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The Buzz

By Daniel S. Berger, M.D.

March/April 2001

Faster Approval of HIV Drugs for Patients with Resistance

It is finally apparent to government policy makers that an increasing number of HIV positive people are in need of more options to combat resistance to available therapies. The U.S. Food and Drug Administration (FDA) recently held a meeting in Washington, D.C. to consider setting new guidelines for HIV drug development. The FDA heard testimony from HIV clinicians and research experts who addressed the growing need for treatments that would be helpful to those patients dealing with resistance to current HIV drugs. Often antiviral medications fail to suppress HIV replication, ultimately leading to rising viral loads. In other words, medications may no longer remain effective because of the virus' ability to change into mutant HIV strains resistant to the effect of the medication.

Combination therapy for HIV disease has saved countless lives, however, many more individuals with high levels of mutant virus have resistance to many common treatments. It is these individuals who are at greater risk for HIV progression and complications, and they are often excluded from research studies involving the new and more effective therapies. In other words, patients who are in the most need of new treatment do not have access to them. In our practice, there is a growing number of people who are on their second, third, or fourth regimen. These are the individuals who most urgently need access to new drugs.

The FDA indicates a readiness to examine the possibility of allowing faster approval of drugs that are potentially helpful to patients with fewer options. The agency is now considering approval of drugs that demonstrate antiviral effect through the use of shorter clinical trials. This would promote the quicker availability of drugs to patients, especially those who need drugs to stay alive.

By reducing the length of time of research trials, drugs can potentially become available to patients with the greatest need much sooner. However, at the meeting's conclusion it was still unclear whether the agency has made any decision in regards to this issue. There is uncertainty as to when a decision will actually be made regarding these potential changes in the approval process. But the AIDS Chief, Heidi Jolson, was quoted as saying a decision may be ready next year.

Dr. Heidi Jolson, the director of the Division of Antiviral Drug Products (FDA AIDS Chief) is leaving the FDA. She supports AIDS treatments for approval while appropriately evaluating safety issues. She also supports the various compassionate track pathways. We hope that a suitable individual is found to replace Dr. Jolson upon her departure and that the issue of promoting a faster approval process for HIV drugs to the sickest patients does not get delayed.


HIV Vaccine Study: Conflict with a Pharmaceutical Manufacturer

Does Remune Have Clinical Utility as a Treatment for HIV Positive Patients?

The prestigious Journal of the American Medical Association (JAMA) recently published a controversial article regarding the results of a large-scale clinical trial using an HIV treatment vaccine called HIV-1 Immunogen (brand name Remune). The article described the results of a large multicenter study of 2,527 HIV-positive participants. Patients with CD4 counts between 300 and 549 cells received either Remune or placebo (fake medicine). The idea for a treatment vaccine is to boost the immune system of HIV positive individuals by exposing them to viral antigens (HIV proteins). The body's own immune response against these proteins would hypothetically assist in one's control of HIV. The study was not a success and was terminated earlier than scheduled by the Data Safety Monitoring Board, an independent group that oversees clinical trials. According to the authors of the JAMA article, the results failed to demonstrate that the addition of the vaccine conferred any effect on HIV progression-free survival and was also associated with a lack of clinical improvement.

Moreover, the strategy for this mode of treatment is a controversial one. HIV-infected patients already possess very high turnover of virus in the blood, which should be enough to stimulate an immune response against the virus. Administering more viral proteins in the form of a vaccine to the already present viral burden of an HIV positive person is not a proven way to fight HIV.

The results published in the JAMA article concluded with the lack of substantial effect of the vaccine and was followed with much drama and criticism of the authors by Remune's manufacturer, Immune Response Corporation. The pharmaceutical company has filed a claim with the American Arbitration Association seeking millions of dollars in damages from the University of California at San Francisco, the affiliation of the lead author of the study. According to Dr. Ronald Moss, vice president of Medical and Scientific Affairs for Immune Response Corp., the purpose of the suit was to have a third party arbitrate and hopefully cause the JAMA authors to incorporate other data that would dispel the already negative view of the product. The University of California has filed a counterclaim against Immune Response, however.

Allegations were made by the manufacturing company that certain details and findings may have been excluded and may have been more positive to their product. These details included data from a subset of 250 randomly assigned patients who had virologic testing done every three months, as opposed to the every six months monitoring done for the more than 2,000 other patients under study. According to Immune Response, of this smaller subgroup of patients, there was some data indicating the presence of HIV-specific immunity that was associated with greater decrease in viral load. However, the JAMA authors were not persuaded by Immune Response's arguments and felt the subset virologic data was not consistent with any significant changes. Additionally, many believe that, in a large study of 2,500 people, if the drug was indeed successful it would have been demonstrable in this large patient group.

Other company complaints were the unexpected presence of low HIV-related illnesses and the high rate of changing antiviral therapy occurring during the study, not planned for, nor were guidelines set in the study design, which Immune Response claims altered the results. However in a letter to me dated November 30, 2000, the JAMA authors clearly state they did not leave out any data that should have been published in this manuscript and eventually concluded that the treatment vaccine was ineffective; their objective in presenting the manuscript was to present an accurate assessment of the study. They were also concerned that "new patients were enrolling" in further studies with this agent and "were concerned that selective data improperly analyzed from the study was being sent to investigators to justify the ongoing or newly planned studies."

Other criticism came from some study investigators and clinicians who did much of the work; the authors James Kahn, et al., failed to recognize these individuals in the manuscript (the authors claim that the company did not provide the names and the company says that isn't true). In addition, some of the investigators disagreed with the JAMA authors' conclusions and interpretation of the study. Consequently, a second manuscript submitted by other lead investigators in cooperation with Immune Response has been accepted for publication in an attempt to refute the present conclusions and offer an additional interpretation of the study. Current JAMA authors plan to also do further analysis of the data. There is much corporate and pharmaceutical money at stake here and so it appears that the controversy will be never ending.

Too often pharmaceutical companies exert much censorship on publication of research because of industry money concerns. There are strong feelings harbored by many physicians that medical research can often be compromised because of the "bottom line."

Daniel S. Berger, M.D. is Medical Director for NorthStar Medical Center, Clinical Assistant Professor of Medicine at the University of Illinois at Chicago and editor of AIDS Infosource (www.aidsinfosource.com). He also serves as medical consultant and columnist for Positively Aware.


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