|
Past Issues
Volume 19, number 12
December 2005
AIDS is Still a Political Crisis
Gregg Gonsalves on Why We Fight
Planning for Tomorrow
Young investigators urged to take on HIV
Home Testing
Is there a future for over-the-counter HIV tests?
Birth Defects and ARVs
No unexpected links seen so far
The Genital Herpes Link
Increased risk for HIV?
Who are the Elite Controllers?
Science wants to meet you
Rage Against the Machine
Anti-Politics and the AIDS Epidemic
By Gregg Gonsalves
By 'political' I mean having to do with power: who's got it,
who wants it, how it operates; in a word, who's allowed to do
what to whom, who gets what from whom, who gets away with it
and how.
– Margaret Atwood "Second Words"
We're so busy putting out fires right now, that we don't have
the time to talk to each other and strategize and plan for the
next wave, and the next day, and next month and the next week
and the next year. And, we're going to have to find the time
to do that in the next few months. And, we have to commit ourselves
to doing that. And then, after we kick the shit out of this disease,
we're all going to be alive to kick the shit out of this system,
so that this never happens again.
– Vito Russo "Why We Fight"
I told a few friends the other day that I was worried that I was
turning into a shrieking harpy. There is no doubt that I have been
horribly angry for the past 15 years. I have watched the AIDS epidemic
flourish, mow down friends, family and colleagues, and, despite
the vast sums of money and hives of activity devoted to combating
the disease, new infections erupt in the millions and millions
more die horrible, painful deaths each year.
I do blame my government, other governments, drug companies, conservative
religious institutions, and a rogue's gallery of other villains,
but, lately, I can't help but think of my own role, our community's
role in perpetuating the epidemic. I've written about this phenomenon
before, but I am still stuck thinking about this, largely because
despite my attempts to provoke a conversation in the HIV/AIDS activist
community about how we do this work, nothing seems to change very
much in our modus operandi.
The AIDS epidemic has everything, in Margaret Atwood's words, "to
do with power: who's got it, who wants it, how it operates; in
a word, who's allowed to do what to whom, who gets what from whom,
who gets away with it and how." AIDS activists knew this once,
the rallying cry of ACT UP was that AIDS is a political crisis;
we know this is still true particularly in places where the fight
is conceived as an essentially political one: by South Africa's
Treatment Action Campaign, by Russia's Front AIDS, by Thailand's
Thai Drug Users' Network, by Costa Rica's Agua Buena Human Rights
Association.
Don't get me wrong, I do believe that AIDS is recognized as a
political crisis by many, many people. Think of the dozens of sign-on
letters written and circulated, the meetings we attend to pound
on the table, the reports, the press releases demanding this, demanding
that. However, I have the sickening feeling that there has been
a tremendous domestication of our political resistance — we
trade on the legacy of our activist past or the reputation of our
fiercest living champions, but as a movement, we have become a
paper tiger.
Let's take the United Nations General Assembly Special Session
on HIV/AIDS in New York in May 2006 where government came to boldly
lie about their records in fighting AIDS and make hundreds of new,
empty promises. UNAIDS staged a series of consultations leading
up to this gathering to develop a framework to achieve universal
access to HIV prevention, care and treatment by 2010. Activists
were hand-picked by UNAIDS to attend most of these consultations,
where UN and government officials listened to the needs of people
living with HIV/AIDS, of sex workers, drug users, women, men-who-have-sex
with men and other "vulnerable" populations, wrote them up in reports
and issued the findings in glossy newsletters put together just
for the occasion. The UNGASS meeting will culminate in yet another
political declaration on HIV/AIDS, based in part on these consultations
and more centrally on negotiations with the governments that compose
the UN's membership on what they can agree to support. Tremendous
amounts of energy, money and time have been invested in these processes
over the past six months. I was part of the "Global Steering Committee" on
Universal Access and attended three meetings and helped to develop
pages and pages of input for UNAIDS, hundreds of my colleagues
have been busy this year finalizing "shadow reports," deciding
who would go to New York City, who would be selected to speak at
the UN, organizing satellite events to highlight important issues.
Will anyone listen to us? Does anyone care what we have to say?
Has anyone asked why the hell we're devoting millions of dollars
and hours to this process, when the previous UNGASS in 2001 resulted
in a "Declaration of Commitment," which was honored neither in
word nor deed? What are the opportunity costs for activists that
are now hip deep in this exercise? What work hasn't been done or
could have been done with this time, this money? The UN system
is a system made for and by governments. Why are we engaging with
a system in which we are not represented and is beholden not to
us but to its member states? Yes, "the international community
must do more about HIV." But the international community doesn't
exist as an institution, there are countries and countries have
leaders. Imagine if all these resources expended by the community
alone for this meeting in New York City had been devoted to national
campaigns demanding that governments honor what they promised five
years ago? Or towards building real infrastructures for national,
regional and international advocacy on HIV/AIDS? Or training each
other on how to push for political change?
I can hear Zackie Achmat's voice in my head calling me an ultraleftist
for refusing to deal with institutions to affect change. Well,
Zackie and TAC engage with their government on a daily basis and
have created a national infrastructure to press for political change.
I am not suggesting that there is no use for the UNGASS meeting,
particularly when it is part of a comprehensive political response
to the AIDS crisis. However, for many people, the UNGASS meeting
has a role that is isolated from any other kind of political activity
and has taken on a significance that it doesn't deserve. For me,
the frenzy around the UNGASS meeting represented an anti-political
moment. The UNGASS's role, its real contribution, to paraphrase
Arundhati Roy, is to defuse political anger and blunt the edges
of political resistance.
How did we get here? Well, not to over-simplify, but I think that
we've seen an NGO-ization of HIV/AIDS that has weakened or destroyed
our ability to build a social movement to fight for our right to
health, to be free of discrimination and violence, to the other
services we need to stay alive and free from HIV infection. We've
also seen people living with HIV/AIDS, sex workers, women, men-who-have-sex-with-men,
ethnic minorities, young people, drug users who are also working
in the field become essential monsters: that is they think and
act as if the greater involvement of people with AIDS (GIPA) or
their "vulnerable" group has a value in and of itself, as if they
have some special purchase on knowledge or rights simply because
of who they are instead of linking those rights to a responsibility
to engage politically in a feminist, anti-racist, anti-homophobic,
pro-sex, pro-harm reduction, and pro-poor struggle that links us
in solidarity, in commonality with each other, with millions of
other people for whom other struggles perhaps matter more than
our own.
What would I love to see? Well, it would be great if we could
have the chat that Vito Russo asked for in 1988. I'd like us to
ask if the institutions and organizations we've built up are really
working towards achieving political change or are actually stymieing
it. How accountable are our NGOs to people living with HIV/AIDS
and communities affected by the epidemic at the district level,
the province, the country, the region, the planet? Are we creating
institutions that seek to justify their own existence, their own
organizational survival and expansion at the expense of challenging
the powers-that-be: governments, UN agencies, drug companies, etc?
Who is setting the agendas for our work? Are these agendas in the
service of achieving specific, local political accountability or
are they making calls for a more diffuse, generalized, international
responsibility? Are we becoming carpetbaggers, itinerant technocrats,
damn missionaries, toting our expertise around the globe trying
to help people in other countries to solve their own problems or
are we trying to promote local solutions to local problems by local
people? Are we just talking about change, rather than mobilizing
for it, trying to make it happen? Are we just managing change,
trying to turn resistance into "a well-mannered, reasonable, salaried,
9-to-5 job," channeling the struggle into a three-day media event
in New York City in May, a weeklong international AIDS conference
in Toronto in August, and endless series of meetings, reports,
conference calls and email exchanges?
I also want to stop talking about GIPA-the greater involvement
of people living with HIV/AIDS. I am sick of GIPA and will not
promote it any longer. Roy Cohn, the vicious, nasty, conservative
asshole had AIDS and he was gay to boot. Roy Cohn sent Julius and
Ethel Rosenberg to the electric chair and sat at the right hand
of Senator Joseph McCarthy in the 1950s when he persecuted hundreds
of decent Americans for communist sympathies, whether or not they
had then or ever been members of the Communist Party. He was not
part of my community. Do women want to claim Margaret Thatcher
as one of their own? Do gay men want to claim Ernst Rohm, commander
of the Nazi storm troopers as a fellow fag? Do Africans want to
claim Idi Amin or Hendrik Verwoerd among their kin? If your own
sense of your history or politics is based on biology, serostatus,
country of origin, gender, sexuality, well, get ready to get in
bed with all of the folks mentioned above. This kind of identity
politics excuses everything and accepts no political responsibility.
It's time we start asking each other: What are you doing to promote
the reproductive and sexual rights of women; to fight rape and
violence against women; to promote access to HIV/AIDS prevention,
care and treatment, to education, to safe and affordable housing
and other basic services regardless of gender, sexuality, ethnic
origin, regardless of ability to pay? What are you doing to legalize
methadone, buprenorphine, syringe exchange and reform drug and
narcotics regulation, protect sex workers from harassment, ensure
they have working conditions that don't endanger their health or
well-being? What are you doing to ensure that young people get
comprehensive information about sexuality, STIs and HIV/AIDS?
Let's base our personal commitment to the fight against HIV/AIDS
not on who we are, but what we do for others and not just for those
who are like us, but those who are different in whichever way each
of us chooses to categorize it. If we hold our organizations accountable,
we have to hold ourselves accountable too.
So, I am one pissed off sister. I am angry at the epidemic, but
angry about a machine we've created that drains the politics out
what is happening around us, that, in fact, fosters both an institutional
and personal anti-politics that fuels the fires of HIV/AIDS. I
don't know when we'll all get the chance to talk, but we need to
have a conversation about where we're going and how we're going
to get there. Otherwise, we'll see each other at the next UNGASS
in another five years' time and realize we've been driving around
in circles, never recognizing we've seen this all before, our journey
hasn't even started and the car is, sadly, out of gas.
Questions, Questions
The Future of HIV Research
By Bob Huff
The Retrovirus Conference is the most important scientific meeting
on HIV of the year. This year's conference, the 13th, was held
in Denver in early February 2006. Most presentations were aimed
at scientists actively working on HIV basic science, clinical science,
or drug development. But a group of leading HIV researchers organized
a special session designed to acquaint younger scientists with
some of the critical unanswered questions about HIV and to entice
them into making HIV their career. AIDS research has made amazing
strides in the 25 years since it was first described in the medical
literature. The disease has gone from being a death sentence to
being a mostly manageable condition for those with access to anti-HIV
drugs. Still HIV is no picnic, and worldwide, millions of people
with AIDS will die this year. It's clear that there is much work
to be done in HIV research. It's also clear that it may be 10 or
20 years before some of the most important scientific goals, such
as a vaccine or achieving immune control of the virus, are accomplished.
The quest for a cure may take much longer.
HIV Pathogenesis
John Coffin, National Cancer Institute, Frederick, Md.
It may sound hard to believe, but 25 years into the epidemic we
still don't know exactly how HIV causes disease. We know that HIV
infects immune cells and that after prolonged damage to the immune
system people with HIV can get sick and die from one the illnesses
that make up the acquired immune deficiency syndrome (AIDS). But
we don't know exactly how this damage to the immune system occurs.
Dr. Coffin's talk surveyed this question and several other key
mysteries in the basic science of HIV.
Though we don't know enough about how HIV behaves in the body,
we do know a great deal about how HIV replicates in cells. For
example, to infect a new cell, the virus must bind to a CD4 receptor
on a target cell's surface. This is why HIV infection is mostly
limited to the CD4-bearing T cells of the immune system.
Most people count T cells in the tens or hundreds, but these are
the number of cells found in just a small sample of blood. There
are actually 5,000 times that number in the body's total blood
supply and many millions more living in tissue, totaling perhaps
a billion CD4 T cells—many of them targets for HIV. Most of the
CD4 T cells that HIV targets typically have a very short lifespan,
and once infected, most T cells will die within a day or two. Meanwhile,
free-floating HIV may survive in the blood only for a few hours,
with between 100 million and 10 billion virions formed and removed
per day.
In the absence of treatment, an estimated 10 million to 100 million
CD4 T cells become infected nearly every day, and the infected
cells make enough new HIV to infect all of the next generation
of CD4 T cells. This constant daily cycle of CD4 cell infection,
production of new virus, and cell death occurs continuously in
most infected people who have not suppressed the virus with antiretroviral
drugs.
While the production and destruction of virus and CD4 cells proceeds
at a near steady state in this furious but silent cycle, over much
longer periods of time, the cycle becomes unbalanced and the total
CD4 cell count begins to decline.
The biggest single unanswered question about HIV is how this slow
loss of CD4 cells occurs. A newly infected person experiences an
extremely high spike in viral load within the first few months.
This is probably due to the abundant supply of target cells and
the lack of any immune control at that early stage. This early
phase of high viremia may also be a time when a person is especially
likely to pass the virus on to others.
Surprisingly, the body is often able to mount an initially effective
immune response to HIV with immune cells that recognize and kill
infected CD4 cells. After the sharp initial rise in viral load
and an equally sharp decline in the CD4 cell count, the appearance
of this immune response about three months into the infection signals
the beginning of a quieter phase, when viral load remains relatively
steady and CD4 cell counts decline gradually. This phase can last
for years, but eventually, in most people, the slow but steady
loss of CD4 cells leaves them without immune protection from everyday
pathogens that healthy people never notice but are deadly to those
with compromised immunity. At that point, during late-phase AIDS,
the viral load may once again reach extremely high levels. Fortunately,
effective antiretroviral therapy can lower virus levels dramatically
well before this point, putting the disease on hold and allowing
the body's immune capacity to recover.
Because the pace of HIV replication is so brisk in untreated people
and because so many millions of virus copies are made each day,
it is not surprising that mistakes are made as the viral genetic
material is copied and processed in the cell. Most copying mistakes
(transcription errors) probably result in a fatally flawed virus.
But, rarely, a "mistake" is able to adapt and thrive better than
the parent virus. For example, a virus might be better able to
evade the body's immune defenses or to escape from control by drugs.
Over time these mistakes, or mutations, accumulate. Eventually
the dominant viral strain found in the blood can differ significantly
from the HIV the person was originally infected with. It's likely
that this is how HIV gradually escapes from immune control.
The viral load test measures the number of copies of HIV RNA in
the blood, but it can also be seen as an indirect measurement of
the number of productively infected CD4 T cells at any one time.
When the viral load is very low it means that few cells are making
new copies of HIV. The viral load test is also a quick way of telling
if antiretroviral therapy is working effectively.
Although antiretroviral therapy can reduce the number of infected
CD4 cells to almost zero, studies have found one or two copies
of HIV RNA in the blood even after seven years of continually suppressed
viral load. These viral embers are hidden in a very small number
of infected CD4 cells thought to exist in a long-lived resting
state, where they are unreachable by drugs. If antiretroviral drugs
are removed, these embers can flare up to become a raging, active
HIV infection. Unfortunately, at this time there is no known way
to reach and eliminate these latently infected cells. In other
words, there is no cure.
Dr. Coffin outlined several major unanswered questions that young
scientists will have to wrestle with: Most importantly, what is
responsible for CD4 cell depletion? Is the virus killing the CD4
cells directly? Or are toxic viral proteins killing them indirectly?
Is it the anti-HIV immune activity of the body's own killer cells
that is doing the job? Maybe it is some byproduct of a highly activated
immune system that is exhausting the CD4 cell supply. Perhaps it
is a combination of several of these factors.
Most perplexing, how can the virus depend on, yet evade destruction
by, the immune cells that should be attacking it? One remarkable
adaptation is the camouflage of the virus's external proteins by
clouds of sugar molecules. These envelope proteins are the best
available target for immune system recognition, but they are hidden
by the sugars. Finding a chink in this sugarcoated armor would
be great news. But HIV is so changeable that even when these viral
proteins become temporarily exposed when HIV binds to a cell, immune
cells may not recognize their target.
Scientists are also studying similar viruses that cause AIDS-like
disease in monkeys, but not humans, to identify crucial differences
and similarities. One key finding may be that the disease-causing
viruses all tend to produce high levels of immune activation, much
as HIV does. Some have compared the explosion of target CD4 cells
produced by runaway immune activation to pouring gasoline on a
fire. Finding a way to tamp down immune activation may be one avenue
of treatment.
Where does the virus in latently infected cells come from? Are
they archived from early permutations of the virus that evolved
before suppressive therapy was begun? Do these resting cells divide
periodically and pass on the viral genome to their progeny? Would
it be possible to wake these cells up and make them go through
a cycle of viral production and cell death? If so, and if all new
infections could be blocked by drugs, then HIV might actually be
curable, according to some theorists. But we still don't know if
infected cells in protected parts of the body, such as the brain,
harbor enough HIV to stage a comeback when the drugs are stopped.
It should be evident from this long list of questions that young
scientists coming into the field of HIV research can expect to
find a lot of exciting and important work to do.
Vaccines
Richard Koup, National Institutes of Health, Vaccine Research
Center, Bethesda, Md.
Policy makers, politicians, and public health officials love vaccines
because they promise a cheap and easy way to eliminate major public
health care problems with a single shot. Finding a vaccine for
HIV has been one of most difficult scientific challenges in fighting
this disease. Beginning in the mid 1980s, various leaders have
periodically said to expect an AIDS vaccine within five to 10 years.
Current estimates bandied about at the Denver conference say it
will be at least ten years before a vaccine can be expected. But
work continues, and vaccine research is increasingly finding the
funding it deserves.
Koup described vaccines as "the most powerful biomedical intervention" ever
developed. Koup suggested that we may be on the brink of a vaccine
revolution as a host of new technologies based on manipulating
genetic material are perfected.
A vaccine works by exposing the body's immune system to a bit
of material that "looks like" a pathogen but does not cause disease
itself. Pathogens can be any disease-causing bug, such as a bacterium,
virus, or fungus. Once the immune system has been primed to recognize
this characteristic bit of matter, it will respond much faster
and more effectively if and when the pathogen bearing that characteristic
shows up in person. Traditional vaccines use killed or weakened
versions of pathogens to educate the immune system to recognize
the real danger.
This simple approach hasn't worked with HIV because the virus
is particularly adept at hiding from the immune system. Meanwhile
HIV targets and destroys the very immune cells that should be fighting
it. Natural immunity does seem to provide some control over HIV,
at least in the beginning, but because HIV is so changeable, over
time this control declines as the immune system no longer recognizes
its foe.
There are two main wings to the immune system: defense by neutralizing
antibodies, which attack pathogens directly; and defense by killer
T cells, which mainly destroy cells that have become infected.
It's probable that a truly effective vaccine will need to engage
both divisions of the immune system in fighting HIV. While there
has been some modest success in stimulating the cell mediated wing
to recognize HIV, the challenge for antibodies has been much greater.
Remember that the proteins carried on the outside of HIV are highly
variable and are shrouded in sugar. We know very well what certain
key parts of these proteins look like, and we can make antibodies
to attack them, but they are as effective as an assassin seeking
his victim at a costume party where everyone is wearing a mask—and
the masks are constantly changing.
The challenge is to make an antibody that will recognize a vulnerable
feature of the exposed HIV protein that is stable both physically
and genetically. A few artificially constructed antibodies have
been able to achieve some success, but getting the body to generate
such broadly neutralizing antibodies on its own in sufficient quantities
remains a challenge with no solution in sight.
Much more is known about inducing cell-mediated immune responses
to HIV—and if HIV would stand still, these responses might offer
very effective viral suppression. Unfortunately the experimental
evidence so far suggests that cellular immunity is not very effective
at blocking HIV from establishing an infection in the first place.
While a therapeutic vaccine could be very important for people
living with HIV (and this is likely the first HIV vaccine product
we will see) what the policy makers and public health officials
really want is a preventative vaccine.
One recent startling finding about the impact of HIV in the gut
has stimulated much interest in the role of mucosal immunity. It's
been shown that shortly after infection, HIV rapidly and dramatically
destroys vast numbers of CD4 T cells that reside in lymphoid tissue
lining the intestines. Because this wholesale destruction happens
within the first two or three weeks of infection, an immune system
that had been primed to recognize HIV might be able to minimize
the damage and possibly alter the natural course of HIV disease.
Other avenues of research are looking at ways to stimulate immune
responses in these vulnerable mucosal tissues.
Because HIV is constantly evolving in the body, the HIV transmitted
from one person to another may have a different genetic signature
from the virus the first person was infected with. As the virus
passes from person to person, over time the genetic "distance" from
the original virus increases. If an infected person moves to a
different part of the world and introduces HIV there, eventually
different identifiable subtypes of HIV will be associated with
different global regions. The evolving genetics may not greatly
affect how the virus works or how it causes disease as much as
they represent changes in the fine details of viral proteins that
could be targets for immune recognition. For example, people have
unique faces that identify them as individuals, and the variation
in facial appearance around the world is great, but everyone still
has eyes and ears that perform consistent functions. The challenge
for designing a vaccine that will work for everyone all around
the world is to find the key unchanging features across all viral
strains that can serve as immune targets.
So to sum up the situation for HIV vaccines, there are a few vaccine
candidates moving forward to clinical trials that may stimulate
some cellular immune response, but while these might offer modest
viral suppression after an infection has taken hold, they will
probably provide only minimal protection from transmission. To
do that, vaccines that stimulate neutralizing antibodies will probably
be needed, and currently those remain out of reach.
Innate Immunity
Ned Landau, Salk Institute for Biological Studies, La Jolla,
Calif.
Our bodies actually have certain systems of innate immunity that
can block viruses, including HIV, from infecting cells. These systems
don't recognize specific pathogens but rather tend to reject foreign
materials such as viral DNA or double stranded RNA that don't belong
in the cell. Nevertheless, HIV has evolved adaptations that have
defeated these systems too.
The viral protein called "Vif" was identified during the 1980s
as a "virion infectivity factor." In most cells, if Vif is deleted,
HIV is unable to replicate. Cells that need Vif to produce viable
HIV are called nonpermissive, because they don't permit replication
unless Vif is present. This suggests that blocking Vif might be
a possible treatment strategy. Experiments that joined a permissive
and a nonpermissive cell together caused the cell to become nonpermissive,
which suggested that there is some natural factor in T cells that
inhibits HIV replication. In 2002 this factor was identified as
a protein called APOBEC3G, one of a family of proteins that performs
DNA processing in cells. In the absence of Vif, the APOBEC3G protein
is packaged into newly formed HIV virions and is carried along
when the virus subsequently infects a new host cell. After HIV
enters a target cell, one of the first replication steps is to
copy the HIV RNA into DNA. But if APOBEC3G is present, then the
DNA copy of the viral genes is inappropriately processed and degraded,
which effectively stops HIV replication from continuing.
So in the absence of Vif, APOBEC3G acts as a kind of natural antiviral
mechanism. But if Vif is present, it binds to APOBEC3G and the
protein is degraded before it can be packaged into the virus. Thus
Vif defeats one of the cell's natural antiviral defenses. Investigators
are now looking at other members of the APOBEC protein family for
antiviral activity and at the role of cellular APOBEC3G in preventing
new HIV infections in resting T cells. It's long been observed
that only activated T cells can be infected by HIV and that resting
T cells resist infection. One research group has recently shown
that if APOBEC3G can be depleted from a resting T cell, then it
becomes susceptible to infection.
In 2004 another cellular protein with potentially natural anti-HIV
activity, called TRIM5, was discovered. Although the monkey version
of TRIM5 can block HIV replication, human TRIM5 allows HIV replication
to proceed. Some scientists suspect that the TRIM protein causes
an invading virus to fall apart just after entry, before it can
successfully unpack its contents. Others think that TRIM5 triggers
degradation of certain HIV proteins or that it possibly causes
the viral machinery to be delivered to the wrong place in the cell.
These unsolved questions are typical of biological science at the
leading edge, and represent opportunities for discovery that will
hopefully attract young scientists into HIV research.
Drugs
Scott Hammer, Columbia University, New York City
The best-attended sessions at the Retrovirus Conference are devoted
to antiretroviral drug therapy—mainly because the biggest and splashiest
research comes from drug trials. A significant market for antiretroviral
drugs has developed in the past decade, and the pharmaceutical
industry is willing to invest large amounts of money in research
to refine and develop new antiretroviral drugs.
This year is the tenth anniversary of learning that triple combination
drug therapy can suppress HIV replication and prolong life. There
are now over 20 drugs approved in the three main classes, and new
drugs are being developed to block the virus at other points in
its life cycle. Several entry inhibitors are well along in development,
and one, Fuzeon, has already been approved as the first of this
fourth class. Another new class of drugs is meant to block the
viral protein integrase, which is responsible for stitching the
viral genes into the cell's DNA. Other targets for drug development
include the packaging and maturation of newly formed virions. For
the most part, antiretroviral drug research is alive and well.
When potent antiretroviral drugs are taken consistently, there
is usually an initial rapid decline in viral load that occurs within
the first week or two. Then, during the next eight weeks or so,
virus levels continue to drop to where they are no longer detectable
by the standard HIV RNA assay. If a person can develop good habits
for taking the drugs on time and can tolerate any side effects,
then there is a good chance that he or she can continue with undetectable
virus indefinitely—with no, or only minimal, evolution occurring
among the few viral holdouts. But not everyone can achieve this
optimal outcome, and more research is need on strategies to extend
the benefits of viral suppression to everyone.
Drug development is largely financed by industry, but government-funded
research is also proceeding on strategies for using the drugs and
treating people who have not responded to their first regimens
or who may need to take a break from therapy. When therapy can
safely be interrupted and for how long remain viable questions
despite the recent, early closing of the large SMART study that
compared continuous treatment to intermittent therapy guided by
CD4 count. Because significantly more AIDS illnesses occurred in
the intermittent group than in the continuous treatment group,
the trial was halted. SMART was the largest and best-organized
trial of this treatment strategy, yet other, smaller studies that
used higher and safer CD4 counts for triggering interruption have
showed promising results. While interruption can't be recommended
as a strategy, the fact that many people will require interruption
due to fatigue, toxicity, or other life issues means that interruption
strategies still deserve to be studied. Knowing the best way to
manage these patients remains a significant unanswered question.
Another strategy under investigation is simplification of treatment
by reducing the number of drugs in the regimen once viral suppression
has been achieved. Studies of this strategy using single-drug therapy
with boosted Kaletra or Reyataz are under way. There is also a
critical, unmet need for drug regimens that can reliably suppress
virus in people with extensive treatment histories who have accumulated
multiple drug-resistant mutations. Some of the most exciting research
is focusing on the possibility of forcing drug-resistant virus
into a weakened state by using nonsuppressive drugs to maintain
mutations that hobble the virus.
Much basic science is being done to understand the impact and
interplay of drug resistance mutations. In the future it will be
important to track the impact of resistance around the globe as
antiretroviral drugs come into broader usage, particularly in the
developing world. Patterns of drug resistance and response may
be different in different parts of the world, depending on which
HIV subtype is prevalent. Other questions from the developing world
that need attention are how best to prevent mother-to-child transmission
of HIV with simple regimens and how best to treat infants and children
who do become infected. One novel drug study is investigating if
taking Viread daily as a preventative measure can prevent HIV infection
in healthy people who are at risk for becoming infected. While
this does not seem like an optimal approach to prevention, given
the state of vaccine research, it may well be a viable stopgap
measure to help hold down new infection rates in vulnerable populations
until something better arrives.
Complications
Judith Currier, University of California, Los Angeles
In discussing the complications of HIV disease, Dr. Currier opened
up a world of unanswered and intriguing questions on everything
from the impact of sex and the environment on the course of an
infection to the litany of side effects that can accompany therapy.
Complications make treating HIV more difficult and there is often
a question of whether to first treat the complication or the HIV.
Many of these questions are most acutely encountered in resource-limited
settings where diagnostics and monitoring of complex medical conditions
are not easily done. Yet studies coming from the developing world
are showing excellent results in initiating and maintaining therapy,
even when complications such as giving tuberculosis (TB) treatment
are thrown into the mix.
Because TB is endemic in so many parts of the world and because
TB is a particularly serious infection in HIV-infected people,
it is now considered the most important complication of HIV. Research
is needed to develop new drugs, new diagnostics, and new treatment
strategies for identifying and treating TB in cooperation with
emerging HIV treatment programs.
Immune reconstitution inflammatory syndrome is a phenomenon that
can emerge a month or two after starting antiretroviral therapy.
It is particularly common in people who start therapy with very
low CD4 cell counts. The acute symptoms of immune reconstitution
syndrome can appear virtually the same as underlying diseases such
as TB or hepatitis C infection. The cause of this syndrome is not
well understood, but some studies point to the reactivation of
pathogen specific immune responses that make it appear the body
is fighting off an infection that has already been cured.
The metabolic and fat wasting side effects of antiretroviral therapy
have also opened up new areas of basic research into fat metabolism,
drugs to mitigate metabolic disorders, and strategy studies on
switching drugs to remove suspected lipotoxic agents from regimens.
Again, the impact of these problems in the developing world is
just starting to be investigated.
From the earliest days of AIDS, people attempting to understand
the disease have found a web of associations reaching into almost
every aspect of human knowledge. In the scientific and medical
sphere alone the breadth of HIV research continues to illuminate
not only this disease but the fields of immunology, infectious
disease, cancer, and many others as well. Unfortunately we have
not arrived at a point when AIDS researchers can relax. Because
of its global spread, the vast number of infected people, and the
many difficulties to overcome before the disease can be effectively
prevented and treated, young investigators entering HIV research
today will find themselves busy for decades to come.
FDA Hearing on Home HIV
Testing
By Bob Huff
Recently, the FDA blood products advisory committee has been considering
what the agency should know before approving an over-the-counter
(OTC) rapid home test to diagnose HIV infection.
The only approved oral rapid test on the market for use by medical
personnel is the OraQuick assay, and although the company has not
yet applied to market the test as a home test, the OraQuick product,
its routine use in clinics and by non-lab personnel in special
projects provided background for the committee's discussion.
At a November 2005 meeting there was universal and enthusiastic
agreement by community representatives that any product or strategy
that could improve testing rates would be welcomed and that OTC
rapid home tests would be a useful addition to current testing
options and may contribute to increased awareness of HIV status,
which could possibly affect new infection rates. But community
representatives—as well as physicians, industry representatives,
and committee members—all stressed the importance of supporting
the home tester with a 24/7 hotline that could provide emotional
support and competent referral to care, all with cultural sensitivity
and in multiple languages.
Most experts thought that the technical specifications of the
OraQuick test, its ability to sensitively detect and discriminate
antibodies to HIV without giving too many false positive results
or missing true infections, were excellent. The test achieves 99%
sensitivity and specificity in controlled studies when used by
trained technicians under ideal conditions. What is unknown, however,
is how well the test will perform when used by consumers at home.
One of the key challenges posed to the committee was to advise
the FDA on what kind of studies would be required to evaluate the
effectiveness of the test under real world conditions. This is
where the unknowns become formidable. At this point no one can
say if the benefits of OTC home testing will outweigh the risks
if the quality of the test results inevitably degrades when used
by untrained consumers. There was also extensive discussion about
the extent of training that can reasonably be offered on a product
package, especially when many individuals may not read the instructions.
While the oral HIV test has been proven simple and reliable to
use by people with only a few minutes of demonstration and training,
home users will not have even that much support. They will need
to follow illustrated instructions that require a minimal amount
of reading. Any positive result must be confirmed. This fact must
be made clear, and explanation of what to do next must be provided.
The correct use of the test brushes the device against the upper
and lower gingival surfaces. Then a fluid is applied to the dipstick,
and the test result is read after 20 minutes.
But untrained users have been observed to fill the test well with
saliva before brushing the proper surface; some have dipped the
stick in the fluid before putting it in their mouths; others estimated
that 20 minutes had elapsed after only five had. Some may use other
body fluids; users may buy one test and share it among several
friends. As simple as the test is, all of the creative and incorrect
ways the procedure can be performed have not yet been imagined.
There is also a high likelihood that many people would inappropriately
use the product as a "morning-after" test, well before any HIV
antibodies have developed.
The committee became bogged down in considering a variety of ways
to address all of the knowledge that must be imparted for correct
test usage. One committee member noted that the package for the
test had become unwieldy, stuffed with all the training DVDs, comic
books, lists of hotlines, and explanatory materials in multiple
languages that had been proposed.
One member recommended keeping the burden on the user light by
sticking to clear instructions: a simple explanation of what the
test does and does not tell, and a clear set of instructions for
what to do if the test is positive. Additional educational material
could be provided, but all agreed that users could not be expected
to read it.
In the end the committee seemed to agree that there was a need
for an OTC rapid home test and that the benefits would likely outweigh
the risks, even if the predictive value of the test were degraded
by a high rate of invalid results. However, where the cutoff between
benefit and harm lies is not known, but it will likely vary considerably
depending on the prevalence of HIV in a particular population.
Much more study is required.
The hearings also made it clear that clinical trials for the test
and the supporting materials with consumers in a real world setting
would be a complicated and lengthy process. As much as one may
be needed, an OTC rapid test is not likely to be approved soon.
ARV Birth Defect Risks
By Polly Clayden, HIV i-Base, London
At the 12th Annual Retrovirus Conference held in Denver earlier
this year, a poster authored by Karen Beckerman and coworkers presented
findings from an analysis of central nervous system birth defects
that found no increase in the rate of birth defects in babies born
to mothers taking antiretroviral (ARV) drugs during pregnancy compared
to babies from the general population.
The Antiretroviral Pregnancy Registry (APR) critically reviews
all reported birth defects associated with ARV use in pregnancy,
including central nervous system defects. Registration by clinicians
is voluntary and birth defect prevalence is compared to the Center
for Disease Control's (CDC) population-based surveillance system.
In addition to analysis of prospective data, APR complements its
analyses by comprehensive review of other data sources including
clinical trials, epidemiological studies, and retrospective data.
Over the period 1989 through July 2005, APR has monitored 5,169
live births exposed to ARVs. Of 1,980 first trimester exposures,
there were 59 birth defects (3.0%, 95% CI 2.3 to 3.8). This overall
rate is not significantly different from CDC's rate of 3.1 per
100 live births (95% CI 3.1 to 3.2).
Of first trimester ARV exposures, four cases of central nervous
system defects were detected among 1,980 live births (0.20 of 100
live births, 95% CI 0.004 to 0.40). Among those with ARV exposure
later during pregnancy, 5 had central nervous system defects among
3,189 live births (0.16 of 100 live births, 95% CI 0.02 to 0.29).
According to national data, about 1 in 235 (0.4%) live births have
central nervous system or eye defects.
The central nervous system defects after first trimester exposure
included holoprosencephaly, brain growth retardation, and two with
hydrocephalus; and, among later exposures, Dandy Walker, lipomeningocele,
caudal thalamic notch cyst, and two with hydrocephalus. The authors
noted that none of these cases were exposed to efavirenz (Sustiva).
Use of efavirenz during pregnancy is contraindicated due to serious
birth defects seen in the offspring of animals and women treated
with efavirenz during pregnancy.
Among retrospective cases, there were four neural tube defects,
three with efavirenz exposure, and a Dandy Walker defect with efavirenz
exposure, which is reported in the product label (Sustiva, BMS,
8 of 2004). There were no central nervous system defects in other
supplemental studies reviewed.
The authors wrote: "Within the detection power of the sample to
date, APR data demonstrate no teratogenicity overall. There does
not appear to be an increased risk of central nervous system defects
in the prospective analysis. In the supplemental data, there do
not appear to be any patterns other than the already identified
efavirenz signal. Prospective reports of ART exposures are critically
important to determine teratogenic potential and may avoid reporting
bias inherent in other forms of data collection."
Comment:
According to the Spina Bifida Asssociation, spina bifida occurs
in 7/10,000 (0.07%) live births in the USA. Thus far, 1,980 first
trimester exposures to any single or combination of antiretroviral
therapy have been prospectively reported to the Antiretroviral
Pregnancy Register, mostly from the USA. Therefore, 12 cases
of spina bifida (spina bifida occulta, meningocele and myelomeningocele)
might have been expected in this population. Only 228 first trimester
exposures to efavirenz have been reported prospectively, with
no cases of spina bifida, and therefore there are insufficient
numbers to comment on the relative risk of efavirenz and spina
bifida.
Amongst retrospectively reported cases there have been 4 cases
of spina bifida (myelomeningocele) of which 3 cases are reported
in association with efavirenz exposure. Given the well-documented
and publicized association or efavirenz exposure with congenital
malformations of the CNS in animals (cymologus macaques) some reporting
bias might be anticipated. The number of babies exposed to efavirenz
in the first trimester is not known, but an estimate of such numbers
would be useful. Until more robust data are available, women of
child-bearing potential should be informed of the reported association
between efavirenz and spina bifida prior to starting therapy and
be informed of their therapeutic options.
Women starting efavirenz therapy should be advised not to rely
solely on hormone-based birth control, such as pills, injections,
or implants, but to use an additional form of barrier contraception,
such as a condom or diaphragm. Women who wish to become pregnant
should talk to their doctor about other ARV options. Women who
become pregnant while taking efavirenz should talk to their doctor
right away.
References
Beckerman K, Watts H, Covington D et al. Assessing the risk
of central nervous system birth defects associated with ART exposure
during pregnancy. 13th CROI, Denver. Abstract 713.
HSV-2 Suppression Reduces
HIV and HSV Shedding
Simon Collins, HIV i-Base
In an important proof of concept study presented at the 12th Annual
Retrovirus Conference, Nicolas Nagot and colleagues from London
School of Hygiene and Tropical Medicine, investigated whether suppressive
treatment for herpes simplex virus (HSV) associated with genital
herpes could have an impact on HIV transmission.1
The study randomized 140 women who were coinfected with HIV and
HSV and were not eligible for ARV treatment, to either 1 gram valacyclovir
daily for three months or placebo. Patients were followed for three
months prior to randomization and for the three months during the
study. HIV RNA and HSV DNA shedding in genital fluids were measured
from cervical swabbing every two weeks.
The mean CD4 count at baseline was 519 and 482 cells/mm3 in
the valacyclovir and placebo groups respectively. Overall visit
attendance was reported as 93% and treatment adherence as 97%.
The reduction in HIV-1 RNA genital shedding was significantly
greater in the valacylovir group than in the placebo group. HIV-1
shedding was significantly less persistent in the treated group.
HIV-1 plasma viral load was also reduced in the valacyclovir group,
as was HSV DNA shedding. The proportion of women shedding HSV at
least once was 18.6% in the valacyclovir arm and 54.3% in the placebo
arm.
Comment:
A recent analysis by Freeman of studies in this area concluded
that a person with genital herpes has an approximately threefold
greater risk of acquiring HIV infection after sexual exposure.2
Genital ulcers provide a reduced physical barrier to HIV and increase
activation of local CD4 and dendritic cells, which are susceptible
to HIV infection. If the source partner is coinfected with HIV
and HSV they may also have higher HIV virus levels in genital fluids
and therefore be more infectious.
Previous studies have highlighted the protective effect of valacyclovir
treatment on the transmission of HSV to non-infected partners3,
and data in this study supporting reduced risk of HIV transmission
is clearly important. A similar benefit may be likely using the
less expensive off-patent acyclovir.
References
- Nagot N, Ouedraogo A, Mayaud P et al. Effect of HSV-2 suppressive
therapy on HIV-1 genital shedding and plasma viral load: a proof
of concept randomized double-blind placebo controlled trial (ANRS
1285 Trial). 13th CROI, Denver 2006. Abstract 33LB.
- Freeman EE, Weiss HA, Glynn JR et al. Herpes simplex virus
2 infection increases HIV acquisition in men and women: systematic
review and meta-analysis of longitudinal studies. AIDS 2006;20:7383.
- Corey L, Wald A, Patel R et al. Once-Daily Valacyclovir to
Reduce the Risk of Transmission of Genital Herpes. NEJM Volume
350:1120 January 1, 2004.
More treatment information is available at www.i-base.info.
Study
Parameters
|
| |
| |
Treated Group |
Placebo Group |
P-value |
| HIV RNA shedding in genital fluids (log copies/mL) |
0.26 |
+0.09 |
0.003 |
| Persistence of HIV RNA shedding (% of women) |
|
|
|
| At every study
visit |
14.3% |
27.1% |
|
| At over half of study visits |
32.9% |
14.3% |
|
| At less than half of study
visits |
32.9% |
14.3% |
|
| Never shed |
25.7% |
14.3% |
0.007 |
| HIV RNA in blood (log copies/mL) |
0.39 |
+0.12 |
<0.001 |
| HSV DNA shedding in genital fluids (log copies/mL) |
0.22 |
+0.18 |
<0.001 |
| Women who shed HSV at least once (%) |
18.6% |
54.3% |
<0.001 |
Who are the Elite Controllers?
By Bob Huff
Who are the elite controllers? No, they're not initiates of Yale's
secretive Skull and Bones Society or members the Trilateral Commission.
Elite controllers are people infected with HIV who have been able
to suppress their virus without using antiretroviral medications.
And Dr. Bruce Walker of Boston wants to meet them and find out
how they do it.
It's been appreciated for many years that some people with HIV
do not progress to AIDS at the same pace as most. Typically, the
immune damage of untreated HIV infection will lead to life threatening
opportunistic infections within eight to 12 years. But some people
have been infected for 2025 years or more and have not yet experienced
the severe loss of CD4 immune cells that signals AIDS.
These people have been termed long-term nonprogressors, and in
the mid 1990s, researchers began studying them to try to understand
why some people progressed to disease and others didn't. The ultimate
hope was that whatever protective qualities these people carried
naturally could be stimulated in everyone. There are also other
long-term survivors of AIDS who have experienced immune damage
but have managed to thwart the virus with treatments, although
these people may also have had help from their immune system or
a genetic resistance to HIV.
For Walker and colleagues at the Partners AIDS Research Center
who are coordinating the study, duration of infection is not the
main criterion; they are looking for anyone who can control their
HIV without drugs. Elite controllers are defined as people with
asymptomatic HIV infection not taking antiretroviral therapy (ART)
who have experienced at least one year with HIV RNA below 50 copies/mL
(undetectable). Participants must have at least three sets of test
results documented within one year. Occasional viral load blips
up to 1,000 copies/mL are allowable.
Walker estimates that there may be 1,500 or more elite controllers
in the United States. The research group has already collected
blood from over 100 people and has set a target of enrolling 1,000
elite controllers into the study. They are also interested in finding
a similar group of people with asymptomatic HIV infection who,
while not undetectable, do manage to keep their HIV RNA levels
under 2,000 copies/mL without drugs. Walker calls these people,
who may be much more common, viremic controllers. A long list of
prominent HIV physicians have signed up to scout for elite controllers,
but individuals who think they fit the criteria can contact Walker's
group in Boston directly to submit a blood sample.
The study plans to use gene sequencing techniques of the Human
Genome Project to construct a haplotype map for each participant,
in hopes of identifying genetic factors that may be contributing
to their ability to control HIV infection. A haplotype map allows
scientists to look for variations in genes as they are commonly
organized on the chromosomes. Advanced data analysis will evaluate
if multiple gene variants are possibly associated with spontaneous
control of HIV. Genetic sequencing and data analysis will be performed
at the Broad Institute in Boston. Additionally, high resolution
HLA typing will be conducted to look for genetic differences in
these immune markers, and adaptive immune responses and antibody
studies will also be performed. The entire genome of each person's
virus will also be sequenced to see if some viruses are more controllable
than others.
These new genetic tools allow researchers to take the closest
look yet at what might make those lucky few who can control their
HIV without drugs different from everyone else. If they can uncover
some previously unrecognized protein or mechanism that is common
to all elite controllers, then the next step will be to look for
a drug than can safely produce the same effect in everybody else.
For more information about this study, contact: Florencia
Pereyra, MD, fpereyra@partners.org.
© 2006 Gay Men's Health Crisis
|
home 
