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October 7th, 2013

CD4 Cell Count at Presentation: A Figure with a Depressingly Small Upward Slope

angry smoke out of earsYou know how to make an ID/HIV specialist angry? Frustrated? Sigh loudly?

Tell a clinical anecdote that involves “late” presentation of HIV diagnosis, in particular someone who has been seeking medical care for various ailments for months or even years without getting tested.

You know — it goes something like this:

“He was seen 3 years ago for zoster [or syphilis or pneumonia or thrombocytopenia], and no one sent an HIV test. Now he’s in the hospital with PCP and 10 T-cells.”

It makes smoke come out of our ears because first, it’s so preventable, and second, it doesn’t seem like we’re making any progress.

Well, that’s not quite true — we are making some progress, just not very much. In Clinical Infectious Diseases, a new paper summarizes the trend in CD4 cell count at diagnosis for nearly 170,000 patients in studies published from 1992 to 2011. Here’s the punch line:

Mean CD4 cell count at presentation increased minimally by 1.5 cells/μL per year (95% CI, −6.1 to 5.5 cells/μL per year), from 307 cells/μL in 1992 to 336 cells/μL in 2011.

Yes, folks, that’s a 1.5 cell/year increase!  Got to show the figure, which no doubt will be much-cited, with considerable hand-wringing:

cd4 at presentation

 

Note in particular the lack of inflection in the late 1990s — you know, the years when HIV became treatable.

As the authors note, these findings raise significant questions about the “treatment as prevention” strategy, at least if the goal is complete elimination of the HIV epidemic. They also make many of our “when to start” debates completely irrelevant for more than half the newly diagnosed patients — their CD4 is already < 350, often substantially so.

The legal impediments to HIV testing are now pretty much gone, thank goodness. So what is the reason for this continued delay in diagnosis?

September 27th, 2013

Yes! An Economic Justification for ID Specialists

16839354_blogWe’re currently in the middle of fellowship interview season, and I overheard the following conversation between two of my colleagues as they contemplated their upcoming interviewees:

ID Doctor #1:  He seems like a great candidate — wants to study hospital and community epidemiology of highly drug-resistant bacterial infections, and has already made major contributions to his hospital’s quality assurance program.
ID Doctor #2: Listen to this applicant:  She’s been working in [insert resource-limited country here] since junior year in college, even continuing to go there part-time during her residency. She apparently started an HIV screening program in rural healthcare settings that has reduced perinatal HIV infections by 50%!
ID Doctor #1:  My next interviewee has his PhD in yeast genetics. I can’t understand his work, but he has three first-author papers in [insert three highly prestigious basic science publications here], and he won the “Top Clinical Resident” at his program last year, proving he’s not just a science drone.
ID Doctor #2:  He sounds terrific. But should we ask these young doctors the really tough question about ID fellowship: Will they be willing to work hard in a medical specialty that pays so poorly?

Look, I get it. We just don’t — and can’t — do the obvious things that bring revenues to U.S. medical providers. First, we do essentially no procedures. Second, the very nature of our patient population makes it impossible to churn through high volumes of clinical visits, either in the inpatient or outpatient setting. And third, for those ID doctors who focus on HIV, the demographics of the patients will almost invariably skew toward the indigent.

Now all of this makes us ID doctors, sniff, feel relatively underappreciated, at least from a financial perspective. You should see the red carpet (salaries, office space, advertising, yachts — OK, not yachts) rolled out for our interventional radiologists who treat varicose veins. Meanwhile, we struggle to find funding for the food at our weekly educational conferences.

Is that fair? Of course not.

But what we ID doctors do must have some value, right? Otherwise why does the demand for ID consults seem infinite, increasing all the time? Does our expertise in management of highly complex medical and surgical patients improve patient outcomes and — gasp — even reduce costs?

“Yes!” says this in-press paper in Clinical Infectious Diseases.

The final corrected proof is not yet available, but set aside your “let’s wait for the final published paper” tendencies, and contemplate these incredible findings about those who get ID consults versus those who don’t:

  • They had a significantly lower mortality. Is there a more important clinical endpoint? Impossible, kind of like trying to beat 5 Aces in poker.
  • They had a significantly lower length of stay in the ICU. We all know that the more days in the ICU, the greater likelihood of badness (a medical condition to avoid) and the higher the cost.
  • They had a significantly lower rate of readmissions. Quality assurance gurus love readmissions data.

What’s more, “Patients receiving ID intervention within 2 days of admission had significantly lower 30 day mortality, 30 day readmission, hospital and ICU length of stay, and Medicare charges and payments compared to patients receiving later ID interventions”. I quoted it in its entirety, because how can you improve on that? Better quality and lower costs? Sounds like just what the doctor ordered for our troubled healthcare system.

There’s some potential bias here, since many of the authors are of course ID doctors themselves; plus, we ID docs love Clinical Infectious Diseases; it’s a journal that speaks right to us. But these concerns notwithstanding, I’m hoping this important study will catch the attention of non-ID providers, hospital administrators, and healthcare economists, and that they will subsequently realize that not everything can be measured in RVUs/hour. Maybe they’ll even send some of that varicose vein-procedural revenue our way so we can have sandwiches at our case conference.

Meanwhile, time to continue interviewing these promising young pre-ID doctors for the best specialty in the world.

September 20th, 2013

CROI Abstract Submissions Now Open, and Old CROI Website Still “Lost” in Cyberspace

cyberspace ...HIV researchers can now submit their abstracts to the 2014 Conference on Retroviruses and Opportunistic Infections — or “CROI”.

(It rhymes with “soy”, as in “soy sauce”; or, if you prefer, “oy”, as in “oy vey”.)

Further details here. General submission for abstracts closes on October 8.

Meanwhile, people continue to wonder what happened to the now defunct CROI website, retroconference.org (not hyperlinked because there’s nothing there).

It’s not just nostalgia — that site was an invaluable repository of abstracts, posters, and web casts, the go-to place for a staggering amount of pre-publication HIV research. Many have despaired that finding the right reference for their grant and paper now requires all kinds of Google wizardry.

And just check out the abstract links in this Really Rapid Review© — all dead. Blah.

You could try this — but the searches don’t really work, it’s just a tease.

So what’s up? Here’s what it says about past CROI material on on the current site:

We would like to acknowledge that the previous CROI website: www.retroconference.org and the associated materials (abstracts, webcasts, etc), are not available at this time. The CROI Foundation previously partnered with a conference manager that constructed, owned, maintained, and has proprietary rights to the display formats and graphical elements of the website. The former website was taken off line by the former manager. The CROI Foundation fully appreciates how important the content from the prior CROI website is to the colleagues and the community it serves and efforts are underway to recover the content from prior conferences …

So why would someone take this information off-line? Additional details here — some sort of  legal fight.

Let’s hope is can be resolved soon, as much of that archived CROI material was very useful.

September 13th, 2013

Clindamycin vs. TMP/SMX for Soft Tissue Infections: A Clinical Trial That Needs Some Marketing

What is this tree doing in this light bulb?At ICAAC this week — the ID conference with the most inscrutable acronym out there — Loren Miller from UCLA presented a clinical trial on treatment of skin and soft tissue infections that has widespread clinical applications, yet may receive little if any attention.

And why is that?

Simply because the drugs (clindamycin and trimethoprim/sulfamethoxazole) have been off-patent for years. Cripes, they’re so cheap that some pharmacies give them away. That’s right — they’re free!

So allow me to market the study a bit.

Here’s the clinical question:

Which is better for uncomplicated skin and soft tissue infections — clindamycin or TMP/SMX?

Clearly the best way to get the answer is to do a randomized, double-blind trial, which is what we have here: Eligible subjects had a skin infection (abscess and/or cellulitis), were not systemically ill, diabetic, or needing hospitalization. If abscesses were present, they were drained.

Participants were then randomized to clindamycin 300 mg three-times daily or TMP/SMX 1 DS tablet twice daily for 10 days, along with matching placebos.  (Note:  Meets length of therapy rules.)

524 study subjects enrolled at 4 US sites; they had a mean age of 27, with 30% younger than 13. 45% had purulent drainage, and virtually all had I and D as part of their management; the remainder had cellulitis alone. Among those who had cultures, more than half had MRSA; 14% of the Staph aureus isolates had resistance to clindamycin.

14 days after enrollment, 80% of the clinda and 78% of the TMP/SMX group were cured. (About half of the “failures” were really loss to follow-up.) Diarrhea was more common in the clindamycin arm; there were no cases of C diff, and no severe rashes to TMP/SMX.

So to conclude, they’re basically the same.

How to choose? Here are some pros and cons.

  • Clindamycin is famously good for beta strep, and active against most (but not all) Staph aureus, including MRSA. But, there’s that diarrhea nastiness, with or without C diff.
  • TMP-SMX is active against virtually all Staph aureus, but whether it’s a beta-strep drug depends on whom you ask (many think it isn’t). And of course, it rarely can cause severe rashes and systemic hypersensitivity reactions.

One possible explanation for the near-equal outcomes is that the two treatments failed in different ways — the clindamycin versus resistant staph, and the TMP/SMX for the strep. Since most would get better with no antibiotics anyway (especially those with drained abscesses), these small differences offset each other.

And some might quibble at the dosing of the TMP/SMX — I’ve heard an awful lot of people say with confidence that the right dose for cellulitis is 2 DS tablets twice daily, though far as I know there are no data confirming this (surprisingly) strongly held opinion.

Regardless, kudos to the investigators for getting this study done. It may not yield a glossy advertisement in a medical journal, but undoubtedly will be very useful, cited by numerous primary care, ID, and emergency room providers all over the world.

September 7th, 2013

FAX machines, and the Special Power of the MD Degree

Everyone hates mindless paperwork.

But certain types are particularly annoying, seemingly designed to send you screaming into the night, dragging a broken fax machine behind you as your brain explodes.

Too strong? Take a look at this fax cover sheet I recently received about a patient who had been receiving IV antibiotics at home:

home care cover sheet

To get at the root of why this particular communication rankles so, let’s do a close reading of the cover sheet — an explication, a detailed description of the prosody and narrative arc, to borrow some words from my English-major days.

Starting at the top, working down:

  • It’s from “Health Information Management”:  Even though names have changed a lot over the years — hardly anyone was named “Sophia” or  “Emma” back when I was a kid — it’s highly unlikely that “Health Information Management” is the name of the person who sent this handwritten note.
  • It’s 5 pages. Pages 1 is this cover sheet. Pages 2, 3, and 4 are boilerplate documentation of what has already been done. And page #5 is a task that raises paperwork to a new level of torture — it asks for my signature in 4 ways: 1) Slow signature; 2) Fast signature; 3) Initials; 4) Printed name. That’s a first for me, let’s hope it’s the last.
  • It’s “Urgent.” Not just Urgent, but urgent!!! How do we know? Look, the word has squiggly underlining — that means it must be really important. But one might wonder why it’s so important when, as mentioned above, the care has already been given (and, for the record, the patient no longer needs their services, he’s much improved). Could it be that that the definition of “urgent” for this company differs quite substantially from a clinician’s? To a clinician, examples of “urgent” problems include a patient who is short of breath, or bleeding, or having chest pain. For this company, “urgent” means “we want to be paid as soon as possible.”
  • They want it “TODAY.” See above, for “urgent”, though now they’ve brought out the all-caps, along with the same squiggly underlining. Clearly, they want me to stop whatever I’m doing and sign the form — 4 times — NOW. One company admitted they stamp all their forms “SECOND REQUEST!!!” — even first requests — as they found this made doctors respond more rapidly to their queries. Sneaky.
  • This is all happening by fax. The fax machine is a virtually obsolete form of communication, soon to take its place besides dial phones, signal flags, and smoke signals. But not for home care companies — they love fax machines. They love them so much that the fax number doesn’t just have the squiggly underlining, it also is BOLDED. I can just imagine the office where Health Information Management sits — wall-to-wall fax machines, each carefully monitored, and each shrill fax tone a thrilling announcement that a doctor’s signed (4 times) order is incoming. What joy. (Small aside about fax machines: Over the telephone, “Sax” sounds just like “fax” — which meant back in the heyday of fax machines in the 1990s, I received plenty of correspondence — even faxes — to a “Dr. Fax.”)
  • They are unable to accept certain signatures. No stamps. No signatures from NPs or PAs. Nothing from residents. In case it’s not clear, they’ve done something very special with the word “unable” — the triple-whammy of ALL-CAPS, BOLD, and of course our friend the squiggly underline. Must be very important. But think about this for a moment:  Can’t residents write orders in the hospital? Prescribe medications to their outpatients? Do various procedures? And PAs and NPs do routine office visits, plus more complex tasks such as covering inpatient medical and surgical services, even performing colonoscopies. So residents, PAs and NPs can do these things — and do them well — but they can’t sign these forms? Maybe the PA and NP curricula don’t include the special class we MDs took on how to sign our name 4 different ways (slow, fast, initials, and print). And that special class isn’t given to just any MD — just those who are board-certified, credentialed, and have completed their post-graduate training. I’d go so far as to say that our ability to sign these forms (4 times) is the true meaning of working to the highest level of our esteemed MD degrees.

OK, I’ll stop now.

August 28th, 2013

Poll: At $14,105/year, Is Dolutegravir Fairly Priced?

12721468_blogThe recently approved once-daily integrase inhibitor dolutegravir is now in pharmacies and, like every new HIV drug, the price — around $14k/year — has generated some controversy.

For the record, here are the per-year wholesale acquisition costs of the three FDA-approved integrase inhibitors.

  • Raltegravir:  $12,976
  • Elvitegravir:  $13,428 (once disentangled from the price of TDF/FTC)
  • Dolutegravir:  $14,105

If you add the $12 or 15K for the ABC/3TC or TDF/FTC respectively, you get the total cost of initial therapy. So these integrase-based regimens cost more than TDF/FTC/EFV (22.5K) or TDF/FTC/RPV (23.2K), and less than boosted atazanavir- or darunavir-based regimens, which are around 30k.

Now obviously these are all big numbers — HIV treatment is expensive — but the flip side is that it’s so staggeringly effective that it generally meets acceptable criteria for cost-effectiveness given the huge added years of life.

But incremental cost-effectiveness is another matter — meaning, is the additional cost of one drug over another justified, and/or good value?

Here, then, are two opposite perspectives on the dolutegravir pricing:

  1. The price is fair, according to the U.S.-based Fair Price Coalition. Dolutegravir is an improvement over currently available options, and the slight premium pricing over raltegravir and elvitegravir/cobicistat is justified. Furthermore, the company met with and heeded community advice on price before the release of the drug — a laudable practice.
  2. The price is unfair, according to the advocacy group HIV i-Base, which is based in London. The makers of dolutegravir went “for gold” in pricing the drug in the United States, and will therefore severely limit the use of dolutegravir in Europe and likely also in resource-limited settings (though prices in these locations are not yet set).

Your thoughts?

Is dolutegravir fairly priced?

View Results

August 26th, 2013

When Eating Guinea Pig, Make Sure to Ask for it Well Done

guinea pigI’ve written before about how ID doctors are no fun to have at cook outs, what with our obsession with well-done hamburgers.

Now, there’s another menu item we can berate grill-meisters on, and that’s guinea pig meat:

At least 81 people fell ill from suspected salmonella poisoning after eating guinea pig meat and other foods from a vendor at a Minneapolis street festival earlier this month, health officials said… Scores of people went to Hennepin County Medical Center and Children’s Hospital of Minneapolis with severe gastrointestinal symptoms after eating the tainted food.

So if you decide to order your guinea pig on the rare side, and then get sick, you have no one to blame but yourself.

Because now you’ve been warned.

 

August 25th, 2013

Death from “Brain-Eating Parasite”: A Reminder of How Little We Really Know

naegleria cdc images 

Sometimes it takes a lot to surprise an ID doctor — we who try to make it seem like we’ve seen it all — but certain infections are either so severe (e.g., necrotizing fasciitis from group A strep) or so rare (e.g., endocarditis from Erysipelothrix rhusiopathiae) that even we are startled.

Doubly startling are those infections that score 10 out of 10 on both the severity and the rarity scale.

No doubt one such condition is primary amebic meningoencephalitis (PAM), the brain infection that tragically just led to the death of a 12-year-old boy in Florida.

The pathogenesis of PAM is straightforward:

  1. Naegleria fowleri live in warm freshwater lakes and ponds.
  2. The parasite enters the body through the nose, usually when someone swims or dives in these waters. (Some cases occur when contaminated water is used for nasal irrigation).
  3. From the nose, the Naegleria travel back into the brain, causing a severe necrotizing infection that is almost invariably fatal.

However, just because we know how it happens, by no means we know why on an individual level.

Said another way, given the millions of people who swim in warm lakes and ponds each year, why have there been only 31 cases from 2003-2012? Why did this poor boy get sick, but his friends did not?

A case like this is a reminder that, no matter how experienced the clinician, the world of infections and how they cause human disease remains a humbling life’s work.

August 20th, 2013

Underreporting of Lyme Disease No Surprise, but a Big Problem

summer meadowIn a welcome update, CDC just presented revised data on the number of Lyme Disease cases annually in the United States. Here are the key facts:

Cases reported by clinicians: 30,000

Estimated number of cases using additional information from insurance claims, laboratories, and patient reports: 300,000

Go ahead, check my math — that’s a whopping 10:1 ratio of actual to reported patients with Lyme, highlighting that this reporting is something we clinicians just don’t do very well.

And it’s no surprise to me at all.

Here’s why:

  • Clinicians are busy doing other stuff, most importantly taking care of their patients.
  • Lyme is one of many reportable diseases — take a look at this list!
  • It’s annoying. If you asked 100 doctors and nurses what they like least about practicing medicine, 74.39% would say “the paperwork.”
  • The forms can’t be completed quickly, as they request detailed information about dates of exposure and onset of illness, presence of diverse associated symptoms, and evaluations for ancillary diseases. Plus, they’re paper forms — a particular problem in an increasingly web-based and electronic medical record world. As for the specific dates of possible exposure and onset of symptoms? “I just lie,” one PCP told me.
  • “Soft calls” won’t get reported at all. Think about the febrile, achy patient in the summer who’s just spent a weekend hiking in the woods, saying ticks were everywhere, then gets treated (appropriately) for suspected Lyme. That may be the billing code the clinician uses, but often as not, no Lyme test is sent.
  • No one’s paying for these reports. Forgive the mercenary tone to the comment, but as these folks will tell you, humans are very predictable creatures — give them some incentive to do something, and they’ll often do it, even if the task is unpleasant.

I don’t have an immediate solution to this problem of Lyme underreporting, but it’s important we try to solve it — to quote Paul Mead from CDC, “Lyme disease is a tremendous public health problem in the United States,” and I completely agree.

So let’s look at a disease with extremely accurate surveillance, and that’s HIV.

HIV reporting is tied to receipt of government funds for HIV treatment and prevention. That’s a huge incentive to get the numbers right. If anything, some sites are known to overreport their cases, which is why name-based reporting is such an important accuracy check on the data.

Lest you think that HIV is different because, well, it’s HIV, believe me there are plenty of places where HIV reporting is woefully inaccurate. Back in the mid-1990s, I joined a group from the Harvard School of Public Health to participate in a scientific symposium on HIV in India. There was a reported explosion of HIV cases in certain regions of the country, and their doctors and researchers set up the conference to address this growing problem.

The first presentation was from a public health official representing the government. He showed data demonstrating that the number of cases in India was still relatively small and confined to isolated regions and “risk groups” — mostly commercial sex workers and injection drug users.

The next presentation was from an active ID clinician at one of the largest hospitals in Mumbai. He showed slide after slide demonstrating the ravages of advanced AIDS in diverse populations (emphatically not all commercial sex workers and IDUs) and then finished with a few data slides on cases at his hospital. Turns out that he had seen as many cases at his one site as had been officially reported to the government from the entire country.

When asked how to reconcile his volume of experience with the previous lecture on the national epidemiology, he responded with two other questions.

So why should we report our cases? What good does it do us or our patients?

Once we can answer those questions for Lyme — as we most certainly can with HIV — then the underreporting problem will be solved.

August 12th, 2013

Dolutegravir Approval Signals a Beginning and the End of Something Very Special

As anticipated, the FDA approved dolutegravir today for HIV treatment, the third integrase inhibitor now available.

This was about as surprising as the arrival of Royal Baby Prince George. We knew dolutegravir was coming soon, just not exactly when or what it would be named.

Here’s a short list of the data we have thus far on this drug from various comparative clinical trials:

Plus, results from another phase III study — vs boosted darunavir — should be available soon.

About the only downsides of this drug are first, that there is currently no single-pill initial treatment (said to be in the works), and second, that the brand name is still another mysteriously unpronounceable choice selected by marketing gurus undoubtedly paid much more than we are.

(“Tivicay.” Let’s see, is it Tivi-SAY, or Tivi-KAY? Or TI-visay or TI-vikay? Or maybe it’s a long I on the first syllable, as in “tie …” Gosh, who knows. Better call the people who know how to say Intelence and Stribild and Fulyzaq.)

Pronunciation aside, this is the beginning of this extraordinarily promising antiviral agent.

But it’s the end of a remarkable stretch of HIV drug development, one that started in 2006 with darunavir, then marched  through with maraviroc, raltegravir, etravirine, rilpivirine, and elvitegravir. The availability of these drugs, now with dolutegravir, means that pretty much anyone who takes their medications will achieve virologic suppression.

Because after the tweak of tenofovir — TAF — what’s next?

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

Learn more about HIV and ID Observations.