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Effective Treatments Lacking for Most Desperate AIDS Patients

PITTSBURGH, August 7, 2001 — New medications are urgently needed for individuals who have drug-resistant HIV, and academia, industry and government must work together to bring them into the clinic, urged AIDS researchers John Mellors, M.D., University of Pittsburgh, and Julio Montaner, M.D., University of British Columbia (UBC), in an editorial in the Aug. 9 issue of the New England Journal of Medicine.

"Antiretroviral therapy is most effective the first time it is prescribed," wrote Drs. Mellors and Montaner in the editorial. But in patients who have had previous exposure to two or all three classes of drugs used in the "cocktails," the therapy is usually unsuccessful in suppressing blood levels of HIV to undetectable amounts. Lacking more effective therapies, some health care practitioners abandon efforts to suppress HIV levels in these treatment-exposed patients, who represent some 30 percent of treated HIV patients in the U.S. alone.

"The lack of viable new antiretroviral therapy options for the most desperate patients not only represents a failure on the part of the scientific, academic and governmental communities, but it also sets the stage for a dangerous epidemic of drug-resistant HIV," said Dr. Mellors, professor of medicine at the University of Pittsburgh School of Medicine and chief of infectious diseases.

Without medications to suppress HIV to undetectable levels, the virus continually mutates into new forms that often do not respond to available drugs. These drug-resistant forms of the virus then are transmitted from one individual to another. Some 5 percent to 10 percent of newly diagnosed HIV-infected patients in the U.S. are thought to have been infected with drug-resistant forms of the virus.

The three classes of drugs from which current antiretroviral cocktails are made are nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors and protease inhibitors.

A number of factors can lead to a patient's inability to get the most benefit from the drugs, including a great deficiency in the immune cell counts, high levels of virus in the blood and non-adherence to the strict and sometimes difficult treatment regimen. Without maximum exposure to the medication, viral levels are not suppressed adequately, the remaining virus mutates, drug-resistant virus is formed and the virus escapes.

Once drug-resistant virus emerges, it becomes more difficult to treat because of cross resistance between the currently available drugs, according to the authors. Specifically, a virus that has become resistant to one drug in a class of drugs often shows cross resistance to other members of the same drug class.

"Clearly we need more and better drugs," said Dr. Montaner, professor of medicine at UBC and co-director of the Canadian HIV Trials Network, based at St. Paul's Hospital, Vancouver. "Furthermore, simply adding drugs to the antiretroviral cocktail does not help people with resistant HIV, and there is potential for serious drug toxicity with so many medications. Several therapies being tested show promise, including the protease inhibitor tipranavir and the fusion inhibitors T-20 and T-1249."

But certain obstacles need to be overcome in the process of getting new drugs through development and into the clinic, according to the authors.

"First, there need to be stricter regulatory requirements during testing. Currently, antiretroviral drugs are gaining approval without ever having been tested on the patients who need them most -- those with drug-resistant HIV," the authors contend. "Secondly, we need the simultaneous release of more than one approved drug into expanded access programs. The practice of staggering the release of new antiretroviral agents is unacceptable, as it allows clinicians to add only one new drug at a time to a failing treatment regimen. This promotes failure of the single new drug and further drug resistance. We need the ability to add several new drugs in combinations."

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