Three New Classes of Drugs May Offer Hope to HIV Patients Resistant to Current Treatments
Several new, early-stage AIDS drugs unveiled yesterday at the Ninth Conference on Retroviruses and Opportunistic Infections in Seattle have demonstrated promise in fighting drug-resistant forms of HIV, the Washington Post reports. The two new types of drugs and the second-generation non-nucleoside reverse transcriptase inhibitors presented yesterday represent a "phase of accelerated development that's likely to keep pace with the current problem of drug resistance," Dr. Brian Gazzard, a physician at Chelsea and Westminster Hospital in London, said, adding, "After a lull for two or three years, the sort of data we're seeing is very exciting." There are currently 15 AIDS drugs on the market, but as many as 30% to 40% of HIV patients have become resistant to one or more of the drugs, according to doctors (Brown, Washington Post, 2/26). "Resistance remains a formidable problem. We can try to stay ahead by coming up with the next generation of drugs. But in the end we will likely lose that race," Dr. Richard Colonno of Bristol-Myers Squibb said, adding, "The advantage of new classes of drugs is that they will work against all the currently resistant virus. You are resetting the clock." All of the drugs remain experimental and none are expected to reach the market in the near future (Haney, AP/Nando Times, 2/25).
Two new "entry inhibitor[s]," drugs that fight HIV by blocking the virus' ability to enter cells, were introduced yesterday. Researchers first began developing entry inhibitors in the mid-1990s after they noticed that some people remained uninfected after repeated exposure to the virus. Many of those people had a variant of the protein CCR5, which is found on the surface of cells. HIV must bind to CCR5 in order to invade the cell and replicate. However, it is unable to bind with the variant form. Schering-Plough's SCH-C blocks HIV by binding to CCR5, leaving the virus without a receptor. In tests in 12 HIV-positive people, SCH-C, used alone, was able to "sharply reduc[e]" viral levels in the patients' blood. Schering-Plough is planning to conduct further tests with higher doses of the drug, but the company is concerned that high doses could have a detrimental effect on patients' hearts (Schoofs/Waldholz, Wall Street Journal, 2/26). The drug appears to interfere with calcium uptake by the heart's muscle tissue, causing "blips" on electrocardiogram heart monitors. However, researchers believe that SCH-C, given in low doses in tandem with other drugs, "probably would not be dangerous" to patients (Garrett, Newsday, 2/26). The company has a second version of the drug, SCH-D, "further back in the pipeline," and Pfizer is also developing a drug that binds to CCR5. BMS also has developed an entry inhibitor, but its version works by targeting the HIV protein gp120, which is used to "latch" onto cells. The compound has not yet been tested in humans and BMS officials did not say when human trials will begin.
Two new, second-generation NNRTIs were also unveiled at the conference yesterday. A study of BMS' DPC 083 demonstrated that it may work successfully against some strains of drug-resistant HIV, but a new compound developed by Tibotec-Virco NV, a small Belgian company, was the "highligh[t]" of the presentation. Used alone, Tibotec's drug, TMC125, "sharply suppressed" viral levels in just one week in patients with resistant strains of HIV, and a second small study found the drug to be "as powerful as five older drugs taken in combination" in patients whose virus was not resistant. Tibotec-Virco will conduct larger clinical trials and could file for FDA regulatory approval as early as 2004 (Wall Street Journal, 2/26). TCM125 is likely to be used in combination with other existing AIDS drugs because many antiretroviral drugs can be "rendered near-useless in weeks" when used alone and the virus is able to mutate.
The third type of drug discussed yesterday was an "integrase inhibitor" being developed by Japan's Shionogi & Co. The drug, S-1360, targets integrase, an enzyme found in HIV that "stitches" the virus' genes into the DNA of the host cell, thereby permanently infecting that cell. The drug was "well tolerated" in animal studies and proved "highly active" against strains of HIV that were resistant to nucleoside reverse transcriptase and protease inhibitors. A small human study in ongoing (Washington Post, 2/26). Shionogi is working with GlaxoSmithKline to develop the drug through a split joint venture called Shionogi-GlaxoSmithKline Pharmaceutical Co. Merck & Co. also has an integrase inhibitor scheduled to begin Phase I clinical testing next month (Wall Street Journal, 2/26).