New AIDS Drugs Might Help Against Resistance
By David Brown
Washington Post Staff Writer
Tuesday, February 26, 2002; Page A02
SEATTLE, Feb. 25 -- A new generation of drugs to fight the AIDS virus is showing promise in early testing, researchers reported today.
Scientists attending the 9th Conference on Retroviruses and Opportunistic Infections -- the annual mid-winter U.S. AIDS meeting -- heard about developments in three new classes of HIV medicines, and about potent new members of one of the existing classes of drugs.
"It is a phase of accelerated development that's likely to keep pace with the current problem of drug resistance" in AIDS viruses carried by patients, said Brian Gazzard, a physician at Chelsea and Westminster Hospital in London. "After a lull for two or three years, the sort of data we're seeing is very exciting."
There are 15 drugs on the market that inhibit replication of the human immunodeficiency virus (HIV) -- the essential strategy for slowing or stopping the disease's progression. All work by attacking two of the three enzymes -- known as reverse transcriptase or protease -- that HIV employs inside a human cell. The new compounds -- some not yet tested in people -- either target the third enzyme, called integrase, or seek to stop HIV before it even enters the cell.
In themselves, the new compounds don't appear markedly different from their predecessors. HIV can also mutate into forms that resists their action, for example. Their importance stems from the fact that they may offer alternatives to people who have run through the existing antiretroviral drugs.
Although there are no good studies quantifying the extent of the drug resistance problem, AIDS specialists say that 30 percent to 40 percent of their patients eventually need to change one of their medicines because of resistance. Antiretroviral drugs are rarely prescribed alone, but usually in combinations of three or more drugs.
One of the new substances, being developed by the pharmaceutical firm Schering-Plough Corp., attaches to the CCR5 receptor, one of two parts of the docking bay that HIV uses to land on (and eventually pierce) cells of the human immune system. It was tried in 12 people with moderately advanced HIV infection who were taking no other drugs.
The patients began with, on average, 40,000 viruses per milliliter of blood. The compound, called SCH C, reduced the amount of bloodstream virus by 68 percent in 10 of the 12 people, and by 90 percent in 4 of them.
Earlier in development is a substance called BMS-806, which interferes with the virus's ability to attach to the other part of the docking bay, known as the CD4 receptor, on immune system cells. Bristol-Myers Squibb Co. researchers screened more than 100,000 compounds to find one with this particular action; the compound blocks gp120, a part of the HIV "envelope" that attaches to the CD4 receptor. It's the first drug candidate to target that step.
In test-tube studies it was active against a wide variety of AIDS viruses. Human tests probably will start sometime this year, said Richard Colonno, a company researcher.
The third new class of drugs described today is an "integrase inhibitor" being developed by Shionogi & Co., a Japanese pharmaceutical company. (Integrase is the enzyme that stitches HIV's genes into the human cell's genes, making the infection permanent.) It was highly active against strains of HIV that were resistant to reverse transcriptase and protease inhibitor drugs -- in other words, all the ones now available.
The compound, called S-1360, was well tolerated by rats and dogs. A small study in human beings is underway.
Researchers here also heard about the early success of a drug specifically designed to avoid resistance problems encountered by nevirapine and efavirenz, the two existing members in its class of drugs, known as non-nucleoside reverse transcriptase inhibitors.
TMC125, made by the Belgian company Tibotec Inc., appears to have an unusually powerful effect on HIV replication. In 12 patients it reduced the amount of circulating virus by nearly 99 percent when given alone for one week. This was equivalent to the reduction seen several years ago in a study of a combination of five drugs.
TMC125 will never be used alone because many antiretroviral drugs are extremely powerful at first, only to be rendered near-useless in weeks as the virus mutates.
Exactly how many AIDS patients in the United States and other wealthy countries are now dying because they exhaust all existing antiretroviral options is uncertain. Reports from academic AIDS clinics suggest the number is small.
At the University of Colorado Health Sciences Center in Denver, the annual death rate of HIV patients under care has fallen from 13 percent in 1995 to 2.4 percent in 2000, said Robert Schooley, an AIDS physician there. Furthermore, half the people who died in 2000 succumbed to non-AIDS illnesses or trauma.
In an unrelated presentation yesterday, Patricia Fleming, an epidemiologist at the Centers for Disease Control and Prevention, said the estimate of the number of people living with HIV infection in the United States is 850,000 to 950,000. That's 50,000 people higher than the estimate made in 1998. Fleming said longer survival, not a rising number of new infections, is the reason for the higher number. |
