An ongoing dialogue on HIV/AIDS, infectious diseases,
May 4th, 2022
More on Relapses after Paxlovid Treatment for COVID-19
Unless you’ve been hiding under a rock, you’ve heard that some people treated for COVID-19 with nirmatrelvir/ritonavir (Paxlovid) experience a relapse in illness shortly after stopping treatment.
It’s both a recurrence of symptoms and a positive antigen test — sometimes after the test became negative. One case report published as a pre-print shows that a relapse can have a very low cycle threshold, meaning a high viral load:
Relapses vary in severity, from very mild and brief to worse than the initial illness. Check out the comments in my previous post for a sampling.
Some posit that the immune system doesn’t get a chance to mount a full response since the drug quickly reduces exposure to viral antigens. Others note that certain individuals experience prolonged viral replication, symptoms, and antigen test positivity, and perhaps it’s this group that’s destined to rebound after the 5 days of Paxlovid use. The drug knocks down replication for a while, but not long enough, so it rebounds.
Maybe it’s both — these aren’t mutually exclusive hypotheses. Regardless, as noted in my prior post, there’s still plenty we don’t know. But given the rapidly increasing use of Paxlovid nationally, I thought it worth this brief update about two important things we’ve learned since then, plus my opinion on a commonly asked question about contagiousness.
First, Pfizer offered additional details from their EPIC-HR study, citing that late viral rebounds occurred in roughly the same proportion of treated and untreated participants in their trial — around 2%:
UPDATE: Pfizer gave me the figures regarding the proportion of people who had Covid rebound in the Paxlovid clinical trial: About 2% of participants who got the drug experienced rebound, compared with ~1.5% of those who received the placebo rebounding within the same time frame.
— Benjamin Ryan (@benryanwriter) April 28, 2022
Whether the rate of relapse is higher than this 2% in clinical practice is unknown. Certainly, it seems that way — it even happened to a famous virologist! — but without knowing the denominator of total treated patients, we can only speculate.
And remember, clinicians have noted biphasic illness patterns since the start of the pandemic, and continue to do so. We’ve attributed that second period of worsening mostly to a robust (and sometimes hyperactive) immune response, but potentially there could be a component of concomitant heightened viral replication.
Second, in communications with clinicians, the FDA and Pfizer have made it clear that the people who relapse are in fact eligible for re-treatment under the Emergency Use Authorization (EUA). In other words, the within-5-day symptom clock starts over with the relapse. This would be justified clinically for our highest-risk patients (severely immunocompromised, medically fragile, or with severe recurrent symptoms), and favored over other outpatient treatments (all of which have logistical or efficacy issues) until we know more. So far, viral resistance has not been identified.
So where does that leave us with regard to infection control issues? In my opinion, we should assume that people who experience a symptomatic relapse with a positive antigen test could transmit the virus to others. Until data prove otherwise — meaning studies show these late relapsers have defective virions that are not replication-competent — this should be the recommended approach for work, school, and socializing. Symptoms plus positive antigen test equals potentially contagious.
In the meantime, I completely agree with this editorialist that we should be doing more to monitor how Paxlovid is doing since the EUA launched. I’m hoping large healthcare systems can quickly assemble observational studies evaluating how often this relapse phenomenon occurs out there in what is often called “the real world” — which means, in this context, “not in a clinical trial”. Prospective studies collecting virologic and immunologic data would also provide great value, especially given the theoretical concern that treatment blunts a favorable immune response.
So let’s keep learning.
You know, baby steps.
April 25th, 2022
Yes, Relapses After Paxlovid Happen — Now What?
Young Monk in the Greek Style, from Mascarade à la Greque, Alexandre Petitot (1727-1801).
Around two weeks ago, one of my long-term, very stable patients with HIV called me saying she’d just been diagnosed with COVID-19. Over 60 with hypertension, and overweight, she qualified for nirmatrelvir/r (Paxlovid) under the Emergency Use Authorization (EUA), and took it without problem.
(Certain details changed for confidentiality.)
In fact, she started to improve within 24 hours of the first dose. Complained a bit about the metallic taste, but was thrilled at this rapid recovery.
She then contacted me again a week later, saying she’d relapsed. More nasal congestion, cough, and fatigue — not as bad as when the illness started, but unmistakably a relapse. Not only that, the home antigen test, which started out as a dark line at the outset, became a barely discernible line after the treatment, and now was clearly positive again.
Her biggest concern was getting back out in the world without infecting someone. She really wasn’t that sick; she just wanted advice about when she could return to work and start socializing again.
“Avoid close contact with others until that test clears,” I said. (Which it did a few days later, and she completely recovered.) But certainly the whole thing was a head-scratcher for both of us.
Turns out these relapses do occur; this was just the first time I saw it. The investigators from Pfizer observed them in their clinical trial EPIC-HR, and reported it to the FDA. Take a look at this figure from their study, which was not included in the NEJM paper, but did appear in an FDA report:
See those lines heading upwards from day 10-14? Those are relapses. Sequencing of SARS-CoV-2 from these cases did not demonstrate resistance mutations either at baseline or at relapse that correlated with resistance. Specifically:
In summary, currently there are no clear signals of baseline or treatment-emergent NIR resistance from the preliminary analyses of clinical trial EPIC-HR. These analyses will continue to be conducted as more complete data from EPIC-HR are obtained and reported.
A detailed analysis of a similar relapsing case is available as a pre-print — viral sequence the same at 3 time points (no resistance or reinfection), respiratory multiplex PCR negative (no new pathogen), good antibody response.
Not surprisingly, as use of Paxlovid increases along with the supply, the anecdotal reports of these relapses increase in parallel. Not just in clinical practice — they’ve popped up on social media and in the press. It’s now become a standard part of my counseling to people, that this return of symptoms and test positivity might happen.
So we know that relapses happen. What don’t we know about these cases? Quite a bit, actually.
- How often does it occur? It’s tricky from the figure to get a clear picture of the numerator and denominator. And of course, that was in an unvaccinated, high-risk population. What about those who are vaccinated?
- What are the risk factors? Could it be that those with baseline high viral loads/low cycle thresholds are at greater risk of relapse? People who are severely immunocompromised? Older? With some variants more than others?
- Does antiviral treatment blunt a helpful immune response? Does the immune system need to see a certain concentration of viral antigens to provide adequate clearance? Or are those who are relapsing just the subset of people who would have had prolonged viral shedding to begin with?
- Should we assume that people who relapse become contagious again? That’s my assumption — and it seems highly likely — but it’s worth proving in a research lab that these viruses are just as replication-competent as the pre-treatment viruses.
- Does the virus develop resistance during this 5-day course? So far this hasn’t been reported in a relapsed case, at least a far as I know. Seems inevitable at some point, however, so worth looking for, again in the context of a research study.
- Should treatment courses be longer? Maybe a longer course is better, but maybe not. How about a 5- vs. 10-day blinded clinical trial, with clinical, virologic, and immunologic endpoints? (Importantly, both 5- and 10-day courses follow the rules.)
- Does this happen with other antiviral strategies? I don’t recall hearing similar patterns with remdesivir or molnupiravir, but then again viral load reductions were less robust. This could be related to the mechanism of action of viral protease inhibitors.
- Should highly vulnerable people with relapses be treated again? Somehow “do nothing” for the most at-risk people with COVID-19 (for example, those on rituximab) doesn’t seem right when we have treatment tools at our disposal. One of my colleagues pointed out to me that neither repeated courses of nirmatrelvir (something I suggested in the above-linked Boston Globe piece) or treatment with molnupiravir would be allowed under the EUAs, as they must be within 5 days of symptom onset. It’s likely also that the bebtelovimab window of treatment (7 days) would be exceeded. That leaves 3 days of IV remdesivir as the only outpatient treatment option, which is very hard to access.
Given all these unknowns, it would be enormously helpful for Pfizer to release further data on their relapsing cases. Not just how often they happened, but also how they did clinically — presumably they did well, given the overall favorable results from the study. Any further information on immune responses? And did they paradoxically have a longer time to viral clearance than the placebo arm?
Fortunately, I’m aware of several research groups who are studying these cases right now here in Boston, and undoubtedly others are doing so elsewhere. We should know more soon.
But what we do know now — and I’ll keep saying this again and again — is that this is one tricky virus, full of surprises.
April 12th, 2022
Should We Prescribe Nirmatrelvir/r (Paxlovid) to Low-Risk COVID-19 Patients?
I usually put a clever caption below these vintage public health posters, but can’t think of one. Happy to take suggestions!
The top recommended treatment for high-risk outpatients with COVID-19 in the NIH Guidelines is nirmatrelvir/r (Paxlovid). It’s quite clear why.
In the EPIC-HR study, unvaccinated people at high risk for severe outcomes had an 89% reduction in the risk for hospitalization or death compared to placebo. If we just look at mortality — another important endpoint, don’t you think? — nirmatrelvir/r beat out placebo by a score of 0 (nirmatrelvir/r) to 13 (placebo).
Let’s add to this very favorable outcome several other benefits:
- The reliable activity against all variants
- The relatively good safety profile
- The short course of treatment (5 days)
- The substantial reduction in viral load, the most of any drug tested to date
- That it is pills rather than an IV
Yes, folks, we have a winner! Sure, it has lots of drug interactions and it tastes terrible, but it’s far and away the best choice out there right now.
So if we recommend this treatment for high-risk people with COVID, what about for symptomatic people who are not at high risk? Not now, but imagine a time when we had sufficient supply. Should we also recommend it for them?
I thought the answer was straightforward, and will give my views below. But I had an inkling that this wasn’t so clear a few weeks ago when one of my smart colleagues held the opposite opinion.
To test these choppy waters, I posted this poll online:
Let's suppose there's an ample supply of nirmatrelvir/r (Paxlovid), and you can prescribe it for anyone with symptomatic COVID-19. Cost not an issue. Based on what we know today, would you do so for "low-risk" cases? Why or why not?
— Paul Sax (@PaulSaxMD) April 10, 2022
Wow. Not only is there a pretty even split, but responses are so interesting, and quite strongly held. It’s fascinating to read them.
(And, by the way Dr. Titanji, good call.)
My own view? Given sufficient supply — and we’re not there yet — I’d certainly recommend nirmatrelvir/r even for low-risk symptomatic people. The motivation lies in the already summarized favorable results of the high-risk study, and hinted at even in the interim analysis of EPIC-SR, the study in low-risk people.
Remember, some low-risk younger people get severe disease. (Here’s a notable recent example — speedy recovery!) The reasons are poorly understood why this happens to some unlucky few (OK, not understood at all), and it’s rare, but all of us have seen these unfortunate cases. Could nirmatrelvir/r reduce the risk for severe disease even in this population?
Highly plausible. Look at the interim results of EPIC-SR which, though not showing benefit in the primary endpoint of time to symptom resolution, did appear to yield clinical benefits for this prespecified clinical endpoint:
A further advantage is the virologic response, which should reduce the likelihood of onward transmission. For those needing negative antigen tests prior to returning to work or school, it’s another plus to hasten this process.
Also, there’s the theoretical benefit that treatment will reduce the risk for long COVID, or other prolonged post-infectious symptoms. Both most certainly occur in people at low-risk for severe disease. Since at its genesis these are virus-induced complications, it’s not crazy to think that inhibiting and shortening viral replication will make these dreaded outcomes less likely. It will be challenging (and take some time) to prove, but it’s an important part of the research agenda.
Finally, treating symptomatic COVID-19 falls right in line with the first principles of our specialty. If there’s a safe, effective, and readily available treatment or prevention strategy for a symptomatic infection that is potentially serious, we treat it — even if most people will do fine.
I’m not alone in my view, obviously — 52% of respondents agreed. One respected ID researcher (who recently experienced her own household outbreak that was “not fun”), emailed me:
I agree with you 100%! I almost commented on that poll to say I thought it was a no-brainer but then saw how many people disagreed and stayed quiet! If it cuts short viral replication, the impact on secondary transmission could be enormous — far more than our vaccine responses are doing. What a huge benefit that could be!
The opposing view says it’s not yet been shown to benefit this population of lower-risk people. That these clinical endpoint results are “fragile” — so few outcomes that it could be an accident (and maybe motivated the increased sample size in the EPIC-SR study). That even if there is a clinical benefit, the number needed to treat will be gigantic. That resistance may develop. That the reduction in transmission effect isn’t proven. That there are places that don’t have this treatment at all, and our indiscriminate prescribing of nirmatrelvir/r will prevent it from being available abroad.
Lots of echoes of the oseltamivir controversies over the years. These are valid concerns, all of them. So I really do get this opposing view.
It’s just not mine.
What do you think?
April 1st, 2022
As the World Around Us Moves On, We ID Docs Just … Can’t
Cheaper (and tastier) than ivermectin — and a whole car load!
Something quite remarkable happened as Omicron tore through the United States in December and January.
Despite triggering a record number of cases — which should have made people more concerned about COVID-19 — Omicron paradoxically did the opposite. It made most of our country decide to move on, even parts famous (or infamous, depending on your view) for being careful. Just to live with this COVID thing — ending vaccine mandates, leaving the masks at home, going back to restaurants, gyms, large parties.
Hey, I get it. When facing something so contagious, something that easily broke through our vaccines, something that even extremely cautious people ended up contracting, we might start having that “what’s the use?” feeling.
Time to get back to normal. Shrugs. Even as cases (and hospitalizations) increase in Western Europe, this relaxed attitude prevails, prompting Dr. Walid Gellad to wonder, Why is everyone so chill?
I’m convinced a major amplifier of this casual response is the reduced per-case clinical severity of Omicron, largely due to partial existing immunity from vaccination, prior infection, or both. This lower severity on an individual level means everyone knows — or experienced themselves — cases that were quite mild.
Typical statements uttered by patients, colleagues, friends, acquaintances during the Omicron surge:
“Felt like a cold.”
“If it weren’t for my positive rapid home test, I still would have come to work.”
“Had one day of feeling blah, then mostly it was lots of nasal congestion.”
“I can’t believe he [referring to a school-age kid] tested positive, he’s as active and energetic as ever.”
“You’ll never believe this, but she [referring to an older family member in a nursing home] tested positive, and we just got off a Zoom call — she seems fine!”
But here’s the problem — the denominator of cases was so ginormous during Omicron that it still led to a staggering number of hospitalizations and deaths. Way more than from flu, even in a bad flu year. People who had weakened immune systems, had multiple medical problems, were still unvaccinated, or were just unlucky to get a really bad case still experienced severe disease. And some fraction of all these Omicron cases will be left with long COVID, evaluation and treatment of which remains in its infancy.
Some people may not have seen this numerator. But believe me, we sure felt it, as did our hospitals. We still needed the ICU beds for some COVID patients, still adhered to strict infection prevention measures for everyone with a positive COVID test admitted to the hospital, still struggled to clear hospital workers (who came down with Omicron just as much as everyone else) for return to work.
You need no further evidence of how the Omicron surge disrupted patient care than to observe how many hospitals delayed non-essential surgeries. Not only is elective surgery important for good patient care (ask anyone who had their surgery delayed), but also this is the most remunerative service provided by most hospitals in the United States. As a result, I doubt there’s a single hospital in the country that didn’t have a negative balance sheet during Omicron.
Now, as we ID docs watch what happened in Western Europe, we can’t help but squirm. “What happens in the U.K. most certainly DOES NOT STAY in the U.K.” should be public health’s advertising slogan for what comes next in the northeastern USA:
ourworldindata.org/grapher/uk-covid-hospital-patients
Already we see the trend starting, with the increase in wastewater concentrations of the virus in most regions, a rise in the reported test-positivity rate, and a slow creep up in people testing positive among those hospitalized. All this generates more calls about exposures in the workplace and at home, about how to get nirmatrelvir, about the latest monoclonal antibody taken down by viral evolution, and this week a zillion people asking about whether to get a booster now, wait until just before a fall surge, or wait for a variant-specific vaccine.
You know, the pandemic life of an ID doctor.
So while much of the rest of the population has moved on, forgive us ID docs if we remain nervous Nellies. We can hope that case numbers will be lower during the BA.2 Omicron surge — and they might be — but we can’t count on it.
Now, I just have to get that smell of onions out of my car …
March 22nd, 2022
What Have We Learned from the Pandemic So Far?
The title slide of an upcoming talk. You can see I’ve made great progress.
Dear Readers,
I need your help.
Recently one of my colleagues reached out and asked if I could give a talk to his research group.
“Just give one of your canned Covid talks,” he said.
Ha.
Needless to say — but I will say it anyway — he’s not an ID doctor. Otherwise he’d know that, as I’ve said before, talks on COVID-19 become outdated as soon as you click the little save button (it’s a floppy disk icon) on your PowerPoint program.
As a result, there’s no such thing as a “canned Covid talk” because you need to update them constantly. The field is constantly changing.
(Small aside here — how long will that particular save icon be up there at the top of Microsoft Office programs? After all, people stopped using floppy disks in the late 1990s. My crack research team revealed that companies completely stopped making them over a decade ago.)
How quickly do these COVID talks become outdated? Much faster than floppy disks. I’ve lectured multiple times on COVID-19 over the past 2 years, to a variety of medical and non-medical learners, and thought it might be interesting to see what a talk looked like just 6 months ago, back in September 2021 — an eternity in COVID time.
(I’ve done talks since then, too, but let’s look at 6 months ago for the full effect.)
It included these obsolete topics that one would be hard-pressed to include in a talk today:
- The Delta variant — see you later!
- The monoclonals casirivimab plus imdevimab and bamlanivimab plus etesevimab — remember those? Can you pronounce them yet? If not, you’re probably spared having to learn.
- The debate about whether remdesivir works — not much of a debate anymore, provided it’s started early enough.
- The latest on baricitinib — now a widely accepted tocilizumab alternative.
No mention of nirmatrelvir or molnupiravir or PINETREE or Evusheld or bebtelovimab or interferon lambda. And definitely no Omicron, that was our “gift” during the holiday season, 2021.
It did include the FDA’s admonition on ivermectin, always good for a few chuckles:
https://twitter.com/US_FDA/status/1429050070243192839?s=20&t=Y2xezMoy7Zau9zJpt1YX9A
That one never gets old, and might stick around for a while in upcoming talks.
Frustrated by the constant churning of content in these COVID talks, I offered my colleague a somewhat different topic, namely:
COVID-19: Lessons Learned (So Far)
… which is why I’m reaching out to you, loyal readers of this site, for help. In a classic case of “be careful what you wish for,” I now realize that this is a gargantuan topic, one spanning pretty much every discipline under the sun. A comprehensive review would take hours (not 50 minutes, with 10 minutes for questions). Frankly, it’s a good topic for an entire PhD thesis.
Overwhelmed, I’ve already checked in on social media — here’s one great response, from Dr. Darcy Wooten:
Life is short, pandemics help expose structural inequalities, rigorous science matters, politicizing medicine is harmful, and vaccines are amazing. In our darkest hours we must hold on to hope. We must keep going.
Impressive what some people can do within the 280 character limit on Twitter! I offered her the opportunity to give the talk in my place, but she declined. Quite understandable — she lives in San Diego, a long way from the Longwood Medical Area. Plus, it’s still freezing here in Boston.
But seriously — what would you include in a talk with this title?
Let me know in the comments. And you can go longer than 280 characters.
March 7th, 2022
How to Induce Rage in a Doctor
Advertisement for Hunt’s Remedy, which cured all diseases but did not require a prior authorization.
If you’re wondering how to make a doctor angry — really, really angry — read on. Because asking us to justify treatment decisions to insurance companies and their pharmacy benefit managers must rank right up there with the greatest tortures of practicing medicine in this country.
Mind you, this isn’t just about my patient, or about me — such infuriating events take place innumerable times in countless offices, hospitals, and clinics around the country every day, wasting everyone’s valuable time with no evidence whatsoever that they improve the quality of care.
Such struggles are an inevitable part of a healthcare system that values profits over people. The debates require a veritable army of staff on both sides to navigate what should often be very straightforward treatment issues.
Here’s a timeline of what happened. It’s Part 2 of the case presented a couple of weeks ago, which appeared with the patient’s permission (certain details changed).
February 6: Patient notifies me he needs a corticosteroid injection for back pain, which is contraindicated with his current HIV therapy due to a potentially serious drug interaction. We set up a video visit to discuss alternative HIV treatment options.
February 7: Televisit. I explain some treatment options, which I outline as bictegravir/TAF/FTC, dolutegravir/3TC, or doravirine plus TAF/FTC. He opts for the doravirine option based on side effects from previous treatments. Prescription sent to pharmacy.
I mention to him that doravirine sometimes requires a prior authorization. I also tell him that with his employer-provided insurance, it most likely will be fine. After all, the guy has a high-powered job in a very well known organization. He must have good coverage.
Furthermore, while HIV treatment remains quite expensive, none of the alternatives I’ve offered costs significantly more than what he’s currently receiving, and some cost less — at least based on the prices available to us.
Ha. Not so fast.
February 10: Message from patient that his pharmacy told him doravirine wasn’t covered. Needs a prior authorization.
I ask our pharmacy team, which consists of pharmacists and pharmacy techs hired for this express purpose, to help with it. They send it in, along with my office note from the televisit which justifies the reason for the treatment change.
February 14: I hear from the pharmacy team — prior authorization has been denied. Oh, and there’s this message:
Alternative Requested: PIFELTRO [doravirine] is NON-FORMULARY. MUST USE EFAVIRENZ, NEVIRAPINE, EDURANT. Call xxx-xxx-xxxx.
Well, this is a joyful Valentine’s Day present. They obviously don’t know his medical history, or much about HIV treatment. Why can I make this assumption?
- Efavirenz caused severe side effects years ago — he can’t take that.
- Nevirapine is not recommended in any treatment guidelines anymore, especially in people (like my patient) with high CD4 cell counts, as this increases the risk of severe hypersensitivity — he can’t take that.
- Edurant (rilpivirine) should not be given to people with low stomach acidity since it won’t be fully absorbed — he can’t take that.
I’ve always wondered — what if we followed these directives, and something truly terrible happened? After all, there are people who have died from nevirapine hypersensitivity, either from toxic epidermal necrolysis or fulminant liver failure or both.
Would the insurance company bear any of the blame, or legal risk? Would they care? I know the answer, sadly.
February 15: I call the phone number, which takes me to the pharmacy benefit manager. It’s the Giant-est of the Giants. How do annual revenues of more than 30 billion dollars sound? Pay for plenty of doravirine with that.
Phone tree. Then hold music. A warning about high call volume and long wait times. Then a person. Below a sampling of the dialogue.
Pharmacy Benefit Manager person #1: Hello, you’ve reached Brett. May I have the client’s member number?
Me: I don’t have it. I have his name and date of birth.
PBM person #1: OK, I’ll take that.
[pause while they look up the record]
PBM person #1: It says here the prior approval was denied. Pifeltro is non-formulary. You must use [pauses] EFAVIRENZ, NEVIRAPINE, EDURANT. [Difficulty reading the HIV drugs implies no knowledge of HIV medicine.]
Me: I know that — this is why I’m calling. But he can’t take any of those.
PBM Person #1: Do you want a clinician-to-clinician consultation?
Me: Yes. That’s why I called — this is the number we were given.
PBM Person #1: OK, let me transfer you.
[Hold music. Another warning about high call volumes and long wait times.]
PBM Person #2: Hello, you’ve reached Blake. May I have the client member #?
Me: I just gave that information to the previous person. Didn’t they pass that along to you?
PBM Person #2: Sorry, no.
Me: I have the name and date of birth, not the client #.
[Information given again.]
PBM Person #2: It says here that your prior approval was denied. You must use [pauses] EFAVIRENZ, NEVIRAPINE, EDURANT [more difficulty pronouncing the HIV drugs].
Me: That’s what the last person said to me, and I already know that. My patient can’t take any of these drugs. This is supposed to be a peer-to-peer consultation.
PBM Person #2: They sent you to the wrong number. I can forward.
[Hold music. Long hold.]
PBM Person #3: Hello, this is Bobby. May I have the patient’s name and client #?
Me: I only have the name and date of birth.
[Information given again. Third time, but who’s counting.]
PBM Person #3: I found the record. The Pifeltro was denied.
Me: Yes, Bobby, I know that, this is why I’m calling. Hoping you can help me. I’m an ID/HIV specialist in practice since 1992, and I’ve known this patient since 1996, including his full treatment history. The recommended alternatives are contraindicated — he can’t take any of them.
[Long pause.]
Me: Hello, do you need any further information?
PBM Person #3: I’m sorry, doctor, but I am not authorized to approve this drug.
Me [more than a little annoyed at this point — in fact here’s a good description of how I looked]: Why then am I speaking with you? This is the phone number I was advised to call. Are you a clinician? Do you have any knowledge of HIV treatment? Do you have access to the notes that were submitted for this claim?
PBM Person #3 [sounds like Bobby is now driving a car while speaking with me]: I’m sorry, Doctor. I am not authorized to approve this drug. If you want to appeal, or the patient wants to appeal, they will need to directly contact his insurance company with an appeal letter.
So why did all this happen? Why did Brett, Blake, and Bobby each fail to help my patient get his prescription covered?
It all starts with the relatively high cost of HIV treatment to begin with — a cost that has increased over 30% since 2012, a rate 3.5 times faster than inflation. Unlike most other industrialized countries, where government payers gather disease experts to review treatment options, then work with the pharmaceutical companies to arrive at a cost, such deliberations here are explicitly blocked and remain controversial.
With antiretroviral therapy so costly, insurance companies enlist the PBMs to negotiate what treatments get covered, what don’t, and how much they’re going to cost. It’s all done behind closed doors, in exchanges that one insider told me are “brutal.” As concisely (and accurately) stated in the opening to this recent perspective, “Prescription drug prices in the United States are opaque.”
The PBMs also sometimes direct where patients can most easily get their prescriptions filled (which may be the same companies, imagine that), and discourage dispensing of less expensive (but not negotiated) products.
If you think this clandestine process is ripe for distortion, obfuscation, and misuse of power, you’d be absolutely right. The lack of transparency means my patient and I have no way of finding out why doravirine isn’t covered — just that it isn’t.
But one thing I can state with 100% confidence — the refusal to cover my patient’s doravirine prescription has nothing whatsoever to do with improving the quality of his care, or following treatment guidelines, or really anything related to his health at all.
It was all about money. And that is sad indeed.
Hey, two more entries for the timeline:
February 25: Received information about the appeal process, and wrote the letter.
March 7: Still waiting …
(Thanks to brilliant colleagues Drs. Aaron Kesselheim and Ben Rome for reviewing this post. And to Dr. Glaukomflecken for making us laugh and cry at the same time.)
February 22nd, 2022
A Personal Tribute to Dr. Paul Farmer — Who Made Everyone Feel Important
Paul Farmer’s unexpected death this weekend has all of us who knew him reeling. This just should not happen to someone so generous, so important, and so visionary about helping others — especially others who, due to being born in impoverished life circumstances, can’t help themselves.
This is not fair at all. We’re heartbroken.
The tributes will deservedly be pouring in over the next few days about his global impact, so here’s a very personal one. One of Paul’s great talents was making you feel important.
It didn’t diminish the experience one bit that he made everyone feel important — when he was talking to you, looking at you, he had you front and center in that big generous heart of his, and everyone else drifted away. These important people could include the President of the United States, the patient who was the fifth consult of a busy day on the inpatient ID service, the members of the band Arcade Fire, or a person with severe tuberculosis in rural Haiti. All are VIPs to Paul.
Several years ago, I cited this supernatural ability of Paul to make everyone he met feel like they mattered when discussing his skills as a doctor working here in Boston. Didn’t matter whether you were a patient, or a consulting surgeon with a short attention span, or a green medical student, or a hospital transport person. Everyone felt this from Paul, regardless of his skyrocketing fame.
One of these important people was my friends’ daughter, Lily. When she was 12, she read Mountains Beyond Mountains and, like countless others, derived inspiration from Paul’s career.
I told Paul about Lily’s enthusiasm for his work. Immediately he offered to sign a copy of his book Pathologies of Power, and told me to give it to her as a present. He inscribed it “For Lily, for later” (he knew it wouldn’t be easy reading for a 12-year-old), and he included his email address (of course). I told him I’d pay for the book, but he flat-out refused.
After I gave her the book, she dropped by one of our post-graduate courses that featured Paul as a speaker to thank him. More important was that he gave her time to talk about his work, and what she wanted to do with her life. She was truly starstruck, and used the experience to inspire a wonderful speech at her bat mitzvah.
(For those who haven’t heard bar or bat mitzvah speeches, they usually reflect pre-adolescent obsessions that then are jerry-rigged by the rabbi into something more generous or religious. Mine probably had something to do with baseball and model rockets — not health equity.)
Later, I thanked Paul for being so generous with both his book and, especially, his time with Lily. (This guy could be pretty busy, you know.) I told him that she featured his work and their meeting in her bat mitzvah speech, and how inspiring his dedication to helping the poor was to her.
Paul would take no credit (he never did) — but he did email me this:
Please send Lily my congrats on her bat mitzvah. I’ll bet that she’s going to talk about social justice and remaking the world for a long time. We need people like her on this planet.
The story doesn’t end here. Each time I saw Paul over the next few years, in addition to catching me up on family and work and whatever latest crisis he and Partners in Health were tackling, he’d smile and ask:
“How’s Lily?”
He’d be pleased to know that she’s currently lobbying at the state house on behalf of non-profit organizations in Massachusetts. It’s not a stretch to say that Paul’s influence led her to choose a career in public policy.
And no, he’d never forget her name. That’s just Paul for you. We’re all important — even when there’s nothing in it for him.
Not a bad lesson for how to live life, is it?
February 18th, 2022
A Return of Antiretroviral Rounds — What Regimen Would You Choose?
Structure of the Solar Rays, Edward Livingston Youmans, 1856.
Years ago, back in the pre- and early internet days, one of the most popular features in the newsletter Journal Watch AIDS Clinical Care was something called Antiretroviral Rounds.
We’d present a case, then have two expert discussants weigh in on what they would do. The link above is a case from ancient history — 1998! — to show how far we’ve come.
Today, in honor of Antiretroviral Rounds, and inspired by a particularly annoying interaction — ok, an infuriating interaction — with a pharmacy over an insurance issue, I bring you a reprise of this feature and ask you to select what HIV treatment you’d recommend. This week, the case; next week, what happened.
(Details shared with the patient’s permission, and slightly modified.)
This man in his 60s has had HIV likely since the early 1980s from treatment of an inherited coagulopathy. He was diagnosed shortly after testing became available in the mid-1980s.
He started treatment with zidovudine, then later added didanosine. Several years of low-level viremia but clinical and immunologic stability followed.
I met him in the mid-1990s, shortly after he moved to Boston. He works in a very demanding job, where he has a leadership position and travels a ton. He’s a workaholic even by American standards, and that’s saying something.
His one and only resistance test showed he had resistance to both zidovudine and didanosine, but preserved predicted activity of tenofovir, lamivudine, and all the drug classes he had never taken. In the early 2000s, he started tenofovir, lamivudine, and lopinavir/ritonavir. He has had virologic suppression since then.
Brief trials of switching treatment to a different drug class led to significant side effects. Efavirenz caused severe somnolence, mood alteration, and sleep disturbance; raltegravir made him feel “like I’ve aged a decade overnight.”
So fast-forward to today, and he’s on the one-pill daily treatment of darunavir-cobicistat-emtricitabine-tenofovir alafenamide. No side effects. Feeling fine.
So what’s the problem? Not surprisingly given his treatment history and age, he has some “diseases of aging.”
- Didanosine caused non-cirrhotic portal hypertension and gastropathy, a condition I’ve learned may lead to unreliable stomach acidity (that will be important for later).
- Years of HIV and tenofovir DF have resulted in osteoporosis.
- He has arthritis in multiple joints, leading an orthopedist to strongly recommended a trial of steroid injections.
Experienced HIV clinicians will hear this recommendation for injectable steroids, and get very worried. The medical literature is replete with reports of marked hypercortisolism and sometimes subsequent adrenal insufficiency from the interaction between “boosters” (this is the cobicistat in his regimen) and injectable steroids. This is the same drug interactions issue getting attention now with the ritonavir in Paxlovid, though that’s relatively easy since it’s only 5 days of treatment, with a couple of more days for the ritonavir effect to wear off.
I have seen numerous cases of this interaction over the years, sometimes with serious consequences (compression fractures, steroid myopathy, sleep disturbance, depression, hyperglycemia, intractable hypertension, fluid retention). This intra-articular treatment is erroneously thought by some not to be a “systemic” treatment, and many clinicians are unaware that cobicistat and ritonavir markedly impair the clearance of many corticosteroids. A second injection is particularly problematic, but it can happen after one shot, too.
Let’s assume the steroid injection is going to go forward. (As an ID doctor, I will not debate the merits of this widely used treatment, controversial as it may be in some settings.)
So it’s time to change the HIV regimen, right? Given his history and only one-class resistance, this shouldn’t be too difficult — but there’s a history of intolerance to efavirenz, and to raltegravir, and he may have unreliable stomach acidity. Note that intramuscular injections would be dicey given the underlying coagulopathy.
What would you recommend, and why?
February 12th, 2022
The Rise and Fall of Ivermectin — 1 Year Later
Cheese consumption and death from bedsheets are highly correlated.
Here’s a confession few board-certified ID doctors will make — there was a brief period when I thought ivermectin could very well be an effective treatment for COVID-19.
It wasn’t when the in vitro data first came out. Therapeutic concentrations were not achievable in humans.
Nor when the anecdotal reports started pouring in, and sometimes making news. A former colleague of mine, a smart and clinically active person practicing in the Midwest, contacted me in late 2020 telling me that they acted as the primary medical consultant for a nursing home. Since they started using ivermectin, no patient had died or even been hospitalized from the disease. OK, a hopeful observation, but not proof.
Not when the figures appeared correlating ivermectin use and lower death rates from COVID-19 in some countries, mostly from tropical regions in South America and Asia. These figures always reminded me of these spurious (and often hilarious) correlations. Did you know that per capita cheese production correlated strongly with the number of people who died by becoming tangled in their bedsheets? Who knew? And what’s the mechanism?
And certainly not when these folks started pushing ivermectin with an enthusiasm that is frankly religious in intensity. This group’s treatment “protocols“, with their hodgepodge of antimicrobials (including ivermectin), immunomodulators, and vitamins — the kitchen sink approach — strain credibility.
Nope — my moment of greatest hope for ivermectin came just over a year ago, when Dr. Andrew Hill presented results from a meta-analysis of several randomized controlled trials, a presentation he would later also give to the NIH Guidelines panel. Andrew is a well-respected clinical researcher, someone well-known in the HIV research world.
In his analysis as first presented, the risk-ratio for mortality with ivermectin was 0.17 (95% confidence interval 0.08, 0.35), an 83% reduction in risk for dying. Outcomes for other endpoints (time to viral clearance, time to clinical recovery, duration of hospitalization) also favored treatment over controls.
Hearing these data, I reached out to Andrew to discuss his findings, and he generously discussed them with me. He acknowledged that the data were incomplete, but remained strongly suggestive of clinical benefit. Furthermore, he’d been in direct contact with the researchers who conducted the largest of these studies. They repeatedly reassured him that the data were sound.
I subsequently summarized my thoughts here in a post entitled, “Ivermectin for COVID-19 — Breakthrough Treatment or Hydroxychloroquine Redux?”; writing:
My take-home view? The clinical trials data for ivermectin look stronger than they ever did for hydroxychloroquine, but we’re not quite yet at the “practice changing” level. Results from at least 5 randomized clinical trials are expected soon that might further inform the decision. NIH treatment guidelines still recommend against use of ivermectin for treatment of COVID-19, a recommendation I support pending further data — we shouldn’t have to wait long.
What happened next? I offered Andrew the chance to submit the meta-analysis to Open Forum Infectious Diseases, which after conducting some additional analyses, he kindly did. Remember, at this time in early 2021, we had no readily available effective outpatient treatments COVID-19. Something inexpensive, safe, and widely available certainly would be most welcome.
After peer review and some revisions, with Andrew and his team reducing the survival effect size for ivermectin to 56% (still highly significant) due to some additional studies, we accepted the paper. We simultaneously solicited a thoughtful editorial from my Boston ID colleague Dr. Mark Siedner, entitled “Ivermectin for the Treatment of COVID-19 Disease: Too Good to Pass Up or Too Good to Be True?”
Well, we now know that the second part of Mark’s brilliant title turned out to be the case — too good to be true. Many of the studies on which the meta-analysis was based were highly flawed, and one was outright fraudulent. The fake data problem came to light just shortly after the meta-analysis appeared in print.
To his credit, Andrew promptly contacted me when the news broke. He immediately offered to retract the original paper, and even better to submit a detailed analysis of what went wrong.
This revised paper has just been published, entitled “Ivermectin for COVID-19: Addressing Potential Bias and Medical Fraud.” It includes this extremely telling figure, which shows how the effect size of ivermectin on survival drops to meaningless with exclusion of the fraudulent and potentially flawed studies:
Read the full paper! But if you don’t have time, here’s the lesson:
These revised results highlight the need for rigorous quality assessments, for authors to share patient-level data, and for efforts to avoid publication bias for registered studies. These steps are vital to facilitate accurate conclusions on clinical treatments.
Indeed. And for whatever role I played as an editor in sustaining the confusion — and sometimes heated conflicts — over this potential treatment for COVID-19, I deeply regret it and apologize. I hope this post, and even more, Andrew’s revision, explain what happened, and hope we all can learn something from this mistake. Certainly I did.
Meanwhile, several large placebo-controlled trials continue to test ivermectin for COVID-19 treatment in outpatients. It still might do something (though at this point I’m not very hopeful). At least one of the studies — COVID-OUT — is fully enrolled, and ACTIV-6 is far along, so more data will be forthcoming soon.
Will these results be enough to quell the controversy about whether ivermectin has a role in treatment COVID-19, settling the issue once and for all? Let’s hope so.
February 4th, 2022
Prior COVID-19 Is No Guarantee of Immunity
19th century apothecary advertisement, Lowell MA. Product has fewer drug interactions than ritonavir-boosted nirmatrelvir.
I’m no immunologist — a fact made vividly obvious to me several years ago when asked to teach a weekly medical student section that included cases and problem sets. The challenge was that the course combined immunology and microbiology.
I was on much firmer ground with the microbiology than the immunology, the latter often a wonderfully complex and mysterious system.
So why, then, am I about to wade into perilous waters and write about something very much immunology-related, a subject I’ve already confessed to being an amateur at? Because to us ID specialists, the immune system plays a critical role in how our bodies respond, clear, and protect us from various infections. We may not be true experts, but it’s highly relevant to what we do.
Additionally, I’m watching a debate unfold among ID colleagues, public health officials, epidemiologists, the lay public, politicians, and yes, even advanced degree-holding immunologists. It’s a debate about a critical issue facing the globe as we march on to the third year of the pandemic.
Namely, does infection with SARS-CoV-2 confer protective immunity?
Views range from “yes, certainly” to “maybe, sometimes” to “it depends” to “absolutely not.”
Everyone can cite their favorite study to back up their opinions — whether it’s an epidemiologic analysis of reinfection rates, or the cases of reinfection after prior COVID-19 that are less (or more!) severe than the first, or an in vitro study demonstrating robust (but then waning!) antibody responses, or how cells from people with prior infection continue to mobilize protective cytokines, or contrarily how prior infection inhibits these helpful cellular responses.
Many of the people lining up on opposite sides of this debate are smart, have impressive credentials, and aren’t shy about expressing their opinions — hence sparks do fly.
This doesn’t help resolve the issue, because of course they cite mostly the scientific studies and opinion pieces that support their views.
So for the price of subscribing to this blog, here’s my non-immunologist’s take, and warning — it’s a messy one with no precise answer:
Prior infection confers some degree of protective immunity. It varies from person to person, depends on the severity of the disease, with “just right” being more protective than mild or severe illness. (Cue classic Goldilocks analogy.) It’s not durable, is not guaranteed, and certainly isn’t going to lead to herd immunity on its own anytime soon.
Nope, no herd immunity by April 2022, just like it didn’t happen by April 2021.
Incomplete immunity conferred by prior episodes of COVID-19 is one critical reason that studies of populations continue to show that the unvaccinated have a markedly higher rate of hospitalization and death than the vaccinated — even though prior infection is becoming more common.
Two years into the pandemic, with major population surges, this remains an undeniable fact everywhere it’s studied — even though a higher and higher proportion of the unvaccinated have already had the disease. If prior infection were strongly protective, the gap between vaccinated and unvaccinated in risk of hospitalization would decrease over time. It hasn’t.
Omicron only exacerbated this reinfection issue, with many of us seeing or hearing about patients with repeat infections, sometimes quite quickly after a first infection:
https://twitter.com/TheBlondeRN/status/1489608641858654219?s=20&t=bairQyDjErYe4NJziFpC9Q
Indeed, if we asked a group of primary care clinicians, emergency room folks, and other front-line providers to raise their hands if they had cared for or heard of people with more than one episode of COVID-19 — usually less severe, but sometimes more — 100% would have their hands up.
Incomplete protection from prior infection isn’t what any of us want to hear. But as we’ve learned again and again, wanting something from this virus doesn’t make it happen. The other night, someone in my family asked me whether now, as Omicron nabbed so many of us who previously escaped, can we at last move past this pandemic and get back to normal?
It’s such a good question!
I just wish I had a more reassuring answer.
In the meantime, let’s get everyone vaccinated, even those with prior infection. It’s a much more reliable way of getting protected, especially from severe disease.
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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