HIV and ID Observations

Remember the HIV vaccine trial press release?  The one announcing the first-ever positive result?

Then the backlash, with people questioning how the analyses were done, and reported?

Now, less than a month later, we have the scientific presentation and the paper appear on the same day.

Read all about it here and here.

If you want the view from 10,000 feet (why is that the chosen altitude for that cliche?), here it is:

• The vaccine strategy combines two vaccine generally thought to be ineffective on their own — canarypox ALVAC-HIV and glycoprotein 120 AIDSVAX B/E — in a “prime and boost” approach
• Over 16,000 patients are enrolled in Thailand in a placebo-controlled trial
• The “modified intention-to-treat” analysis, which excludes those who are found to be HIV positive at entry, shows a modest but statistically significant protective effect, reducing the infection rate by about 30%
• There is a trend towards a protective effect in the intention-to-treat and per protocol analyses
• In those who were vaccinated and became infected, there was no effect on CD4 cell count or HIV RNA

Numerous questions remain, many of them summarized in this accompanying editorial:  Why did it work when the individual strategies didn’t?  How durable is the protection?  How do the strains causing infection relate to those in the vaccine?  Did the per-protocol analysis fail to show a significant protective effect solely because of a smaller sample size?  Would the vaccine work if tested on higher-risk populations?  What effect will this study have on the ongoing vaccine development effort, both in the lab and in trials?

Answers to some of these questions may be forthcoming.  Regardless, the surprising results of this study serve as a reminder of just how mysterious the immune system remains — despite some incredibly smart people working on it with lots of resources.

Because if you asked the vaccine cognoscenti to vote a little over a year ago on which strategy in clinical trials would end up with a positive result — the “prime and boost” one published today or the adenovirus vector approach –  the latter would have won in a landslide.

Here’s a surprising report in Science:

Studying peripheral blood mononuclear cells (PBMCs) from CFS patients, we identified DNA from a human gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), in 68 of 101 patients (67%) compared to 8 of 218 (3.7%) healthy controls … These findings raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS.

I confess, I had never even heard of “xenotropic murine leukemia virus-related virus” (wow that’s a mouthful) before this report, but apparently virologists have been aware of it for some time, due to a possible association with prostate cancer.

The story behind the Whittemore Peterson Institute reporting these findings is almost as interesting as the paper itself.  From their web site:

In September of 2004, a group of dedicated citizens and clinicians proposed the concept of a medical institute for the millions of patients in the US suffering from the disorders known as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), fibromyalgia and other closely related illnesses. They were concerned by the lack of available doctors to understand and serve the growing numbers of patients with these complex chronic illnesses.

According to the coverage of the story in the Times, the Institute got its start with a several million dollar donation from Annette and Harvey Whittemore, whose child has been suffering from CFS for over twenty years.  The Times piece goes on to quote Dr. William Reeves from CDC, who sounds quite skeptical about the findings.

“We and others are looking at our own specimens and trying to confirm it,” he said, adding, “If we validate it, great. My expectation is that we will not.”

My take on all this?  Despite our being down this road before on CFS — EBV, HHV-6, candida, enterovirus, parainfluenza, Lyme, to list a few putative causes — without much to show for it scientifically, I’m all for having multiple groups working on trying to find the cause of this awful disorder, even if it seems likely that there is more than one cause.

And judging from some of the pained, angry, and frustrated comments posted here, I’m clearly not alone.

Well, that didn’t take long:

Researchers from the U.S. Army and Thailand announced last month they had found the first vaccine that provided some protection against HIV. But a second analysis of the $105 million study, not disclosed publicly, suggests the results may have been a fluke, according to AIDS scientists who have seen it.

In short, two additional analyses (intention-to-treat and per protocol) do not show a statistically significant protective effect.  In other words, the study subjects who followed the protocol most closely (per protocol) had less protection from the vaccine strategy.

What the …

But even in the original report, the protective effect didn’t seem all that great — statistically significant, yes, but maybe not clinically significant — so when you add how cumbersome this vaccine is to administer (and probably to manufacture), as well as these new findings, the likelihood of this vaccine strategy making its way to clinical use seems vanishingly small.

So what can we still hope from this study?

At best, some understanding of the correlates of protection.  Maybe.