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Past Issues
Volume 18, number 7/8
July/August 2004
IAC
2004 Photo Gallery
All photos courtesy of Bob Huff
Thai Drug Users Speak Out
Opening night speech at the International AIDS Conference
The X4 Files
Sampling the science on HIV co-receptors in Bangkok
Build a Better HIV Blocker
Oral entry inhibitors on the horizon; at end of rainbow
VOTE Health!
What the U.S. presidential candidates propose for reforming health
care
Low-cost Diagnostics
The field evolves but still has a long way to go
Positively Aware
Charles Clifton remembered in his writing
Welcome to Bangkok
By Paisan (Tan Ud) Suwannawong
Thai Drug Users' Network
Good evening, ladies, gentlemen and friends. Welcome to Bangkok.
Sorry if I am a little nervous, but I am not used to speaking
on stage; I am more experienced with speaking on the street.
First I would like to say thank you to the people who supported
my invitation to speak, and thank you to the International AIDS
Society, because it means a lot to me, to speak from the perspective
of a drug user living with HIV.
I would like to tell you a little bit about myself.
I grew up in one of Bangkok's biggest slums, not far from here.
I saw many people using drugs, but never imagined that I would
become a drug user myself.
The first time I smoked marijuana, it felt like a challenge because
all the public campaigns said drugs were "bad" and "dangerous." I
found it wasn't true, so I continued to smoke it.
Then I started smoking heroin, and became addicted without realizing
it. I didn't have any money, I was feeling withdrawal symptoms,
and my friend offered to share his heroin and inject me. Yes, it
was scary the first time.
I got arrested at least 20 times. Most of the time, I did not
have any drugs on me. The police would plant drugs on me and force
me to confess, and beat me if I did not sign their document. I
could not carry a needle around, because if the police arrested
me, the charge would be more serious.
I heard about the risk of getting HIV from sharing needles, but
when you are craving heroin, you don't think about anything else.
You just want to inject.
I was in prison twice. The conditions were terrible and we had
to stay in our cells for more than 15 hours a day. For me, there
is nothing worse than losing your rights and your freedom. I am
not surprised that people use drugs and inject in prison, even
if they never used or injected before.
I believe that I got HIV in prison because I injected almost every
day there.
Getting off drugs is not easy. Many times, I went into drug treatment
just to please my family, get away from the police, or take a break
because the amount of drugs I needed was getting expensive, not
because I wanted to quit; and the attitudes of the treatment staff
only made me feel worse.
Other times, I really did want to quit. But can you imagine how
it feels to leave a treatment program and go back home, with nothing
to do? How difficult it is to find a job and explain where you've
been? My own family would watch my every move; I could see in their
eyes they did not trust me. I was too embarrassed to see my friends,
whose lives seemed so successful.
It was so lonely. I felt I had nothing at those times. The only
thing I could think of was to go back to using drugs.
Finally I got off drugs 13 years ago. I knew I really needed help.
I decided to go to a "TC," or "therapeutic community." This is how
I found out how I got HIV. The test still is a requirement for entering
the TC. There was no pre- or post-test counseling. In fact, my results
were given to my sister, not me.
Today, not much has changed. Drug users are still seen as morally
weak and bad people. We face stigma and discrimination in society
and in the health care setting. We experience constant police harassment
and ineffective services.
In Thailand, injecting drug users or "IDU" are the only group
whose 50% HIV prevalence has not changed in 15 years. One third
of all new HIV infections are IDU-related, and this number is increasing.
Yet there has been no effective response from the government.
In a recent war on drugs in Thailand, over 2,500 people were killed
extra-judicially in the first three months of the campaign.
More than 50,000 people were arrested, hundreds of thousands were
forced into military-run rehabilitation centers, and drug users
were forced underground and away from services that were already
difficult to access.
Last year, the Thai Drug Users' Network developed a proposal for
a peer-driven HIV prevention, care and support intervention for
injectors, and submitted it to the Global Fund.
We had to bypass the country coordinating mechanism and lobby
with the help of international AIDS activists to get political
support for our proposal. In October, we were awarded a $1.3 million
grant, but we still haven't received the money.
Even though the Thai government says its current policy is to
treat drug users as "patients," not "criminals," it is still illegal
to be a drug user. We continue to be arrested and offered the choice
of prison or military-run rehabilitation centers. Is this harm
reduction or harm production?
Every minute, a person is infected with HIV by using a dirty needle.
Globally, 1 in 3 of all new HIV infections outside of Africa is
IDU-related. In fact, contaminated needles account for the largest
share of new infections in Eastern Europe and Asia.
The World Health Organization (WHO) says drug users have an equal
right to all levels of care, but in practice, we are denied access
to ARV treatment, as well as basic prevention interventions like
clean needles. Methadone is still illegal in many countries and
should be on the WHO Essential Drug List.
There are many harm reduction interventions which have been proven
to help IDU stay free of HIV, including clean needles and methadone.
We need these means of prevention in place NOW! And we need access
to treatment NOW!
Drug users, like other politically, socially, or economically
marginalized groups, are easily abused by the government and others,
who exploit them for money or services.
We often do not enjoy even the most basic human rights. In Thailand,
this is true for sex workers, MSM, migrant workers and undocumented
citizens as well.
The world we live in today is not a world of sharing but of advantage-taking,
profit-seeking, and competition to "get ahead." It is a world motivated
by greed and controlled by corporations, which do not recognize
the value of a human being. While an elite few amass enormous wealth,
basic needs are denied to many millions.
Today, many of our governments are run by these elite, who are
more interested in protecting their personal investments than promoting
public welfare. They invest public resources in projects whose
profits go into the pockets of their friends instead of providing
for the welfare of society. Governments privatize our public utilities,
as well as our education and health care systems.
Social welfare programs and other forms of assistance become issues
of charity, not rights or entitlement. As a result, our public
hospitals are overloaded and under-funded, severely compromising
the availability and quality of treatment and care offered.
Of course, tackling AIDS isn't just about health care and antiretroviral
drugs. Prevention, harm reduction, poverty reduction and decent
living standards are all part of the process; but governments,
like the United States, or international organizations, like the
World Trade Organization, make the task much more difficult.
Market-driven policies and the emphasis on "abstinence-only" have
already proved to be harmful or, at best, totally useless.
It is outrageous that today, conservative groups, especially in
the U.S., are advancing a moralistic ideology that contradicts
scientific evidence about HIV prevention.
Though condoms and clean needles are the most effective tools
we have to prevent the transmission of HIV, programs that promote
them are not funded, or are de-funded.
Evidence shows that widespread access to ARV leads to huge improvements
in health and quality of life, with significant reductions in health
care and other costs, because of improved health and productivity
among people living with HIV/AIDS and their families.
The most painful experience I can think of, after living with
HIV for 13 years, is being poor and HIV-positive. Again and again,
I watched many friends die in front of me, from terrible opportunistic
infections, simply because they were poor and could not afford
treatment.
What kills us is not AIDS, but greed.
Multi-national pharmaceutical companies inflate the prices of
their drugs without thought for poor people. They use their wealth
to influence U.S. and European government policy to ensure that
intellectual property rights are weighed in their favor.
Other governments say they are too worried about adherence and
drug resistance to offer treatment, when the truth is they don't
want to pay or suffer repercussions from their trading partners
by breaking patents.
Four years ago, Thai people with HIV/AIDS asked the government
to use a compulsory license for ddI, but the government was too
afraid of trade and other sanctions from the U.S. Ultimately, we
took Bristol Myers-Squibb to court and won the right to produce
tablet-form ddI locally.
In the final judgment, the Thai Court ruled that, because patents
can lead to high prices and limit access to medicines, patients
have the right to sue the patent holder.
This was a very important battle that we won.
But the war is not over.
Recently, the Thai government entered the Free Trade Agreement
negotiations with the United States. WE know the U.S. unilaterally
pushes for intellectual property protection that is stricter than
what is agreed internationally.
This means that Thailand, now producing generic ARV for most who
need it, will no longer be able to sustain this important program.
We are demanding the Thai government refuse to trade away the health
of its people by negotiating intellectual property protections
for medicines.
The U.S. government and its policies affect the ability of people
all over the world to enjoy their basic rights and needs. Many
poor countries cannot provide basic services like health care because
they have to pay back enormous debt to the U.S. and Western Banks.
While thousands die of AIDS everyday from lack of funds, there
is unlimited funding for war. Billions of dollars are freely available
for the killing and destruction in Iraq, while the Global Fund
is out of money.
This is because of the broken promises of rich donor countries
that refuse to pay their fair share.
I have no simple solutions for achieving world peace, but I do
know that the U.S. government, led by that criminal, George Bush,
wages war and occupies countries like Iraq in the name of peace.
The U.S. is too arrogant to listen to the UN, and the Thai government
shows its loyalty to the U.S. by sending Thai troops to Iraq.
Four years ago, at UNGASS, after activists demanded an urgent
response to the global AIDS treatment crisis, Kofi Annan called
on all the world's governments to develop what he described as
a "war chest."
This became the Global Fund.
At the last international AIDS conference, WHO launched its Ô3
by 5' initiative; yet, today, 6 million people are still waiting
for their drugs.
AIDS doesn't wait and neither do we.
Faced with the abuse of power and greed of corporations, we cannot
wait for our governments to act.
Governments and corporations hate activists because we know what
they are up to, and we are pulling the masks of fake concern from
their face to reveal their true nature.
But to me, activists are to be honored. Activists are my true
friends. They stand by my side when I face discrimination and injustice.
They have the courage to stand up to those in power who use their
positions for their own benefit. They are the ones who can help
provide a way forward to fight AIDS and injustice in this world.
Access for all is the theme of this conference and the dream of
many of us here. Yes, it's not easy to achieve in the world we
live in today, but the world belongs to all of us to change.
Five years ago, doctors, nurses and many other people told me
and my friends that ARV was an impossible dream. Recently, Thailand
announced that it would provide ARV to all who need it, starting
with 50,000 people by the end of this year. Today, I urge all of
us to dream, of a day when our world will be filled with love,
sharing and peace. And I believe that when we dream together, our
dreams come true.
This talk was presented at the opening plenary of the International
AIDS Conference in Bangkok on July 11, 2004
The X4 Files
By Bob Huff
It's become conventional wisdom that the International AIDS
Conference (IAC) is no longer the place to find cutting-edge
research on HIV science. And although Track A, the basic science
track at the conference, had fewer posters and presentations
than the tracks for clinical research, prevention, social issues
and policy, a respectable 618 basic science presentations were
submitted and 439 accepted to the 2004 IAC in Bangkok. Here's
selection of abstracts covering one aspect of HIV basic research
of emerging importance.
As most people who follow HIV therapies have learned by now, HIV
infects a new target cell through the process of entry,
which can be described as having three basic stages. First, a protein
on the surface of HIV attaches to a CD4 protein on the surface
of a target cell. This step, attachment, allows the viral
protein to change its shape so that it can bind with a different
kind of protein on the cell's surface, called a co-receptor. Then,
after co-receptor binding and a few more intermediate
steps have been accomplished, the virus can finally pull itself
into contact with the cell's surface, where the two merge in a
process called fusion. After fusion is complete, the viral
payload can be delivered and the process of hijacking the cell
and turning it into an HIV factory is well on the way.
Fuzeon, the only approved entry inhibitor, acts to block the fusion
process at the point when the virus is pulled into contact with the
cell. As for the other steps, several experimental drugs are in development
to block attachment and co-receptor binding. As a number of orally
available entry inhibitor candidates move through the drug development
pipeline (injectable Fuzeon was approved in 2003), concerns are being
raised about a subset of the class, known as CCR5 blockers. Because
there are two basic types of cellular co-receptors that HIV can use,
drugs are being developed that block both kinds. The most common
co-receptor protein that HIV uses for entry is called CCR5 or R5,
for short. In someone who is newly infected, R5 is often the only
kind of virus that can be found. But in about half of the people
who develop advanced HIV disease, the virus begins to use another
co-receptor called CXCR4, or X4. The shift to using X4 is considered
a bad sign because it is often accompanied by a dramatic increase
in the rate of T-cell depletion. It is not entirely clear if HIV
with the X4 phenotype causes accelerated T-cell loss or if it is
only a symptom of some other shift in the T-cell ecology, but everyone
agrees: you want to avoid developing an X4-using virus.
This means there is a critical open question about using the new
R5 blocking drugs: will they cause HIV to start using X4? And will
that be worse than letting the R5-using virus chug along at its
own, slower, but no less dangerous pace? So far there's no solid
evidence that blocking R5 will lead to HIV mutations that prefer
using X4. But there is increasing evidence that some people may
have small amounts of X4 virus in their bodies that could be given
a green light to take over if their R5-using cousins are shut down.
Again, it's not clear if these were acquired at the time of infection
or if HIV can mutate step-by-step from exclusively using R5, to
using both R5/X4, to using only X4. While there is now an experimental
phenotype assay that can detect R5, X4 and dual R5/X4-using virus
in a person's blood, it may not be sensitive enough in all cases
to identify X4-using variants that are hiding in tissues or are
only present in very small numbers. Now, as several pharmaceutical
companies are getting ready to start large phase III trials for
their R5 blocking drugs, discussion of the X4 problem is heating
up.
A Better Blocker?
One attractive feature of blocking CCR5 is that there may be little
or no toxicity penalty to pay, since some people are born without
CCR5 proteins on their cells and seem to suffer no ill effects.
(Yes, it is rare for these people to become HIV infected, and
when they do — via other co-receptors, no doubt — they
tend to have a very slow course of progression.) But blocking
CXCR4 may not be as trouble-free, since a lack of the protein
has been shown to lethally prevent infant mice from developing
normally. Nevertheless, a couple of X4-blockers have been used
in human safety studies with no disastrous results. Ideally,
it seems, one would want to use an X4-blocker in tandem with
an R5-blocker to prevent the possibility of an X4-using HIV variant
escaping and causing accelerated immune damage. But, in the first
few upcoming trials, at least, the R5 blockers may have to work
without a safety net as researchers rely on the imperfect assay
to screen out those at risk for switching to an X4-using virus.
If all goes according to schedule and no unforeseen problems
with toxicity arise (and there is no guarantee that they won't),
the first oral entry inhibitors could possibly appear in expanded
access studies by late 2006 and be approved for sale in 2007.
Bangkok Rocks
Here's a look at some of what we learned about the R5 and X4 co-receptors
at the International AIDS Conference in Bangkok.
It's recognized that HIV with the X4 phenotype is rarely, if ever,
transmitted — even when the donor predominantly carries X4
virus. In sexually transmitted infections, it is thought, dendritic
cells (DC) patrolling the body's mucosal frontier are the first
immune cells to contact HIV. However, instead of infecting the
DC, HIV is internalized into a bubble-like vesicle and eventually
carried to a lymph node, where it is introduced to circulating
T-cells, normally the next line of defense in the immune response
to foreign viruses. Unfortunately, these T-cells are the very cells
that HIV prefers to infect. This is where HIV actually takes root
in a new host.
So, why do R5 viruses seem to be favored for starting new infections?
In a laboratory-based study by J. Alcami and colleagues in Madrid,
infections of T-cells by X4-using HIV were observed to be greatly
reduced in the presence of dendritic cells, while infections by
R5 strains were enhanced. This, the authors say, suggests that
dendritic cells may produce a chemokine, or signaling factor, that
effectively prevents X4 HIV from establishing a new infection — while
having the opposite effect on R5 virus. In other words, if dendritic
cells are the gatekeepers to HIV infection, they may routinely
filter out X4 virus, which allows R5 viruses to initially become
the dominant strain. (Bermejo, A1043)
Epi Snaps
Although most people's HIV infections start out using the R5 co-receptor,
in about half the X4 strain will eventually appear at some point
during their lives. But how quickly does this happen, and to
whom? In Bangkok, two studies presented retrospective analyses
of co-receptor usage in a large number of samples and correlated
the R5 phenotype with viral load, CD4 count and other variables.
A study by Harrigan retroactively evaluated samples and records
from 806 participants in a cohort of treatment naive-adults in
British Columbia, and a study by Moyle evaluated data and co-receptor
phenotype in a collection of 169 stored samples from treatment-naive
individuals. In general, both studies confirm that, within a
given sample population, as the duration of HIV infection increases
and CD4 counts decline, the prevalence of the exclusive R5 phenotype
decreases and X4 and dual R5/X4 phenotypes become more common.
In the Harrigan cohort, detection of the R5/X4 or X4 phenotype
increased from 6% in people with CD4 counts above 500 cells/mm3 to
over 50% in those with CD4 counts below 25 cells/mm3.
There was only one exclusively X4 phenotype sample in the cohort.
The odds of having an X4-using virus increased by about 1.5-fold
in those with CD4 counts between 200 and 500 compared to those
above 500 cells/mm3; the odds were 5- to 7-fold greater
in those with CD4 counts between 25 and 200 cells/mm3;
and jumped to 17-fold greater in those with fewer than 25 CD4 cells/mm3.
(Harrigan, B3117)
In the Moyle study, detection of the R5/X4 phenotype ranged from
about 7% in samples with CD4 counts above 300 cells/mm3 to
46% in those with CD4 counts below 100 cells/mm3. There
were no exclusively X4 phenotype samples. The mean CD4 count for
the R5 samples was 307 versus 117 cells/mm3 for the
R5/X4 samples. (Moyle, B5725)
In neither study was viral load a significant predictor of co-receptor
usage phenotype. In the Harrigan cohort, injection drug use was
not correlated with having R5 or X4 HIV; in the Moyle study there
was no difference between B and non-B HIV subtypes.
Crowd Control
A study by Ito and colleagues of the National Institutes of Health
in Bethesda, Maryland investigated how competing "swarms" of
HIV with different co-receptor usage phenotypes might interact
within lymphoid tissue. They found that X4-using HIV variants — including
R5/X4-using strains — were able to suppress replication
of their R5-using competitors. Meanwhile, the R5 viruses had
no effect on the X4 interlopers. The researchers identified several
chemokines stimulated by X4 HIV that seemed to be responsible
for suppressing the R5 variants. When a cocktail of these chemokines
was added to lymphoid tissue with only R5-using HIV present,
the same suppressive effects were observed. The authors suggest
that a better understanding of these chemokine-induced effects
could possibly lead to the development of a new approach to anti-HIV
therapy. (Ito, A3057)
Max Factor
Early in the history of the epidemic one of the first distinguishing
phenotypes of HIV described by scientists was the ability of
some strains to cause groups of infected cells to fuse into clumps
called syncytia. Syncytium inducing (SI) HIV was recognized as
a highly virulent form and it became associated with rapid progression
to terminal AIDS. At one point it was thought that syncytium
formation was HIV's main mechanism for killing T-cells; to this
day it is not entirely clear what is responsible for T-cell death
in AIDS and multiple effects are suspected, ranging from apoptosis
(cell suicide), to immune exhaustion through overstimulation
to direct killing. Eventually, SI and non-syncytium-inducing
(NSI) HIV were correlated with the X4- and R5-using phenotypes
and the SI and NSI nomenclature was generally put on the shelf.
Researchers from the lab of Jay Levy in San Francisco investigated
the patterns of gene expression in T-cells stimulated by infection
with two different phenotypes of HIV, the old-school SI and NSI
variants. The quantities of various RNA gene products from the
test cells were analyzed using microarrays that can detect thousands
of known gene products to see which were upregulated and which
were downregulated when compared to uninfected cells. They found
that SI HIV tends to upregulate genes involved with production
of a cellular factor called tumor necrosis factor (TNF), which
is associated with immune hyperstimulation, a state often implicated
in T-cell depletion. (Bonneau, A4381)
The observation that people with AIDS have high levels of TNF
in the blood was also made very early in the epidemic. At Bangkok,
a group led by A. Valentin of the National Cancer Institute in
Maryland reported on their recent studies of TNF levels in 63 patients
(30 controls) and the impact that TNF has on virus production and
co-receptor availability. They found that TNF inhibited replication
of R5-using HIV strains while having no effect on X4 HIV. TNF was
also observed to downregulate the number of CCR5 co-receptors that
appear the surface of T-cells, which could explain why R5-using
viruses have such a hard time of it when TNF levels are increased.
(Valentin, A1048)
Couple this with Bonneau's finding that X4 HIV stimulates TNF
production, and you have one possible explanation for how the shift
from R5 to X4 predominance occurs. Of course, these shifts may
be happening all the time on a small scale in isolated tissue compartments.
What causes the overall population of HIV to shift? And why does
the appearance of X4 virus signal the demise of so many T-cells?
From Cradle to Grave
Choudhary and colleagues from the University of California, Irvine,
investigated the effect of HIV infection with an X4 strain on
thymocytes, precursors to T-cells that reside in the thymus,
a kind of incubator for immature immune cells. (Choudhary, A3008)
One theory for the accelerated CD4 cell depletion associated with
X4 HIV maintains that the virus is capable of killing T-cells while
they are still in their thymic cradle. In the experiment, thymocytes
were infected with HIV and microarray technology was used to monitor
changes in the expression of 22,000 gene products. They also assayed
for various indicators of apoptosis. The most significant finding
was that HIV infection induced apoptosis through a pathway involving
a protein called caspase. This was confirmed by artificially inhibiting
caspase, which had the effect of blocking apoptosis in infected
cells. These results suggest that if the war between R5- and X4-using
HIV comes to the thymus, the impact on CD4 cell production could
be very dramatic indeed. There is still much to be learned about
how and where HIV causes all the harm it does. Fortunately, we
don't need to understand every detail of HIV pathogenesis to continue
developing newer and better therapies.
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References:
Bermejo M, et al. Impact of CXCL12 production by dendritic
cells in HIV infection. The XV International AIDS Conference,
2004. Abstract MoOrA1043
Bonneau KR, et al. Differential gene expression in primary
human CD4+ T cells infected with nonsyncytia-inducing (NSI)
and syncytia-inducing (SI) isolates of HIV-1 recovered from
the same individual. Abstract TuPeA4381
Choudhary SK, et al. HIV-1 induces Apoptosis in infected
Thymocytes. Abstract MoPeA3008
Harrigan PR, et al. Prevalence, predictors and clinical
impact of baseline HIV co-receptor usage in a large cohort
of antiretroviral naïve individuals starting HAART.
Abstract MoPeB3117
Ito Y, et al. CXCR4-tropic HIV-1 suppresses replication
of CCR5-tropic HIV-1 in human lymphoid tissue by selective
induction of CC-chemokines. Abstract MoPeA3057
Moyle GJ, et al. Prevalence and predictive factors for CCR5
and CXCR4 co-receptor usage in a large cohort of HIV-1 positive
individuals. Abstract WePeB5725
Valentin A, et al. Differential effects of TNF on HIV-1
expression: R5 inhibition and implications for viral evolution.
Abstract MoOrA1048
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HIV Co-Receptor Drugs on
the Horizon
By Bob Huff
A Canadian company, Anormed Inc., is carving out a specialty niche
for itself as a developer of drugs that bind to chemokine receptors,
such as CCR5 and CXCR4. They were the first to put an X4 blocking
drug into people with HIV and proved that the concept was viable.
Unfortunately, the company's first X4 drug candidate, AMD3100,
produced heart rhythm abnormalities in several patients during
Phase I testing and only demonstrated limited efficacy at achievable
concentrations. Undaunted, Anormed has come back with a new, structurally
different candidate, called AMD070, an orally available drug that
has now been tested in healthy subjects and was shown to be available
in the blood at concentrations thought sufficient to suppress HIV.
In Bangkok, results were presented from a Phase I dose escalation
study of AMD070 in uninfected adult men conducted by the federal
AIDS Clinical Trials Group (ACTG). Single 50mg doses were initially
given to three individuals then escalated to 100, 200 then 400mg
in subsequent groups of three. Next, multiple (7) doses were given
at 100mg every 12 hours to a cohort of six individuals, then escalated
to 200mg in a subsequent cohort. A group of six men also received
single 400mg doses with and without food to evaluate bioavailability
in a fed state.
In the single dose studies, the maximum concentration of drug
(Cmax), the total exposure to the drug over time (AUC),
and the rate the drug was cleared from the body (half life) each
tended to be proportional to the dose, although there was a great
deal of variability between the subjects within the dose groups
for each of these parameters. The half life was estimated as 6
to 10 hours. The single 400mg dose produced blood concentrations
at 12 hours that were above the EC90, a value derived
from laboratory studies as the drug concentration required to achieve
90% of its maximum antiviral response. Multiple dosing doubled
the concentrations seen with single dosing at 12 and 24 hours.
However, multiple dosing at 100mg could only sustain concentrations
above the EC90 for 4 hours. Taking the drug with food tended to
lift blood levels, but not significantly. The only adverse events
reported were several headaches.
The next step for this drug will probably be a proof-of-concept
study in people with R5/X4 or X4 HIV to see if it can actually
produce an antiviral effect in people at these concentrations.
If that pans out, then the drug will move forward in the development
process of setting a dose and enrolling larger trials. Anormed
should plan to continue performing pharmacokinetic studies similar
to those reported here, but in more diverse populations, including
women and people with liver disease. All too often we have seen
a dose selected after study in very homogenous populations that
proves to be either too toxic or have too little activity in certain
segments of the patient population. In particular, the interpatient
variability seen in this early study suggests that one size may
not fit all — let's just hope that AMD070 doesn't need ritonavir
boosting. (Stone, B4475)
Bangkok also offered preclinical reports on two other X4 drug
candidates. A group of researchers from Okinawa gave a late breaker
report on KRH-2731-5HCl, an orally available CXCR4 blocker that
suppressed X4 and R5/X4 replication in a cell line at very low
concentrations. They describe the potency of the drug as 10-fold
greater than AMD070. Addressing worries that X4 blockers might
disrupt important natural immune functions, the paper reports that
the drug did not inhibit immune responses in mice with human-like
immune systems. (Murakami, LBOrA01)
Finally, Swiss researchers reported on a peptide mimetic compound
called POL2438 that they said suppressed R4 HIV in a cell line
at very low concentrations with no toxicity. (Klimkait, A1307)
The Big Dogs Bark
While the X4 blockers are likely to be crucial in the clinic, all
of big money is riding on getting an R5 drug to market, probably
because the toxicity issues were expected to be much less problematic.
Pfizer, Glaxo Smith-Kline, and Schering are the big players here
(Anormed has its own CCR5 blocker in preclinical development;
lab-based studies showed synergy when used in a combo with their
X4 drug). Schering was first into people with its SCH-C compound,
but cardiac abnormalities at high doses forced them to switch
to a fallback candidate, SCH-D, a structurally different drug
with improved potency and no worrisome side effects so far.
At Bangkok, Pfizer presented five posters on its CCR5 blocker,
UK-427,857, including results from a 10-day proof-of-concept study.
Patients with CD4 counts above 250 cells/mm3 (currently
off treatment or treatment-naïve) were randomized to a series
of escalating doses or to placebo. Dosing began at 25mg once-a-day
(QD) and increased to 300mg twice-a-day (BID), including one arm
at 150mg BID taken with food. Monitoring continued for 30 days
after treatment was stopped at day 10.
All doses from 100mg QD onward produced mean viral load reductions
better than -1.0 log copies/mL. At the 150mg BID dose, food reduced
the peak concentration and total exposure (AUC) to the drug by
about half, although there was no difference in viral load reduction
at that dose whether taken with food or not. This may be because
blood concentrations of CCR5 blockers are not as important as how
many R5 receptors become occupied by drug molecules and how long
they stay. It seems that these drugs tend to stick to their targets
and not let go, a quality that could extend the effective potency
of a dose by several days. In this study, high levels of receptor
saturation were achieved at every dose except 25mg QD.
All persons enrolled were assayed for HIV co-receptor usage phenotype
and were required to have an exclusively R5-using strain at time
of enrollment. Of the 66 patients exposed to the drug, 2 experienced
an emergence of a dual R5/X4 strain by day 11 of the study. One
of these individuals reverted to R5 phenotype by day 40, but the
other's dual phenotype HIV persisted throughout the first 6 months
of follow-up. Because the assay can not pick up sequestered or
very small populations of X4-using HIV, the risk of forcing a population
shift is evident in this small, initial study. However, in the
person whose X4 phenotype persisted, no evidence of accelerated
immunological or clinical deterioration has yet been reported.
A more detailed presentation of this individual's case is anticipated
at an upcoming conference. Adverse events were mild to moderate
and included headache and dizziness. A separate report found no
impact on QT interval, the cardiac rhythmic parameter that was
perturbed by Schering's first R5 blocker. (Fatkenheuer, B4489)
Glaxo Smith-Kline (GSK) has licensed GW 873140, an orally available
CCR5 inhibitor from ONO Pharmaceuticals in Japan, and has already
performed multiple-dose testing in uninfected persons that demonstrated
safety and favorable pharmacokinetics. At Bangkok, GSK reported
on the compound's in vitro anti-viral activity in a range of patient-derived
cells infected with various laboratory HIV strains and clinical
isolates, including non-B subtypes. The drug had consistent activity
at very low concentrations with most R5 isolates and cell lines
tested. Screening for activity in HIV strains and subtypes that
exist outside of the most lucrative markets is an important test
of a drug's ultimate relevance. In the future we would like to
see every new drug candidate broadly challenged as GSK has done
with GW 873140. (Demarest, A1231)
Progenics Pharmaceuticals showed results in modified SCID mice
for their anti-CCR5 monoclonal antibody, PRO 140. In this bit of
good news for mice with HIV, PRO 140 was able to reduce viral load
to undetectable levels within 8 days; viral suppression persisted
for 6 to 12 days after the last dose. They also report that pharmacokinetics
in a mouse model were favorable. (Franti, A1230)
Being first to market with an oral entry inhibitor is a high stakes
race for Pfizer, and they are sprinting to make it happen. The
company is said to be planning an innovative development track
that takes a Phase II dose finding study and rolls it straight
into a Phase III efficacy trial once the dose is set. This is a
bit of a gamble because they will have to start investing in Phase
III preparations before much of the key information about the drug
(like the dose) is in hand. The payoff, though, is that they can
shave six months or more off of the time it takes to get to market.
After Schering had to switch to its fallback candidate SCH D, and
with GSK's late entry into the entry inhibitor sweepstakes, Pfizer
sees itself poised to dominate the next big thing in HIV therapy.
If the Phase II trials get going soon, and if Pfizer maintains
its aggressive course, the drug could possibly become available
through expanded access programs in 2006 and be on pharmacy shelves
by 2007. Now, who's going to step in and help tiny Anormed pick
up the pace on AMD070?
References:
Demarest J, et al. A novel CCR5 antagonist, 873140, exhibits
potent in vitro anti-HIV activity. The XV International
AIDS Conference, 2004. Abstract WeOrA1231
Fatkenheuer G, et al. Evaluation of dosing frequency and
food effect on viral load reduction during short-term monotherapy
with UK-427,857 a novel CCR5 antagonist. Abstract TuPeB4489
Franti M, et al. In vivo control of HIV-1 replication with
PRO 140, a humanized monoclonal antibody to CCR5. Abstract
WeOrA1230
Murakami T, et al. KRH-2731-5HCl: A new potent and orally
bioavailable X4 HIV-1 inhibiting CXCR4 antagonist in vivo.
Abstract LbOrA01
Stone N, et al. Biologic Activity of an Orally Bioavailable
CXCR4 Antagonist in Human Subjects. Abstract TuPeB4475
|
The Presidential Campaign
Health Reform Proposals
By Laura Caruso
This is an excerpt from a GMHC report: Prescriptions
for Reform: A comparison of the Bush and Kerry health care access
proposals and their impact on people with HIV/AIDS (PDF).
The success of any government's health care system depends on
whether health care is affordable, accessible, promotes quality,
offers maximum coverage for its citizens, supports innovation,
and provides access to the newest technology. It is by these standards
that Americans, especially people living with HIV/AIDS, should
judge the 2004 candidate's campaign proposals. The following outlines
the plans offered by the President Bush and Senator Kerry.
Strengthening public programs and maintaining
AIDS funding
President Bush
Implements the Medicare Modernization Act (MMA), to be fully
rolled out in 2006, which will:
- Add a prescription drug benefit to Medicare
with safeguards against high out-of-pocket costs for low-income
individuals;
- Provide Medicare beneficiaries with the "choice
of individual health plan" as well as a "choice of doctor or
hospital" by increasing funding and flexibility for the Medicare
managed care program;
- Provide coverage of disease prevention (cancer
screenings, diabetes, osteoporosis).
Pursues capped federal allotments for Medicaid programs on a
state-by-state basis through a Medicaid "reform" proposal as well
as waivers of existing federal Medicaid law.
Temporarily extends the Medicaid transition benefit for families
moving from welfare to work.
Creates a new Medicaid option to allow people with disabilities
to have greater flexibility over directing their care in the home
and community (New Freedom Initiative).
Supports modest increases in funding for ADAP, including $20
million to reduce waiting lists in 2004.
As part of Ryan White Care Act (RWCA) reauthorization, provides
Health and Human Services (HHS) with more discretion over RWCA
funds and the authority to determine whether groups are making "good
use" of their monies, as well as expand the number of religious
groups funded to help people with HIV/AIDS.
Commits to doubling the number of community health centers by
2006, so that they can serve an additional 6.1 million patients.
Senator Kerry
Addresses perceived problems in the new Medicare law (e.g. aims
to reduce the number of retirees losing coverage due to the law,
reduce HMO overpayment).
Expands Medicaid by having the federal government pay for the
coverage of all 20 million children on Medicaid if states:
- Expand Children's Health Insurance Program (CHIP)
coverage up to 300% of federal poverty level (FPL) (enrollment
bonuses are included);
- Expand family coverage to 200% FPL (states will
get enhanced matching rate);
- Ensure childless couples and single adults have
coverage at or below the poverty level.
Promotes automatic CHIP enrollment at school, continuous 12
months of eligibility, facilitated enrollment, dropping the five
year wait for legal immigrant pregnant women and children, and
allowing disabled children to keep their insurance if parents return
to work.
Opposes block granting of Medicaid program, and provides $25
billion for state fiscal relief in first two years of term.
Supports the Early Treatment for HIV Act (ETHA), which would
give states the option to expand Medicaid to cover HIV-positive
individuals who are not yet disabled.
Increases RWCA to end ADAP waiting lists (no dollar amount provided).
Supports development of federal guidelines that integrate HIV
prevention into primary care in Medicaid.
Supports community health centers (no specific commitment).
Expanding health insurance access and making
coverage more affordable
President Bush
Offers new health care tax credits for use in the individual
market or in state-created pooled purchasing groups:
- Single adults will be eligible for up to $1000
a year if income is below $15,000; the credit phases out by $30,000;
- Families with two or more children could receive
up to $3,000 a year in tax credits if income is below $25,000;
the credit phases out by $60,000.
Promotes high-deductible individual market insurance linked
to Health Savings Accounts (created by the MMA, accounts that allow
for virtually tax-free savings for out-of-pocket costs); allows
premiums to be tax deductible.
Supports Association Health Plans, which would allow small employers
to pool together to purchase health insurance for employees. Such
coverage would be exempt from state regulation.
Allows premium payments for long-term care insurance to be fully
tax deductible
Supports tax exemptions for people who take time to care for
spouses or parents with long-term care needs.
Senator Kerry
Creates a new pool modeled on the Federal Employees Health Benefits
Program (FEHBP) for small and large businesses, individuals, and
families that need to purchase health insurance. For the uninsured,
tax credits will be available for those who purchase the new group
option for premiums exceeding 6% and up to 12%, based on income.
In addition:
Small businesses would be eligible for tax credits up to 50% of
premiums;
- Americans ages 55-64 without access to employer-based
insurance may receive a 25% tax credit;
- Low-income unemployed would be eligible for
refundable tax credits up to 75% for COBRA or the new group option.
Creates a premium rebate pool that would reimburse employee
health plans and the new pool for 75% of catastrophic costs above
a certain threshold ($35,000 in 2006, $50,000 in 2013) to reduce
premiums and make them more predictable. To qualify for this reinsurance,
employers would have to pass along savings to workers, cover most
workers, and use disease management. Senator Kerry claims this
would save approximately 10% of premium costs, or up to $1,000
off a family plan.
Supports Executive Order to ensure participants in the new pool
will be guaranteed the right to family health benefits for their
domestic partners.
Reducing health care costs
President Bush
Reforms the country's medical malpractice system by:
- Allowing unlimited compensation for economic
losses;
- Capping non-economic damages at $250,000;
- Limiting punitive damages to "reasonable" amounts;
- Prohibiting payments from being made in a single
lump sum;
- Reducing amount that doctors must pay if plaintiff
has received payments elsewhere;
- Requiring defendants pay judgments in proportion
to fault.
Reduces Medicaid costs through an anti-fraud policy.
Expands the use of information technology which could reduce
administrative costs (see below).
Senator Kerry
Reforms the country's medical malpractice system by:
- Opposing capped damages;
- Stopping bad claims unless reasonable;
- Supporting mandatory sanctions for claims that
are presented for improper purposes;
- Requiring states to have non-binding mediation;
- Opposing award of punitive damages in medical
liability unless proof of intentional misconduct.
Eliminates loopholes that pharmaceutical companies use to keep
generic drugs off the market.
Requires pharmacy benefit managers that do business with the
federal government to be transparent and show savings accrued from
industry and bulk purchasing.
Helps states use Medicaid's ability to negotiate drug prices
to cover other populations.
Provides incentives to states to implement more efficient contracting
to leverage better prices.
Promotes disease management by linking it to new financing increases
(see above).
Expands the use of information technology, which could reduce
administrative costs (see below).
Reduces the amount of uncompensated care in the system by expanding
coverage.
Improving quality and promoting a strong
health care system
President Bush
Supports legislation that would implement a Patient's Bill of
Rights with a provision that would limit a patient's right to sue.
Promotes "consumer-driven health care" in which consumers have
access to better information about medical treatments and health
providers, including the quality of nursing homes.
Encourages the use of electronic medical records with strong
privacy protections. Sets goal of having electronic medical records
for most Americans within 10 years.
Calls for an increase in National Institutes of Health funding
that would "improve the prevention, detection and treatment of
diseases;" opposes stem cell research except under tightly-constrained
circumstances.
Increases funding for bioterror preparedness efforts.
Supports legislation that allows medical professionals to work
together to share information with the anticipation of fewer medical
errors.
Senator Kerry
Supports legislation that would implement a Patient's Bill of
Rights, as well as mental health parity.
Provides financial incentives, like a "Technology Bonus," for
providers to institute electronic medical records, patient registries,
and computerized prescribing systems.
Supports efforts to reduce ethnic and racial disparities in
health care.
Requires private insurers to be using electronic medical record
technology if contracting with Medicare, Medicaid and for the Federal
Employee Health Benefits Program by 2008.
Supports stem cell research.
Creates "Quality Bonus" that moves toward a "pay-for-performance" system
to improve health outcomes and reduce errors.
Cost of plans and numbers of newly insured
President Bush
According to the U.S. Office of Management and Budget and the Treasury
Department, President Bush's health care plan costs $104.3 billion
over 10 years including the long-term care policies. The Administration
states these initiatives will cover 4 million to 6 million Americans.
According to Ken Thorpe of Emory University, President Bush's
plan costs $90.5 billion over 10 years, excluding the long-term
care provisions and Medicaid savings, and covers 2.4 million Americans;
however, the number of covered Americans will decrease because
the dollar value of the refundable credits decline over time.
Senator Kerry
According to Thorpe, Senator Kerry's health plan costs $653 billion
over 10 years and would increase the number of insured Americans
by 27 million. Senator Kerry has indicated that his plan would
be financed by repealing the tax cut that President Bush implemented
in 2001 for families with incomes above $200,000.
| Issues/ Positions |
HIV/AIDS Community |
President Bush |
Senator Kerry |
| Supports capped allotments/capped federal funding
for Medicaid |
No |
Yes |
No |
| Supports Medicaid state fiscal relief |
Yes |
No |
Yes, proposes $25 billion in first 2 years in office |
| Supports Early Treatment for HIV Act |
Yes |
Unclear |
Yes |
| Supports implementation of Medicare Modernization
Act as passed by Congress |
Part D formularies must include all HIV medications; must
contain other provisions that will help people with HIV/AIDS |
Yes |
Yes, with changes to ensure low drug prices for Medicare,
prevent retirees from losing coverage, and reduce HMO overpayment |
| Supports permitting the federal government to negotiate
drug prices for Medicare |
Yes |
No |
Yes |
| Supports reimportation and efforts to reduce cost
of prescription drugs by closing loopholes when generics
go to market |
Yes |
No |
Yes |
| Supports increased funding for the Ryan White CARE
Act |
Yes, CARE Act needs $3.1 billion to deliver services to all
people with HIV/AIDS in need of care |
Appropriated $2 billion in 2004. Budget calls for $35 million
increase in FY 05, which includes a $20 million emergency ADAP
allocation |
Yes, supports funding to "end ADAP waiting lists and provide
an appropriate standard of care;" funding level not specified |
| Supports tax credits for individuals |
Not a priority |
Yes |
Yes |
| Supports Health Savings Accounts |
No |
Yes |
No |
| Supports Association Health Plans |
No |
Yes |
No |
| Supports new Federal Employees Health Benefits Program
pool |
Yes |
No |
Yes |
| Supports premium rebate pool |
Unclear |
No |
Yes |
| Cost of plans |
N/A |
$90 billion – $105 billion over 10 years |
$653 billion over 10 years |
| Number of newly insured Americans 6 million |
N/A |
2 million to |
27 million |
CD4 Monitoring in Resource-Limited
Settings The State of the Art at Bangkok
By Bob Huff
With conventional CD4 T-cell counts and viral load tests all but
unaffordable for routine use in resource-poor settings where low-cost
antiretroviral medications are now being offered, there has been
a disorganized scramble to come up with alternative ways to monitor
therapy. One approach has been to simplify or modify existing technology
to squeeze out greater efficiency. Researchers have been experimenting
with generic versions of expensive reagents and test materials
and using them in smaller quantities to attain significant savings.
A major maker of laboratory-based cell counting equipment now offers
a rugged, battery powered unit that can be taken into the field
to perform CD4 tests. Less successful have been attempts to substitute
the easily obtained total lymphocyte count (TLC) for the far more
specific CD4 count. These adaptations, while helpful, still require
significant investments in equipment, training and maintenance.
What is needed, and what remains on the horizon, are low-cost ($2-$4)
technologies that leapfrog past existing systems to offer simple,
rapid, robust point-of-care diagnostics, similar to what is available
for diabetes or for detecting HIV antibodies.
At the International AIDS Conference in Bangkok, a generous handful
of posters and presentations found promise in some of these approaches
and put several nails in the coffin for total lymphocyte count
as a CD4 surrogate.
CD4 Counts!
The standard method for enumerating CD4 T-cells uses a flow cytometer,
a machine in which the cells of interest in a sample of blood
are tagged with fluorescent monoclonal antibodies and passed
in a single-cell column in front of laser light. When the light
illuminates a cell, the light is scattered in a pattern that
can be read by a photosensor to indicate the cell's size. Simultaneously,
when the laser light strikes an antibody, it glows brightly and
the cell is counted by a sensor attached to a microscope. Several
different antibodies are typically used to identify different
types of white blood cells. A computer calculates the number
of CD4 T-cells by analyzing the size of the cell and which of
the antibodies it has been tagged with. The overall process is
called fluorescence-activated cell sorting (FACS). CD4 counts
are expensive because FACS machines are expensive, the antibodies
are expensive and trained persons are necessary to perform the
tests and maintain the equipment.
A group of researchers loosely organized as the Afford CD4 Group,
led by Professor George Jannosy of London, have sought to simplify
cell sorting protocols and reduce the price per test by using generic, "home-brew" monoclonal
antibodies instead of commercial reagents.
Researchers in Thailand performed a quality comparison of state-of-the-art
two- and three-color cell sorting (using multiple monoclonal antibodies)
with a simplified protocol called panleucogating that can use just
one monoclonal antibody. However, this method only produces the
relative percentage of CD4 T-cells in the blood; determining the
familiar absolute CD4 count requires additional steps. They also
compared panleucogating using generic reagents with the same technique
using commercial reagents. Results from each of the methods correlated
well with the others for determining CD4 percentage in 142 HIV-positive
samples and 26 HIV-negative samples. The authors estimate that
panleucogating with generic reagents could reduce the cost per
test from $11.50 to $2.30 each. While these saving are significant,
this method still relies on an initial investment in equipment
that can run from $20,000 and up with expensive yearly maintenance
contracts. (Pattanapanyasat, B3087)
Researchers in Barbados compared a panleucogating protocol to
a sophisticated four-color method of cell counting using commercial
monoclonal reagents. The coefficient of correlation was a respectable
0.97 over the entire range of counts (25 to 989 cells/mm3).
The authors conclude that panleucogating is "an accurate method
for enumerating CD4 T-cells and has major cost implications for
the sustainability of the National HIV containment program in Barbados." (Sippy,
B3108)
Flow Show
With its cute and compact off-road vehicle on display, the Cyflow
booth was a popular spot on the commercial exhibition floor of
the International AIDS Conference. Partec Inc., a manufacturer
of lab-based cell counting equipment, makes a portable flow cytometry
system called Cyflow that is designed for use in resource-limited
areas. The machine is less expensive and more robust than conventional
FACS systems, uses less expensive reagents, and is able to produce
an absolute CD4 count without additional instrumentation. The
trade show exhibit demonstrated a complete, mobile CD4 counting
lab, ready to roll into the bush. Cyflow is able to produce an
absolute CD4 T-cell count using two monoclonal reagents. Several
posters at Bangkok evaluated the quality of the Cyflow system.
Researchers in Cambodia evaluated the precision of the Cyflow
system by performing multiple repeated counts of the same samples.
They also performed comparisons of results produced by Cyflow with
those produce by a lab-based FACS. The coefficient of variance
for the precision of the machine varied between 2.8% and 4.9%.
The correlation with FACS was very high, with the Cyflow tending
to undercount by about 20 cells on a mean CD4 count of 289. The
system detected CD4 counts below 200 cells/mm3 with
sensitivity of 100% and a positive predictive value of 97%. (Teav,
B3089)
Researchers in Thailand compared Cyflow with two different FACS
systems (3-color FACScan and 2-color FACScount) and reported high
correlation between the results, with Cyflow producing mean counts
41.5 and 18.0 cells/mm3 lower than the two FACS systems
in the range of 100-300 CD4 cells/mm3. The authors note
that Cyflow offers advantages in cost and sample preparation, "but
it requires technical expertise." (Pattanpanyasat, B3176)
In Malawi, investigators compared Cyflow to FACS on 311 blood
samples. The mean difference in CD4 counts by Cyflow was -8.68
cells compared to FACS, with a correlation coefficient of 0.92.
The authors note that "local district laboratory staff found the
Partec machine easy to manipulate and robust under routine field
conditions." (Fryland, B1149)
Researchers in Rwanda compared results from Cyflow (4-parameter,
direct volumetric counting) with FACS (bead-based, FACScount) on
samples from 73 HIV-positive pregnant women. Mean CD4 counts were
346 cells/mm3 with FACS and 377 cells/mm3 with
Cyflow. (Jervais, B3172)
One limitation of performing CD4 counts in resource-limited settings
is that there may be a significant time lag between when samples
are collected and when they finally reach a testing facility. Researchers
in Cambodia compared CD4 counts obtained by Cyflow on samples collected
the same day and on EDTA-preserved samples kept at room temperature
(<30C) for 4 days. In 27 samples tested, the correlation between
fresh blood and aged blood was high, with aged blood samples tending
to come in about 5 cells lower on a mean CD4 count of 241. (Teav,
B3110)
No Flow Slow Go
Dynabeads is a low-cost, low-throughput, method of counting CD4
cells that does not rely on expensive flow cytometry equipment.
CD4 cells are tagged with the Dynabeads and counted under a conventional
light microscope. Researchers in Japan compared a simplified
Dynabeads protocol to FACS in samples from 242 patients. The
correlation coefficient between the methods was 0.91, sensitivity
of 79% and specificity of 94% for samples below 200 cells/mm3.
Sensitivity improved to 97% with samples above 350 cells/mm3.
The authors estimate the cost of Dynabeads and other disposable
materials to be less than $3.00 per test. While this price is
attractive and equipment needs are not forbidding, this technique
relies on operator expertise and its precision is subject to
operator fatigue. Not a satisfying solution. (Bi, B2038)
Total Lymphocyte Washout
The practical value of using total lymphocyte count (TLC) as a
surrogate for absolute CD4 cell counts in adults came in for
hard knocks from nearly every study that evaluated it. One focus
of inquiry is to find what "cut-off" value of TLC corresponds
to the all-important CD4 cell count of 200, which signals the
advent of AIDS and an urgent need for OI prophylaxis and ART
therapy. Currently, the World Health Organization says that TLC
of 1200 cells/mm3 should be the key number, although
these reports call that into question.
CD4 counts were correlated with TLC for 747 participants in HIVNAT
clinical trials in Thailand to determine the value of TLC for monitoring
response to ART. Samples were collected at baseline and at weeks
12, 24 and 48 after beginning ART. Of 3578 paired samples, 29%
had CD4 <200 cells/mm3. At baseline, TLC <1200
cells/mm3 had a sensitivity of 40% for predicting CD4 <200
cells/mm3 (specificity = 94%). Sensitivity was reduced
to only 20% at week 48. "Thus, TLC is clearly not a good surrogate
marker for monitoring HAART." (Ruxrungtham, B3154)
Researchers in Bahia, Brazil evaluated paired CD4 and TLC for
498 patients during May to December 2003. A TLC cutoff of 1000
cells/mm3 predicted CD4 count <200 cells/mm3 with
sensitivity of 44% (specificity = 98.5%) and had a positive predictive
value of 70.2%. Raising the cutoff to TLC <1500 cells/mm3 improved
sensitivity to 76.9%, although the positive predictive value at
this level was only 38.7%. The authors conclude that TLC estimates
of CD4 counts for monitoring HAART are inaccurate. (Angelo, B3164)
Researchers in Jakarta, Indonesia evaluated 1062 paired CD4 and
TLC results obtained between January 2002 and September 2003. Of
355 samples with TLC <1200 cells/mm3, 81% had CD4
counts <200 cells/mm3, while 20% of samples with
TLC >1200 cells/mm3 had CD4 counts <200 cells/mm3.
The authors conclude that if TLC alone were used to determine when
to start ART, "then 39% of HIV infected Indonesians would be misclassified." (Donegan,
B3177)
Researchers in Malvinas Argentinas, Argentina evaluated paired
TLC and CD4 counts from 66 patients. While TLC <1500 cells/mm3 significantly
predicted CD4 <200 cells/mm3 (p=0.01), sensitivity
was 65% and specificity was 69%. With a cutoff of TLC <1200
cells/mm3, sensitivity was 50% (specificity = 89%) and
with a cutoff of <1000 cells/mm3, sensitivity was
45% (specificity = 93.4%). The authors find that the sensitivity
and specificity of TLC to predict CD4 cell counts <200 cells/mm3 is
low, although lower cutoffs improve specificity. (Hojman, B7219)
Based on paired FACS and TLC data from 2419 patients, researchers
in Pune, India derived an equation (CD4 = 0.24*TLC-5.97) to calculate
CD4 counts using TLC values. They found that TLC was significantly
correlated with CD4 (r=0.43; p<0.001). Using a TLC cutoff of <1500
cells/mm3 predicted CD4 counts <350 cells/mm3 with
sensitivity of 72% and specificity of 78%. The positive predictive
value was 79% and negative predictive value was 91%. However, for
CD4 counts <200 cells/mm3, the equation was only 49%
sensitive. (Thakar, B3105)
In Sagamu, Nigeria, investigators collected blood samples from
64 patients during a one year period ending in September 2003.
CD4 counts were evaluated by FACS and by Dynakit, and TLC was calculated.
While FACS and Dynakit were significantly correlated (r=0.831;
p=0.001), TLC did not correlate with either method (FACS: r=0.061;
p=.573). The authors conclude that TLC "is not a reliable substitute
for CD4 countÉin this resource-limited setting." (Osho, B3096)
The one report to speak favorably of TLC also found fault with
the CD4 count when it came to spotting opportunistic infections
(OI).
Researchers at a major London, England hospital retroactively
identified all patients with an AIDS-defining opportunistic infection
(n=1097) to see if CD4 counts or TLC within the three months prior
to the illness was more predictive of having an OI when compared
to patients who did not develop OIs. TLC was significantly correlated
with CD4 count (r=0.70; p<0.001) and the optimal cut-off for
TLC was 1500 cells/mm3. While patients with TLC between
1000 and 1500 were 40% more likely to have an OI than those above
1500 (sensitivity = 68.6%; specificity = 75.6%), when using the
CD4 count cutoff of 200 cells/mm3, those with CD4 between
150 and 200 were only 34% more likely to have an OI (sensitivity
= 73.8%; specificity = 75.6%). The authors conclude that while
CD4 <200 cells/mm3 is taken as the "gold standard
for therapeutic intervention, this has relatively low specificity/sensitivity
and results suggest that TLC is only moderately less reliable." (Jones,
B3120)
Symptomatic Erratic
Another report found value in TLC only when it was paired with
careful clinical evaluation. Researchers in Kampala, Uganda evaluated
paired TLC and CD4 results along with clinical features in 202
patients enrolled between June 2002 and November 2003. The correlation
between TLC and CD4 was significant (r=0.72; p<0.0001). TLC <1200
cells/mm3 predicted CD4 count <200 with a positive
predictive value of 100% (negative predictive value = 32%), although
this cutoff identified only 63 of 137 patients with WHO stage
2 or 3 and CD4 counts <200 cells/mm3. The authors
conclude that despite a good correlation between the methods, "it
requires a combination of TLC and clinical features in an algorithm
to identify patients with CD4 cell counts less than 200 cells/mm3 in
Uganda." (Semitala, B4531)
There has been some interest in quantifying the success of making
treatment decisions based on symptoms and clinical features, such
as weight gain after starting ART. Yet the limits to this are apparent.
Researchers from the Centers for Disease Control (CDC) in Atlanta,
Georgia investigated if weight gain could serve as a surrogate
marker for response to ART by reviewing medical records from 709
patients with weight measurements at the time of and subsequent
to beginning ART. Overall, the cumulative probability of having
at least a 10% weight gain at 12 months was 0.15. The probability
was increased in those starting ART with <200 CD4 cells/mm3 (0.31)
and for those starting ART with BMI <20 (0.33). Although weight
gain of 10% or more occurred in about one third of patients with
low CD4 counts or low BMI, weight gain was not correlated with
viral load reduction. The authors conclude that "weight gain following
HAART initiation does not necessarily mean that there is virologic
improvement." (Teshale, B3101)
Researchers in Uganda operating an ART program evaluated methods
of screening for eligibility for therapy in 907 patients. Patient
history, review of records, and physical exam to determine CDC
Class C and B symptoms as well as other signs of HIV disease were
performed. Following screening, CD4 counts were obtained and compared
to clinical findings. Of 376 patients with CD4 counts <200 cells/mm3,
39% met the clinical criteria for starting ART and 91% of those
with CD4 counts >200 did not meet the criteria. The sensitivity
of the clinical criteria was 39%, specificity was 91% and the positive
and negative predictive values were 76% and 68%, respectively.
The authors conclude that CD4 testing would be important to detect
the two thirds of patients who qualify for starting ART. (Solberg,
B2035) There seems to be no good way around having an absolute
CD4 count in hand to make decisions about when to start therapy
and to monitor response to therapy once it has begun. Some recent
innovations seem to provide acceptable results with significant
cost savings. Yet they fall short of an ideal solution to the need
for low-cost, point-of-care monitoring. To get the most out of
the expected scale up of treatment in the coming years, a breakthrough
in diagnostic technology must be made a priority.
References (all The XV International AIDS Conference,
2004):
Angelo ALD, et al. Evaluating the absolute lymphocyte count
as a substitute for CD4 count in the follow up of AIDS patients
under HAART. Abstract MoPeB3164
Bi X, et al. Modifications of dynabeads method for enumerating
CD4+ T cell count in resource-limited situations. Abstract
TuPpB2038
Donegan E, et al. Preliminary report on absolute lymphocyte
counts as an indicator for anti-retroviral treatment in Indonesia.
Abstract MoPeB3177
Fryland M, et al. The PARTEC CyFlow counter for CD4+ T-cell
counting produces high quality results and is robust when
evaluated under routine field conditions in Malawi. Abstract
TuOrB1149
Hojman MA, et al. Total lymphocyte count and Initiation
of highly active antiretroviral therapy in resource-limited
settings. Abstract ThPeB7219
Jones R, et al. A Cohort Study To Review The Efficacy of
Total Lymphocyte Count (TLC) as a Predictor of AIDS defining
Opportunistic Infection (ADOI) In HIV Infected Patients.
Abstract MoPeB3120
Osho OB, et al. Absolute lymphocyte count as a substitute
for CD4 count in a limited resource area; Sagamu, Ogun state,
Nigeria. Abstract MoPeB3096
Pattanapanyasat K, et al. Generic reagents and the PanLeucogating
protocol: Is this the way towards affordable CD4 enumeration
in Thailand? Abstract MoPeB3087
Pattanapanyasat K, et al. Evaluation of a new single-platform
volumetric flow cytometer for enumeration of absolute CD4
T-lymphocyte counts in HIV-1 infected Thai patients. Abstract
MoPeB3176
Ruxrungtham K, et al. Total Lymphocyte Count (TLC) is not
a good surrogate marker for Monitoring Antiretroviral Therapy
(ART) in HIV-1 infected Thai patients: HIVNAT cohort analysis.
Abstract MoPeB3154
Semitala FC, et al. Total lymphocyte count of 1200 is not
a sensitive predictor of CD4 lymphocyte count among patients
with HIV disease in Kampala, Uganda. Abstract TuPeB4531
Servais J, et al. Comparison of two flow cytometry methods
for the determination of CD4 counts in Rwanda: RWA/021 TRAC/NRL
project, Lux Development. Abstract MoPeB3172
Sippy N, et al. Comparison of the Panleucogating technique
with four-colour heterogenous gating for CD4+ T cell enumeration
in HIV infected individuals in Barbados. Abstract MoPeB3108
Solberg P, et al. Comparison of clinical criteria and CD4
cell counts to determine eligibility for antiretroviral therapy
in Uganda. Abstract TuPpB2035
Teav S, et al. Alternative CD4 counting using Cyflow in
Cambodia: precision and comparison with Facscount. Abstract
MoPeB3089
Teav S, et al. CD4 lymphocyte counts with Cyflow in Cambodia:
stability of sample results over time. Abstract MoPeB3110
Teshale EH, et al. Can weight gain be used as a marker for
viral load response in HIV-infected patients following initiation
of highly active antiretroviral therapy (HAART)? Abstract
MoPeB3101
Thakar MR, et al. Absolute lymphocyte count is a useful
marker of HIV-1 disease progression in HIV-1 imfected Individuals
in Pune, India. Abstract MoPeB3105
|
The Past, The Present and
The Future
By Charles Clifton
1959 – 2004
I'm tired from "tops" who believe they can't contract HIV. I'm
tired from "bottoms" who c ontinue to roll the dice. I'm tired
from irresponsible HIV-positive barebackers. I'm tired from irresponsible
HIV-negative barebackers. I'm tired of the belief that barebackers
are always gay men. I'm tired, because it ain't true. I'm tired
of condoms. I'm tired for everyone waiting for the results to come
back from an HIV test. I'm tired.
I'm tired for intravenous drug users who share contaminated needles.
I'm tired for men who refuse to use a condom. I'm tired for the
women and men forced to have sex with men who refuse to use a condom.
I'm tired for sex workers who can't use a condom. I'm tired for
young people who don't have sex education. I'm tired of prevention
that doesn't seem to work. I'm tired.
I'm tired from individuals who promote conspiracy rather than
care. I'm tired from those who don't believe in re-infection. I'm
tired from medications that make people sick rather than well.
I'm tired from people who could, but don't, adhere. I'm tired for
everyone in America, Africa, Asia and Eastern Europe who would
adhere, but can't. I'm tired from a system that profits from homelessness,
hunger and mental illnesses. I'm tired from illiteracy. I'm tired.
I'm tired from some that believe women and children, the incarcerated
and drug users don't deserve our attention. I'm tired because some
believe that gay men don't deserve our attention. I'm tired from
blacks that blame whites. I'm tired from whites that blame blacks.
I'm tired from men who blame women. I'm tired from women who blame
men. I'm tired from MSMs, SAMs, "trade" and "on the downlow." I'm
tired of categories. I'm tired.
I'm tired of incompetent negatives. I'm tired of unqualified positives.
I'm tired of bureaucracy. I'm tired of cynics. I'm tired of the
hypocrites. I'm tired of the dishonesty. I'm tired because I don't
know what to do. I'm tired of being stressed, depressed, and overwhelmed.
I'm tired because I don't have time to do more. I'm tired because
I don't feel like doing more. I'm tired.
I'm tired from Slavery. I'm tired from Emancipation. I'm tired
from Jim Crow. I'm tired from Civil Rights, Women's Rights, Gay/Lesbian
Rights and now Healthcare Rights. I'm tired from prejudice and
hatred. I'm tired from ignorance. I'm tired that mistakes from
the past continue to be repeated. I'm tired.
I'm tired from John F. Kennedy, Martin Luther King, Jr., Robert
Kennedy and my father. I'm tired from the events of September 11,
2001. I'm tired for this nation. I'm tired for this world. I'm
tired for everyone who has ever lost someone to a senseless act
of violence. I'm tired for everyone who will lose a loved one in
the coming days, weeks and months.
I'm tired of grieving. I'm tired of remembering. I'm tired of
wondering. I'm tired that I still grieve the death of Antonio,
who died 15 years ago on October 8th. I'm tired of marking the
anniversary of his death. I'm tired of wondering of what might
have been. I'm tired of hoping. I'm tired of coping. I'm tired
of dates that always remind me of how tired I am. I'm tired of
wondering what's next, who's next. I'm tired of this road.
I'm just tired.
Charles E. Clifton
From: Editor's Note
Positively Aware
November/December, 2001
Charles Clifton was the executive director of Test Positive
Aware Network in Chicago. He was also editor of Positively Aware,
TPAN's excellent journal of HIV treatments issues. Charles was
on the steering commitee of the AIDS Treatment Activists Coalition
(ATAC); chaired the community advisory board of the Retrovirus
Conference; and chaired the executive committee of the North
American Treatment Action Forum (NATAF).
© 2004 Gay Men's Health Crisis
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