An ongoing dialogue on HIV/AIDS, infectious diseases,
September 23rd, 2018
Picking Your Next ID Journal Club Paper? MERINO or POET Trial? Two ID Fellows Debate
Late afternoon/early evening at an academic medical center. Bright young doctors sit in a hospital workroom, putting the finishing touches on what are undoubtedly the most comprehensive and, yes, simply the best consult notes in their respective patient’s electronic medical records.
Best ever.
ID Fellow #1: Hey, pretty soon we have to do Journal Club, right?
ID Fellow #2: Yep, coming up. And you’re first! And I’m the following week. Most important question — do they feed us at these conferences?
ID Fellow #1: Not sure — this is one of the hardest things about fellowship. You never can tell when there’s food. During residency, there was always food.
ID Fellow #2: Agree, big drop off. That food issue and late afternoon consults might be the hardest thing about this year.
A bit more work is done on their respective masterpieces — one a 2000-word opus summarizing a 6-week hospitalization involving several surgeries and a prolonged ICU stay, the other a 9-year history of recurrent lower extremity ulcers in a diabetic with vascular disease.
ID Fellow #1: I think I’m going to choose the MERINO trial — piperacillin-tazobactam [he didn’t really say “piperacillin-tazobactam,” but used the Z-word, alas] vs. meropenem in ceftriaxone-resistant [mostly ESBL] bacteremia. Mero was better! Great to have a definitive result.
ID Fellow #2 (somewhat warily, since obviously she was going to pick the same paper): Yes, meropenem was better, but not superior — in other words, pip-tazo was not demonstrated to be noninferior to mero in the primary endpoint, which was all-cause mortality at 30 days after randomization. (Sensing weakness.) You sure you have the statistical chops to discuss this?
ID Fellow #1 (clearly wavering): Erm … not sure. So not noninferior? Yikes, that double negative is confusing. But it will give me a chance to review the purpose of noninferiority studies. I remember in my med school stats class, one of my favorite teachers said we should replace “noninferior” with “Not too much worse than …” Always liked that. You know, real English.
ID Fellow #2 (thinking that MERINO is now taken, so might as well be generous with her knowledge): Hey, if you really want to get down the statistical rabbit hole in MERINO, there’s a great review I read online about it — I can text you the link. Plus, the investigators amazingly did a really interesting thread on Twitter, answering some of the most common questions they’ve been getting. How great is it that?
ID Fellow #1 (sensing that he may be out of his league on MERINO): OK … maybe you should do MERINO. I was also thinking of the POET trial — IV vs. oral antibiotics for endocarditis. Oral was noninferior. Highly relevant, and I still get to show off by discussing noninferiority trials.
ID Fellow #2 (delighted that she now has MERINO back): Great choice! Could be “practice-changing”; always good to cover a study where you can bring out that powerful phrase. Plus, no gels or blots or GWAS to explain.
ID Fellow #1: Yep, it’s a great study. But I do have some issues. The eligible patients had to receive at least 10 days of IV therapy before randomization — why 10 days?
ID Fellow #2: Follows the rules.
ID Fellow #1: Amazingly, there was no MRSA! And only around 1% had injection drug use as a risk factor — both limit generalizability. Plus, the oral regimens are weird. Fusidic acid? What the [word unintelligible] is that? And putting the drugs used in the supplementary appendix was a bizarre decision, almost like they were trying to hide something. You can tell it was presented at a cardiology and not an ID meeting. We’d never tolerate that.
ID Fellow #2 (worried he might go back and take MERINO): So are you saying you don’t like the study?
ID Fellow #1: No, I think it’s great — imagine how many fewer vanco levels we’d need to chase if PO antibiotics became standard of care for endocarditis! It’s just not perfect. But it’s the exact sort of study we should see more often. It asks an important clinical question, and answers it.
ID Fellow #2: You mean like oral vs. IV antibiotics for osteomyelitis?
ID Fellow #1: Exactly! Hey, what happened to that study?
They go back to putting the finishing touches on their notes. The signed notes get transmitted electronically to an ID attending — who feels deep gratitude about working with such a smart and dedicated bunch, believe me.
September 16th, 2018
Supermarket Chain CEO Defends High Prices of Water, Salt, and Other Items as a “Moral” Requirement
Inspired by recent events in antibiotic pricing.
SACRAMENTO, CA. The head of a national supermarket chain is defending a recent substantial increase in the price of water, salt, and other food and kitchen essentials, arguing that this change is the equivalent of a “moral” requirement.
Last month, iFoods Plus Stores announced that common low-cost items such as water, salt, paper towels, and carrots would all have major price increases.
A 12-oz plastic cup of tap water at the food counter will increase from $0.25 to $2.50, and a 26-ounce container of salt will now sell for $6.99 rather than $0.99. A package of two rolls of paper towels will set a purchaser back $19.99, 10 times up from its previous price of $1.99.
Citing occasional price increase from Whole Foods, Trader Joe’s, Walmart, and other food sellers, iFoods Plus CEO Jack Stevenson said his store’s price increases were not only essential to maintain profits, but were “morally the right thing to do.”
“Our first priority is our shareholders,” said Stevenson. “We live in a capitalist system, and not to take advantage of opportunities to hike prices in settings where we have little competition would be ethically wrong.”
When pressed, he added “Our customers’ well-being and comfort are also important,” but was unable to explain what he meant by that statement.
Some of the price increases have raised concerns among iFoods Plus shoppers, many of whom rely on the stores since the company favors locations with few or no other market options.
And consumer groups say that the increases are unjustified, since most of these items have long been available, and do not represent innovation or research done by the company.
“Water consists of two hydrogen atoms and one oxygen atom, and is considered an essential building block of life on earth,” said Karen Hartfield, head of a food pricing watchdog group. “iFoods Plus did no research and spent no money developing the product. They just get water from the tap.”
Hartfield went on to say that salt, or sodium chloride, is a commonly used household flavoring. In general use long before the beginning of recorded history, salt has been off-patent internationally since 2700 B.C., when generic companies used Chinese pharmaceutical treatises to make salt from seawater.
“Paper towels are, well, just paper,” she said.
In the most dramatic example of skyrocketing prices at iFoods Plus, a one-pound bag of baby carrots, previously $1.99, is now listed at $99.99 — a 5000% increase.
“These carrots are very popular, and quite delicious,” noted CEO Stevenson, “So I’m just charging what the market can bear.”
He further acknowledged inspiration by another company that pulled off a similar price hike. “That man was a genius, and clearly schooled in high-level ethics and moral thought.”
Stevenson also said the price of the small bag of carrots would be reduced to $59.99 with a special Customer Assistance Program. Eligibility criteria include demonstration of vitamin A deficiency, or genetic testing indicating that a person is part rabbit.
Note — in case you didn’t know that there were no patent laws in 2700 B.C., this is satire.
September 9th, 2018
Doravirine Sets a New Standard for NNRTIs — But What Role in HIV Treatment Today?
“Hello, we are Pifeltro and Delstrigo.”
The HIV drug class called “non-nucleoside reverse transcriptase inhibitors,” or NNRTIs, must have something of an inferiority complex.
First, anything defined by what it is not is already in trouble. Believe me, hepatitis C was thrilled when it could shed the “non-A, non-B hepatitis” label.
Second, despite their high antiviral potency and good tolerability, the NNRTIs have always been an afterthought to the protease inhibitors (PIs) when discussing how combination therapy transformed the effectiveness of HIV therapy back in the 1990s. Take a look at this classic paper — over 5000 citations and counting — especially its famous figure.
However, from a global perspective, it has been NNRTI (not PI)-based regimens in that have had the greatest impact in years of life saved from antiretroviral therapy.
Let’s add to the NNRTI list of accomplishments by citing that no study of initial therapy has ever demonstrated superiority over efavirenz from a purely virologic perspective (not even dolutegravir); that a meta-analysis did not show a difference in clinical outcomes between PI and NNRTI-based therapies; and that efavirenz-based regimens appear (ironically) to be quite safe for the fetus during conception and pregnancy.
So — now that I’ve defended the drug class, let’s introduce the latest member, doravirine, which was approved by the FDA during their busy last week of August.
Approval of both doravirine individually and the coformulated doravirine/lamivudine/tenofovir DF tablet was based on the results of two clinical trials.
Given with TDF/FTC or ABC/3TC, doravirine was non-inferior to darunavir + ritonavir with a better lipid profile at 48 weeks, and superior at 96 weeks due to fewer adverse events. Similarly, the once-daily single tablet was compared to TDF/FTC/EFV in a double-blind trial, and also found to be non-inferior.
Dosed 100 mg once-daily, doravirine has several advantages over existing drugs in the NNRTI class:
- Few drug interactions, in particular none with acid-reducing agents.
- Can be taken with or without food.
- A more favorable lipid profile, lower incidence of rash, and fewer CNS side effects than efavirenz.
- A novel resistance pathway, with activity against viruses with K103N or Y181C mutations. By contrast, the V106I and F227C mutations selected by doravirine do not cause in vitro resistance to either rilpivirine or etravirine — and may induce hypersusceptibility to certain NRTIs.
These advantages notwithstanding, the role of doravirine or the coformulated tablet in HIV treatment today is uncertain. Major HIV treatment guidelines now list integrase inhibitor based regimens as preferred for initial therapy, and the drug has not been compared to an integrase inhibitor in any clinical trial. Furthermore, the single tablet option contains tenofovir disoproxil fumarate, which has more renal and bone toxicity than tenofovir alafenamide.
Still, since this appears to be a “best in class” drug, doravirine has enough advantages that it is a useful advance in HIV therapy, if not a transformational one. Think of the following patients, for example:
- Those who can’t tolerate integrase inhibitors.
- Someone looking for efavirenz or rilpivirine alternatives within the same drug class, due to concerns over CNS side effects or use of acid-reducing agents, respectively.
- Off-label use as part of a switch strategy for patients with susceptible virus. (A switch study is ongoing.)
- As a cost-saving strategy, depending on listed and negotiated prices — in particular for the single tablet, since the non-doravirine components are generic.
Of note, doravirine is also under study with the potent and long-acting agent MK-8591 as part of a two-drug strategy. MK-8591 is an NRTTI, the second T standing for “translocation”.
Two final points: The drug is abbreviated “DOR” — not “DRV,” which was already taken by darunavir.
And the brand names are Pifeltro, for doravirine alone, and Delstrigo, for the coformulated single tablet — note that “STR” in there? One can assume that stands for “single tablet regimen.”
Still, together they sound like the name of a famous Sicilian puppet duo, best known for their slapstick comedy routines.
September 3rd, 2018
Eravacycline Approved by FDA — How Might It Be Used, Today and in the Future?
WPA Recreation Project, 1939
While last week the world was sunning on the beach, hiking in the woods, eating ice cream, and performing careful tick-checks, the hard workers at the Food and Drug Administration hunkered down in Silver Spring, Maryland to get three anti-infectives approved — eravacycline, doravirine, and doravirine/TDF/3TC.
Maybe they saw the weather reports — hot and humid, this is the D.C. area! — and figured they might as well stay inside. Take advantage of the climate control and finish off these applications!
Let’s consider the antibiotic approval first.
As the name suggests, eravacycline is a tetracycline derivative, but with a much broader antibacterial spectrum. This includes many highly resistant gram negatives (including some carbapenem-resistant organisms and acinetobacter), MRSA, VRE, and anaerobes. Pseudomonas aeruginosa is an important exception to its broad coverage.
The drug’s approval was based primarily on clinical trials demonstrating non-inferiority to ertapenem in intra-abdominal infections, and a second study versus meropenem with similar results — hence this is the indication in the label. Treatment for complicated UTIs vs levofloxacin didn’t go well, so the drug is not recommended for UTIs. Because eravacycline is hepatically metabolized, there’s no need for dose-adjustment in renal failure.
As with tigecycline (to which one inevitably draws parallels), gastrointestinal side effects predominate, though appear to be less common — good news, since nausea is far and away the most common dose-limiting side effect for tigecycline. Infusion site reactions are more common than with the carbapenems.
Encouragingly, the company plans to price the new drug at the lower end for a recently approved antimicrobial, bucking a common trend for new drugs.
So we have this new antibiotic — how will it be used?
To echo a common refrain of most recently approved agents, eravacycline will not immediately be a first-line option for its approved indication, intra-abdominal infections.
However, if we get a bit creative, one could envision an important role for eravacycline in certain patient scenarios — with the caveat that some are admittedly speculative and definitely off-label.
Roughly in order of plausibility (most to least), here are several potential treatment settings for eravacycline:
- If tolerability is confirmed in clinical practice to be better than tigecycline, in place of that often troublesome drug.
- In a patient with intra-abdominal infection, documented allergy to beta lactams, and known to harbor fluoroquinolone-resistant organisms.
- For someone at very high C. diff risk — especially if eravacycline proves to be as low risk as other tetracycline-class drugs.
- In therapy of ceftriaxone-resistant gonorrhea — this will need a clinical trial, of course, to establish efficacy and dose.
- For treatment of non-tuberculous mycobacteria, in particular M. abscessus — but first it would be optimal to see in vitro activity, and preferably approval of the oral formulation (regardless of what it’s approved for).
As for the brand name, Xerava — is it just me, or is this a trap for a drug name mix-up?
I’m thinking, of course, of a very widely used oral anticoagulant!
August 23rd, 2018
Eye Worm, MALDI-TOF, New Lyme Testing Approach, Dogs Fail as C. diff Testers, Uiyk (?), and More — A Summer Is Getting Shorter ID Link-o-Rama
Ben Taylor (aka Mometo) (1970–), The Host (2014). Cover of Emerging Infectious Diseases, August 2018
A recent chilly spell here in Boston recalled a universal truth about aging — that summer seems to get shorter every year.
As far as I can tell in my unscientific poll of everyone who will engage with me on this topic, there are no exceptions to this rule. Everyone thinks summer is shorter than when they were kids, even though the calendar says summer lasts around 90 days — every year.
Why is the sun going down so soon? Is it already mid-August? No more free summer weekends? Didn’t it just get warm? Winter coats in catalogs? Back-to-school specials at the office supply stores? Halloween costumes at Costco? Summer is over already???? ARGHHHH!!!!
On to an ID Link-o-Rama, this one designed to accompany the late afternoon slanting sunlight that seems to say, “Too soon, too soon.”
- One in seven children born to mothers who acquire Zika during pregnancy has a birth defect. It’s clear Zika can be devastating to the developing fetus. What’s not so clear is what drives the highly unpredictable epidemiology, as the incidence is sharply down.
- Here’s a crystal clear review of what happens in a MALDI-TOF machine. Given the increasing use of this technique for pathogen identification, we might as well know what goes on inside that black box. Highly recommended.
- HIV virologic suppression rates in clinical practice have nearly tripled since the introduction of combination therapy in the late 1990s. 32% in 1997 to 86% in 2015 — that’s pretty, pretty good. The endlessly energetic Carlos Del Rio weighs in further here.
- A promising new class of antifungals has an absurdly weird-sounding name — ibrexafungerp. You read that right — and it’s pronounced “eye-BREX-ah-FUN-jerp,” in case you want to impress your friends. The always-brilliant PharmD Brandon Dionne had the best take on what this sounds like (yuck):
Very promising new class of antifungals, but what a terrible name. Ibrexafungerp. It's like the sound someone makes when they vomited a little bit then swallowed it. 🤢 https://t.co/mYbHQuDrUv
— Brandon Dionne (@BWDionne) August 8, 2018
- The Tdap vaccine during pregnancy does not increase the risk of autism. Isn’t it sad that someone even has to do this study?
- Should we change the way we test for Lyme Disease? This alternative approach uses two different non-immunoblot methods, and apparently is more sensitive without adding to the false-positive rate. Certainly it promises to be faster (immunoblots seem to take forever). Sign us up!
- Good concise summary of what’s new (and what isn’t new) in Lyme. These two experts aren’t quite ready to adopt this new testing strategy, though they acknowledge its advantages. Regardless, interesting always to read their perspective.
- “My dog got his Lyme vaccine — why can’t I get one too?” If you’ve been asked that by one of your patients, the linked article from New York Times provides an excellent summary of the vaccine we once had, and why it’s no longer available.
- Another observational study shows no difference in clinical outcomes between ampicillin plus ceftriaxone versus ampicillin plus gentamicin for enterococcal endocarditis. No, it’s not a randomized trial, but when you consider that the amp plus ceftriaxone group had more renal disease and more comorbidities — biasing results against that group — you have to wonder why one would choose the aminoglycoside option, especially in the elderly.
- The earlier a resident does an elective in ID, the more likely they are to choose it as a specialty. Makes intuitive sense, but nice to see this documented. One of the rarely talked about changes to residency training since the introduction of work-hour restrictions is the reduction in opportunities to do subspecialty electives.
These two Capnocytophaga canimorsus cases sure got a lot of attention. It’s fortunate these infections — linked to dogs, see the word “canine” in the name? — are very, very rare. Right Louie? That’s right, very rare — who’s a good boy?- An artist experienced multiple parasitic infections after visiting the jungles of Gabon for several weeks, including the infamous Loa Loa eye worm. In the spirit of “Everything is copy,” he used the experience as inspiration for his art (featured on the cover of Emerging Infectious Diseases) — and almost netted the same level of media coverage as the capnocytophaga cases.
- Confirming a diagnosis of HIV while someone is on PrEP can be tricky. Here’s a guide to work through these sometimes “ambiguous” results. If you haven’t experience this clinical scenario yet — for example, someone on PrEP with a reactive HIV screen but other tests negative — prepare yourself to walk through these issues by reading this excellent paper.
- Maybe dogs can’t reliably sniff C diff after all. Tough Link-o-Rama for the doggies! From this excellent coverage of the published study: ““If there was a breakfast tray on that patient’s bed, Chase [the dog] was way more interested in the breakfast tray than he was in trying to find C. difficile spores,” … Another problem: “The dogs found it hard to pass a toilet without drinking out of it.”
- There are way too many measles cases in the USA, but things are really bad in Europe. Already there have been 37 deaths — all preventable with one of the most effective vaccines we have! This tweet from ID colleague Eli Perencevich comments astutely on the absurdity of this tragedy:
https://twitter.com/eliowa/status/1032281718844141568
- Ibalizumab is effective in patients with multi-drug resistant HIV. This humanized IgG4 monoclonal antibody blocks viral entry, and is given as an infusion every two weeks. Notably, drug development of ibalizumab started around two decades ago, when we had many patients who could not achieve virologic suppression because of resistance — a situation uncommon today. That a phase III trial had only 31 patients and that the FDA approved it anyway demonstrates two things: 1) There are very few people who need this drug; 2) those who do need it really really need it — it can be life-saving. Trivia question — why is it called “ibalizumab-uiyk“?
- There are significant knowledge gaps about TB diagnosis and treatment among medical residents. Given how rare TB cases have become in the USA — especially in certain regions — these results are unsurprising, but still important. Mandatory ID consult for cases where TB is highly suspected? Certainly would advocate consultation when the diagnosis is confirmed.
- Fosfomycin susceptibilities are a mess. That’s the only conclusion one can draw from this interesting study of different testing methods, which highlights the difficulties of obtaining a reliable result outside of the cumbersome agar dilution method — a challenge that will become even more important when IV fosfomycin becomes available in the USA. (H/T to ID Journal Club for the link, see below for more information.)
- It’s been quite the season for Infectious Diseases and baseball. Two cases (!) of hand, foot, and mouth disease landed separate New York pitchers (one Yankee, one Met) on the disabled list. Not only that, Cleveland outfielder Leonys Martin sounds like he had sepsis or toxic shock syndrome. Speedy recovery!
Three more items before you head back to beach.
- Shout out to the excellent ID Journal Club, where Dr. Nicolás Cortés-Penfield summarizes recent ID literature in clever, concise snippets. He’s been doing it for around a year — may he long have the energy to continue!
- On The OFID Podcast, PharmD extraordinaire Dr. Susan Davis joins me to highlight the critical role ID pharmacists play in improving patient care.
- On The Curbsiders Podcast, I spend a bunch of time talking about tick-related infections, in case you can’t get enough of these critters.
Hey, next week I’m on vacation — so summer can’t be over quite yet, right?
August 12th, 2018
Apologies, Our E-Mail Notifications Are Not Reliably Going Out
Last week, I wrote something I really wanted my long-time friend and colleague, Susan Larrabee, to read. Susan is the HIV social worker-extraordinaire I’ve been working with for a million years, give or take a few.
The piece covered how rewarding it is to care for people with HIV. If anyone could affirm that view, it’s Susan. She’s the kind of cherished colleague who provides an instant antidote to burnout. If you’re working with someone like that, lucky you!
But here’s how our conversation went when I popped into her office looking for her approval:
Me (hopefully): So what did you think of that piece?
Susan: What piece?
Me (trying to hide my disappointment): The one I wrote on my blog — you know, on caring for people with HIV. Thought you’d really enjoy it.
Susan: Didn’t see it. And I was wondering — why did you stop writing your blog? Too busy?
Me (annoyed): @#$%&!
(Those punctuation marks, by the way, are called a grawlix — used to represent expletives or swearing in comic strips. Now you know.)
The reason Susan thought I’d stopped writing the blog is because we’re having technical issues here at NEJM Journal Watch. Our reader email notifications aren’t reliably going out when there’s a new post. For some of you, that’s the only way you know when there’s something written here.
For example, Susan. For all her brilliance regarding human emotions and motivational interviewing techniques, she would be the first to admit she’s technically challenged. She is as likely to subscribe to an RSS feed as she is to hack the operating system on someone’s Tesla. She might not even know that a Tesla has an operating system.
(“What’s a Tesla?”, asks Susan.)
I feel bad about this problem of ours, since those of you who signed up for the email notifications took the time to do so — I’m very grateful to you for that.
But rest assured our technical team at NEJM Journal Watch is working behind the scenes to try and fix this “bug” — which, though not literally infectious, is at least non-communicable.
So thanks for bearing with us while we try to figure out what’s going on.
In the meantime, here are few other ways to be notified of the new posts:
- Follow me on Twitter (@PaulSaxMD) You’ll get notification about all the posts that appear here, plus bonus information about ID, medicine in general, baseball, and dogs, among other critical topics. Making fun of #predatoryjournals is particularly fun on Twitter.
- Follow NEJM Journal Watch on Facebook
- Sign up for the Physicians First Watch daily newsletter — you should do that anyway, it’s great!
And here are two dogs who aren’t quite so sure about becoming vegetarians:
August 5th, 2018
Why Caring for People with HIV Is Still Great
Earlier this year, I wrote a piece about friends and colleagues of mine who have left HIV clinical practice. Something about it touched a nerve. It’s one of the most commented-on pieces in the history of this blog.
Read this for a typical response.
Admittedly, it was kind of a downer — but it might have been slightly misinterpreted. A lot of the problems my friends cited could have easily applied to almost any area of clinical practice; these challenges were by no means limited to HIV care.
They mentioned the inscrutable and user-unfriendly EMRs, the lack of appreciation for cognitive specialties, the pain of “quality metrics” that require endless box-checking, the difficulties of funding care for the underserved. Safe to say that every primary care clinician in the country feels the same pain.
So, here’s a flip side to caring for patients with HIV, and it’s not just me resorting to the form that prompted my family to give me this T-shirt as a commentary on my sunny personality. I truly believe that HIV care remains an extraordinarily gratifying aspect of ID clinical practice. Which is why it’s critical that ID doctors continue to do it.
Here, in a bulleted list for clarity, are a bunch of things that make HIV care spectacularly rewarding:
- You can save someone’s life. Antiretroviral therapy is miraculous. Every ID/HIV specialist has had patients with advanced HIV disease and multiple complications literally rescued from the jaws of death by these lifesaving drugs. If you’re a clinician who doesn’t do surgery, it doesn’t get better than this, folks.
- You can really get to know your patients. You might be surprised given my youthful appearance (ha), but I’ve been doing this a long time. Fortunately, my career has included that breathtaking time in the mid-1990s, when suddenly we had effective HIV treatment. As a result, I’ve been following some of my patients for more than two decades. I know Brian’s favorite Dorchester restaurant since he moved from the South End, Felicia’s daughter’s name and what play she’ll be in this semester at college, Cliff’s excitement about this year’s Red Sox, how long Mark drives on his truck route each day, how Evelyn has never missed an episode of Grey’s Anatomy (there have only been 317), Ira’s struggles with his latest software release, and what vintage car Tony is working on in his shop. (And yes, I changed their names!)
- You will care for an extraordinarily diverse group of people. Despite stereotypes, there is no “typical” person with HIV, just like there’s no “typical” person with most infectious diseases. They will come from every race, occupation, country, and tax bracket. Our clinic cares for patients in their late teens up to their late 80s; our oldest patient just died of non-HIV-related causes shortly after her 90th birthday.
- You will continue to learn a lot about non-ID medicine. The aging of the HIV population forces us to keep up with all these interesting and common non-ID-related problems and issues — diabetes, hypertension, osteoporosis, atherosclerotic disease, cancer screening, neurocognitive decline, depression, venous thrombosis, chronic renal disease, atrial fibrillation. As a long-term patient of mine said to me the other day, “The HIV part is great. It’s all the rest of the stuff that I struggle with!”
- The field is constantly changing — for the better. Although almost all of the patients who regularly attend clinic visits are virologically suppressed, HIV treatment is always evolving — there’s a constant push to make what’s already great even better. That patient who was successfully treated in 1998 with d4T, 3TC, and indinavir, suffering through neuropathy, kidney stones, and ingrown toenails (yes, that was a complication of indinavir), may well be receiving a single pill with none of these side effects today. Ongoing research is pushing toward long-acting therapies (a once-weekly pill? a shot every 3 months?) — and, potentially, a cure. I wouldn’t bet against either eventually becoming a reality, though admittedly the cure part is still a ways off.
- The science of HIV prevention has never been stronger. As exciting as we find the information that people on suppressive HIV therapy cannot transmit the virus to others, imagine how this feels to our patients? It is wonderful giving them this news. It is both liberating and, just as important, helps diffuse some of the stigma that has stubbornly stuck to HIV ever since AIDS came on the scene in 1981. For people without HIV, pre-exposure prophylaxis (PrEP) is nearly as much of a game-changer. Will one of the HIV vaccines currently in clinical trials be the next advance?
- Your expertise will be valued in both the outpatient and inpatient setting. While most people with HIV are healthy and followed as outpatients, there is still a significant and important amount of care done in the hospital. These include patients with opportunistic infections and cancers, as well as non–ID-related issues that may influence HIV treatment selection. The mix of inpatient and outpatient care brings a wonderful diversity to the experience.
So, for you ID doctors out there, please keep doing HIV patient care — it remains among the best things I do as a clinician, and I don’t expect that ever to change.
Until we have a cure, that is!
July 29th, 2018
Really Rapid Review — International AIDS Conference 2018, Amsterdam
The International AIDS Conference — or “AIDS 2018” — returned to Amsterdam for the first time since 1992.
It’s worth pausing, with gratitude, to remember that 26 years ago antiretroviral therapy consisted of three available drugs — zidovudine (AZT), didanosine (ddI), and zalcitabine (ddC).
All were marginally effective, with limited durability and significant toxicity. In fact, the big debate in the early 1990s was whether treatment of HIV before symptom onset was worthwhile at all.
We had no NNRTIs, PIs, or integrase inhibitors. Aside from recommending condom use and abstinence, we had no strategies to prevent HIV among sexually active adults.
Fast-forward to today, where the goal is to have everyone with HIV on treatment for both their individual benefit and to end the epidemic.
Gratitude indeed!
Here are some highlights from the meeting which took place last week, a Really Rapid Review© of important (or just interesting) studies that caught my eye. Apologies ahead of time for missing your favorite — as always, let me know in the comments section what I missed!
- As initial therapy, dolutegravir plus lamivudine was non-inferior to dolutegravir plus TDF/FTC at week 48. Additional favorable results from the much-awaited GEMINI studies included no treatment-emergent resistance, comparable activity in patients with HIV RNA >100,000, and (not surprisingly) less effect on renal and bone markers. The only caveat was a lower response rate in those with baseline CD4 <200 due to miscellaneous reasons (not virologic failures). Unclear what caused this imbalance.
- Zero HIV transmissions among serodiscordant MSM couples if the infected partner had virologic suppression. This follow-up to the PARTNER study of serodiscordant couples — all not using condom — enrolled additional gay men to provide greater assurance about this remarkable benefit of HIV therapy in this subgroup. Those who are quantitatively minded (!) might be reassured that there were no transmissions with an estimated 76,991 episodes of condomless anal intercourse. Results also published here. The audience hearing the presentation burst into spontaneous applause with presentation of these results. Yes, as I have noted here numerous times, the Swiss were right a decade ago, which allows me to use that pretentious (but appropriate) word “prescient.”
- Investigators updated the preliminary data on dolutegravir during conception and the risk of neural tube defects. Publication of their initial report is here in the NEJM; reported at the conference were additional newborn outcomes for women who conceived while on DTG, with no additional cases through July 15. This brought the estimated incidence down to 4/596 (0.67%, 95% CI 0.26%, 1.7%) — still higher than the approximately 0.1% incidence seen with non-DTG ART (mostly EFV). Further observations are expected through March 2019, which may help clarify this important issue.
- More women initiating ART with DTG rather than EFV-based regimens in late pregnancy achieved an undetectable viral load. Note that there is no evidence that DTG treatment started during pregnancy is associated with any adverse outcomes in the newborn, though it does seem that babies metabolize this drug slowly.
- On-demand PrEP with TDF/FTC in France appears to be working as well as daily treatment. This is an analysis of effectiveness in the community, not a clinical trial, among approximately 1500 individuals (mostly MSM) choosing between on-demand or daily PrEP. Both interventions had zero seroconversions with 7 months of follow-up, with an estimated 85 infections averted based on historical data. Note that the recently released IAS-USA Guidelines also endorse on-demand therapy as an option.
- Melbourne and San Francisco demonstrated impressive declines in new HIV diagnoses. The rapid initiation of ART for newly diagnosed individuals is strongly correlated with this improvement. Here’s an amazing statistic — in 2016, there were only 233 people newly diagnosed with HIV in all of San Francisco, less than half the number (523) in 2008.
- When divided by quintile, states with the highest PrEP uptake had a decline in new HIV infections, while those in the lowest quintile had stable to increased HIV incidence. This association was made stronger by the observation that estimated virologic suppression rates were similar in each of the quintiles. I can’t quite understand how they made this last estimate, but it does support that PrEP reduces HIV acquisition in communities with higher use.
- Dolutegravir plus rilpivirine maintained virologic suppression at 96 weeks. This two-drug regimen is approved for patients currently suppressed who have no resistance to these dru
gs. There were three patients with virologic rebound and RPV resistance, none with DTG resistance. While the study did not give follow-up on these 3, presumably they could be successfully treated with NRTIs plus DTG or BIC, so the consequences of this resistance are small. - In treatment-naive studies, bictegravir-FTC-TAF demonstrated high efficacy in patients with high baseline HIV RNA or low CD4 cell counts. The same was true for the comparator arms — dolutegravir plus TAF/FTC or dolutegravir/ABC/3TC. These per-protocol analyses show that with vanishingly few exceptions, patients stable enough to enter our clinical trials of current ART will achieve virologic suppression if they take their medications.
- The single tablet of DCF-TAF was effective in a prospective “rapid start” study. Impressively, 29% of the 107 patients were enrolled within 48 hours of HIV diagnosis. This combination tablet (just approved) does not require results of resistance, HLA-B5701, or hepatitis B testing.
- Should we routinely be doing resistance testing before starting therapy today if the first regimen is INSTI-based? This analysis (disclosure: I’m a co-author) suggests that such testing is no longer cost-effective. Remember, our current transmitted drug resistance does not impact outcomes in INSTI-based regimens.
- One patient developed DTG resistance when started on TDF/FTC plus DTG as initial therapy. As with the previously reported case, the patient had a low CD4 cell count and high viral load (CD4 39, HIV RNA 457,000), and an active infection. She was also receiving rifampin as adjunctive treatment for Staph aureus, with appropriate doubling the dose of DTG. Resistance occurred via the R263K pathway, with rapid virologic rebound. The case is a reminder both how rarely this occurs, and that clinical trials do not include our most difficult to treat patients — they need especially close follow-up after starting ART.
- As second-line therapy after failure of NNRTI-based regimens, DTG plus NRTIs is superior to LPV/r plus NRTIs. These 48-week results confirm the practice-changing data presented last year, and were consistent across most baseline characteristics favoring DTG. A separate presentation provided some resistance data, though hopefully more are forthcoming. Two individuals experienced virologic failure with DTG resistance with an unusual G118R mutation. Surprisingly, neither of them had much NRTI resistance.
- Resistance to the second-generation integrase inhibitors dolutegravir, bictegravir, and cabotegravir is highly correlated. The G140S + Q148H mutations plus any other integrase mutation can lead to high-level resistance. In other words, it does not appear that resistance to one of these agents could be salvaged with different one — fortunately this resistance remains quite rare. The incidence of resistance to cabotegravir in the upcoming phase 3 studies of long-acting cabotegravir-rilpivirine will be a critical secondary endpoint.
- Doravirine was superior to darunavir/ritonavir at 96 weeks. This difference was driven by a higher discontinuation rate in the darunavir/ritonavir arm. Approval of doravirine is anticipated in October 2018.
- Approximately 1% of doravirine-treated patients in treatment-naive studies developed resistance. For those of you who like to memorize resistance mutations, V106I and F227C were commonly identified. Two interesting aspects of doravirine resistance are 1) most of the isolates retained susceptibility in vitro to certain other NNRTIs (especially etravirine); 2) the F227C containing viruses were hypersusceptible to MK-8591, and these two drugs are now in Phase 2 studies.
- Two studies evaluated dolutegravir monotherapy as a maintenance strategy — and both provide further evidence that we shouldn’t do it. The first was in patients initially treated during primary infection, who may have a lower HIV reservoir. In this small study, it appeared to work — but of course we can’t measure viral reservoirs in practice, so results are of little practical value. Furthermore, one patient with chronic infection was enrolled erroneously and failed. The second study (“MONCAY”) in chronic HIV infection had excessive virologic failures after week 24, with 2/5 patients developing DTG resistance. Time to stop MONCAYING around, folks!
- Heart failure appears to more common in people with HIV than in uninfected controls. This did not appear to be mediated by atherosclerotic disease. It’s possible this is an effect of viral replication, since at the start of the study most of the patients were not receiving ART.
- In acute hepatitis A, the clinical illness with HIV was milder but more prolonged compared to those who were HIV negative. These data come from a large outbreak in Taiwan among MSM, 63% of whom were HIV posititive. Hepatitis A vaccination appeared to be critical in controlling the outbreak.
- Vedolizumab had no effect on time to virologic rebound after ART interruption in people with HIV. (Results reported within the linked plenary session.) Remember hearing about the remarkable effect of antibodies to Alpha4Beta7 integrin in SIV infected macaques? A refresher — it appeared to block virologic rebound after ART treatment discontinuation. Not only did the intervention not work in humans, but the effect was not reproduced in monkeys either. Oh well.
- A minority population of CXCR4 virus pre-stem cell transplant led to virologic rebound in a patient who received cells from a CCR5-negative donor. This case report highlights the unique nature of the one case of HIV cure, and is a reminder that it will take more than host engraftment of CCR5-negative cells to have the same result.
- HIV therapy augmented with both vorinostat and HIV immunization did not reduce the viral reservoir. The study was performed in patients treated initially during acute HIV, the group widely believed to be most amenable to eradication strategies. This is the so-called “kick and kill” approach of stimulating the latent reservoir and then striving to eliminate it with an augmented immune response. Both the vorinostat and the vaccines did their jobs, but the reservoir remained stable. Oh well (again).
Amsterdam remains a gem, a marvelous city with distinctive architecture, great food, nice people, picturesque canals, and incredible museums. It was even better than the last time I was here — seemed cleaner, bustling but less congested (at least with car traffic), and decidedly less seedy. The fact that it was unbelievably hot didn’t deter many of us (including me) from biking around town, joining the throngs who regularly take advantage of the flat terrain and the extensive bike lanes.
But visitors beware — when it’s time to go home, the airport is a chaotic, crowded mess. The warnings to arrive 3 hours before departure time should not be taken lightly. I’d call the airport a zoo, but that might be insulting to some zoos!
.@KLM: Worst airline & cust svc experience ever. Long lines @Schiphol, checked in, then >45 min line for baggage drop. Still 30 min pre-takeoff, told to rebook bcs too late to check baggage, but no seats avail x2days! So, to LHR on BA, hotel, int’l change fee to ATL=$1800!
— Melanie Thompson (@drmt) July 28, 2018
Poor Melanie! Hartsfield will seem downright peaceful by comparison.
Next year’s meeting will be in Mexico City, July 21-24, 2019. It too is a wonderful, vibrant city (and where I’ve had some of the best restaurant meals in my life) — but based on the traffic the last time we were there, bike transport seems highly unlikely!
So what did I miss?
July 22nd, 2018
FDA Approves First PI-Based Single-Tablet Treatment for HIV — How Will It Be Used?
You too can learn to play the Symtuza.
The latest HIV drug approval from the FDA came this past week with the release of a single-tablet treatment containing the following drugs:
- Darunavir (DRV) 800 mg
- Cobicistat (c) 150 mg
- Emtricitabine (FTC) 200 mg
- Tenofovir alafenamide (TAF) 10 mg
Often abbreviated “DCF-TAF,” this is the first full treatment regimen in a single pill with a protease inhibitor. The approval is based on two large randomized clinical trials.
The AMBER study compared this DCF-TAF single tablet to a control arm of DRV/c plus TDF/FTC in 725 treatment-naive individuals. Virologic outcomes were similar, with renal and bone endpoints favoring DCF-TAF. There was no emergent PI resistance; one patient developed M184V in the DCF-TAF arm.
The EMERALD study enrolled 1,141 patients already virologically suppressed on a boosted PI plus TDF/FTC based regimen. (This is the largest HIV switch study ever done, for the record.) Prior virologic failure was permitted. Participants were then randomized 2:1 to receive DCF-TAF or to stay on their current regimen. Both approaches maintained virologic suppression, with no discontinuations for virologic failure. There was no emergent HIV drug resistance, and again renal and bone outcomes favored the DCF-TAF arm.
These data persuasively argue that this convenient coformulation is every bit as good as the separate tablets. There are many people still receiving darunavir-based regimens — it’s our best tolerated protease inhibitor — and most patients prefer the simplicity of having one pill, one prescription, and one co-pay.
However, the DCF-TAF tablet faces several challenges that may limit widespread adoption:
- Many HIV treatment guidelines favor integrase inhibitor (INSTI)-based therapy over boosted PIs. These guidelines can cite several studies where INSTIs were better tolerated and/or more effective than boosted PIs. The FLAMINGO study, for example, demonstrated the superiority of dolutegravir over darunavir/ritonavir.
- The low risk of resistance with boosted PIs is also seen with the second-generation INSTIs dolutegravir and bictegravir. This high resistance barrier in the boosted PI drug class was once a distinguishing characteristic, but no longer.
- Pharmacokinetic boosters should be avoided in HIV treatment whenever possible. The drug interactions with ritonavir and cobicistat are extensive and frequently clinically relevant. Here’s a nicely done series done by my colleagues reviewing local data on the important interaction of ritonavir with injectable corticosteroids.
- Several observational studies have linked treatment with HIV protease inhibitors to increased cardiovascular risk. Atazanavir appears to be the lone exception, possibly mediated by its signature side effect, hyperbilirubinemia.
- The tablet will be expensive. The price is reportedly $41,000/year. If confirmed, this will be the costliest of the available single-tablet treatment options. With more generic antivirals available yearly, the price of HIV therapy is drawing greater scrutiny.
- Are we moving to a “less is more” approach to HIV therapy? There is already a two-drug option approved for maintenance of virologic suppression (dolutegravir plus rilpivirine), and the release of data from the GEMINI studies of dolutegravir plus generic lamivudine is imminent. Such approaches make the four drugs included in the DCF-TAF tablet seem like too much of a good thing.
These concerns notwithstanding, as noted above there are many patients currently on darunavir-based treatments. Not everyone can tolerate INSTIs (CNS side effects are probably the most common reason for cessation), and many treatment-experienced patients already have resistance to NNRTIs. For these individuals, I suspect this new single-pill option will prove popular — provided the price and payer issues are settled.
Now, as for the brand name — “SYMTUZA” — to me it brings to mind the name of a Nepali musical instrument.
A highlight of their visit to a remote village was a brilliant trio performed on the Babucha, the Dakkari, and the Symtuza.
How about you?
July 15th, 2018
On-Service Digest, July 2018 — with Special Section Just for Staph aureus
“Hey, medicine is fun!” she said, high-fiving enthusiastically with one of her co-interns.
I’m currently on-service for the inpatient ID consult team, and this is July.
At a teaching hospital.
Here’s where some would play scary music. After all, the interns and fellows have just started! YIKES!
But no scary music for me — I love working with the July newbies.
Because whatever they lack in experience or efficiency, they more than make up for it with enthusiasm and motivation. They’re on that steep upward slope in the learning curve, and it’s fun to experience this firsthand.
Plus, there’s plenty of extra help around, and this year we hit the jackpot. In addition to an excellent first-year ID fellow, our team also has a resident with a distinguished ID pedigree and a medical student who has done ID research. If that weren’t enough, we also have a terrific ID PharmD who has his own keen residents.
Yes, we almost have enough people on rounds to field a decent softball team. We make quite the sight entering and leaving the elevator.
So what have we learned so far? Here are few items, ranging from obvious to obscure, inspired by a similar roundup last December.
- Here’s a terrific review for all clinicians of contemporary hepatitis C treatment. Sofosbuvir/velpatasvir (SOF/VEL) and glecaprevir/pibrentasvir (GLE/PIB) are the best options for initial therapy — pangenotypic, highly effective (>95% cures), well tolerated. Why choose anything else? Also, most patients need minimal monitoring — test for cure 12 weeks after treatment stops and monitor for re-infection if at ongoing risk. Provided they don’t have advanced liver disease (and referral to a hepatologist), that’s pretty much it!
- Compared to other candida species, Candida glabrata has both more azole and echinocandin resistance. This is particularly the case in transplant and oncology centers that use extensive antifungal prophylaxis. In vitro, Candida parapsilosis also shows reduced susceptibility to echinocandins, but the clinical significance of this finding is uncertain.
- TMP/SMX is likely fine for treatment of HIV-related cerebral toxoplasmosis. Small caveat — there has never been a fully powered comparative trial versus pyrimethamine/sulfadiazine. However, there is extensive international experience with TMP/SMX, plus increasing clinical use in the U.S. since Shkreli/Turing Pharmaceuticals raised the price of pyrimethamine from $13.50 to $750 per dose.
- Asplenia or hyposplenism is an important risk factor for severe babesiosis. Others risk factors include older age (>50, ugh), receipt of cancer chemotherapy, advanced HIV disease, and treatment with TNF blockers or rituximab. The last of these is a particularly bad player in persistent infection.
- Among patients with HIV, those with poor adherence often have little or no resistance. They don’t take enough of their medications to select for resistance. Further proof comes from several treatment-experienced trials of second-line therapy or beyond — baseline lack of resistance is associated with worse outcomes. Poor adherence carrying through to the second-line therapy explains this apparent paradox.
- Doxycycline reduces the risk of C. diff in hospitalized patients. This is one of many reasons it remains many ID doctor’s favorite antibiotic.
- In treatment-naive patients, dolutegravir plus lamivudine is non-inferior to dolutegravir plus TDF/FTC. Full results to be presented soon. This should mean that prices for HIV drugs come down — but it won’t be so simple, as explained in this excellent perspective from the NEJM.
- Carbamazepine and phenobarbital induce the metabolism of dolutegravir. For phenobarbital, the effect is likely to be substantial enough to make co-administration with dolutegravir contraindicated.
- Cefiderocol is an investigational cephalosporin with activity versus highly resistant gram negative infections. This includes many carbapenem-resistant isolates. It is a novel “siderophore cephalosporin,” meaning it’s transported through the outer membrane of bacteria through iron transporters (at least, I think that’s what it means).
- Obesity and diabetes are risk factors for invasive group B strep infections. This is now a more common pathogen in older adults than it is in newborns, a fact that surprises many medical students.
- Prednisone reduces the risk of immune reconstitution inflammatory syndrome (IRIS) in patients with HIV-related TB. IRIS was diagnosed in 47% of those in the placebo arm, versus 33% in prednisone arm. There was no difference in mortality.
- Corynebacterium striatum, commonly found as part of normal skin flora, can cause clinically significant infections. Vancomycin is the preferred initial therapy, as the organism is increasingly resistant to beta-lactams and quinolones. Other options include linezolid and daptomycin, based on susceptibility testing. Device, hardware and line-related infections are most commonly reported, along with respiratory tract infections in immunocompromised hosts and patients with COPD.
Special Staph aureus section — hey, this is inpatient ID, remember?
- Oxacillin is marginally better tolerated than nafcillin. Nafcillin has more renal-related adverse effects. However, cefazolin is better tolerated than both of them — but is it as active? Let the debate rage on.
- Penicillin-susceptible Staph aureus (PSSA) can be treated with penicillin. This presumes that the laboratory has definitively concluded it’s susceptible; since not all labs do this, however, the endocarditis guidelines recommend oxacillin or nafcillin for PSSA, even though penicillin is more active in vitro. (We tend to use penicillin at our hospital.)
- Adjunctive rifampin does not improve outcomes in Staph aureus bacteremia. Rifampin still has a role in prosthetic valve endocarditis, as it targets bacteria in biofilms which could induce late relapse. However, there is no need to use rifampin to clear the initial bacteremia, and giving it with a high burden of infection could select for resistance.
- There is an ongoing clinical trial comparing IV to oral antibiotics in uncomplicated Staph aureus bacteremia. Called SABATO (for “Staph aureus Bacteremia Treatment Options” — clever!), the trial will enroll patients after 5–7 days of IV therapy, randomizing them to continued IV versus oral TMP/SMX. If they have sulfa allergies, MSSA patients will get clindamycin, and MRSA patients will get linezolid.
- Mortality from Staph aureus pneumonia remains high. This is especially true when it’s a complication of influenza. And if it’s pneumonia due to MRSA, linezolid may be preferable to vancomycin.
- For surgical prophylaxis when concerned about MRSA, vancomycin alone isn’t enough. Vancomycin plus cefazolin is recommended. And count this as additional evidence that vancomycin has many weaknesses.
Hey, this list of medical/surgical specialties and classic rock songs left off Infectious Diseases!
Happy #ClassicRockDay July 13th y’all! Here’s a fun list of songs representing different medical specialties #medtwitter Feel free to add more to the setlist! #Physiatry is well represented with Walk This Way by @Aerosmith 🏃🏻♀️🏃🏾♂️🇺🇸🤘🏼@AAPMR @AAPhysiatrists 🎼 pic.twitter.com/12tLDQR90m
— Vinny Francio, MD (@VinnyFrancioMD) July 13, 2018
Here’s the obvious answer (with apologies to Peggy Lee and her very different song of the same name):
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
Learn more about HIV and ID Observations.
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