1. In Tests, AIDS Vaccine Seemed to Increase Risk By LAWRENCE K. ALTMAN and ANDREW POLLACK Published: November 8, 2007 http://www.nytimes.com/2007/11/08/health/08hiv.html?ref=health

2. Troubling Development In a puzzling and potentially troubling development, an AIDS vaccine tested in a closely watched trial might have increased the risk among vaccine recipients of becoming infected with H.I.V., researchers reported yesterday at a scientific meeting in Seattle. But the researchers said not enough data existed to determine the meaning of the findings about the vaccine, which is made by Merck. The increased risk was principally among a group of people who had pre-existing levels of immunity to a common cold virus known as adenovirus type 5, which was modified to become a critical part of the vaccine. Researchers emphasized that the vaccine itself could not cause AIDS, but one theory is that the cold virus may have activated the immune system in some way to make certain recipients more susceptible to becoming H.I.V.-infected when they were exposed to the AIDS virus. But participants at the meeting also emphasized that the findings could be a statistical fluke and that nonbiological factors might have accounted for the difference. Examples of such factors are rates of circumcision and sexual practices among trial participants.

3. Merck Halted Trial In late September, Merck unexpectedly halted the trial of its experimental H.I.V. vaccine because it failed in its two main objectives, to prevent infection and to lower the amount of H.I.V. in the blood among those who became infected. The vaccine was being tested among 3,000 volunteers at high risk of developing AIDS in nine countries, including those at immunization centers organized by the National Institutes of Health in the United States. Merck’s was seen as one of the most promising experimental AIDS vaccines to have been tested on people. Many scientists and advocates of AIDS research have called the failure of the experimental vaccine a major setback. “The new analyses are both disappointing and puzzling” because they offer no explanation for the vaccine’s failure, said Dr. Anthony S. Fauci, the director of the National Institute of Allergy and Infectious Diseases, a partner in the vaccine trial. In September, a preliminary analysis of about half those in the trial suggested that those vaccinated were becoming H.I.V.-infected at roughly the same rate as those receiving a placebo. There were 24 H.I.V. infections among those vaccinated compared with 21 who received a placebo.

4. Significant or not? But the new analysis looked at all the trial participants and found a wider difference — 49 in the vaccinated group compared with 33 in the placebo group. Further analysis showed that the imbalance was much more apparent among those who had the highest level of pre- existing immunity to the cold virus used in the vaccine. Among 778 male volunteers who had a high level of pre-existing adenovirus immunity, 21 of those receiving the vaccine developed H.I.V. infections compared with 9 in the placebo group. Researchers told reporters by telephone that when such an analysis is performed after a trial is stopped, defining what is statistically significant is difficult. The difference between the groups with low levels of adenovirus immunity was smaller — 28 among the vaccine recipients compared with 24 who received a placebo. That difference was not statistically significant. Verification of the hypothesis requires extensive laboratory tests.

5. Clinical Trials Gold standard is the “double blind” test –Provider doesn’t know the treatment –Patient doesn’t know the treatment Standard of Proof –Must prove that the proposed treatment is better than either Current treatment No treatment

6. Clinical Trials Stopping rules –Prior to start of trial, the experimenters must propose “stopping rules” if treatment is doing harm. –Null Hypothesis – Treatment works no better than placebo. –Type I and Type II error Type I – True Null hypothesis is rejected. Type II – False null hypothesis is not rejected. –Stopping rules Procedures that allow interim or sequential analyses in clinical trials at predefined times and that specify the conditions or criteria under which the trial shall be terminated while preserving the Type I error at some prespecified level. http://books.nap.edu/openbook.php?record_id=10078&page=130 Think about 1 tailed and 2 tailed issues!

7. Moral Hazard Issues In this case moral hazard would suggest that the treatment itself may be affecting behavior. If those who were vaccinated thought they couldn’t get HIV/AIDS, they might engage in riskier behaviors. There is a sense that the (relatively successful) current HIV/AIDS treatments may have had these impacts.