AZT May Help in Early HIV Stages, Study Shows : AIDS: Drug appears to stall loss of key CD4 cells. Results are preliminary and conflict with a recent U.S. study, experts say.
A little-noticed international study offers the first evidence that the drug AZT may help people with HIV infection in the earliest stages of the disease.
The results, although appearing to conflict with a recent American study, are potentially significant for the majority of individuals infected with the human immunodeficiency virus--those who have yet to develop symptoms or laboratory evidence of significant immune system problems.
An international coordinating committee declared the trial successful and halted it in January “on the grounds that a significant benefit of treatment with (AZT) had been reliably demonstrated,” according to the Wellcome Foundation in London, which manufactures the drug and organized the study. AZT, or azidothymidine, was offered to all participants.
Both the Wellcome Foundation and leading American AIDS experts urged caution in interpreting the results, which have received minimal publicity in the United States, stating that they are preliminary and require further analysis.
The results are at odds with findings of a major American study of AZT, published last week. The Veterans Affairs Cooperative Study found that starting treatment with AZT early in the course of infection delayed the development of AIDS but did not increase life span more than starting the drug after symptoms worsen. Officials of the VA study could not be reached for comment Monday.
The Wellcome findings are “obviously of great interest . . . (but) we still do not know as much (about how to prescribe AZT) as we need to know,” said Dr. Paul Volberding of San Francisco General Hospital, who is directing the principal American trial of AZT in early HIV infection. “We have two studies (the VA study and the Wellcome study) hitting the public attention that seem to be saying diametrically opposing things.”
Nevertheless, the Wellcome Foundation said its findings, if confirmed, will be used to “help support regulatory applications” in the United States and other nations to permit wider use of AZT.
“If the interim analysis (of the data) is confirmed with the final analysis, the implication is that the drug is of benefit for all HIV-infected people,” said Prof. David Cooper, director of the National HIV Clinical Trials Center in Sydney, Australia, and chairman of the study’s international coordinating committee.
While Wellcome sponsored the study, the research was conducted and interpreted by Cooper and other AIDS experts outside the company. Cooper said he expected to present the final data at the international AIDS conference in Amsterdam in July.
The study, known as Wellcome trial H56-020, involved nearly 1,000 HIV-infected people in Australia and nine European nations. Wellcome’s American subsidiary, the Burroughs Wellcome Co. of North Carolina, was not involved in the project.
The results are primarily based on laboratory tests for CD4 cells, key immune system cells that are destroyed by HIV. Others studies, such as the VA trial, have measured overall survival or delays in the onset of AIDS.
The normal number of CD4 cells in the blood is between 800 and 1,200 per cubic millimeter of blood. The number of CD4 cells progressively decreases in an HIV-infected person. This weakens the body’s ability to fight germs and prevent the development of cancers.
The severe infections and many tumors characteristic of AIDS usually develop when the CD4 cell count falls below 200. Some researchers believe that the ravages of AIDS could be forestalled indefinitely by preventing the decline in CD4 cells.
The new study is the first to show that AZT may benefit infected individuals with between 500 and 750 CD4 cells. AZT cut in half the rate at which the CD4 cell count fell below 350. It also appeared to decrease the rate at which early HIV symptoms, such as yeast infections in the mouth, develop. Previous studies have shown that AZT benefits those who are further along in the disease--with CD4 counts of 500 or lower.
The significance of CD4 cell data has been widely debated. In recent years, this measurement has gained considerable credibility in AIDS research. Last year, CD4 cell test results played an important role in the U.S. Food and Drug Administration’s approval of the AIDS drug DDI.
In the United States, AZT is now recommended for HIV-infected people with fewer than 500 CD4 cells per cubic millimeter of blood. AZT is not recommended for those with higher numbers of CD4 cells, who are at relatively low risk of becoming ill.
“One of the most important public health decisions (the federal government) could make for people with HIV infection” would be to change the recommendation that limits AZT use to people with CD4 cell counts lower than 500, said Dr. Daniel Hoth, director of the division of AIDS at the National Institute for Allergy and Infectious Diseases in Bethesda, Md. “(This) is too important a decision to make based on the amount of information which is currently available.”
In the Wellcome study, participants received either AZT or a placebo; the patients and their physicians were not told which treatment was being used. By the end of 1991, 991 people had been followed up for an average of 26 months.
The participants included 436 individuals with between 500 and 750 CD4 cells at the beginning of the study. In this group, 9% of those receiving AZT worsened to a level of 350 CD4 cells or lower or developed early HIV symptoms, compared to 18% of those treated with the placebo, the Wellcome Foundation said. Four times as many patients progressed to the level of 350 CD4 cells than developed HIV symptoms.
An additional 211 participants began with between 400 and 500 CD4 cells. In this group, 20% of those receiving AZT worsened to 350 CD4 cells or fewer or developed early HIV symptoms, compared to 38% of those treated with the placebo. No significant differences were found for those who began the study with more than 750 CD4 cells.
The probability was one in a thousand that these differences were due to chance, the researchers said.
The findings are “highly significant,” Cooper, chairman of the study’s coordinating committee, said in a telephone interview from Australia. “I have a feeling with the final analysis . . . (the results are) even going to be more significant.”
The dose of AZT used in the study was 500 milligrams twice a day, which is twice the recommended AZT dosage for asymptomatic HIV-infected adults in the United States. The researchers said the early AZT treatment “did not appear to cause any serious side effects.”
In recent years, there has been a growing belief among some American AIDS experts and many patients that treatment against HIV should begin as early as possible in order to prolong life until better treatments become available.
But other AIDS experts have cautioned that the decision about when to start AZT and other medications should be individualized. The recent VA study suggests that AZT may lose its benefit if it is started too soon, perhaps because of the development of resistance to the drug and potential side effects, such as anemia and stomach upset. AZT treatment also costs thousands of dollars a year.
Dr. Douglas Richman, an AIDS expert at UC San Diego, said the long-term significance of using AZT to maintain the CD4 cell count above 350 is not known because most people in this category have no HIV symptoms. The Wellcome study “got an answer to the question (that AZT helps keep the CD4 count above 350) but we are not sure the question is the right one,” he said.
Within the next year, two continuing studies are expected to provide more information about AZT use in the early stages of HIV infection.
These studies are the Concorde trial, which has enrolled about 1,750 HIV-infected individuals in France and Great Britain, and protocol 019 of the AIDS Clinical Trials Group in the United States. The American study includes about 1,200 HIV-infected people with more than 500 CD4 cells. They have been tracked for at least three years.
Early this month, Hoth, Richman, Volberding and others reviewed the preliminary data from the Wellcome trial and reached a “unanimous” decision to continue protocol 019, Richman said. So far, Volberding said, the protocol 019 data have not shown significant advantages of AZT for individuals with more than 500 CD4 cells.
