The National Institute of Allergy and Infectious Diseases (NIAID) has opened a multi-site clinical trial to evaluate a new three-drug combination therapy for human immunodeficiency virus (HIV) infection. Preliminary laboratory experiments have shown that the drug combination can block the replication and spread of HIV in the test tube.
The toxicity of currently approved anti-HIV drugs, and the ability of the virus to mutate and become resistant to these agents within six to 12 months of beginning their use, has made the evaluation of novel combination regimens a top priority of the NIAID AIDS research program," says Anthony S. Fauci, M.D., NIAID director.
The new trial will enroll 400 adults at 16 units of NIAID's AIDS Clinical Trials Group (ACTG). The study, known as ACTG 241, will assess the safety and tolerability of a three-drug regimen of zidovudine (AZT), didanosine (ddI) and nevirapine, in comparison to the two-drug combination of AZT and ddI plus a placebo. In addition, study investigators will obtain preliminary information about the anti-HIV activity of the two regimens.
AZT and ddI, as well as zalcitabine (ddC), currently are licensed for the treatment of HIV infection. The drugs all inhibit a viral enzyme, reverse transcriptase, necessary for the replication and spread of HIV. Nevirapine, an investigational medication, also inhibits reverse transcriptase, but appears to work on a different site of the enzyme.
With support from the National Institutes of Health (NIH), investigators at Massachusetts General Hospital and Harvard University found that, in cell culture experiments, high levels of AZT, ddI and nevirapine in combination stopped the growth of HIV and its spread to other cells. They reported this research in the Feb. 18, 1993, Nature. In addition to NIAID, the National Cancer Institute and NIH's Medical Scientists Training Program provided funds for the research.
Investigators theorize that such combination therapy, which uses two or more different drugs simultaneously to attack reverse transcriptase, might slow HIV's development of resistance. Although the laboratory results appear promising, it is difficult to extrapolate from laboratory experiments to patients, cautions Dr. Fauci.
An ongoing pilot trial with 24 patients at the University of Alabama at Birmingham is examining how the AZT/ddI/nevirapine combination is metabolized by the body and assessing short-term side effects. Preliminary results with nevirapine alone and in combination suggest that nevirapine is well-tolerated, with rash as the most common side effect. ACTG 241, however, will be the first study to examine the long-term effects of the three-drug regimen.
To be eligible for ACTG 241, HIV-infected persons must have Fewer than 350 CD4+ T cells per cubic millimeter (mm3) of blood and six or more months of previous single-drug or combination therapy with AZT, ddI or ddC. CD4+ T cells are the crucial immune system cells depleted during HIV infection, predisposing HIV-infected individuals to serious opportunistic infections. Investigators plan to enroll 100 patients with 50 or fewer CD4+ T cells/mm3, 150 patients with 51 to 200 CD4+ T cells/mm3 and 150 patients with 201 to 350 cells/mm3.
Participants will be randomly assigned to one of two treatment regimens: a two-drug combination of 600 milligrams (mg.) a day of AZT, 400 mg./day of ddI plus placebo or a three-drug regimen of the AZT/ddI combination plus 400 mg. of nevirapine daily (200 mg. for the first two weeks). All medications will be given orally, and neither the investigators nor the participants will know which regimen a patient receives. The total duration of treatment for each arm of the study will be 48 weeks.
The following 16 ACTG units are participating in ACTG 241:
Albert Einstein College of Medicine, Bronx, N.Y. Cornell University Medical Center, New York Harvard University, Boston, Mass. Indiana University, Indianapolis Los Angeles County-University of Southern California Medical Center, Los Angeles Mount Sinai Medical Center, New York Northwestern University Medical School, Chicago, Ill. San Francisco General Hospital, Calif. University of Alabama at Birmingham University of California, San Diego University of Cincinnati College of Medicine, Ohio. University of Colorado Health Sciences Center, Denver University of Miami School of Medicine, Fla. University of Minnesota Health Science Center, Minneapolis University of North Carolina School of Medicine, Chapel Hill University of Pennsylvania, Philadelphia
Drugs for the trial are provided by Bristol-Myers Squibb (ddI), Burroughs Wellcome (AZT) and Boehringer Ingleheim (nevirapine). Richard T. D'Aquila, M.D., is chairman of the trial and Martin S. Hirsch, M.D., serves as co-chair. Both investigators are from Harvard.
NIAID, a component of the NIH, supports research on allergy, immunology and infectious diseases. NIH is an agency of the U.S. Public Health Service, Department of Health and Human Services.
The ACTG, established in 1987, is a nationwide clinical trials network that conducts studies to evaluate the safety of new drugs, drug combinations and vaccines in adults and children at various stages of HIV disease. The ACTG has 61 units affiliated with major medical centers in 34 U.S. cities.
For further information about ACTG 241 and other AIDS clinical trials, call 1-800-TRIALS-A, Monday through Friday, 9 a.m. to 7 p.m., EDT. For press inquiries only, please call Greg Folkers at (301) 402-1663.