HIV-1 Immunogen fails to extend HIV progression-free survival
Addition of HIV-1 Immunogen to antiretroviral therapy (ART) failed to enhance efficacy compared with that achieved by ART alone, report Dr James O. Kahn and associates, of the University of California, San Francisco, in the November 1st issue of the Journal of the American Medical Association.
However, the manufacturer of HIV-1 Immunogen, the Immune Response Corporation, has initiated binding arbitration proceedings with the University of California, San Francisco, and Dr James Kahn, charging that the article contains incomplete and inaccurate information. Commenting on the JAMA article, Dr Robert T. Schooley, of the University of Colorado Health Sciences Center, in Denver, told Reuters Health, “In this patient population, it’s difficult to argue that there are major differences between the control and the treated groups.”
The investigators randomised 2527 patients from 77 sites in the United States to receive HIV-1 Immunogen or placebo. The patients presented with CD4 cell counts between 300 and 549 cells/µL and were either on stable ART or were not receiving antiretroviral therapy. HIV-1 Immunogen was administered intramuscularly every 12 weeks for 13 planned vaccinations. Because of apparent lack of efficacy, the trial was terminated early after an average of 120 weeks of follow-up.
Fifty-three subjects in each group experienced a primary end point: death, or opportunistic infections or malignant neoplasm. Oral candidiasis and lymphoma were the first and second most common manifestations of disease progression. Twenty-three in the HIV-1 Immunogen group died, compared with 19 in the control group. No significant differences were observed between the groups with regard to viral load, CD4 percentage, or body weight.
The investigators observed an increase of 10 cells/µL of CD4 cell percentage in the HIV-1 Immunogen group compared with placebo, which “might not be large enough to be clinically significant,” they add. “At least a 5-fold increase in the lymphocyte proliferation assay to HIV and p24 antigen at week 24 and 48 was observed in 45% and 34% of patients randomised to HIV-1 Immunogen, respectively,” compared with 1% at both time points in the placebo group. “What we observed is significant statistically,” Dr Kahn told Reuters Health. “Unfortunately, that biological assay did not correlate with decreasing clinical disease progression, which is what we hoped for.”
Immune Response Corporation (IRC) in Carlsbad, Calif, which sponsored the study, argues that the JAMA article excludes data from a protocol-defined random subset of 10% of enrolled subjects whose viral and immune response was evaluated every 3 months rather than every 6 months. “When you look at data from this subset, there are significant differences at multiple time points between the Remune group and placebo group,” Dr Ronald B. Moss, IRC vice president, told Reuters Health. “There was a highly significant immune response favouring Remune. The patients with an immune response were the same as the ones who developed a low viral load.”
Dr Moss claims “Dr Kahn cherry-picked his data, which is scientific misconduct and unethical.” Immune Response Corporation also claims that Dr Kahn’s group failed to allow all study investigators full review of the article before its submission to JAMA. “When you submit an article to a scientific journal there are rules about financial disclosure,” Dr Moss continued. “I can’t say that this is factual or not for Dr Kahn, but many academic researchers are working with competing pharmaceutical companies. Academic researchers can cut and slice data and that’s their right to do that, but we as a company and the investigators clearly voiced that all of the data should be out there.”
In response, Dr Kahn told Reuters Health, “When you run a large trial, you have to stay focused on the end points of the study. IRC had no conflict with any of this. Their conflict was, why can’t we include a subgroup analysis that shows the product works? The subgroup analysis would be on 250 of the cohort,” Dr Kahn continued, “that in our statistical analysis still didn’t differ from placebo. “IRC said if you look at the subgroup analysis and you do the analysis in this way, you can see there is a benefit,” Dr Kahn explained. “That’s what’s called a post hoc analysis. It was not part of the study analysis we were going to do.” Dr Kahn added, “It doesn’t make sense to proclaim a subgroup with an incorrect statistical metric applied to it as being beneficial when the whole population shows no benefit.” Immune Response Corporation has “been very deceptive in their interactions with us, and I think [they are] trying to put a spin on the data that everyone sees through,” Dr Kahn concluded.
Dr Schooley added, “Whenever you try to assess a study, the first thing you want to do is look at what they initially set out to show, and did they do it. The problem is when you go back later and say ‘what else was there?’ you can do what is called ‘data dredging’ and be misled by that.”
Source: Reuters Health