's carrageenan belongs
to a family of compounds called sulfated polymers, which are believed
to coat HIV and keep it from entering host cells. BufferGel, made of a
foaming agent already used in many vaginal products, mixes with the
vagina's natural acidity to create a pH level hostile to HIV. Then
there are antiretroviral products like PMPA gel, which work like
current AIDS therapies by blocking HIV replication. Since the '80s,
hundreds of compounds have been screened in test tubes for their
ability to prevent pregnancy and kill pathogens, says Henry L.
Gabelnick, PhD, the director of a microbicide research consortium
called CONRAD that in 2000 received $25 million from the Gates
Foundation. After the devastating failure of Nonoxynol-9, he says,
"people began looking for formulations that were less irritating and
compounds that would bind the virus."
The finalists -- most of which have passed the small Phase II tests
for safety and initial indications of effectiveness -- all offer
promising approaches. The big problem now is money. The Rockefeller
Foundation Microbicide Initiative, a working group of consultants,
researchers and pharmaceutical analysts, estimates that total
product-development costs for the first generation of microbicides will
run more than $750 million (by contrast, the average drug, including
HIV medicines, costs $500 million to develop.) Sadly, the Initiative
projects only $230 million in public funding for microbicide
development through the year 2005.
One solution would be for deep-pocketed pharmaceutical giants to
partner with the current loose network of academics, nonprofits and
plucky, indie biotechs such as ReProtect, the Baltimore company that
developed BufferGel. But prevention has never been Pharma's bread and
butter. "As a society, we talk a lot more about therapy than
prevention," says Kevin Whaley, PhD, who helped develop BufferGel.
"With microbicides, we're introducing a whole new category, and that's
just stunning to some people." To make matters worse, the female condom
and the Today Sponge, two products seen as business-case precursors to
microbicides, were thought to enjoy strong market potential but turned
out to be unmitigated flops. Annual worldwide sales of the female
condom peaked at a miserable $6 million (in comparison, "male" condom
sales have reached $295 million in the U.S. alone), and the sponge
raked in a paltry $20 million -- hardly the numbers to justify
microbicides' not-insignificant development costs.
For the most part, pharmaceutical giants are watching microbicide
testing from the sidelines and withholding their wallets. Janet
Skidmore, a spokesperson for Merck, explains that her company's HIV
prevention commitment lies, and will remain, firmly in vaccine
territory. "Given our experience in the vaccine field, it's just the
more effective approach for us," she says. She denies that this
decision is based on economics or microbicides' early clinical
stumbles. "We feel strongly that the best way to approach this pandemic
is with a vaccine."
But if Merck and its brethren were in fact to consider the "return
on investment" numbers compiled by the Rockefeller Foundation
Microbicide Initiative, they'd likely flee in horror. While the group
rates current microbicides as "promising" and predicts that their
global market size could reach $900 million by 2011, it places each
candidate's statistical chances of clinical approval and market entry
at only 25 percent. Even worse, projections show that any corporate
backer of a first-generation microbicide is likely to incur financial
losses in the tens of millions of dollars. For a microbicide to be
effective in the developing world, it has to be cheap -- as little as
35 cents per dose -- obliterating profit margins.
Researchers and academics argue that as long as the clinical trials
are publicly and philanthropically funded, a pharmaceutical company
that owns or acquires a successful microbicide does stand a chance to
make money. "It's not going to be a billion-dollar blockbuster,"
Gabelnick says. "But the market for spermicides now is only $40 to $50
million, and that hasn't kept personal-product companies from selling
them." He also envisions a two-tier pricing system to balance out the
cheapness of microbicides in poor countries. "People forget that a
cycle of oral contraceptives sells for $30 in a pharmacy, but donor
agencies probably get them for 30 cents or less," he says, adding that
in many developing nations such as Brazil, India and China, there's a
sizable, growing middle class that can absorb a higher price point.
That a viable, potentially lucrative microbicide market exists in
developed countries is something that UC/Berkeley epidemiologist
Bethany Young Holt, PhD, is seeking to prove with a
soon-to-be-published study of young American women. "Across the board,
women are uncomfortable talking to their male partners about sex --
whether they're rich, poor, white or black," she observes. Holt held
focus groups to gauge women's interest in microbicides. Their responses
were encouraging and even produced sexy packaging ideas, like a sleek
gel (strawberry flavored preferred) contained in a lipstick-like case
-- the must-have purse item of the coming decade.
For now, all eyes are on the holy grail of FDA approval, which could
take another five years. But the war chest for microbicide development
remains disturbingly light, with money coming in piecemeal from the
government, academic grants, private foundations and small biotech
firms. According to the Washington, DC-based Global Campaign for
Microbicides, an organization that raises public awareness and
political and financial support, only 1 percent of the federal AIDS
research budget -- $35 million -- is currently allocated to microbicide
research.
For veteran activists such as Anna Forbes, the Global Campaign's
field organizer, this is a frustrating state-of-affairs. "When we treat
microbicides like the ill-fated, red-haired stepchild, we're just
cutting off our nose to spite our face," she says. "This could be
revolutionary."
If microbicides are going to take hold, there needs to be a major
public education push. According to the Kaiser Family Foundation, only
2 percent of Americans have even heard of microbicides.
A stronger show of political force will also be necessary, which is
why people like policy officer Lara Stemple are working on campaigns
like the California Microbicides Initiative (CaMI) in Los Angeles. CaMI
and other groups have secured the sponsorship of eight senators and 38
house representatives for the Microbicide Development Act, which would
appropriate money for a new microbicide program at the National
Institutes of Health. Given the unpredictable AIDS climate under the
Bush administration -- with abstinence dominating the federal HIV
education agenda and a paltry $200 million committed to the UN global
AIDS fund -- even Forbes concedes that the chance of passage is slim.
But just introducing the act will generate legislative awareness and
serve as a starting point for creative funding strategies. "Global AIDS
is a hot issue on Capitol Hill," she says. "And if we can position
microbicides as part of the issue, then it has a much better chance of
making it."
With the profit sector playing possum until the proof comes in,
what's urgently needed is funding from public and philanthropic
sources. "We're looking for our Mrs. McCormick," Stemple says, invoking
the wealthy widow who, with reproductive-rights activist Margaret
Sanger, unsuccessfully lobbied the pharmaceutical industry to develop a
safe, effective oral contraceptive. In 1951, Katherine Dexter McCormick
put her International Harvester money where her mouth was, hiring the
scientists to produce the research that ultimately led to the
birth-control pill.
Before then, liberating women's sexuality from pregnancy might have
seemed like speaking over wires, flying through the air or rocketing to
the moon -- once quixotic, even foolish, then suddenly, perhaps
accidentally, attainable. When a microbicide liberates women's -- and
gay men's -- sexuality from HIV, it could finally put the brakes on
history's worst-ever public-health catastrophe. But in the absence of
sufficient dollars and awareness, the revolution in the sheets will
require what is sometimes equally hard to come by: movement in the
streets. "It's clear microbicides are needed, and that they're
imperative," Forbes says. "Since we're not able to attract corporate
support, we have to make it happen ourselves."
ENEMY AT THE GATE Researchers have spent 20 years and hundreds of millions of dollars
trying to figure out how to undo HIV once it's in the body. But as
virology and reproductive biology expert David Phillips, PhD, and his
peers labor to prove the anti-HIV power of microbicides, a key mystery
persists: How does the virus get into the body in the first place?
Theories of infection abound. Phillips believes that most acts of
unprotected sexual intercourse with an HIV-infected partner won't
result in transmission without certain mechanisms to facilitate viral
entry. "It's like if a bunch of people drink contaminated water," he
says. "Some will get sick. Others won't." The ideas about transmission
vary, but ultimately any could be true -- or not. "There's so much we
still don't know," Phillips says bluntly.
Most experts assume that semen carries the virus into the cervix,
vagina or rectum, allowing it to invade other cells, which then
circulate it bodywide. One leading theory holds that the fatal carriers
are dendritic cells -- the ones that signal the immune system to
produce antibodies. According to this view, dendritic cells pick up the
virus and take it back to the lymph nodes, contaminating them.
Another top hypothesis links HIV infiltration to epithelial cells,
which line the vagina, intestines and interior of the lungs. Even
though these cells are designed precisely to protect these sensitive
organs from infection, for some reason they are vulnerable to viral
violation, especially in the rectum.
With a number of theories in play, the ideal microbicide would cover
as many bases as possible, making the virus unsavory to dendritic cells
and preventing the virus from binding to epithelial cells. But even if
a microbicide trial is successful, it will be very difficult, if not
impossible, to isolate which infection mechanisms were blocked. "It's
my job to worry about them all," Phillips says. Clearly, the mystery of
infection is fertile ground for future research.
