The AIDS Drug Pipeline

From the WebMD Archives

March 4, 2002 -- Muscular new anti-HIV drugs promise to kick sand in the face of the world's biggest bully. They can't make the brute leave the beach -- but they just might make it leave people be.

Sixteen of these drugs are approved for treating people infected with the AIDS virus. That's not enough. Why? They simply don't cure HIV. Even powerful combinations of the drug only keep the virus at bay.

This means that the virus is always lying in wait, hoping that a person will miss a few doses a month so that it can make a comeback. And when it does it will have learned new tricks that let it defeat more and more of the treatments. HIV that's resistant to one drug often is resistant to some of the others. Sooner than anyone would like, the lifeline of 16 available drugs starts to unravel.

Help is on the way. Reports at the just-ended annual Retrovirus conference -- the most important U.S. AIDS conference -- offered progress reports on a slate of potent new drugs. A couple of these drugs are nearing FDA approval. Most are in earlier stages of human tests. A few are still on the drawing board.

Among the new drugs are two entirely different classes of drugs, offering hope to people who carry virus resistant to multiple drugs. Others are some of the most powerful anti-HIV agents yet discovered. And still other findings point to once-a-day dosing and ways to reduce side effects for existing drugs.

Keeping HIV Out

They call them entry inhibitors. It's a totally different attack on HIV. The idea is to keep HIV out of cells by throwing a monkey wrench into the virus's cell-snatching machinery. Several new drugs hope to do this. Farthest along is T-20. Approval is expected in early 2003. It's already available on a compassionate-use basis for patients who've used up all other options.

"This is absolutely the next important drug in HIV," Jacob Lalezari, MD, director of San Francisco's Quest Clinical Research, tells WebMD.

Lalezari's team showed that T-20 adds to the anti-HIV effect of an extremely potent combination of already-approved drugs. It's added effect is seen whether or not a person carries HIV resistant to other drugs.

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The downside: T-20 has to be taken by injection. This inconvenience means that the drug probably will be saved for people to use only after their first- and second-line anti-HIV drugs fail.

However, T-20 might be a great "morning-after" drug for people recently exposed to the AIDS virus. Current anti-HIV drugs fight the virus only after it's penetrated deep inside the body. T-20 keeps the virus from getting a foothold in the first place.

There are several other entry inhibitors in various stages of development.

New Nukes

Nucleoside RT inhibitors -- NRTIs or "nukes" in the lingo of HIV research -- have been the mainstay of AIDS therapy since AZT came out in 1987. The "RT" in NRTI is the target -- it's the tool the virus uses to change its RNA genetic code into the DNA code that takes over a cell. Seven now are approved, including Viread, a close relative to the NRTI family.

What's new in nukes:

  • DPC 817 kills HIV that's already developed resistance to AZT (Retrovir) and lamivudine. It's in early human trials.
  • BCH-13520 kills HIV resistant to other nukes. In the test tube, HIV has a hard time getting around this drug. Animal tests are underway.
  • GS 7340 is a form of Viread designed to work better as an oral drug. It looks good in animal studies.

New Non-Nukes

Non-nucleoside RT inhibitors -- NNRTIs or non-nukes -- attack the same target as nukes, but in a different way. One of these drugs, Sustiva, is among the most potent anti-HIV drugs ever seen. The search is on for equally powerful drugs without as many side effects. New non-nukes include:

TMC125 is so potent that all by itself it works as quickly as an extremely powerful five-drug combination. Human trials show that it works against HIV that's resistant to other non-nukes.

DPC 083 promises to be even stronger than Sustiva with fewer side effects. Human tests continue.

Integrase Inhibitors

Integrase inhibitors target yet another crucial HIV target. Integrase is the sewing kit HIV uses to splice its own DNA into the DNA of a cell. There aren't yet any approved integrase inhibitors -- but that could change:

  • S-1360 is a new drug already in human tests. It's worked very well in animal studies.
  • Merck has an as-yet-unnamed integrase inhibitor ready for human tests, according to The Wall Street Journal.

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Protease Inhibitors

Protease inhibitors -- PIs -- blunt the scissors HIV uses to cut newly made pieces of virus into the right shapes. The newest of these drugs, Kaletra, gained approval in 2000. Studies presented at the Retrovirus conference show that Kaletra can be taken in once-a-day doses.

New Ideas

Researchers are working on new ways to skin the HIV cat:

  • A class of drugs with a jaw-breaking name -- metalloporphyrins -- attacks the HIV RT target in an entirely new way. Their properties seem just right for a human drug, but studies are still in the test-tube stage.
  • A creation called double-stranded RNA (dsRNA) is a smart bomb. It's just two strands of RNA twined together. Once inside a cell, it seeks out and destroys any RNA that looks like one of its strands. Since HIV is an RNA virus, this plan would seem to have obvious advantages. It's still in test-tube studies.

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