An ongoing dialogue on HIV/AIDS, infectious diseases,
May 15th, 2023
Types of HIV Papers — A Quick Guide
I spend a lot of my time reading HIV clinical research papers. A lot.
So here, for your viewing pleasure, is a poster I updated and modified from a brilliant xkcd web comic (using this tool), describing some common HIV clinical research themes.
Suitable for framing, it should prove helpful as you embark on your next research project.
A brief commentary on the contents of these papers:
- Switching suppressed people with HIV (PWH) on antiretroviral therapy (ART) to almost anything maintains viral suppression. This is true for both biologic and behavioral reasons: there’s no viral replication at baseline, and only people with proven good medication adherence are eligible to participate. That means if it doesn’t work — like the raltegravir plus maraviroc switch — it’s pretty bad.
- Older people with HIV have more comorbid medical problems — yes, aging sucks for everyone. Everyone! No exceptions to the rule, alas.
- Here are a bunch of abnormal cytokines that nobody measures in clinical practice. They’re abnormal, yes. Clinical significance? Ummm … let me get back to you on that one. Or let me ask someone who loves cytokines, like the innovative and wonderful Dr. Irini Sereti.
- Low-level viremia drives us crazy, so we studied it — but you still won’t know what to do. I’m lucky to work with a guru of low-level viremia (among other things), Dr. Jonathan Li, a translational virologist and senior author on this fascinating study. He knows more about this annoying lab result — its causes and implications — than anyone on the planet. Good to have his number on speed dial, if “speed dial” is still a thing in a post-landline age.
- Another unsuccessful broadly neutralizing antibody (bnAb) study, but this won’t keep us from trying again with something else. Let’s try an even broader one! One that’s more potent! Let’s “extendify” it, using techniques of “extendification”, so it can be given less often! Then it might work. But if not, we’ll try again!
- Some phylogenetic trees and/or single-nucleotide polymorphisms (SNPs) that you won’t understand. Or at least, I won’t understand. Throw in a genomewide association study (GWAS) with a Manhattan plot, and let the confusion start.
- Poor adherence to preexposure prophylaxis (PrEP) is associated with getting HIV (I know, shocker). These are important studies from a behavioral health perspective, such as this recent one. But let me put this a different way — what if you had a strategy that clearly worked, but it wasn’t used? Would it still work?
- D’oh! Some people with HIV were diagnosed late because the clinicians caring for them for years never sent an HIV test. A remarkably common clinical error, even in 2023, sadly. Quoting this noted researcher in the title’s first syllable.
- This HIV cure intervention using drugs you’ve never heard of looks really promising — in a mouse. Or if not panobinostat, vedolizumab, or ipilimumab, how about some CRISPR?
- The incidence curves in this randomized trial of an HIV vaccine versus placebo overlap with depressing precision. Here’s the latest, alas. Oh well, it’s important to keep trying.
- No, we still haven’t found a good use for maraviroc. But still trying! Trivia buffs will know the clever brand name of this rarely used antiretroviral agent — Selzentry. Get it?
- Here’s a resistance mutation that only older HIV doctors have memorized. Guilty as charged. I’m still miffed that E138K is a resistance mutation for both nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and integrase inhibitors. What’s up with that?
Ok, that’s a wrap. Am sure I left off some major themes, what else would you include?
Hey, dog lovers — is this you? (It’s definitely me.)
Greeting humans vs their dogs pic.twitter.com/NeGbEtd1n8
— Emma Pope (@emmerpope) September 21, 2022
May 8th, 2023
As the Public Health Emergency Comes to an End, How Are We Feeling About This?
As you no doubt heard, on Friday, May 5, 2023, the WHO declared the end of the global health emergency from COVID-19.
Here in the U.S., the federal public health emergency will expire on May 11. That’s Thursday, just a few days from now.
These events reflect two realities that, while seemingly contradictory, make these decisions reasonable — my constitutionally worried ID-doc mentality notwithstanding.
On the one hand, COVID is far from gone. Our patients, family, and friends are still getting this pesky bug, many of them now repeat episodes. And it always bears mentioning that, for certain people with weakened immune systems or multiple other medical problems, COVID is the cause, or the trigger, of severe illness. Some will get long COVID, though fortunately the incidence of this complication has declined over time.
Some worry about the increase in cases that will likely occur in the South as summer heats up and people move indoors. Or they are concerned about the most recent genetic offspring of Omicron, the scarily named Hyperion (XBB.1.9.1) or Arcturus (XBB.1.16).
All valid points. But let’s look at the other side of the current reality. Deaths due to COVID globally and in the U.S. have been below April 2020 levels and stable for over a year. The same holds true for hospitalizations for severe COVID-related illness.
The cause? Widespread immunity, giving protection from severe illness:
By the end of 2022, an estimated 99% of the US population had some form of immunologic exposure to SARS-CoV-2 (infection or vaccination or both). https://t.co/7iioxJUG8h
— Paul Sax (@PaulSaxMD) May 2, 2023
If you don’t like that study, here’s the CDC’s version, which they presented last week:
So COVID isn’t gone. But it sure is different now.
Importantly, not gone also are innumerable other infectious threats, including RSV and influenza and tuberculosis and Lyme disease and malaria and Staph aureus and you-name-it. No global or federal emergency for them — though I suspect first-year ID fellows all think we should have one for staph.
The passing of the COVID emergency inevitably brings to us ID docs certain feelings and recollections, even if it’s just the creepy feeling that if we let our guard down this SARS-CoV-2 thing is going to pounce again.
Even writing that makes me nervous. To be concise, it’s a combination of relief and trepidation.
So … how are you feeling about this?
Interested in hearing from both the ID and non-ID community!
April 28th, 2023
What is the Future of HIV Primary Care?
Here’s a figure I’ve made for an upcoming talk, which is entitled “The Future of HIV Care.” It summarizes several eras in HIV treatment, finishing up with the current unprecedented successful phase where most people with HIV take 1–2 pills a day, have virologic suppression and no clinically apparent immunodeficiency. HIV is often the least of their medical problems.
To put this into context, a patient at our hospital recently found out that the cause of their several months of fatigue and weight loss was HIV, and expressed relief that it wasn’t diabetes or cancer. And on hearing this comment, all the people on our HIV treatment team agreed that the management would indeed be easier, and more likely successful.
I don’t mean to diminish the potential severity of HIV, which of course can, undiagnosed and untreated, still be lethal. Far too many people in this country with HIV are either undiagnosed, or diagnosed and not engaged in regular care or treatment. Getting them on therapy remains an urgent individual and public health priority.
But for those in care, as an example of medical progress, HIV treatment stands out as a phenomenal success.
This success begs the question, once again, of the role ID specialists should play in the management of people who have HIV once they are on stable ART. When I last covered this topic here on this site nearly a decade ago, we were in the tail end of Era #4 above — and since then treatment has only gotten better.
For emphasis, I still believe ID doctors and HIV specialists should play a primary role in handling new HIV diagnoses, managing opportunistic infections and other complications, interpreting resistance testing, and helping guide treatment switches, especially as new options arise. The nuances of figuring out the best candidates for long-acting cabotegravir-rilpivirine certainly have put a recent premium on our expertise.
But the stable septuagenarian on one-pill ART whose major problems are hypertension, osteoarthritis, and, yes, type 2 diabetes? Who among us can claim that we’ve kept up sufficiently with these non-ID issues to be their ideal primary provider? If you, as an ID specialist, were given the option of attending an educational session from a brilliant speaker on “Advances in the Management of Invasive Fungal Infections” or “Advances in the Management of Type 2 Diabetes,” which would you choose?
We should not give up HIV care, but potentially shift it to be handled more like other medical specialties. Oncologists and rheumatologists, to cite two examples, play the dominant role in their respective diseases when treatments are active and monitoring is intense. But neither specialty takes on full primary care once the patients are rock-solid stable.
Pushing against any such distribution of HIV care to generalists is that most (importantly, not all) of the primary care workforce hasn’t been doing very much in HIV management. It’s notably concentrated in a very small fraction of U.S. clinicians. As an example, a patient of mine recently was told by their PCP that they wouldn’t order their routine monitoring tests — CBC, comprehensive metabolic panel, and HIV RNA — because “only ID can do that.” This is of course an extreme example (and certainly not true), but the anecdote shows how far from HIV general practice is for most people doing primary care.
Another important perspective comes from our patients, some of whom we’ve followed for decades. They may not be comfortable switching primary care, especially with a disease that still sadly confers some societal stigma.
So let’s re-do the poll and see what you think. As usual, I very much welcome in the comments section your opinions about this issue — and will select a few choice views for the talk!
Thank you.
April 21st, 2023
A Change-of-Season ID/HIV Link-o-Rama
The warm weather takes its sweet time to arrive here in Boston, teasing us with an occasional comfortable day, but reverting frequently to chilly temperatures and high winds until mid-to-late May at the earliest. The afternoon sunlight might say, “Spring is here!”, but the nightly temps in the upper 30s/low 40s definitely say otherwise. Brrr.
Anyway, here are a bunch of assorted ID/HIV links of note, as the weather in Boston can’t decide between winter and summer — and eventually will skip spring entirely, as usual:
- Postexposure prophylaxis with one 200-mg dose of doxycycline reduced the risk of bacterial sexually transmitted infections (STIs). Based on this and two other studies from France, there is little doubt this strategy works. The key will be implementing it in the right population, which for now appears to be men who have sex with men (MSM) or trans women with a history of recurrent or multiple STIs. And of course, long-term risks (resistance, other adverse effects) remain unknown.
- An experimental RSV vaccine given during pregnancy reduced the risk of “medically attended” severe RSV-associated lower respiratory tract illness in infants. This was one of the co-primary endpoints; the vaccine was not significantly better than placebo for any medically attended RSV-associated lower respiratory tract illness within 90 days after birth. An accompanying editorial appropriately describes the “complex policy decisions” about whether to offer this vaccine to pregnant women, as another RSV vaccine did show a signal of increasing the risk of premature birth — one not observed here.
- A large study of statin versus placebo in people with HIV was stopped early due to efficacy. Participants were at low-to-moderate risk of myocardial infarction (MI), and had stable HIV disease; pitavastatin reduced the risk of major cardiovascular events by 35%. One particular area of interest will be how strong the signal of benefit is across baseline characteristics — I suspect that relative risk reduction will be preserved, but for some, the absolute risk will be quite low, limiting uptake. But add this study to the “put statins in the water” team.
- Prophylactic piperacillin-tazobactam prior to pancreatoduodenectomy (better known as a Whipple procedure) reduced postoperative complications significantly more than cefoxitin. The study stopped early due to the large beneficial effect of pip-tazo (which is how I avoid saying the expired brand name). This is the kind of clinical trial for common clinical strategies in ID we should see more often! I strongly suspect this one will change clinical practice guidelines.
- HIV incidence was higher among men choosing event-driven rather than daily PrEP. An important paper given both the relatively understudied population (MSM in West Africa), and the results — adherence to the event-driven strategy was significantly lower, clearly influencing the outcome.
- In a randomized clinical trial, participants receiving fluvoxamine plus inhaled budesonide had fewer ER visits or hospitalizations or complications due to COVID-19 than those getting placebo. Note that the dose of fluvoxamine is 100 mg twice daily, 2 times higher than in the negative COVID-OUT study. These positive randomized clinical trials (see metformin) in people immunized and/or previously having had COVID-19 ironically offer more direct evidence of clinical benefit in this immune population than molnupiravir — and some would say nirmatrelvir/r as well.
- In Staph aureus bacteremia, combination therapy with cloxacillin plus fosfomycin was no better than cloxacillin alone. We’re still awaiting a combination therapy study that shows “more is better” for this challenging clinical entity. The study was presented at the European Society of Clinical Microbiology and Infectious Diseases, often abbreviated to “ECCMID” — which is rapidly emerging as one of the premiere clinical infectious diseases meetings in the world.
- A man died of rabies even though he received appropriate postexposure treatment. In this, the first report of such postexposure prophylaxis failure, the authors speculate that his immunocompromised status was the cause. And while each detailed report of rabies reads like something from a horror movie — and keeps us ID docs up at night — an excellent accompanying commentary reminds us that rabies is very, very rare in the United States. Fortunately.
- Treatment with nirmatrelvir/r was associated with a lower risk of developing long COVID. Observational studies such as this one, which cannot adjust for unmeasured confounders, do not prove that treatment reduces the risk of long COVID, but they strongly suggest it — especially with the favorable results of the ensitrelvir placebo-controlled, randomized clinical trial, which I have summarized previously.
- A high dose of a nonpathogenic, nontoxigenic, commensal strain of Clostridia species significantly reduced the risk of recurrent Clostridioides difficile infection compared to placebo. The treatment, called VE303, came originally from healthy human stool samples, then was amplified using clonal cell banks. Though this is a small study requiring confirmation, these data plus those from the SER-109 trial strongly suggest that microbiome-based treatment will one day be part of C. difficile treatment and prevention strategies.
- Can fecal microbiota transplantation (FMT) be a viable treatment for patients who suffer from recurrent multidrug-resistant urinary tract infections (UTIs)? This is a tiny (n=5) but promising case series, showing reduced frequency of UTIs and decreased hospitalizations after FMT. Every ID doctor knows just how common multidrug-resistant UTIs are today, with much attendant misery.
- The “adjuvanted” HBV vaccine (Heplisav) induced protective antibody responses in 100% of vaccine-naive people with HIV (PWH). Importantly, the usual response to this vaccine among adult PWH is suboptimal (20-70%), so these are remarkably good results. A study with this vaccine in PWH who don’t respond to hepatitis B vaccine is ongoing.
- Candida auris is spreading — fast. A particularly worrisome observation from this CDC surveillance study is that echinocandin resistance was 3 times higher in 2021 than in the previous two years. Yikes.
- An outbreak of blastomycosis in a Michigan paper plant has sickened nearly 100 people. One person has died. This is the first non-lab occupational outbreak of this endemic fungal infection I can recall, and it is still undergoing investigation.
- A physician-patient described the experience of being sent home on IV oxacillin. The clinicians treating her chose this strategy despite her protests (she preferred an oral option) and, not surprisingly, the experience was not a good one. This account should be required reading for all who do hospital-only patient care to understand just how dismal the “OPAT” — outpatient parenteral antimicrobial therapy — experience can be.
- Should masks still be required in all healthcare settings at all times? It’s a nuanced pro and con look at universal masking in hospitals and clinics, ultimately concluding that the time for this strategy has passed. The authors are infection preventionists, many of whom I know well (disclosure). Certainly, there are strong opinions on this matter on both sides of the debate — here’s an alternative view.
- Universal testing of admitted patients for COVID-19 may have unintended negative consequences. In this prospective study of 2,794 admissions, 129 (4.6%) tested positive by PCR, and 54 (41.9%) were asymptomatic. From this group, 39 had a cycle threshold of >35 and were deemed noninfectious. Nonetheless, 23 had adverse consequences, such as delayed medical care, canceled surgeries, or inappropriate treatment. The flip side, of course, is that universal testing also may prevent in-hospital transmissions. We’re clearly in a transition phase in healthcare for both universal masking and testing!
- Differential time to positive blood cultures acts as a helpful diagnostic tool in diagnosing central line-associated bloodstream infections (CLABSIs). In this systematic review of over 20 studies, if the blood culture from the central line turned positive 2 hours faster than the peripheral blood culture, CLABSI was highly likely. An important caveat is that this didn’t do very well for Staph aureus or Candida spp., but we generally recommend line removal for these pathogens anyway.
- Antibiotic exposure is associated with an increased risk of inflammatory bowel disease. As noted by my colleague Dr. Sanjat Kanjilal, who alerted me to this paper, this large, population-based study shows that antibiotics have way more “off target” effects than just resistance, C. diff., and side effects.
Hey baseball fans — how are you liking the pitch clock? I’m loving it!
Landon Knack throwing an entire half inning vs. Pedro Báez throwing 1 pitch. pic.twitter.com/wHa2p6K7k8
— Rob Friedman (@PitchingNinja) February 27, 2023
April 8th, 2023
Travel Clinics and a Travel History to Beat All Travel Histories
Dear All,
I’ve received some very helpful and quite critical comments about the original post that was here. Having re-read the original, I’m acknowledging my mistake and want to apologize to my colleagues, many of whom do travel medicine with true expertise, excellent intentions, and for the benefit of travelers everywhere. My bad for not emphasizing this fact in the first part of the post.
Awaiting input from my editors, I temporarily removed it yesterday, but now have replaced it below. There are some edits to parts that I especially regret, but the essence is there.
Thanks everyone for reading, and helping me keep this a useful, supportive, and I hope educational place.
Paul
Confession: I have mixed feelings about travel clinics.
On the one hand, they provide a useful service to people who might be unaware of the dangers of the exotic places they plan to visit. It’s a place for sensible counseling:
Don’t eat street food! Don’t play with the stray dogs! Don’t swim in the Omo River!
Travel clinics offer a cornucopia of vaccines — yellow fever, typhoid, hepatitis A, rabies. A good travel doctor or nurse — optimally an experienced and enthusiastic traveler themselves — really knows the risk of Japanese encephalitis on your 3-week trip to Myanmar. They also have wise advice about malaria prophylaxis and other treatments to take along, just in case.
Plus, falling outside of many insurance plans and serving a generally well-to-do crowd, travel clinic is one of the few places ID doctors generate revenue in the outpatient setting. These money-makers are so few and far between for us that it’s hard to pass them up.
We have an active travel clinic, and the patients are really happy to have this convenient, one-stop service. They love it! And our travel clinic providers are great. Demand is sky-high, showing a reassuring return to pre-pandemic travel.
All good so far.
On the other hand, travel clinics sometimes cater to the worried well, offering dubious value if the destination is simply a long trip, the planned activities not so risky. Does the business traveler to Bangkok or Johannesburg, the honeymooner to Fiji, or the tennis enthusiast going to a resort outside of Buenos Aires really need to go to a travel clinic before their trips? Of course not, yet I’ve seen all of these examples come through our doors.
Additionally, the education component can paradoxically make the worried traveler feel worse. A recently retired ID doctor here in New England regularly did travel clinic at his hospital, but so hated to travel himself that he sometimes bluntly told his patients — “Look, if it were me, I wouldn’t go.” No doubt he was responsible for a high volume of canceled first-class airfares.
Last, some of the people who really need travel clinics can’t access them because, as mentioned, insurance often doesn’t cover it. This creates a two-class level of care analogous to traveling business vs. coach, but since it involves healthcare, is far more disquieting.
Travel clinics are on my mind because I recently had the distinct pleasure of reconnecting with a college friend, Mike Reiss. Professionally a comedy writer (he’s one of the original writers for The Simpsons, among other credits), Mike loves to travel.
Or more accurately, Mike’s wife Denise loves to travel, and Mike is totally smitten with Denise and will do whatever she wants.
Let me emphasize that “loves to travel” barely begins to describe their enthusiasm. They’ve now logged well over 100 countries, travel regularly to places you have not been (trust me on this one), and have had some remarkable experiences — many of which Mike details in his podcast, What Am I Doing Here?, which I highly recommend.
Mike chatted with me recently, and our conversation is incredibly funny — that’s because everything Mike talks about is incredibly funny! Listen here at the bottom of this post, or wherever you get your podcasts. You won’t want to miss it. His travel history reads like a parody of an ID certification exam question.
And Mike, here’s some friendly advice — if you don’t want to go to a travel clinic, here are the big four I’d recommend for a traveler like you, easy stuff you can get from your primary care doctor:
- Get the hepatitis A vaccine. Two shots, you’re good for a lifetime.
- Typhoid vaccine if indicated — either the shot or the pills.
- Take some azithromycin with you in case of severe traveler’s diarrhea.
- If you’re going to a malaria hotspot, take malaria prophylaxis.
Even better, check out the CDC’s travel web site. I use it all the time.
March 27th, 2023
Three Effective Treatments for COVID-19 Not in Treatment Guidelines — at Least Not Yet
A few weeks ago, in a patented (and copyrighted and trademarked) Really Rapid Review™, I summarized some of the Greatest Hits from CROI 2023. The conference included new data on not just HIV, but also a grab bag of opportunistic infections, STIs, viral hepatitis — and, as has been the case since 2020, COVID-19.
You know, right in the wheelhouse of readers like you.
At least most of you. Wrote one longtime fan after that post:
Paul,
That was undoubtedly the most boring blog post you’ve ever done.
Mom
Um, certainly no one ever accused my mother of hiding her true feelings!
Risking again putting this very same reader to sleep, I bring you now more data presented at CROI — three studies highlighting promising outpatient COVID-19 treatments. The full presentations are now available on the CROI website, and I’ve linked them below:
1. Ensitrelvir. A SAR-CoV-2 protease inhibitor like nirmatrelvir, ensitrelvir at two doses was compared to placebo in a randomized trial done in people at low risk for severe outcomes — meaning younger (12–69 years old), mostly vaccinated, and lacking risk factors for severe disease.
Ensitrelvir shortened the duration of symptoms by about a day (the primary endpoint) and hastened the time to the first negative SARS-CoV-2 viral test. Perhaps most importantly for this group at low risk for hospitalization but still vulnerable to long COVID, a questionnaire targeting symptoms of long COVID conducted at 3 and 6 months showed a significant reduction in the treatment group compared to placebo. The protective effect was greater in those with more severe disease at start, the people at greatest risk of getting this complication to begin with.
Based on these results, I think these are the strongest data we have that antiviral therapy reduces the likelihood of developing long COVID. Yay to that. Note that ensitrelvir already has approval for treatment of COVID-19 in Japan.
2. Metformin. In the quest for “repurposed” drugs for COVID-19, the hits (dexamethasone, tocilizumab, baricitinib) lose badly to the misses (lopinavir/ritonavir, hydroxychloroquine, ivermectin, azithromycin, colchicine, fluvoxamine, numerous others), especially for outpatient treatment. Could metformin be the exception?
At CROI, the investigators of the COVID-OUT study presented data on their randomized clinical trial of metformin versus placebo. Treatment was significantly better in a composite outcome of emergency department visits, hospitalizations, or death; the drug also demonstrated a significant antiviral effect. Furthermore, long-term follow-up found that treated patients were less likely to receive a diagnosis of long COVID by their providers.
Add to these benefits the widespread familiarity that clinicians have with this drug, its well-established safety profile, and its extraordinarily low cost, and we might have a winner here, folks.
3. Pegylated interferon lambda. Need I say more?
I won’t pretend there aren’t issues with these three studies. Here are a few worth exploring:
- Ensitrelvir: The study evaluated two doses of the drug, 125 mg and 250 mg once daily; the lower dose appeared to be more effective, for unclear reasons. Plus, the long COVID endpoint analysis I highlighted was not protocol-specified, and hence must be considered exploratory.
- Metformin: The primary endpoint of the metformin COVID-OUT study, which included home oxygenation results as part of a composite clinical endpoint, was negative. Subsequently, the investigators learned that the home oxygenation results were unreliable, which undoubtedly introduced a lot of noise into analysis of this endpoint. Note that the positive secondary endpoint for metformin (emergency room visits, hospitalization, or death) did make it onto the Research Summary (see figure — edit mine), but it’s not the message most take from the published paper.
- Pegylated interferon lambda: The TOGETHER trial enrolled patients in Brazil (mostly) and Canada; this study previously yielded favorable results with fluvoxamine. Given the subsequent negative results with fluvoxamine, should we be skeptical of any data coming from this study?
Still, there’s a lot to like here with all three treatments, especially given our limited current options now that monoclonal antibodies are gone. And importantly, the three outpatient therapies — Paxlovid, molnupiravir, intravenous remdesivir — have their own issues, some of which I’ve summarized previously.
Some might think we’re done with COVID-19, so why invest in studying further treatments? To those people, let’s face facts — this respiratory virus isn’t going anywhere, still accounts for hundreds of deaths a week in medically vulnerable populations, and causes enormous disruption in workplaces and schools. An annual bump in cases each respiratory virus season is all but a certainty given what we’ve seen the past three winters.
If you’re interested in hearing more details about these novel treatments, how they might compare to what we currently have, and how they could be investigated further, listen to the discussion I had with University of Minnesota’s Dr. David Boulware on an IDSA podcast, just released. He truly deserves the label “clinical trialist extraordinaire,” which is how I introduce him.
It’s available on the IDSA site along with a transcript, or wherever you get your podcasts, or right at the bottom of this post.
Hey Mom — am sure you’ll love it!
March 16th, 2023
Oral Antibiotic Therapy for Endocarditis — Are We There Yet?
Two terms in clinical research appear frequently in abstracts, conference presentations, and published papers — “clinical practice” and more recently, “real-world.”
Many research snobs turn up their noses at both, finding them imprecise or pretentious. I confess to flinching each time I read “real-world” — isn’t everything “real-world”? If not, what’s the opposite? Mouse studies? (They’re certainly the real world from the mouse’s perspective, though not in a way that they would like.) Work done “in silico”? Trial participants recruited from the film Avatar?
But having collaborated in several real world studies over the years, I realize there is a reason to signal that data come from actual clinical practice — that is, derived from people in care, outside the specified and restricted domains of a prospective research protocol.
One such paper just appeared in Clinical Infectious Diseases, entitled “Real-world Application of Oral Therapy for Infective Endocarditis: A Multicenter Retrospective, Cohort Study”.
Here I’d argue that this “real-world” description is highly appropriate — because, as the authors note, despite evidence from randomized clinical trials on the efficacy and safety of oral therapy to complete treatment for endocarditis, uptake of this practice remains highly limited. We need people to report what they’ve seen after implementing this novel strategy.
The authors cite experience within their healthcare system in 46 patients treated with oral therapy, compared with 211 who received IV. Importantly, these cases occurred after their system implemented an “Expected Practice” document sanctioning oral therapy in stable patients with no contraindications.
Here are the results:
Looks great! As no fan of outpatient parenteral antimicrobial therapy (OPAT), I was delighted to see that adverse events occurred significantly less often in the oral treatment group.
Skeptics will argue that the biggest limitation of these data is that, like all nonrandomized studies, baseline differences between the two groups could have influenced the outcomes independent of the type of treatments they received. Specifically, the IV-only group was older with more comorbidities, while the oral antibiotic group had a higher proportion with a history of injection drug use. A multivariable regression analysis factoring in these differences did not demonstrate a significant impact on outcomes, but unmeasured differences cannot be accounted for.
Limitations notwithstanding, the study provides helpful reassurance about the practice of using oral therapy to complete treatment for endocarditis — a practice that would have been unimaginable a decade ago.
Curious to hear from readers, especially ID docs, pharmacists, and other clinicians doing hospital-based medicine — are you using oral therapy for endocarditis?
If so, in what settings?
February 28th, 2023
Really Rapid Review — CROI 2023, Seattle
In a recent chat I had on a local TV network on this year’s respiratory virus season, the host mentioned that “this year felt very post-pandemic”, prompting me reflexively to knock wood — and I’m not a superstitious person.
But even we ID doctors must acknowledge the dramatic improvement in COVID severity this winter compared to the last two, both of which were severe enough to make the Conference on Retroviruses and Opportunistic Infections, or CROI, stick to the virtual-only format. And, of course, historically, CROI was the very first scientific conference to go this route, way back in March 2020, a period about which the less said the better.
(Involuntary shudder.)
But on to this year’s CROI, which was available in-person or virtual, taking place once again in Seattle, a place it’s been several times before. It’s our premiere scientific conference, covering not just HIV, but also sexually transmitted infections (STIs), hepatitis, and now SARS-CoV-2, with many excellent studies on all these scourges.
This week, in this Really Rapid Review™, I’ll cover the non-COVID studies, with take-home messages and sometimes a brief comment. You’ll see the abstract numbers in brackets and links to either the abstract (if available) or to the invaluable NATAP site, which somehow continues to aggregate many of the actual slide presentations and posters in real-time. Bravo for that, and long may it live!
- The prognosis for people with HIV has markedly improved since 2012 [870]. This multi-national, large (n=33,598) cohort study demonstrated a significant drop in risk of death during this period, regardless of cause. The leading cause of death was non-AIDS-related cancers, an observation likely to resonate with all HIV providers. Among HIV factors, CD4 <350 and RNA >200 were the strongest predictors of death.
- After treatment failure with NNRTI + 2NRTIs, DTG plus DRV/r was both noninferior and superior to standard of care [198]. This is the first time a boosted PI plus an INSTI has bested a regimen of recycled NRTIs plus a boosted PI. Given the widespread use of DTG + 2NRTIs as fixed-dose “TLD”, which also performed well in this study, I suspect the DRV/r + DTG strategy will not be used much. FYI, the study is called “D2EFT” for “Dolutegravir and Darunavir Effectiveness in adults Failing first-line Therapy” — you knew that, right?
- Switching stable PWH on BIC/FTC/TAF to long-acting injectable CAB-RPV every 2 months resulted in noninferior virologic suppression at 12 months [191]. 670 PWH were randomized 1:2 to continue versus switch to 2-monthly CAB-RPV. While the results met the criteria for noninferiority, there were 5 people on CAB-RPV (3 with resistance) with viral loads >50 in the injectable group, versus 1 in the BIC/FTC/TAF group (no resistance). Counseling people considering CAB/RPV that this therapy comes with a small (but non-zero) risk of failure with resistance is important. Treatment satisfaction improved with the switch. This is the SOLAR study, for “Switch Onto Long-Acting Regimen” — now that’s a good name!
- Switching from BIC/FTC/TAF to CAB/RPV does not lead to weight loss [146]. Data are from the above clinical trial. Meaning — do not use “maybe they will lose weight” as the motivation for the switch to long-acting injectables. Some people gain weight, some people stay stable, some people lose.
- What influences switches to either BIC/FTC/TAF or DTG/3TC [532]? The former is chosen more for those with low CD4 or risk factors for poor adherence; the latter for renal impairment or obesity. So even though these have similar indications, they are not used identically in clinical practice. (Co-author disclosure.)
- Having a detectable viral load in the year preceding a switch to CAB-RPV is a risk factor for detectable viremia following the switch [516]. This study, from the UCSD clinical program that has adopted CAB-RPV more enthusiastically than any other clinic site I’m aware of, found that 25% of switchers end up having detectable viral loads post switch — I’m sure engendering much anxiety! Importantly, one of the investigators told me that failure with resistance in their clinical cohort occurs at a rate comparable to the clinical trials (approximately 1-2%).
- PWH with uncontrolled viremia achieved high rates of virologic suppression on CAB-RPV [518]. More from the UCSF Ward 86 cohort, using CAB/RPV in a non-FDA-approved strategy. Out of 133 PWH who were very much not the usual candidates for this treatment, 57 had viremia. Suppression was achieved in 55 — astoundingly good — with only 2 developing treatment failure. A corresponding modeling study [517] showed this strategy would greatly prolong survival, even with conservative estimates about efficacy (co-author disclosure). We need this success with IM CAB/RPV in people with viremia replicated elsewhere! If it is, I suspect it could enter treatment guidelines, of course with all kinds of caveats and cautionary language.
- Lenacapavir plus two long-acting broadly neutralizing antibodies (bNAbs) given every 6 months maintained virologic suppression for 26 weeks [193]. Out of 20 participants, 1 rebounded — unclear why. A study entry requirement was pre-treatment resistance testing showing susceptibility to the bNAbs — a big hurdle if this form of treatment is ever going to be practically deployed. Another hurdle — saying the names of the bNAbs. From an always amusing friend:
- Islatravir (ISL) causes a dose-related drop in lymphocytes that resolves over several months [192]. Welcome back, islatravir! The suspected mechanism of this drop is intracellular accumulation of ISL-triphosphate, leading to apoptosis — not mitochondrial toxicity. The dose moving forward will be 0.25 mg daily, which should be active against wild-type and M184V-containing viruses; the weekly dose (when combined with lenacapavir) will be 2 mg. These data preceded presentations on two phase 3 switch studies of doravirine/islatravir (DOR/ISL) in stably suppressed PWH.
- Stable PWH on any regimen maintained virologic suppression comparable to their baseline treatment when switching to daily DOR/ISL [196]. There were no treatment failures on DOR/ISL versus 3 in the continued baseline regimen in this open-label study.
- Stable PWH on BIC/FTC/TAF maintained virologic suppression when switching to daily DOR/ISL [197]. This was a blinded study and encouragingly showed no difference in treatment-related side effects except for a drop in lymphocytes. (0.75 mg daily of ISL used.) There was a question from the audience about weight changes, which were not presented, but are in the public domain — no significant changes at 48 weeks after the switch. For the record, I have it on good authority that we’re not supposed to call this regimen “door-isil”.
- The weight trajectory of over 20,000 PWH in Kenya switching to dolutegravir differed by baseline regimen [617]. People switching off efavirenz had a sharp increase in weight, one not observed with baseline nevirapine — a reminder that weight effects within drug classes are not uniform, as only efavirenz (among the NNRTIs) appears to have this weight-suppressive effect.
- Weight decreases when TAF/FTC + DTG is switched to “TLD” and increases when the switch is from TDF/FTC/EFV [671]. These changes are exactly as one would predict, as the “T” stands for TDF — which has been shown in multiple studies to suppress weight, in particular when combined with EFV. The mechanism remains unclear. Linked the published clinical study from CID.
- An in vitro model showed that dolutegravir, but not doravirine or efavirenz, disrupted estrogen-mediated fat differentiation [147]. Is this the explanation for the greater weight gain on INSTIs for women than men? By the way, the full title of the presentation was A LOSS OF ERα ATTENUATES DTG-MEDIATED DISRUPTION OF THERMOGENESIS IN BROWN ADIPOCYTES, in case you were wondering. (Abstract not available.)
- Could alteration in GI microflora explain the weight differences between regimens [248]? Gut microbiota among 27 PWH switching treatment from TDF/FTC/EFV to BIC/FTC/TAF showed increased diversity (generally a sign of health), but also increased sC163 (an inflammatory marker associated with obesity) — cause versus effect? There were no controls in this study.
- When controlling for baseline risk factors, integrase-inhibitor-based regimens were not associated with elevated cardiovascular risk [149]. This is reassuring data from the Swiss HIV Cohort study, contrasting with published data from a different cohort. I confess I held my breath when reading the title of the presentation, as this class of drugs is now critical to HIV treatment worldwide.
- Multivariable analysis of a clinical trial comparing BIC/FTC/TAF and DTG+F/TDF showed that TAF looks better for HBV [116]. Predictors of HBV suppression were HBeAg-, HBV DNA <8 log, ALT >ULN and treatment w BIC/FTC/TAF. Longer follow-up of this study, presented originally at the AIDS 2022 meeting, will be important as the TDF-based regimen may eventually catch up.
- Doxycycline given as post-exposure prophylaxis after sex reduced the incidence of syphilis, chlamydia, and gonorrhea in MSM [119]. In a second randomization, the meningococcal B vaccine reduced the incidence of gonorrhea. Called the DOXYVAC study, this was one of several key presentations on the doxycycline preventive strategy during the conference.
- An analysis of bacterial resistance from the Doxy-PEP study found no increase in resistance to GC, Staph aureus, or commensal Neisseria species with PEP [120]. Reassuring data! One caveat is that resistance could happen eventually if this strategy were widely adopted. As a reminder, Doxy-PEP also found that bacterial STIs declined in MSM and trans women who took PEP, as did the original ANRS study (albeit not for GC). That makes 3 favorable studies for doxy-PEP and STI prevention in MSM.
- In women at high risk in Kenya, doxycycline PEP did not reduce bacterial STIs [121]. It’s uncertain why this intervention was not effective in cisgender women — adherence was good, and a separate PK study [118] implied that it should have worked.
- A modeling study applying favorable data on doxycycline PEP to MSM and trans women found that adopting this strategy for those with prior STIs would avert a substantial number of future infections [122]. Not surprisingly, a robust discussion ensued at this session about whether guidelines should recommend doxycycline PEP for certain populations. Though I’m not on guidelines committees for STIs, I’d vote yes — with ongoing surveillance studies for assessment of resistance. Although we use doxy-PEP for tick bites for Lyme areas, this intervention for STIs is likely to be much more frequent.
- Mpox in PWH who have advanced HIV-related immunosuppression can be a severe, disfiguring, and life-threatening opportunistic infection [173]. Mortality was 27% (!) in those with CD4 <100, and the clinical course suggests an IRIS-like phenomenon when ART is started. There is a graphic (and unsettling) display of the Mpox lesions in the published paper. These cases underscore how critical it is for PWH to get on HIV therapy before the disease progresses and also to get at-risk people vaccinated.
- A study of over 6000 women receiving TDF/FTC for PrEP found that the adherence correlates with protection were similar to what’s observed in men [516]. Effectiveness increased steeply with 4 or more pills/week. Previous studies suggested that women required higher levels of adherence than men.
- HIV acquired while receiving PrEP with cabotegravir may be clinically silent and difficult to diagnose [149]. The investigators described delayed detection, negative antigen/antibody tests, and a paucity of symptoms. They even gave this syndrome a name — LEVI, for “Long-acting Early Viral Inhibition” syndrome. Not bad. The key is to use HIV RNA for diagnosis, but these are still going to be very challenging. Here’s a real-life case, occurring in clinical practice.
Had an amazing time at #CROI2023! We were able to share our real world case of breakthrough HIV-1 infection in the setting of on-time, appropriately monitored CAB-LA for PrEP @howardbrownhc.
We greatly appreciated the insightful discussions which I’ll try to summarize below. pic.twitter.com/iLI7WtJSMj
— Anu Hazra (@AnuHazraMD) February 22, 2023
- A complex TB treatment strategy of 8 weeks (!) of bedaquiline + linezolid added to INH, PZA, and ethambutol was noninferior to the standard 6 months of therapy [113]. The study, called TRUNCATE-TB, was just published in the New England Journal of Medicine. But before getting too excited, there are caveats about implementing this challenging approach — lots of them! There is a good summary of these concerns in the accompanying editorial and in this thread.
Of course, there were numerous additional interesting studies not mentioned here, apologies if I left out your favorites — feel free to cite them in the comments.
And it was really fun to visit Seattle again, a place with a strong familial connection. Plus, the sparkling new wing of the convention center hosted the conference.
The weather? Cold and rainy — winter in Seattle, you know — and it even snowed a bit the last day. No one ever accused the CROI organizers of picking their winter locations in tropical paradise, that’s for sure.
February 14th, 2023
Interferon Lambda for COVID-19 — Looking Good, but Still Not Available
Way back in the spring of 2022, I was asked to give an update on outpatient treatment of COVID to a group of general internists. The talk featured this slide on the TOGETHER trial of peginterferon lambda:
These data came from a press release from the company developing the drug. It’s dated March 17, 2022.
I added the highlight over the last bullet to make fun of my very bad prediction. Oops. Clinicians who treat COVID, or have known people treated for COVID (which covers essentially 100% of the U.S. adult population at this point), realize we still don’t have interferon lambda as a treatment option, now nearly a year later.
I summarized the reasons for my initial optimism in an opinion piece for the Boston Globe written with Dr. David Boulware (clinical trialist extraordinaire), namely:
- Efficacy shown even in vaccinated people
- Worked across all variants
- Dropped viral loads faster
- Side effects comparable to placebo
- “One and done” treatment
- No drug interactions
- Might work against other viral infections too!
Yep, the TOGETHER trial interferon results — published this past week in the New England Journal of Medicine — look really solid.
It’s not a perfect clinical trial. There were some issues with the drug supply during the study, and the blinding, and some have criticized the primary endpoint. There were apparently enough concerns that the FDA did not agree to meet with the company to discuss an Emergency Use Authorization. But all studies have weaknesses. I don’t think these are sufficient to invalidate the results.
Plus, it’s worth remembering that our current COVID treatments are hardly flawless. None of our treatments has documented efficacy in vaccinated high-risk outpatients. Other issues:
- Molnupiravir may not be effective at all — and has legitimate safety concerns.
- Paxlovid has a boatload of drug interactions and that annoying rebound syndrome that we still don’t know how best to predict or manage. Grrrr. (That’s annoyance.)
- Three days of intravenous remdesivir is cumbersome to set up, requiring either a visit to an infusion center or dedicated home care services, and hence is out of reach for many.
- Omicron and its subsequent mutations made all the previously available monoclonals inactive. So if you spent many hours learning how to spell (or pronounce) bamlanivimab, casirivimab, imdevimab, etesevimab, sotrovimab, tixagevimab, cilgavimab, or bebtelovimab, consider that a sunk cost.
I’ll acknowledge that reduced disease severity lowers the urgency of introducing a new therapy for COVID. Nevertheless, hundreds of people a day are still dying, and this virus isn’t going away anytime soon. Here’s a not-so-bold prediction — we’ll see a surge of cases pretty much every late fall and winter for the foreseeable future.
And having interferon available for COVID would greatly facilitate studying its use in other viral respiratory tract infections. Its mechanism of action, augmenting the host immune response to viral infections, could show activity across a broad spectrum of such pathogens — influenza (including H5N1) and RSV most notably, but even other common viral pests (metapneumovirus, rhinovirus, the pre-SARS-CoV-2 coronaviruses). I contacted the TOGETHER study’s senior author, Dr. Jeffrey Glenn, who wrote:
I have been advocating for a trial I call the RELIEF (REspiratory viruses treated with Lambda IntErFeron) study, where patients who present with acute respiratory symptoms are immediately randomized to lambda or placebo, and we sort out later what virus they have. This could generate more data in COVID, but importantly advance the ball further by generating new data for other viruses of pandemic potential. We could leverage the same great infrastructure of the TOGETHER trial and hopefully generate game-changing data.
So, here’s hoping this promising and novel therapy gets another chance, perhaps in this confirmatory study.
Oh, and by the way, my Globe piece prompted this email from my daughter Mimi:
Go dad!! Great title.
Yep, it’s one of my better ones.
February 6th, 2023
New Ways with Language — Some to Adopt, Some to Question
Back in my second year of medical school, my classmate and good friend John and I had a memorable teacher in our Introduction to Clinical Medicine course, someone we still talk about today. A general internist with a specialty in addiction, he was a big bear of a guy sporting a ponytail, beard, open-necked shirts (sometimes of the Hawaiian variety) and beads.
You know those stereotypes of Boston academic physicians with bow ties and tweeds? The opposite of that.
One of his emphatic messages was to stop labeling people by their diseases. “He’s not an alcoholic,” he’d say, after we’d done an awkward medical student history and physical at a local inpatient detox center. “He’s a person with alcoholism. That’s the disease he has, not the person he is.”
It wasn’t just for people with addictions. He said the same was true for people with diabetes, or asthma, or anything. They’re people, not their diseases.
At the time — the mid 1980s — this was not at all a commonly held view in medicine. Our other teachers, and certainly the residents we looked up to, bandied about disease-first labels all the time. Alcoholic, IVDA (intravenous drug addict), chronic lunger, end-stage AIDS victim, schizophrenic, sickler, and on and on.
Even worse, these labels could come with a room or bed number. “Shooter in 4 needs two sets of blood cultures.” Cringe.
Fast-forward to today, and I’m delighted to say that our teacher was onto something important by not wanting to label people with their disease. The language we once used seems not only unnecessary, but stigmatizing.
In an effort to move away from such labels, Dr. Sara Bares has written a wonderful viewpoint in Clinical Infectious Diseases on this very topic. She kindly invited me and others to collaborate, but she did the bulk of the very fine writing. I highly recommend it.
In fact, my main contribution was to acknowledge that change can be hard — and harder for those of us accustomed to language done a certain way. For this particular effort, however, I’m convinced the challenge is worth it. Clinicians and researchers should do whatever we can to avoid using stigmatizing language for our patients with their diseases, whatever they might be.
I confess to having the opposite reaction to certain other requested changes in language, especially those that seem driven more by fashion or, even worse, virtue signaling. Such requested changes, while well meaning, come off as peculiar; at best, they’re even unintentionally funny (in the “ha ha” definition). For example, the first time the term “chestfeeding” crossed my path (over the more anatomically correct “breastfeeding”), I thought it was a joke.
What is accomplished by this awkward change, or even more important, what is lost? Isn’t that what mammals do as one of their core nurturing traits? Use their breasts to feed their young? And shouldn’t we be encouraging and facilitating breastfeeding (over formula or expressed milk feeding) whenever possible as optimal for infant health? Cripes, the origin of the word mammals is even named after this function.
At worst, extreme mandated changes in language come across as dogmatic and performative, serving only to criticize, alienate and anger people who won’t adopt them. They are fodder for political opponents, using examples to show how out of touch the other party might be.
In the same week that Sara published her paper on people-first language, Nicholas Kristof of the New York Times wrote about the effect of different and more extreme language changes. He cites, of course “chestfeeding,” and includes a whole panoply of other bewildering terms for consideration.
His concern?
While this new terminology is meant to be inclusive, it bewilders and alienates millions of Americans. It creates an in-group of educated elites fluent in terms like BIPOC and A.A.P.I. and a larger out-group of baffled and offended voters, expanding the gulf between well-educated liberals and the 62 percent of Americans 25 or older who lack a bachelor’s degree — which is why Republicans like Ron DeSantis have seized upon all things woke.
It’s no wonder that one of my colleagues — who could not be more humanistic and thoughtful in both her clinical practice and actions — told me that in an upcoming seminar she’s leading on fighting racism in the hospital, her biggest fear is “when, not if, I mess up the latest terminology.”
Language evolves. It’s time to welcome non-stigmatizing language in medicine and research, but that doesn’t mean all medical terminology needs to flip to the latest fashion. In other words, Dr. Beads-with-Ponytail was 100% right not calling people by their diseases — but I doubt he’d ever say “chestfeeding.”