The Wall Street Journal - 11 July 1996
Michael Waldholz, Staff Reporter of The Wall Street Journal

Researchers said they will present the new results at a special session for "late-breaking" scientific developments scheduled for this afternoon at the 11th International Conference on AIDS meeting here. The researchers said preliminary data arising from the first human trial pairing two protease inhibitor drugs showed that the combination therapy eliminated most all the AIDS virus in the circulating blood of 43 patients who have been taking the treatment daily for six weeks. Scientists cautioned that some latent virus is still lurking in some body tissue that could re-emerge if therapy is discontinued.

By presenting an unusually early peek at preliminary results of the study, researchers are certain to buttress the growing evidence that the new protease drugs -- approved in the U.S. since December -- represent a stunning medical advance in the 15-year fight against AIDS. The researchers said one reason for releasing data early is that some doctors and their patients are already mixing several of the potent protease drugs despite the lack of research showing if the combination is safe or effective, or exactly what dose of the drugs to use.

In the new study, doctors at several U.S. and Canadian medical centers are giving patients infected with HIV, the AIDS-causing virus, a twice-daily dose of two protease drugs, Abbott Laboratories' Norvir, also known as ritonavir, and Roche Holding AG's Invirase, also called saquinavir. Protease drugs block an enzyme that is critical to HIV replication.

In recent studies, these protease inhibitors, as well as another called Crixivan (indinavir) that is sold by Merck & Co., have produced impressive results when each was used in a drug "cocktail" containing two older types of AIDS medicines, such as the antiviral agent, AZT. This three-drug therapy, although very expensive, cumbersome to use and prone to annoying side effects, is nonetheless showing an unprecedented effect in bolstering sick patients' immune systems, improving patient health and forestalling life-threatening infections.

The study being released today "is the first experiment showing we can safely use two protease drugs together," said Martin Markowitz, a researcher at the Aaron Diamond AIDS Research Center, New York and one of the physicians conducting the two-drug test. Especially impressive, Dr. Markowitz said, is that combining the two drugs sharply augments the antiviral punch of each of the two protease inhibitors, most especially Roche's Invirase.

The apparent synergy between the drugs results from a remarkable bit of good fortune, the scientists said. Roche's Invirase is actually one of the most potent and least toxic of the new protease drugs, at least in test-tube studies. But in clinical practice Invirase has the weakest effect of the new drugs because most of the compound is destroyed by an enzyme in the liver.

Abbott's Norvir, quite by chance, blocks much of the action of the liver enzyme. Thus, when coupled with Norvir, Invirase gets released into the bloodstream in much higher concentrations than normal.

The addition of Norvir to Invirase "turns a puddle into a tidal wave," said Dr. Markowitz. He also believes Norvir may also be able to significantly increase the potency of Merck's Crixivan, as well as two other protease drugs in development, and he hopes to undertake studies of other protease combinations soon.

In interviews here earlier this week, representatives from Abbott and Roche said that while they believe the new two-drug combination will become a standard therapy for treating many HIV-infected people, they strongly urged doctors and patients to await the outcome of the full study before combining the drugs on their own.

The study has actually enrolled 120 patients to date. But only the 43 being discussed today have been in the study long enough to produce reportable results. The study used a dose of Invirase about one-half to one-quarter the amount used in three-drug combination therapy that doctors have been using in recent months. But even at the reduced dosing, Invirase's potency when combined with Norvir is increased 100-fold, said Miklos Salgo, a Roche research manager.

Even so, the two-drug combination will still be very expensive -- about $12,000 to $14,000 for a year's worth of treatment -- and burdensome to take, requiring 12 to 16 pills a day. Norvir's bothersome side effects, most notably, nausea, are only somewhat muted in the new therapy, the researchers said.

Many experts have cautioned that the protease drugs wouldn't work together or might produce a resistant strain of the virus. But the researchers said they saw no evidence of heightened resistance. Indeed, "the rate of virus decline [in the blood] is the fastest we've seen with any of the new drug combinations tested so far," said John Leonard, an Abbott research manager.

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