TEST DETECTS ANTI-HIV DRUGS' EFFECTS ON CELLS
By Merritt McKinney
Reuters 13 March 2002
New York -- Some of the drugs used to treat HIV, the
virus that causes AIDS, are known to interfere with the basic
activities of the body's cells, which can lead to side effects.
Detecting the cellular effects of the medications has not been easy,
Now scientists in Canada have developed a blood test that can measure
the effects of anti-HIV drugs on cell structures called mitochondria.
The screen can detect drug-related damage to mitochondria even before
side effects begin, which could give doctors time to adjust a
The power plants of cells, mitochondria create the energy that cells
need to function normally. But a class of anti-HIV drugs called
nucleoside analogues, which include medications like AZT, can
interfere with the ability of mitochondria to produce energy. If
patients taking nucleoside analogues, which are often prescribed as a
part of combination therapy for HIV, develop this so-called
mitochondrial toxicity, they may experience fatigue, shortness of
breath, weight loss and a rapid heartbeat.
One way to detect mitochondrial toxicity is to measure levels of
lactic acid in the blood, which often rise when mitochondria are
damaged. But this test is not very reliable.
Now a team led by Dr. Julio S. G. Montaner at the University of
British Columbia in Vancouver reports the development of a test that
can detect mitochondrial toxicity by measuring levels of mitochondrial
DNA in the blood.
The researchers tested the effectiveness of the screen in three groups
of people: a group of HIV-positive individuals on nucleoside therapy
who had developed symptoms of mitochondrial toxicity; a set of
HIV-positive people who were not taking any anti-HIV drugs; and a
group of HIV-negative people.
Levels of mitochondrial DNA were "significantly depleted" in patients
with HIV who had symptoms consistent with mitochondrial toxicity.
Though these patients had high levels of lactic acid in the blood, the
test developed by Montaner and his colleagues detected mitochondrial
toxicity even before lactic acid levels rose. Once the patients
stopped taking their anti-HIV therapy, levels of mitochondrial DNA
In contrast, HIV-positive individuals who did not have symptoms of
mitochondrial toxicity had higher levels of mitochondrial DNA. Their
levels were lower than those of the HIV-negative group, however,
according to the report in the March 14th issue of The New England
Journal of Medicine.
Montaner told Reuters Health that he hopes the screen will make it
possible to learn how mitochondrial toxicity develops so that it can
be prevented or treated. He and his colleagues are conducting several
studies of the screen, including additional research to see if the
test can be used to predict whether certain drug-related side effects
will develop. They also are testing the benefits of several
treatments, including vitamin supplements, to treat mitochondrial
toxicity in its early stages.
"It is unclear at this time how frequently mitochondrial toxicity is
at the bottom of some of the side effects that we currently see in the
clinic among patients on antiretroviral therapy," Montaner told
Reuters Health. But it is "quite clear," he said, that severe
mitochondrial toxicity is to blame for rare, but sometimes fatal,
severe cases of a condition called lactic acidosis.
It is possible, but not yet proven, that changes in mitochondrial DNA
levels could prompt a physician to change a patient's therapy,
according to Montaner. There is preliminary evidence that some
nucleoside medications are less likely to cause mitochondrial-related
side effects than others.
"If this kind of data could be confirmed, one could conceive of
mitochondrial-sparing regimens which could be appropriate for any
individual, but particularly so for individuals who have evidence of
mitochondrial toxicity," he said.
Montaner noted, however, that the test, or assay, is not yet
available. "We are currently evaluating the value of the assay in
epidemiological and clinical trials," he said. After these trials are
completed, "we will be in a better position to discuss whether or not
using the test in the clinical setting is appropriate," Montaner said.
Source: The New England Journal of Medicine 2002;346:811-820