United Press International - Tuesday, 31 October 2000
Janet Filips

"We planned the study to ask the question, 'Could HIV-1 Immunogen delay disease progression or death?' " said Dr. James Kahn, lead author of the study published in the Nov. 1 issue of the Journal of the American Medical Association. Immunogens are substances that stimulate the formation of antibodies.

Kahn, who is associate professor of medicine at both the University of California, San Francisco and its affiliate the Positive Health Program at San Francisco General Hospital Medical Center, ticks off the disappointing negative results: "I'm very confident that HIV-Immunogen did not affect disease progression or death. I'm very confident there was a small or modest increase in T cells. And there was no effect on HIV viral load."

The immune system makes T cells, often called killer immune cells. They attack cells infected with HIV, the virus that leads to AIDS. The less virus in the blood ("viral load"), the less the chance of HIV turning into full-blown AIDS.

But Kahn's assessment of the data, which was analyzed by senior author Stephen Lagakos, PhD, professor of biostatistics at the Harvard School of Public Health, has brewed a legal storm with the study's corporate sponsor, Immune Response Corporation.

In September, after months of negotiations with Kahn and the University over the research findings, Immune Response -- a biopharmaceutical company based in Carlsbad, Calif. -- took the unusual step of filing a request for binding arbitration with the American Arbitration Association.

Immune Response is asking for $7 million to $10 million in damages, a nominal amount according to a company spokeswoman, compared to the $30-$50 million it spent on the massive trial.

According to the UCSF, the company sought to block the study's publication, withheld the final batch of data and withheld the addresses of about half the investigators spread at 77 national sites so the authors could circulate the paper before publication, as is customary. The university is seeking an order requiring the company to hand over the final batch of data.

"We think we have about 95 percent of the critical clinical data set," author Kahn said, "but we think we're missing 20 percent of the laboratory data and 25 percent of the safety data."

For its part, Immune Response says it never wanted to block the study or suppress data; it simply wanted the authors to include the results from a more-intensive substudy of 252 participants. It says it has the support of many of the national investigators.

The company strongly believes the data from this pre-selected group of patients shows a promising effect of HIV-1 Immunogen (to be called Remune if approved by the Food and Drug Administration) on T cell levels and virus levels. The data should be shared with other scientists, says Immune Response. Further, the company says the biostatistician had access to the 77 study site addresses.

"You're just morally bound to test whether or not Remune has some benefit in helping prolong reduction in viral load," says company spokeswoman Laura Hansen. "If you're seeing these trends, gosh, figure it out."

The University of California believes the figuring is finished. "The study authors did their own analysis of that data and found there was no benefit," said Chris Patti, university counsel.

"The company has argued that the authors ought to include the company's analysis in the paper. The authors feel that analysis is invalid, and they don't want it in there," explained Patti. "The whole point of having independent analysis is so the company isn't able to influence the reporting of results, as the company is trying to do."

The trial of HIV-infected adults began in 1996. None of the 2,527 enrollees had disease that had progressed to the point of AIDS. Most were simultaneously undergoing conventional treatment with various anti-retroviral or anti-HIV drugs; HIV-1 Immunogen was an add-on therapy. Participants were free to change their drug regimen during the trial. Half the volunteers received HIV-1 Immunogen; the other half, a placebo vaccine.

As a double-blinded study, neither the investigators nor the patients at the 77 participating sites across the United States knew if they were injected with placebo or with HIV-1 Immunogen. HIV-1 Immunogen is an inactivated form of the HIV virus, stripped of its exterior coating which the manufacturer hopes will bolster the immune responses of HIV-infected patients.

On its original timetable, the trial was to continue until investigators had followed each volunteer for 2-1/2 years. But the study was halted five months early, in May 1999, at the recommendation of independent data safety panel monitoring the trial because it saw similar outcomes between the treatment and control groups.

After the end of the study was announced, shares of Immune Response fell 36 percent, according to a Reuters news story at the time.

During the trial, 42 volunteers died: 23 from the HIV-1 Immunogen group; 19 from the control group. The 71 volunteers who became ill with opportunistic infections or malignancies were similarly balanced between the treatment and control groups.

Those results, said David Baltimore, PhD, president of the California Institute of Technology, are "hardly a surprise. Because there's no evidence that any kind of antibody-inducing immunogen has ever been successful in dealing with HIV-related infection. This is, I'm afraid, what I expected." Baltimore was not involved in the study.

Baltimore, who won the 1975 Nobel Prize for his work in virology and chairs the AIDS Vaccine Research Committee of the National Institutes of Health, said it was important to study the approach, despite his own expectations, "since people have been talking about strategies like this for a while."

Kahn, the study's lead author, said he'd felt hopeful that the compound would enhance immune function and, in conjunction with other therapies, help control the virus.

"Any new way to help manage a patient should be investigated and explored," said Kahn, who chairs the committee for human research at UCSF. "This one did not help delay disease progression or death."

Baltimore believes few scientists expected the compound to prove itself as effective. "It was a long shot, in my mind," he said. Investigators in the study "may have really believed in it; but an outside look would be less optimistic."

Meanwhile, Immune Response remains upbeat about HIV-1 Immunogen. Spokeswoman Hansen said the company will attempt to publish a paper on the aspect of the trial that is not included in Kahn's article. And its partner, the pharmaceutical company Agouron, a subsidiary of Warner-Lambert Company, is in the midst of another trial evaluating the compound's safety and effectiveness.

No arbitration date between the company and UCSF has yet been set.
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