HIV and ID Observations

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

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November 3rd, 2019

Learning the Names of HIV Drugs Is Horribly Difficult — Here’s Why

Happens every time. We start teaching about HIV, and at first, everything is going great.

Epidemiology, pathogenesis, diagnosis, clinical presentation. The students are right there with us.

However, then we start covering treatment — and things immediately get tricky.

Because no matter how engaged and brilliant they are, and no matter how scintillating we are, when the long list of antiretroviral agents appears, their eyes glaze over with fatigue.

Instant somnolence. Like someone turned up the temperature in the room, dimmed the lights, and passed out soft blankets and pillows.

And it’s no wonder! There are lots of drugs, with a dizzying array of names, abbreviations, combination tablets, and mechanisms of action.

We haven’t helped matters by following these RULES OF HIV MEDICINE, all of which were designed by evil creatures (with advanced degrees in medicinal chemistry and marketing) to make learning HIV medications terrifying. Here are these baleful rules:

  • All drugs must have at least three names. Generic, brand, and 3-character abbreviation. To make matters worse, some have more than three names, starting with the very first drug way back in 1987, zidovudine. It was also called AZT (that’s what most people called it), ZDV, and Retrovir (that’s 4, including zidovudine). It also showed up in Combivir and Trizivir, for good measure. Now that’s just mean.
  • HIV specialists must refer to them by different names at different times, for no apparent reason. Do we do this to maintain our special status? To be whimsical? To deliberately confuse others, just for sport? Whatever the motivation, it’s working wonderfully to keep this knowledge the very definition of arcane.
  • Names of combination tablets should have nothing in common with their parent drugs. Some recent examples:  Combine Tivicay and Epzicom — what do you get? Triumeq, of course. Descovy plus Edurant? Odefsey! See, isn’t this fun?
  • Some of the abbreviations must bear no resemblance to either the generic or the brand name. Example — what does “3TC” have to do with the word “lamivudine,” for which it is the widely accepted abbreviation? Hint: nothing. Unless you check its chemical structure. And who, we might ask, will be doing that? And since emtricitabine is very similar to lamivudine (you knew that, right?), emtricitabine is abbreviated “FTC,” which makes all kinds of sense since emtricitabine starts with an “F.” (Oh wait. No it doesn’t.) The first time this disconnect between the true and abbreviated name came up was with the abbreviation for the drug zalcitabine, which was abbreviated “ddC”, for a chemical name that no one used. That’s right, two small “d”s followed by a capital “C.” Careful readers will note that zalcitabine has neither a single “d” nor a capital “C.” Fortunately, few prescribed this lousy drug anyway, which made its suitably horrific brand name (“Hivid”) just a faint stain on the history of HIV drug development.
  • Names of different drugs might sound alike, but will have nothing whatsoever to do with each other. Nelfinavir (Viracept) and nevirapine (Viramune) give us an example where both the generic and the brand names sound kind of similar. But they are completely different drugs — different dose, mechanisms of action, side effects. About the only thing they have in common was that they are both HIV treatments. You think people have confused them? You bet.
  • Drugs should change their names when they come out in different formulations. Take a look at the various name changes when tenofovir disoproxil fumarate (TDF) spawned tenofovir alafenamide (TAF) — this generated a whole new crop of confusing drug names, as both are extensively coformulated. But the trickiest (and saddest) story is saquinavir, the very first protease inhibitor. First it was Invirase, taken as three 200 mg capsules three times a day. Due to poor bioavailability, Invirase was later changed to the humongous soft-gel capsules called Fortovase, taken as six capsules three times a day. (Yes, that was the dose — it was practically a patient’s whole diet.) Then, with the realization that humans could not subsist on a drug that was six large capsules three times a day, saquinavir went back to being Invirase, but now had a new size (500 mg), and was taken as two tablets twice daily with ritonavir twice daily. Got that? Of course not.
  • The order in which drugs are listed in combination pills will be different in different sources. After years of litereally everyone writing TDF/FTC as the abbreviation for the pill that contains tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), along comes the first PrEP study, which reversed them. Not only that, they used a dash rather than a slash — “FTC-TDF.” Because why? And with three- and four-drug combinations, which drugs goes first? What’s the order? Alphabetical? By mechanism? Your guess is as good as mine.
  • If people are getting used to the three-letter abbreviations, go ahead and abbreviate the drugs in combination tablets with one letter, not three. This is a relatively recent trend, but one that people eager to make HIV drugs harder to learn surely must support. Example: When darunavir is given with ritonavir, it’s often written “DRV/r.” Ritonavir is changed to a lower case “r” (and not abbreviated RTV) to denote that it is not being used as an antiviral, but as a pharmacokinetic booster. Makes sense, sort of, except that nobody shared the code. However, the slash implies that it’s a combination tablet, which it most certainly isn’t. When we write or say “DRV/c,” or Prezcobix, however, this is a combination tablet, with the “c” standing for “cobicistat.” So cobicistat is also abbreviated as one letter, unless you are fans of the cute-sounding “COBI,” which is four letters, and for the record is pronounced like the former Los Angeles basketball star and the famous Japanese beef, but definitely has nothing to do with either one of them. But why stop there and let darunavir have all the fun? Let’s move right on to “ECF-TAF,” which stands for elvitegravir, cobicistat, emtricitabine (FTC, remember?), and tenofovir alafenamide (TAF). Certainly it makes all kinds of sense to use single letters for three of the four drugs in this combination tablet, then three letters for one of them — following a dash. Right? I mean come on, it’s so obvious.

So what’s a poor clinician to do? Some great responses here, I especially liked this one:

My solution (ha) to this mess will come in Part 2 of this topic. In the meantime, I welcome your input about how we should go about teaching (or learning) this material.

And it’s obviously time to reprise this classic. Take it away, Trip!

Categories: Health Care, HIV, Infectious Diseases, Medical Education

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October 27th, 2019

The Enduring Appeal of Live, Face-to-Face, Real-Time Continuing Medical Education

These guys clearly have no future.

Around 15 years ago, after high-speed internet became a de facto part of work life and was rapidly becoming more widely available at home, I attended a meeting with other medical educators to decide what to do about our various post-graduate courses.

The wisdom in the room was that most continuing medical education (CME) would soon migrate online, replacing live courses.

It just made too much sense — CME could be done at home, or from the office, and would not require the cost or hassles of travel, parking, and hotels. Online CME would minimize time away from the office, and would also be more family-friendly.

The message I took away from this meeting about our beloved courses?

They were doomed.

My wife, a practicing primary care pediatrician, agreed — why would anyone travel to go to CME courses when they could get the same required credits in the comfort of their own homes? And she’s hardly ever wrong.

But this is one of those rare times where everyone got it wrong. Live CME courses never went away. In fact, in the annals of bad predictions, the anticipated demise of face-to-face CME is right up there with Decca records’ choosing not to sign a certain Liverpool-based rock band because “guitar groups are on their way out.”

Yes, there are plenty of online CME opportunities. But live CME remains extraordinarily popular — in a survey done of clinicians by a marketing company, 80 percent reported that live conferences were the CME activities they participated in most often. Live CME was also the format they preferred above all others.

I’m thinking about this today because tomorrow is the first day of our annual course, “Infectious Diseases in Primary Care”. Not only have we had steadily increasing attendance for years, we’ve also been able to add an additional optional symposium on HIV and viral hepatitis for the PCP. The attendance at our course is twice what it was 15 years ago.

And we’re hardly alone. (Though I like to think our trying to get our very best teachers cover the most important topics are at least possibly responsible.)  Our hospitalists at the Brigham started a course a few years ago that has been staggeringly successful — so big it sells out every year. I hear from my colleagues at other academic medical centers that they also continue to have excellent demand.

So what gives? I can think of a few explanations.

  • People concentrate better and retain more information when they’re away from the distractions of work and home life.
  • People value networking with colleagues as much as the educational content.
  • With a shift toward salaried positions and away from traditional fee-for-service, CME is built into the contract as a benefit; also, time away from the office is no longer a negative for personal revenues.
  • Physician Assistants, Nurse Practitioners, PharmDs, and other non-physician health professionals increasingly want the same medical education, greatly increasing the pool of participants.

Any others? Whatever the reasons, it seems that live CME is here to stay, at least for now.

And for the record, I would have signed them.

Categories: Health Care, Infectious Diseases, Medical Education

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October 21st, 2019

Amoxicillin for Chronic Low Back Pain? Are You Kidding Me? In Defense of a Controversial Clinical Trial

The BMJ just published a randomized trial comparing amoxicillin to placebo for people with chronic low back pain.

I kid you not.

The appearance of this trial elicited all kinds of snark from the medical community. Here, check this out, along with the responses:

Dr. Juurlink, definite points for that <checks notes> stage direction! Love it.

But allow me to defend the people who did the study, and go even further — this is exactly the sort of practical, hypothesis-testing trial I wish we’d see more often.

Consider the problem — chronic low back pain. The bane of Western Civilization, it occurs in a quarter of the adult population. The misery from this condition results in millions of annual office visits a year, countless days out of work, and heavy economic losses.

Usually we don’t know the cause. And for severe sufferers, our medical treatments and surgeries offer inconsistent benefits.

Along comes the idea that a subset of back-pain patients — those with certain inflammatory changes on imaging, called “Modic” after the person who described them — might have a low-grade infection as the cause of this inflammation.

The theory is that a degenerating disc provides a suitable spot for this infection to settle, presumably after transient bacteremia. It would have to be a very indolent, slow-growing infection, as people with chronic low back pain don’t have fevers or other symptoms of acute infection, and also lack laboratory evidence of infection or inflammation.

Hi there. Nice seeing you again. Aren’t I a cutie-bacterium?

Based on animal and human data, the leading candidate for this kind of infection is none other than our old friend Cutibacterium acnes, shown here again in a very good mood.

(Maybe it’s happy because, as I’ve written before, Cutibacterium acnes used to be Proprionobacterium acnes. The new name is a zillion times better, especially if it’s pronounced like a cute little puppy, and not like a paper cut, or like an old coot.)

We ID doctors are quite familiar with C. acnes as a relatively common cause of prosthetic joint infections, especially of the shoulder; dermatologists know it as one of the primary bacteria involved in <checks notes> acne.

C. acnes also sometimes pops up in blood cultures, usually as a contaminant — but maybe those aren’t contaminants after all!

(Cue dramatic music here.)

The idea that C. acnes could contribute to chronic low back pain has been supported by the occasional isolation of the organism during spine surgery, and animal models showing the bug could induce these Modic changes in rabbits. This information led to a controversial randomized clinical trial comparing amoxicillin-clavulanate to placebo in adults with chronic low back pain, showing significant improvement in the treatment arm.

A subsequent systematic review concluded:

… further work is needed to determine whether these organisms are a result of contamination or represent low grade infection of the spine which contributes to chronic low back pain.

All of which brings us back to the recent study, which enrolled 180 people with chronic low back pain and Modic changes (of two types) on imaging. They were randomized to receive oral treatment with either 750 mg amoxicillin or placebo three times daily for three months. The primary outcome was a validated disability score a year later. They set a difference of 4 points on the scale as being clinically meaningful.

The results showed that the amoxicillin group had significantly lower disability scores than the placebo group, but the difference did not meet the threshold for being clinically important (it was only 1.6 points). Plus, nearly twice as many in the amoxicillin arm experienced a drug-related adverse event.

I certainly agree with the authors’ conclusions that the “results do not support the use of antibiotic treatment for chronic low back pain”, especially if you consider the added potential problems of encouraging antibiotic resistance and alteration of the human microbiome.

But kudos to them for doing the research — even negative studies are important. It could have been an H. pylori and peptic ulcer disease, but was C. pneumoniae and CAD instead.

But just imagine if it worked!

 

Categories: Health Care

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October 14th, 2019

Common Questions About the Shingles Vaccine — Answered Here!

National Library of Medicine

Here’s an interesting email from my friend and ID-colleague Dr. Carlos Del Rio (shared with his permission):

Went Tuesday to see my PCP for a routine visit and had my second dose of Shingrix that day. I had gotten my first dose about 3 months ago and had severe chills and even a fever of 38.5 after the first dose. With the second dose the response was not as severe but did have chills and rigors for about 18 hrs. Stupid of me, but the next day I went to get my labs checked, and everything was fine except my HS-CRP which was 14.72 (nl < 10 and in the past I had been < 1.0).

Anyway…..Shingrix is a good vaccine but it is a tough one to take and really gives you a nice TNF storm!

For the few of you out there in ID-World who don’t know him, you must understand it takes quite the force to slow down the high-energy machine that is Carlos. He is the very definition of indefatigable. So it’s not surprising he told me he went to work after both shots, rigors and all.

(Brief aside — congratulations, Carlos, on your well-deserved award!)

But Carlos’ post-shingles vaccine experience reminds me that we’re now two years into the recombinant zoster vaccine (RZV, Shingrix) era, and that immunization for this common adult infection — shingles, or zoster — has brought with it all sorts of new questions.

So here are a bunch of common ones we ID doctors field on a regular basis:

  • Who should get it? The vaccine is recommended for essentially all immunocompetent people over 50. So if you were born anytime before October 1969, this means you. People conceived during the Woodstock music festival or right after the Miracle Mets won the World Series are off the hook, at least for a few months longer. Two shots, separated by 2-6 months.
  • “Immunocompetent” adults — so nobody else? While immunosuppression is not a contraindication to the RZV, the data supporting its use in this population have not yet informed current guidelines. For now, it’s totally reasonable to offer RZV to people over 50 receiving low-dose immunosuppression, or to those with stable HIV on treatment, or to individuals who have had an autologous stem cell transplant. For higher degrees of immunosuppression, adopt an individualized approach — and remember that there is a theoretical concern that the adjuvant in the vaccine might stimulate organ rejection or a flare of an underlying autoimmune condition. We’ll see if this turns out to be a legitimate worry, so far it hasn’t.
  • No upper age limit? Use your judgment — if it’s a healthy 88-year-old with few medical problems, go ahead and give it. The risk of shingles increases as we age, and such a person will likely live several more years and could benefit from the vaccine. However, if it’s someone with multiple serious comorbid medical problems, then skip it. And yes, there are side effects — see Carlos’ email — which might be difficult for the frail elderly to tolerate.
  • What about people younger than 50 who have had shingles? While it’s understandable that they might be interested in the vaccine, it’s not been tested in people under 50, and is not formally recommended in this group. Reassure them that recurrent shingles is actually quite rare, especially within the first few years of an attack.
  • My patient never had chickenpox. Should they still get the zoster vaccine? Generally yes. For people born in the U.S. before 1980, essentially all have latent infection with varicella zoster virus — they either had a mild case of chickenpox or don’t remember having it. There might be a small fraction of people over 50 who never had chickenpox, test negative for antibody, and don’t want to risk the side effects of the vaccine. For them, consider the vaccine optional! (Many would recommend the chicken pox vaccine instead.)
  • How long after a case of shingles should my over-50 patient wait before getting the vaccine? No one knows. But since active zoster boosts a person’s immune response, it makes sense to wait at least until the current episode has completely resolved. I then add some additional time derived from the sophisticated ID time machine calculators. “At least 6 months” sounds reasonable, doesn’t it?
  • We had a shortage of the vaccine, now it’s now been more than 6 months since some of our patients had their first dose. Do they need to start over? Fortunately (for many reasons), no. Just give it when it becomes available.
  • Speaking of the shortage, what’s going on? Because of high demand for the vaccine, there have been widespread shortages of RZV ever since the vaccine became available. While these seem to have eased somewhat, especially in the last 6 months, not all practices or clinics or hospitals have it in stock. Fortunately, there’s a handy vaccine finder tool that I hear is quite reliable for pharmacies that offer the vaccine. Many hospital-based clinics also have it (we do).
  • Should I still give the new vaccine to people who got the old one? Definitely — not only is the RZV vaccine more effective, but that original live-virus vaccine (Zostavax) becomes less effective over time, and works less well when given to older patients, especially those over 70. If your patient got the live virus vaccine more than 6 years ago, they may not have any residual protection at all.
  • I hear the side effects are pretty bad — could they be worse than shingles? While no doubt the new zoster vaccine causes more side effects than most other vaccines, the clinical trials showed that serious side effects — those leading to death, hospitalization, need for urgent medical care — were no more common in vaccine recipients than in those who got placebo. Educate your patients that they might experience arm pain, fevers, fatigue, and myalgias and that these symptoms could be bad enough to have an impact on their daily activities. (This happened in 17% of study participants.) What this means practically is that I don’t recommend giving the zoster vaccine the day before a major life event, travel, or a demanding job requirement. And no harm taking a dose of acetaminophen or ibuprofen for symptom control.

But let’s go back to Carlos for a moment, and how these side effects he experienced compare to herpes zoster:

And to be clear, Shingrix side effects way milder than having shingles!

Completely agree! My experience — arm pain (check), fatigue (check), myalgias (check), and low-grade fever (check). But it was all over in a day, I promise.

And with the acknowledgment that we ID doctors see cases of zoster on the more severe end of the disease spectrum, we have all seen shingles accompanied by a host of really nasty complications. These include encephalitis, stroke, facial nerve paralysis, corneal involvement, vertigo, bacterial superinfection, and, most commonly, disabling unremitting pain (post-herpetic neuralgia) — pain for which there is often little effective therapy.

So the simple answer to the last question — are the side effects from the vaccine worse than shingles? — my answer is an emphatic no! I still strongly recommend it for my patients, colleagues, and friends of a certain age.

And look, my colleagues agree:

Back to the Summer of ’69 (the real one) …

(H/T, as always, to the incomparable Immunization Action Coalition site for clear, helpful information.)

Categories: Health Care, Infectious Diseases, Patient Care
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October 7th, 2019

Our HIV Testing Algorithm Has a Major Problem — Here’s How to Fix It

Mostly, HIV testing works great. It’s long been so accurate that we can strongly support HIV testing even in relatively low-risk people.

The 2014 revised lab testing guidelines made it even better, recommending a combined antigen/antibody screening test (called the 4th generation test), and replacing the Western blot with the HIV-1/2 differentiation immunoassay as the preferred confirmatory test.

However, if you’re a primary care, ID/HIV, or OB/GYN clinician who sends a lot of HIV tests, you’ve no doubt received the following perplexing result::

4th Generation Human Immunodeficiency Virus (HIV) Combination Antigen/Antibody:  Repeatedly Reactive

HIV-1/2 Antibody Differentiation Immunoassay:  Negative

Interpretation:  INDETERMINATE for HIV-1/2.

There are many problems with this outcome, which is common enough that it turns out to be the most common question about HIV testing by far. But three years have passed since I last addressed it, so let’s explore again and figure out how to fix it.

First, the reasons it’s so problematic:

  1. In patients at high risk for HIV, this is a critical result that should prompt rapid action. An indeterminate result with a positive HIV screen and negative HIV-1/2 differentiation assay could be acute HIV — patients may be in the “window” period before they have developed a sufficient antibody response. Why? It’s worth remembering that when we moved from the 3rd- to the 4th-generation screening test, we shortened the window period by adding p24 antigen to the screening test only. It’s now around 14 days after HIV acquisition. By contrast, the confirmatory differentiation test still only detects antibody. Window period for this test? A median of 33 days. And that difference may occur exactly when people with acute HIV are most symptomatic. Bad.
  2. In patients at low risk for HIV, this is a confusing result that almost never means anything and prompts only worry. Since we appropriately do a lot of HIV testing in low-risk people — especially pregnant women — the prior probability that they actually have acute HIV is extraordinarily low, especially if they are asymptomatic. The screening test’s 99.6% specificity is great (Lyme testing is jealous). But this means that around 4/1000 times, the HIV test will be positive even in a person without HIV — the prevalence of acute HIV in most screened populations is way lower than that. As a result, in many centers (including ours), most of the reactive HIV screens with negative confirmatory tests ultimately end up being false-positive screens.
  3. Sorting out what your patient has — acute HIV or a false-positive HIV screen — is straightforward medically, but far from easy from a logistical perspective. Sure, a subsequent negative quantitative HIV viral load means it’s a false positive, and a positive one (at pretty much any value) indicates acute HIV — simple to interpret medically. But try explaining that to a worried patient on the other end of your notification phone call, or telling them they have to come back in for another test to just be sure that your impression (whatever it may be) is correct. With so much testing done today as a matter of routine screening, we might end up having to do some of the risk assessment over the telephone, a distinctly uncomfortable scenario — especially tricky in an era when lots of our communication is via “patient portals” or some other non face-to-face method. Notably, some labs will “reflex” their indeterminate tests to a qualitative HIV nucleic acid test (NAT), but in discussion with my colleagues around the country, this is far from routine.
  4. Most medical centers can offer turnaround on a quantitative HIV viral load far faster than the HIV differentiation assay. This is particularly true if the screening test is done at your hospital’s lab, with reactive tests then sent to a reference laboratory. In our hospital, for example, when clinicians suspect acute HIV — patient may be at risk, or have symptoms — they often appropriately send an HIV viral load at the time of initial presentation. We then have this bizarre outcome where the HIV screen returns positive, the viral load comes back very high within a couple of days, and then — after a 3 or 4 day further delay — the differentiation assay return negative. In one such case, the HIV resistance genotype was also ordered at baseline, and it came back before the (negative) differentiation test!
  5. The tests are a nonsense word salad smothered with Thousand Island dressing. Read that result at the top in its entirety — what a bunch of gobbledygook. Look, we ID/HIV specialists know what these words mean, but ask some primary care clinicians or obstetricians, they will have no idea. Or ask them what it’s like to enter “HIV” in the order box of their electronic medical record. Chaos! (See image on the right — click on it for the full effect.) It’s completely understandable why they might be confused — this isn’t their specialty. So read the tests again, and pity the non-ID specialists: 4th Generation Human Immunodeficiency Virus (HIV) Combination Antigen/Antibody.  HIV-1/2 Antibody Differentiation Immunoassay. Good grief. How about just, “HIV screening test” and “HIV confirmatory test”?

How can we fix this? As usual when it comes to HIV testing, we turn to the top expert in this area, Dr. Bernie Branson. Fortunately for all of us, he just wrote a sensational review of HIV testing for Infectious Disease Clinics.

Here’s what Bernie says:

With current technology, it would be more efficient to reverse the current confirmatory testing sequence and, after a reactive Ag/Ab combination assay, perform a quantitative HIV-1 RNA viral load test to both confirm the diagnosis and contribute to immediate clinical management.

Of course! Confirm the reactive screen with an HIV-1 viral load! How sensible! This will give us the most critical result much more rapidly.

A detectable (at almost any level) HIV-1 viral load would prompt immediate HIV therapy, important for reducing HIV transmission, preserving immune function, and possibly providing our best candidates for HIV cure strategies when they become available.

With a negative HIV-1 viral load, the HIV-1/2 antibody assay (done next) would pick up the small proportion of those who are elite controllers, or are on ART and haven’t told you (HIV-1 antibody positive, viral load negative); have HIV-2 (HIV-2 antibody positive); or just had a false-positive HIV screen (HIV-1/2 antibody negative).

And those worried about a (slight) delay in diagnosis for HIV-2? This will occur rarely — with the prevalence of HIV-2 in this country exceedingly low, a CDC scientist recently described the routine use of this test as “High Burden, Low Yield”. 

So what are the barriers to making this change a reality?

  • There is no FDA-approved quantitative viral load test for HIV diagnosis. There is a qualitative HIV viral load test approved, but it is not widely available, requires plasma (see below), and a positive result would still warrant doing the quantitative test. According to Bernie’s paper, some are available internationally. Time to bring them here!
  • Many labs draw serum, not plasma, when doing HIV testing. Available quantitative viral load tests have been validated on plasma only. This makes the “reflex” strategy cited above in item #3 impractical. Apparently, serum-based quantitative viral load tests are also available in other countries.
  • Viral load testing is much more expensive. Tests considered “molecular” by payers cost a ton, even though the technology to do them has dramatically improved and become more efficient. This progress should theoretically make them more affordable, but some labs may be reluctant to give up the high price and revenues.

The above issues are not insurmountable barriers, but they will take time to overcome. But as an optimist by nature, I’m convinced this will happen — it just makes too much sense. And look, you apparently agree:

Until then, we’re stuck with this strange situation where the “confirmatory” test ironically may not confirm anything at all — either during acute HIV, or when the screening test is a false positive.

Fortunately, it doesn’t have to be this way — time to make the change!

Categories: Health Care, HIV, Infectious Diseases, Patient Care, Policy
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September 28th, 2019

What Is the Best Treatment for Advanced HIV Disease?

One of the things that keeps me on Twitter — besides cute dog videos — is the periodic realization that the platform can help patients.

Which is, after all, why most of us do this doctor thing — to help people get better.

Example:

So let’s consider this case from the energetic and amusing Canadian ID doctor Sebastien Poulin, which he posted a couple of weeks ago.

He was kind enough to share a few more details of the case with me via email (certain details slightly changed):

Middle-aged man admitted with fatigue and weight loss. Evaluation notable for oropharyngeal candidiasis, moderate pancytopenia, intra-abdominal lymphadenopathy (mesenteric and perihepatic), homogeneous hepatomegaly without splenomegaly.

HIV test positive. CD4 13; HIV RNA 2 million. Started on TDF/FTC, dolutegravir. Also TMP/SMX for PCP prophylaxis.

Three weeks later, blood culture turns positive for M avium complex.

Two questions immediately occurred to me with this challenging case:

Question #1:  Is this this TDF/FTC plus DTG regimen the optimal choice, or should we add (or use) boosted darunavir?

Certainly TDF/FTC plus DTG is a guidelines-endorsed first-line regimen, and the clinical trials of DTG as first-line therapy demonstrate good activity across a broad range of baseline viral loads and CD4 cell counts.

But consider the three case reports of treatment failure with emergent DTG resistance in initial treatment with three-drug therapy:

  1. Fulcher, et al, Clin Infect Dis 2018;67(5):791-4:  HIV RNA — 1,970,000. CD4 — 78. Active infection — PCP.  Relevant concomitant medications — None.
  2. Pena MJ, et al. Open Forum Infect Dis 2019;6(1):ofy332:  HIV RNA — 457,000. CD4 — 39. Active infection — Staph aureus.  Relevant concomitant medications — rifampin (DTG dosed twice-daily).
  3. Lübke N, N Engl J Med 2019; 381(9):887-9:  HIV RNA — 1,400,000. CD4 — 22. Active infection — TB.  Relevant concomitant medications — rifabutin (DTG dosed once-daily). [Special note from me: got to love when OFID scoops the NEJM!]

All of these cases involved people with HIV who had advanced HIV disease, high viral loads, and active infections. All ultimately achieved viral suppression with inclusion of darunavir-based therapy.

Remember, patients like this, or the case posted by Sebastien, did not qualify for the registrational clinical trials of dolutegravir. Even stable patients with severe immunosuppression and high viral loads were uncommon. The same limitation applies to studies of bictegravir/FTC/TAF.

In contrast, consider the NAMSAL study — 66% of entrants had a viral load of ≥100,000, and 31% had a viral load of ≥500,000. Responses to both the efavirenz and DTG-based strategies was notably lower in these participants.

So how comfortable should we be using DTG or BIC-based regimens in someone with a baseline viral load of 2 million and a CD4 cell count of 13? An ongoing clinical trial might help us answer the question, but until results are available, what to do?

Question #2:  Should rifabutin be part of the treatment for MAC?

In a prospective, comparative clinical trial of treatment for HIV-related disseminated MAC, the three-drug regimen of clarithromycin, ethambutol, and rifabutin improved survival compared with either clarithromycin plus ethambutol or clarithromycin plus rifabutin.

So the answer to this Question #2 seems pretty obvious. Yes!

But we might wonder whether these data are still relevant to Sebastien’s case. Only 14% of the participants in that study were receiving PI-based ART. Plus, the study enrolled from 1994-1998, when combination ART was markedly less effective and more toxic than today — and was especially difficult to tolerate for patients with advanced HIV disease and active opportunistic infections.

As a result, the current OI guidelines say the following about adding a third drug for disseminated MAC:

Some experts would recommend addition of a third or fourth drug for people with HIV with high mycobacterial loads (i.e., >2 log CFU/mL of blood), or in the absence of effective ART.

You know that whenever the “Some experts” phrase makes an appearance, there are no strong data to direct us one way or another. And who these days knows a patient’s quantitative “mycobacterial load”?

Let’s look again at our cases of dolutegravir failure with resistance — two out of three received rifamycin drugs. Rifampin strongly induces DTG metabolism, which requires doubling the dose to 50 mg twice daily (the clinicians did this in case #2). Rifabutin has much less of an effect, so no change in dose is required. Still, experience with rifabutin and dolutegravir in clinical practice must be quite limited.

So back to our questions:

  1. Is this this TDF/FTC plus DTG regimen enough, or should we add (or use) boosted darunavir?
  2. Should rifabutin be part of the treatment for MAC?

Let’s do a poll on #1. Please use the comments section to let us know why you made your choice, as well as your thoughts on the rifabutin quandary in question 2.

What would you use for intial HIV therapy in this case?

View Results

As for cute dog videos, there’s this:

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September 15th, 2019

A Former Medical School Dean Invents a False Dichotomy in Curriculum Content, and Advises Physicians to Stay in Their Lane

Aristotle, who famously said this.

Over on the editorial pages of the Wall Street Journal, a piece appeared last week with the following provocative title and subtitle:

Take Two Aspirin and Call Me by My Pronouns
At ‘woke’ medical schools, curricula are increasingly focused on social justice rather than treating illness.

Dr. Stanley Goldfarb, former associate dean of curriculum at the University of Pennsylvania, argues that current medical schools focus so much on advocacy, social justice, and various (left-leaning) causes that students don’t have time to learn how to care for patients.

And what are some of the distractions these medical students must endure as they try to master the craft of medicine?

Cultural diversity, gun control, climate change, health disparities. Teaching about these topics “comes at the expense of rigorous training in medical science.”

He cites no actual data that this is true, of course, which means it’s his opinion — an opinion I strongly suspect he harbors based on how he feels about these topics himself.

Regardless of how we feel about them, however, most will recognize the “back in my day we studied real medicine” tone. This one turns up frequently when many of us old-timers weigh in on the state of medical education today, be it in medical school or residency. You know, “back in the days of the Giants”, bringing to mind the “OLD MAN YELLS AT CLOUD” internet meme.

But back to the topic of his piece — is it really a new phenomenon that medical schools include a societal (as well as individual) view of medicine, and that students show interest in these topics?

Absolutely not — back when I went to medical school a million years ago (ok, in the early 1980s), we were urged always to consider our patients in the context of their community, and also to think broadly about what we could do as doctors to improve not just individual, but also community health. While patient care was a the core of our efforts, my classmates ended up choosing a huge range of different passions to pursue.

A quick list: Basic science research. Clinical research. Public health and epidemiology. Health disparities, both here and globally. Domestic healthcare policies. Healthcare finance. Teaching. The medico-legal interface. Investment banking and consulting. One even started her own footwear company!

In short, one of the great things about medical training is that it’s adaptable to a wide range of health-related pursuits. Since what we include in a medical school curriculum cannot possibly cover everything — more true today than ever — why not include topics that are important from a societal level too? Don’t these influence patient outcomes?

Of course they do — sometimes powerfully so, something most University of Pennsylvania doctors readily acknowledge, citing the vast economic disparities evident right there in Philadelphia.

And it appears the University of Pennsylvania agrees, as evidenced by the letter they have sent to students and faculty:

Please know that the views expressed by Dr. Goldfarb in this column reflect his personal opinions and do not reflect the values of the Perelman School of Medicine. We deeply value inclusion and diversity as fundamental to effective health care delivery, creativity, discovery, and life-long learning. We are committed to ensuring a rigorous and comprehensive medical education that includes examination of the many social and cultural issues that influence health, from violence within communities to changes in the environment around us.

Additional Penn faculty quickly weighed in on the editorial, noting that “social and health policies have always determined who gets sick and who gets care, and where, and how.” Unlike in the Wall Street Journal piece, these authors include some clear examples — the Flint Water Crisis, urban gun violence, underdiagnosis of cardiovascular disease in women and depression in African Americans — on how poverty, race, and bias influence individual and public health.

As for Dr. Goldfarb’s opening salvo:

The American College of Physicians says its mission is to promote the “quality and effectiveness of health care,” but it’s stepped out of its lane recently with sweeping statements on gun control.

Don’t get me started.

 

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September 8th, 2019

The Curious Case of M184V, Part 2 — and More!

The inspiration for today’s post comes from two recent emails from ID/HIV colleagues — thank you.

Here’s the first, from Dr. Mehri McKellar from Duke:

Hi Paul,

When are you going to do part 2 of The Curious Case of M184V, Part 1?

I am waiting patiently. 🙂

Mehri

Mehri, wait no more, because here it is! And thank you for the reminder, which is quite timely since there’s now greater clarity than ever about M184V, and what to do with that next regimen.

That first post summarized why we even care about this mutation, and what makes it so special — and so curious. Specifically:

  1. It’s the most common NRTI mutation observed with treatment failure. HIV docs averse to memorizing mutations should definitely put this one on their short list anyway — sorry, some you just have to know.
  2. Despite finding it frequently in people on treatment with viremia, we rarely see it transmitted in newly diagnosed patients. Latest data had it at  < 1% in the United States.
  3. M184V is selected by 3TC (lamivudine) or FTC (emtricitabine), leading to high-level phenotypic resistance. Despite this resistance, 3TC and FTC retain some antiviral activity.
  4. It impairs viral fitness. Viruses with M184V just don’t grow as well in vitro.
  5. It improves susceptibility to tenofovir, zidovudine, stavudine. By contrast, it worsens susceptibility to abacavir and didanosine.

Part 1 also mentioned that, despite how common this mutation was in clinical practice, we still didn’t have clarity about the best treatment option with this mutation. The date of that post was May 21st, 2017, and here’s the good news — there’s been quite a bit of progress on this front.

The most important data come from the DAWNING study, which evaluated people who had failed first-line treatment with two NRTIs and an NNRTI, then randomized them to receive either dolutegravir or lopinavir/ritonavir, plus at least one active NRTI as measured by baseline genotype testing.

The study was an overwhelming win for the dolutegravir strategy (84% vs. 70% viral suppression in the DTG vs. LPV/r arms, respectively), prompting early termination of the trial. The results certainly made us much more comfortable using dolutegravir plus NRTIs as a second-line treatment option, even in patients harboring some NRTI resistance.

Not surprisingly, most participants (84% in DTG arm, 81% in LPV/r arm) had M184V at baseline, which if present did not alter the primary study results favoring DTG. Most of the subsequent NRTI regimens chosen included either TDF or ZDV.

(Time for a complex, kind of geeky, digression. DAWNING let the investigators choose what NRTIs they used to combine with DTG or LPV/r. In the WHO guidelines, which assumed no genotypes available, and hence possible K65R, people previously receiving TDF were advised to go on ZDV, and the converse. As a result, it is likely that in DAWNING some of the participants who had M184V alone went on ZDV, even though they didn’t “need” to — tenofovir would have been active. And we hate to use ZDV these days, don’t we? Plus, two people in the study did have subsequent treatment failure with integrase resistance — but none of them had M184V alone.)

So, DAWNING takes care of people who are failing therapy with isolated M184V — the best approach is to give them DTG with at least one active NRTI, with tenofovir the ideal choice, given its enhanced activity (see Point #5, above). Often we’ll keep the FTC (or 3TC) along for the ride, since it’s so nontoxic and, as noted in Point #3, still has some activity.

But what about suppressed patients? What if they have M184V, and you’re interested in switching?

Here we can get some information from the 4030 study, presented this year at IAS. (I was the presenting investigator.) People with viral suppression on DTG plus TAF or TDF/FTC were randomized to TAF/FTC + DTG or to switch to the single pill BIC/FTC/TAF. Unlike most switch studies, prior failure with resistance was permitted, and participants were stratified by NRTI resistance into three groups:

  1. Tenofovir resistance (either K65R or 3 or more TAMS)
  2. Any other NRTI pattern (which includes M184V, either alone or with others)
  3. No NRTI resistance

The overall results demonstrated noninferiority of BIC/FTC/TAF to DTG plus TAF/FTC. These results held up regardless of the baseline resistance category.

Ah, but what about those challenging patients with both tenofovir resistance plus M184v? (This is the and More! part of the title.)

Time for another email, this time from another ID/HIV specialist — Dr. Risa Hoffman, from UCLA!

Hi Paul,

In the study you presented at IAS – did any people have both K65R and M184 (or in other words, resistance to both TAF and FTC/3TC?). We are doing a journal club on the ever-favorite topic of using bictegravir/FTC/TAF or a similar regimen in the presence of NRTI resistance…. I’m still looking for the answer about using this regimen when someone has mutations to both the TAF/TDF and FTC (I think you posed this question to the DAWNING study team at CROI…). Seems risky.

Thanks!

Risa

This is the kind of detail one can’t put in a 10-minute conference presentation, so here it is:

Of the 30 participants in that first category (which is resistance to tenofovir by either K65R or lots of TAMS), 21 also had M184V/I (13 BIC, 8 DTG). Of these 21 participants, 4 had K65R with M184V (3 BIC, 1 DTG), and the rest (17) had TAMs with M184V (10 BIC, 7 DTG).

And none in either arm had treatment failure at week 48.

So where does that leave us?

In the setting of treatment failure, I’m quite comfortable that patients with M184V alone can be successfully treated with tenofovir (TAF or TDF)/FTC plus DTG. BIC/FTC/TAF would probably work too, though it hasn’t been tested.

For people who are already suppressed on an integrase-based or NNRTI-based regimen, they can be successfully managed with either DTG plus tenofovir/FTC or BIC/FTC/TAF, even if they have more than just M184V for NRTI resistance. There is enough residual activity of the NRTIs to let the high resistance barrier integrase inhibitors (DTG or BIC) do most of the work.

Two key remaining questions:

  • For treatment failure with K65R plus M184V, what is the best approach? ZDV is highly active against these viruses, but who wants to use it? Should it be DTG plus DRV/r? Something else?
  • For suppressed patients on NRTIs plus a boosted PI (and there are a lot of them in the world), can they be switched to DTG plus TAF/FTC or BIC/FTC/TAF? Even if we don’t know their resistance history?

When clinical research answers those questions, it will be time for The Curious Case of M184V, Part 3.

Hey, it’s still officially summer, at least until September 23 — let’s go swimming!

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September 2nd, 2019

New Antibiotics for CRE, Draft Lyme Guidelines, Cost of Measles Outbreaks, and More — a Labor Day ID Link-o-Rama

Labor Day! Could summer really be over?

Nah, we still have a few weeks — and as I’ve noted several times, this time of year (September-October) gives us far and away Boston’s best weather season.

On with the links.

(H/T to Keith Law for finding the cartoon.)

To finish — slow and steady wins the race (at least sometimes). I’ve watched this video too many times not to share it on this site, as it’s strangely compelling.

 

 

 

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August 25th, 2019

Save the Dates! International Scientific Conferences You Can’t Miss

On this beautiful summer Sunday, I’m sorting through a series of invitations to international scientific meetings.

So many options.

See, they really want me. And how do I know that my participation will be so important?

Just look how personalized the greetings are — clearly intended for me and me alone. I’ve included actual screen shots of the invitations as evidence for the careful thought that went into sending me — yes, me — these invitations.

To say I’m flattered barely begins to describe how these emails make me feel.

First up, from an “Auston Matthews”, who describes himself (herself?) as “Program Manager”:

Here’s what I wrote back:

Dear Mr./Ms. Matthews,

I’m very well indeed! And how are you? How are you enjoying the role of Program Manager?

Now that we’re done with the niceties, let me assure you — the privilege and honour are 100% mine. Being a Speaker towards the 3rd Global Experts Meeting on Infectious Diseases would be something special. I’ll highlight it on my CV in bright yellow marker. Please relay that (plus my best wishes) to the Organizing Committee Members, who no doubt are busy in London planning an exciting meeting.

Before I make my flight arrangements, where is “Bankok”? Is that near Bangkok?

With warm regards,

Dr. PE Paul E

Next — an email from a certain “Henry Walter, Conference Manager”, who generously offers me the chance to visit Rome!

Academic medicine, what a global endeavor!

My response:

Dear Henry Walter,

May I assume we both can communicate on a first-name basis, since you used mine? Hope that’s not too presumptuous!

And you bet I’ll participate in that conference! Not only were the first three iterations of the International Conference on Neurology and Brain Disorders (INBC) scintillating, but I’ve heard that the 4th — INBC 2020 — will absolutely rock.

Let’s speak ASAP about my topic, as I have some ideas. How about a lecture entitled, “Degenerative Brain Diseases of Fish”? After all, I’m the expert.

Hope this sounds INBC-worthy to you. I know the standards are very high!

Sincerely,

Default Value

On to invitation number three, which represents the very pinnacle of personalized conference invitations. It comes from a “Dr. Irene Frank”, whose title is “Executive Director, Coalesce Research Group”. They’re based in Greenville, South Carolina, in case you were wondering.

Here’s what I wrote back:

Dear Dr. Frank,

First, very warm wishes back to you! Speaking of, it must be hot this time of year down in South Carolina, ha ha.

Second — Plenary Speaker at Nano 2019, what an honor! I’m speechless. But don’t worry, I’ll get over it by November, and will be ready to go for my plenary talk. I’ll make sure it’s something BIG about this small (nano, get it?) topic. Ha ha again.

Third — just curious, is it hard to organize a conference in Osaka all the way from Greenville, South Carolina? Is there a direct flight? It’s amazing how you folks at Coalesce Research do all that you do, so impressive.

Finally, before formally agreeing to speak, I have to ask — how will you be introducing me? It’s just not clear from your invitation. And I confess — sometimes I feel like a nowhere man, sitting in a nowhere land, making all these nowhere plans, for nobody.

Regards,

“,”

Take it away, guys.

(Part of an occasional series, as these folks show no signs of tiring. And h/t to friend John Winkelman for the inspiration.)

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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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