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,
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.
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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.
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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