The first U.S. multi-center study examining the safety and effectiveness of the drug Ro 24-7429 that in laboratory tests blocks replication of HIV, the virus that causes AIDS, will be modified to study higher doses, the National Institute of Allergy and Infectious Diseases (NIAID) has announced. In addition, NIAID will halt three of the four treatment arms testing lower doses because the drug has not shown such activity in participants studied to date.
Richard Haubrich, M.D., from the University of California at San Diego Medical Center is scheduled to discuss the data from the trial, AIDS Clinical Trials Group (ACTG) 213, during an oral presentation on June 10, at the IX International Conference on AIDS in Berlin, Germany. NIAID and Hoffmann-La Roche Inc., manufacturers of Ro 24-7429, collaborated on the trial.
Ro 24-7429, unlike the three antiretroviral drugs currently approved for AIDS therapy, zidovudine (AZT), dideoxyinosine (ddI) and dideoxycytidine (ddC), appears to halt HIV replication in cells chronically infected with HIV, not just preventing the initial infection of cells. The drug stops HIV reproduction by interfering with the action of a viral regulatory protein, TAT.
The preliminary analysis of data collected from the first participants to complete the 12-week Phase I-II trial has shown that three doses of Ro 24-7429 have not stopped viral replication nor have they increased the number of certain immune cells, CD4+ T cells, that HIV targets. Investigators will continue to study patients already enrolled in a fourth arm, examining therapy using Ro 24-7429 in combination with AZT or ddI. Study scientists plan to begin new treatment arms in ACTG 213 that would examine higher doses of Ro 24-7429. Hoffmann-La Roche Inc. has other studies of Ro 24-7429 under way.
ACTG 213 began in November 1992, with patients randomized to receive for 12 weeks one of three doses of Ro 24-7429, 25 milligrams (mg), 50 mg or 100 mg every eight hours or 200 mg of AZT every eight hours or a body weight-dependent dose of ddI every 12 hours. At the end of 12 weeks, study scientists gave the highest dose of Ro 24-7429, 100 mg. every eight hours, to patients receiving AZT or ddI.
To enter, all participants had to be HIV-infected and not have taken any antiretroviral therapy for 28 days prior to the study beginning. Also, participants had to have counts of the immune system CD4+ T cells ranging from 50 to 500 cells per cubic millimeter of blood. ACTG 213 study sites include Case Western Reserve University in Cleveland, Ohio, Harvard University in Boston, Mass., The Johns Hopkins University in Baltimore, Md., and the University of California at San Diego.
Studies sponsored by Hoffmann-La Roche, Inc., and completed at Johns Hopkins before ACTG 213 began found that patients tolerated Ro 24-7429 well and the major side effect was rash. These studies compared single and multiple doses of the drug to determine the drug's safety and how it was processed in the body.
By interfering with the action of the TAT protein, Ro 24-7429 halts the transcription of HIV's genetic material from DNA to RNA in the infected host cell, according to laboratory studies. This transcription is a necessary step for virus replication. Without TAT, the transcription is impeded, new virus is not made, fewer cells are infected and opportunities for HIV to mutate and develop drug resistance decrease.
NIAID, a component of the National Institutes of Health, supports investigators and scientific studies at universities, medical schools, hospitals and research institutions in the United States and abroad aimed at preventing, diagnosing and treating such illnesses as AIDS, tuberculosis, allergies and asthma. NIH is an agency of the U.S. Public Health Service, part of the U.S. Department of Health and Human Services.
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"A Randomized Study of Safety, Tolerance, Pharmacokinetics, and Activity of Oral Ro 24-7429 (Tat Antagonist) in Patients with HIV Infection." R.H. Haubrich, ACTG 213 Team, University of California, San Diego Medical Center.
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