After receiving helpful emails from a number of NIAID communications staff, it appears (although it does not seem to be certain as yet) that the Phambili trial DSMB were not privy to any more information about the STEP trial results than has already been reported. Specifically, among STEP participants that received one immunization there were 5 infections in the vaccine group and 10 in the placebo group, but among participants that received at least two immunizations (and were uninfected for the first 12 weeks of the trial), there were 19 infections in the vaccine group and 11 in the placebo group. Overall totals came to 24 infections in the vaccine group and 21 in the placebo group.
What remains very unclear at this time is why the Phambili DSMB considered there to be a possible risk of enhancement of HIV infection based on these data, when the STEP DSMB (as reported in the announcements regarding their findings that were released on September 21) did not. None of the differences between the vaccine and placebo groups are statistically significant or even reach what might legitimately be called a trend. Nevertheless, Business Day in South Africa picked up on yesterday’s releases and quoted the Principal Investigator of the Phambili trial, Glenda Gray, as saying: “in the US, among men who had sex with men, there seems to be an increased risk of susceptibility (of HIV infection) among people who got the vaccine.”
The only explanation (or maybe not - see next post) at this juncture is that it is the difference between people that received one immunization (where the non-significant results appear to favor the vaccine group) vs. people that received at least two immunizations (where the non-significant results appear to favor the placebo group) that caused the Phambili DSMB concern. If you ignore the statistics – never a wise thing to do when looking at clinical trial results – then it might appear that there is a 180 degree shift in the balance of infections when recipients that received one vs. two immunizations are compared. Perhaps this suggested to the DSMB that the second immunization had some kind of enhancing effect. But then the converse of this interpretation is that one immunization may have had a protective effect. One of the potential problems with phase IIb trials like STEP is that the relatively small overall sample size (just 1,500 people in the initial analysis) can lead to this type of confusion; one possibility is that a larger trial might have found statistically significant evidence of enhancement but it is equally – if not more - likely that the 19 vs. 11 difference is the result of chance.
Both TAG and the AIDS Vaccine Advocacy Coalition are calling for NIAID to further clarify yesterday’s statements regarding the possibility of enhancement in the STEP trial.
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