The Washington Post

Thursday, February 3, 2000

New Class of AIDS Drugs Touted

By David Brown

SAN FRANCISCO, Feb. 2 -- A new class of drugs that work by preventing the AIDS virus from entering cells, rather than by interrupting its activity once it gets there, may eventually offer more treatment options for people who've run through the current types of AIDS drugs.

Most of the so-called "entry inhibitor" drugs in development have been tested only in the laboratory in cells and animals. One that's been given to AIDS patients requires multiple daily shots, and is not likely to be practical for large numbers of people. Nevertheless, the principles behind the drugs appear to be sound.

"The progress made to date is extremely encouraging," said Daniel Kuritzkes, an AIDS specialist at the University of Colorado Health Sciences Center in Denver. However, he cautioned against the expectation that entry inhibitors will be immune from problems (such as drug resistance) seen in the medicines already in use.

"Everything we know about HIV drugs is likely to remain true with these ones, as well," he said on the final day of the Seventh Conference on Retroviruses and Opportunistic Infections, a gathering of AIDS researchers.

Entry inhibitors have arisen, in part, from a better understanding of how human immunodeficiency virus (HIV) gets inside lymphocytes and the other blood cells that are the microbe's principal targets. That understanding, in turn, has come from both molecular and epidemiological studies. For example, one of the experimental drugs discussed here seeks to mimic a rare human mutation that renders some people extremely resistant to HIV infection.

HIV penetrates cells by first linking with two receptors, or docking bays, on the cell's surface. That permits the virus and cell membranes to melt together, which releases the virus's contents into the cell's interior. About five years ago, biologists identified a small number of people who lack some or all of a receptor called CCR5, which HIV uses to enter cells at the time of initial infection.

People with a reduced number of CCR5 receptors could acquire HIV infection, but tended to have a long, indolent course of disease if they did. Those with no CCR5 were virtually immune to infection.

At the meeting yesterday, a scientist with Progenics Pharmaceuticals, a biotechnology company in New York, reported that in laboratory tests, a substance that blocks CCR5 protects human cells from HIV infection. Equally important, HIV did not appear to develop mutations that allowed it to "escape" the blockade. Whether that will remain true on further tests, especially in human beings, is a crucial question still unanswered.

There are other strategies in the works to block HIV if it finds a way around CCR5. One is a compound called AMD3100, made by the Canadian company AnorMED, which blocks a receptor called CXCR4.

While HIV uses CCR5 to infect cells early in the course of HIV disease, over time the virus evolves to use CXCR4, which is an entirely different receptor. The switch is an ominous sign, because microbes that use CXCR4 are especially aggressive, and patients usually have a rapid downhill course.

AMD3100 blocks these virulent strains of HIV in cells in the laboratory and in mice. A trial of the drug in people is underway. If it proves successful, the compounds will be most useful in the very people most desperate for new therapies--people who are very ill and whose HIV is resistant to the antiviral medicines now on the market.

The drug farthest down the development pipeline is T-20, made by the North Carolina company Trimeris. It prevents the virus and cell membranes from fusing, and thus is in the "fusion inhibitor" subgroup of "entry inhibitors."

About 50 patients, who had taken 11 antiviral drugs on average and had developed resistance to many, have been taking T-20 for more than six months. About half show a meaningful reduction in the amount of virus.

How much of the patients' improvement is attributable to T-20 is impossible to say, as they also switched some of their other medicines at the same time. (Previous studies have shown that HIV can develop resistance to T-20 in as short a time as a month when the drug is given alone.) Nevertheless, the patients as a group were doing better than expected.