Here's another report which was taken from results seen by other MDs. It also notes that at the time Crix represented 70% of the protease market, which may also account for the name Crix-belly. The report indicated that more studies were being started to look at the condition and associations more closely. The metabolic changes can result in hospitalization and can be life threatening in some instances and resulted in label changes on protease inhibitors.
I didn't see any "insignificant" characterization of the condition in the article. Although there was no recommendation to abandon treatment in general, there was some concern about hitting hard and early, especially in asymptomatic patients:
Protease Inhibitor Side Effects Take
People by Surprise
by Alan Huff, D.C.
Ellen, a 42-year-old white female bookkeeper, has been on triple combination therapy
for the last 12 months. During this time she has had an undetectable viral load. But,
Ellen relates, "The most unusual development has been breast enlargement. My breasts
got round, full and plump and they stand out like the dancers in Las Vegas who have
had implants." She continues almost with disbelief, "I was a 34A [bra] cup and went to
a 36D cup. I went to my doctor who told me that I should go find a boyfriend. We did
not realize it was the Crixivan. I should send the drug company the bill for my new
bras." Ellen has found an e-mail discussion group, Crix-List@PinkPage.com
(http://www.pinkpage.com/Crix/), instituted so that people can share their experiences
on Crixivan (Merck's protease inhibitor indinavir). There are hundreds of entries each
month from individuals reporting all manner of possible side effects, including other
women like Ellen, who say the changes in their bodies remind them of when they were
pregnant.
Over the last year a growing number of patients on protease inhibitor-containing
regimens have reported a variety of unusual symptoms. These range from changes in
body composition and blood sugar and lipid levels to hemolytic anemia to abnormal
bleeding in HIV-positive hemophiliacs. It is clear that many people are experiencing
unexpected metabolic changes after starting combination therapy. What is not clear is
the exact cause or the potential for permanent damage.
Triglyceride, Cholesterol and Blood Sugar Levels
As of May 1997, there were 83 reports to the FDA of new or exacerbated cases of
diabetes or hyperglycemia (high blood sugar) in HIV-infected patients who were
receiving protease inhibitor therapy. As of November 1997, the number of reports had
increased to 230. Of the 83 original cases, 27 required hospitalization, including six
that were life threatening. Fourteen of the patients, who were known to be diabetic at
baseline, experienced loss of glucose control. Average time to onset was 76 days after
initiating protease inhibitor treatment, but in some reports symptoms appear in as little
as four days. Five cases resulted in ketoacidosis, a serious diabetes-related condition
that is characterized by a fruity mouth odor, nausea, vomiting, dehydration, weight loss,
and if untreated, coma or death. The initial 83 reports led the FDA to issue a Public
Health Advisory in June. Physicians were warned that protease inhibitors may
contribute to these conditions and advised to closely monitor patients' glucose levels.
Diabetes and hyperglycemia were reported in varying degrees for all four protease
inhibitors, although no causal relationship has been established. The FDA maintains that
these events occur infrequently and does not recommend that patients stop using
protease inhibitors. At this early stage, with such a limited number of cases reported,
the benefits still outweigh the risks. In addition, many patients who developed diabetes
while on protease inhibitors were able to control the condition with treatment.
Nonetheless, all four protease inhibitors were required to revise labeling to include this
potential side effect.
Michael Dube, M.D., of the Los Angeles County-University of Southern California
Medical Center, has become increasingly concerned that protease inhibitors alter the
way the body handles blood sugar (glucose). He so far has conducted research on
eight non-diabetic patients before and after starting indinavir. When he administered
oral glucose to the patients, Dr. Dube found some reduction in the amount of insulin
secreted in all eight after two weeks on indinavir, but these results could not be
duplicated at eight weeks. (Insulin is a naturally occurring hormone released by the
pancreas in response to increased blood sugar levels. The hormone regulates the
body's use of sugar as well as some of the processes involved with fats, carbohydrates
and proteins. Inadequate secretion of insulin results in hyperglycemia and the signs of
diabetes, including heightened thirst and hunger, increased urination, weight loss
without apparent cause, fatigue and dry, itchy skin.)
Dr. Dube notes that glucose and lipids are intimately linked. In fact, there have been
many reports of elevated levels of such lipids as triglycerides and cholesterol in patients
on protease inhibitor therapy. Excess lipids in the bloodstream can lead to
arteriosclerosis (hardening of the arteries) and heart disease. John Gerber, M.D., of the
University of Colorado, explained how he handles elevations in blood triglycerides in
his patients, "I figure when triglycerides get above a thousand (normal levels are
35-200 mg/dl), I choose to stop the medication. This is because of my concern
regarding pancreatitis. I have not seen pancreatitis in any reports, but we know high
triglycerides can precipitate this condition."
Dr. Gerber also elaborated on the combination of protease inhibitors and cholesterol
lowering agents for those patients who have experienced high cholesterol levels. He
stated certain drugs, such as lovastatin and simvastatin, both used to lower cholesterol,
are metabolized in the liver by the cytochrome P450 family of enzymes, specifically the
3A4 pathway (CYP3A4). The protease inhibitors are also metabolized by this
pathway, so there is a potential for drug interactions at this site that might lead to side
effects. Abbott's protease inhibitor, ritonavir, actually inhibits the CYP3A4 enzymes.
This means a person taking ritonavir might not break down lovastatin and simvastatin
adequately, leaving high levels of these drugs in the bloodstream. Dose adjustments
might be needed to avoid possible toxicities that could be fatal. "I think people need to
pay attention to drugs that are metabolized by 3A4 and have a very low threshold in
regards to toxicity," Dr. Gerber stated.
Red Blood Cell Destruction and Hemorrhaging
This past summer, Merck added a warning label to indinavir as a result of 20 cases of
hemolytic anemia. The condition causes a premature destruction of red blood cells, and
the most common symptoms are fatigue, jaundice and discolored urine. The condition
progresses rapidly and requires treatment, including possible discontinuation of the
protease inhibitor.
People with hemophilia have had special concerns about protease inhibitors and blood
loss: The FDA notified physicians in July 1996 of the first 15 reports of spontaneous
bleeding among hemophiliacs treated with one of the protease inhibitors. There are
now at least 55 such reports worldwide. At the 6th European Conference on Clinical
Aspects and Treatment of AIDS held in Hamburg last October, there was a
presentation (abstract 380) on 17 Spanish hemophiliac patients who had indinavir
added on to prior AZT/3TC. Five of the seventeen (29.4%) experienced bleeding,
including three hematomas.
Hematomas, in which blood flows into body tissues and causes swelling, have been the
most commonly reported serious bleeding. However, there have been some cases of
hemarthroses, or bleeding into a joint. This is the type of hemorrhage most common
among hemophiliacs. Again, the FDA has stressed there is no conclusive evidence that
links such occurrences specifically with protease inhibitor use but does recommend that
health care providers monitor hemophiliac patients for spontaneous bleeding episodes
whenever any of the protease inhibitors are used.
Changes in Body Composition
Perhaps the first unusual symptoms to be seen in people taking protease inhibitors
were growths of atypical fat-like tissues in the stomach (popularly called "Crix belly,"
although other protease inhibitors may have similar effects) and upper back ("buffalo
humps"). Other patients, such as Ellen, began to notice breast enlargement. These
abnormal fat deposits can be accompanied by loss of mass and strength in the limbs
and buttocks, as in the case of another participant on the Crix-List. This patient
described muscle wasting in the arms, chest and legs as well as fatty growths in the
upper back and neck area that increased in size after starting indinavir. The benign
growths were surgically removed and diagnosed as "lipomas" (tumors consisting of fat
cells). Other postings to the list describe the condition as "lipodystrophy" (an
abnormality in the use of fats in the body). Whether these fatty growths are related to
the increases in blood lipids has not been determined.
In a presentation at the Interscience Conference on Antimicrobial Agents and
Chemotherapy (ICAAC) this fall, Peter Ruane, MD, of the Tower ID Medical
Associates in Los Angeles, described buffalo humps in nine of his patients (poster
I-185). One patient opted for surgical removal of the growth through liposuction, and
another is considering the option. Interestingly, all of the patients had elevated levels of
serum triglycerides and seven of nine had elevated serum cholesterol.
Adon Rios, MD, an oncologist in Houston who has specialized in AIDS treatment and
research from the beginning of the epidemic, does not see buffalo humps as clearly
harmful, but an unexplained fatty growth of tissue is always a concern for an oncologist.
As with Dr. Ruane, some of his patients have had their buffalo humps removed
surgically.
Symptoms of this condition include general discomfort when patients lie on their back
during sleep or maintain their neck in an upright position while awake. No clear cause
or damage has been identified with the condition, though most of the patients
developed the condition shortly after initiating triple combination therapy with protease
inhibitors, indinavir in particular.
Cushing's syndrome, a condition with similar physical manifestations, has been ruled
out for the time being. Although patients with Cushing's syndrome also develop
hump-like growths in the neck and stomach regions, this is due to a high level of the
hormone cortisol, which has not been observed in the people with HIV who exhibit
similar growths.
In a recent letter to The Lancet (RL Hengel et al. The Lancet. Nov. 29, 1997;
350(9091): 1596), a group of doctors from Emory School of Medicine in Atlanta
reported on a patient who developed a buffalo hump within six months of beginning
treatment with indinavir. Blood tests revealed only minimally elevated blood glucose
levels. Electrolytes and cholesterol were at normal levels. Further testing ruled out
Cushing's syndrome. This abnormality was diagnosed as benign symmetric
"lipomatosis," an uncommon condition consisting of unusual tumorlike accumulations of
fat in body tissues, usually seen in male alcoholics. Various reports also indicate an
association with glucose intolerance and hyperlipidemia (an excess of fat in the blood).
But the Atlanta patient was not an alcoholic. His viral load was too low to assay, and
he has continued on his regimen without any worsening of the fatty growth. In their
letter to The Lancet, his physicians conclude, "The temporal association between
starting his medications and developing his 'buffalo hump,' the effect of protease
inhibitors on P450 enzymes, and the recent associations between indinavir use and
glucose and lipid metabolism lead us to believe indinavir may be implicated in the
development of benign symmetric lipomatosis."
Plans for Future Research
There is as yet no hard data to indicate that this desultory list of symptoms is connected
to protease inhibitor use or if any of the conditions are linked to each other. The Forum
for Collaborative HIV Research has proposed conducting controlled prospective
studies to shed light on which of these abnormalities, if any, are due to protease
inhibitor use and why. Several investigations are in development. The first will be a
survey to assess the prevalence and nature of metabolic symptoms that are occurring in
patients with AIDS. It will consider changes in weight and weight distribution, along
with the background medical and family history of participants. The second study will
follow a group of people on antiviral therapy and collect data over time on
triglycerides, cholesterol, glucose, testosterone, cortisol, insulin and other factors as
well as body fat composition. Other studies are needed to evaluate the pathogenesis of
arteriosclerotic heart disease.
About 70% of patients on protease inhibitors are on indinavir. According to a
representative from Merck, the company plans to have greater communications with
clinics and patients regarding these unusual conditions. A site on the World Wide Web
may be established to answer questions, as with other cases of unexpected side
effects. At least for now, Merck requests that people not refer to atypical fat growths
around the mid-section as "Crix belly." The company had no comment regarding the
bill for Ellen's new bras.
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