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.

My two favorite newspapers (New York Times and Wall Street Journal — sorry, hometown paper) have just covered opposite ends of a topic on the edges of ID practice — namely, colonic micro-organisms.

Too few?

Too many?

Wrong type?

In the Times, a review of the probiotic debate:

Probiotics are live micro-organisms that work by restoring the balance of intestinal bacteria and raising resistance to harmful germs… So what health problems can probiotics really help? After gathering at a Yale workshop to review the available evidence, a panel of 12 experts concluded that there was strong evidence that several probiotic strains could reduce diarrhea, including that associated with antibiotic use. Several studies have also suggested that certain probiotics may be useful for irritable bowel syndrome.

I suspect the “experts” were gathered specifically because they had interest in this topic, and hence may be predisposed to a favorable review of the data.  Still, there might be something to it, and I’m  crazy about yogurt — full summary of their report here, which was published in 2008.

Far more fringey, however, is the whole “colon cleansing” craze, covered in the WSJ:

The typical American diet of processed foods, pharmaceuticals, stress and lack of exercise is clogging up our lower intestinal tracts, leaving them inflamed and lined with waste—and leaking toxins into the body that cause problems ranging from headaches and chronic fatigue to arthritis and cellulite. All that “stubborn fecal matter” also contributes to bulging bellies and expanding waistlines, cleansing proponents claim.

Eliminating the buildup, either with supplements or laxatives, or by flushing the colon with warm water—a practice known as “hydrotherapy” or “colonics”—can dramatically improve a person’s health and well-being, proponents claim …

Gastroenterologists pooh-pooh [I did not make that up!] many of these claims …

What follows is a very thoughtful review — and a clear debunking — of what seems to be a major form of quackery out there.  For example, here are the claims of one such service:

Colon cleansing benefits intestinal tract problems, absorption, bowel disease, constipation, digestive system, parasites, yeast infection. Helps control blood pressure, restores pH balance, restores proper digestion, reduces bad odors.  Colon cleansing also clears intestinal blockage, relieves bloating, helps purify blood, kills bad bacteria, viruses. These are just of few of the many benefits one can receive by cleaning the intestinal tract.

The problem, of course, is the scientific data backing up these claims are pretty much non-existent.  But hey, it’s just $25 for the “Oxygenated Colon Cleanser,” and $35 for the “Super-Oxygenated.”  FREE SHIPPING!

Ultimately, I think one of the gastroenterologists quoted in the WSJ piece really nails it here:

“There is a degree of obsession that goes along with this,” says Dr. Landzberg… Even “natural” laxatives, such as the plants senna and cascara, can harm the bowel, Dr. Landzberg says, adding, “The public has grown increasingly wary of the side effects of pharmaceuticals. I would like to see people bring that same degree of healthy skepticism to ‘natural’ products.”

Wise words indeed.

As every card-carrying ID specialist knows, hardly anything is more common these days than patients with — and questions about — MRSA.

And one question I’ve been hearing increasingly these days is “Could I be getting my recurrent infection from Rufus?”

To which the answer is, unfortunately, yes.

(I had a dog named Rufus.  No offense intended to people out there actually named Rufus.)

Now along comes this article in the New York Times, which no doubt will stimulate the economy by prompting massive sales of hand-sanitizers, plus a flurry of trips to the vet to have Otto cultured.

(That’s Otto — our cat — in the picture, FYI.)

The article is self-explanatory — pets get MRSA, they can spread it to their owners and back — but did they have to put this caption under the picture of the dog?

INFECTION Don Graff of Belle Mead, N.J., with his English setter, Sunny. The dog contracted MRSA after a spider bite [emphasis added] but was given medication and has improved.

Spider bite!  If there’s one thing this medical writer should have figured out in her background research for the piece, it’s that MRSA infections are frequently mistaken for spider bites.

And I’d bet good money that Sunny (the English setter) never had one — for which I’m sure he’s quite relieved.

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.

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 …

This might seem bizarre, but one of the reasons I chose to go into Infectious Diseases as a field was the names of the diseases (and often the micro-organisms that caused them) sounded so darn cool.

For example, if you were a science fiction writer you could hardly come up with a better-sounding name for a mysterious disease than “toxoplasmosis.”  Or its full name, “Toxoplasma gondii”.

Major Pribulon, I’d advise against taking your Colonial Defense Armada into Sector 18, Ambrilla Zone — I hear reports of a widespread outbreak of TOXOPLASMOSIS.

Wow, that sounds scary.

Anyway, from the only toxoplasma diagnostic reference lab in the United States — the one at Stanford, founded by Jack Remington, now headed by Jose Montoya — comes this fascinating paper on risk factors for acquiring toxoplasmosis in this country.  It’s a case-control study using 148 newly-acquired cases from their serology lab, comparing them with 413 negative controls.  Here are the significant risks:

• eating raw ground beef or rare lamb
• eating locally cured, dried, or smoked meat
• working with meat
• drinking unpasteurized goat’s milk
• having 3 or more (!) kittens
• eating raw oysters, clams, or mussels

Interesting that having 1 or 2 kittens was not a risk factor, and neither was gardening.  Raw shellfish consumption is one I hadn’t heard before; there are several plausible explanations:

Oysters, clams, and mussels are filter feeders that concentrate T. gondii, as has been shown under experimental conditions. Sea otters in California have been found to be infected with T. gondii, and it is likely that they are often infected by eating mollusks, which filter T. gondii from seawater. The seawater in California is thought to be contaminated by T. gondii oocysts that originate from cat feces, survive or bypass sewage treatment, and travel to the coast through river systems.

And don’t forget:  stay out of the Ambrilla Zone, Sector 18.

Over on the CID web site, they have the revised version of the “IDSA Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus”. It’s a great document, filled with useful references and a particularly strong table where to find other consensus guidelines (diabetes, hyperlipidemia, mental health, others).

My vote for what will be most commonly-cited part of the guidelines it Table 5 (Recommended Baseline Lab Tests) — though Table 9 (Vaccines) could be a close second.

Some potential areas of controversy:

• No recommendation for routine screening for osteoporosis
• No recommendation for routine anal pap smears in MSM
• LP for all patients with late-latent syphilis or syphilis of unknown duration

Regarding the bone density, I suspect this will will be recommended one day, though agree for now it’s premature.

However, I’m sure there are many who will be surprised that the anal paps are not routinely recommended.  Solid quote:

Anal cytologic screening (ie, anal Pap smears) in HIV infected women and MSM is not considered to be the standard of care at this time but is being performed in some health care centers. Additional studies of screening and treatment protocols for anal dysplasia are in progress to clarify this issue.

Seems that it is done uniformly at clinics that have enthusiasts, or zealots — plus a high-resolution anoscopy plus biopsy protocol.  (”If you’re at Disneyland, you go on the rides.”)   We don’t really know yet whether this screening prevents cancer.

For the LP issue — I know it’s in the STD Guidelines, but do you really LP all such cases in your HIV patients?

Below is a highly-subjective list of some of the highlights from the Cape Town IAS meeting. I’m sure I missed something — it’s impossible to see everything at these large conferences.  Corrections/additions welcome!

My miss-rate might be particularly high since the international AIDS meetings are appropriately focused on HIV treatment in resource-limited settings (especially Africa) whereas my perspective is as a US treater/researcher.  That said, studies from these countries often have important take-home points for all of HIV medicine.

Apologies over, on to the content:

Immediate therapy increases survival for asymptomatic patients in Haiti (WESY201). This landmark study (CIPRAHT001) randomized asymptomatic patients with CD4 cell counts between 200 and 350 to start treatment immediately with ZDV/3TC + EFV or to wait until CD4 fell to 200.  An independent DSMB stopped the study early after finding 23 deaths in the “standard” therapy arm vs only 6 in the early treatment group.  The difference in the risk of infection-related deaths was particularly striking–  1 vs17 — and the standard therapy group also required greater intensity of lab follow-up and had higher treatment-related toxicity.  The results are a strong challenge to the WHO treatment guidelines (essentially to start rx with cd4 at 200), and can be added to the growing list of studies that find early ART is better than waiting.

Incidentally, the presentation was kind of hidden since apparently the study was submitted after the late-breaker deadline.  Too bad — I hope it gets a larger venue at CROI.

Treating pregnant women with ART for at least 6 months post-partum reduces breast-feeding transmission (WELBB101). Women in Botswana with higher CD4 cell counts were randomized to either ZDV/3TC/ABC or ZDV/3TC + LPV/r, and those with lower counts got standard ZDV/3TC/NVP. The individual regimens are less important than the fact that they continued treatment for 6 months post-partum, and were instructed to breast feed (switching to formula feeding in developing countries might avert some HIV infections, but the overall outcome for the infants is worse — even when clean water can be provided).  The results showed a transmission rate of only 1%, which is the lowest ever reported for a transmission study that includes breastfeeding — and not dissimilar to what is observed in industrialized countries.

Implications?  Seems to me that the myriad byzantine regimens being tested in this setting — including various single-dose NVP strategies, giving the babies prolonged “post-exposure” prophylaxis even though they are not infected, prescribing a “tail” of NRTIs to the moms to reduce resistance with the NVP — can all be replaced just treating the mom with standard antiretroviral therapy.  Of course easier said than done, but since when shouldn’t we try to do what’s best for pregnant women, which in general is the same thing as for non-pregnant women?  Let the controversies ensue, I know they are heated. Read more of this post »

The international AIDS meeting finds its way today to South Africa, the country with arguably the greatest needs for HIV prevention and treatment.

This is not the first time the meeting was in this country, of course — in 2000, the World AIDS Conference took place in Durban, a truly landmark event in the history of the epidemic.

Aside from the obvious fact that HIV/AIDS was at that time largely ignored by the South African government, so that having the conference here was a major symbolic step forward, what else transpired?

• President Mbeki, in his opening speech, continued to focus on poverty — not HIV — as the cause of AIDS, with no concrete mention of antiretroviral therapy as either treatment of HIV nor as a way of preventing perinatal transmission.
• By contrast, Judge Edwin Cameron — openly HIV positive — stood up in front of thousands as the picture of health, describing how this was all due to his taking two pills twice a day.  (His regimen:  ZDV/3TC + NVP.)  He pleaded to make treatment more widely available.  It was riveting.
• Tony Fauci introduced us to the idea of “STI’s” — structured treatment interruptions — with several purported benefits, including decreased toxicity of treatment, “auto-immunization”, and lower cost.  No, it didn’t work out so well, but it became a major research agenda for the next 5-plus years. The paradox of STI was perfectly encapsulated by my colleague Abie Zuger, who noted that while Aftricans were desperate for treatment, her patients in the US were almost as desperate to stop, so bad were the side effects of therapy at that time.
• There was yet another study comparing ZDV/3TC plus either ABC or indinavir; ATLANTIC compared d4T/ddI plus one of either IDV, 3TC, or NVP; lopinavr/r was still called “ABT-378″; and the “next frontier” in antiretroviral therapy was correctly identified as entry inhibitors, with enfuvirtide right around the corner, and CCR5 antagonists already in development.
• The whole issue of mitochondrial toxicity, and its link to lipoatrophy and lactic acidosis, was coming into clearer focus.  Although many studies had begun to target d4T as a main culprit, there was still some debate.
• Nelson Mandella closed the conference with a beautiful speech — there was a general sense of hopefulness that contrasted markedly with the opening ceremony.

I also remember that the conference was superbly run from the technical perspective, and that the Durban beaches were gorgeous.  I purchased a pair of plastic flip-flops that my son still wears, and a cute bowl for my wife that has a giraffe handle.  The sun set very early in July way down here in the southern hemisphere.

Oh, and I learned then that South Africa is a long long way from Boston, and I was just reminded of that fact after a 24 hour trip here.  I am in awe of the stamina of my colleagues who make this trip on a regular basis.

Updates on interesting stuff here to come.

As I’ve noted here several times (some might say ad nauseum), I am convinced that Massachusetts’ arcane law requiring written informed consent prior to HIV testing is a barrier to more widespread screening — an opinion that is shared by virtually every clinician I’ve asked about this issue.

Last week, there was an announcement about progress (of sorts):

Clearing the way for HIV testing to become almost as routine as checking for cholesterol, state public health officials issued an advisory yesterday saying that the written consent required by law can be included in general permission forms patients sign for medical care.

Until now, Massachusetts doctors have typically given patients separate consent forms to authorize HIV testing, but yesterday’s directive makes clear that one form is sufficient, as long as the general consent form explicitly mentions HIV testing. Separate permission forms pose a barrier to testing for patients and healthcare providers alike, health officials said.

I’m of two minds about this.  On the one hand, we could simply do away with the law — something that most other states have already done, with Connecticut’s pending legislation providing a wonderfully common-sense approach on how to do this.

In addition, putting HIV in with the general consent for medical care seems both 1) kind of sneaky (does anyone actually read all that paperwork?) and 2) perpetuating HIV exceptionalism, since no other specific diseases are mentioned.

These concerns notwithstanding, I’m all for anything that makes it easier for people to find out their HIV status.  As noted in this article, 31% of people in MA find out they have HIV within 2 months of an AIDS diagnosis.

And that’s 31% too high.