Remune rejected. (Will a manual recount be required?).

In a scenario reminiscent of the 2000 presidential election, The Immune Response Corporation (IRC) tried unsuccessfully to block the publication of the results of Study 806, a study aimed at assessing whether Remune (also known as the Salk vaccine or HIV-1 immunogen) in combination with antiviral drugs could keep persons healthy for a longer period of time than antivirals alone. IRC is demanding $7 million dollars in damages from the researchers who published results in The Journal of the American Medical Association.[1] The researchers concluded that Remune did not add any clinical benefit to antivirals.

Why the controversy? IRC is complaining that the published article was written without taking into account all of the data. The researchers, on the other hand, contend that after the study was stopped prematurely, the company refused to provide them with the entire data set for their analysis.

Why is this important? Study 806 represents the largest randomized trial of HIV-infected persons in the last decade and the first large-scale trial to study an immune-based therapy. (An immune-based therapy is a therapy that tries to harness the body's immune system to fight a pathogen, rather than a therapy that directly fights the pathogen itself. A vaccine is an example of an immune-based therapy.) It may also be an example of the problem that will be faced by other immune-based therapies in the future.

From the beginning Remune was viewed with skepticism by some segments of the scientific and activist communities. The vaccine was intended to work therapeutically. That is to say, it was not intended to prevent people from getting infected with HIV, but instead it was intended to help stimulate the immune systems of person already infected with HIV. The scientific underpinnings of Remune were hotly debated for some time before it was decided that the only way to determine whether it worked was to conduct a large clinical trial using the product.

Thus, Study 806 came about. In this study 2527 patients were randomized to receive Remune plus an adjuvant (a substance intended to increase the effect of the vaccine) or just the adjuvant as a control. The patients studied were relatively healthy, having CD4 T cells between 300 and 549 cells/[mm.sup.3]. Patients were allowed to take antiviral drugs in addition to Remune or placebo.

In the end, researchers concluded that Remune did not have a positive impact on disease progression or death, viral load, body weight or CD4 T cell percentage. The mean CD4 T cell count in the Remune group was about 10 cells higher than in the placebo group. The researchers concluded that the difference in CD4 T cells was too small to have a clinical difference in patients.

It may be possible, though unlikely, that once all the data are analyzed by IRC they may be able to come to a different conclusion. However, it is clear from the published data that Remune does not have a dramatic effect on disease progression. In fact, it may have no effect whatsoever. And one cannot help but wonder whether such massaging of the data by the sponsor is in anyone's best interest.

The results of the Remune trial highlight the issues recently discussed at an FDA meeting regarding the proper standards for measuring the efficacy of immune-based therapies. (See FDA meeting on immune-based therapies development, centerforaids. org/rita/alerts/FDA.htm). At that meeting there was some consensus that immune-based therapies cannot be expected to have the same magnitude of effect that antiviral drugs have on markers such as CD4 T cells and viral load. Given the prevalence and the interim success of antiviral therapy, it is likely that immune-based therapies will only be tested in the context of antiviral therapies. This will make it increasingly difficult to tease out what contributing effect immune-based therapies have on the long-term health of HIV-infected patients.

The question posed at the FDA meeting and by the results of this study is whether the standards for approval and marketing of immune-based therapies should be different from those set for antiviral drugs. Clearly, immune-based therapies have different mechanisms of action that might work to control HIV disease in ways that have not yet been anticipated. The problem is that knowledge of the immune system and its workings is still in its infancy. Without a clear understanding of what markers to look for, scientists are left to look to clinical endpoints like disease progression and death as markers for the efficacy of an immune-based therapy.

Undeterred by the setback of the published results, IRC continues its efforts to study Remune in other parts of the world. Most recently, Thailand approved a 2-year extension of a similar clinical study of Remune in HIV-infected individuals.[2]

REFERENCES

[1.] Kahn JO, Cherng DW, Mayer K, Murray H, Lagakos S. Evaluation of HIV-1 immunogen, an immunologic modifier, administered to patients infected with HIV having 300 to 549 X [10.sup.6]/L CD4 cell counts: A randomized controlled trial. JAMA. 2000;284(17):2193-2202.

[2.] Trinity Medical Group USA Announces Continuation of HIV Clinical Trial [press release]. San Rafael, CA: Trinity Medical Group USA, Inc., November 13, 2000.