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May 21st, 2015

Which Infectious Diseases Do We Fear Too Much? Which Not Enough?

the-house-of-fearMy friend (and HIV/ID colleague) Mauro Schechter sent me a funny email the other day — from Brazil, where he lives and works:

I just read your post and watched the news clip about Powassan. And you still wonder why we think you Americans are paranoid disease freaks? 65 cases in 12 years in a population of 350 million, and you’re worried??? [The three question marks are his.] Definitely something to get worried about.
Mauro

His last sentence registered 10 out of 10 on the sarcasm meter, and of course Mauro has a point — the risk of getting a severe case of Powassan encephalitis is tiny, even in tick-filled New England. Can’t we Americans find something more appropriate to be afraid of?

On the other side, we’ve had a couple of cases in our hospital, and it really can be quite serious. More importantly, we USAers have a deep-rooted fear of not having enough to fear, and a new tick-related illness fits that void quite nicely — especially on a slow news day.

Which made me wonder — which Infectious Diseases do we fear too much? Which not enough? Here’s a list, compiled with extensive scientific rigor and years (ok, minutes) of painstaking research:

FEAR TOO MUCH:

  • Rabies. It’s hard to say that a disease that is nearly 100% fatal and causes thousands of deaths a year can be feared too much, but that’s the bizarre situation with rabies in the United States. The reality is that we have typically 1-2 cases of rabies here each year, and there is no evidence that this is likely to increase anytime soon. Yet think about all those urgent calls, late night trips to the emergency room, and series of rabies vaccine given for possible “occult” exposure to bats. Remember this Canadian study? They estimated that the number of people needed to treat to prevent one case of rabies after bat-in-bedroom-but-no-bat-bite (longest compound phrase I’ve ever written) could be as high as 2.7 million! Not surprisingly, the Canadians no longer recommend rabies vaccine after bats are found in the bedroom. We still do.
  • Pharyngitis, possible strep throat in adults. The most feared complication of strep throat is arguably acute rheumatic fever, but: 1)  Strep throat is mostly a disease of children and young adolescents, most adults have some viral thing (see below for an important exception); 2) Most acute rheumatic fever occurs in kids as well — even many ID doctors of a certain age (that means older than I) have never seen acute rheumatic fever in an adult;  3) The incidence of acute rheumatic fever has been incredibly low for years in our country, for reasons independent of antibiotic use.
  • Conjunctivitis. This ugly, uncomfortable malady makes people really, really scared, and brings out horrible fears of contagion in the school and workplace. You’d think it was a serious, and highly contagious ID emergency. It isn’t.
  • Mosquito-related Encephalitis. 2005 was a relatively bad year for Eastern Equine Encephalitis — and there were 21 cases in the whole country. But most years there are only a few, yet this doesn’t stop the near annual news media terror when some mosquitoes test positive. Or a horse dies! Or the mosquito spraying starts! Fear of West Nile Virus means a dead bird can lead to panic, triggering unnecessary calls to the Department of Public Health. Plus there was this bit about canceling high school football. As with rabies, it’s important to acknowledge that these conditions can be incredibly serious, and life threatening — but should they occupy such a big space in our collective fear center?
  • Bronchitis. First a little cold, which lingered, but now it’s become bronchitis. Terror, and cue up the Z-Pak!

FEAR TOO LITTLE:

  • Influenza. “It’s just the flu”, people say. But people are wrong, pretty much every year. Let’s hope our vaccine gets better  — how about one that you only need every five years, not one that needs to be repeated more often than renewing your car’s registration? Progress in the flu vaccine — whenever that happens — will have a transformative effect on community health.
  • Clostridium difficile. The emergence of the hypervirulent strain of C. diff should profoundly change the risk vs benefit calculation with any antibiotic prescription. Has it? I know one oral surgeon who will never use clindamycin again, after a “routine” post-operative course caused severe C diff, leading to a colectomy in a previously healthy patient. But how about before the prescription?
  • Infectious endocarditis and other bacterial complications of injection drug use. The outbreak of IDU-related HIV in Indiana is appropriately getting plenty of press — HIV is still an incurable disease, much-feared among everyone, including those who inject drugs. But all ID doctors know that the rise in use of heroin has led to a much more pervasive epidemic of endocarditis and other serious invasive bacterial infections. And these are emphatically much harder to treat than HIV, and so much more immediately life threatening. Do people with addiction fear these as well?
  • Atypical mycobacteria. There should be a support group for patients with non-tuberculous mycobacterial infections. Pulmonary and non-pulmonary infections from these diverse bugs can be incredibly tricky to diagnose and treat, yet hardly anyone in the non-medical public knows about them. Why is that?
  • Fusobacterium necrophorum. The adolescent or young adult with severe exudative pharyngitis, systemic toxicity, and a negative strep test could easily be dismissed as having “only” viral pharyngitis. Yet we now know that a subset will be PCR positive for fusobacterium, the primary cause of septic jugular vein thrombophlebitis (Lemierre’s syndrome), a potentially devastating complication.
  • MRSA. New drugs notwithstanding, and even with a decline in incidence (what’s causing that?), MRSA remains the most difficult to treat commonly encountered infection out there. Just ask any ID fellow — what other common infection persists so stubbornly, or recurs so frequently, despite “appropriate” antibiotic treatment?
  • Vaccine-preventable diseases of childhood. Self-explanatory.

Would be interested to hear what conditions you think should be on these lists. And as the days grow longer, and we get closer to peak Lyme season, I thought long and hard about where Lyme should go, and concluded it could be on both lists — feared too much by some, too little by others.

See if you can guess why.

May 13th, 2015

WHO Guidelines on Naming Diseases Are Well-Meaning, Sensible — But Kind of Boring

gehrig baseball cardFrom the World Health Organization (WHO), a recommendation on how to name a new disease:

The best practices state that a disease name should consist of generic descriptive terms, based on the symptoms that the disease causes (e.g. respiratory disease, neurologic syndrome, watery diarrhoea) and more specific descriptive terms when robust information is available on how the disease manifests, who it affects, its severity or seasonality (e.g. progressive, juvenile, severe, winter).

Ok, I get it. If you name a disease — especially an Infectious Disease— after a person, place, or even animal, that name can bring with it all kinds of problems. Tourist travel and trade down. Animals unnecessarily killed. People stigmatized.

We ID doctors are no stranger to this stigma by association, as all of us have faced the incredulous responses from seemingly kind strangers when we tell them what we do for a living.

“Well, someone has to do it,” they might say, as if we spend all our time putting ourselves in harm’s way of numerous nasty contagions. Bet they never say that to an ophthalmologist or radiologist.

So yes, there is stigma associated with infections of all sorts, and we have to be sensitive to that.

Not surprisingly, some have already criticized WHO that they are just practicing a particularly overzealous form of political correctness.

I’m not sure I’d go that far.

But think of what will be lost if and when these WHO guidelines are adopted: many of the current disease names designate something meaningful about epidemiology — MERS, for example, stands for Middle East Respiratory Syndrome, which quite accurately describes a disease that for now is overwhelmingly occurring in the Middle East. MERS may one day pull a West Nile Virus on us and become global. But even the West Nile Virus name, while no longer strictly correct, reminds us that the disease was first recognized in a particular region of Africa. Is that so terrible?

Plus, the English major in me can’t help but find a good story, or even poetry, in many of these inappropriately named diseases or organisms. For example:

  • Lyme Disease. My friend Howard Heller, an expert in tick-related infections, says that Lyme was actually discovered in Old Lyme, Connecticut, and not Lyme itself — but it would have been too confusing to call it “Old Lyme Disease”, which would imply there’s also a “New Lyme Disease” out there. How fascinating! And while Lyme is a big problem in all of New England, I don’t see the name of this disease keeping down property values in southern Connecticut one bit.
  • Powassan virus. Let’s stay with the ticks for a moment. Named after the region in Canada where it was first described, Powassan is the latest scary thing transmitted from our tick enemies. Here’s a little TV clip on Powassan from our local news station, where the interviewer energetically tries to drum up drama despite my efforts to make it clear that severe forms of Powassan are (fortunately) pretty rare so far. What if it were called “summer tick encephalitis (sometimes) virus beta”? Compared with Powassan — abbreviated POW! — that “generic” name sounds pretty blah, and am sure the networks would agree.
  • Listeria monocytogenes. The bacterium that medical students love to love, listeria was named in honor of the pioneer of sterile surgery, Joseph Lister. How can we take that away from him? And I’m sure you could find many ID doctors gladly donating their name in honor of some interesting virus, bacteria, fungus, or parasite. Sign me up! The closest thing I have is this diabetes drug. And this weight loss one. Should have been an endocrinologist, could use the royalties.
  • Rocky Mountain Spotted Fever. Back to the ticks. This one just sounds great, almost a line of pure poetry by itself — read it out loud for proof. Never mind the fact that the disease isn’t very common in the Rocky Mountains (peak incidence is in the southeastern states). Still, I ask you — how could we ever call infection with Rickettsia rickettsii anything else? It also gives us ID doctors a trick question to ask people at parties, where we are highly desired guests. Specifically, “Where is a person most likely to get Rocky Mountain Spotted Fever?” [Answer: North Carolina] is the converse of “What color was George Washington’s white horse?” [Answer: White].
  • Iodamoeba bütschlii. When he read that Haemophilus aphrophilus had (sadly) changed its name, Joel Gallant sent me an email: “Tell me it isn’t true! I love saying ‘Haemophilus aphrophilus’ as much saying Iodamoeba bütschlii,’ ‘Orientia tsutsugamushi,’ or ‘o’nyong’nyong fever’!” So who is our little friend with the umlaut? A non-pathogenic protozoan, Iodamoeba bütschlii was named after German biologist Otto Butschli by Stanislaus von Prowazek — who later had the cause of epidemic typhus named after him — Rickettsia prowazekii! Analogous to authors who review each other’s books, these biologists simply named organisms after each other, increasing their fame and fortune. You must agree it’s an impressive name for a parasite that doesn’t actually cause any disease.

Importantly, the WHO states that their guidelines apply to future diseases, so we won’t lose any of the above gems — or St. Louis Encephalitis, or Legionnaire’s Disease, or Kew Gardens Spotted Fever, or Pott’s Puffy Tumor. Or Coxackievirus. Or Mad Cow.

And somewhat grudgingly, I agree with Dr. Dr. Keiji Fukuda, assistant director general for health security at the WHO, that a boring name is better than one that stigmatizes people, diminishes trade or tourism, or leads to the unnecessary slaughter of thousands of animals. In defence of the charge that the policy is just political correctness run amuck, he gives an eloquent defence here in this NPR interview.

But I disagree with him about one thing — a few minutes into the interview, he says “we now live in an era where probably very few people are going to know who Lou Gehrig is.”

Now that is simply untrue.

 

Gets me every time.

May 6th, 2015

An Apology to Subscribers, and Five Random ID/HIV Questions to Ponder

Some of you have been kind enough to enter your email address in the little box on the right side of this page, which gives you a “subscription” to this site. It looks like this:

Subscribe

We thank you for signing up! Delivery is usually prompt and reliable (even during this past winter’s historic snowstorms), and the price can’t be beat (free).

But this week, due to a fascinating technical glitch — text copied from the FDA web site included a prohibited character, a little empty box — no e-mail notification was sent out with the latest post. Our apologies! For the record, the post included various thoughts on the nettlesome problem of fat accumulation syndromes in HIV, and a terrific video from that famous ID specialist John Stewart.

In exchange for this inconvenience, we’re offering a full refund — plus a bonus Five Random ID/HIV Questions to Ponder

  1. Could this investigational zoster vaccine really be 97% effective? Total game-changer for shingles prevention if it turns out to be this effective and safe.
  2. Are we going to call the newest azole antifungal “isavuconazole,” or by it’s weird real name, “isavuconazonium?” Strongly hoping the former.
  3. What percentage of ID doctors know exactly what “MALDI-TOF” stands for? My guess:  54%.
  4. Has anyone prescribed elvitegravir or cobicistat as individual agents? Probably — it’s a big country. But why did they do this?
  5. Why did several people in Colorado catch plague from a sick dog? Yikes, a few chewed shoes you expect. But plague?

Speaking of plague …

May 4th, 2015

A Drug for Neck Fat, and Some Thoughts on Fat Accumulation Syndromes in HIV

man-scale-boxersIt’s not often that a FDA drug approval for cosmetic dermatologists and plastic surgeons will get the attention of HIV/ID specialists, but this past week was an exception. From the FDA report:

The U.S. Food and Drug Administration today approved Kybella (deoxycholic acid), a treatment for adults with moderate-to-severe fat below the chin, known as submental fat … Kybella is a cytolytic drug, which when injected into tissue physically destroys the cell membrane. When properly injected into submental fat, the drug destroys fat cells; however, it can also destroy other types of cells, such as skin cells, if it is inadvertently injected into the skin.

Those of you who don’t practice HIV medicine might not know this, but various fat accumulation syndromes remain a bedeviling problem for our patients. And while I have absolutely zero experience with this new fat-melting injection stuff, I doubt I’m the only HIV specialist who didn’t immediately think of a few patients who could be candidates. Here’s a representative image, courtesy Medscape.

For these patients, the office visit will generally go something like this, almost invariably with someone who has been doing great on treatment for years:

HIV MD: Hi —-, your numbers look terrific — viral load undetectable, CD4 normal, liver and kidney tests fine.
PATIENT: Good to hear! Anything I can do about this weight gain? And this big belly? And look at my neck! I was looking at my drivers license recently, and I look totally different!
HIV MD (Uh-oh, this is a tough one.): Well, there’s diet and exercise.
PATIENT (Does he think I don’t know that? Jeesh.): Yes, of course. What I mean is, are these meds causing me to get fat? If so, should I switch treatment to make it better?
HIV MD (Doing his/her best.): It’s not really the medications themselves, not directly. And switching the meds isn’t going to help. The reason for weight gain on HIV treatment is complicated, and caused by several things … (Various hypotheses outlined, none of them straightforward or easily remediable.)
PATIENT (Oh well. I still think it’s the meds.): OK, thanks.

Now about those “various hypotheses” — below is a short synthesis of what might be going on, by no means meant to be authoritative or comprehensive, but just to get the conversation started:

  1. Untreated HIV induces a catabolic state. This is particularly the case for patients with advanced disease, where energy expenditure exceeds intake, leading to weight loss. This is the main reason why HIV alone caused wasting, even without a diagnosis of an opportunistic infection. Classic review article here from 23 years ago!
  2. The main driver of this catabolic state is decreased appetite. In research done in the pre-ART era, a careful analysis of energy intake and expenditure among untreated HIV patients showed that their actual metabolism was often lower than normal — or at most, a little increased — but their food intake was dramatically reduced. The cause of this anorexia is most likely high levels of circulating inflammatory cytokines, such as tumor necrosis factor. This decrease in food intake is often not noted by patients — who may remark, when newly-diagnosed with HIV and very low CD4 cell counts, that they have recently had “successful” weight loss for the first time in their adult lives.
  3. Effective HIV therapy reverses this catabolic process. Once a person starts on ART, inflammatory cytokines drop, appetite improves, and, as I tell my patients, “the virus is no longer eating any of your food.” The result is not surprisingly weight gain, which is gratifying, even thrilling, especially if there had been serious weight loss.
  4. The weight gain from effective HIV treatment can be both rapid and too much of a good thing. News flash — there’s an obesity epidemic in most of the world. Not surprisingly, once HIV is treated, our patients become just like the non-HIV population — prone to excessive consumption of processed, packaged, and high caloric junk. In fact, they might be more likely to eat these foods since they are hungry all the time. If they had previously been quite sick from AIDS, then they might also be deconditioned and hence less likely to exercise. And if they’re older, they already have a naturally slower metabolism. Both advanced HIV disease and older age are risk factors for increased weight gain on treatment.
  5. Rapid and excessive weight gain leads to fat accumulation. In a different form of pathologic “refeeding syndrome” than described in the medical textbooks, the rapid weight gain from HIV treatment can cause fat deposition, most commonly in certain anatomic sites. Probably the best described is excessive abdominal visceral fat, which is associated with increased cardiovascular risk and that big belly the above “patient” described. But abnormal fat accumulation isn’t just limited to abdomen, and every HIV clinician has patients with significant fat deposition in the neck (both anterior and posterior) and upper trunk.

You’ll note that the above list does not cite any specific HIV drugs responsible for this process. That was intentional.

Remember when we used to say that the NRTIs caused lipoatrophy, and the PIs fat accumulation? Turns out we were half right (the first part): the best data we have from randomized clinical trials emphatically does not conclusively implicate one class of drug any more than others. Here’s the most recent of these studies, comparing fat gains with raltegravir, atazanavir, and darunavir-based regimens. I’m sure if you polled a hundred HIV specialists before this study was done, 99 would have bet that raltegravir would be associated with the least fat gain. And 99 would have lost that bet, as all were essentially the same.

So for now, what can we do? A few options:

  1. Education. We need to do a better job educating our patients about this potential effect of HIV treatment. (Note I don’t say “side effect.”) It’s a return-to-health phenomenon, so the weight gain is a good thing. But a bit of advice about high-quality foods (I’m a big fan of this Michael Pollan book), watching calories, and exercising might do something to prevent excessive weight gain. And we have to be clear it’s not the HIV meds. Switch strategies expressly for this purpose are likely to fail.
  2. Tesamorelin. The growth hormone releasing hormone analogue with the sonorous name, tesamorelin is FDA-approved for visceral fat accumulation in HIV. On the plus side it clearly does reduce central fat in some patients. On the minus side it’s a twice once-daily injection, it’s expensive, the effects quickly reverse when it’s stopped, and it doesn’t work in all patients. But for a select few, it does the trick.
  3. Make friends with a good plastic surgeon and cosmetic dermatologist. Though several years ago the makers of a facial filler tried to engage HIV specialists in doing these procedures, let’s be frank — it’s best left to the people who do this kind of thing for a living. Some patients will have great results.
  4. Lobby and advocate. Lots of these treatments aren’t covered by insurance, making them unavailable to those who really need them. That’s a shame, because in severe cases these are highly stigmatizing and dramatically reduce quality of life — they should be covered!
  5. Research. If there’s a specific cause to this weight gain and fat accumulation problem, let’s see if we can figure it out. Fortunately, there are lots of smart people who continue to study the mechanisms of this process.

Meanwhile, if anyone has experience with this new drug for neck fat, let me know!

And enjoy this video, just because we’ll miss him…

April 22nd, 2015

Seriously — How Much Would You Pay for a Curbside Consult?

ron pYes, seriously.

Let me start with an email exchange I had with a PCP recently:

Hi, Paul, quick question 😉 This lady, 49 YO woman from Haiti, asymptomatic, totally healthy. Got TSpot done for immigration purposes, it’s positive with negative chest Xray. Treated with INH 6 months in 2001. She travels to Haiti annually so could had been reexposed, though doesn’t report being with anyone with TB. Do I need to treat her again? THANKS!
Carla

To which I responded:

Hi Carla, unless there’s been a significant re-exposure and immunosuppression, no need to re-treat.
Paul
p.s. You know we could start getting paid for these “eConsults.” How much do you think they are worth?

So it’s now Carla’s turn to answer my question:

Priceless!!!! Seriously, not sure, since some questions are more complicated than others. Sometimes it’s straightforward like this, and sometimes you have to review more data so that should be compensated more no?

Carla helped me out here, especially with her first response — priceless indeed. But the second part — where she suggested that this “straightforward” question is worth less a more complex one — hints at why estimating the value of these consults is so difficult.

And it’s important that we figure it out, and soon. With the inevitable move to “value-based” insurance contracts, many ID doctors are getting the push to formalize these clinical relationships. That’s a good thing, as clearly getting advice from a colleague can be a more efficient way to provide quality care than referring everyone for a formal consultation, and it puts a value on what previously was almost always done gratis.

Back to the question in the email — is it so straightforward? Clearly not to Carla, who as a generalist has to manage all medical problems not just ID ones, but to us brilliant ID doctors, sure. An IGRA (the T-Spot) and tuberculin skin test are basically two different ways of looking at the same thing (evidence of immune response to TB), and I’ve already been asked this question (or one like it) several times. Plus, I can touch-type (as I’ve bragged elsewhere, I could crank out over 70 words/minute in my 8th grade typing class), and happened to be sitting at my desk daydreaming about puppies playing baseball when the email popped into my in box.

Even if you account for the distraction factor — it was hard to get that puppy image back — it still took only a few minutes.

And as I’ve calculated before, if paid on an hourly basis, this comes out at a whopping $6/consult, or almost enough for a couple of fancy coffees at Starbucks. If we believe the good news from this latest Medscape salary survey that ID doctors are no longer in the basement when it comes to annual salaries — sorry, pediatricians — we’re only up to $8/consult (add a bagel to your coffee order).

So when it comes to curbsides, if you pay by time/consult, we ID doctors could be in deep trouble — the faster we do it, the less time-value it has, and the less we make. It’s quite different with surgeons — they get paid more with greater experience and efficiency.

Furthermore, though the fee-for-service model is horribly broken for ID as a specialty — no way to win on either volume or procedures — our clinical productivity is still mostly measured by how many patients we actually see. Every curbside we do is potentially a patient visit that didn’t happen. Note again how we differ from surgeons and other procedural specialists — from a revenue perspective, they have an incentive to keep simple non-operative cases out of their clinics.

Finally, the consultant is taking on some non-zero medicolegal risk. Should that be somehow factored into the compensation? In this excellent review — which is very pro-curbside — the author states that courts have consistently concluded that there is no actual medicolegal risk to the person being curbsided provided there is no relationship between him/her and the patient. However, he also accurately states: “Of course, even in the absence of actual liability, there is always a possibility that the consulted physician will be sued for medical malpractice. Although such a physician should ultimately prevail as a matter of law, the entire process is best avoided [emphasis mine].” Hard to disagree!

Other payment models are out there for informal consults, such as getting a flat rate per consult regardless of complexity (how much?), or getting a percentage of your salary covered for being “on call” for this service (what percentage?). And of course many will still have to live with the status quo of getting nothing — gratitude counts for something.

Provided, of course, it doesn’t end with (pet-peeve alert) “Thanks in advance!” A simple “Thanks” is perfectly fine.

Now, how much would you pay?

How much should an ID doctor be paid for a curbside consult?

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April 15th, 2015

Does Scientific Language Come Across as Wishy-Washy?

milk toastI had the opportunity to interview author Seth Mnookin recently for a podcast on Open Forum Infectious Diseases, and it was a real treat. He’s Associate Director of the graduate program in Scientific Writing at MIT, and the author of the The Panic Virus: The True Story Behind the Vaccine-Autism Controversy.

Not surprisingly given his title, Seth thinks a lot about how language conveys information about health and science. While researching the topic of vaccine safety for his book, he discovered the striking difference in how the various sides communicated their message to the public:

When you had an NIH official or a CDC official making a statement and then you had a parent, it almost seemed to me like they were talking in two different languages … So when a doctor or Harvey Fineberg would be on TV and say, “Well based on all of the evidence that we have, we’re reasonably confident that there’s no concern that vaccines cause autism that we know of at this point, etc.” In science that means, “Yeah, we’re really sure about this.” But in English that means, “Yeah we have no idea what we’re talking about and we’re about to find out that actually we’ve been doing something horribly wrong…”

And the parents challenging vaccine safety? They couldn’t be more sure of themselves:

A great example of this is when Jenny McCarthy was on Larry King’s show and she was talking about her child, and she said, “The story that I have about my child is science.” [She also said something almost exactly like this on Oprah.] A point that I try to stress is that actually the plural of anecdote is not data, and that the fact that there is a story to be told about something does not make it true.

In research, we’re taught to be curious, questioning, and skeptical — but this doesn’t play well on the big stage. If the message is as clear as the overwhelming case for vaccine safety and efficacy, we have to just say it.

There’s more interesting stuff in the full interview, including how he chose to tackle this tricky subject, how big of a problem the hard-core anti-vaccine activists actually are right now, and when the police start to take seriously various threats on your life (not kidding about that, unfortunately).

Full podcast is here, transcript here.

April 8th, 2015

New HIV Treatment Guidelines, and the End of an Era

babe-ruth-bows-out2-jpgThe new Department of Health and Human Services (DHHS) HIV treatment guidelines are out, and thanks to skillful direction by Alice Pau, it’s as usual a must-read document — all 288 pages, of course!

There are several major changes, so a good place to start is the all-important “What’s New in the Guidelines” summary page. Some of the biggest modifications come in the “What to Start” section:

  • There’s now a more focused list of “Recommended regimens” — it’s down to just 5. Specifically, TDF/FTC plus DTG or EVG/c or RAL (that’s 3), ABC/3TC/DTG (4), and TDF/FTC plus DRV/r (5).
  • The regimens that are limited to patients with low HIV RNA are now classified either as “Alternative” — TDF/FTC/RPV — or “Other” (ABC/3TC plus EFV, ABC/3TC plus ATV/r).
  • TDF/FTC plus ATV/r is now an “Alternative” regimen, largely due to the results of ACTG 5257.
  • TDF/FTC/EFV is now an “Alternative” regimen, largely due to issues of tolerability.

With the caveat that as a member of the Guidelines panel, I can only give you my personal perspective (not that of the committee), here are a few comments on this last one — the demotion of efavirenz from “Recommended” to “Alternative” — which seems to me a pretty big deal.

First the good stuff about EFV, which was approved by the FDA way back in 1998:

  1. In clinical trials, efavirenz has been better or as good virologically than all its comparators for years and years. I still remember the shock when we learned that EFV creamed indinavir — a potent protease inhibitor, who would have predicted that? — and subsequently it won or tied in numerous head-to-head studies. That success continued until the drug was compared to integrase inhibitors (in particular dolutegravir), but note that rates of virologic failure were still just as low with EFV even in this comparison. And is there any agent that so consistently does well in patients with high baseline HIV RNA and/or low CD4?
  2. Efavirenz has such a long half life that regimens with the drug are remarkably forgiving, even if people forget to take it every day. It’s so forgiving, in fact, that studies suggest you can do fine taking it only 5 days a week, or at a reduced daily dose. Not that we recommend these strategies, but still — we all have patients on EFV-based regimens who admit that they skip it periodically (usually because of side effects, but that’s a different story), yet they maintain virologic control.
  3. Although no HIV treatment is cheap, TDF/FTC/EFV is less expensive than most of the other initial regimens we use today.
  4. Efavirenz (with TDF/FTC or TDF/3TC) is the default initial treatment globally, where it is widely available as a single pill taken once a day. That counts for a lot — obviously the vast majority of people with HIV in the world don’t live here.

So what’s the issue? Why then is it now an “Alternative” rather than a “Recommended” option? In my opinion, it comes down to progress we’ve made in improving side effects. Many choices are available now that are simply easier for patients — and clinicians, who can skip the time on pre-treatment education and management of tricky side effects. Specifically:

  1. All the clinical trials comparing EFV with integrase-based options demonstrate significantly lower rates of central nervous system (CNS) side effects with the latter. As already noted, in the head-to-head study against dolutegravir, drug discontinuations due to adverse events led to a superior result for DTG. The same thing happened when EFV was compared to RPV — in the low viral load stratum, RPV was superior because it was better tolerated.
  2. Virtually everyone who starts EFV gets some sort of CNS side effect of varying severity in the first week or two. Not a good idea to start the day (or even a week) before a big presentation, or travel, or some other major life event. In most patients, these CNS side effects diminish rapidly over the first few weeks of therapy. However, a minority still have some residual weirdness going on long term — dizziness, abnormal dreams, morning grogginess. Some learn to live with it and are fine, but others don’t realize how off they’ve been feeling until they stop the drug. (Brief aside — what’s up with the small fraction of patients who choose to take EFV during the day? That always perplexed me.)
  3. More serious CNS side effects can rarely occur, in particular depression. In this retrospective analysis of four randomized clinical trials, patients randomized to EFV-based regimens had a more than two-fold increased risk of suicide or suicidal ideation compared with those not receiving EFV. And while the absolute risk was overall low, this is a severe enough adverse effect that one should be very cautious about using the drug in anyone with a history of depression. Although observational cohort and claims data have not shown this association, remember that this is a tricky thing to find in such data, and that in clinical practice we avoid prescribing EFV to patients with psychiatric disease.
  4. Every ID/HIV doctor has had patients who just can’t take this drug, and it’s not from depression. OK, anecdote time — here are a few of mine:  The guy who drives for a living who knew immediately he wasn’t as alert on the road taking EFV. The person whose dreams were so vivid that they were essentially indistinguishable from hallucinations (and not pleasant ones). The high-functioning scientist who simply couldn’t concentrate at work. The person (actually a few) with severe rash and fevers. Of course some of the vivid dream stories were pretty funny — my favorite was someone who dreamt that her kitchen had been extensively renovated, including specific selections of cabinets and appliances. Imagine her disappointment when she came downstairs to find the scruffy old kitchen unchanged!

Yes, I still have patients on EFV-based treatment who are doing great, and they don’t want to switch — that’s fine, no reason to do so. But the bottom line is that I haven’t prescribed TDF/FTC/EFV to a patient starting HIV therapy in nearly three years. Too many other good options out there now.

Hey, progress is a good thing!

I did this poll before — now let’s try it again, a year and a half later:

I still frequently use efavirenz-based regimens as initial therapy.

View Results

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April 3rd, 2015

Melting Snow ID Link-o-Rama

DonAdamsA few ID/HIV tidbits to contemplate as we go from slipping on ice and snow to dodging the mud:

Hey, it’s Holy Week. Colored (sometimes green) eggs and ham! Peeps! Matzo balls and brisket! Jelly fruit slices! For those of a less traditional spiritual bent, enjoy this:


H/T to Joel Gallant for the vid.

March 28th, 2015

Quick Question: Should HIV-Negative People in Serodiscordant Relationships All Get PrEP?

18480762_blogFrom a very thoughtful and experienced primary care provider came this query:

Hey Paul, quick question —
One of my patients, an HIV-negative gay man, is in a long-term relationship with one of your HIV-positive patients — my patient says his partner has been on successful HIV treatment for years. Obviously I can’t check his partner’s record to confirm this, but my patient is quite reliable and why should he be lying about this? He says they always use condoms.
He asked me today if he should go on PrEP — should he? He seems awfully low risk, denies other sexual exposures, etc.
Feel free to suggest that I send him to see you for a formal consult.
Thanks,
Roy

Unless you’ve been hiding under a rock (cold and damp down there, isn’t it?), you know by now that pre-exposure prophylaxis (PrEP) works incredibly well to prevent HIV in high risk, seronegative men who have sex with men (MSM) — even better than we thought, according to the recent PROUD and IPERGAY studies presented at CROI.

Related to my colleague’s query, note that the USA guidelines clearly state the following is an indication for PrEP in MSM:

Is in an ongoing sexual relationship with an HIV-positive male partner 

So end of story — PrEP should be started, right?

But there are several reasons why it’s not quite so obvious what to do in this exact situation — which is actually quite common:

  • Treatment of HIV is all but 100% effective in preventing transmission of the virus. Remember the “Swiss Statement” that condoms weren’t even required if the positive member of serodiscordant couple was virologically suppressed? The results of HPTN 052 and observational studies (most recently this one) support this prescient claim.
  • Eligible participants in the MSM PrEP studies were at “high risk” for getting HIV. In IPERGAY, for example, to be eligible a person needed to report “condomless anal sex with > 2 partners within the past 6 months.” A man in a monogamous relationship with an HIV positive partner on suppressive therapy — who also uses condoms — would never have been enrolled.
  • The incremental risk reduction — if any — of a man taking PrEP whose sole partner is already on suppressive ART could never be justified on a “number needed to treat” or cost-effectiveness basis. This is pretty obvious, but is worth explicitly stating, if only so that when such treatment is prescribed, we all acknowledge that it’s done for other reasons.

So what might those reasons be? First, as my friend and colleague Raphy Landovitz puts it, “people aren’t completely honest with their providers about the who’s and whats of their sexual relationships – including as it relates to condom use.” Remember HPTN 052, and those “unlinked” HIV transmissions from outside the couple? That alone should give us pause.

Second, some patients I’ve seen understandably remain very nervous about catching HIV from their partners, even if on suppressive treatment — PrEP provides them an additional layer of security. The TDF/FTC is acting here more as a benzodiazepine than an antiviral. Again, per Raphy: “It restores peace-of-mind to something that the HIV/AIDS epidemic has stolen from gay men.”

From a practical standpoint, here’s what I have done:
  1. See him (the HIV negative guy) alone. Or if he’s uncomfortable seeing his partner’s doctor, offer to have him see one of my colleagues.
  2. Reassure him that the discussion is 100% confidential.
  3. Tell him the pros and cons of PrEP. Efficacy, safety, and cost, of course, but also the characteristics of the patients in the studies — that they were high-risk HIV negative gay men.
  4. Inform him that PrEP has never been explicitly tested in the HIV negative partners of people on suppressive ART in a monogamous relationship — and likely never will be since the risk of transmission is already so low.
  5. Let him decide.

In my anecdotal experience thus far, some have chosen to go on PrEP, and some haven’t.

And whether those who opted in did so because they’re actually at higher risk than they’re disclosing, or for peace of mind, or some combination — does it really matter?

March 21st, 2015

ID Learning Unit: Coagulase-Negative Staph, and the “Anti-Zebra” Residents’ Report

CoNS in blood cultureAt the risk of betraying a deep streak of nerdiness, I confess to being a huge fan of Residents’ Report. This infatuation goes back to my medical student days, when the occasional chance to watch the Chief Medical Resident — who seemed the smartest doctor on the planet — lead a discussion of an interesting case inspired all kinds of aspirations.

Alas, I was never chosen to be Chief Resident, but have been lucky enough to sit in on my fair share of Residents’ Reports over the years, including one this past week. And so glad I did, as current Chief Resident Mary Montgomery tried a new twist on the genre: Instead of presenting a fascinating rare case — a “zebra” — or a challenging ongoing diagnostic dilemma, she chose a couple of extremely non-zebroid (that’s a word) cases that involved coagulase-negative staph (CoNS), a bug that frankly most of us think is pretty ho-hum.

But you know what? It was a great report, educational and entertaining, and here’s what we learned about this commonly encountered (but frequently challenging) entity:

  • In the microbiology lab, a coagulase test is done on suspected staph isolates, looking for tell-tale clumping of plasma. Clumps = coagulase-positive (Staph aureus); no clumps = coagulase-negative. Watch!
  • There are over 30 species of CoNS, with Staph epidermidis the most common — but you rarely see micro reports listing Staph epidermidis, since identifying the particular CoNS species is rarely helpful.
  • Staph saprophyticus is a CoNS species that is the second most common cause of uncomplicated UTIs in young women. Fortunately, it’s sensitive to most antibiotics used to treat UTIs.
  • CoNS are the most common isolates from blood cultures, and also the most common contaminants. Distinguishing true- from false-positive blood cultures can be tricky, in particular with CoNS, and this home-grown study provides some guidance — indeed, it’s incorporated into our ancient electronic medical record. (See above image — soon to be retired, alas, in a move of EPIC proportions.) Question: Has this study been updated by anyone?
  • Clinically important infections with CoNS frequently involve prosthetic joints, mechanical heart valves, indwelling vascular catheters, ventricular shunts, vascular grafts, pacemaker or defibrillator leads, orthopedic hardware — in short, artificial ingredients!
  • Treatment of choice for CoNS infection acquired in the hospital is vancomycin, since more than 80% are resistant to beta lactam antibiotics.
  • CoNS are good at sticking to things, and have a virulence factor called arginine catabolic mobile element (ACME), which they unfortunately sometimes decide to transfer to MRSA. I hate when they do that.
  • Production of biofilms — slime, think of the stuff that makes rocks slippery in a stream — makes CoNS difficult to clear from prosthetic material. Here’s a whole book about biofilms, great for leisure reading.
  • Among antibiotics, rifampin seems to be the best at penetrating biofilms, hence its use as adjunctive therapy for many infections involving prosthetic material.
  • Around 8% of native valve endocarditis is due to CoNS, and these patients have a high likelihood of requiring surgery. In my anecdotal experience they have an extremely indolent course, but not when the CoNS is Staph lugdunensis.
  • Speaking of, Staph lugdunensis is a particularly aggressive form of CoNS, a wolf in sheep’s clothing that acts much more like Staph aureus than its wimpy coagulase negative brethren. It’s usually sensitive to beta lactams, too.

Of course I could go on and on about this last bug — we ID doctors adore Staph lugdunensis, which is both fun to say and is one of those factoids that separates us from the mere mortals out there who can’t be bothered to remember this arcane stuff.

Here’s a tip for you non-ID doctors:  You can really impress your ID specialist friends by bringing up Staph lugdunensis when discussing a case, or even just in casual conversation:

Non-ID doctor: Hey, have you watched the new House of Cards season yet?
ID doctor: No, am waiting until I have time to binge-watch it.
Non-ID doctor: Makes sense. By the way, Staph lugdunensis.
ID doctor: Impressive!

Yes, I know. Time to get a life.

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

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