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Past Issues
Volume 17, number 9
September 2003
Mucosa Nostra
Understanding sexual transmission of HIV
Guided by Epidemiology
A talk with microbicide pioneer Zena Stein
More than Protection
Deenen Robinson looks at what women have to gain
Pushing the Point
The Global Campaign coordinates international advocacy
Neighbor to Neighbor
Profiles of microbicide advocacy in the U.S.
Drug News
Kaletra solo startles ICAAC
FDA: Global Citizen
Jen Curry on choices the agency must make
Women, Men and Microbicides
By Bob Huff
We’ve heard a lot about HIV entry inhibitors in 2003. The
new injectable fusion blocker Fuzeon (T-20, enfuvirtide) is the
first member of this new class of HIV drugs to hit the market, and
several oral drugs intended to block HIV entry into cells at other
steps are just starting clinical trials. As a class, the entry inhibitors
are designed to keep HIV from merging with a new cell in someone
who is already infected. But before HIV can put down roots and start
infecting those billions of immune cells, at least one viral particle
must make its way past the body’s skin or mucosa — barriers
that are supposed to keep the outside out, and the inside in. This
premiere moment is called transmission, and new understanding about
how the virus first enters the body is stimulating progress in the
fields of therapies, vaccines, and topical microbicides.
Direct blood-to-blood transmission of HIV seems straightforward.
People infected through a transfusion, blood products or shared
injection equipment probably received a significant dose of the
virus in multiple forms that efficiently found its way into their
immune system. Immediate post-exposure prophylaxis with antiretroviral
(ARV) drugs has a good record for preventing blood-borne infections
from needle-stick accidents and may prevent some sexually transmitted
infections as well. Another main route of exposure is through mother-to-child
transmission during pregnancy or birth. It was eventually discovered
that most newborns could be spared from infection by reducing the
viral load of the mother with antiretroviral drugs before labor,
or in some cases, by choosing C-section over vaginal delivery.
But sexual transmission of HIV is the leading source of infection,
and although infections between men having sex were most common
at the beginning of the epidemic, nowadays infections passed between
men and women are pushing the scale of the world AIDS crisis into
uncharted territory. With an estimated 14,000 new infections occurring
every day, and as many as 42 million infected worldwide, preventing
new infections between men and women is an unmet emergency. The
most available lines of defense are education, behavior change and
condom use. Simply not having sex or assiduously using a condom
every time can do wonders for reducing the infection rate. But like
all miracle cures, education and condom use has proved too good
to be true. Most new infections occur among young people —
a group powerfully motivated to have sex — and among people
with little control over the material conditions of their lives,
such as men and women in resource poor areas who lack the power,
education and opportunities to protect themselves.
Beyond education and condoms, public health policy has pushed for
development of a vaccine. In a few historical cases, vaccines have
been able to effectively protect mass populations from communicable
pathogens at a rock bottom, one-shot and on-with-your-life cost
that sounds like salvation. As HIV spreads unrestrained in some
regions; when as many as 40 percent of a nation’s citizens are in
danger of becoming infected, even a partially effective vaccine
that can’t reliably protect any particular individual would have
a huge impact on the social catastrophe of AIDS.
But a vaccine for HIV has proved difficult to solve. In every year
since the mid-1980s, someone has estimated that a vaccine will appear
in the next 5 to 10 years; wise scientists now refuse to guess when
one will come. Because HIV infects and influences the very immune
system called upon to fight it, vaccine research remains vexed by
unanswered questions of basic science. Meanwhile others have been
looking for simpler solutions. Over a dozen years ago, seeing the
rising worldwide death toll prefigured in epidemiology and social
reality, some public health thinkers (such as Zena Stein) began
to propose novel ways to augment conventional, barrier-based prevention
methods. They first recognized that male condoms would never be
a viable option for every woman because, among many reasons, the
technology depended upon male participation to be effective. In
too many cases and cultures, men simply refuse to accept condoms,
and women become infected, powerless to object. With the chances
of infection during one episode of heterosexual sex put at 1 in
200 or less, even a partially protective method could lower that
risk and start saving lives.
Enter the Microbicide
One clever proposal for keeping HIV out of the body is to apply
a liquid or gel substance before sex that could block infection
by physical, chemical or medicinal means. Known generically as a
microbicide, the idea was derived from products to prevent pregnancy
that were already on the market. (One contraceptive product, N-9
or nonoxynol-9, was initially thought to have anti-HIV properties
until it was discovered that N-9 actually increased susceptibility
to HIV infection by breaking down the body’s natural cellular barriers
to microbes.) Despite the exciting potential for an inexpensive
method that can be used without the participation of a partner,
microbicide research has met with some of the same problems slowing
vaccine development. And microbicides have posed a new set of challenges
altogether, ranging from applicator design to placebo validation.
Simply coming up with a gel to stop viruses from sticking to their
targets has not proved as elementary as many thought.
A highly effective microbicide would likely protect against HIV
transmission in multiple ways and might even act against several
other kinds of microbial invaders. Begin with the gels and foams.
These are based on a medium that would be inserted, squirted or
secreted into a vagina or rectum and may or may not carry other
active ingredients. But before a product can be found effective,
it must first be found safe, tolerable and acceptable. For example,
if the product is a gel, the physical properties must be right —
not too sticky, too runny, or prone to dry out. These are qualities
that matter to the user, and different users are likely to have
different needs and preferences. Then there are the chemical properties
to consider. Some forms of gel might be designed to simply keep
HIV from ever coming into contact with the mucus membranes that
line our vulnerable body cavities. Or it may contain chemicals to
help maintain the naturally protective acidic environment of the
vagina. Another gel might be optimized to carry an active ingredient
that disrupts HIV’s lipid membrane. Still another type might be
best for delivering an antibody, a vaccine or a drug to the mucosal
tissue so it can penetrate into the submucosal layers and become
active. A good gel must avoid harming the mucosal barrier cells
or any submucosal cells that become exposed through tiny breaks
and tears in the vagina, cervix or rectum. It must not cause irritation
if it is left on overnight, especially to unsuspecting penises.
Furthermore, the gel must not set off any local or general immune
response in the vast majority of people who use it; the last thing
you want to do is attract immune cells — the primary target of HIV
— to the scene. All of these stringent requirements mean that any
gel expected to perform in a mass-produced microbicide — not to
mention the active ingredients it carries — must be thoroughly tested
to prove it is safe.
Although there is a long list of potential microbicide candidates,
only a handful of products have advanced far enough through the
clinical trials process for them to realistically become available
within the next five years. And lack of investment by industry and
government is holding back more rapid development. The cadidates
furthest along the pipeline work in non-specific ways; most by impeding
viral access to vulnerable mucosal tissues.
How HIV gets through mucosal tissue
Our Mucosa — Basic Biology
The biology of the mucosal tissues that line our body parts susceptible
to infection determines how likely and how preventable sexual transmission
of HIV will be. These tissues are composed of various types of epithelial
cells arranged in either layers or in columns. The vagina, outer
cervix, anus and foreskin (of an uncircumcised penis) are covered
by overlapping layers of epithelium in a fish scale-like structure
called pluristratified mucosa. The upper cervix and rectum are lined
with a single layer of columnar shaped epithelium called monostratified
mucosa (see illustration). There is also a brief transition zone
that bridges these tissue types in both the vagina and the rectum.
Another theoretically infectable region of mucosa is in the mouth
and throat, although saliva seems to provide a natural microbicidal
action and infection of these tissues, while it does occur, is relatively
rare.
In healthy, intact pluristratified mucosa, as in the vagina, one
mechanism for infection is thought to use a type of immune cell
called a dendritic cell, which moves through the submucosal layers
of tissue and sends its dendrites (octopus-like arms) into the stratified
epithelium to scan for foreign pathogens. Dendritic cells (DC) carry
a cell-surface receptor called DC-SIGN that is capable of binding
to HIV’s gp-120 spike. In CD4 T-cells, the predominant target for
HIV, attachment of one of the viral envelope spikes to a CD4 receptor
begins the process of fusion and infection. But in dendritic cells
(mature cells at least; immature DCs may be infectable), attachment
to HIV causes the virus particle to be taken inside a bubble-like
vesicle within the cell where it stays while the DC continues its
immune patrol of the mucosa. After the dendritic cell finally leaves
the mucosa and makes its way back to the immune system’s regional
headquarters in a nearby lymph node (a process that may take several
days), it puts the HIV virion on display for other immune cells
to inspect. When a CD4 T-cell comes along that recognizes the virus
as an outsider, contact is made. Unfortunately, HIV uses this very
act of self-defense to enter the CD4 cell and hijack it into making
new viral copies. As new HIV virions start to bud off from the infected
cell, they quickly board other CD4 cells in the lymphatic neighborhood
and the primary infection is launched. Within days, millions of
immune cells are infected and distributing the virus throughout
the body.
How the leading microbicides work
In healthy, intact monstratified mucosa, the process is thought
to be a little different. Although it’s not exactly clear how, it
seems that a receptor on the columnar cells with properties similar
to DC-SIGN attaches to HIV and causes it to be internalized into
the cell where it is passed through to the other side in a process
called transcytosis. Once deposited on the submucosal underside
of the epithelial barrier, the virus may come into contact with
a patrolling CD4 cell or other immune sentry cell and infect it
directly. As with dendritic cells, the CD4 cell likely carries the
virus back to a lymph node where the infection is amplified.
But mucosal tissue is rarely completely healthy and intact, and
variations on these paths to infection may be common. Microscopic
nicks and tears in the mucosal barrier due to physical abrasion
may allow direct contact between the outer environment and the submucosal
immune cells to occur. The monostratified cells of the rectum are
particularly vulnerable to physical damage during sex. Vaginal infections
such as chlamydia or herpes may disrupt the protective mucosa and
enhance HIV transmission by attracting target immune cells to the
inflamed region. There are other wrinkles and exceptions to these
basic modes of sexual transmission. For instance, not all virus
is free floating; HIV may also be transmitted via a virus-laden
cell in the semen that crosses the epithelial barrier like a Trojan
Horse. But once HIV has made it into the mucosa, the barrier-based
methods have failed. The next challenge for microbicide research
is to find ways to stop an infection in its earliest stages.
Products at the Head
of the Pipeline
|
| Product name |
Pipeline status |
Sponsor |
How it works |
| Carraguard |
Phase II safety studies in progress.Phase III to begin in
2004 . |
Population Council |
Forms protective coating |
| PRO2000 |
Phase IIB planned. |
Indevus Pharmaceuticals |
Forms protective coating |
| Buffergel |
Phase IIB planned. |
ReProtect LLC |
Maintains normal vaginal pH |
| Savvy (C-21G) |
Phase I/II completed. |
Biosyn, Inc. |
Disrupts viral membranes |
| Emmelle (dextrin-2-sulfate) |
Phase II safety studies in progress. |
Multiple Sponsors |
Forms protective coating |
| Ushercell (cellulose sulfate) |
Phase II in progress. |
Mulitple Sponsors |
Forms protective coating |
The Bottleneck in Microbicides Development
In the absence of major pharmaceutical industry participation,
a number of universities and small, independent biopharmaceutical
firms have taken the lead on microbicide research. But in
order to fund their research, these entities require public
grants and — to the extent they can raise it — venture capital.
The result: chronic underfunding and a clogged research pipeline.
In 2002, a major economic analysis of the field concluded
that if a single pharmaceutical company were managing all
microbicide research leads, that company would have to invest
$775 million over five years to ensure the production of at
least one safe, effective product. The Rockefeller analysis
was a “bare bones” scenario that only considered the costs
directly related to product development, omitting other necessities
like basic research, discovery of new leads and work to assure
that the products will be acceptable and accessible to users.
The report also showed that if current funding levels continue,
the amount spent on microbicide research and development (R&D)
worldwide between 2001 and 2005 would total about $230 million.
This leaves a $545 million shortfall at minimum between current
funding levels and the expected cost of getting one successful
microbicide on the market. Even the recent generosity of the
Bill & Melinda Gates Foundation doesn’t cover that gap.
Over 60 potential microbicides have been identified to date,
yet most are stuck in the preclinical phase because funding
to move them into human trials isn’t available. The few candidate
products of proven safety have not moved forward in 2003 as
planned because their sponsors are unable to support the cost
of large Phase III effectiveness trials.
Microbicide R&D cannot advance efficiently without substantially
increased governmental and foundation funding. At present,
the U.S. National Institutes of Health (NIH) invests only
about 2% of its AIDS-related research budget in microbicide
R&D.
Anna Forbes -Global Campaign for Microbicides Advocacy |
New Research
Certain areas of advanced microbicide research overlap with work
going on in the HIV vaccine field seeking to target the virus with
exquisite selectivity. In the early pipeline are proposals ranging
from small molecule inhibitors to mucosally-directed vaccines. At
the AIDS Vaccine Conference held in New York City in September 2003,
some new ideas emerged about how HIV enters the body that may help
focus the development of a topical (applied to the skin) method
for preventing sexual transmission using antibodies to neutralize
infectious HIV.
One new observation has to do with the specific kind and quality
of HIV that can be transmitted sexually. It’s long been recognized
that only viruses that use the CD4 cell’s CCR5 receptor during entry
seem to be present in newly infected people. It was thought that
the barrier epithelium or dendritic cells filtered out the CXCR4-using
HIV at the point of transmission. This less-common form of HIV sometimes
appears later in the disease and is associated with rapidly progressing
AIDS.
New work by Eric Hunter and colleagues from the University of Alabama,
Birmingham (UAB) now suggest that the kind of virus most likely
to be transmitted may also be especially vulnerable to immune attack
— that is if the immune system has been prepared to recognize it.
Their work drew upon a highly productive research project conducted
by UAB in collaboration with researchers in Zambia. The study has
followed a cohort of sero-discordant (one positive, one negative)
couples in Lusaka for over eight years. Couples in the study are
counseled about safe sex and provided with condoms. About 8 percent
of the partners become infected each year; yet because counseling
and condoms are effective, this is a reduction from an expected
infection rate of 20 percent per year.
The researchers obtain blood samples from participants throughout
the study. If a partner becomes HIV-positive, the pair’s samples
are analyzed to determine the genetic sequence of the gp120 viral
envelope protein responsible for attachment and entry. Hunter presented
8 cases of transmission, with 4 from male to female and 4 from female
to male. In every case, the received virus was of the CCR5-using
type. Unexpectedly, the genetic analysis showed that a particular
envelope region on the received virus was unusually compact, lacking
several features characteristic of a typical virus as found in established
infections. Furthermore, this envelope region of the received virus
did not resemble that on the virus obtained from the donor’s blood.
What was particularly exciting about this finding was that the received
virus was unusually susceptible to neutralization by several specific
antibodies, while the virus obtained from the donor’s blood was
protected against these antibodies. This may mean that a virus that
is especially suited for sexual transmission may also be especially
vulnerable to antibody neutralization. If so, then there is a possibility
that, one day, these antibodies might be elicited in the mucosa
by a vaccine or perhaps delivered by a microbicide to attack newly
transmitted virus.
While the UAB study did not find a virus in the blood of the donor
that matched the virus that was transmitted, they were not able
to look at virus that may have been contained within the genital
tracts. It is possible that a protected compartment allows the transmission-specialized
virus to exist without competition from the more accessible viral
strain coursing through the blood.
Although some vaccines under investigation seek to benefit chronically
infected individuals by stimulating cellular immunity, the findings
about a vulnerability in transmitted virus mainly applies to the
uninfected, since HIV seems to begin mutating a protective carbohydrate
(glycan) cover for its vulnerable spots soon after a primary infection
has taken hold. However, there has been some evidence that these
vulnerable epitopes may eventually reappear on gp120 as an infection
matures; once the evolving shield of protective glycans begins to
let down its guard against those early, presumably long gone, antibodies.
Although some vaccines under investigation seek to benefit chronically
infected individuals by stimulating cellular immunity, the findings
about a vulnerability in transmitted virus mainly applies to the
uninfected, since HIV seems to begin mutating a protective carbohydrate
(glycan) cover for its vulnerable spots soon after a primary infection
has taken hold. However, there has been some evidence that these
vulnerable epitopes may eventually reappear on gp120 as an infection
matures; once the evolving shield of protective glycans begins to
let down its guard against those early, presumably long gone, antibodies.
With so much still to be learned about the basic science of HIV
infection, and so much intractable about the social reality that
allows HIV to flourish, the impact of either an effective vaccine
or microbicide remains many years away. Yet workers in the field
remain hopeful — and with good reason. The energy and commitment
evidenced by microbicide and vaccine advocates, and the increasing
elucidation of the underlying science, argues that an eventual breakthrough
is inevitable.
The International Epidemiologist
A Talk with Zena Stein
By Jen Curry
For many years in the early part of the U.S. epidemic, there
was a general denial that women were at risk for getting AIDS from
sex. Even when it was clear that women were being infected, the
risk was not taken seriously. Now, half of new HIV infections occur
in women. How did you, as an epidemiologist, go about understanding
what you were seeing when this new disease first appeared?
When I began my very first work with AIDS it was still called “Gay-Related
Immune Deficiency.” The cases were mostly in gay men, but we knew
it was blood borne because hemophiliacs got it from blood transfusions,
and some patients who got it were injection drug users. And we began
to ask, well, if gay men are getting it through sex, then why wouldn’t
women get it too? For a long time people just kept saying, “Women
don’t get it.” I started talking with a colleague — and this is
before we knew it was a virus causing the disease — and we said,
“Women must be getting it. And there must be some reason why women
get it.” We did some very exciting work going around to different
scenes where people were having sex, to see if the women knew anything
about these men they were having sex with. Some of these were men
who usually had sex with other men. And it made sense. Think of
the social circumstances: gay men cross over into women’s society.
But people didn’t really believe us. It took time and effort and
continually saying “Well, women do get it this way.” My proposal
to the NIH for further study was turned down because “it wasn’t
a woman’s disease.”
How did looking at the epidemiology given your previous work
on pregnancy help you understand what was happening with infants
born to HIV-positive women?
The transmission of disease from women to children has always been
central to family health and reproduction. I think what especially
intrigued me was when I realized that transmission only occurred
in one of three children. So, why doesn’t it always occur? My colleague
and I tried to think of ways we could come closer to understanding
in which babies does transmission occur, and why? And we thought
of looking at planned C-sections, to see if the baby wouldn’t get
infected through the canal and if we could reduce transmission to
babies. Another study about twins came out around the same time,
where the first twin didn’t get infected very often, but the second
twin down the birth canal was more often infected. So we realized
that the environment of the birth canal must be a place where the
transmission takes place. Which indeed was true, and is why most
of our mother to child prevention protocols say, as long as you
get to the woman before she goes into labor, transmission rates
go down. And now we also know, nevirapine given before labor lowers
the viral load and reduces transmission by quite a lot. Knowing
the circumstances of the birth was the key.
When was it that you really began to see the need for a microbicide
that women could have some control over?
When I began to think about AIDS in Africa, people kept talking
about male condoms. I talked a lot with a friend and colleague who
is a sexologist about how, before we had the hormones to prevent
pregnancy, we had condoms the male condom, or a woman could use
a diaphragm. Neither of these were 100 percent effective, but they
were reasonably effective. The male condom goes back in history
much farther than the diaphragm, but once the diaphragm started
emerging in the 1920s, the responsibility started shifting from
men and their condoms to the woman to use the diaphragm. Then in
the 1960s it moved completely to the woman with “the pill,” which
was very effective for contraception, so that if something happened
the man could say, “Well, the girl didn’t take the pill.” The threat
of pregnancy was largely eliminated by the pill but now the onus
was on the woman. And now we have emergency contraception, which
enables you to mess up occasionally and we have legalized abortion
too, if you want it. These are big advances for women, to have this
control over pregnancy. But they don’t protect against HIV.
When I first started writing about microbicides, I used to say
we needed a “woman-controlled” method and argued that it could or
should be a secret from the man — clandestine. It’s been a long
time since then and I’ve come to understand that that’s really not
quite right. First of all it depends on the relationship. In many
relationships, women don’t want to hide anything from their partner
because if they do, they upset the relationship. It’s better to
discuss it. If you can discuss it, you could argue, then he can
use a condom. True. If you can discuss it, he might be quite relieved
to know he doesn’t have to worry about a pregnancy. But if he discovers
that you’re doing something and not telling him, or if he expects
children and won’t accept contraception, that’s very tricky. If
he wants her to get pregnant, he may start to wonder if there’s
something wrong with her when she doesn’t get pregnant. And different
groups of women use and need different strategies for getting around
this.
Another problem is that the microbicide must be clandestine at
the time of sex or before, because the maximum period of time it
can be applied before sex is very important for efficacy. Even so,
microbicides are not going to be as good as condoms — everybody
knows that — still they can go mostly unnoticed. But I don’t think
you can or should betray your relationship with these clever, funny
devices.
What specific problems do you think activists should be focusing
on?
Women in certain parts of Africa who already have two or three
children — they’re not always the ones getting infected. But if
a woman is 17 or 18, she may go in to the clinic for a few years
of contraception and use a barrier. But at some stage, she will
want to get pregnant, and I think nobody’s dealing with that.
And then, there’s the sweeping problems no one wants to address:
the economic and political realities that are driving transmission.
For example, we see it quite plainly in South Africa among men —
migrant gold miners from the rural areas — who consort with sex
workers and are a source of STIs (sexually transmitted infections).
And before HIV, it was syphilis. They’d go away for work and then
they’d go back home and their wives often got infections of the
cervix. There have always been jokes about commercial travelers
— in Sub-Saharan Africa it’s truck drivers all along the regular
routes they travel — and these things are true: when men are separated
from their families, they get more STIs. The trucks come down and
the sex workers are around where the drivers stop. So, the workers
in occupations involving migrant laborers or work far from home
need special education, because the breaking up of families is an
integral part of such industies and economies. And it’s less the
sex workers than the truck drivers who should be the subject of
special education. All the studies suggest that sex workers won’t
push for condom use by their driver or miner clients because that
reduces what the client is willing to pay.
What do you see as some of the main stumbling blocks for microbicides
becoming responsive to the needs of different women?
Well, one thing is the way they’re planning to deliver it — by
squeezing it in. We’ve got to get new technology there. There’s
a ring you can put against your cervix that’s currently being used
for contraception. Now, if the ring can be made to carry a microbicide,
and if women choose to use the ring, then you won’t have this bother
of putting the stuff in — it will already be there. If the microbicide
just sits in this little container by the bed, then you won’t have
proof of concept from your clinical trial. If we find that women
aren’t really using the microbicide during sex, then this problem
of improving the method of delivery has got to be taken seriously.
Another important thing to many women is whether they can become
pregnant. For example, Carraguard may not be contraceptive; but
some of the others will likely be. For some women, and for some
societies, it’s extremely important to be fertile. That will be
the next problem, assuming we observe some efficacy in the trials:
after the ten years it takes to get a microbicide, at the end we
won’t know whether it’s contraceptive or not. We’ve a long way to
go before we have a microbicide that women who want at least one
or two children are going to use.
I don’t think the microbicides delivered as we are doing it now
in the trials are going to be terribly effective. They are possibly
only about forty or fifty percent effective, but nobody knows because
we haven’t got anything to compare them with. The only comparison
we have is with 95 percent consistency from the direct use of a
condom. So I am in favor of not only of having a microbicide approved
but of also having the female condom, and one of these cervical
devices. We need an array of options for a woman.
There is no simple path to achieving more effective methods
for woman-initiated STD/HIV risk reduction. Women who desire both
pregnancy and protection from HIV/STDs may not have a safe and effective
microbicide available in the foreseeable future.
—Zena Stein, Treatment Issues, July 1997
Women, Power and Microbicides
By Deneen Robinson
Do women in the U.S. really need a microbicide? Good question.
It seems to me that most of us — whether in Vietnam or in Texas
— could use some form of protection that would allow us to control
our risk for HIV and other STIs without depending upon a partner.
This being the case, an ideal microbicide — one a woman could use
ahead of time; that provided near 100 percent protection and was
not apparent to her partner — would be welcomed. As one woman said
to me, “I want something I do not have to ask him if we can use.
I am always scared that he is going to say no and then what am I
going to do?” Many women are afraid that their partner will refuse
to wear a condom. Others are afraid that they will be harmed either
physically or emotionally if they insist on using condoms. In some
relationships, simply suggesting the use of a condom can cause suspicion,
rejection and even violence. A good microbicide would help alleviate
some of these women’s fears and hopefully reduce their risk of getting
HIV.
Condoms offer excellent protection, but too often they are not
used and women cannot control their use. Studies have shown very
low use of male condoms even in favorable circumstances. The lack
of enthusiasm for male condoms makes microbicides a potential option
for men as well, including gay men. Ideally, microbicides should
be capable of protecting the insertive and the receptive sexual
partner, making them attractive for men who have sex with men as
well as for any man who does not want to use condoms because of
the loss of sensitivity and intimacy.
But any microbicide now on the horizon probably won’t offer perfect
protection. Most likely, when the first microbicide does become
available, it will still have to be used in combination with another
form of prophylaxis to provide an individual with a high degree
of reliable protection from HIV. The Global Campaign for Microbicides
says, "Even when microbicides reach the market, it is unlikely that
they will match the efficacy of male and female condoms for HIV
prevention. Logically, it is safer to keep a virus from coming into
contact with one’s body than it is to try to disable it once is
there."
There are also concerns that women will not use or will stop using
other prophylactics when they start using the microbicide and will
therefore increase their risk of getting or spreading disease. The
other side of that argument is that for the women who most need
a microbicide, condoms were never a good option to begin with. At
least with a microbicide, women who cannot use condoms will have
some opportunity for protecting themselves from sexually transmitted
infections, including HIV. It is better to have some type of protection
than none at all, which is the situation now faced by too many women.
Advocating for Ourselves
Despite the need for an effective microbicide, it will be several
years before we get one, and there will be little chance for getting
a microbicide without continued advocacy from scientists, governments,
and especially the men and women who will be using them.
In the United States, the word microbicide still does not resonate
with some of the very women who are perceived to most need options
for protecting themselves from HIV. In discussions with a number
of women age 20 to 55 in my town, the majority of them could not
even define the term microbicide, let alone explain how they would
be used. It is disturbing that scientists and advocates are struggling
to get a microbicide to market for consumers who do not yet understand
its relevance to their lives. In a group in Dallas, Texas, an activist
gave a talk to help a group of HIV-positive women understand the
use of microbicides. After the presentation, one of the participants
said to me, “What was that about? I am not going to use that while
having sex — no way.” Obviously this means that we need to begin
reaching out to women who will eventually be using microbicides,
even while we are trying to get a product past Phase II trials.
We must begin to advocate for ourselves. The advocacy of women legitimizes
the need for more research to produce an effective microbicide.
How do we get more women involved in the campaign for a microbicide?
How can we get more women empowered to protect themselves from disease?
Education is a start. We must find a way to get information to women
in communities where microbicides will be most beneficial — communities
where the risk is greatest. This includes HIV-positive women, teenage
girls at Planned Parenthood clinics, transgendered women, college
students, sex workers, homeless women, and married women showing
up in domestic violence shelters. In addition to providing people
with information, we must teach the importance of advocacy. Historically,
the women who could benefit the most from a microbicide (or female
condom, or needle exchange, or responsive medical care, and so on)
have been the least active in advocacy. The reasons are the same
as why women need a microbicide in the first place. Getting women
involved will be difficult if we do not talk about microbicides
in a way that resonates with their experience. This means it is
our job to pay attention to the realities of sexuality, economic,
geographic, and family differences regardless of whether we’re talking
with rural women, poor women, sex workers, married women or lesbians
about this issue.
The power in relationships between men and women is too often unequal.
Women tend to have less power in relationships than men — and not
only in India and Africa, which is what people usually talk about
when discussing microbicides — but here in Texas as well. As a result,
many women learn that speaking up on the job, in school, at home,
or in a relationship, can have negative consequences. The inability
to control the method of prophylaxis used during sex and the resulting
risk of disease is a symptom of this lack of power.
Of course, none of these problems will end with the creation of
a microbicide, however we may see the tide begin to turn. Another
participant from a local Dallas support group said, "I want a relationship
where I do not have to worry about the fight over condoms. I get
tired of always having to ask him to put one on. I really hope someone
will create something that I can use for my own protection.” As
women begin to have more control over their sexual health, the balance
of power in their relationships might begin to change. This shift
could have consequences for how women operate in relationships and
society. Hopefully, the most dramatic change will be a reduction
in the growing number of women who test positive each year for HIV
and other sexually transmitted infections.
Eventually, a microbicide will appear that benefits women. Having
additional protection against HIV and STIs would be a great breakthrough,
but another important benefit will be if it helps women gain more
control in their relationships and their lives.
Building a Microbicides Advocacy
Campaign
By Anna Forbes and Megan Gottemoeller
The Global Campaign for Microbicides is a broad-based, international
coalition initiated in 1998 to build support among policy makers,
opinion leaders, and the general public for increased investment
into microbicides and other user-controlled HIV prevention methods.
The Campaign uses advocacy, policy analysis, and social science
research to accelerate product development, facilitate widespread
access and use, and protect the needs and interests of users, especially
women worldwide.
People cannot demand what they have yet to envision, so one of
chief functions of the Global Campaign is to make microbicides a
visible possibility, thus catalyzing public demand for new options.
In the U.S., the Campaign’s legislative advocacy strategy targets
the U.S. Congress and microbicide research funding at the NIH, the
CDC and the U.S, Agency for International Development (USAID). The
strategy was designed and implemented in collaboration with the
Alliance for Microbicide Development and the International Partnership
for Microbicides. To date, it has resulted in an increase of tens
of millions of dollars at NIH and CDC, and the USAID appropriation
for microbicide R&D may rise to $22 million in 2004. The Microbicide
Development Act, authorizing federal spending and creating a designated
program at the NIH, was introduced with bipartisan support in the
Senate in April 2003.
In Canada, women’s health and AIDS advocates have been similarly
successful in generating increased attention to microbicide research
by the Canadian Parliament. The UK/Ireland Campaign for Microbicides,
established in 2002, is working on raising awareness in the British
Parliament, and has participated in briefing the European Parliament
on microbicides.
Because of the vast differences in resources between U.S. and Europe
and regions in south Asia, Africa, and Central America, microbicides
advocacy in the global South is less focused on mobilizing resources
and more on demonstrating demand. This includes creating opportunities
for people who will be using microbicides in clinical trials over
the next few years to actively participate in the research and development
process.
Advocacy organizations in countries like India, Nigeria, and Uganda
are forming local networks to articulate policy needs relevant to
their national situations. For example, advocates in Kampala recently
organized a forum for national parliamentarians and policy makers
to discuss the position Uganda should take toward microbicide clinical
trials in that country. A community stakeholders meeting in Delhi
in October 2002 resulted in a statement of principles on prevention
options for women in India.
Because much of the clinical research, particularly the Phase III
efficacy trials of microbicides, will take place in highly affected
countries, the Global Campaign is working with community organizations,
national networks and research institutions to support meaningful
community involvement in the design and implementation of these
trials. Community involvement is widely recognized as a key component
of both scientifically rigorous and ethically sound clinical trials.
However, U.S. and European activist models of community involvement
may not translate directly into global south settings. To that end,
the Global Campaign works with NGO, community-based, and research
entities to develop, implement, and document innovative approaches
that have worked to get local communities meaningfully involved
in the research process.
With nearly 200 worldwide NGO partners to date, the Global Campaign
serves as a conduit through which this global demand can be harmonized
and collectively articulated at an inescapable volume. Through unified
advocacy strategies and a growing body of resources and materials
made freely and publicly available to anyone who wants to use them,
the Campaign links and amplifies participants’ voices. The work
of the Campaign is coordinated by its secretariats, housed at NGOs
in Washington DC, London and (soon) South Africa. But, in essence,
the Campaign is nothing more than a shared idea: that receptive
sex partners must have a way to protect themselves that they can
control, and that advocates must take responsibility for determining
when, how and in what fashion this technology becomes available
to all who need it.
For more information: www.global-campaign.org or phone:
(202) 454-5048.
| Profiles of Grassroots
Advocacy
The Global Campaign for Microbicides in North America is
involved with groups in several U.S. and Canadian cities.
Primarily these are collaborations with family planning, women’s
health, and AIDS organizations, with the local groups undertaking
to serve the dual purpose of local community education and
legislative advocacy. The work of these independent groups
is extremely varied, and reflects both the geographic diversity
and the specific backgrounds and interests of the individuals
pushing the efforts forward. Here are some snapshots of microbicide
advocacy in the U.S.
New York’s group, housed by GMHC and the Harm Reduction Coalition,
is a loose collection of individual members who have done
HIV treatment activism, needle exchange work, and community
education. As one member put it, “We’re about as grassroots
as you can get. We tend to be people who understand the need
for more options, and the relationship between global poverty,
and women’s health.” Contact: Talata Reeves at GMHC, (212)
367-1360.
In Connecticut, a group has focused on developing a campus
organizing project, involving young women and (some men) from
four schools in the state, including a Catholic university.
The group employs two student interns who organize dorm workshops
on microbicides, letter writing campaigns and speaker’s training
for other women. The group works with Connecticut Planned
Parenthood and the AIDS Education and Training Center (AETC).
They have produced a video on microbicides and have partnered
with a community ethnography institute that received a grant
from the National Institute for Mental Health (NIMH) to perform
an acceptability study of microbicides among high-risk injection
drug using women in New Haven. See www.global-campaign.org/localsites.htm
for contact information.
Microbicides as an Alternative Solution (MAS) is a northern
California group that is involved with grassroots education.
They have been organizing community forums for over six years
and are one of the oldest groups in the country. Recently,
they produced a comic and brochure series for San Francisco
teenagers about microbicides and sexual choices. Contact:
www.microbicidesnow.org
The California Microbicides Advocacy Coalition (CAMI) is
a spin-off of MAS organized to advance microbicide research
by coordinating policy among a coalition of California biotech
companies, community advocates, and research partners.Contact:
Alison Regan, (213) 736-4806.
One of the newer and most energetic groups is based in Georgia,
whose zealous members visit Southern colleges, radio stations,
and HIV-positive support groups, talking about microbicides
to anyone who’ll listen. The group has an active speaker’s
bureau of women, men, and PWAs, who have addressed many diverse
audiences such as the gay men’s chorus, students at a women’s
college, radio talk shows, and Atlanta’s AIDS Survival Project.
Contact: Terri Wilder, (404) 502-4710. |
Kaletra Goes it Alone
By Bob Huff
At the 43rd Annual ICAAC Conference in Chicago, Joseph Gathe, a
clinical investigator and HIV clinician at a large inner city clinic
in Houston, Texas, presented a poster reporting 24-week results
from a controversial pilot study that employed only one antiretroviral
to treat HIV-infected patients starting their first regimen. The
30 patients in the study were treated with the twice-a-day protease
inhibitor Kaletra, a co-formulation of lopinavir with low-dose ritonavir
added for pharmacokinetic enhancement. At week 24 of the 48-week
study, the one-drug strategy had produced virologic efficacy comparable
to that seen with standard triple-drug HAART.
The study group contained a large proportion of individuals with
advanced HIV disease, with 54% having both a CD4 count below 50
and viral load above 100,000. Overall the group had a mean viral
load of 260,000 copies/mL and a mean CD4 cell count of 170. Persons
with active, life-threatening AIDS were excluded. Nearly all of
the subjects were male; 60% were white, 20% black and 20% Hispanic.
Kaletra dosing was adjusted by weight, with patients weighing less
than 70kg receiving 3 capsules twice-a-day and those over 70kg receiving
4 capsules. Viral load and CD4 cell counts were monitored during
usual patient visits to the Ryan White funded free clinic. No pharmaceutical
support or other outside funding was available to the study.
By week 24 of the 48-week study, 8 of the 30 participants had left,
with 2 lost to follow-up, 2 withdrawing due to GI intolerance, 1
due to active hepatitis B infection and 1 because of non-adherence.
One patient was deported. Another patient was excluded because of
virologic failure, although the details of this case were not reported.
Of the 22 patients who remained on treatment, 21 (95%) achieved
virologic response defined as viral load less than 400 copies at
week 24. Using an intent-to-treat analysis, with 21 of 30 patients
achieving viral load below 400 copies, the 24-week response rate
was 70%. The mean reduction in viral load for those remaining on
the study to week 24 was 2.57 log copies/mL. The average CD4 count
had increased by 219 cells at week 24. No significant toxicity was
seen and no genotypic or phenotypic resistance mutations were detected.
A single patient remaining on the study failed to achieve viral
suppression below 400 copies and added saquinavir to his regimen
at week 32. The failing individual’s baseline viral load was 500,000
and had declined to about 1500 at week 24 then rose to just under
5,000 at the time of treatment intensification.
Dr. Gathe pointed to results from a dose-finding trial that administered
lopinavir/ritonavir alone to 32 patients for 3 weeks before adding
NRTIs. By week 3, the mean viral load decrease was -1.85 log copies/mL.
At week 2, the mean decline in viral load in patients receiving
monotherapy was similar to that of those on a 3-drug combination
(-1.73 vs. -1.68 log copies/mL). (Murphy RL, et al. AIDS 2001;15:F1F9)
He also cited a 48-week trial of Kaletra that reported finding
no genotypic or phenotypic resistance in subjects experiencing virological
failure. This suggested that, in the event viral suppression could
not be maintained with single drug Kaletra, subsequent susceptibility
to intensification would likely not be in jeopardy. (Walmsley S,
et al. NEJM Volume 346:20392046)
Triple combination therapy produced welcome and dramatic benefits
for patients when it was widely introduced in 1995. Since then,
the idea of “monotherapy” has become synonymous with an era of inadequate
treatment options and a high death rate from AIDS. Increasingly,
however, economic pressures are stimulating research into strategies
that may possibly conserve scarce resources without compromising
outcomes. Dr. Gathe will continue this study to 48 weeks and is
preparing a follow-up study of single-drug HAART that will begin
enrolling later this year.
Gathe JC, et al. Pilot study of the safety and efficacy of
Kaletra (LPV/r) as single drug HAART in HIV+ ARV naive patients.
Interim analysis of subjects completing at least 24 weeks of a 48
week study. 43rd ICAAC, Chicago, 2003. Poster 845.
FDA: Global Citizen
By Jen Curry
In August 2003, the U.S. Food and Drug Administration’s (FDA) Antiviral
Drugs Advisory Committee met to discuss clinical trial designs for
topical microbicides. The FDA has received several sponsor applications
to conduct trials of candidate microbicides with an eye to approval.
From the agency’s standpoint, two anxieties hung over the discussion.
The first was the sobering lesson of the COL1492 study of nonoxynol-9,
which turned out to actually increase HIV risk. The second was agency
skepticism, and palpable fear, about releasing a product that might
be less effective than what is considered the U.S. gold standard:
condoms.
The microbicide advocacy and research community brought its own
anxieties, over cost (that sponsors can not afford, or do not want
to fund these trials, or that funding will dry up if one of the
first trials fail) and a pervading dread that if the field does
not move forward soon, an incalculable number of lives will be lost.
Earlier this year, two products (Buffer Gel and Pro 2000) were
slated to go head-to-head in HPTN 035, an 8,000 woman, placebo-gel
controlled trial. But the FDA asked for changes, arguing that the
trial should aim to produce data that could support product licensure.
They proposed a dramatically more stringent statistical test and
added a fourth arm that offered no treatment, only the condoms and
counseling that every arm received. These changes would have boosted
the number of participants by several thousand and added millions
to the cost. When the NIH said it wouldn’t fund such a costly trial,
the design was amended to a Phase IIB, 3,100 woman trial that will
include the fourth, no-treatment arm.
At the FDA meeting, the committee was asked to consider the no-treatment
arm. They also discussed if one trial could serve as well as two
without difficult to meet statistical tests and how long a Phase
III trial must last. Each of these questions involves complications
that could set back microbicide clinical research by years. And
on each issue, the FDA seemed to take a hard line.
One thing this meeting did was force the microbicide community
to come together and think hard about the strategic plan for microbicide
R&D. The testimony that day reflected an overwhelming consensus
that FDA must not heap requirements onto these trials that would
spike their cost, cause delay, produce uninterpretable data, or
otherwise drain a resource-scarce field. In particular we heard
that a no treatment, condom only arm could introduce confounding
behaviorial variables, which may result in uninterpretable data
or a false declaration of product failure.
What we need to know from the FDA is whether any of these candidates
are safe and moderatly effective. That’s the strict regulatory question
before them, it’s the question that matters to countries that desperately
need these products, and it’s the question the agency should stick
to. The FDA should not concern itself with hypothetical questions
about what might happen to condom use if a microbicide were available.
While the FDA only has jurisdiction within the U.S., it’s influence
extends much further. It must recognize this and think creatively
and flexibly to consider strategies that allow for moderately effective
products to be detected and moved forward — not weeded out.
A product demonstrating moderate effectiveness (5060 percent) would
not likely be approved for U.S. licensure. But in another country,
that same product might be considered essential. As committee member
Lynn Paxton put it, “If I’m a regulator in a country where 1 out
of 3 women is infected, I might be willing to take a risk.”
So, what does this mean for the FDA? Does it have an ethical obligation
not to set policy that would harm people outside of the U.S.?
The European regulatory agency (EMEA) and the World Health Organization
(WHO) has initiated an entirely new process to approve and review
drugs for safety and effectiveness in a developing country context.
The Alliance for Microbicide Development, representing consensus
from the research community, asked the FDA to “recognize contextual
realities” of global AIDS and urged the Agency to “actively engage
in the new WHO/EMEA process.” Seeking to balance speed, flexibility
and good science, this process may offer a way to accommodate the
differing risk/benefit demands that we will continue to see globally.
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