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by Steve McGuire
In an energetic, post-ICAAC
presentation, Frank Palella, MD, urged people living with
HIV and clinicians who work with them to put some of the
adverse effects of antiretroviral treatment into a larger
perspective. The point of departure for Dr. Palella’s talk
was the growing concern in the HIV community about metabolic
toxicities and body-shape changes (sometimes called “body
habitus changes”) that, for many people, are associated
with use of some antiretroviral (ARV) drugs.
Perhaps the most distressing
concerns for many individuals arise from the visible, cosmetic
changes that many begin to experience after starting highly
active antiretroviral therapy (HAART). These changes include
loss of facial fat, leading to the appearance of sunken
cheeks; accumulation of fat around the waistline; buildup
of fat at the back of the neck between the shoulder blades
(“buffalo hump”); loss of fat in the arms and legs; and
thickening of the neck. Although for many people, these
changes in appearance can be quite stressful, they also
represent just the tip of the iceberg of metabolic issues
and other ARV treatment matters that HIV specialists are
trying to address.
Today’s wide-ranging debates
about metabolic toxicities and body-shape changes, explained
Dr. Palella, who is assistant professor of medicine at Northwestern
University School of Medicine, are taking place in the context
of another critical debate—when to start HAART and what
combination of drugs to start with. Earlier recommendations
to start ARV therapy for almost everyone when the CD4 T-cell
count reached 500 or to “hit early and hit hard” have now
been replaced by more complex considerations of issues like
possible long-term toxicities, quality of life, and so forth.
Some HIV specialists are even recommending delaying the
start of ARV therapy until the CD4 count reaches 200. Indeed,
one reason for this recommendation is to avoid what some
believe to be long-term toxicities of ARV treatment, such
as metabolic abnormalities and body-shape changes.
Critical data from HOPS
To help explain possible
causes of lipid abnormalities and body-shape changes, as
well as what they may imply for an individual’s ARV therapy,
Dr. Palella drew on the vast amount of data coming from
the HIV Outpatient Study (HOPS). HOPS is a huge study of
some 7,000 HIV patients at 10 key treatment centers across
the United States. (The largest of the centers is at Chicago’s
Northwestern Memorial Hospital.) The study collects and
analyzes data from these patients’ specific treatment regimens,
outcomes, adverse events, survival rates, and other information.*
The following are just
some of the key issues that the HOPS data are helping Dr.
Palella and other researchers address:
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What are all
of the factors, besides possible adverse drug events,
that are associated with lipid abnormalities and body-shape
changes?
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Can a single
definition of lipodystrophy be agreed upon?
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Is HAART associated
with reduced mortality and morbidity?
Using a variety of graphs
and charts, Dr. Palella stressed that use of HAART, which
began in early 1996 with the introduction of protease inhibitors
(PIs), has a clear association with a dramatic drop in the
number of deaths from HIV-related illnesses. In fact, for
people who are able to take HAART, the number of deaths
plunged by 90–95 percent. He also pointed out that during
that same time the rates of illness due to pneumocystis
carinii pneumonia, mycobacterium avium complex, and cytomegalovirus
have also greatly declined. Furthermore, the HOPS data indicate
that earlier initiation of ARV therapy is highly beneficial:
People who began therapy with CD4 counts between 200 and
350 cells, as opposed to delaying therapy until below 200,
had a five-times lower death rate. In addition, those who
started therapy at between 350 and 500 CD4 cells had almost
half the death rate as those who delayed starting therapy.
Dr. Palella urged that,
for those wondering whether use of HAART is really a good
idea, “we have to have a long memory, because prior to 1996
AIDS was the leading cause of death for men between the
ages of 20 and 60 and the second leading cause of death
for women. But today the death rate has been dramatically
reduced. So, when talking about lipoatrophy and other metabolic
effects—even if we believe that adverse drug effects play
a role—we have to keep in mind what the alternative to not
treating is.”
Among the arguments in
favor of starting ARV therapy at a higher CD4 count Dr.
Palella pointed to the following:
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Control of HIV
replication is easier to achieve and maintain.
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Immune deficiency
is delayed or prevented.
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The risk of developing
drug-resistant virus is lower.
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The risk of HIV
transmission may be decreased.
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Adverse events,
like metabolic abnormalities, may be more likely in people
with lower CD4 counts.
Whether delaying therapy helps
to avoid cumulative adverse events represents the “black hole
that all of the lipid abnormality issues fall into,” stated
Palella. “This is because we do not have a complete understanding
of the extent to which the drugs that we use in fact contribute
to what are called ‘drug-related adverse events.’ ”
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“…we do not have a complete
understanding of the extent to which the drugs that we use
in fact contribute to what are called ‘drug-related adverse
events.’ ”
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Multiple factors linked
to fat changes
After this explanation of
how HOPS information clarifies the relationship between use
of HAART and the drop in HIV-related death and disease, Dr.
Palella focused on how careful analysis of HOPS, and other,
data have begun to shed light on the host of factors that
seem to be associated with the development of metabolic and
body-shape problems with HIV infection.
First he sketched out some
of the issues being addressed in trying to define lipodystrophy.
Four general sets of abnormalities, which overlap with each
other to varying degrees, come into play in any working definition
of lipodystrophy:
- Blood lipid abnormalities—high
total cholesterol, high low-density lipoprotein (LDL or
“bad” cholesterol), and high triglycerides.
- Fat accumulation—around the
waist, between the shoulders (buffalo hump), and around
the neck.
- Lipoatrophy—fat loss, especially
in the face, arms, and legs.
- Dysregulation of glucose metabolism—meaning
problems in processing sugars, possibly leading to insulin
resistance or even diabetes.
Dr. Palella explained that
these abnormalities can occur in different combinations in
different individuals. For example, one person may experience
high cholesterol and loss of facial fat, but none of the others.
Another person may have insulin resistance and abdominal fat
accumulation, while a third may experience some degree of
all four types of abnormality.
As early as 1996, reports
began to appear of diabetic problems occurring in some patients
who were taking protease inhibitors, so the concern about
metabolic abnormalities in HIV treatment is not new. Because
virtually all HAART regimens at that time contained at least
one PI, that class of drugs was thought to be the most likely
cause of the abnormalities. With a variety of failed efforts
to explain what the association could be, Dr. Palella said,
“attention shifted to the nucleoside analog class of drugs
[Zerit, Retrovir, Videx, Epivir, Combivir, etc.], and that
is where it has stayed for the last couple of years, especially
when talking about fat atrophy.”
Now that analysis of a variety
of factors associated with different manifestations of metabolic
abnormalities has become available, for example from the HOPS
data, some things have become clearer. “While some drugs themselves
might account for certain aspects of these problems, especially
the association of blood lipid abnormalities with use of protease
inhibitors, a close association of one drug and the development
of one of these abnormalities does not imply that there is
any association with development of any of the other abnormalities.”
Dr. Palella went on to explain
that HOPS investigators looked at data from about 1,100 patients
in the study to try to uncover two things:
- The prevalence of either fat
gain or loss
- What factors, either drug-related
or non-drug-related, might be associated with fat changes.
HOPS investigators identified
the following associations:
- Having an AIDS diagnosis for
longer than three years.
- Being older than 40.
- Having a low CD4 T-cell count.
- Being Caucasian and male.
- Fat loss of more than one kilogram
(2.2 pounds) per square meter of body area.
The two medications most
associated with these abnormalities were Crixivan and Zerit.
However, Dr. Palella stressed that real accountability for
the occurrence of the problems could not be assigned to either
drug because these were the most commonly used medications
among that group, with more than 85 percent of them being
treated with Zerit. He compared this situation to “walking
into a room full of dark-skinned people who are all HIV-positive
and saying that they’re positive because they’re dark-skinned.
Of course, you can’t say that, because the real reason is
that these just happen to be the people that you’re looking
at now.”
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We should never think
that withholding therapy for anybody at risk for HIV disease
progression is something that is admissible.
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Another later analysis of
HOPS data found an association between an individual’s CD4
nadir (the lowest level that her or his count had reached)
and the development of facial fat loss. This analysis found
that the lower a person’s CD4 count got, the higher the likelihood
of developing sunken cheeks or skinny limbs. Furthermore,
the risk was even higher for someone whose CD4 count was low
and stayed low.
Although other studies have
since agreed with the HOPS findings, this analysis was the
first real confirmation that there are other factors besides
drug treatments that are associated with the development of
fat loss and fat gain, and possibly with other metabolic abnormalities.
“If we were to make up a laundry list of lipodystrophy, metabolic
disorders, and things that might be associated with them,
over the last couple of years we’ve gone from focusing on
drugs in general—and sometimes even on specific classes of
drugs—to focusing on the bigger picture: duration of infection,
severity of disease, age, degree of immune reconstitution,
and possibly gender and race.”
Where does mitochondrial
toxicity fit in?
Dr. Palella also touched
on another issue that often comes up in the context of discussions
of HIV-related metabolic and lipid disorders—mitochondrial
toxicity. (Mitochondria are tiny structures inside certain
types of cells. One of the main responsibilities of mitochondria
is to help convert foods into energy that the body can use.)
Some studies have indicated that use of ARV therapy can damage
mitochondria. One possible result of such damage is higher
than normal levels of lactate in the blood. (Lactate is a
byproduct of the use of sugar by muscles during exercise.)
When lactate levels reach a critically high level, a condition
called lactic acidosis can result, with a variety of symptoms
that may include nausea, vomiting, abdominal pain, and difficulty
breathing. In a very small number of cases, patients have
experienced a severe weakening of muscles in the legs and
arms.
While the results of lactic
acidosis can be extremely severe when they do occur, Dr. Palella
cautioned that too many people with HIV and physicians have
come to think of mitochondrial toxicity, high lactate levels,
and body-shape changes as all part of the same problem. He
went on to stress that no carefully designed studies to date
have been able to confirm that any connection at all exists
between damage to mitochondria and changes in lipid levels
or fat distribution. He further cautioned that, although ARV
therapies may or may not be involved in any one of these abnormalities,
no data have yet been able to confirm that any one drug or
class of drugs is clearly linked to the development of specific
metabolic abnormalities.
No retreat on treatment
progress
To drive home his core message
that patients and providers alike should keep their attention
more on the larger context of HIV treatment, rather than on
possible adverse events, Dr. Palella suggested an analogy:
“If we were talking about a cancer, like small-cell carcinoma
of the lung, and we had combination chemotherapy that could
result in durable remission—with more than 90 percent reduction
of death rates—but the therapy had to be continued for many
years. And if we found some metabolic abnormalities that may
or may not be due in part to use of the drugs, would that
ever be considered justification for delaying or modifying
what is known to be life-saving therapy? Absolutely not. We
should never think that withholding therapy for anybody at
risk for HIV disease progression is something that is admissible.
Especially since the majority of metabolic changes described
here, like high cholesterol, insulin resistance, and high
triglycerides, are treatable. People who are taking ARV therapy
are living their lives, holding down jobs, raising families,
and so on. Therapy is saving lives that we could not save
a decade ago, and I don’t want to go back to that time again.”
Steve McGuire is a Chicago-based
writer and consultant specializing in medicine, public policy,
and non-profit issues.
* Much of the credit for
analyzing the HOPS data belongs to Kenneth Lichtenstein, MD,
of the University of Colorado, who is one of the lead HOPS
investigators.
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