HIV and ID Observations

An ongoing dialogue on HIV/AIDS, infectious diseases,
all matters medical, and some not so medical.

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January 13th, 2020

Diagnostic Tests for Syphilis Continue to Perplex Even the Experts: An Unanswerable Question in Infectious Diseases

Here’s a tricky clinical scenario:

  1. An elderly person with cognitive decline or some other non-specific neurologic symptom sees a clinician.
  2. Clinician sends a syphilis screen with a T. pallidum enzyme immunoassay (TP-EIA), which returns positive.
  3. Lab runs a confirmatory test — a T. pallidum particle agglutination test (TP-PA), or similar, which also returns positive.
  4. The lab then runs a rapid plasma reagin (RPR) test, which returns negative.
  5. There is no known prior clinical or lab history of syphilis exposure, diagnosis, or treatment.

Now what are we supposed to do?

I bring this up because Dr. Thomas Fekete raised just this issue on the IDSA’s ID Exchange message board, generating a spirited discussion.

(I’m citing this discussion and quoting with his permission.)

And every card-carrying ID doctor has been asked what to do in just this setting numerous times since labs started using TP-EIA — and not RPR — for syphilis screening a bit over a decade ago. In one study, this pattern (two positive treponemal tests and a negative RPR) occurred in approximately 3% of individuals undergoing testing.

Here’s why the next step is so controversial:  This exact pattern describes three separate clinical scenarios, each of them requiring very different next steps. Here are the potential interpretations:

  1. The result is consistent with, but not diagnostic of, neurosyphilis. Recommendation: Perform a CSF exam to rule out neurosyphilis. This is hardly a trivial undertaking, especially in the elderly. Further complicating this next step is that the CSF exam is notoriously poor at either ruling in or ruling out neurosyphilis. Plenty of false-positives and false-negatives.
  2. The result suggests late-latent syphilis with an RPR that has reverted spontaneously to negative. Recommendation:  Treat with benzathine penicillin 2.4 million units by intramuscular injection, weekly for 3 doses. In this interpretation, clinicians must consider the likelihood of clinical neurosyphilis to be sufficiently low that this result is unrelated to the neurologic symptoms — which begs the question, why was the test ordered in the first place?
  3. The result demonstrates prior treated syphilis, with an adequate serologic response. Recommendation:  No treatment or further testing necessary. Lots of antibiotics have activity against T. pallidum, so antibiotics administered for other indications over the years have inadvertently provided sufficient treatment.

Let’s add to the quandary by quoting Dr. Fekete on two key points:

I cannot find modern information about the incidence of true tertiary or neurosyphilis in elderly patients with this [testing] profile … These patients would not have come to our attention in the old system for syphilis screening.

Where are the prospective clinical series outlining either actual clinical neurosyphilis — or even CSF abnormalities — in those who have this serologic profile?

Plus, in the pre-TP-EIA era, when we used RPR for screening, neurosyphilis would have been considered “ruled out” unless there was a strong prior probability of this disease (which there hardly ever is).

Sometimes ignorance is bliss!

Want a further wrinkle? Some believe that the recommended treatment for latent syphilis — benzathine penicillin, with its long half-life but low CSF concentrations — adequately treats neurosyphilis as well. The thought here is that the immune system plays a role in clearing the infection, so no need for high CNS concentrations of penicillin — except perhaps in people with immunosuppression, as is seen in untreated HIV.

The data supporting this view (like many other aspects of clinical syphilis) are largely uncontrolled and somewhat dated — but strongly endorsed and frequently cited by advocates nonetheless.

But this position is vociferously challenged by others — again with largely anecdotal and outdated data. This group, now in the majority, inform the current CDC guidelines for treatment of neurosyphilis, which recommend high-dose intravenous penicillin G for 10-14 days — a burdensome treatment not easily (or cheaply!) administered to the  elderly, especially those with cognitive impairment.

It’s not as if this neurosyphilis quagmire were a new problem; indeed, the diagnosis of neurosyphilis has been fraught for decades. Often the leading strategy adopted by a hospital or a practice is the one endorsed the most passionately (or most loudly, in case conference) by the local expert or experts.

All this controversy makes this case scenario a classic Unanswerable Question in Infectious Diseases. And perfect for a poll!

So have it at — and educate us by using the comments section to justify your vote.

A 78-year-old man with no known prior history of syphilis or other sexually transmitted infections is evaluated for mild cognitive decline. As part of the work-up, he has the following blood test results:  TP-EIA positive, TP-PA positive, RPR negative.

What would you recommend next?

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January 6th, 2020

The Decade’s Top 10 Biggest Changes to ID Clinical Practice

Here’s a question for you ID and HIV and other clinicians out there as you start 2020 — what are the 10 biggest changes to ID/HIV clinical practice over the past 10 years?

Not necessarily what are the biggest stories or biggest advances (though they certainly are eligible) — but more specifically, when you are seeing patients, what are we doing or seeing or thinking now, in early 2020, that we never could have done in 2010?

You’ll see by reading this list that 10 years is plenty of time for progress — hooray for that. So with the up-front apology that my list inevitably reflects where I practice (USA, New England) and what I focus on academically (HIV), off we go with 10 big changes, one for each year — there obviously could be many more!

#10.
Then (2010): “Vancosyn” or “Vitamin L” (levofloxacin) for everyone? No problem …
Today (2020):  Certain antibiotics, once considered quite safe, now have well-recognized severe side effects.
On the inpatient side, there’s now broad agreement that giving vancomycin and piperacillin-tazobactam together increases the risk of nephrotoxicity. This awareness has led to dramatic reductions in the use of “Vancosyn,” which was all but ubiquitous on medical and surgical services a decade ago. And the toxicities of fluoroquinolones deserve their own brilliant graphic:

#9.
Then (2010):  Order an HIV test? What a pain.
Today (2020):  Written consent for HIV testing no longer required.
In 2010, labs required that formal written consent, signed by the patient, be on file before running an HIV test. This was an actual law in most states! While one might argue that such a policy made sense in the mid-1980s due to fears of discrimination and lack of effective HIV treatments, it was absolutely bonkers (that’s the medical term) in 2010, so many years after we had lifesaving HIV therapy, and were still facing a large proportion of those with HIV undiagnosed. And yes, Massachusetts was the last state to drop this outdated law — not proud about that fact! Fortunately today, a clinician who wants to order an HIV test now just needs to document that the patient verbally agreed to testing — easy peasy. Was that so hard?

#8.
Then (2010):  MRSA is taking over!
Today (2020):  MRSA is way less common.
If you’d asked me in 2010 to estimate what proportion of our hospital’s Staph aureus isolates would be MRSA in a decade, I’d probably have guessed 75%, or if I was feeling glum that day, 90% — the trend in the early 2000s was just up and up and up for this pesky and difficult-to-treat pathogen, and it was by far the most common microbiologically confirmed cause of skin infections. However, for reasons no one can quite understand, MRSA rates are down everywhere — both in inpatients and outpatients. (Our hospital’s antibiogram now lists MRSA as 27% of Staph aureus isolates.) Not only that, penicillin sensitivity locally among staph is making a comeback, too. No one predicted that.

#7.
Then (2010):  Otitis media — antibiotics needed now!
Today (2020):  Observation, rather than immediate antibiotics, is now an accepted strategy for certain cases of childhood otitis media.
I put this one in for the pediatricians, especially one particular pediatrician! Although treatment guidelines endorsed observation for otitis media in 2013, apparently only in the past few years have parents grown comfortable with this approach.

#6.
Then (2010):  CD4 700? You don’t need to start treatment, let’s monitor blood tests, see what happens.
Today (2020):  The “When to Start” debate in HIV therapy ended — everyone should be treated.
In 2010, we might have monitored someone with high CD4 cell counts for a while, allowing them to be viremic for months or even years if they remained asymptomatic. We would never do that today because the START study randomized people with HIV who had no symptoms and high CD4 cell counts to immediate versus deferred therapy, showing a clear clinical benefit for early treatment. Plus, there’s the #2 Big Change listed below as an additional factor favoring treatment.

#5.
Then (2010):  Recurrent C. diff? Let’s try another round of vancomycin, maybe with a long taper.
Today (2020):  Fecal transplants for relapsing C. difficile colitis are now standard of care.
After a period of initial (and quite understandable) disgust and reluctance from patients and clinicians alike, clinical data on the efficacy of fecal transplants for relapsing C. difficile colitis are now strong enough to give it a place in the most recent treatment guidelines. These clinical trials data have has been strengthened by largely favorable anecdotal experience. While not a panacea — some patients don’t respond, and there are ongoing safety and regulatory issues — the fact that fecal transplant has such a major role in treatment of any condition would have been unfathomable in 2010.

#4.
Then (2010):  Worried about acquiring HIV? Make sure you and your partner use condoms.
Today (2020):  Pre-exposure prophylaxis (PrEP) for HIV is an established HIV prevention strategy.
As I’ve mentioned before (and will continue mentioning forever, since it’s in hindsight so bizarre), the first time I  heard of this concept was in the 2002 CROI in Seattle, when keynote speaker Bill Gates was asked about people without HIV taking ART to prevent infection. (Why someone was asking the CEO of Microsoft this question is still not clear to me!) His response concisely summarized HIV prevention in that time: “Wouldn’t a condom be easier?” Fast-forward to the IpReX study, the FDA approval of TDF/FTC for PrEP in 2012, several follow-up studies — and today PrEP is broadly endorsed in national guidelines for HIV prevention.

#3.
Then (2010):  We have to bring tuberculosis diagnosis and treatment into the 21st century!
Today (2020):  TB diagnosis and treatment are both much better.
On the diagnostics side, the The GeneXpert MTB/RIF system has been absolutely transformative, both in high prevalence countries (where it establishes the diagnosis much faster and more reliably than smear), and here as well, where we can rapidly rule out the diagnosis and stop respiratory precautions in low risk cases. Treatment of latent TB now has several  shorter options than the old standard of care 9 months of INH. And for multi-drug resistant disease, Dr. Catherine Berry’s comparison says it all!

XDR-TB treatment

2010
“Cat IV” low priority, minimal access
6-7 drugs, daily IM aminoglycoside
2 yrs treatment
Daily vomiting, hearing loss
10 to 20% cure

2020
3 to 5 drugs
All oral
6 to 18 months
PN, ON, myelosuppression
?up to 90% cure

2022
Watch this space

#2.
Then (2010):  The most important thing you can do to protect your partner from acquiring HIV is to always use condoms, even if you’re on treatment.
Today (2020):  “Undetectable = Untransmittable” is now a mainstream part of HIV medicine.
Though the prescient Swiss Statement appeared in 2008, it was not until release of the HPTN 052 data in 2011 that this “treatment as prevention” idea gained mainstream acceptance — only to be further supported by the PARTNER and PARTNER2 studies. The bottom line is that we now routinely tell people with HIV that they are not contagious to others if they’re on suppressive HIV therapy. Few (if any) non-Swiss people would have been so bold to say that in 2010.

#1:
Then (2010):  Treatment of hepatitis C will be injectable interferon and multiple tablets of ribavirin. Not only that, you’ll need to take it for 12 months, endure many side effects, some of them quite severe — oh, and it will have a 20–30% chance of the treatment working.  Sorry about that.
Today (2020):  Hepatitis C is cured with 8–12 weeks of well-tolerated, oral treatment in around 99% of people.
I still don’t think we quite appreciate just how miraculous an advance this is, so I’m making it an emphatic #1 biggest change in ID clinical practice. (And Monica Mahoney, PharmD agrees, so it must be right.) As one of my patients said, after having relapsed during interferon treatment twice previously, and finally being cured with sofosbuvir/velpatasvir:  “Curing things is good. You doctors should work on more of that.” Agree!

What would be your Top 10? And of course my order won’t be your order, but that’s what the comments section is for!

Categories: Health Care, HIV, Infectious Diseases, Patient Care, Research

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December 30th, 2019

Welcome to Mandatory Online Module Land!

(What follows is an attempt to derive some humor from those annual online “required learnings” assigned to us each year. Because if you’re in pain, you are not alone!)

Step right up, Ladies and Gentlemen! Allow me to welcome you to Mandatory Online Module Land — the fantasy theme park Health Professionals around the world can’t stop talking about!

Fire Safety, Natural Disasters, Chemical Spills, Infection Control, Patient Confidentiality, Tornadoes — important topics all! We’ve figured out how to make them into an online, interactive experience that pulses with excitement.

Here, let us share some of the passionate and enthusiastic feedback we’ve received from health professionals at institutions around the country:

Thinking early retirement versus career change right now.

At the end of 16–18hr days, it is really harrowing to get emails telling me that I was “delinquent” on a training module.

34 modules! Took 2.5 hours; 5–10 multiple choices question quizzes per module to “pass.”

Living this misery right now.

So painful those mandatory trainings.

I’m around 3hrs in and still have those 3 annoying “can’t win” modules left …

Ah … the mandatory trainings. The straw that breaks the camel’s back.

I did this for about 3.5 hrs before the whole family came for Christmas— I have several modules left.

I won’t do it unless I get a text from coordinator telling me they might pull me off service.

I would say it takes me 10–15 hrs a year all said and done. And if I am generous, they include about 5–10 minutes of useful information.

Most of them are boring and cover useless information.

Took me FOUR hours and it was worthless: “don’t worry you’ll learn as you go.” Bad for physicians: horrible for patients.

Doesn’t that sound wonderful? Of course it does, and we should know — we created the modules, and are therefore the experts.

We have highly validated studies demonstrating that health care professionals who finish these trainings are better than those who don’t.

Better at what? They’re better at finishing the trainings! Isn’t that enough?

To make a good thing even greater, we’ve added three innovative features to make visiting Mandatory Online Module Land even more fun (as if that were possible).

  1. We’ve tied completion of the required modules to your earnings. No, we don’t pay you for the time it takes to visit Mandatory Online Module Land and complete the modules. But we do withhold salary for not finishing on time — which, if you think about it, is the same as paying you! Isn’t that generous? Hey, we could have charged you for the privilege of all this learning!
  2. We’ve given you an few extra days to complete them. You spoke, and we listened. Though visiting Mandatory Online Module Land is fun fun FUN, and the perfect way to spend the holidays, some of you have alternate plans. Some advice:  next year, plan ahead and include a visit to Mandatory Online Module Land during that last week of the year! How about that for a New Year’s resolution?
  3. Certificates! Yes, each completed Mandatory Online Module comes with a Validated Certificate of Completion, suitable for framing, laminating, or some other enshrinement. Display them in your office or exam room! Or print them out and mail to your parents, giving them even more reason to be proud of their highly accomplished offspring!

And for those of you too forgetful to add a trip to Mandatory Online Module Land to your travel itinerary before the due date, we’ve got the reminders down to a science.

Let’s pretend your visits to Mandatory Online Module Land have not yet been completed. We can’t imagine why anyone might delay — what other important things does a Health Professional have to do?

Maybe it’s catching up on your Netflix queue? Editing your videos on TikTok? Some other “worthwhile” (ha ha) pursuit? Hey Doc or Nurse or PA or other Health Professional, lemme tell you — time’s a wastin’! Get back to those modules!

Well no worries — we’ve got you covered! As the due date draws near, through the miracle of computer automation, each day you’ll awake to a personalized, friendly email message from me (whoever I am) — sometimes you’ll get two messages, we care that much!

“Good morning, Health Professional,” these messages will read. “You are delinquent.”

If that’s not supportive, what is?

 

 

Categories: Health Care, Medical Education, Policy

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December 23rd, 2019

FDA Defers Approval of First Long-Acting HIV Therapy, Surprising Everyone

We HIV/ID specialists are lucky. For over two decades, steady progress in HIV treatment brings regular excitement to our field.

Some of these advances are incremental, but others represent major leaps forward. One such example of the latter is long-acting injectable therapy with cabotegravir (CAB) and rilpivirine (RPV) for maintaining viral suppression. This strategy — two injections every 4 or 8 weeks — obviates the need to take antiretroviral therapy daily.

Based on the results of the phase 3 efficacy studies called ATLAS and FLAIR, we know that injectable CAB/RPV is safe, well-tolerated, and (among those who chose to participate in the studies), highly popular. Patient-reported outcomes in study participants consistently showed they vastly preferred the long-acting therapy to the pill or pills they took previously.

It has been widely known for several months that FDA review of this injectable cabotegravir/rilpivirine strategy would take place before the end of this year. Most people (including me) expected FDA approval.

(Jeepers, the treatment even already has a brand name — Cabenuva, which sounds like a beach resort town in Mexico.)

However, recently we learned that the FDA sent a “complete response letter” (CRL) back to the filing company ViiV without approval. The reason?

The reasons given in the CRL relate to Chemistry Manufacturing and Controls (CMC). There have been no reported safety issues related to CMC and there is no change to the safety profile of the products used in clinical trials to date.

With the caveat that we don’t have the actual copy of this “CRL” (what strange code language in this announcement), it’s reassuring that no additional concerns have come up in this review regarding safety.

What’s tricky is the “CMC” part. I confess that aside from understanding what the individual words chemistry, manufacturing, and controls each mean in plain English, I didn’t fully grasp what CMC means when specifically applied to drug approvals.

Fortunately, my local Boston ID colleague (and our former ID fellow!) Dr. Katy Stephenson does:

CMC means chemistry, manufacturing and controls. It’s the regulatory section where you describe how the drug substance and drug product is made and tested for quality control. For example, when a drug is licensed and released with an expiration date, where does that date come from? It comes from product testing by the company and that data is submitted in the “CMC” portion of the FDA application. It even includes info on the packaging.

One can envision how this aspect of quality control could pose challenges for this treatment strategy. Storage, distribution, and packaging of cabotegravir and rilpivirine will be completely different from other antiretrovirals.

Meanwhile, HIV clinicians and our patients will need to wait a bit longer for approval of this regimen. Until we hear more details, we won’t know how long. But the data from clinical trials are solid enough that approval should be forthcoming eventually.

Which will then lead several fascinating questions, and (silver lining) we now have a bit more time to think about them:

  • What proportion of those who are suppressed on simple therapy (one or two pills a day) will want to make the switch?
  • The clinical trials only included people with no treatment failure or resistance — will we expand the treatment beyond this group?
  • What will it cost?
  • Will it require prior approval? If so, how will we make the case to the payers for a person who is doing well, which will by definition be essentially all the eligible patients?
  • How will we “operationalize” it in the clinic? (Just writing “operationalize” gives me, a college English major, substantial pain — but it hurts a little less when I put it in quotes.)
  • What pharmacies will dispense it?
  • Will it be placed on hospital formularies? (Thinking probably not.)
  • Is the oral lead-in necessary?
  • What will we do about people who miss doses, or are lost to follow-up?

In other words, when — not if — CAB/RPV gets approved, this will be quite a bit different from any HIV treatment we’ve had before, with all sorts of questions and challenges.

Meanwhile, for those of you clinicians working the holidays, here’s what it’s like for us ID doctors:

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December 15th, 2019

Should Oseltamivir Become an Over-the-Counter Drug?

News broke last week that oseltamivir — most commonly known by its clever (expired) brand name, Tamiflu — may be heading to pharmacies soon as an over-the-counter (OTC) drug, available without a prescription.

After hearing this, I immediately thought of several reasons both supporting and opposing this change — an ideal question for a poll!

Clearly, way more ID-oriented clinicians support the status quo, with oseltamivir remaining available by prescription only. This 70%/30% split shows they feel even more strongly about it than the Brits did in their opposition to Jeremy Corbin.

(Too soon? Sorry.)

But even more fascinating than the poll results were the comments after the poll, many of them thoughtful and backed by clinical and scientific data. These were evident on both sides of the question.

I’ll summarize some of the more interesting opinions below. First, the NAY votes:

  • Does the drug even work? A longstanding controversy, linked to concerns that the initial publications included only favorable data. Many cite various Cochrane Reviews (there have been several) as a reason to consider oseltamivir only modestly effective at best. Symptom improvement of only 1 day, or even less than that? Big deal, take some analgesics, curl up in bed, and wait it out.
  • Most people have little idea what influenza actually is, using the term “flu” for all kinds of symptoms. “Stomach flu”, for example, is a commonly used lay term. Clearly oseltamivir would do nothing for this illness.
  • “Flu-like symptoms” are a common harbinger for several severe infections, and people who start themselves on oseltamivir will delay seeking attention for these conditions that need alternative treatments. Some of these might be respiratory infections such as pneumonia; others are systemic infections that cause fevers and chills first (such as pyelonephritis, streptococcal skin infections, and endocarditis).
  • Some will jump the gun and think they need to start oseltamivir at the first sniffle, when all they have is a cold. Distinguishing influenza from other respiratory viral illnesses can be challenging — and the common cold (mostly from the zillions of rhinoviruses out there) is way more common (naturally) than influenza, especially when it isn’t flu season.
  • Not only that — if people take it for a common cold or a “stomach flu”, they’ll be both wasting their money and risking side effects for no benefit. We don’t know what OTC oseltamivir will cost, but suspect it won’t be cheap — and this is an out-of-pocket cost, no insurance, with costs passed on to the patient. And no drug is 100% safe. Systematic reviews cite nausea and vomiting as the most common side effects of oseltamivir, but headache and psychiatric symptoms also may occur.
  • Increasing access to oseltamivir will breed influenza resistance to it. A huge worry, one that we see globally already with ready access to antibacterial drugs. Do we want to risk this with oseltamivir and influenza? Of course not.
  • We have enough trouble getting people to take their flu shot — now it will be even harder since they can get ready access to flu treatment. It’s like statin drugs and an unhealthy diet, right? License to ignore good medical advice.

Now, the YAY votes:

  • Oseltamivir works best if started soon after the onset of flu symptoms — hence improving access to the drug is critical. Clearly sooner is better — the package insert says it should be started within 48 hours after symptoms start; studies show the greatest benefits if started in the first 6-12 hours. And who can reach their provider that quickly? What if it’s a weekend? What if your provider doesn’t believe it works? (See above.)
  • Just the fact that there’s a controversy about whether it works shows it must work better than existing OTC “cough and cold” drugs, which are widely used. Can’t argue with that, as most of the colorful pills, liquids, and lozenges in that aisle are useless.
  • The most rigorous and comprehensive overviews of the oseltamivir studies demonstrate conclusively the benefits of treatment. The key strength of this widely cited Lancet paper is that it used individual patient level data from the trials, which are much more reliable than aggregate study results. Those at high risk for influenza complications appear to benefit the most, reducing the need for antibiotics or hospitalization. (Addendum: And now I can link this recently published trial as additional evidence!)
  • If people can get the drug easily at a pharmacy, it will limit the time they spend in doctors’ offices or hospital emergency rooms, reducing the risk they’ll spread flu to  vulnerable other people. The elderly, the immunocompromised, those with multiple comorbid medical conditions (especially cardiac and pulmonary), pregnant women — they frequently visit health care settings, and the last thing they need is to spend time in waiting rooms with someone who has active influenza. Many hospitals (ours included) advise people to stay home if they have flu symptoms (unless of course they also have shortness of breath, difficulty staying hydrated, or other worrisome issues). “Sharing Isn’t Always Caring” say the signs in our hospital — clever.
  • Making it over-the-counter doesn’t mean it needs to be in the aisle with the cough and cold “remedies” — a pharmacist could release it based on a symptom questionnaire or other screening tool. New Zealand and Japan have taken this approach — the drug is “behind the counter”, so not literally OTC — and this strategy apparently limits inappropriate use.
  • There is no evidence that use of oseltamivir in people without influenza selects for influenza resistance. Indeed, without influenza being actually the diagnosis, the drug may not be doing any good — but it’s not leading to resistance. And in the countries that have it without prescription already, resistance to oseltamivir has not (yet) led to more local resistance.
  • Influenza resistance to antivirals is unpredictable (to say the least), and not necessarily triggered by overuse. Take a look at this slide set reviewing the issue! Quoting Dr. Marc Lipsitch (who shared the slides): “The usual paradigm of use driving resistance doesn’t appear to hold.”

So where do I stand on the issue?

Gosh, this one is complicated.

While all the YAY and NAY votes make sense, for their own reasons, ultimately I thought about what I currently do in clinical practice.

When a patient calls me during flu season saying that they have fevers, chills, muscle aches, dry cough, and a runny nose, and that this illness  “hit them like a truck” — I call in a prescription for oseltamivir rather than ask them to come in for an exam, blood tests, or a flu swab.

Why put them through this punishing trip to the hospital? Why expose other patients and health care providers?

Sure, it could be something else. And sure, it’s important to screen for other symptoms, and to tell them to come in if they’re not improving.

But the call to me seems like an unnecessary barrier; a good pharmacist can conduct the appropriate symptom screen and save people the hassle of reaching their providers by phone. They wouldn’t recommend osteltamivir for symptoms of “stomach flu”, or for a runny nose only, would they?

So bring on behind the counter oseltamivir, available without a prescription! Under the guidance of a wise pharmacist!

And remember — Tamiflu was selected as the one of the greatest expired (it’s now generic) antimicrobial brand names ever by Dr. Raphy Landovitz in this important podcast. 

So go ahead, listen again to the whole thing.

And now that you’ve read this far, how would you vote?

I'm a reader, and this statement best describes me:

View Results

Thanks to those who offered the numerous thoughtful responses and insights offered in the original poll. Let’s see what this one shows.

Categories: Health Care, Infectious Diseases, Patient Care, Policy
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December 8th, 2019

A Midyear Letter to First-year ID Fellows — With Sympathy, Gratitude, and Hope!

Dear First-Year ID Fellows:

Right around now, some of you might be feeling a bit prickly. The workday is long, the supply of daylight dwindles daily, and the cold winds blow in from the north. While friends outside of medicine gear up for holiday time off, your plans might include some hospital coverage. Some of you have already worked Thanksgiving Day (and we thank you for that).

This testy feeling is totally understandable and appropriate — we definitely get it. Doing ID consults on hospitalized patients is hard — doing them during the first year of ID fellowship particularly so. For the record, let’s explore the reasons:

  • Nobody gets ID consults on straightforward cases. I’ve said it many times, but it bears repeating — if the diagnosis is clear, the treatment going fine, and the patient improving, they won’t call you. Remember the Four States of Clinical Medicine? If not, here’s a reminder:Maybe someone set up a clinical obstacle course just for ID, because all your consults come from Boxes 2, 3, or (shudder) 4 — actually, most from Box 4. Our job: move the patient back to Box 1 (best) — or at least Box 2 (second best) or Box 3 (third). Not always easy.
  • Certain ID consults challenge our emotions as well as our intellect. The previously healthy young person with a poor-prognosis hematologic malignancy and fevers despite broad antibiotic and antifungal coverage. The elder matriarch or patriarch of the family with a devastating stroke and recurrent aspiration, large family huddled in the room. The young man (it’s usually a man) with a spinal cord injury from a gunshot wound and severely infected pressure ulcers. The too-late HIV diagnosis with progressive multifocal leukoencephalopathy (PML) unresponsive to antiretroviral therapy. The person with diabetes who continues to lose their battle with vascular disease, requiring multiple amputations. Substance use disorder and all its various infectious complications. Wow, ID consults can induce sadness.
  • Most surgery goes well — but when it doesn’t, the ID part is particularly painful. I have enormous respect for my surgical colleagues, who do things for patients I could never do in a million years. But when surgery goes wrong, and there are infectious complications, can anyone find a tougher role for the ID consultant than this? Since we’re on the floors more than the surgeons, sometimes it feels like we bear the brunt of the patient’s and their family’s disappointment and anger as much as — if not more than — the surgeons themselves. I doubt that’s true, but it can feel that way. Ouch. Particularly Ouch! when you’re a first-year ID fellow.
  • There’s a ton we don’t know — and not knowing what we don’t know is part of being a first-year fellow. Back when I was a clinical fellow, I rounded repeatedly on a sick patient in the ICU who had fevers every single day. He had been admitted around the time of the signing of the Magna Carta, so it had been a lengthy hospital stay, to say the least. Despite our meticulous care and trying every antibiotic strategy known to humankind, every day — another fever. You know the case — a Fever of Too Many Origins. Frustrated, I repeatedly turned to my attending for help. Surely this esteemed ID faculty member with years of experience will solve the endless fevers problem. His response?  “Sometimes we don’t know what’s going on, but we have to keep on trying anyway.” Not particularly articulate, but … Yep.
  • Different supervising faculty have different expectations. Just when you’re getting comfortable with Dr. Attending #1, who wants short notes, targeted histories, just the antibiotics, only the WBC and creatinine, and then your bottom line impression and plan, along comes Dr. Attending #2, who wants every detail of the history, including every infinitesimally small data point — all the medications (with doses), all the labs (including the calcium and troponin), all the micro, and all the imaging, culminating in a note with the length of Mandell, Volume 1. (That’s 1919 pages, in case you’re wondering.) What’s the right approach? That’s the problem — there is no right approach for everyone. Just different clinical styles — but you, First-Year Fellows, are the ones who have to adapt.

Despite the above challenges, I hereby boldly proclaim that there is reason for optimism and genuine hope.

Reason #1:  You are nearly half-way done. The end of this month is not just holiday season; it’s also the 50% mark on your first year. (I did the math.)

Reason #2:  Your replacements are on the way. Match Day was last week. New fellows are really coming, and coming soon!

Reason #3:  The hospital is quiet during holiday season. Yes, superstitious clinicians never make such optimistic predictions — but aren’t we people of science? Speaking as someone who has worked Christmas nearly every year since the start of the Clinton presidency, I can assure you that the hospital census goes way down in late December.

Reason #4:  Free cookies, cakes, candies, and other snacks. These will start magically appearing on the hospital floors any day now, culminating in a peak supply on December 25.

Reason #5:  The days will soon start getting longer. Sometime right after December 21, 2019, the Earth’s axis will gradually start tipping a bit more toward the sun each day. Promise!

Reason #6:  You have already learned a tremendous amount of clinical ID! It is remarkable how steep the learning curve is for you ID fellows. Only around 6 months into your training, you frequently arrive at diagnoses and recommendations for consults that require little, if any, modification from us attendings. Your histories draw information from the patients, the families, and the outside hospitals; you relay our thoughts accurately and concisely to the referring teams. Cases that previously would have been overwhelming you now handle with aplomb. Keep up the good work, we appreciate it!

Reason #7:  A man can play “All Star” on melons. If that’s not reason for optimism, what is?

(Start at 1’40” if you’re having a busy consult day.)

(Four States of Clinical Medicine graphic by Anne Sax.)

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December 1st, 2019

On World AIDS Day 2019 — Wouldn’t It Be Nice…?

With apologies to a 1960s band with a flair for complex harmonies and evoking warm ocean breezes (as the first winter storm barrels in), here’s a miscellaneous list of wishes for World AIDS Day.

Wouldn’t It Be Nice …

  • If everyone with HIV could be on suppressive antiretroviral therapy? Here are the latest estimates, showing we’re only a bit more than halfway there:

  • If antiretroviral therapy had no side effects? Our treatments are so much safer and better tolerated than they were — hooray! — but they’re not perfect. Weight gain is the latest adverse effect of greatest concern; Dr. Andrew Hill presented a superb summary on the topic at the recent European AIDS Clinical Society (EACS) meeting.
  • If all those at high risk for acquiring HIV could receive PrEP? Here in the United States, the high price of PrEP draws the most attention as a barrier. However, the issue is far more complicated than just price (though that doesn’t help) — it starts with the fact that those at greatest risk of acquiring HIV here (young MSM of color, especially in the Southeast) are the least likely to be engaged in any longitudinal healthcare. And many countries don’t cover PrEP at all.
  • If HIV stigma disappeared? All of us follow patients who have so internalized the societal stigma of having HIV that they can’t bear to tell anyone about their diagnosis — not even close family members or friends. Some have lived with this pain for decades. Boy, HIV really needs a stigma-ectomy.
  • If the pricing of HIV medications in this country actually made sense? Imagine a world where setting the price of HIV drugs were a transparent process based on actual value, and didn’t involve convoluted, secret negotiations between payers, manufacturers, and pharmacy benefit managers? What a wonderful world that would be! (That’s a different song.)
  • If the confirmatory test after a reactive HIV screen were an HIV RNA (viral load) rather than a HIV-1/2 antibody differentiation assay? As I’ve written before, this would greatly speed getting people an accurate diagnosis, and furthermore dramatically reduce the “worry days” with a false-positive screen.
  • If every HIV resistance test a patient ever had were kept on a secure but easy-to-navigate site? HIV resistance testing entered clinical care in the late 1990s. It has been provided through multiple different labs with a dizzying array of reporting formats and interpretations. Poorly suited to display on electronic medical records, these reports are best seen in their original format. Perhaps a Dropbox-like repository, with a folder for each patient containing the reports? You’re welcome.
  • If there were an effective HIV vaccine? As two major clinical trials proceed — HVTN 702 and 706 — we eagerly await results!
  • If HIV could be cured? Last, but not least. We learned of our second case of likely HIV cure early this year at CROI, and a third is out there too. All three, however, required a stem cell transplant. While hardly a scalable approach, these cases prove that prolonged, drug-free remissions are achievable.

Surf’s up!

 

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November 25th, 2019

Vaccine Defenders, U=U Holds Up, Zika Is Gone, and Other ID Things to Be Grateful For, 2019 Edition

A High Wind in the Park, London, 1819.

An excellent episode of the Freakonomics podcast introduced me to the headwinds vs tailwinds asymmetry, and how we humans perceive life.

It goes like this: We go for a walk, a run, or a bike ride, and the wind faces us dead-on, making the exercise a struggle.

(In windy Boston, the wind is always in my face. Always always always.)

When the route changes, there’s a brief moment of relief, but it’s short-lived. What we remember about the experience is the headwind, certainly not the boost the tailwind might have given us on the way home.

The researchers on that podcast argue that this same blindness to various good things, privileges, and benefits is how we perceive all of our life. We’re intrinsically wired to complain about the barriers and struggles.

In short:

Barriers and hindrances command attention because they have to be overcome; benefits and resources can often be simply enjoyed and largely ignored.

While evolution might have hard-wired this attitude in us for survival purposes, it can also make us into a bunch of unappreciative whiners.

Which is why the flip-side — expressing gratitude — is so important. Research consistently shows it makes us happier. And it definitely makes us better company, an important consideration as we approach the holiday season.

In that spirit, in what’s become a Thanksgiving Holiday tradition, I list below a series of ID/HIV things to be grateful for in late 2019. And hey, there’s so much to be grateful for!

  • Brave, authoritative, and respected voices continue to speak out against the anti-vaccine movement. There are many such voices out there, and IDSA has done a terrific job as an organization, but I want to highlight especially Dr. Peter Hotez. He appears regularly in public and in print to defend vaccines, risking his own safety; he has also written a moving and personal book entitled Vaccines Did Not Cause Rachel’s Autism: My Journey as a Vaccine Scientist, Pediatrician, and Autism Dad. Check out the ratings for this book on Amazon, and you’ll find a painful dichotomy — either 5 stars or 1 star — with the negative comments demonstrating how vicious the anti-vaccine movement can be.

  • An Ebola vaccine works! In perhaps no other disease will a vaccine play such a critical role in getting control of an outbreak. This is wonderful, very welcome progress!
  • U = U (undetectable equals untransmittable) continues to hold up. Perhaps the most transformative finding in the history of HIV medicine — that people on successful HIV treatment don’t pass the virus on to others sexually — remains a rock-solid fact. I’ve included U = U here before several times, but why not continue to celebrate it?
  • HIV incidence in many urban regions in the USA drops. In New York City, for example, 1,917 people were diagnosed in 2018, a 67 percent decline from 2001. Treatment as prevention and PrEP are yielding these impressive results.
  • Zika is all but gone. Remember how crazy things were in 2016? Especially for couples who wanted to have children? And for us ID doctors (and primary care and OBs) trying to advise them? Yes, Zika could come back (and likely one day will), but let’s be grateful for our current situation compared to that insane period.
  • New antibiotics, some with new mechanisms of action, expand our treatment options. No, they’re not perfect, and some are only incremental advances, or targeted at rare clinical situations — but great anyway to have lefamulin, pretomanid, omadacycline, eravacycline, meropenem-vaborbactam, imipenem-relebactam, cefiderocol (with some confusing data on this last one, still to be sorted out). Now let’s try to fix the economics of antibiotic drug development!
  • Additional studies continue to demonstrate the clinical benefit of ID consultation on outcomes. Just a few recent examples — candidemia, sepsis, and long-term outcomes in Staph aureus bacteremia. The parade goes on and on!
  • A “Shorter is Better” philosophy about duration of antibiotic therapy moves into clinical practice. And with this updated super list from Dr. Shorter-is-Better himself, Brad Spellberg, why not?

  • Pragmatic clinical trials in ID give us important new strategies for therapy. The most notable examples in the past year are the POET and OVIVA trials, demonstrating the noninferiority of oral to IV therapy for endocarditis and osteomyelitis. More of these, please!
  • The “Ask the Experts” section on the Immunization Action Coalition remains a gold mine of useful information.  I’ve mentioned it before, but that doesn’t mean I can’t still be grateful! Barely a week goes by without my consulting this site.
  • Shorter treatment courses for latent TB gain traction. Drug interactions aside, who doesn’t prefer 4 months of rifampin to 9 months of INH? Can 1 month of isoniazid/rifapentine be far behind?
  • New guidelines for diagnosis and treatment of Lyme Disease are imminent. The draft guidelines have already been released — final version expected soon.
  • Dolutegravir-based regimens are increasingly available globally. In many settings that previously had only efavirenz (first-line) and lopinavir/ritonavir (second line), dolutegravir represents major progress — for both treatment-naive and treatment-experienced patients. It will be important to see how this big change in strategy works out, which is the primary goal of this observational study.
  • ID fellows continue to amaze us. Smart, mission-driven, and hard working, they take on the most complicated cases in the hospital with aplomb. As my down-the-hall neighbor Dr. Sigal Yawetz says:

Happy Thanksgiving! What are you grateful for this year?

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November 18th, 2019

The Best Guide to HIV Drug Names — Yours for Free!

Earlier this month, I noted something that all of us ID/HIV specialists should readily concede — namely, that learning the names of the HIV drugs is fiendishly difficult.

Afterwards, I heard from a few old-timers (that is, people like me). They acknowledged that we were lucky to experience the roll-out of these medications (and their convoluted names) in real time, which made learning them easier.

And some people currently struggling with the names wished for a logical code to the nomenclature, analogous to the HCV drugs. The HCV protease inhibitors, for example, all wrap up with -previr, e.g., telaprevir (may it R.I.P.) up to glecaprevir. And the NS5A inhibitors end with -asvir, e.g., velpatasvir and pibrentasvir.

By contrast, what do we get with HIV drugs? While all of the integrase inhibitors have -tegravir in their names — hooray! — the NRTIs, NNRTIs, and PIs are a mess.

Specifically — why do all the NNRTIs end with -ine (nevirapine, rilpivirine, doravirine) except efavirenz?

(Brief aside — efavirenz. What a bizarre word. No wonder it causes CNS toxicity.)

Plus, don’t many of the NRTIs end with -ine as well?

Of course they do (zidovudine through emtricitabine) — that is, until they don’t (abacavir). And this NRTI just happens to end with -avir, which is how all the HIV protease inhibitors end.

Bedlam!

To help the confused masses, some of you kindly sent along your “cheat sheets,” many of which were better than the one I posted. All of them shared the strategy of excluding drugs we no longer use, which simplifies things a lot.

This one, from Dr. Kristen Brown, was excellent — it even includes a few resistance pearls — useful! However, due to the complexity of resistance, this will need eternal tweaking (even this one), so Kristen says she might retire that section.

But, as she noted, there was another choice pick — and that was from Dr. David Serota (a.k.a. @serotavirus).

After I reached out to him, he not only shared it in PDF and PowerPoint format, he allowed some niggling input from me (mostly for consistency), and said it was fine to post here. Furthermore, for a small fee, he’s offering signed, laminated copies, suitable for framing.

So without further ado, I bring you the very best HIV medication cheat sheet available as of November 2019:

So, here are a few things that make this so great:

  • It excludes the old drugs we never use anymore — except for Trizivir, which he kept because he just likes that name.
  • Generic names are first, followed by their three-letter abbreviations, then their brand names — the right order.
  • Brackets and arrows create the branded coformulations.
  • Boosters (ritonavir and cobicistat) are a single small letter (DRV + r), and their single-pill coformulations are separated by a slash (DRV/c).
  • The legends box clearly explains the confusing world of TAF vs. TDF and the two boosters.

Critics might say this is still too complicated.

Yes, it’s still complicated — but why do you think they pay us the big bucks?

(Ha, ha, ha.)

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November 11th, 2019

When TV Gets ID Wrong — Or At Least Not Quite Right

A busy week for Infectious Diseases on television!

First, Dr. Aditya Shah, an ID doctor at Mayo Clinic, treated us to several snippets of truly idiotic ID-related drama in a network television show.

After seeing them, I commented:

Hey, my services to this show to help you talk about infectious diseases without sounding dumb are available at a very reasonable price.

My offer stands! For this show! And all of television! If you never want to sound stupid about Infectious Diseases again, call me!

For those of you who wandered over here to an ID blog without much ID background, here’s why the linked very tense hallway exchange sounds (and looks) particularly moronic:

  • “Howard has a superbug.” Doctors hardly ever use this term. Yes, it’s commonly used in the popular press to describe a drug-resistant infection — but think of it like “germ”, another word you rarely (if ever) hear doctors say when talking to other doctors.
  • “A C. diff infection?” He looks genuinely surprised, although C. diff is one of the most common infections in hospitals today. Plus, has there ever been a single clinician in the world who uses the term, “a C. diff infection”? Nah. Just C. diff.
  • “It’s resistant to all medication.” The clincher! Because even though C. diff can be difficult to treat, this is due to alteration in the normal microbiome, not antibiotic resistance. We don’t even do susceptibility testing — which makes one wonder what could possibly be written on that piece of paper they are reading.

Second, the press picked up — in a big way — a paper that reported the discovery of a “new HIV strain.”

To clarify, it’s a new subtype, called “subtype L”, and it was identified by scientists at Abbott Laboratories using new techniques on stored blood specimens.

We have no reason to doubt their findings, which seem sound enough, and it’s a plus that our major diagnostic labs keep track of HIV genetic diversity.

But it’s hard to come up with other HIV research where the amount of news coverage (huge) was so disproportionate to the clinical impact of the finding (zero).

As my virologist colleague Dr. Jon Li says, “Media reports play on our fascination and fear of mutating viruses.” Perfectly stated! But to get back to the non-existent clinical implications, this “new” subtype L would:

  1. be picked up by standard HIV diagnostic tests,
  2. respond to antiretroviral therapy,
  3. probably never be encountered anyway, since only three examples have been found, most recently nearly 20 years ago.

One of our local news stations chatted with me about it here — I think they did a good job reframing the “story” to be about more important issues in HIV today.

Next time they may want to speak to my mother, who commented:

Interesting news story in that it’s all negatives.
Not a new strain.
No change in diagnosis.
No change in treatment.
Not something to be worried about.

I told you she was smart!

Finally, we have another “brink of HIV cure” report, as a biotech company called American Gene Technologies (AGT) “submitted a nearly 1,000-page document to FDA.”

And within its pages just may lie the cure for HIV/AIDS.

It’s hard to comment whether this company’s immune-based approach to HIV cure will ultimately be a promising strategy — it’s in the very early stages of development, with Phase 1 studies tentatively starting soon.

But watch the accompanying video — which statements make you roll your eyes the most?

  • “Since the late 1980s, a few antiretroviral drugs …” Look at this list! The word “few” means “a small number of” — there are way more than a few.
  • “No treatment actually cures HIV — that’s until now …” Hey, we all hope for the best with this novel approach, but no one has been cured with it yet.
  • “[Taking HIV drugs] is a life sentence of taking that toxic chemotherapy …” Yikes, this is overly harsh. Most people with HIV have few side effects from treatment, many have none. Plus, is the analogy of taking medication every day to imprisonment appropriate? Do we say people with high blood pressure have a “life sentence” of taking anti-hypertensive medications?
  • “The single-dose drug has a simple purpose — to eradicate HIV once and for all so that people can live.” Aren’t people with HIV living now? Isn’t survival for people on treatment comparable to those without HIV?
  • “We wanted to get these people out of jail and back to a normal life.” Good grief, he’s back to that prison metaphor again.

Before anyone accuses me of being overly skeptical about AGT’s approach, I am thrilled that scientists both in academia and industry are working on an HIV cure. And I’m hopeful a cure will one day be a reality for my patients and the millions of others with HIV — whether it’s AGT’s strategy or the work of other investigators.

But we definitely need cautious, scientific reporting — and way less hype.

Meanwhile, that Dr. Shah sure is funny.

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HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

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