AIDSWEEKLY Plus, 24 June 1996
Daniel J. DeNoon, Senior Editor

A three-drug combination has set a new standard for AIDS therapies.

Copies of HIV RNA - now considered the best surrogate marker for HIV disease - dropped to undetectable levels (below 200 copies/ml) in the plasma of more than 90 percent of subjects receiving the triple combination of the protease inhibitor indinavir (Crixivan, Merck), zidovudine (AZT, Glaxo- Wellcome), and lamivudine (3TC, Glaxo-Wellcome).

No patient maintaining treatment has had a rebound of HIV. Some subjects have completed nearly a year of therapy.

CD4 counts in patients receiving the three-drug combination increased by about 120 cells/(micro)L and did not decline over time.

"Merck has set the benchmark for a triple combination," said researcher Dean Winslow of Agouron Pharmaceuticals Inc. Agouron is currently developing its own HIV protease inhibitors.

Merck researcher Emilio Emini reported the findings at the International Business Communications (IBC) workshop "HIV Protease Inhibitors," held June 11, 1996 in San Francisco, California.

"If it [indinavir] is appropriately used in the clinic it can avoid one of the banes of anti-HIV therapy: the development of resistance," Emini said. "In fact, one can for the first time play the resistance game against the virus. ... These results are all the more striking because all of these viruses were AZT resistant at baseline, just like you see in the real world."

Patients enrolled in the indinavir/AZT/3TC study were HIV positive with a CD4 count of 50-400 cells/(micro)L and more than 20,000 HIV RNA copies/ml plasma. They also had to have taken AZT for at least six months. Patients were randomized to one of three arms: indinavir alone, indinavir plus AZT plus 3TC, and AZT plus 3TC.

The few patients in whom HIV remained detectable after receiving the three-drug combination therapy could be identified by the time they had been taking the drugs for six months.

"By 24 weeks the game is up," Emini said. "By this time everyone who is going to drop to undetectable levels has done so."

Emini suggested that the long-term suppression of the virus seen in this clinical trial represented "a paradigm shift" in the way anti-HIV drugs are evaluated.

"Now the goal of therapy is to lower virus load as much as possible - to undetectable levels - for as long as possible," he said. "Treatment comparisons should compare the number of patients who become aviremic and how long they remain that way."

Despite having undetectable levels of HIV, study participants remained infected with the virus. Patients who completely discontinued indinavir had an increase in HIV virus levels. The HIV detected at this time was not resistant to indinavir, as shown both by in vitro studies and by the fact that patient viremia again became undetectable when treatment resumed.

"What one has to keep from happening is this: replication of residual virus," Emini said. "There is a genetic barrier the virus must overcome to develop resistance.

In earlier studies of the indinavir monotherapy, patients who received suboptimal doses of the drug developed indinavir- resistant virus. The virus did not respond when these patients subsequently received higher doses of the drug.

"Initial therapy has to be with the highest effective and tolerable dose of the most potent inhibitors," Emini warned. "Once started, therapy must be maintained. ... If therapy must be interrupted, stop the drug, then begin again. Do not dose- modify downward."

The most serious side effect of indinavir is the development of nephrolithiasis (kidney stones). Emini said that this adverse event occurs in only 2 percent of patients who drink the recommended 1.5 liters of fluid each day. Anecdotal reports from patients receiving the drug, however, suggest that the real-world incidence of flank pain may be higher.

Emini noted that indinavir/rifabutin and indinavir/ketoconazole interactions occur and require dose modifications.

In an article in the May 1966 issue of GMHC Treatment Issues, writer Dave Gilden reported that until full-scale production facilities are on-line in late 1996, Merck has enough indinavir to provide the drug to only 30,000 U.S. patients. Supplies to these patients will be guaranteed.

Merck's wholesale price for the drug is $4,380 per year. Gilden reported that the provider for nearly all of the drug - the mail-order pharmacy Stadtlanders, Pittsburgh, Pennsylvania - originally charged $6,022.50 per year. This 37.5 percent markup was reduced to a 15 percent markup via discounts to holders of Community Prescription Service discount cards (available for $18 per year). However, traditional medical insurance companies must still pay the full price.

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