HIV and ID Observations

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

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October 31st, 2021

Interesting and Important Studies from IAS 2021 and IDWeek That Caught My Eye

Vintage Halloween postcard, 1913.

As noted in my previous post, attending virtual meetings poses some serious challenges.

The biggest obstacle:  trying to do one’s regular job while periodically checking in (or more likely not checking in) on the meeting. And while I might have been able to pull off some Really Rapid Reviews© after a few virtual meetings, not so for the last two.

So instead, I’ve packaged 2 into 1, hoping this gives you sufficient value for your blog-reading dollar, lack of really rapidness notwithstanding.

Here, then, are some highlights from these two meetings, in a not-so-rapid (but I hope still interesting) review. The International AIDS Society (IAS) 2021 took place in July, IDWeek in early October.

As usual, but even more so now with virtual attendance, I’m bound to miss some important studies. Let me know in the comments what those might have been.

IAS 2021 is first up:

Single high-dose liposomal amphotericin-based treatment for HIV-associated cryptococcal meningitis is just as effective and less toxic than standard of care. This devilishly difficult-to-treat opportunistic infection continues to take a major toll globally, in particular in Sub-Saharan Africa, where this study (called Ambition-cm) took place. The comparator arm (daily amphotericin for a week with 5FC) is both less convenient and has more side effects. Two questions: 1) Can we make liposomal amphotericin and 5FC more widely available? 2) Does this study have implications for us here, where we use two weeks of induction amphotericin and 5FC?

PrEP failures with TDF/FTC may have drug resistance at HIV diagnosis: While the title of the abstract cites “High rates of drug resistance …”, the actual infection incidence was reassuringly rare. This study was done in Africa, giving us a far different view of PrEP than here — 75% women. Out of over 100,000 PrEP users, HIV was diagnosed in 208, and 27 had resistance mutations. Note the higher than expected incidence of K65R, probably because of subtype C virus, along with the transmitted NNRTI mutations.

No selection of INSTI resistance among women in HPTN 084 who acquired HIV while receiving cabotegravir. Good news, and the results contrast with the small rate of resistance seen in HPTN 084 among MSM. One very challenging HIV diagnosis occurred in a woman who had (in retrospect) very early acute HIV (detectable virus but below 40 copies/mL), was randomized to cabotegravir, then had viral suppression and no seroconversion until week 33 of the study. Once this gets into clinical practice, assessments for HIV breakthrough will be challenging! 35/36 of those in the TDF/FTC arm who failed PrEP had suboptimal adherence.

On-demand TDF/FTC PrEP just as effective as daily PrEP among MSM in China. Analogous to the PREVENIR study, here the participants could choose how they wished to take the PrEP — daily or with the 2-1-1 on-demand strategy. In other words, the study was not randomized. An interesting observation — they enrolled MSM who chose not to go on PrEP at all; perhaps not surprisingly, they had the highest HIV incidence.

DTG/3TC maintains viral suppression in patients with a variety of baseline regimens. Unlike the TANGO study, where all participants were on TAF-based ART, in this study (called SALSA) they could be on any standard ART regimen, provided no history of treatment failure or resistance. The results demonstrate again that DTG/3TC is clearly a safe strategy virologically for this population. Note that there was more weight gain in the switch arm, likely because around half the baseline regimens included TDF (see first summary from IDWeek, below, for an explanation). An ongoing study — called PASO-DOBLE, get it? — will investigate whether maintenance therapy with DTG/3TC offers objective benefits over BIC/FTC/TAF, such as improvements in metabolic, bone, and various aging outcomes. Here’s a slide summary I made of that study, including the requisite dancers!

Lenacapavir as a subcutaneous injection every 6 months in treatment-naive patients achieves high rate of viral suppression at week 16. There were several different strategies in this phase 2 study which ultimately include two-drug maintenance, but the most novel were those that included lenacapavir given subcutaneously every 6 months (after an oral lead-in) with TAF/FTC. Over 90% had virologic suppression at week 16 (a planned interim analysis); BIC/FTC/TAF had 100%. One case of treatment-emergent resistance to both lenacapavir and FTC occurred in a participant who started treatment with a baseline viral load just over 100,000 cop/mL, implying that the resistance barrier to this novel drug isn’t as high as second-generation INSTIs.

No apparent worsening of outcomes from COVID-19 among people with HIV. This registry-based study included 21,528 hospitalizations, out of which 220 were people with HIV. Given the gazillion studies that have looked at this issue, it’s reassuring to note that not all demonstrate that HIV is a risk factor for more severe COVID-19 disease. My hunch? If you take our healthiest PWH (on ART, viral suppression), and carefully control for demographic factors and comorbidities known to worsen COVID-19, there won’t be much of an effect, if any, of having HIV.

Giving ART to “blipping” HIV controllers improves some immunologic markers. In this observational analysis of 301 controllers followed for a median of nearly 15 years, 90 started ART for various reasons — 83 with viremic “blips” before starting, and 7 with always undetectable viral loads. For those in the former group (the “blipping controllers”), ART led to reduced activated CD4 and CD8 T lymphocytes and total CD8 T cells, and increased CD4/CD8 ratio but did not increase the CD4 cell count. No changes were observed in those who were always undetectable. Whether to treat people with this virologic phenotype remains one of the truly unanswered questions in HIV today.

Patients with a history of K65R from prior virologic failure and currently suppressed on ART switched successfully to BIC/FTC/TAF. The study included 71 people, half of whom also had M184V (hence resistance to both tenofovir and FTC). Viral suppression has been maintained in all of them now followed for a median duration of 47 weeks. These results are perhaps not surprising given the results of the NADIA study with TDF/3TC + DTG in people with treatment failure (many of whom had K65R), but they are reassuring to see nonetheless with this slightly different integrase inhibitor. My colleague Serena Koenig is studying this strategy in a randomized clinical trial being done right now in Haiti. Isn’t it remarkable how NRTIs retain activity even after genotypic (and high-level phenotypic) resistance?

Shifting now to IDWeek, with a few HIV and in particular COVID-19 studies of note:

A meta-analysis of seven clinical trials in 19,359 HIV-negative people shows that TDF is associated with weight loss. The strength of this comprehensive study is that the control arms received placebo, and that any “return to health” (which leads to weight gain) from treatment of HIV is excluded. The mechanism by which TDF induces weight loss is not clear, but we should definitely counsel our patients that discontinuing this drug may lead to weight gain. Some big questions remain — why does TDF do this more in some people than others? What is the mechanism? Is it harmful or salutatory? And — not relevant here, but clearly the case — why is the effect strongest when TDF is given with EFV?

Antibody responses to COVID-19 vaccines may be impaired in some people with HIV. Leading predictors of a good response were CD4 cell count (higher better), suppressed HIV RNA (suppressed better than viremic), and which vaccine was given — mRNA-1273 (Moderna) did better than BNT162b2 (Pfizer).

Another dual monoclonal antibody treatment reduces the risk of hospitalization and/or death in outpatients with COVID-19. The antibodies are BRII-196 and BRII-198, and the effect was in line with other treatments — a 78% reduction in risk. Provided there is no viral escape, I suspect the distinguishing characteristics of these various treatments will be their pharmacologic properties — half-life, formulations, mode of administration, cost. If that’s not enough for you …

Regdanvimab reduced the risk of hospitalization in high-risk outpatients with COVID-19.  Hospitalizations occurred in 4.0% of the treatment group, and 8.7% receiving placebo, a 70% reduction in risk. (Amazing how consistent these results are.) Apparently regdanvimab binds to a different location in the spike protein than the other monoclonals.

AZD7442 (Tixagevimab/Cilgavimab) given as pre-exposure prophylaxis to high-risk outpatients significantly reduced the risk of acquiring symptomatic COVID-19. After 83 weeks of follow-up, only 8/3460 (0.2%) of the AZD7442 group vs. 7/1737 (1.0%) of those receiving placebo developed COVID-19, a 77% reduction in risk. Importantly, the study population was not vaccinated, and only 4% were high-risk based on being immunocompromised. Nonetheless, the results strongly suggest that AZD7442 — given as two 1.5 ml IM injections — will be a viable prevention strategy for the not insignificant population of immunocompromised people who have suboptimal responses to vaccines. The company has requested Emergency Use Authorization (EUA) for this indication — there will be many patients eager for this treatment!

Another study demonstrates that casirivimab and imdevimab improves outcomes for hospitalized patients. We’ve known about the survival benefit of this treatment for seronegative patients from the RECOVERY trial for several months. Here a similar finding of benefit — a reduction in mortality — was found for the seronegative patients, with no signal of harm in those who were seropositive. This treatment (better known as REGEN-COV) is now limited in the United States to outpatients at high risk for COVID-19 disease progression, or for post-exposure prophylaxis. The results of these two studies suggest that modification of the current EUA to allow inpatient use, at least for seronegative patients, cannot come soon enough!

Remdesivir for 3 days given to outpatients with COVID-19 significantly reduced the risk of hospitalization. Only 2/279 of those receiving remdesivir required hospitalization, vs. 15/283 receiving placebo, an 87% reduction; there were no deaths in either arm. No effect was observed on nasopharyngeal viral load, raising the question — are we measuring the right surrogate? While giving remdesivir for 3 days to an outpatient to someone with active COVID-19 would be no picnic, these results are in many ways the strongest efficacy data we have for the drug — and underscore that if giving remdesivir to hospitalized patients, it should be started early (inclusion criteria required symptoms for a week or less). The same likely applies to any antiviral agent.

Am sure there are plenty of studies that I missed, but these in particular caught my eye. And for now at least, in-person meetings have started to return, with many (all) also having a remote option — so-called hybrid meetings. Denver will host a hybrid CROI in February 2022, and we just had a hybrid EACS in London, where my friend Joel Gallant attended.

Here’s his front-line experience:

I’m attending the hybrid EACS in London in person, my first face-to-face conference since the pandemic began. It’s strange to be sitting in a large, largely empty conference room watching a bunch of speakers give pre-recorded virtual talks on a big screen. In many cases there’s no one on stage at all. It’s as though the Zoom meeting has been turned into a spectator sport. But at least it’s easier to get a table for lunch than at most conferences.

Don’t you love pandemic silver linings?

Hey, in case you have some leftover pumpkins after Halloween, here’s something you can do with them.

Categories: Health Care, HIV, Infectious Diseases, Patient Care, Research
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October 12th, 2021

A Few Thoughts on “Attending” Virtual Meetings

Ouistiti (marmoset), from Buffon and de Sève’s Quadrupeds (1754). Apparently the French say “ouistiti” instead of “cheese” before a photo — perhaps somebody who’s actually from France can confirm or refute.

Once upon a time, long, long ago, before SARS-CoV-2 and COVID-19, many of us in academic medicine attended in-person scientific meetings that took place annually around the world.

I was one such person — usually 2-3 times a year. My primary charge at each of these meetings was to assemble the best, or most interesting, or most controversial clinical science and summarize it. Usually, I did this the weekend after the meeting, writing it shortly after walking my dog Louie on Sunday.

He was a very helpful editor.

I called them Really Rapid Reviews©, posted them here, and sent a stern letter to the US copyright and patent offices saying that under no circumstance could anyone copy them and sell them for profit. My crack legal team would be all over violators with the full force of the law.

While that last part (the copyright-patent-legal part) might not be true, the rest of the above narrative is 100% verifiable in these archives.

But then COVID-19 happened. Virtual meetings replaced the in-person scientific ones. I was so overwhelmed after Virtual CROI 2020 — through no fault of the conference, hey it was March 2020 — that I barely remember any of the content, though I did manage to cover one very important study.

Fast-forward roughly 18 months to now. Yes, many of us still “attend” (note the quotes) these virtual meetings — which means for most of us that you go to work as usual and try to snatch some free time to watch pre-recorded presentations on things that sound interesting.

Or you don’t. “Many sessions are like articles I’ve put aside and never get around to reading,” says Dr. Neil Clancy, offering up a perfect analogy. The problem? “Virtual really doesn’t help me disengage from clinic or other duties,” says Dr. Woc-Colburn. Exactly.

If this isn’t enough of a struggle — and believe me, it is — each meeting’s website has a different format, fraught with perilous glitches, sign-in pages that forget who you are, distracting “rooms” and “avatars”, and search function dead-ends. Don’t they know by now that the search function is the #1 key feature in all of these virtual meetings?

Plus, what about the non-meeting activity that happens at meetings? Says Dr. Neil Stone, “Nothing quite replaces the interpersonal connections made at conferences. The conversations you have over a drink at the end of the day are often far more important than sitting listening to the talks, the content of which you often know of in advance.” Indeed this is true!

Grrrr. You can tell I’m not a huge fan of the virtual format — it’s wearing me out.

But for the sake of argument, let me take the side of the virtual meeting proponents.

  • There’s that COVID-19 thing — yep, still here, and putting crowds together doesn’t sound like the safest activity. Remember the Biogen Leadership Conference?
  • For people with little flexibility in their work or family responsibilities, in-person meetings are out of the question — hence virtual meetings offer the opportunity for a much broader group to attend. No need for the quotation marks around the word attend this time.
  • Regardless of your work or home duties, in-person meetings cost a lot, take a ton of time, and are absolute beasts from a carbon footprint standpoint. Let’s not feed that beast!

These are all legitimate points.

Which is why my hope for a post-pandemic world — whatever that means — is that we’ll have the option of both. That’s what’s planned for CROI 2022, and expecting the same from many others.

Looks like you agree:

Oh, and since someone asked, the Really Rapid Review© of two recent meetings are all but written. No, they’re not so rapid anymore, but who’s keeping track these days.

Categories: Health Care, Infectious Diseases, Medical Education

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October 1st, 2021

A Thank You to One of Our Best Patient-Teachers

Harvard Medical School and Brigham and Women’s Hospital lost one of their best teachers this week.

No, it wasn’t a distinguished professor or astute clinician.

It was one of my long-term patients, who had given himself selflessly to teach dozens of medical students, residents, and (especially) ID fellows over the nearly 30 years I’d known him. Let’s call him Tony. Boy, are we going to miss him.

He worked in a fancy haircutting salon in Boston, where he was highly popular. We first met in the hospital room of his longtime boyfriend in the early 1990s, a grim time for HIV disease. His partner was dying of aggressive lymphoma; I was consulted on the case because of persistent fevers, but there was little we could do.

When our brilliant and perceptive social worker realized that Tony — clearly a kind and friendly man — would soon be alone, she reached out to him.

“How are you doing?” she asked.

“Not so well,” Tony said. “My test is positive too. And I hate my doctor.”

Yes, that could have been a red flag for a difficult patient. But it turns out Tony’s doctor really wasn’t a good match — he was highly judgmental about the fact that Tony had HIV. “He spends more time telling me not to spread it to others than he does trying to help me. I can’t stand the guy.”

So I became his doctor. Over the next few years, Tony’s CD4 cell count fell, he suffered several HIV-related complications, and required admission to the hospital a few times — but through it all he remained cheerful and unfailingly nice. When able, he continued to work full time at the salon, sometimes walking over to the Ritz-Carlton to blow dry a fancy person’s hair before an important event.

“It’s important to them!” he’d say, proud of being in demand. “Plus the money is great.”

Tony had a humble background — he was born in another country, raised in a “rat-infested” (his words) apartment by immigrant parents who didn’t speak English, and he never attended college.

No matter. He got along with everyone — not just the fancy ladies (it was mostly ladies) at the Ritz, but also our aforementioned social worker, our front-desk staff, our nurses, and most notably, our ID fellows.

Over the next 29 years, he must have seen at least a dozen different fellows as they went through their fellowships. He treated each one of them like his primary ID/HIV doctor, never once acting as if they (as trainees) were just “pretend doctors” waiting for the “real” doctor (me) to show up. You can’t imagine how important and empowering that attitude is for doctors in training.

Plus, he agreed to speak at Harvard Medical School classes several times a year, sharing his stories about what it means to live with HIV in the United States. In these sessions, he generously offered his unedited views on American medicine, never sparing certain doctors he’d met with lousy bedside manner.

“He treated me like I was his next down payment on his Cape house,” he said about one particularly aggressive surgeon. “Cha-ching!”

Nope, he wasn’t shy. But what great teachable moments for these young doctors-in-training.

Why do some patients embrace this role in our teaching hospitals? What is it about their personality, and makeup, that gives them the generosity of spirit to help train clinicians? And conversely, why do some people go to a teaching hospital and resent, ignore, or avoid the students, residents, and fellows, treating them as an inconvenience? Don’t they know what the word “teaching” in “teaching hospital” means?

Although I don’t know the answer to these questions, I can assure you that we physicians are exceedingly grateful to the former group for their taking on this very important role — something I told Tony repeatedly over the many years I knew him.

One of the privileges of being an HIV specialist all this time, of course, is witnessing the transformation of this previously fatal disease into one that’s treatable. Tony faithfully took combination antiretroviral therapy as soon as it became available in 1996, and it saved him from dying of HIV. His virus has been under control since then.

Not dying of HIV means that regular diseases of aging start to take their toll, and these did not spare Tony, in particular because he was a lifelong smoker — severe osteoporosis, arthritis, COPD — and innumerable aches and pains plagued him. When he started to lose weight earlier this year (he was already rail thin) a workup quickly established he had pancreatic cancer. “It’s the cancer that gives cancer a bad name,” one Dana-Farber doctor memorably told me.

It was only a couple of months from his diagnosis to his death this past week. He was surrounded by his family, friends, and most importantly, his current partner.

When I mentioned just how grateful I was for all the generous teaching Tony had done over the years, his partner shared that he drank his morning coffee each day always from the same mug.

“It’s a Harvard Medical School mug,” he said. “Has to be that mug.”

Makes sense.

And not bad for a guy who never went to college.

Categories: Health Care, Medical Education, Patient Care

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September 22nd, 2021

What I’ve Been Busy Doing, Besides Seeing Patients — and Bonus Animal-Related Infection Podcast

A 1914 postcard from New Zealand, where dogs have amazing abilities.

Long-time readers of this site (and I thank you deeply for that) might have noticed a lengthier gap than usual between today’s post and the previously published one.

Nearly three weeks! Wow! What on Earth is he doing? He must be really busy. That or just lazy.

In order to reassure you that the former is a better explanation for the silence than the latter, here are a few non-patient care things gobbling up the time that typically would go into crafting one of these posts:

1. ID fellowship interviews. COVID-19 notwithstanding, we continue to attract some truly brilliant, mission-driven, and just wonderful young physicians to this field. And can you blame them? It’s by far the most interesting and challenging medical subspecialty, arguably now more than ever.

But the process of reviewing applications, doing the interviews, and submitting our reports takes time — as it should. By the way, check out this paper that surveyed applicants and program directors after the first year of “virtual” recruitment to ID. Seems like virtual here to stay, at least in some capacity.

Just wondering — how many of those interviewees only put on the top half of their interview suits, and stuck with jeans, sweats, scrubs, or shorts for the bottom half? Zoom can’t tell!

2.  The NEJM FAQs on COVID-19 vaccines. Or should I write Covid-19 vaccines? For reasons only the editors understand and are keeping secret from me, here on NEJM Journal Watch we write it as COVID-19, while in NEJM itself, it’s Covid-19. Go figure.

But if you know of another content area with greater changes day by day — sometimes hour by hour — than these amazing vaccines, it would be news to me. These FAQs require constant attention and updating, and even then one feels hopelessly behind. Talk about a Sisyphean task, one that might not get easier for some time.

Note that I am both very proud (and surprised) that I spelled “Sisyphean” correctly without looking it up and very grateful to Amy Herman at NEJM Group for her help on this giant project.

3.  An opinion piece on the strange lack of guidance for booster doses with the one-shot J&J vaccine. Is the one-shot Johnson & Johnson vaccine less effective than the mRNA vaccines? Yes. Do we have evidence that giving an mRNA vaccine to prior adenovirus vaccine recipients boosts responses? Yes. Doesn’t even J&J think that its vaccine needs more than one dose?

Probably yes — their opinion further amplified by their press release of some of the ENSEMBLE2 data, though my co-author on the New York Times piece, Dr. Michael Lin from Stanford, still has some concerns:

We’ll see. Regardless, it’s just so strange that with all the chatter about boosting the Pfizer-BioNTech (especially) and Moderna vaccines, the 14 million Americans who got one shot of J&J still wait for guidance. “Soon,” say many experts. Will be glad when that day comes.

4.  Debating the top animal-related infections, with Dr. Jeanne Marrazzo. She’s the Chief of ID at the University of Alabama, a long-time friend and ID colleague, a scintillating conversationalist, and a true animal lover. One of my junior colleagues considers her a “hero” in ID. Who could be better for this O-F-I-D podcast? Note that I didn’t specify what I meant by “Top Animal Infection” — could be very serious, or having a cool life cycle, or just an amazing name, or having a great clinical anecdote, or some combination of all of the above.

So listen, learn, and laugh! And let me know in the comments if we left out one of your favorite animal-related infections. There are just so many.

(Quick aside — I got the idea for these silly drafts from one of my favorite writers in the world, Joe Posnanski. I even wrote him a fan letter! He does even sillier drafts with comedy writer Michael Schur on his “Poscast”, and gave me permission to do these Infectious Diseases ones since they don’t have overlapping content. He’s about to release a massive book, The Baseball 100. If you have even the slightest interest in baseball, I can’t recommend it strongly enough.)

(Transcript here, and also available on iTunes, Spotify, Overcast, or anywhere you get your podcasts.)

Categories: Health Care, Infectious Diseases

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September 3rd, 2021

No, COVID-19 in Anti-Vaxxers Does Not Make Me Happy

Octopus Car Wash, Minneapolis, Minnesota; 1981. John Margolies’ Photographs of Roadside America (public domain).

High-profile people who deny the seriousness of COVID-19, or strongly oppose vaccination, also contract — and sometimes succumb — to the disease.

Surprise, surprise.

The list is long, but recently has included a group of well known conservative radio hosts. Broadcaster Marc Bernier from Daytona Beach, Florida, died of COVID-19 recently.

Bernier called himself “Mr. Anti-Vax”, so it follows logically that he was not shy about expressing his opinions. His last statement on social media compared government advice that people get vaccinated to Nazism.

He was dead less than a month later.

This week, Joe Rogan, a famous podcaster who explicitly discouraged vaccination among young healthy people, announced that he has the disease.

Unlike Bernier, Joe Rogan is recovering (at least as of his last communication). For treatment of COVID-19, he “threw the kitchen sink at it.”

While we might think that someone who refuses vaccination would take the same “natural” approach to therapy — allowing the body’s healing processes to save him without exogenous help — think again. He received monoclonal antibodies (a good move), ivermectin (shrugs), azithromycin (doesn’t work), prednisone (can make mild COVID-19 worse), an “NAD drip” (huh?) and a “vitamin drip” (available now pretty much everywhere).

Best V.I.P. treatment that money can buy! But for the record, our taxpayer dollars are paying for the one thing that probably helped, the monoclonals.

What I find fascinating about these cases of COVID-19 in disease-deniers and anti-vaxxers is our response — as a society in general and as ID doctors in particular.

If one reads the comments on line or on social media, here are some of the common attitudes:

  • Anger. They got what they deserve.
  • Glee. Schadenfreude in its purest form.
  • What a waste. It’s unfair they take up limited resources for treatment.
  • Natural selection. It’s Darwinian evolution playing out.
  • A weary sadness. I just … can’t anymore.

It’s this last one — sadness — which overwhelmingly dominates ID doctors’ response. Some examples:

Deep sadness and ‘If only’– for them, their families and countless followers and their families …Sadness. Also validation. Followed by sadness about the validation … I will admit to feeling a sense of karma, but mostly it is just more and more sadness … Sad and powerless … Very depressed. It makes the weight of the last 18+ months heavier and heavier and it’s difficult to know how much more we can carry …When I think of their sphere of influence and their many unvaccinated followers’ deaths, which aren’t reported, it makes me incredibly sad …

At its most extreme, it’s a numb feeling, as highlighted here:

So don’t ask us if we’re glad to hear about another anti-vaxxer getting COVID. We’re not glad.

We’re very, very sad — and tired, too.

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August 12th, 2021

Could This Be Our First Effective, Inexpensive, Widely Available Outpatient Treatment for COVID-19?

The Geometric Landscapes of Lorenz Stoer (1567)

It’s fluvoxamine.

This rarely used antidepressant, long off-patent, has quietly been going through high-quality clinical studies for treatment of COVID-19. It certainly won’t be endorsed or promoted by any deep-pocketed pharmaceutical company, but deserves some attention nonetheless.

Here’s why I think we might finally be onto something with this “repurposed” drug, even after stumbling numerous times with hydroxychloroquine, lopinavir-ritonavir, ivermectin, azithromycin, doxycycline, colchicine, et al.

First, there is a legitimate mechanism of action — actually, multiple mechanisms, as it has anti-inflammatory, anti-platelet, and potentially antiviral activity independent of its psychoactive properties. If you want to get into the weeds, read this nice summary. But of course many drugs have in vitro mechanisms of action that don’t pan out.

Next, Dr. Eric Lenze and colleagues published a small double-blind clinical trial — well-designed and conducted — which showed benefit. Out of 152 participants enrolled, clinical deterioration occurred in 0 patients treated with fluvoxamine vs. 6 (8.3%) patients treated with placebo, a difference that was statistically significant.

But the problem with such small studies is that a tiny shift in outcomes for the treatment group would substantially change the conclusion. In other words, the results were “fragile.” The authors appropriately concluded that further larger studies were necessary.

After this trial, there was an observational study of opt-in versus opt-out fluvoxamine among newly infected workers at a horse racing track. Despite having more symptoms at baseline, the opt-in group receiving fluvoxamine had better outcomes than those who declined treatment — specifically, 0/65 hospitalizations for fluvoxamine, vs. 6/48 who chose observation only.

But the observational nature of this study also couldn’t provide a high enough level of evidence to change practice. What if the people choosing fluvoxamine were just more “health seeking” — and hence healthier — than those who declined, biasing the result? A highly plausible explanation for the results.

Still, these studies got enough attention to warrant further research, and even a spot on 60 Minutes. The research includes the innovative TOGETHER trial, led by a multinational group of investigators primarily in Canada and Brazil.

Here’s the “adaptive” study design, which shows the tested candidate drugs and the novel way the investigators drop unsuccessful treatments:

Eligible participants must have had symptom onset within the previous 7 days, a positive test for SARS-CoV-2, be older than 18, and have at least one risk factor for disease progression. The primary endpoint for these outpatient treatments was a composite of emergency room visits or hospitalizations due to the progression of COVID-19. The participants enrolled in 10 study sites in Brazil.

The group already published the negative results of their first study, showing that neither lopinavir-ritonavir nor hydroxychloroquine prevented progression to hospitalization or death better than placebo — which means those treatments have been appropriately dropped.

Time to move on to the next bracket, which included fluvoxamine, metformin, and ivermectin! Interim results were presented for the first time last week at an NIH meeting. The metformin didn’t do much of anything, and has been dropped; the ivermectin did a bit more, but still nothing practice-changing or statistically significant, with a relative risk of progression of 0.91 (95% confidence interval 0.69-1.19).

But the fluvoxamine treatment was much more promising. Among the 1480 participants randomized, fluvoxamine reduced the risk of disease progression by 29% (thanks to the lead investigator Dr. Edward Mills for this updated slide):

Most of the secondary endpoints also favored fluvoxamine, though the differences were not always statistically significant given the smaller event rate. No data on safety were presented, but Dr. Mills verbally stated that there were no unexpected toxicities.

No, an interim analysis of an ongoing study is not enough to change treatment guidelines — but it’s getting close, especially given the lack of other options and the favorable safety profile. The results are strong enough for the investigators to stop this comparison in this study, and no doubt a pre-print and submitted paper should be coming soon for further review.

Look, we’ve all been burned by promising studies of these repurposed drugs, and it’s quite reasonable to reserve final judgment until we see the complete data, and even other studies. Both the University of Minnesota COVID-OUT study and the NIH’s ACTIV-6 study include fluvoxamine arms.

But this already feels different from hydroxychloroquine and company given the high quality of the research. And it raises many interesting questions, including:

  • Would the results be additive to monoclonal antibodies, which we know work well in early disease but remain limited in availability, expensive, and cumbersome to administer?
  • How about combined with inhaled budesonide? Or with molnupiravir? (As an ID specialist with a research focus on HIV, you can tell I think combination therapy is a very good thing.)
  • Should it be tried in inpatients, especially for those requiring oxygen, for whom anti-inflammatory approaches seem most beneficial?
  • Would it work in other countries?
  • On a global level, would fluoxetine be just as effective, as this SSRI is far more widely available?
  • What should clinicians do now? Should they prescribe fluvoxamine for newly diagnosed patients with COVID-19? If so, for which ones?

No, I don’t have the answers. But this looks like progress, which during a pandemic is always great to see.

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August 2nd, 2021

Provincetown July Celebration a Challenging Stress Test for the COVID-19 Vaccines

When the complete history of the COVID-19 pandemic is eventually written — and boy oh boy, can’t wait for that — certain events will feature prominently as sites of notable outbreaks.

The Diamond Princess cruise ship

The Biogen Leadership conference

The Skagit Valley Chorale practice

The Sturgis motorcycle rally

The Amy Coney Barrett White House reception

And now:

The Provincetown Independence Week celebration

So what sets the last one apart from the others? And why did it lead to a change in CDC guidance about masking indoors for vaccinated people?

The answer to question #1 is, of course, that the other events occurred before we had effective vaccines and the highly transmissible Delta variant.

But what about question #2? Why the reversal on masking indoors for people who have been vaccinated?

In addition to the sheer number of cases that occurred in vaccinated people, here’s the primary reason, in graphic form from MMWR:

The vertical axis is the cycle threshold value, a measure of how much virus is in the sample (lower is more virus). And as is plainly evident, these results are similar for vaccinated and unvaccinated people.

These suggest that vaccinated people with COVID-19 could spread the virus to others as easily as unvaccinated people. It’s not proof, as it discounts the immune response, which may dampen contagious virus and shorten the duration of viral shedding.

It’s also in contrast with other studies that do show lower viral burdens over time in people who have been vaccinated — including this highly relevant recent study from Singapore:

Regardless, it underscores the plain fact that anyone with symptoms consistent with COVID-19 needs to isolate until recovery, vaccination status notwithstanding. For those diagnosed, we may even need to institute different isolation protocols, since the higher viral loads seen with Delta could mean more transmissions further out from onset of symptoms.

Already, the CDC has recommended that vaccinated people exposed to COVID-19 should get tested afterward, a return to pre-vaccine guidance. Should we also recommend antigen testing in breakthrough cases before return to work? (PCR may continue to detect non-viable viral fragments long beyond the contagious phase.)

What the outbreak can’t tell us is how bad this would have been without vaccines at all. Yes, there were lots of cases, but so far relatively few hospitalizations, and no deaths. Yikes, the mind boggles.

Because if anyone is under the impression that Provincetown is the kind of sleepy Cape Cod small town made famous through Edward Hopper’s dreamy artwork, think again — this July celebration is the diametric opposite. All who attended reported plenty of crowded bars, restaurants, and dance parties, with many shared accommodations among travelers.

You could hardly imagine a better environment for SARS-CoV-2 transmission. These settings plus the Delta variant provided the ultimate stress test for the vaccines.

What the outbreak also can’t tell us is how commonly asymptomatic people who are vaccinated acquire SARS-CoV-2 and then transmit it onward. This question has been filling up the email inboxes of every ID specialist out there.

I suspect it’s uncommon. But let’s not be overconfident about anything related to this tricky virus, which has bedeviled us with unpredictable twists and turns from the start. Humility!

Yes, that’s a scary figure. What to do in the meantime as Delta is surging?

Get as many eligible people vaccinated as possible. Remember, the vaccines reduce transmission risk in two ways:

  1. Decreasing the probability of infection in the first place, either symptomatic or asymptomatic
  2. Decreasing the duration of infectiousness for those who do get infected

That first effect is ironclad — no virus, no transmission. The second one is a bonus. The evidence is strong that both of these are in play with COVID-19 vaccines, as summarized in this superb review.

So approve the vaccines already, FDA! This will allow broader implementation of vaccine mandates in schools and workplaces.

Plus, when possible, we should limit socializing indoors to gatherings with other vaccinated people. Since not everyone can be vaccinated — kids under 12, for example — if you’re planning a large indoor event, go ahead and ask people to get tested ahead of time. We might ask even if everyone is vaccinated, especially if the event has immunocompromised guests. Good tests are widely available over the counter that can give results back in 15 minutes. Let’s use them!

And whatever is causing COVID-19 case numbers to decline rapidly in the United Kingdom and India, here’s hoping it happens here as well.

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July 13th, 2021

To First-Year ID Fellows, Incredible Gratitude and Respect — Especially for This Past Year

Image by Pexels from Pixabay

Two things happened earlier this month in most U.S. hospitals — the academic year started, and the number of people hospitalized with COVID-19 reached a low point not seen since the early phase of the pandemic.

(No, hospitalizations are not down everywhere. We ID docs are very much aware that COVID-19 isn’t over. But the national numbers are historically low — single digits in my hospital right now.)

The turn of the academic calendar means it’s a good time to express gratitude to the ID fellows who just finished their first year — especially this year, because unless you went through it yourself, I would argue that these past two years could not have been more difficult for these trainees. Historically so.

Let’s start with early 2020, the second half of senior medical residency for most ID fellows just completing their first year.

In normal, non-pandemic years, senior medical residency acts as a wonderful consolidation of all that’s learned in the preceding two years. With fewer clinical demands, senior residents can master the intricacies of inpatient medicine, teach on intern and medical student teams, handle their outpatient clinics, check out subspecialty electives, and participate in research projects. Senior residents also plan the next phase of their lives by either applying for fellowships or looking for a “real” job.

And yes, there’s a certain amount of gliding on cruise control. Plus all kinds of wonderful camaraderie, celebrations, and parties.

But 2020 offered nothing like this for senior medical residents. Here’s Dr. Eric Bressman’s account when he was Chief Medical Resident at Mt. Sinai Hospital, describing spring 2020 in New York:

Pretty soon we were just completely inundated, both at Sinai and Elmhurst, Elmhurst even more so. And while we were working a lot on the weekends, during the week it was all administrative in terms of completely remaking the structure of our floors, completely remaking the schedules of the residents to design a safer experience, both for the patients and for the residents. And we were pretty quickly working 24 hours [a day] to try and get that done, and I probably didn’t have a day off for two months.

Safe to say that there was no cruise control for these residents. Lots of unplanned inpatient coverage needed, especially in the ICUs. And the celebrations and parties? Prohibited for infection control reasons.

Plus remember this — for people who had applied to and then matched in ID, they chose ID before COVID-19 was even a thing. What had they signed up for?

Yes, when they arrived to start fellowship last July, case numbers were down in some regions. But the first year of ID fellowship already has enormous challenges for multiple reasons, even without a pandemic. It’s hard! Rewarding too, but no piece of cake. A brief summary, including several items highlighted in a previous post:

I didn’t previously mention the “weird demotion,” but it’s true. July rolls around, and BAM! First-year ID fellows become beginners again. An internship redux, only now their entire clinical service consists of patients that medical and surgical teams can’t handle on their own (orange and red boxes in figure above). Challenging!

Then, as 2020 progressed, into the tricky mix of first-year ID fellowship came COVID-19 again.

In Boston, it was like a ghoul from a horror movie prematurely left for dead, only now back and just as strong and as scary as ever. COVID-19 wards reopened. ICUs again had critically ill patients, some of them shockingly young. Consults and pages about testing, treatment, and infection control all took off, including at night — but this time the rest of the hospital activities continued at the same time, in parallel. There was plenty of non-COVID-19 ID work to be done. Yikes.

I distinctly remember walking into our fellow work room one dark afternoon in December, two fellows sitting there nervously at their computers. For a bit, no words — then one said to me, quietly:

We all have COVID fear …

A completely understandable reaction to a completely terrifying situation, one we all shared. Only I strongly suspect, for reasons cited above, that the level of post-traumatic stress disorder experienced by first-year ID fellows seeing COVID-19 cases go up again probably clocked in at the 99th percentile or higher.

It was the combination of recapitulating their difficult senior residencies, the legitimate concerns about being overworked, the need to be the expert on a disease with still so many unknowns — plus the very real fear of personally catching the infection.

Which is why, when the first supplies of the vaccines became available to healthcare workers, and queries went out to prioritize vaccine recipients, the answer for us in ID was a no brainer. First-year ID fellows! Of course!

So thank you, just-graduated first-year fellows. You did an amazing job under such difficult circumstances. Enjoy both the relative calm that second-year brings with it, and this helpful owl trying to interpret a CT scan:

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July 1st, 2021

Five Reasons Why ID Doctors Are the Paperwork Champs

As they often do, the inquisitive folks over at Medscape polled doctors around the country on various topics.

This one hit home:

Say what you will about Medscape’s methodology, or representativeness, or need for statistical analysis.

But we’re clearly #1 in the Paperwork and Administration category — and it’s not particularly close.

It’s also the very definition of a Pyrrhic victory — who wants this prize? — so let’s examine why this might be.

1. We take the best histories. We should celebrate this skill, as it is clearly our most important clinical procedure. After all, what other procedures do we generally do? That’s right, none.

But detailed histories take time — time to collect, and even more time to document.

Witness:

https://youtu.be/zHep6D_xxOo

These detailed histories, mind you, serve an important medical function and improve patient care — so often the critical missing piece of information arises in the process of collecting these data. I can much more strongly defend these histories than the common practice of cutting and pasting gobs of laboratory and other data into the note, the purpose of which is inversely proportional to its length.

Let the record show, however, that we were not put on this planet to provide the ideal source for a hospital discharge summary. Just imagine if we could collect royalties on every discharge summary that included a big chunk of an ID consult note — wow, we’d be golden.

2. We evaluate and manage complex patients — as a rule. Every doctor thinks their patients are the most complicated.

But since most straightforward ID problems are handled quite nicely by generalists, and no one gets an ID consult on patients who are doing well, the ID doctor’s rating of complexity is like the scale used on the WeRateDogs site:

That’s right — every case ranks at least an 11 on a 1-10 complexity score. Often higher. Like Muffin going for a swim up there. 14/10, go baby go.

In one of my favorite examples, I’ll cite again the landmark STOP-IT trial on the duration of antibiotic therapy for abdominal infections. Every ID specialist looked at the inclusion criteria — intraabdominal infection and adequate source control (emphasis mine) — and thought, “Who are these patients with adequate source control? Do they even exist?”

We have a resident rotating on our consult service right now who just did a consult on one such patient, and she couldn’t believe the complexity (certain details changed): The abdominal infection saga started in early-2020, and included a diverticular abscess, intestinal perforation, enterocutaneous fistulae, ventral hernia repairs, infected abdominal mesh, 8 separate admissions to three different hospitals, and innumerable polymicrobial cultures growing nearly every bacterial species in the MALDI-TOF database. Plus several different candida isolates.

“Adequate source control.” Ha ha ha.

3. We don’t give up. Shared, with permission, is this rant:

https://twitter.com/Boghuma/status/1407837071667040259?s=20

In the thread is further information that this application process started two months ago. Oh, and a later update — it’s still not resolved.

Who hasn’t faced the same thing when trying to get outpatient coverage for a novel antimicrobial? Omadacycline, anyone? Albendazole (the pricing of which is a true crime)? Tedizolid? Isavuconazole? I suspect we could fund an entire ID salary on the person-hours it has taken us to get our first few patients started on injectable cabotegravir-rilpivirine, which included a request for prescriber information that I didn’t even know existed.

And don’t get me started on clofazimine, which once upon a time was available by prescription, but now — just read about this painful process. Arghh.

COVID-19 brought with it an entire world of paperwork that previously didn’t exist, just like the virus SARS-CoV-2. Anyone who has tried getting monoclonal antibodies approved for inpatients with persistent COVID-19 probably thinks “EUA” stands for “Extra Unnecessary Activity.”

But we don’t give up. Because getting these obscure (and often frightfully expensive) drugs for people with difficult-to-treat infections is very much in our job description. So we do it.

4. We all have OCD — obsessive-compulsive disorder. I’ll never forget the sign-out I received from the graduating first-year fellow when starting my ID fellowship. A veritable tome, it weighed in at over a dozen single-spaced typed pages, each of them with the complete history, a detailed description of notable hospital events (surgeries, positive cultures, complications), antimicrobial courses (with doses), microbiology results, and assorted other factoids.

“I know it’s a lot,” she said, handing it to me. “But I’ve highlighted in yellow the things that need to be done today, and in blue those that might be important later.”

It was a color-coded masterpiece.

Look, we know we have a problem — and so does the rest of the medicine world, who gently tease us it about it periodically.

Here, take a look at the responses to this post:

Many good responses, but this one truly captures it, from Dr. Joseph DeRose:  “I do this as a prompt to tell myself to be concise … never works.”

Yep.

5. We don’t feel comfortable delegating work to others. I’ve thought about this one ever since my friend and neighbor, a thoracic surgeon, told me he had no trouble with our complex new electronic medical record.

“Barely look at it,” he said. “That’s what our PAs are for.”

Yes, he’s got a veritable army of support staff taking care of his patients — not just skilled PAs, but nurses, secretarial staff, scribes — and their responsibilities include note writing, prescription refills, prior approvals, insurance issues, filing, OR scheduling, patient transport, and likely also when to put new birdseed in his finch feeder.

No doubt this support he gets versus your typical ID doc is proportionate to the RVUs (otherwise known as RVU$) generated by an thoracotomy compared to a fever of unknown origin consultation. Still, the disparity remains quite stark.

But it’s not just that — often even when we ID doctors do have support staff to help us, we end up just doing things ourselves. I found one of my colleagues standing by the fax machine, in the process of sending a lengthy document to a skilled nursing facility so the staff there had the latest discharge summary on her patient. I asked her why she didn’t ask one of our (very nice) clinic staff to do it for her, and she looked at me as if I were some sort of prima donna physician, too elite to get his hands dirty using our ancient fax machine, which requires a hand-crank for power.

Yes, she’s as dedicated a doc as you could imagine — but is faxing documents a good example of a highly trained physician “practicing at the top of their license”?

So those are the Top 5 Reasons why ID is #1 when it comes to paperwork.

I’m sure there are others, but I don’t want to get all OCD about it!

Categories: Health Care, Infectious Diseases, Patient Care

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June 14th, 2021

The Time for Hospitals to Require COVID-19 Vaccination Among Employees Is Now

Drs. Harry Meyer and Paul Parkman examine the rubella vaccine. National Library of Medicine.

Imagine you work at a hospital.

Patients come and go, admitted through the emergency room, or electively for surgery. Or they arrive for the day — maybe it’s an outpatient visit, or to receive chemotherapy or an infusion of biologic agents, or to undergo various imaging and other tests.

Some of them, of course, have weakened immune systems and won’t be fully protected by the COVID-19 vaccines. Others may not have received the vaccines based on poor access to healthcare or other social determinants.

Now imagine that you, healthcare worker, contracted COVID-19 because you’ve chosen not to be vaccinated. You feel well — in fact you are completely asymptomatic, blithely clicking the NO SYMPTOMS box in your hospital’s entry screen — but you’re in that brief period of being highly contagious.

And, as a result, you are the source of a COVID-19 transmission within the hospital to one or more of these vulnerable patients, and maybe some hospital coworkers (who could also be immunocompromised) as well.

How would that make you feel?

Importantly, the above chilling scenario is anything but hypothetical. An outbreak in a nursing home occured when one of the unvaccinated employees infected multiple residents and other staff. Even though 90% of the residents had been vaccinated, three of them died.

As cases continue to drop in the United States, we might need reminding that this is a highly contagious virus — even more so with the latest variants, which are 50% more transmissible than the original virus from China. Key graphic below, with estimated R0 for the increasingly dominant alpha and delta variants:

There is a solution, of course, one which would make the likelihood of in-hospital transmission to patients much less likely.

Hospitals can institute policies requiring that all employees be vaccinated.

Medical exemptions, of course, would be allowable. Some also would argue that documentation of prior infection would be sufficient — reinfection is rare. I’m fine with both, though do recommend vaccination for people with prior disease.

But what about the limbo “emergency use authorization” status of the vaccines? Shouldn’t we await full FDA approval? According to the U.S. Equal Employment Opportunity Commission, employers may require vaccines for onsite workers as a means of protecting the safety of others despite this status.

This approach of mandatory immunization follows the model of required influenza vaccination (already widely in place nationally), but is arguably much more important — COVID-19 is more lethal than the flu, and the vaccines are more effective. Such a win-win-win for the individual, the hospital, and for public health overall.

As a result, it’s a policy we ID doctors — especially infection preventionists — strongly endorse. That’s why I was ecstatic when hearing that Houston Methodist, Penn Medicine, and Johns Hopkins, among others, all had put such rules in place. Our hospital is considering similar action.

Penn Medicine staff articulated their rationale in a NEJM Perspective, entitled Incentives for Immunity — Strategies for Increasing Covid-19 Vaccine Uptake. They cite a systematic review showing that requiring vaccination for employment is the most effective strategy to increase vaccination rates.

Vaccine requirements have enormous potential to improve public health. We know that school immunization policies here in the United States have kept our outbreaks of vaccine preventable illnesses among children much less common than in other countries, and we’ve actually eliminated one scourge entirely:

With vaccination requirements, more than 90 percent of children are protected against devastating diseases like polio and measles. Through vaccination requirements, smallpox was eradicated from planet Earth.

With the caveat that those interested in the musings of me, an ID doctor, are likely to think similarly, it appears that most agree that this is the way to go — if not now, then after full FDA approval:

But not all agree. More than 100 employees of Houston Methodist sued the hospital, saying that the mandate forced them “to participate in an experimental vaccine trial as a condition for continued employment.”

This is nonsense — getting the vaccine is not participation “in an experimental vaccine trial” — and fortunately a federal judge agrees, and dismissed the lawsuit. I’m hopeful that this action will pave the way for many other healthcare facilities to institute similar policies.

The bottom line is that it is a privilege to be in the position of taking care of patients, and with that privilege comes the responsibility of keeping them as safe as possible.

And that means getting vaccinated.

Categories: Health Care, Infectious Diseases, Policy

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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.