The National Institute of Allergy and Infectious Diseases (NIAID) and The Upjohn Company have launched a study to evaluate a potent new anti-HIV agent, both alone and in combination with one or two other drugs, in HIV-infected persons. The new drug, U-90,152, has blocked the replication and spread of HIV in laboratory tests.
The currently licensed drugs, zidovudine (AZT), didanosine (ddI), and zalcitabine (ddC), have made significant contributions to the care of persons with HIV infection," says Anthony S. Fauci, M.D., NIAID director. "However, toxicity and the fact that the virus can mutate and become resistant to these drugs within six to 12 months limit their usefulness as single-drug therapies. This combination study with U-90,152, a new type of drug, is part of our ongoing effort to develop more effective approaches to treatment."
Like AZT and the other approved drugs, U-90,152 inhibits a viral enzyme, reverse transcriptase, necessary for the replication and spread of HIV. However, unlike these drugs, U-90,152 belongs to a novel, highly potent new class of compounds called BHAPs, or bisheteroarylpiperazines. BHAPS and related drugs are known as non-nucleoside reverse transcriptase inhibitors. AZT, ddI and ddC belong to another class of drugs called nucleoside analogues that also inhibit reverse transcriptase, but appear to work on a different site of the enzyme.
H. Clifford Lane, M.D., NIAID clinical director, explains the rationale behind combining different classes of drugs in HIV therapy: "Our current understanding suggests that the HIV reverse transcriptase gene mutates at distinct sites in response to different drugs that inhibit the enzyme. For HIV to become resistant to two classes of drugs, it would have to develop mutations at two sites. The chance of one virus developing both mutations and still being able to replicate is quite small, and becomes even smaller when a third drug is added to the combination treatment."
The use of combination therapy is an established strategy in the treatment of infectious diseases," he adds. "Drug combinations have been used for decades for diseases when the development of resistance limits therapy, such as in the treatment of tuberculosis and many cancers."
Previous and ongoing studies have demonstrated the promise of BHAP compounds in HIV therapy. In the September 1992 Virology, Dr. Lane and colleagues at the Upjohn Company and Georgetown University reported that BHAP compounds can sterilize HIV-infected cell cultures, the first time this had been observed with a reverse transcriptase inhibitor. Additional work on this class of compounds has been carried out through the National Cooperative Drug Discovery Group, NIAID-sponsored collaborations of government, university and private industry scientists.
Investigators at the NIH Clinical Center in Bethesda, Md., will enroll HIV-infected patients into the new study of U-90,152 in two phases, each of which will last 24 weeks.
For the initial part of the study, participants must have 100 to 300 CD4+ T cells per cubic millimeter (mm3) of blood, no serious signs or symptoms related to their HIV infection, no history of serious side effects to ddI or AZT and no previous treatment with non-nucleoside reverse transcriptase inhibitors. CD4+ T cells are the crucial immune cells depleted during HIV infection. A healthy, uninfected person usually has 800 to 1,200 CD4+ T cells/mm3.
In the first phase of the study, up to 40 patients will be randomly assigned to receive either a three-drug combination of U-90,152, AZT and ddI or a two-drug combination of just AZT and ddI. Investigators will gradually increase the dose of U-90,152 for each new group of five patients to determine the maximum dose that is well-tolerated.
In the second phase of the study, up to 40 additional participants with 100 to 300 CD4+ T cells/mm3 will receive either U-90,152 alone or in combination with AZT. The initial dose of U-90,152 in this phase of the study will be the maximum tolerated dose established in the first phase. Patients with fewer than 100 CD4+ T cells/mm3 will also be enrolled during this second phase to evaluate the effects of the combination regimen in patients with more advanced disease.
The trial is designed to assess the relative safety of the therapies, and will provide information on their side effects. The study also will examine how the drugs are metabolized by the body, and provide preliminary information on the relative effectiveness of the therapies in slowing the progression of HIV disease.
Dr. Lane says his group's preliminary findings with BHAP compounds are consistent with a report in the Feb. 18 Nature in which investigators at Massachusetts General Hospital, supported by the National Institutes of Health (NIH), showed that a combination of three drugs -- AZT, ddI and nevirapine -- could successfully stop the growth of HIV or its spread to other cells.
Nevirapine also is a non-nucleoside reverse transcriptase inhibitor, but differs significantly in chemical structure from BHAP compounds. A clinical trial of the combination of AZT, ddI and nevirapine will open later this spring in the AIDS Clinical Trials Group (ACTG), one of NIAID's three nationwide clinical trials networks.
An ongoing trial, ACTG 199, is evaluating another BHAP drug, U-87,201, in 20 patients.
NIAID and the Clinical Center are components of the National Institutes of Health in Bethesda, Md. NIAID supports research on allergy, immunology and infectious diseases, including an extensive AIDS clinical research program at the Clinical Center, a 500-bed hospital on the NIH campus.
HIV-infected persons and their physicians may obtain further information on the new BHAP trial by calling 1-800-AIDS-NIH.
Enrollment information for all NIAID AIDS clinical trials can be obtained by calling 1-800-TRIALS-A, Monday through Friday, 9 a.m. to 7 p.m., EST.