| 
Past Issues
Volume 17, number 4
April 2003
Contents
No-Care Equals Bad Care: A Talk
with Sam Bozzette
Formidable challenges for providers lie ahead
Testing HIV-Positive in New
York City:2001 HIV/AIDS Surveillance Report
High rate of concurrent HIV & AIDS in NYC numbers
HIV Pathogenesis Reports From
the 10th Retrovirus Conference
HAART to Heart Talk
Continued controversy over HAART-related vascular disease risk
ConFuzeon Reigns
More details of Roche's T-20 distribution plan
A Report on the International
Treatment Preparedness Summit
You Have HIV… And You
Have AIDS
Why are so many people coming so late to care?
No-Care Equals Bad Care
A Talk with Sam Bozzette By Bob Huff
Much of your research has focused on the systems through which
people receive medical care and how those systems affect the actual
outcomes of care in terms of, say, fewer hospital days or improved
quality of life. In a broad sense, this kind of research is part
of a trend to patient-centered care, in which those being treated
are considered an integral part of the health care system. Where
does this interest come from, why is it especially significant for
HIV, and where does it lead?
I am an admirer of the patient-centered care movement and its
ethical roots in the principle of respect for autonomy; respect
for the person. In a way it's similar to the principle of patient
satisfaction. Not satisfaction with the amenities of the care, but
whether people receiving care felt they were being treated with
the respect they deserved; that people felt providers were putting
their interests ahead of, say, business considerations; and that
people felt they were being given enough information to participate
in decisions regarding their care in an appropriate fashion. These
all flow from the principle of respect for the person.
Another thread woven into patient-oriented care is the idea of
the activated patient, which came out of work that had been done
around the role of the patient in the so-called chronic disease
model. At some point someone realized that people with chronic diseases
spend only a small slice of their lives in contact with the health
care system. The rest of the time they're managing themselves. Of
course the fifteen minutes or half-hour spent with the provider
each month is a very powerful and important vignette, but it's still
only a vignette. The rest of the time they may be very much on their
own. You see this in diseases like diabetes where people have relatively
unstable blood sugars and are continually reacting to the measurements
they take. Imagine if HIV replication were that dynamic and you
had a viral load test that you could do at home. HIV is very dynamic
but it doesn't respond to eating an ice cream cone. Or as another
example, if people with high blood pressure decide to stop their
drugs or go off their diet, they may have heart failure. But they're
tasked with the day-by-day managing of their disease. So this idea
of the activated patient is another thread in the patient-centered
care movement.
My interest in the broader outcomes of care initially came out
of a desire to rationalize medical decision-making. In the early
days of HIV care before we had effective drugs, we didn't have a
lot going for us. Those were truly the bad old days. But in a perverse
way, because we didn't have anything, we didn't have the burden
of history to hamper us. We didn't have to worry about what our
teacher's teachers had said about HIV — they'd never heard
of it. And since there was no constraining tradition, we were able
to ask, "How are we going to make rational decisions with this
disease?" You see, when you make a rational decision you're
trying to optimize something. In those days we knew we certainly
weren't going to fix anybody — we didn't even expect to get
somebody to retirement age. So, what was there to optimize? We wanted
to help people get as much as they could out of what they had in
the time they had left. It seemed to us that we needed to start
looking at a broader range of outcomes and considerations —
including the drawbacks of taking medications, such as what side
effects were happening and how the side effects made people feel.
In the 1980s, when we were doing the early AIDS clinical trials,
we were using toxicity grading scales from oncology research. I'd
look at these things and see that Grade 4 organ toxicity was defined
perhaps as some enzymatic test ten times the upper limit of normal.
Then I'd look at Grade 2 nausea and see something like: "Requires
frequent powerful antiemetics." So I'd think, okay, one of
these is a serious reportable reaction and the other is not considered
serious or reportable. But if I had a relatively limited time on
this earth, which would I rather have? Grade 3 diarrhea was defined
as something like: "Persistent despite continuous medication."
This was Grade 3 — how could Grade 4 be any worse? So that
made many of us think that maybe we should be incorporating some
of these broader outcome measures that took a person's quality of
life, ability to function, and the efficiency of care into account.
This kind of thing had mostly been used in population-based research,
although people were starting to use them in clinical trials for
heart disease, some cancers, and a few other diseases, and we began
talking about using them in HIV.
Obviously, a lot has changed since then, and even though we're
doing a whole lot better in keeping people alive, there's still
no magic bullet and people are still struggling with tradeoffs.
But I believe we're all thinking about the tradeoffs much more clearly
these days. If you look at the federal HHS Treatment Guidelines,
the sections about when to start treatment and what to use are impressively
sophisticated with respect to the notion of tradeoffs. And when
you look at the innovation that's come from our major clinics —
the antiretroviral adherence programs, directly observed therapy,
the beepers, and so on — it's very impressive. I also think
that community-based and provider-based efforts at educating people
living with HIV, whether on therapy or simply being monitored prior
to taking therapy, have been impressive. A remarkable number of
people with this disease in this country are incredibly well-informed.
Every survey shows that information levels are very high —
and it's not like that for every disease by any means. If you look
at the accuracy of information that people have about HIV, particularly
people who are managing their own HIV, it's very impressive. These
are all real advances.
So where is all this going in the future? I think there are two
large challenges looming. I think the focus on activating, educating
and involving patients needs to continue, because getting patients
involved in decision-making, on their own and as a community, has
paid tremendous returns. It's given us great gains over the past
ten years, and it needs to continue, but that's not where the biggest
gains up ahead are going to come from. I think there are two other
fronts where we have much more to accomplish and a great deal to
gain. First, I think it's a given that we need more antiretroviral
agents and hopefully a vaccine. So, assuming an atmosphere of continued
investment in developing therapeutic and prophylactic technologies,
it seems to me that some kind of assistance with physician decision-making
will inevitably be needed. I think the amount and complexity of
information that clinicians will have to process is going to start
running ahead of anyone's ability to grasp. I worry about this because
we know that physician experience and training are linked to good
outcomes. Here in this hospital we have Doug Richman, one of the
world's experts in virology. If you've got a patient with this or
that mixture of resistance, you can go ask Doug what to do. But
not everybody has that resource, so when the time comes that there
are twenty to thirty drugs to choose from, how will providers decide
what to do? I believe assisting physician decision-making is going
to be a big challenge and addressing it will produce important gains
in the quality of care people receive in the future.
But the biggest challenge is going to be getting more people into
care. Data seems to show that people are coming into care too late,
and that many of the people who die from HIV do so either without
benefit of treatment or very shortly after their initial diagnosis.
With all of these new technologies you'd think that we would be
preventing AIDS. Why are people being reported with HIV and then
turning up with AIDS six months later? Why are people still dying
so soon after being discovered to be positive? It's because they're
not in care. Too many people in this country are not in care, and,
if you think about it, not having care means poor quality care.
Even someone who is found to be infected but doesn't have indications
for treatment still deserves knowledge, deserves monitoring, and
has a right to care. The lack of care is bad care.
To me the biggest unaddressed concern for patient-centered care
is the no-care patient. A substantial number of people who are getting
no care — it's not clear how many this is — are actually
people who know of their infection. I think I've seen estimates
that roughly half of people with HIV who are not in care actually
know their status. And those people fall into two groups: first,
the people who find out their status and then flee, because they're
scared or in denial. And the other group are people who have bad
access for some reason. Maybe they enter a system and they have
a bad experience. Perhaps they're plugged into some health care
system that's not particularly sophisticated about HIV; they're
not handled appropriately, they feel shunned or they feel disrespected
or discriminated against, and they just don't go back. Or maybe
they're in a traditionally underserved population and have poor
access to begin with. They might get emergent care for some reason
and are tested, but there is no provision for ongoing care. They're
told that they're HIV positive and they're told that they should
be in regular care, but there's no system to deliver them the care.
So, we've got to do something. We've got to encourage people to
come forward. We have to do this in ways that respect privacy and
respect autonomy and are not coercive. Reporting or testing programs
alone aren't the answer. That's just surveillance — which
is useful — but it's not the same thing as care. People can
find ways to know their status, but you still need to let them know
that it's good for them to be in care, even if being in care simply
means being checked out now and then. Hook them up. I'm not talking
about drugs or chemotherapy for everybody; I'm just talking about
some system where they can get monitoring and get good information.
And when they're ready for treatment, they can get that too.
So I think that getting people with HIV involved and optimizing
their care was a huge victory. Making sure that the choices don't
run ahead of patients' and providers' abilities to make good therapeutic
choices is becoming an increasingly urgent priority. But I firmly
believe that the biggest priority, in terms of unmet need, is taking
care of people who have no care. I'd like to see the community —
everybody — take up that challenge.
Samuel A. Bozzette, MD, PhD is affiliated with the UCSD School
of Medicine, the Veteran Affairs San Diego Healthcare System and
the RAND Institute.
| The Long-Term Safety
Problem: Seeking an Answer in Large Database Studies
Large administrative database studies have a great potential
for detecting the rare drug-related adverse event. These are
things that aren't going to pop up in relatively small, relatively
short-term clinical trials, which is the way HIV drugs are
typically approved. Approval based on short-term data has
worked to our benefit, I think. Yet, as more drugs become
available, a return to risk aversion may be on the horizon.
I hear people in Europe saying that maybe 48-week drug trials
are not long enough; that maybe we should be talking about
two-year or three-year phase III trials. Nevertheless, many
people believe that somehow, some other kind of study has
to start looking for the kind of things we all agree we would
care about if we knew were drug-related adverse effects.
So, can we do that without subjecting a drug to the very
long trial that it would take to pick up that rare effect
in a traditional clinical trial? There are going to be rare
adverse events occurring in real-world usage that would take
a really long, really huge Phase III clinical trial to pick
up — if it ever did. Subjecting new drugs to such long
studies would profoundly decrease our ability to get new drugs
into the clinic. And it would have the more subtle effect
of discouraging investment. The worst thing anybody could
do would be to make pharmaceutical executives think that investing
in HIV is a bad idea. And if it looks like concerns about
toxicity are going to push people do longer or bigger trials,
it's going to make drug companies believe that it's going
to be tougher to get these drugs approved.
Potentially, a system where large living databases like the
VA's supplements data from traditional trials could help reassure
people about safety without putting pressure on pivotal clinical
trials to be longer and bigger than they need to be to prove
effectiveness and reasonable safety. – SB |
Testing HIV-Positive in
New York City
2001 HIV/AIDS Surveillance Report
HIV and AIDS in New York City: An Overview
- As of March 31, 2002, 76,504 New Yorkers were diagnosed and
known to be living with HIV or AIDS.
- An estimated 25,000 additional people are living with HIV but
have not yet been diagnosed.
- 1.7% of blacks, 1.1% of Hispanics and 0.6% of whites are diagnosed
and known to be living with HIV or AIDS.
- 14,200 New Yorkers have been diagnosed with HIV since HIV reporting
began in New York State on June 1, 2000.
- A cumulative total of 133,171 New Yorkers have been diagnosed
with AIDS since AIDS case reporting began in 1985.
- 4,905 AIDS cases were diagnosed in 2001.
- The cumulative number of known deaths among reported AIDS cases
is 80, 524.
- The number of deaths among reported AIDS cases declined by
16% between 2000 and 2001.
- Over 26% of people diagnosed with HIV during 2001 received an
AIDS diagnosis within 31 days.
- Diagnoses of HIV concurrent with AIDS occurred significantly
more frequently among males, blacks and Hispanics, and in older
persons.
- 35% of HIV diagnoses were among women.
- More than 80% of all HIV diagnoses, AIDS diagnoses, and deaths
occurred among blacks and Hispanics, although these groups make
up only 52% of the population.
| HIV diagnoses during 2001 |
| |
Total with HIV |
Without AIDS |
With AIDS |
| Total |
6,779 (100%) |
4,978 (73.4%) |
1,801 (26.6%) |
| |
|
|
|
| Male |
4,414 (65.1) |
3,173 (63.7) |
1,241 (68.9) |
| Female |
2,365 (34.9) |
1,805 (36.3) |
560 (31.1) |
| |
|
|
|
| Black |
3,633 (53.6) |
2,604 (52.3) |
1,029 (57.1) |
| Hispanic |
2,012 (29.7) |
1,509 (30.3) |
503 (27.9) |
| White |
1,015 (15.0) |
778 (15.6) |
237 (13.2) |
| Asian/Pacific Islander |
93 (1.4) |
64 (1.3) |
29 (1.6) |
| Native American |
9 (0.1) |
7 (0.1) |
2 (0.1) |
| Unknown |
17 (0.3) |
16 (0.3) |
1 (0.1) |
| |
|
|
|
| Age 0–12 |
64 (0.9) |
62 (1.2) |
2 (0.1) |
| 13–19 |
132 (1.9) |
116 (2.3) |
16 (0.9) |
| 20–29 |
1,049 (15.5) |
874 (17.6) |
175 (9.7) |
| 30–39 |
2,447 (36.1) |
1,847 (37.1) |
600 (33.3) |
| 40–49 |
1,991 (29.4) |
1,389 (27.9) |
602 (33.4) |
| 50–59 |
816 (12.0) |
523 (10.5) |
293 (16.3) |
| 60+ |
280 (4.1) |
167 (3.4) |
113 (6.3) |
Source: HSEP Quarterly Surveillance Report, Vol.
1, No. 1, January 2003. Maps reprinted with the permission of the
NYCDOHMH.
Copies of the full report are available at: www.nyc.gov/html/doh/html/pub/pub.html
Or request a copy from hivreport@health.nyc.gov
HIV Pathogenesis Reports From
the 10th Retrovirus Conference By Jo Ann Berg
The 10th Annual Retrovirus Conference held recently in Boston featured
several presentations on novel ways to look at HIV pathogenesis
(how the virus causes disease) and how the virus might evade attacks
by each of the three main immune defense systems: cell-mediated,
humoral and innate immunity.
Problematic Proliferation
Dr. Marc Connors of the National Institute of Allergy and Infectious
Diseases (NIAID) in Bethesda, Maryland, reviewed his group's recent
study on long-term nonprogressors (LTNPs) with HIV, and suggested
"a new paradigm for the loss of immune control of HIV."
It's been commonly held that most people with HIV are unable to
maintain immune control over the virus because they lack a sufficient
number of CD8 (or cytotoxic) T cells (CTLs). As an important component
of cell-mediated immunity, CTLs function mainly to find and kill
cells infected with pathogenic invaders such as HIV [see
note 1]. However, after comparing LTNPs with more rapid progressors,
Dr. Connor's group found no difference in CD8 T cell quantity —
but they did find qualitative differences. They reported that CTLs
from the nonprogressors proliferated (rapidly divided) when exposed
to HIV-infected cells, whereas the CD8 T cells from the progressors
did not divide.
In addition, the CTLs from the LTNPs made large amounts of perforin,
a substance that is crucial for the ability of CTLs to kill infected
cells [see note 2]. Dr. Connors
stressed there was no defect in perforin per se, since the few CTLs
from faster progressors that did proliferate were also able to produce
perforin. In other words, the two functions are coupled, so CTLs
that don't divide don't upregulate their expression of perforin,
and consequently can't destroy infected cells.
His group further found that the non-dividing CTLs seem to be
permanently stuck in this mode, since no matter how they tried to
stimulate them in the laboratory, the cells would not divide and
produce perforin. Dr. Connors presented two models that might explain
the intransigence of the non-proliferating CTLs: first, the cells
may not be receiving all of the necessary signals they need to differentiate
and divide [see note 3]. Alternatively,
the cells may have divided so many times they are "burnt out"
and hence too tired or old to divide any more, a condition known
as replicative senescence.
Connors concluded that a successful vaccine or treatment needs
both to drive CTLs to proliferate and to prevent them from "qualitatively
changing" to the non-proliferating mode.
The Evolving Glycan Shield
Whereas CTLs are a component of cell-mediated immunity responsible
for destroying HIV that's already inside of cells, the other arm
of the adaptive immune system is called humoral (from the Latin
for liquid) and patrols the environment outside of cells. This arm
of the immune system consists primarily of antibodies that are secreted
by B cells and are carried in blood plasma (the portion of blood
containing only liquid and no cells) [see
note 4]. Antibodies are supposed to take care of newly replicated
virus looking for cells to attack, but HIV seems somehow able to
escape their grasp. Dr. George Shaw of the University of Alabama
in Birmingham presented new evidence for a model of how HIV might
resist antibody attack, although he noted that this model might
be but one of several possible mechanisms of antibody-resistance
[see note 5].
Contrary to some studies that have detected only small amounts
of slowly developing anti-HIV antibodies, Dr. Shaw said his lab
saw "massive amounts" of anti-HIV antibodies developing
within only ten weeks after HIV infection. But although these anti-HIV
antibodies were able to neutralize (prevent the virus from doing
harm) HIV and lower viral load, viral mutations soon allowed HIV
to "escape" the neutralizing antibodies (NAbs).
Surprisingly, Dr. Shaw found that few of the anti-HIV antibodies
were directed to sites, or epitopes, on viral proteins that are
the usual neutralizing antibody targets on other viruses, such as
those involved with the attachment of the virus to cellular receptors.
Instead, the anti-HIV antibodies were directed to parts of the virus
that bind glycan (sugar) molecules to its surface. (The antibodies
don't directly attack the sugar molecules since the same sugars
also coat many of the body's natural proteins; such antibodies would
cause an autoimmune reaction.)
Dr. Shaw also showed that antibody-containing blood plasma taken
from an individual at later stages of infection was better able
to neutralize virus collected from the same person at an earlier
stage of infection than it was contemporary viral isolates or virus
that developed months later. For example, virus from the 16th day
after infection was neutralized by plasma from day 212 far more
effectively than by plasma from day 16. Plasma from day 16 had no
effect on virus from day 212. This indicates that vulnerable epitopes
in early viral isolates had somehow become protected over time.
It's long been known that HIV is heavily coated with sugars and
some have speculated that the sugars keep the viral binding sites
covered until just before they're ready to attach to a cell. Yet
Dr. Shaw found that none of the sugars on HIV were directly covering
the virus' attachment proteins. Rather, many widely spread glycans
somehow "cooperatively pack over the entire envelope spike
to prevent" antibody access through steric (spatial) hindrance.
Steric hindrance produces a kind of force field barrier that blocks
antibodies from contacting their epitopes on the attachment proteins.
It also means that the "glycan canopy" would only need
to partially overlap those epitopes to prevent antibody access.
Since most of the HIV mutations that Dr. Shaw observed were associated
with its sugar binding regions and not its cell attachment sites,
he proposed that the "cooperatively packed" glycans continually
evolve (change) into ever-denser packs. In this way they would deter
any newly arising antibodies, yet not prevent HIV from efficiently
attaching to its target cells. Shaw dubbed this an "evolving
glycan shield."
If this was the case, he suggested, then the evolved HIV resistance
to antibody attack was not a generalized resistance, but rather
the virus' adaptation to each individual's specific antibodies directed
at the sugar binding sites [see note
6].
In his summation, Shaw noted the surprisingly large number of antibodies,
as well as the unexpected occurrence of viral escape mutations at
sites other than the common neutralizing epitopes. He concluded
that vaccine-induced anti-HIV antibodies would likely not have much
impact after acute infection; but he held out hope they might help
prevent a new infection from being established since both the inoculum
and efficiency of sexual transmission of HIV are low.
Fauci Ties it All Together
No Retrovirus Conference seems complete without a talk on HIV pathogenesis
by Dr. Tony Fauci, director of the NIAID. This year he presented
studies comparing the effects of low (i.e., undetectable) viremia
and high viremia on three different types of immune cells: latently
HIV-infected CD4 T cells, B cells, and NK or natural killer cells.
First he showed how his lab used a new biological tool called a
microarray gene chip to compare which genes are expressed (turned
on) in latently infected CD4 T cells, depending on whether the "latent"
cells come from a person with undetectable viremia or high viremia.
His research group found that high viremia resulted in latently
infected cells expressing many genes whose protein products helped
the cells "to be permissive for the production [and release
from the cell] of HIV." He said the upregulated genes were
not caused by broad, non-specific activation of the latently infected
CD4 T cells, since they observed that genes upregulated when CD4
T cells are non-specifically activated are not the same genes that
are expressed during high viremia. He therefore posited two other
mechanisms by which high viremia could induce the expression of
genes whose products help latent HIV start to replicate or reproduce.
First, different combinations of "aberrantly-expressed cytokines"
(hormone-like substances which cells release in order to communicate
with neighboring cells) may be turning on genes that promote HIV
replication. Second, perhaps the virus' envelope or other viral
proteins were helping to trigger HIV replication. He added that
this study demonstrates there really is no HIV latency during periods
of high viremia. He said that a semblance of true HIV latency is
approached only in aviremic individuals, since they were found to
secrete little or no virus from their latently infected CD4 T cells.
Dr. Fauci next compared the effects of low and high viremia on
B cells. He found that during high viremia, B cells, like the CD8
T cells described above, lost their ability to proliferate, which
he attributed in part to their inability to upregulate a receptor
on their surface called CD25. Before B cells can proliferate they
need to receive a signal from CD4 T-helper cells that is transmitted
through the B cell's CD25 receptor to the genes in its nucleus.
The molecule that delivers this signal is a cytokine called IL-2
or Interleukin-2, and thus the CD25 receptor is also known as the
IL-2R or IL-2 receptor. Since many of the B cells in viremic patients
lack the IL2R, they rarely receive a signal to proliferate and consequently
do not function properly. This B cell defect was not found in aviremic
patients.
Finally, Dr. Fauci compared the functioning of NK cells in viremic
and aviremic patients. NK cells can destroy infected cells in a
manner similar to CTL killing, but they arise earlier during infection
and never become as specific in their killing as CTLs. Immunologists
have described NKs as a bridge between the innate and adaptive immune
systems and consider them very important for virus control. Dr.
Fauci's group found that, as with B cells, high viremia results
in the aberrant expression of NK cell receptors, thus causing these
cells to malfunction. On the other hand, the NK cell receptors in
aviremic patients appeared much the same as those from uninfected
controls.
Since Dr. Fauci noted that some of the patients experiencing high
viremia were on HAART, he seemed to be emphasizing the importance
of maintaining as low a viral load as possible while on therapy.
While the viremia-caused defects he described don't cause the affected
immune cells to die, Dr. Fauci said that they "likely play
a cumulative role in the pathogenesis of HIV disease," and
may serve as the basis for some future "strategic avenues of
approach to therapy."
Notes
Note 1. CD8 T cells can also
release various soluble factors that don't kill infected cells,
but rather prevent the viruses inside those cells from reproducing.
Whereas this function may be more important in early infection,
it's generally believed that to maintain good long-term control
the CD8 T cells must function primarily as killers.
Note 2. Perforin punctures
holes in the membranes of HIV+ cells, enabling the CTLs to then
discharge various toxins called granzymes into the infected cells.
The granzymes then stimulate signals in the cell that tell it to
apoptose, or commit cellular suicide.
Note 3. The lack of signals
from CD4 T-helper cells that have been killed (either directly or
indirectly) due to HIV may seem the obvious reason why CTLs are
not getting adequate support to proliferate. However, for various
reasons many scientists do not believe the lack of CD4 T cell help
is the whole or even necessarily part of the story. For example,
when Connors' group stimulated the non-proliferating CTLs with IL-2,
which is the main soluble factor released by CD4 T-helper cells,
the CTLs still refused to proliferate.
Note 4. Before the more specific
adaptive immune system has time to kick in, another line of defense
called innate immunity acts as a first responder to pathogens. Innate
immune responders consist of cells and soluble factors that are
not specific for any particular pathogen, but rather act in a general
way to rid the body of pathogens. Scientists have recently come
to appreciate that the type of innate immune response initially
engendered helps determine the type of adaptive response that will
subsequently occur. Unlike innate factors, each individual CTL and
antibody has a unique shape that will only react with the specific
parts of pathogens that match that shape, much as each lock has
its own key.
Note 5. Some of these other
tricks HIV may use for escaping antibodies are "carbohydrate
masking, epitope variation, oligomeric exclusion, and conformational
entropic masking."
Note 6. In the words of Shaw's
paper in Nature, "a rapidly evolving, non-glycan reactive,
effective NAb repertoire matched by a similarly evolving glycan
shield that obstructs NAb from binding at neighboring sites."
Connors M, The differential ability of long-term nonprogressors
and progressors to restrict HIV replication is not caused by loss
of recognition of autologous viral sequences. Abstract 318, 10th
Conference on Retroviruses and Opportunistic Infections, Boston
2003.
Shaw GB, Antibody neutralization and escape by HIV-1. Abstract
166. 10th Conference on Retroviruses and Opportunistic Infections,
Boston 2003.
Wei, Decker, Shaw, et al., Antibody neutralization and escape
by HIV-1. Nature 2003 Mar 20;422(6929):308–12.
Fauci A, Pathogenic mechanisms of HIV disease: The multi-faceted
effects of virus replication and viremia on the host. Abstract
119, 10th Conference on Retroviruses and Opportunistic Infections,
Boston 2003.
HAART to Heart Talk
By Bob Huff
The powerful antiretroviral (ARV) drugs taken by people with HIV
and AIDS caused a revolution in treating the disease after death
rates plummeted when effective combination therapy was widely introduced
in 1996. But almost immediately, clinicians began to worry about
increasing blood levels of cholesterol and triglycerides seen in
patients receiving the drugs. Coupled with an increasing incidence
of diabetes and accumulations of visceral fat in people on therapy,
many worried that these classic predictors of heart disease portended
a wave of cardiovascular illness in this patient population. While
fears of a coming epidemic in ARV-associated heart problems have
yet to be borne out by epidemiology reports, there are new studies
showing that people with HIV may indeed be developing physical changes
that could dispose them to coronary or cerebral vascular disease.
Yo D:A:D
The D:A:D study is an ongoing large observational cohort study involving
over 23,000 people in the U.S., Europe and Australia that is trying
to assess the risk of heart attack in people with HIV who are taking
antiretroviral therapy. The study has been collecting information
about myocardial infarction (MI) since 1999. In an interim report
presented at the 10th Retrovirus conference, the D:A:D investigators
reported increasing risk of myocardial infarction after four years
on HAART, although overall, rates of MI remained low. One hundred
twenty-six participants had a heart attack while in the study, and
about a quarter were fatal. Most heart attacks occurred in men,
middle-aged and older.
While this is the first large study to suggest an association
between longer time on ARV and an increased risk of serious heart
problems, there are a number of limitations. First, there was no
link shown between heart disease and any particular drug or even
class of drugs. Second, a large number of participants in this study
had additional risk factors for developing heart disease, such as
smoking and being older. Finally, while time on therapy might contribute,
the association between the length of time in the study and heart
attack could just as well be due to advancing age or the long-term
effects of HIV itself.
One counter-intuitive finding was that either fat accumulation
or fat wasting seemed to have a protective effect against heart
attack. Some have speculated that this might be because people with
physically obvious lipodystrophy may be motivated to begin measures
to forestall heart disease, such as taking lipid-lowering statins,
stopping smoking or getting more exercise. With the risk of heart
attack in the D:A:D study running a modest 1.26 times above averages
in non-HIV populations, adopting such protective measures is likely
to more than counteract any increased risk due to antiretroviral
drugs. And one fact is undisputed: the risk of dying from untreated
HIV is dramatically reduced by antiretrovirals.
VA Voom
Another large study of the risk of heart attack and stroke in people
taking HIV meds was recently reported by the Veterans Affairs (VA)
healthcare system in the New England Journal of Medicine.
This study examined medical records of over 36,000 HIV patients
(almost all men) of the VA system between 1993 and 2001. Contrary
to the D:A:D findings, the VA study saw no associations between
being on antiretrovirals and developing vascular disease.
One limitation of the VA study is the relatively short period of
time that most patients had been receiving drugs. Only about 1,000
people had been on protease inhibitor-containing ARV combinations
for periods greater than four years.
So while these large observational cohorts give contradictory signals
about whether there is a link between heart disease and HIV meds,
they both dispel the worry that there is a huge, tip-of-the-iceberg
epidemic of treatment-related illness lurking just ahead. However,
the authors of both studies agree that more study is warranted and
that focused research on the role of individual drugs needs to be
conducted.
Sludge Factor
Even as fears of a coming cardiac catastrophe have eased, evidence
continues to accumulate that people with HIV — on drugs and
off — are experiencing worrisome vascular abnormalities (atherosclerosis).
At the 10th Retrovirus Conference, researchers from San Francisco
General Hospital reported on an investigation into the incidence
of abnormal intima-media thickness (IMT) of the carotid artery within
a cohort of 106 HIV patients. The carotid artery conducts the main
supply of blood to the brain. IMT is measured by ultrasound assessment
of the thickness of part of the arterial wall and is recognized
as a sensitive predictor of myocardial infarction and stroke. In
this observational cohort, in an attempt to find independent predictors
of increased IMT, abnormal IMT values were correlated with laboratory
and patient history parameters such as cholesterol levels and cigarette
smoking, as well as with ARV use and duration of HIV infection.
In addition to the snapshot taken of IMT in the main cohort, a subset
of 22 patients was evaluated for progression of IMT over a period
of one year.
The results revealed increased IMT in this cohort as compared
to averages obtained from studies in non-HIV populations. Statistically
significant predictors of increased IMT included age, LDL cholesterol,
high blood pressure, and having had a fall in CD4 cell count below
200 at any time in the past. A patient's duration of HIV infection,
HIV viral load, or current CD4 count were not found to be predictive
of IMT. Non-significant associations were reported for smoking and
for the length of time that patients had been taking protease inhibitors.
In the subset of 22 patients assessed for changes in IMT over
one year, IMT progressed at a rate four to five times greater than
changes reported in previous progression studies in non-HIV populations.
The investigators concluded that carotid intima-media thickness
is increased in this cohort of HIV-infected individuals as compared
to non-HIV historical controls, and that increases were independently
associated with the traditional risk factors for cardio-vascular
disease, such as cholesterol and hypertension, as well as with HIV-specific
factors such as history of low CD4 count.
Another ongoing study of IMT by the federal AIDS Clinical Trials
Group (ACTG) is looking more closely at the role of ARV drug classes.
Preliminary results reported from three matched cohorts found no
significant differences in IMT between those on PI-containing or
non-PI-containing regimens, and no difference between HIV-positive
and negative participants. The PI patients had a mean time on treatment
of over four years. These observations were baseline snapshots only;
the study will continue to see if progression rates differ between
the groups.
One question remaining unanswered by these studies is the role
— if any — played by ARV therapy in increased IMT and
the risk of vascular disease. Some researchers feel that chronic
inflammation from HIV infection itself may be responsible for the
observed IMT changes. For patients with additional risk factors
such as smoking or family history of heart disease, the answer may
never be clear.
Friis-Moller N, Exposure to HAART is associated with an increased
risk of myocardial infarction: The D:A:D Study. Abstract 130,
10th Conference on Retroviruses and Opportunistic Infections,
Boston 2003.
Bozzette SA, et al., Cardiovascular and cerebrovascular events
in patients treated for immunodeficiency virus infection. NEJM,
2003 Feb 20; 348(8):702–10.
Hsue P, Increased atherosclerotic progression in patients
with HIV: The role of traditional and immunologic risk factors.
Abstract 139lb, 10th Conference on Retroviruses and Opportunistic
Infections, Boston 2003.
Currier J, Carotid intima-media thickness in HIV-infected
and uninfected adults: ACTG 5078. Abstract 131, 10th Conference
on Retroviruses and Opportunistic Infections, Boston 2003.
| Sam Bozzette on the VA Study
The study we just published about the risk of cardiovascular
or cerebrovascular disease in people on HAART took advantage
of the fact that the very large VA medical system has a common
database across all centers. We had 36,000 patients, with
1.5 million antiretroviral prescriptions, and there were 2000
cardiovascular or cerebrovascular events. Retrospective, administrative
database studies like this have limits on what kinds of answers
they can give, but ours does describe the experience of this
very large cohort. It's kind of like asking 36,000 of your
friends how they did. There's a definite message in the answer
to that question so we thought it would be a contribution
if we could pull that data together.
When we started this VA study, we weren't asking whether
or not effective antiretroviral therapy with protease inhibitors
was going to marginally affect the rates of cardiovascular
disease in some small way. People were worried that we had
a disaster brewing. People were worried that cardiovascular
and cerebrovascular events were going to be so common as to
be canceling out the benefits of therapy in people with advanced
disease who clearly needed it. But if you look at the admission
and mortality graphs in our paper, you can comfortably say,
"Okay, there's no emergency here." Is there an effect?
There could be. We still can't forget about lipids or heart
attacks — they need additional careful investigation
that cannot be done in the administrative databases. |
ConFuzeon Reigns By
Bob Huff
T-20 has finally been launched and Roche is struggling to get it
into orbit.
According to Kathy Presto of Roche (Fuzeon's mission control director),
as of March 26, only two days after the drug's price had been published,
633 prescriptions had been received and demand was reflecting a
diverse mix of payers, with roughly 30% private insurance and 70%
public payers. Due to limited production capacity, Roche estimates
that only 1,500 patients can be added during the first month after
launch. Also, because of the high price of Fuzeon and the limited
circumstances in which it is most likely to be useful, Roche has
established a gatekeeping system to handle physician requests for
the drug.
Each prescription that is received by Chronimed, Roche's exclusive
pharmacy source for Fuzeon, is date- and time-stamped on a first-come,
first-served basis and each patient is guaranteed that a supply
of drug will be held for them while their reimbursement situation
is worked out. Chronimed will perform a preliminary screening for
ability to pay, then pass along the prescriptions to Roche's reimbursement
specialist group for verification. Roche can then refer difficult
cases that require advanced processing to another contract company
that "really knows how to work the system." The goal is
to see that everyone who submits a prescription is served, although
it remains to be seen if that can be achieved and how long the wait
will be for those unable to pay for the $20,000+ drug.
Patients with no ability to pay will be evaluated by several, somewhat
flexible, criteria, says Roche, and those with no recourse to third
party payers will ultimately be covered by the company's patient
assistance program. Eligibility will hinge on a number of variables
besides income and insurance coverage and could include the size
of the patient's household and whether the applicant is a head of
household, the state of residence and number of dependents. Non-U.S.
citizens will not be eligible. For now, at least, no medical criteria
will be used to allocate Fuzeon, although that could change if the
demand puts a severe strain on the supply.
The state AIDS Drug Assistance Programs (ADAPs) are keenly interested
in having Roche establish a clear definition of medical need for
Fuzeon so they can rationally allocate the drug within their systems.
Since there is no CD4 or viral load indication for Fuzeon, the best
recipe for success may be that a person has other active drugs available
to them. If the list of active drugs is two or less, then Fuzeon
may be appropriate. Determining an optimal background regimen when
few choices are obvious calls for educated judgement based on resistance
testing and the patient's treatment history. Physicians with light
HIV case loads are less likely to have the expertise to make those
judgements. Hopefully, Roche will be able to assist clinicians in
making these complicated decisions without inappropriately pushing
Fuzeon for people who don't need it.
Volunteers in the U.S. clinical trials have been guaranteed uninterrupted
access to Fuzeon. They will be transitioned from the study supply
to the commercial supply and Roche will continue to pay until third-party
payment can be secured. Presto said, "We will not interrupt
Fuzeon for trial participants even if they never get any other reimbursement."
By year end, the 1,500 U.S. trial participants could consume up
to 17% of the commercially available drug supply.
One outstanding question is what will happen when a person earns
too much for their state's ADAP, yet still can't afford T-20. Or
if their private insurance won't deal with Chronimed. The answers
will become clearer as Roche gets a month or two into the process.
The Price is WAC
Roche has announced that the wholesale acquisition cost (WAC) of
Fuzeon will be about $20,000. A more commonly quoted price is the
average wholesale price (AWP), which typically runs about 25 percent
higher than the WAC. The price paid by ADAPs and Medicaid is likely
to be less than WAC. People who can afford to simply write a check
will pay the highest price for Fuzeon. On launch day, a Chronimed
employee quoted a cash-and-carry price of $2,200 a month, or $26,400
a year for the drug.
State ADAP Directors Meet Pharma Reps
During the latter part of March, a coalition of state ADAP directors
met with major pharmaceutical makers in Washington, D.C. to try
to win lower drug prices and ease their programs' budget crises.
Participants are being tight-lipped about the discussions, but news
reports singled out Roche as the sole maker willing to meet state
programs in the middle with a deal over the price of Fuzeon. Of
course when you're starting at $20,000 a year, meeting in the middle
might end up being in the $15,000 range — $3,000 higher than
many ADAP programs initially budgeted for the drug. Talks with the
other PharmCos will continue.
A Report on the International
Treatment Preparedness Summit By Andy Quan
Over a few days in early March, 2003, dozens of flights touched
down in Cape Town, South Africa unloading AIDS activists from around
the world. Nearly 125 participants from 67 countries came to attend
the International Treatment Preparedness Summit, an event "organized
by an ad-hoc coalition of treatment activists from around the globe"
and sponsored by over a dozen donor organizations.
They were joined by representatives from these donor organizations
as well as by volunteers and local organizers with the main aim
of establishing organizations and movements for increasing treatment
access where none exist, and strengthening those that already exist.
The key method for doing this was by addressing the issue of treatment
education — how individuals and institutions can understand
HIV and AIDS treatments better — which will then hopefully
lead to treatment advocacy — how we can better fight for and
obtain access to treatments for HIV and AIDS which include, in addition
to antiretroviral drugs (ARVs), treatment and prophylaxis for opportunistic
infections (OIs), substitution therapy for drug users, monitoring
and diagnostic tools, and the basic health infrastructure to deliver
them.
Our host organization, the Treatment Action Campaign (TAC), provided
inspiration for many as participants spoke with Zackie Achmat and
other TAC members. Their model of feisty, inspired, and practical
organizing certainly has elements that can be replicated in other
locations. TAC asked for global support in April for their civil
disobedience campaign against their government's inaction in dealing
with HIV and AIDS.
Listening to the activists at the conference, what I heard was
that people and organizations need basic capacity-building and training.
In order to build any treatment access movement, we need to work
to strengthen our individual parts: find ways for community-based
organizations and groups to keep operating, to keep their activists
alive, to make the principle of Greater Involvement of People Living
with HIV and AIDS (GIPA) a reality, to build advocacy-skills and
more.
I continue to be amazed at the energy and passion felt by community
activists about the Global Fund. It is clear that the community
feels ownership of the Fund and wants to ensure that it meets the
needs of those whom it was set up to serve. Key discussions included
how to ensure strong community participation in County Coordinating
Mechanisms and how to write proposals that include strong treatment
components. At the same time, I hope that activists around the world
view the Fund as part of a solution, rather than the whole solution.
Some national governments can afford to put more resources into
responding to AIDS; the existence of a Global Fund should not be
an excuse for them to not do so. Debt relief could be another way
for funds to be freed up for treatment access.
There are currently follow-up regional meetings planned for most
regions. An Eastern and Central European meeting in Belarus will
take place in upcoming months as well as a Latin American and Caribbean
meeting. The African participants met the day after the summit to
further develop their African Treatment Action Movement. It is Asia
with its differences in local situation and languages that makes
follow-up meetings more difficult, but there will be possibilities
for treatment advocacy at various Asian meetings. The success of
regional meetings to carry forward an agenda could be the most important
marker of success for this summit.
All in all the summit was a great success, and the more so for
how quickly it was put together. An incredible group of volunteers
worked hard to bring the event to fruition, and already, days after
the end of the conference, work is continuing and e-mails are flying
around the globe.
Our friends, colleagues, and brothers and sisters from around the
world are dying senselessly, but we are doing something about it.
We are working with urgency and commitment and the summit was a
best-case example of this.
Andy Quan is affiliated with the Australian Federation of AIDS
Organizations (AFAO) and the Asia-Pacific Council of AIDS Service
Organizations (APCASO).
You Have HIV… And You
Have AIDS By Bob Huff
New York City recently published a new generation of AIDS statistics
that marries its traditional AIDS reporting with new data drawn
from HIV reporting that began in mid-2000. The result is a picture
of AIDS in New York that is shocking.
There were nearly 7,000 people newly diagnosed with HIV in New
York City during 2001. Over one-quarter of them already had AIDS
when they tested positive, and, two years later, that proportion
has jumped to 36 percent. Nearly half of the 4,900 AIDS diagnoses
delivered during 2001 were received by people who tested positive
that year. Why are so many people with HIV waiting so long to get
tested? Why are so many people waiting until they are at risk of
fatal illness to seek medical care?
The new numbers from the New York City Department of Health don't
answer those questions, but the demographics are striking. Eighty-seven
percent of people with a concurrent HIV and AIDS diagnosis in New
York during 2001 were black or Hispanic. Concurrent is defined as
AIDS diagnosed within 31 days of the HIV diagnosis — roughly
enough time for an under-200 CD4 cell count to come back from the
lab. Most people with concurrent HIV and AIDS were in their 40s
and 50s, although 11 percent were 29 or younger. That's 200 new
twenty-somethings with AIDS.
The affluent Chelsea neighborhood of Manhattan claims the largest
percentage of people living with HIV/AIDS (PLWHA) in New York (3.3%),
yet it has one of the lowest death rates of PLWHAs in the city (15.9
per 1,000 PLWHAs). Meanwhile, in Harlem, where PLWHAs are about
2 percent of the population, the death rate is nearly 2.5 times
higher (42 deaths per 1,000 PLWHA). Higher death rates are also
reported in the Bronx and Brooklyn (38 and 36 deaths per 1,000 PLWHAs,
respectively) compared to Manhattan and Queens (26 and 27 deaths
per 1,000 PLWHAs, respectively).
What can't be told from these statistics, but can be inferred,
is the role that access to medical care must play in whether someone
tests positive before progressing to AIDS, or in how likely someone
is to die from their HIV infection. A 1997 study by the Commonwealth
Fund reported that no matter where they reside in New York City,
people lacking medical insurance are far more likely than the insured
to face barriers in gaining access to health care. "Citywide,
they are two to three times more likely to go without needed medical
care, to not see a physician, and to lack a regular doctor."
Private insurance comes along with a steady job. The best insurance
buys the best care and belongs to people with the best jobs. Medicaid
coverage can be good but is notoriously sporadic. Someone may be
covered in January and cut loose by December if they have not jumped
through the hoops of yearly certification. It's a system that seems
designed to keep people from depending on it. Consequently, too
many people in this city still head to the emergency room when their
health needs attention. And too many people find out they have AIDS
at the ER.
Twenty years into the epidemic, studies show that many doctors
are still too squeamish to ask about HIV risk behaviors during routine
exams, and too many still fail to offer testing. This neglect may
be worse in immigrant communities where the topic of sex is sensitive
or taboo. Why are AIDS death rates so high in lower Manhattan where
Chinatown is? Stigma is the number one reason people are afraid
to be tested in India and South Africa. Yet HIV stigma is alive
in every New York borough.
Of course, none of this explains why 7,000 people tested positive
in 2001. And the statistics don't begin to address the bleeding
question of how many people actually became infected that year…or
this. What they do suggest is a continuing failure of the system.
And things are only getting worse. With clinics closing, a retreat
from science-based prevention, and shrinking state and city budgets,
what will the 2003 numbers say? We've just been told that federal
HIV/AIDS prevention and care dollars to New York are going to be
cut by 12 percent. New York remains at the epicenter of the U.S.
epidemic and the government's retreat from reality is compounding
our disaster. Lack of care is an indictment of our healthcare system,
but failure to care about the consequences is a political problem.
The only cure for that is public outrage.
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