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Past Issues
Volume 19, number 7/8
July/August 2005
Methamphetamine Meet
Diverse groups gather to explore solutions to growing meth crisis
Treating Crystal Meth Dependency
Yves-Michel Fontaine maps the drug treatment landscape
Mixed Messages
How do we talk about meth?
Sources of Meth
Speed is everywhere. But where does it come from?
Let's Work Together
Allan Clear and Luciano Colonna on what comes after the conference
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
1 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.
2 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.
3 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
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