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AIDS

Combination drug therapy for AIDS buys time, but is not a cure

In the battle against AIDS, drugs are beginning to play an important role. A promising approach suggested by laboratory studies has met with recent success. It involves drugs that inhibit the AIDS-causing HIV virus in the test tube. There are two basic kinds of these anti-AIDS drugs. The most widely used are AZT and its analogs, which block virus gene replication by gumming up the virus RNA (the genes of HIV are made of RNA, not DNA, as are those of many other human viruses, like flu). A second basic kind of anti-HIV drug are so-called protease inhibitors, which block the enzyme (called a "protease") which chops HIV's long "raw material" proteins into useable lengths – sort of like depriving a homebuilder of his saw.

When combinations of these two kinds of drugs were administered to people with HIV over the last four years, their condition was markedly improved. A combination of a protease inhibitor and two AZT analog drugs entirely eliminated the HIV virus from the bloodstream of many HIV positive patients.

Why three drugs? Why not just one? A random mutation can confer resistance to one drug – unlikely, but unlikely things do happen. People do get hit by lightening, or bit by bulldogs, or shot in the head by stray bullets – but what is the probability that you will be hit by lightening while being bit by a bulldog, just as a stray bullet penetrates your skull? A given cell in the human body might by rare chance mutate to resistance to one of the anti-AIDS drugs, but three independent rare mutations to drug resistance, all in the same cell at the same time, is simply too unlikely to ever happen.

This approach of using multiple anti-AIDS drugs in combination has proven very successful. Widespread use of this so-called "combination therapy" has cut the US death rate dramatically since its introduction in the 1990s, from 43,000 AIDS deaths in 1995 to 31,000 in 1996, and 21,000 in 1997.

Unfortunately, combination therapy does not appear to actually succeed in eliminating HIV from the body. While the virus disappears from the bloodstream, traces of it can still be detected in the lymph tisssues of the patients. These tissues, rich in macrophages, are the sort of cells in which HIV infections usually get their start. When combination therapy is discontinued, HIV virus levels in the bloodstream once again rise.

It is also unfortunate that combination therapy is proving very difficult to maintain over the long term. The schedule for taking the three drugs is very demanding-- many pills must be taken, carefully timed to match eating and sleeping. Also, the three drugs have many side effects, not all of them pleasant. Faced with these difficulties, many

therapy schedules go askew, either because of mistimed doses of one or more of the three anti-AIDS drug, or, increasingly, because of outright abandonment of treatment by the discouraged patient.

Perhaps reflecting these difficulties, the dramatic drop of American AIDS deaths from 1996 to 1997 (fully 42%, almost cutting AIDS deaths in half!) has not continued. The drop from 1997 to 1998 been followed by a far less impressive 20%. In New York City, where AIDS death rates had dropped 63% in 1996-1997, AIDS deaths dropped only 25% in 1998 – and not at all in the second half of 1998.

Why are the death rates ceasing to fall? The side effects and rigors of combination therapy -- the many pills that HIV positive patients must take each day on a rigid schedule -- is surely partly to blame. There is also the unpleasant possibility that strains of HIV are becoming resistant to the drug combinations, although no evidence points this way yet.

Meanwhile, the rate of new infection with HIV in the U.S. is no longer declining, health officials at a meeting in Atlanta of AIDS experts said. It appears to have stabilized at about 40,000 new Americans infected each year. About 70% of those infected are men, 30% of those infected are women.

It is difficult to avoid the conclusion that the AIDS epidemic is not over in this country. The AIDS death rate may soon start to swing back upward. There is a major effort underway by AIDS experts focusing on improving AIDS prevention. In view of the bad news about the long-term impact of combination drug therapy, such renewed efforts to slow the spread of AIDS deserves our strongest support.

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