Thanks for the link on crix-belly. As I suspected, the name came more from initial reports on patients that happened to be on Crix, than a statistical study indicating that it was more associated with Crix than other proteases. The affect on metabolic disease seems to hit several markers and a weight gain of 40 pounds seems to be used (so I suspect that the incidence is much higher if a more modest weight gain is used to define the condition). Here's an interview that seems to be the basis for the report that you linked:
Article:
Protease Inhibitors' Metabolic Side Effects: Cholesterol,
Triglycerides, Blood Sugar, and "Crix Belly." Interview with
Lisa Capaldini, M.D.
Date:
08/15/97
Issue:
277
Author:
James, John S.
[In the last few months we have heard increasing anecdotal reports of a condition
which has been named "Crix belly." People may gain 40 pounds or more of fat
remarkably quickly in the lower abdomen, and there may also be some muscle wasting
in the arms and legs. The cause is unknown. This problem was not seen before the use
of protease inhibitors; it is not known if it is associated primarily with indinavir
(Crixivanr), for which it was named, or if it may be caused by other protease
inhibitors as well. Nothing has been published so far.
[Last month we asked Lisa Capaldini, M.D., an AIDS physician in San Francisco,
what she was seeing that our readers should know more about. She said that more
attention was needed to certain lipid (fat) and other metabolic problems which appear
to be related to protease inhibitor therapy.
[The interview below was conducted on August 8, 1997 and went to press four days
later. Because this information is so new, the picture could change rapidly over the next
few weeks or months. Those seeing this article at a future time should seek out the
most current information then available.]
ATN: What have you seen of metabolism problems with the protease inhibitors?
Dr. Capaldini: So far we have identified three metabolic disorders associated with
protease inhibitor therapy as a class. First we saw high triglycerides; triglycerides are
one of the two kinds of lipids, or fats, we measure in the blood. Most peoples'
triglyceride level runs between 100 and 200. High triglycerides clinically can cause
pancreatitis, and have been found to be associated with (but not necessarily cause)
hardening of the arteries.
The second condition is high cholesterol in patients whose previous cholesterol levels
have either been normal, or as is common with advanced HIV, low. The pattern of
high cholesterol is elevation of the "bad" or LDL cholesterol, compared to the
so-called "good" or HDL cholesterol. This is the unfavorable pattern of LDL to HDL
cholesterol associated with hardening of the arteries, which can lead to heart attacks,
strokes, and peripheral vascular disease.
The third condition is high blood sugar. Usually the levels are not high enough to cause
symptoms or, to our knowledge, to cause any of the complications associated with
diabetes. They are typically 110 to 150 -- which is not normal, but is not in the range
usually associated with symptoms, which would be over 250.
We do know, from experience before the use of protease inhibitor therapy, that HIV
infection tends to predispose people to both high blood sugars and high triglycerides.
But these were usually seen in patients with much disease activity; they were almost a
marker of HIV activity, and therefore were often associated with patients with
unusually low cholesterol. On the other hand, it is clear that we did not have the high
cholesterol problem before protease inhibitors were introduced.
It is worth mentioning that the endocrine system seems to be one of the least affected
systems of the body in HIV disease; androgen deficiency is the only common
endocrine disorder associated with HIV disease. So it is a contrast that we are seeing
metabolic disorders as a result of our therapy, when were not seeing much of these
problems before.
"Crix Belly"
ATN: The Crix List, an electronic mailing list on the Internet, has discussions of "Crix
belly", reports of people gaining 40 pounds or more in a very short time. [For more
information about the Crix list and how to join it, see pinkpage.com.]
Dr. Capaldini: No one understands what is causing this condition. In appearance,
"Crix belly" is closest to a medical condition called Cushing's syndrome. People gain fat
on their lower belly and flanks, and often notice a loss of muscle tissue in their arms
and legs. This acquired condition is associated with a disorder of cortisol, when you
have too much of it. There is no data yet to suggest that high cortisol levels are being
caused by Crixivan, but it is remarkable how much Crix belly looks like Cushing's
syndrome in appearance.
This condition is very disturbing to patients, especially those who started these drugs
when they were asymptomatic or minimally symptomatic, and now are hoping for
long-term benefits. Aesthetically it is disturbing; also, we do not know what it means
physiologically.
ATN: Does it seem to be more specific to Crixivan than to other protease inhibitors?
Dr. Capaldini: That is what I have heard, and seen anecdotally in my practice --
although about 70 to 80 percent of my patients on protease inhibitors happen to be on
Crixivan, so whether the effect is specific to the drug, or just seen with it more often
because more patients are using that drug, is not clear.
ATN: Has there been any experience in your practice with people trying to control this
condition either by discontinuing protease inhibitor therapy entirely, or by changing
from Crixivan to another protease inhibitor?
Dr. Capaldini: I have no knowledge about that, either in my practice or otherwise. I
have two patients who have both had terrific responses to Crixivan, in viral load and
T-cell improvements, and because of that are apprehensive about switching,
particularly given all the conflicting cross-resistance data that is coming out. Despite
that, at least these two people in my practice are considering switching to another
protease inhibitor, with the hope that it is a Crixivan-specific effect and that stopping
the drug will reverse it. But we do not yet know whether it is drug specific, or whether
it will reverse if the drug is discontinued.
ATN: Have you heard from Merck about this effect?
Dr. Capaldini: Not yet. I think the news is just starting to trickle down the anecdotal
pathway. [Note: Merck is interested in hearing from either physicians or patients about
this or any other problem with Crixivan. Call the Merck National Service Center,
800/672-6372.]
Note that there is also a separate condition which has been called Crixivan belly, which
seems to be more associated with the protease inhibitors as a class, not just Crixivan --
people getting bloating or heartburn or rapid transit time diarrhea problems. But when
people use the term Crix belly, they are usually referring to getting fatty tissue in the gut,
with leg and arm muscle wasting.
Clinical Course, and
Potential Treatments
ATN: About how often do these different metabolic problems occur, and when in the
course of the therapy?
Dr. Capaldini: The metabolic conditions tend to show up after about a year of
protease inhibitor therapy -- although I have seen patients' cholesterol change from
abnormally low, to more normal for them, as early as three to six months into therapy.
At first I thought that was a good sign, indicating that metabolism was returning to
normal. It was only about six months ago that my first patient had his cholesterol level
go from a normal range to a high range. In this person's case, there is a strong family
history of coronary artery disease. But I have seen high cholesterol both in patients
with and without such family history.
ATN: How concerned are you?
Cholesterol
Dr. Capaldini: It is important for patients taking protease inhibitors to understand that
simply having a high cholesterol rarely results in harmful events (heart attacks, strokes,
and dysfunction of the peripheral blood vessels, a condition called claudication). The
vast majority of people who have those problems have multiple risk factors, including
hypertension, diabetes, obesity, inactivity, and smoking. It is unusual for somebody to
have only one risk factor and have anything come of it. On the other hand, the risk
associated with cholesterol depends on the level; if it gets quite high, for example over
400, then even as an isolated risk factor it can cause disease.
So no one should be stopping their protease inhibitor or panicking because their
cholesterol has risen from say 200 to the 250 range. I have encouraged my patients to
sit tight until we can discover (1) is this a stable phenomenon, or is it likely to get worse
over time, and (2) are any adverse clinical outcomes likely to result?
There are well tolerated, easy to take drugs that safely lower cholesterol in the general
population; they are called HMG-CoA reductase inhibitors (lovastatin, etc.), and they
work by keeping the liver from recycling fat in the gut. They are quite safe. There is
probably an interaction between them and ritonavir (Norvirr); but as we know there
are very many drug interactions with that drug. So we could treat this; the real issue is
should we treat it?
For people who have tried lipid-lowering drugs in the past, the prior generation were
poor; they were unpredictably effective and tended to cause a lot of gastrointestinal
side effects. This newer class of drugs is both reliably effective and amazingly safe. It
may well be that for some patients, adding one pill a day of these drugs is an
appropriate intervention; we just do not know yet.
Triglycerides
Regarding the high triglyceride problem, most experts do not intervene unless the level
is over a thousand, or in some cases over 500 -- around the threshold which may
predispose to pancreatitis. The treatment for high triglyceride is a lipid-lowering drug
called Lopid (generic name gemfibrozil); it is usually very well tolerated, and is taken
twice a day.
Some patients have found that they can get their triglycerides from a high range to a
lower range -- not normal but safer -- by modifying how much fat they eat. For
patients who are not having trouble maintaining their weight, that is a reasonable
approach. But some patients need to keep more fat in their diet just to maintain their
weight; for them the lipid-lowering drug might make sense.
Blood Sugar
Concerning high blood sugar, many people are confused and think that if their blood
sugar is outside of the normal range, they have to take medicine for it. That is not the
case. Most physicians do not treat a high blood sugar problem unless it is causing
symptoms or unless it is consistently over 150. And for most of those who do need
treatment, that means taking a pill once or twice a day, and learning how to do blood
sugar monitoring. I have never had a patient on protease inhibitor therapy get the
severe form of diabetes that was reported a couple months ago, where patients were
hospitalized with severe diabetic conditions. The patients I have identified have had
gradually escalating blood sugar, usually with no symptoms at all, and it has been quite
easy to take care of.
Crix Belly
ATN: Going back to the Crix belly problem, it might be useful research to try lowering
these values into the normal range after someone had gained the first ten pounds or so,
to see if the problem might be stopped.
Dr. Capaldini: Because we have no idea what is causing this problem, we do not
have a handle on where to intervene.
Antiretroviral Treatment Strategies
ATN: Are these metabolic side effects changing your views on treatment?
Dr. Capaldini: To me as a primary care doctor, these metabolic phenomena are an
excellent example of why the "hit hard, hit early, it's the virus stupid" approach may not
be as straightforwardly correct as it looks. The argument behind this strategy has been
that (1) we know that HIV causes the disease, and (2) we know that it is harder to
control the virus when there is more virus in the body, and (3) viral load increases with
time; therefore, it seems intuitively obvious that everyone should be on combination
therapy as soon as they know they are HIV positive. Those of us who have questioned
that approach -- not its logic, but in how it works clinically -- are concerned that we
do not know the long-term safety or benefits of these drugs, and that as a general rule
of thumb, the earlier in a disease you treat a patient, the more problems you may have
with long-term medication side effects.
So these metabolic disorders, while they may not turn out to be associated with any
long-term problems, make me feel uncertain about recommending combination therapy
including protease inhibitors to patients with very early disease. My concern is not only
because of any question about whether we can control the virus long-term with current
agents, but because of the unknown trade-offs between early control of viral
production and the long-term consequences of medication side effects.
In the old days of the nucleoside analogs, sequential monotherapy, AZT and 3TC etc.,
when a drug caused a problem it was a simple matter to stop giving it and replace it
with another drug. With protease inhibitors, these therapeutic decisions are more
complex. We do not feel it is safe to decrease doses, because of the possibility of
developing viral resistance to the drugs -- especially because recent data suggests that
once a patient's virus becomes resistant to one protease inhibitor, it may also be
resistant to all of the other currently available protease inhibitors. So that makes
changing dosages, stopping or starting these drugs, quite a bit more problematic than
with the other HIV drugs.
ATN: What should patients do now?
Dr. Capaldini: If they get these side effects, they should not stop their drugs and then
call their doctor. These metabolic side effects do not seem to be causing any
short-term risk -- yet it is quite risky to stop and start protease inhibitor therapy,
because of the danger of the virus becoming resistant. Unfortunately it will probably
take six to 12 months for us to even have practice guidelines for these lipid disorders.
Discussion with
Carl Grunfeld, M.D., Ph.D.
Note: After the interview AIDS Treatment News talked to Carl Grunfeld, Professor of
Medicine at the University of California San Francisco, who is studying these
conditions. He emphasized several points:
In 1992, before the protease inhibitors, his group reported a 33% decrease in LDL
cholesterol (a large decrease) due to HIV infection. Abnormally high cholesterol levels
which people had anyway may be returning due to effective antiretroviral treatment.
His group first reported the high triglycerides associated with HIV infection. Others
reported that this effect was increased with ritonavir (other drugs were not tested).
The blood sugar problem is rare. And a full spectrum of conditions has been
reported; there does not seem to be any pattern resulting from protease inhibitor
treatment.
The weight gain, etc. should not be called Crix belly, because it may not be specific
to Crixivan -- or even to protease inhibitors as a class. A handful of cases may have
occurred before protease inhibitors. To him as an endocrinologist it has not looked like
Cushing's syndrome -- but if physicians suspect Cushing's syndrome, they should test
patients for that, and this issue could be settled.
No one knows what is causing this condition; and so far, no one has shown that it is
harmful. Standard body composition measurements have failed to show the nature of
the problem. As a next step in the research, Dr. Grunfeld suggested measuring regional
body composition, using CT, or MRI, or possibly DEXA. Regional body composition
is an experimental technique, and protocols will need to be developed. |
