AIDS TREATMENT NEWS Issue #354, November 3, 2000
John S. James

Because we learned about this dispute shortly before press time, we have not had time for our own investigation. But in this case we see credible people on both sides--and beyond the obvious issues, some difficult ones which did not come out in the headlines. Of course it is wrong when companies take legal action to pressure researchers and universities to spin scientific results their way--that is a no-brainer, and the community must support researchers' right to report, especially when persons have volunteered for participation medical research studies. This is part of an enormous problem ["when an investigator has a financial interest in or funding by a company with activities related to his or her research, the research is lower in quality (2 references), more likely to favor the sponsor's product (5 references), less likely to be published (2 references), and more likely to have delayed publication (1 reference)"(6)], and to that extent, the public was well served by the press coverage.

But tougher questions about how best to serve the public interest arise from the fact that today immune-based therapy is an enormously important research area, and yet there is no satisfactory way to test such treatments for clinical efficacy in patients (see "FDA Meeting on Approving Immune Therapies: Background and Comment," AIDS TREATMENT NEWS #353, October 20, 2000). Immune Response Corporation did what it had to do and ran a huge trial originally designed to look for differences in survival between those who did or did not receive Remune, the HIV immunogen developed by the late Dr. Jonas Salk; both the treatment and placebo arms had more than a thousand patients each, who were allowed to use any antiretroviral therapy they chose (including experimental treatments, or including no antiretroviral therapy at all), in addition to the immunogen or placebo, which was administered every three months. But after the trial was designed, the introduction of protease inhibitors reduced overall AIDS deaths enough that the trial could not have detected that the treatment improved survival even if it did--so the trial was quickly changed to include AIDS-related illnesses as well as deaths as end points.

But later, in May 1999, when the Data Safety Monitoring Board (DSMB) secretly unblinded the data, it recommended that the trial be stopped; "the basis for the recommendation was the lack of evidence of a difference between the HIV-1 Immunogen group and the control group with respect to clinical progression and that continuation of the study was unlikely to lead to a demonstrable difference between the groups."(2) "Before the study began, the predicted clinical endpoint event rate was 6% progression per year, meaning that 6% of 2,500 patients would progress to an AIDS defining condition or death each year. However, when the study was stopped, only 0.73% per year progressed using the original Centers for Disease Control AIDS-defining conditions."(7) Due to the dispute with the company, the study leadership was unable to obtain the final data, and published from the data submitted to the DSMB, with updates during the summer of 1999.

The treatment certainly did increase HIV-specific immunity as shown by lymphocyte proliferation assay (p<.001),(2) but this measure is not currently accepted as a surrogate marker of drug efficacy, because there is no proof at this time that increasing this response is clinically beneficial to patients.

The company has long had a reputation of looking for creative ways to interpret its data, which angers some researchers and activists. A serious communication problem with unconventional ways to look at data is that even if they are valid, outside analysts have a hard time verifying that--because they must ask, "If we were given unlimited access to the raw data, and months to play with it (months which we don't have), might we have found equally convincing ways to come to very different conclusions?" Yet when facing a serious situation where conventional ways of analyzing studies of immune-based treatments do not work, it might or might not serve the public interest to insist on strict adherence to established data-interpretation rules. Sometimes it is necessary to push ahead on faith in what one is doing, break some rules and take some risks, or nothing will happen.

The controversy over the publication of this study re-emphasizes the importance of developing workable, well-accepted standards for the relationship between researchers and industry. But here again there are complications. For example, telling sponsors to keep hands off of the scientific publication clearly seems like a good idea. But in this case the press, investors, and the public ended up with a bottom line which is at least questionable, if not wrong--that the "HIV vaccine was not effective" in general and not just in this trial. Certainly this study did not find a clinical benefit--but if no such finding were possible because of unrelated improvements in HIV treatment, the study did not find that the treatment was not effective, either; rather, the result was inconclusive. Can standards decree that a sponsor has no legitimate interest in preventing such misunderstandings?

In this trial the treatment consisted of killed HIV plus an adjuvant--a substance which makes vaccines work better. The placebo consisted of the adjuvant alone. Has it been ruled out that the adjuvant itself might have been beneficial, without the killed virus--since the volunteers already had their own HIV, including dead virus, on board? This seems unlikely, given the lack of HIV-specific lymphocyte proliferation in the "placebo" arm--but much is still unknown, and if the adjuvant itself were effective, the study result could have been negative even if the product being tested were beneficial.

Other Important Findings

The paper included other information which should not be overlooked because of the distraction due to the controversy.

"This study provided the first information regarding disease progression among a large group of well-treated patients with CD4 cell counts between 300 and 549 x 10(6)/L that was collected in the controlled setting of a randomized trial. The progression rate of 1.8 per 100 person-years of observation was one third of what had been reported in the literature prior to the widespread introduction of protease inhibitors. This provides additional evidence of the long-term benefits of highly active antiretroviral therapies..."

The study also found a surprisingly high incidence of lymphoma, "the second most common clinical progression event" (the most common was oral candidiasis).

References

1. Hilts PJ. Company tried to bar report that H.I.V. vaccine failed. THE NEW YORK TIMES. November 1, 2000, page A20 (national edition).

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

3. Cho MK, Shohara R, Schissel A, and Rennie D. Policies on faculty conflicts of interest at US universities. JAMA. November 1, 2000; volume 284, number 17, pages 2203-2208.

4. Boyd EA and Bero LA. Assessing faculty financial relationships with industry: A case study. JAMA. November 1, 2000; volume 284, number 17, pages 2209-2214.

5 Korn D. Conflicts of interest in biomedical research. JAMA. November 1, 2000; volume 284, number 17.

6. DeAngelis CD. Conflict of interest and the public trust. JAMA. November 1, 2000; volume 284, number 17.

7. Immune Response Corporation press release, October 31, 2000.

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