San Francisco Chronicle - Wednesday, January 5, 2000
Carl T. Hall, Chronicle Science Writer

Doctors said the findings, reported today in the Journal of the American Medical Association, underscore the dangers of indiscriminate use of the latest weapons in the fight against AIDS.

One drug, ritonavir, a so-called protease inhibitor marketed by Abbott Laboratories Inc. under the trade name Norvir, showed liver toxicity problems five times as severe as the other drugs studied.

Researchers at Johns Hopkins University, led by Dr. Mark Sulkowski, studied 298 patients who were prescribed anti-viral drugs during a two-year period ended in January 1998. In 31 cases, standard tests for elevated liver enzymes showed severe toxicity -- defined as enzyme levels five to 10 times higher than the upper limit of the normal range.

Sulkowski said less pronounced toxicity was also "quite common," but only the most severe problems, which forced patients to halt treatment, were tabulated in the study.

The danger of side effects from AIDS drugs, including liver damage, has been known for years, but the new study appears to be the first careful attempt to quantify one of the most significant health risks.

"These drugs are hard on the liver," Sulkowski said. "We just didn't know how common (these problems) can be."

The Johns Hopkins team focused on liver toxicity in part because of the growing problem of AIDS patients who also harbor the virus that causes chronic hepatitis C.

HCV, as the hepatitis virus is known, also attacks the liver, and is estimated to be present in about one-third of all those infected with the AIDS virus in the United States. Researchers estimate that co-infection with hepatitis C is found in 90 percent of those who acquired HIV through intravenous drug use.

Given the higher dangers of liver damage from ritonavir, Sulkowski said, clinicians may be wise to look for a different drug when treating co-infected patients.

"Ritonavir was far and away the most toxic drug," he said. "If you have a choice, it may be prudent in a patient with HCV to avoid using ritonavir if you can."

The study also looked at three other protease inhibitors -- saquinavir, indinavir and nelfinavir -- and an older category of drugs such as AZT, called nucleoside analogues. Both types of drugs are generally used in combination to fight the AIDS virus.

One limitation of the study, however, is that it examined particular drug combinations and dosages that may no longer be in widespread use, because drug companies continue to introduce new formulations and doctors frequently alter practices in light of patient reports and ongoing research.

Drugmaker Dupont Merck, for example, has recently introduced a once-daily pill called Sustiva (efavirenz) that appears to be relatively free of liver-related side effects when used in standard multidrug combinations. It was not included among the drugs studied by Sulkowski and his colleagues.

Despite the potentially severe side effects on the liver, Sulkowski said, patients should not be frightened away from potentially life-saving AIDS drugs if their doctors are recommending them.

On the plus side, the study showed most AIDS patients, even those with hepatitis C co-infections, were not overwhelmed with liver- toxicity problems. Overall, only 12.2 percent of the HIV-HCV co-infected patients had to stop treatment with any protease inhibitor because of effects on the liver. And once those patients stopped the drugs, none suffered any permanent liver damage.

In a prepared statement, Abbott Laboratories said its own clinical trials, which enrolled 900 patients, found abnormal liver function only one-third as often as did the Johns Hopkins study.

A spokeswoman said the drug has been shown to be safe and effective, with appropriate monitoring. But she also noted that the new study is the first to look at the Abbott drug's side effects in direct comparison with the other medications.

Dr. Jay Levy, professor of medicine and director of AIDS research at the University of California at San Francisco, said the new study results were not surprising in light of anecdotal reports from AIDS clinics.

He said the findings show a clear need for caution before even starting anyone on potent anti-viral medicines. Besides toxic effects, he noted, the AIDS drugs can also create drug-resistance problems when used improperly.

"These drugs are marvelous," Levy said, "but you've got to recognize their side effects. They're powerful and very effective when used at the appropriate time. But there are trade-offs."
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