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May 25th, 2023

The Legacy of a Disappointing HIV Clinical Trial — Does It Still Apply to HIV Today?

A long, long time ago, back in the early exciting days of raltegravir, the first HIV integrase inhibitor, we learned something important from a clinical trial with disappointing results. The trial bore the (barely) hidden name of the company that developed the drug — SWITCHMRK, get it? — and had a profound impact on how we managed virologically suppressed patients for years.

What did we learn? Namely, that it was risky to switch stable people from their “high resistance barrier” regimen of lopinavir/ritonavir plus NRTIs to raltegravir plus NRTIs if they harbored viruses with NRTI resistance. Some of the participants who had a history of treatment failure who switched ended up experiencing virologic rebound with integrase inhibitor resistance, which made the switch to raltegravir not noninferior (sorry for the double negative) to continuing lopinavir/ritonavir.

The interpretation was that despite the potency and excellent tolerability of raltegravir — massively better than lopinavir/ritonavir — it wasn’t enough to maintain viral suppression reliably unless the NRTIs were also fully active. Based on these results, for years we steered clear of use of this valuable drug class in any setting where we couldn’t use at least one other fully active drug.

(My friend and colleague Joe Eron was the lead author on this study. I will note once again that Joe easily makes the top-5 in smarts in the HIV research world, no exaggeration, and that this was a very reasonable study design at the time, negative results notwithstanding. Unrelated, I wonder if Joe will attend this June 4 minor league baseball game in Charlotte, called Joe-Nanza, which aims to assemble the largest number of Joes at any single sporting event in history. It’s just a 2-hour drive from Chapel Hill!)

So now that we’ve reviewed SWITCHMRK, and a special event featuring Joes, let’s fast-forward to today, and contemplate a case. I’m sharing it with permission from Dr. Jezer Lezama, an ID doctor from Mexico who was looking for help (case details slightly edited):

PWH multi-drug resistance, w/high level R to PIs, NRTIs, NNRTIs, only etravirine partially active in 2013 but w/o previous exposure to integrase inhibitors. Rescue Tx: DRV600/r BID + RAL + ETV with viral suppression since then. Simplify? To which regimen?

He provided the 2013 resistance genotype, and yes, this is a challenging virus:

There’s a lot there to digest, so allow me to provide a quick interpretation, sparing you the trip to the Stanford HIV Drug Resistance Database:

  • NRTIs: The virus has the “TAM-1” pathway (M41L, L210W, T215Y), plus another thymidine-associated mutation (D67N), so even tenofovir activity is reduced. M184V, the magical 3TC/FTC mutation, partially reverses this tenofovir resistance.
  • NNRTIs: For this drug class, we find the important Y188L mutation, which confers high-level phenotypic resistance to all NNRTIs except etravirine. Trivia buffs will recall that Y188L is present on HIV-2 isolates, which is why NNRTIs don’t work against HIV-2.
  • PIs: Not much to like here — there are 3 major darunavir-associated mutations (I54L, L76V, I84V), two minor darunavir mutations (L33F, V11I), plus a couple of other major PI mutations (M46I, L90M). I bet there’s some fosamprenavir treatment failure in the past. If this person had a phenotype done, I suspect the fold-change loss of susceptibility would suggest that the darunavir isn’t doing much in this regimen, twice-daily dosing notwithstanding.
  • INSTI:  Not done, but presumably no resistance.

Fortunately, the brief history does give us good news about how he’s doing clinically — virologic suppression since 2013 on the “TRIO” regimen of twice-daily darunavir, twice-daily raltegravir, and twice-daily etravirine. As I’ve mentioned before, I cannot begin to describe how transformational HIV drug development was in the late 2000s, when we suddenly had these three new tools (especially raltegravir) for our highly-adherent PWH with multidrug resistance.

Some experienced an undetectable viral load for the very first time in their lives. It was truly a cause for celebration. Yay!

Dr. Lezama’s specific question now is — can he simplify the treatment to bictegravir/emtricitabine/tenofovir AF? Why or why not?

What do you think? Next week we’ll review the results.

Can this patient simplify treatment?

View Results

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:

  1. 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.
  2. Older people with HIV have more comorbid medical problems — yes, aging sucks for everyone. Everyone! No exceptions to the rule, alas.
  3. 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.
  4. 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.
  5. 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!
  6. 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.
  7. 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?
  8. 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.
  9. 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?
  10. 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.
  11. 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?
  12. 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.)

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:

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.

Should ID doctors still do primary care for stable people with HIV?

View Results


April 21st, 2023

A Change-of-Season ID/HIV Link-o-Rama

Bug, from Martin Frobenius Ledermüller’s Microscopic Delights (1759–63)

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:

Hey baseball fans — how are you liking the pitch clock? I’m loving it!

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.


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 three I’d recommend for a traveler like you, easy stuff you can get from your primary care doctor:

  1. Get the hepatitis A vaccine. Two shots, you’re good for a lifetime.
  2. Take some azithromycin with you in case of traveler’s diarrhea.
  3. 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:

That was undoubtedly the most boring blog post you’ve ever done.

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

“Look up there! It’s Microsoft and Amazon stock!” National Archives, 1962.

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!

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:

  1. Efficacy shown even in vaccinated people
  2. Worked across all variants
  3. Dropped viral loads faster
  4. Side effects comparable to placebo
  5. “One and done” treatment
  6. No drug interactions
  7. 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.

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

Learn more about HIV and ID Observations.