Abizarre and unexpected set of vascular and lipid
syndromes appears to afflict an as-yet-undetermined percentage of
HIV-infected patients taking what is called highly active antiviral
therapy. The syndromes, the subject of several presentations at the
12th World AIDS Conference in Geneva, Switzerland, were
among the most serious side effects of the therapy that has
revolutionized AIDS treatment in industrialized nations.
HAART, as the treatment is more generally known, usually
consists of 2 nucleoside reverse-transcriptase inhibitors and a
protease inhibitor. Usually, 1 of the reverse-transcriptase inhibitors
crosses the blood-brain barrier. These drugs interfere with the life
cycle of the retrovirus at the point at which RNA is translated into
the DNA that can be incorporated into the genetic blueprint of the
cell. Protease inhibitors work later in the life cycle of the virus,
preventing release of virions from the cellular machinery that has been
subverted into a virus factory.
The syndrome consists of a lipodystrophy, with fat disappering from the
limbs and distant areas of the body while concentrating in the trunk.
There are often unusual fat deposits in the abdomen and a "buffalo
hump" of fat in the upper shoulders. There were also some levels of
serious insulin resistance and, in some cases, frank diabetes mellitus
associated with the syndrome. Of even greater concern are high
cholesterol and triglyceride levels—above where most physicians in the
world would begin to treat, said David Cooper, MD, immediate past
president of the International AIDS Society and a practicing physician
at St Vincent's Hospital in Sydney, Australia.
The nucleoside reverse-transcriptase inhibitors block the action of the
retroviral enzyme that translates the RNA of the virus into DNA that
can integrate into the genome of the cell. But the protease inhibitors,
only recently approved for general use, are the reason that AIDS
treatment has gone from abysmal to fairly effective in those patients
who can follow the complicated and often onerous regimens. However, the
protease inhibitors are also the source of the lipid problems seen in
HAART-treated patients.
Protease inhibitors interfere with the end of the viral life cycle,
when the virus is ready to release virions from the cells. It seems
bizarre that they are somehow also involved in lipid changes that have,
at times, been life threatening in the 2 years since they came into
widespread use.
Cooper said that about 60% of his patients have suffered the syndrome
in some form but that it is severe in only 10% to 20%. The factors
most often associated with the syndrome are the length of time the
patient has been taking a protease inhibitor and the type of
protease inhibitor. Ritonavir, 1 of the first protease inhibitors
developed, is probably 1 of those most likely to be associated with the
problem, although all are to some degree, Cooper said.
"Only 7% of patients taking protease inhibitors had normal lipid
values," said Andrew Carr, MD, one of Cooper's colleagues. In
describing 116 patients taking the protease-containing regimen, Carr
said only 18% reported lipodystrophy 22 months after beginning the
therapy. Of 76 patients who received glucose tolerance tests, 23% had
abnormal values, he said.
Before treatment, 59% of the patients who had never before received a
protease inhibitor had cholesterol and triglyceride values below the
normal, healthy value, said Carr. After treatment, only 7% of protease
patients had normal lipid values.
Krista Dong, MD, of Brown University said 20 women in her study
reported changes in their bodies, with some developing trunkal obesity
and a buffalo hump. However, she said, levels of cortisol were found.
"In HIV-negative persons, this body habitus is associated with
dyslipidemias and cardiovascular mortality," she said. "Most
studies have reported these effects exclusively in men."
Although some women had changes in cholesterol and triglyceride levels,
"the most frequent changes in habitus were increases in stomach and
breast size. The gains in breast size were big enough to cause 1 woman
to have to purchase dresses that were 2 sizes larger than she usually
wore," said Dong. The waist-to-hip ratio was still 0.8%, she said.
"Many had a BMI [body mass index] associated with obesity."
Cholesterol levels were elevated in most patients, and HDL levels were
lowered, said Dong. Triglycerides were elevated 33%. Dong said the
serum lipid abnormalities and body fat changes are apparently a
frequent side effect of HAART therapy. "In non–HIV-infected people,
these levels have been associated with risk of angina, stroke, and
diabetes," she said. She advised long-term studies to determine if
these kinds of sequelae can be expected in people taking these
therapies as well.
Although no one knows how serious these changes are or if they will
have the same effect that increased values have in normal people, some
physicians have reported anecdotal cases of serious problems. In a
recent issue of The Lancet, Bruno Gallet, Marc Pulik,
Philippe Genet, Pierre Chedin, and Michel Hiltgen, of the departments
of cardiology, hematology, and AIDS and endocrinology at Victor Dupouy
Hospital in Argenteuil, France, reported 2 cases of heart attack and
angina while patients were receiving HAART treatment.
One was a 33-year-old HIV-infected man who was admitted to the hospital
because of inferoposterior wall myocardial infarction. He had been
taking the protease inhibitor ritonavir for 14 months previously, along
with stavudine and didanosine—a typical 3-drug cocktail. However, he
also smoked
Cholesterol and triglyceride levels were elevated, and coronary
arteriography showed a subtotal occlusion of the right coronary artery.
PTCA was successful, but 4 months later, the patient had a recurrent
myocardial infarction. Coronary arteriography showed reocclusion, and a
second PTCA was done with coronary stenting.
Case 2 involved a 32-year-old HIV-infected man who was admitted because
of anterolateral wall myocardial infraction. He had been treated for 18
months with indinavir, lamivudine, and stavudine. Plasma HIV RNA was
649 copies per milliliter 5 months before admission. He smoked 40
cigarettes daily. On admission, cholesterol and triglyceride values
were normal. Peak serum creatine kinase was 290 U/L. Coronary
arteriography showed a 90% stenosis of the left anterior descending
artery, and PTCA with coronary stenting was successful.
A 54-year-old HIV-infected man presented with angina. He had been
treated for 21 months with lamivudine and ritonavir, and saquinavir was
added 13 months before he arrived at the hospital. Initiation of
protease inhibition was followed by a striking rise in cholesterol and
triglyceride levels 11 months before presentation, leading to treatment
with fenofibrate. An exercise test induced chest pain with ischemic
ST-segment depression. When the patient declined coronary
arteriography, acebutolol, transdermal nitroglycerin patches, and
aspirin were started. Angina resolved, and an exercise test while the
patient was taking medication was negative. (Lancet.
1998;351:1958–1959.)
Although the news of the side effects of the treatment was greeted with
alarm at the conference, Cooper warned that what he has seen does not
warrant the removal of patients from protease-containing therapy. More
research needs to be done into why patients are suffering
cardiovascular-related complications, he said.
He said the cardiovascular complications need to be treated, but the
mechanism of the problem must be completely elucidated before a
determination can be made about which drugs should be used. There is
some indication that the statins are not effective and might act
synergistically with the protease inhibitors.
"It's risk-benefit," said Cooper. "These drugs [protease
inhibitors] stopped people from checking out of the planet." It's a
matter of treating the problems, according to Cooper, not a matter of
taking people off life-saving treatment.
© 1998 American Heart Association, Inc.
Cardiovascular News
Vascular and Lipid Syndromes in Selected HIV-Infected Patients
1 pack of cigarettes daily.
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