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, however.

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 patient's therapy.

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 rebounded.

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