HIV and ID Observations

Emphatically yes — to the tune of >600,000* years of life gained nationwide.  So says a nifty paper being presented at the annual IDSA meeting today by Mike April, under the direction of Rochelle Walensky.

(*Original abstract said 549,437, cited in the link; number at the actual presentation, though, was 609,656.)

Bottom line is that laws that limit HIV testing (such as requiring written consent, ahem) lead to later diagnoses, and hence shorter projected life span for those with HIV.  As always with such models, one could quibble with certain assumptions, but the results remain robust through a wide range of sensitivity analyses.

In fact, the only way that switching to an opt-out testing policy could fail to improve survival is if opt-out discouraged a large group of people from getting tested at all — for which there’s not the slightest bit of evidence whatsoever.

Are you listening Massachusetts?  I think you are .

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.

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.

“Are you writing another funny blog post because there’s no baseball?” asks my son J.

As “funny” is very much in the eye of the beholder, that remains to be seen.  But here are a few things on my mind the last few days:

• No data supporting N95 over surgical masks for flu.  One huge logistical issue dodged — at least for now.  But Consumer Reports, that darling of objective reporting, seems to think they’re just great. Since “minimax” is the operative strategy for infection control, look for this controversy to go on for a bit.
• Speaking of flu, I’ve been hearing for weeks (from a certain someone) how chaotic this H1N1 vaccine situation will be in pediatric practices.  And here’s proof.
• LONG (wow) piece on E. coli O157:H7.  Not unreasonable, given the potential severity of the illness and the tortuous route hamburgers take en route to our kitchens.  (Yuck.)  Did I mention before that this is one of the few ID issues that my wife and I take a hard line on?  Make those burgers well-done, thank you.
• Hey, did you catch the 10AM agenda in tomorrow’s General Court of the Commonwealth of Massachusetts?  Can’t miss that.
• Finally, did a throat infection bring down the mighty Tyrannosaurus rex? Perhaps if the dinosaur doc sent a “hold” tube to the lab, they can make the diagnosis retrospectively.

Good luck Tigers/Twins fans!

So says this press release by the US Military HIV Research Program:

A Phase III clinical trial involving more than 16,000 adult volunteers in Thailand has demonstrated that an investigational HIV vaccine regimen was safe and modestly effective in preventing HIV infection. According to final results released by the trial sponsor, the U.S. Army Surgeon General, the prime boost combination of ALVAC^® HIV and AIDSVAX^® B/E lowered the rate of HIV infection by 31.2% compared with placebo … In the final analysis, 74 placebo recipients became infected with HIV compared to 51 in the vaccine regimen arm. The efficacy result is statistically significant. The vaccine regimen had no effect on the amount of virus in the blood of volunteers who became HIV-infected during the study.

This is great news, of course; we’ve become so used to hearing gloom and doom about HIV vaccine studies that one can’t help but be excited, despite the relatively low (but statistically significant) rate of protection.

Still, one suspects such a combination vaccine could be logistically difficult to manufacture and administer , especially since one arm of the strategy employs the live-canarypox virus ALVAC vector, and 5 injections were required.

Plus there is the issue of cross-clade protection — the vaccine was designed to protect against the most common strains circulating in Thailand (B and E).  While B is quite common in North America and Western Europe, is is far less so in Sub-Saharan Africa, where the HIV epidemic is the most severe.

Nonetheless, if you put this news along with the proven protective effects of male circumcision and HIV treatment — the latter I believe to be greatly underestimated by the medical and non-medical community — things are definitely looking up in the HIV prevention arena.

Further details on the study will be presented at the AIDS Vaccine Conference, October 19-22 in Paris — interestingly a return to the same city where HIV was discovered.

The alphabet soup that characterizes HIV therapeutics has always been one of its quirky challenges — for example, who could possibly know that 3TC, CBV, TZV, EPZ, and LAM all refer to drugs that are (or contain) lamivudine?

This drives our ID fellows nuts, and is certainly a strong deterrent to non-HIV specialists to learning the field.

(Maybe that’s why they pay us the big bucks… oh wait.)

And while we’ve grown comfortable with the abbreviations for the 3 oldest drug classes — NRTI, NNRTI, and PI — what are we to do with integrase inhibitors?  Some candidates:

• “II” — sounds funny when you say it (”eye-eye”), and could be confused with “eleven” depending on the font
• “INSTI” — for “integrase strand transfer inhibitor”; I’ve already seen this one around a lot, but have also seen it written “InSTI” (lower-case n), which is hard to type
• “INI” — for “INtegrase Inhibitor”; same upper vs lower-case issue as “INSTI”, and saying “INI” always has an anatomic (especially umbilical) connotation to it

Still not sure where we’ll end up with this one, but I suspect “INSTI” will rule the day.

Interested in researching the cause of AIDS?  Well go ahead and give NetBase Solutions’ healthBase a try, but don’t expect much in the way of filtering:

One of the most unfortunate examples is when you type in a search for “AIDS,” one of the listed causes of the disease is “Jew.” Really. The ridiculousness continues. When you click on Jew, you can see proper “Treatments” for Jews, “Drugs And Medications” for Jews and “Complications” for Jews. Apparently, “alcohol” and “coarse salt” are treatments to get rid of Jews, as is Dr. Pepper!

To be fair, the site seems to have cleaned up its act quite a bit since this report — here’s an example of a search I just did.  Most of the results are now much more plausible, but there’s still some wacky stuff there.  HIV is the number two cause of AIDS (number two?), and number five is “Abbott” — and I don’t they’re referring to the guy up there in the baseball uniform.

Look, I’m all for using the internet for medical information, and acknowledge I can barely function without it these days.  But this kind of advanced search engine takes lots and lots of human oversight, and for now the swarm of medical data out there in web-land can be as misleading as it is vast.

(Hat tip to Graeme M for the link.)

Browsing through the program book, I see these topics extensively covered:

• H1N1 and seasonal flu, in all their glory — transmission, pathogenesis, treatment, predictions
• Highly resistant GNR — acinetobacter, carbapenemases, ESBL, etc.
• MRSA — my personal favorite
• C diff — though perhaps a little less this year?

While no one expects ICAAC to be an HIV-focused meeting, usually there are a few important papers presented — last year, for example, NA-ACCORD and raltegravir in treatment-naives debuted at ICAAC.

But unless I’m missing something, I don’t see anything this year on the HIV front of comparable importance.  One year blip or a sign of the times?

(FYI, the CDA — that’s the California Dental Association — is also having a meeting here.  Their meeting-goers have much better teeth than ID doctors/microbiologists.)

From the FDA Advisory:

There have been postmarketing reports of cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme, as well as hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Intelence therapy should be immediately discontinued when signs and symptoms of severe skin or hypersensitivity reactions develop.

These rare — but potentially life-threatening — reactions have been reported with all the NNRTIs.  From my extremely unsophisticated perspective (the less said about my biochemistry performance in med school the better), the molecular structure of these drugs look quite different.

So what is it with this drug class?

A few ID/HIV items to cover before summer “unofficially” ends (Sept 1?  Kids back at school?  Labor Day?):

• Will US Public Health officials recommend infant male circumcision to prevent HIV?  They might be considering such a move, but I suspect it will not be strongly promoted.  After all, none of the studies demonstrating its efficacy have been done in developed countries, and the pattern of the US epidemic — predominantly gay men and women of infected male partners — excludes the very group circumcision has been shown to protect:  circumcised heterosexual men.  Look for lots of CDC-ese in these guidelines, with terms such as “consider” and “might choose” and “be offered.”
• Getting lots of questions from my patients about the H1N1 vaccine.  Some decent interim answers here.  When available?  (Don’t know yet.)  Who will get it?  (The young, pregnant women, those at risk for severe flu)  Will there be enough?  (Maybe.)  Will the regular flu vaccine still be needed?  (Yes.)  Will this season’s flu vaccination programs/clinics/sites be civilized affairs with minimal panic, anger, waiting lines, frustration?  (I hope so, but the media will do their best to portray the situation otherwise.)
• Anyone see this movie on chronic Lyme?  Would love to hear your impressions.  I have not seen it — but this will definitely be a Netflix choice when it a appears on DVD.  (Note that I did not link to Netflix; I’m a big fan, but they are the most egregious purveyors of annoying pop-up ads in the universe right now.)
• How’s this for a new definition of contagious?  Be reassured:  my little teaser photo has been thoroughly autoclaved.

Enjoy the sunshine …