HIV and ID Observations

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.)

A:  Depends who you’re asking.

The best guidance I ever received on how to write a good note came from my residency program director, who told us that a note needn’t be encyclopedic to be excellent; in fact, he urged us to get away from the “second-year medical student” style, which typically includes absolutely everything.

Instead, he urged us to write, as concisely as possible, notes that included the following:

1. What is going on with the patient
2. Why we think so
3. What we’re going to do about it

All this gets thrown on its head, however, when you get an email like this one:

Hello Dr. Sax,
Just a reminder that I will be meeting with you to discuss your billing audit results on Thursday 5:30 pm, right after your outpatient session is completed.
Judy

In this meeting, I predict Judy will tell me that the occasional visit I coded as “Level 5″ really should have been “Level 4″, or even “Level 3″ — since even though the case was incredibly complicated and involved reviewing years of treatment history, lab results, and prolonged communication with outside providers and the patient and his family members, I somehow neglected to include the requisite # of “Review of Systems” (10 required), with explicit mention of past, family, and social history, as well as a 9-system physical exam.  Oh, and the sentence:  “Time spent reviewing impression and plan with patient and family:  — minutes.”

Yes, abuses by MDs and hospitals on billing have been well documented.  Cases like this one are obviously serious, and cannot be condoned.  It could be argued that these periodic “compliance reviews” (my session this week with Judy) are merely the just rewards of a previously unpoliced system.

But does anyone think that the current rules we have in place — with these explicit guidelines for what constitutes a complex case based on who knows what (”Review of Systems?”  c’mon!) — is anything other than an invitation to game the system with fancy software, macros, templates, lots of copy-and-paste, and other such tricks?

And what happened to what should be the primary purpose of the note — which is to communicate the critical items of the medical encounter?

That’s the saddest part — it’s gone.

File this under, “physicians behaving badly”:  The nearly universal MD practice of going to work while sick.

The ironic thing is we think we’re being selfless — after all, if we don’t show up, our patients will need to be rescheduled, or someone will need to cover, or some administrative/teaching task will not get done — but let’s imagine for a second that we actually asked our patients what we should do.

Answer:  Go home.  Get better.  Don’t infect me.

Or, to quote the signs that have appeared in our hospital since H1N1 hit, “If you have a cough, sore throat, and fever, please do not enter the hospital unless you are here for care.”

(Patients with these symptoms who are here for care are instructed where to obtain a surgical mask.)

One primary care internist, writing in the New York Times, seems to have kicked the habit:

As a resident, my greatest pride was in never having missed a day for illness. I’d drag myself in and sniffle and cough through the day.  Once, I’m embarrassed to admit, I trudged up York Avenue to the hospital making use of my own personal motion sickness bag every few blocks while horrified pedestrians looked on. Now, though, I see the foolishness of this bravura.

Sadly, I think she’s in the minority.

Fresh back from lovely Montreal, where the temperature (I’m glad to report) climbed into the balmy 40’s …

Here’s a rapid-fire listing of the Greatest Hits.  As I’m sure to be leaving something off this list, happy to accept other suggestions:

1. Interleukin-2 does not work.  The ESPRIT and SILCAAT studies are over. Yes, the CD4’s increase, but compared to antiretroviral therapy alone, there’s absolutely no clinical benefit, and plenty of side effects.
2. Should we be starting antiretroviral therapy at even higher CD4s? At ICAAC, the NA-ACCORD group said starting before 350 improved survival; here they said it was 500!  The ART-CC disagreed, slightly (their estimate was around 350).
3. Switching from lopinavir/r to raltegravir increases the risk of virologic failure in suppressed patients. Likely explanation:  undetected NRTI resistance at baseline.  This study should have no bearing on the use of raltegravir in either treatment-naive or treatment-experienced patients — essentially, the drug must be used with at least one other fully active agent.  (Oh yeah, the lipids improved, not surprisingly.)
4. Treating HIV during TB treatment increases survival compared with waiting until TB therapy is completed. One of the most interesting things about this study is that TB treatment outcomes were similar — but those who delayed therapy obviously had HIV disease progression.  By contrast, a small study of cryptococcal meningitis from Zambia suggested that early ART was harmful — the first time early ART has been associated with worse outcomes.
5. Treating HIV significantly reduces the risk of HIV transmission to a seronegative partner. This study from Zambia and Uganda involved nearly 3000 discordant couples (!), and the effect was dramatic — especially when one considers that HIV therapy was only given if clinically indicated (i.e., not to prevent transmission).
6. …But the risk of transmission is not zero. Some studies showed persistent HIV shedding in semen despite effective antiretroviral therapy.  No surprise — but this doesn’t diminish my enthusiasm for #5 above, as the reduction in risk from treatment is huge.
7. Antivirals and cardiovascular disease. D:A:D is updated, and continues to implicate abacavir, and a French Hospital Database study does the same — and both now cite lopinavir/r as associated with increased risk as well.  An ACTG database study does not find an association with abacavir, but a prospective randomized switch trial (to ABC/3TC or TDF/FTC) does — in the updated analysis, the difference was statistically significant.  Regarding abacavir, pathogenesis studies were all over the place — split about evenly whether positive or negative.  Peter Reiss gave a sensational summary on this complex issue — web cast highly recommended if you have 15 minutes to spare.
8. Lopinavir/r is better than nevirapine for women who previously received single-dose nevirapine. This might seem intuitively obvious, but it answers an important question that has generated enormous controversy over the years.  (Plus the first author is a beloved colleague.)
9. Two non-ritonavir boosters are introduced. (Details here and here.)  Yes, data are early, but something without the GI and lipid effects would be welcome indeed.  Whether we really will need PK boosters at all remains an open question, but for now they clearly are needed for PIs and the investigational integrase inhibitor elvitegravir.
10. A microbicide works.  Sort of.

So what’s missing?  Not a single phase III study of a novel agent, nor a phase IV comparative trial of existing drugs done in the developed world.

Yes, it’s a very “quiet” phase in HIV drug development — too quiet.  If this poster is a harbinger of what’s coming with integrase resistance, let’s hope it’s not quiet for long.

Happy New Year!

In the spirit of list-making that seems to permeate the world right about this time, we’ve just published our own list over at AIDS Clinical Care.  Check it out — our editorial board this year did a superb job of summarizing the field.

I have a strong feeling that next year’s version will have some much more hopeful news on prevention, perhaps through pre-exposure prophylaxis (PrEP), or treatment as prevention, or both.

As for advances in vaccines, um … perhaps the less said the better?

Many HIV/ID specialists first heard of Abraham Verghese from his book My Own Country: A Doctor’s Story, which was published in 1994.  He told us what it was like to be a newly-minted ID doctor, thrust into treating the first cases of HIV/AIDS in a remote town in Tennessee during the mid-1980s.

Compelling stuff — I thought the book was terrific.  (And apparently I’m not alone, as I’ve received it as a gift no fewer than 3 times.)

In this week’s New England Journal of Medicine, Verghese has a wonderful perspective piece on a phenomenon that will be all-too familiar for doctors working in academic medical centers:

On my first day as an attending physician in a new hospital, I found my house staff and students in the team room, a snug bunker filled with glowing monitors. Instead of sitting down to hear about the patients, I suggested we head out to see them. My team came willingly, though they probably felt that everything I would need to get up to speed on our patients — the necessary images, the laboratory results — was right there in the team room. From my perspective, the most crucial element wasn’t.

What follows is a beautiful description of the tension between the “traditional” ways of clinical medicine — which involve taking real histories and doing actual physical exams — and the new way, which uses in place of the real patient “an entity clothed in binary garments: the iPatient.”  And what’s wrong with treating the iPatient?

Pedagogically, what is tragic about tending to the iPatient is that it can’t begin to compare with the joy, excitement, intellectual pleasure, pride, disappointment, and lessons in humility that trainees might experience by learning from the real patient’s body examined at the bedside. When residents don’t witness the bedside-sleuth aspect of our discipline — its underlying romance and passion — they may come to view internal medicine as a trade practiced before a computer screen.

Even if you don’t believe in his premise — that something is lost when “the iPatient’s blood counts and emanations are tracked and trended like a Dow Jones Index” — this is a nifty bit of medical writing.  You’ll find here none of the sanctimony such pieces often have (”in my day, we spun our own hematocrits, and were the better for it …”), just common sense about the potential consequences of focusing more on the computer screen than the person being treated.

Highly recommended.

Tons of interesting stuff at this year’s combined ICAAC/IDSA meeting, most of it in non-HIV related Infectious Diseases.  In aggregate, literally hundreds of posters, presentations, and symposia on MRSA, C diff, osteomyelitis, complicated UTIs, hospital-acquired pneumonia, antibiotic resistance … It’s a great meeting to catch up on general ID, and the literature review sessions alone are practically worth the price of admission.

But there are almost always a few major HIV-related studies presented as well, and this year was no exception.  These two understandably got the most attention:

1. Early antiretroviral therapy increases survival [Kitahata H-896b].  The NA-ACCORD study compared all-cause mortality among more than 8,000 patients with HIV followed since 1996.  Compared with those starting therapy with a CD4 cell count between 200 and 350, patients starting with CD4s between 350 and 500 had a 70% reduction in the risk of death.  Wow.  [Addendum:  Our astute editor at AIDS Clinical Care points out that this is really a 43% reduction, as the relative hazard for mortality for the group deferring is 1.7.  Still wow.]  Usual caveats on the limitations of cohort studies apply, but this was a very well done study with a huge sample size; its conclusions were further bolstered by the observation that virologic suppression rates did not differ between the two groups — implying comparable levels of medication adherence.  Stay tuned for a similar analysis of those starting with a CD4 > 500 cells — whispers that we’ll see this info at next year’s CROI in Montreal.   Will this be the final word on the “when to start treatment” question we’ve been debating now for two decades?  Should pretty much every patients with HIV be on therapy?  What will happen to the planned “START” randomized trial?  I sense unless something truly unanticipated happens with drug toxicity, we’re going to be starting a lot of asymptomatic patients on treatment over the next few years.
2. Raltegravir vs efavirenz as initial therapy [Lennox H-896a].  Can something be as good as efavirenz (essentially our current gold standard)  for initial therapy?  Apparently yes — raltegravir was “non-inferior*” to efavirenz when combined with TDF/FTC in a large phase III, double-blind study:  Virologic suppression rates at 48 weeks were 86% for RAL compared to 82% for EFV.  There were also lower rates of drug-related averse events in the raltegravir arm, with protocol-specified CNS toxicity occurring in 18% of efavirenz and 10% of raltegravir-treated subjects.  We’ve been using the 2NRTI + NNRTI or PI  approach as initial therapy for a long time — here at last is a new approach. 

And for the record, I’m a big fan of this combined ICAAC/IDSA meeting, but it will be separate for at least the next two years at least.  Oh well.

*The use of the term “non-inferior” always sounds like pedantic statistics-ese to me.  86% “non-inferior” to 82%?  But it does mean something specific — best described to me as “not too much worse than”, with “too much worse” generally defined as within 10-12%.  But the lower-limit of the 95% confidence interval can’t be below this 10-12%, and that’s where peculiar statements such as “86% is noninferior to 82%” come from.

After a lecture on HIV for Primary Care Providers in our course last week, the most controversial topic was, not surprisingly, the use of post-exposure prophylaxis (PEP) for both occupational and non-occupational exposures.  And today, after an entire lecture on PEP to a group of HIV providers in our AIDS course, again the subject drew numerous questions — and strong opinions — from the audience.

Since this is a relatively data-free zone, one turns to the guidelines for advice.  But not surprisingly, they offer tons of wiggle room for a clinician to do pretty much anything he or she wants in all but the most florid exposures or non-exposures.

(Can there be a florid non-exposure?)

So here’s a case we just posted on AIDS Clinical Care. (Drawn from real life, of course.)  Emergency room resident sticks herself with a needle while suturing a patient’s wound, a patient who’s HIV positive with an undetectable viral load on treatment. Oh, and the resident is pregnant.

To give PEP or not to give PEP?

During the course, often the best questions and anecdotes come during the breaks.  Here are a few:

1. Tons of questions about our favorite nemesis, MRSA.  What works for chronic carriers?  How do you manage family members who you suspect would be culture-positive (and the source of recurrences), but are not your patient?  What if the vet won’t culture the family dog?  What are the guidelines for infection control in the outpatient setting?  What is the best non-linezolid (which still costs > $150/day) oral antibiotic?  What’s the right dose of trimethoprim-sulfa?  (Many advocates for two double-strength tablets twice daily.)  Number of definitive answers to any of the above questions?  None. I guess misery loves company.
2. A primary care MD working at a college health clinic gave me some insight into just how far we still have to go to make those revised HIV testing guidelines a reality.  In this campus-based practice, if one of the students requests an HIV test, or the clinician thinks an HIV test is indicated, several restrictions are in place that go way beyond the state-mandated requirement for written informed consent.  First, extensive pre-test counseling is required; second, only one of the providers is allowed to order the test (so the student must return to see that clinician if he is not available that day); third, mention of HIV testing in the medical record is forbidden; and fourth, the results of the test do not appear in the student’s chart.  (They are kept in some locked remote location, no doubt.)  Hey, can we stop this madness already?  Is there any evidence that such policies help anyone?  (The MD at our course was complaining about them, not surprisingly.)  Of note, the revised HIV testing recommendations — explicitly outlining the rationale for eliminating barriers to testing — are now over two years old.
3. Only two course participants thought I was Paul Farmer.  Interestingly, one of them thought I was Paul Farmer immediately after he gave his lecture, during the coffee break, when the real thing was standing right across the room. My clue she had the wrong Paul Edward was when she told me my work inspired her to apply to medical school when she was growing up in Port-au-Prince.  There are definitely worse people one could be mistaken for — back when I had more hair (lots more hair), someone thought I was a dead ringer for this guy. Yikes.

Fluoroquinolones — the “floxins”, every medical house officer’s favorite antibiotic class — will carry a black-box warning about the risk of tendinitis and tendon rupture. We’ve known about this side effect for years, why now the change? In FDA speak:

FDA’s recent evaluation of the medical literature and the post-marketing adverse event reports submitted to the Adverse Events Reporting System (AERS) confirmed that serious reports of tendinitis and tendon rupture with the fluoroquinolones continue to be reported in similar or increased numbers.

In other words, the rate of this side effect hasn’t increased. Or it has.

Regardless, it’s a good idea to get this information out to practitioners. The use of these drugs is so pervasive I suspect some clinicians believe that patients suffer from levofloxacin deficiency. (Cure: give levofloxacin.) Since they’re used so commonly, even rare severe side effects are important.

And when Achilles tendon rupture occurs, it’s pretty devastating. Pain, then surgery, then immobility for months. I’ve seen 3 cases, one of which ironically occurred in a pediatrician — who I bet won’t prescribe a quinolone to kids even if the drugs ultimately get approved for pediatric use. One hopes that telling a patient to stop the drug and avoid exercise if pain or swelling occurs while on a quinolone might prevent the tendon from rupturing.

Will this change prescribing practices, either in the hospital or office setting? Doubtful — the side effect is pretty darn rare, and it seems to be a local ordinance in some hospitals that every patient must receive at least one dose of levofloxacin before discharge. Nonetheless, it’s a good reminder that even our best drugs have some warts.