Early Tests of New AIDS Drug Are Promising
An experimental AIDS drug that is chemically related to AZT may be effective against the AIDS virus “with little toxicity,” National Cancer Institute researchers said Sunday at the American Federation for Clinical Research meeting in Washington.
Administration of DDI, or dideoxyinosine, to 23 patients as part of a pilot study was “associated” with improvements in immune system function and a decreased amount of AIDS virus in the bloodstream of most patients, according to Dr. Robert Yarchoan, the cancer institute researcher who directed the study.
Most of the patients in the study also appeared to improve clinically. For example, some gained weight and reported increased energy. But Yarchoan cautioned that longer studies involving hundreds of patients will be necessary to determine the long-term effectiveness and side effects of DDI.
Side Effects of AZT
AZT, or zidovudine, is the antiviral drug that has been shown to prolong the lives of some AIDS patients for a year or more. But its effectiveness may be limited by serious side effects, such as anemia or severe gastrointestinal problems.
“DDI can be administered for up to six months with minimal toxicity in the majority of patients with AIDS or AIDS-related complex, including patients who could not tolerate AZT,” Yarchoan said in a telephone interview.
DDI warrants further study in a larger trial that would include a direct comparison to AZT, he said.
Another potential advantage of DDI, which can be taken as a pill, is that it appears to have beneficial effects when administered two or three times a day, Yarchoan said. By comparison, AZT usually must be taken every four hours.
Dr. Alexandra Levine, an AIDS researcher at the USC Medical Center in Los Angeles said she was encouraged because the “very preliminary data” on DDI indicates “some efficacy even at a less than maximal dose.” Levine has referred several patients to the on-going cancer institute study.
Because of AZT’s severe side effects, many AIDS patients can only tolerate reduced doses of the drug. Others must discontinue it entirely.
In addition, AZT resistant strains of the human immunodeficiency virus, the cause of AIDS, may develop in patients who have been on the drug for six months or more.
Replacement Drugs
As a result, a high priority in AIDS research is the development of new drugs that can either replace AZT or be used with it. A common way to identify such drugs is to test variants of a partially effective drug, such as AZT, to find compounds that are more effective and less toxic.
The cancer institute’s DDI study started in July, 1988. The 23 patients had either acquired immune deficiency syndrome or serious AIDS-related conditions. Nine had been unable to take AZT.
As is common in so-called “Phase I” studies, a steadily escalating series of doses of DDI were tested on groups of three to four patients, Yarchoan said. The study was designed to determine the absorption of DDI into the bloodstream, the maximally tolerated oral dose, and the minimal dose necessary to suppress HIV replication. The goal was to determine a proper dosage for more extensive tests.
DDI was given intravenously for two weeks and then was continued orally for six months or more.
Side effects included seizures in two patients, a rash in one and reports of headaches, increased irritability and insomnia. Two patients developed low white blood cell counts.
Yarchoan said that while the list “sounded like a lot” of side effects, it was in fact a small number of problems to detect in a study designed to determine the maximally tolerated dose of a drug. In addition, some of the reported problems may have been been related to the patient’s underlying HIV infections, not to the experimental drug.
The researchers saw a number of potentially beneficial effects, including substantial increases in the key immune system cells, known as “T-4” white blood cells, in many of the patients on the higher doses of DDI. The researchers also found decreases in the concentration of “p-24 antigen,” a laboratory test that reflects the amount of the AIDS virus in the circulation.
Higher Doses Being Tested
Yarchoan said higher doses of DDI are still being tested because the maximally tolerated dose has yet to be reached.
When taken orally, DDI is given with antacids because it would be destroyed by harmful stomach acids, according to the report. About 35% of the drug appears to enter the blood stream. The rest apparently is destroyed or not absorbed.
Like AZT, DDI penetrates into the cerebrospinal fluid, the liquid bathing the brain and spinal canal. Thus, it may be effective against the often-severe central nervous system effects of HIV.
At the molecular level, both AZT and DDI interfere with the replication of viral DNA. Another related drug in human tests is dideoxycytidine, or DDC, although its usefulness may be limited because some patients develop severe nerve pains.
DDI is manufactured by the Bristol-Myers Co. of Wallingford, Conn. It is also being tested in small trials at New York University Medical Center, the University of Rochester Medical Center and Boston City Hospital.
