The AIDS Beacon™

The HIV vaccine clinical trial, RV144, that was hailed as a success in September is now under scrutiny by other researchers and activists, who say the results may have been due to chance. What has caused this backlash, and why are the results now in question?

Study RV144

Results of the study, RV144, were formally published in the October issue of the New England Journal of Medicine, and presented at the annual AIDS Vaccine 2009 conference in Paris on Tuesday.

The trial was conducted by the United States Military and the Thai Ministry of Health in Bangkok and involved over 16,000 Thai volunteers, who received six injections over six months. In September, the researchers announced that the vaccine had a 31.2 percent protective effect (see related Beacon news).

However, the scientific community has criticized the results because of the way in which study participants were included or excluded in the calculations.

Questions Raised About Study RV144

The questions about the study revolve around the issue of statistical significance. Statistical significance is calculated in order to confirm that a study’s results are meaningful and not due to chance.

At the end of a clinical study, participants are put into three categories. These are:

Intent-to-Treat (ITT): this group includes everyone in the study, even if they were later found to be unsuitable for other reasons. In this case, the Intent-to-Treat group included seven subjects who were actually HIV-positive before the study began.

Modified Intent-to-Treat (mITT): excludes certain subjects who are later found to not meet eligibility requirements for a study, but includes everyone else, even if they did not receive the full trial treatment. In this case, the Modified Intent-to-Treat group is everyone in the clinical trial except the seven HIV-positive subjects. Some people in the mITT group did not receive all six injections of the HIV vaccine.

Per-Protocol (PP): this group includes only the subjects who completed the trial and received the full treatment or dosage. For study RV144, this is everyone who received all six injections on time. This is the smallest group, with the fewest number of people.

For study RV144, only the results for the mITT group meet the usual scientific standards of statistical significance. This means that if researchers look only at the PP group – the subjects who received every vaccine injection on schedule – they cannot rule out the possibility that the results were due to chance, rather than actual protection by the vaccine.

RV144 Results Criticized And Defended

Colonel Nelson Michael, the primary investigator of the U.S. Military HIV Research team, has defended their handling of the data, and contested the convention of statistical significance.

“Not everything that is statistically significant necessarily is biologically informative and vice versa,” he stated while answering a question from the audience at the vaccine conference in Paris.

Michael suggested that other researchers and the media alike have disproportionately interpreted the purpose of the study. He emphasized that the trial was meant to test a “proof of concept,” that the unlikely combination of two vaccines would have a preventative effect at all.

The trial was not meant to provide a vaccine for complete immunity against HIV or to suggest a precise administration regimen.

The way in which the study results were released, however, has also been criticized. When the results became public on September 24, the researchers did not mention that they had chosen to present data from a selected group of participants, the mITT group.

“Following the repeated failures in AIDS vaccine research over the years, the premature and partial reporting of select – and favorable – vaccine trial data here underscores an inherent and glaring conflict of interest,” said Michael Weinstein, president of AIDS Healthcare Foundation (AHF) in a press release.

“For National Institutes of Health-funded scientists or U.S. government researchers to also evaluate and discuss the significance of their own research is akin to allowing students to grade their own papers,” added Weinstein.

AHF, the largest U.S. non-profit HIV/AIDS health care provider, is calling for the trial results to be reviewed by an independent outside body.

Many scientists still consider the results to be promising. Research audience members at the Paris conference congratulated the study team on their work.

Deborah Jack, chief executive of the National AIDS Trust in the United Kingdom, called the Thai trial “a milestone in the search for a vaccine against HIV.”

Jack also highlighted the potential for this study to lead to a more successful vaccine. “These results are an incredible opportunity for scientists to discover new clues about HIV and learn how an HIV vaccine could work in practice.”

For more information on study RV144, please see the results in the New England Journal of Medicine and the conference slides and audio from the AIDS Vaccine 2009 conference Web site.