Paxlovid was granted EUA based on a study conducted when delta predominated ending January 2022 to include a few subjects infected by the earliest omicron variants. Crucially, subjects were unvaccinated and had no evidence of prior infection. Thus, the study submitted by Pfizer for EUA was for conditions that no longer exist. As such, I fail to see how anyone would prescribe Paxlovid these days. There may be a weak justification for patient over 65 years, based on the Israeli study. Even so, the viral mutations make for a moving target that continually keep ongoing studies a step or two late for clinical application.
Like all drugs, Paxlovid is not benign. Before prescribing to anyone, I'd like to see convincing evidence of safety and efficacy for actual currently circulating variants. A study that supposedly demonstrates efficacy against "long covid" is so fraught with pitfalls that critical thinkers will remain incredulous. For starters, what is the definition of "long covid"? With 200 possible symptoms, the research team can easily get the result they want by p-hacking and other manipulations.
This comment isn’t related to the post, but I’m hoping Dr. Cifu reads and responds. Whenever I read about vaccines, there is always the conclusion that they are worthwhile, regardless of effectiveness in limiting transmission or infection rates, because “vaccines limit severity’. Is this currently true? It’s a stated reason why boosters were needed, but documentation that the boosters reduced severity beyond what was obtained with original dosage didn’t seem to be proven.
And now, there is a new variant XBB. Yet despite its recent appearance, the same vaccine claim is being made. From MSN today, “When it comes to evasion of vaccine protection, it’s important to recognize that vaccine protection is not all or none,” Dr. Adalja says. “Even with immune-evasive variants, vaccine protection against what matters most—severe disease—remains intact.” Is it true that a booster will reduce disease severity more effectively than if someone was vaccinated with the original dosage? Is the answer different for XBB versus Omicron? I’ve only seen the nursing home study, which didn’t seem to be persuasive.
Thanks for reading and commenting. You'll note in the post that I specifically mentioned the original vaccine. Getting vaccinated in late 2020 through the 1st half of 2021 was critical. Like all vaccines, not everyone vaccinated benefited but given we had no immunity to SARV CoV-2 and mortality was high (0.25-8% depending on population) the vaccine was critical and hugely beneficial. Now, I just don't know. With vaccine induced immunity and previous infections the vaccines has an effect but I think the absolute benefit in most people is small. I think, at this point November 2022, getting vaccinated depends on an individuals history, personal health, and approach to their own health care. Hope that helps.
Nov 17, 2022·edited Nov 17, 2022Liked by Adam Cifu, MD
Adam, Nicely done.
Perhaps obvious to all here, but probably deserving of calling out, is that I have yet to understand what "long covid" is, and how it is differentiated from "long post-viral something else". For that matter, it is often symptom-similar with CFS/fibromyalgia.
There are now 200 symptoms linked to "long covid". This reminds me of one of those medical school lessons -- if there are 200 drugs to treat a disease, all you know is that none of them work. If there are 200 symptoms, all you know is that you have not characterized whatever it is...disease or not.
The other really major issue to which you alluded is the "bad" coding in the EMR. Having done endless work on this over the years, that data is close to worthless for this kind of exploration. It is likely a larger confounder than you have underscored. What other codes were there for these same patients? Why those 12? Why not another 12? Who checked to see if the codes corresponded to the same thing in each patient (they often do not). Etc.
Still a good commentary. In my opinion, not harsh enough, though. I am spending considerable time doing damage control on the NYT article which people keep bringing/sending to me.
As others have mentioned, it is not nearly as worthless as the NEJM masking article (and the accompanying editorials) that were just published. A critique of that mess would be a good thing for this column. it breaks my heart that the NEJM (to which, at great struggle, I bought a lifetime subscription in medical school) has become an archetype of yellow journalism.
I'll be honest. "peer reviewed" doesn't mean much anymore. Was the recent NEJM (are they a medical journal? Like Rolling Stones is about music? Or ESPN is about sports? yeah right) study on masking in Boston area schools peer reviewed? As I've said many times, "scientist" and "doctors" took a hit during the pandemic. With very few exceptions, they are all weak herd following sheep. However I respect almost all who write on this substack - whether I agree or not. The general populous of doctors? sheep. At least in the coastal elite cities. Worse than sheep, actively bought into the Big Pharma marketing team Sheep.
As for "left leaning journal" it's hard not to use them since they are the vast majority. I've been burned by NY Times too many times to even consider it a newspaper. I lean conservative, but I'm not a "right wing nut" by any measure. But after a while, the S/N ratio becomes too bothersome to even bother reading anything by them. "BUT WHAT ABOUT FOXNEWS, YOU NUTJOB??" some may ask. They too fall into the "don't really matter" category. Although they tend to be (a little) better. I now rely on non-corporate media. Matt Taibbi, Greenwald, Breaking Points etc. *That* is where I get my daily dose of news while the Democratic arm of the MSM and the Right wing arm of Fox battle it out. Let me put it bluntly, if NY Times as an entity was on fire, I wouldn't even cross the street to piss on it to put out the fire.
Tragic that we can't trust media nor now even journals. We once thought that media would hold the powerful accountable or at least explore the various aspects of their fact finding, but no longer.
I've been wondering about that. Has it always been like this with the media and we never knew? Kind of like "were there always pedophiles" and we just know about it more now do to mass communication?
But I feel like it's a newer phenomenon with the liberal well to do elites joining the ranks of newsroom. I mean Peter Jennings didn't even graduate HS or was just had a high school degree. And I feel like press was more gritty, more blue collar back in the days. But it could just be my bias (read hatred) about current media.
I think the advent of journalism schools has trained many in liberal ideology. That class can't readily identify with the masses or even understand them. And it seems few are really seeing an issue from various viewpoints.
It is true that sensationalism has created fears that we would not have been as concerned about in the past. The number of child abductions, etc are quite low yet parents are afraid of letting their kids free range.
Thanks Adam---- All good points-especially supporting my strong doubts that EMR ICD screening is a very poor way to detect Long COVID (better for pathologically document forms of PASC ie MACE, DM etc). Second it appears to me that PAXLOVID effectiveness is diminishing int he OMICRON era ( as morbidity plumets even in at risk patients ( the PANORAMA/molnupiravir study and others show that severe outcomes are dramatically diminishing in all groups except the most vulnerable) finally as recent 'pre print ' by Michael Mina suggests Paxlovid in a ciommunity setting -failed to protect (and was numerically inferior) for 1 viral clearance; relapse (both clinical and virologic) based on a non randomized pragmatic trial. Having said that I still use it in my high risk and in particular our immunocompromised patients.
Nov 17, 2022·edited Nov 17, 2022Liked by Adam Cifu, MD
Thanks, Adam. This kind of posting is so helpful and should inform medical students and trainees about the tools used to review the medical literature critically.
I have a perception and question regarding paxlovid. So many reports regarding the clinical course of treated patients, including President Biden, with paxlovid show that "relapse" after initial clinical and virologic response to medication is possible, if not probable As physicians know, just because the package insert recommends a five day course, off label use of any drug is quite legal and common. As a pediatrician, the majority of drugs that I prescribed over my 40+ year career had to be "off label" because they were not studied or FDA-approved in children. It seems to me that an 8 to 10 day course of paxlovid should be studied for acute treatment and impact on long COVID in response to the obvious lack of durability of the five day course. It is not an expensive drug so cost to the patient should not be an issue. Why has this not be done? Have you considered this approach in your patients? If not, why not? Many thanks in advance for your insights.
The clinical design for FDA studies always involve a bit of arbitrariness. Five days is the course for oseltamavir (Tamil) for influenza whereas ten days has been the arbitrary duration of most antibiotics. Recent studies have shown that shorter courses of antibiotics are often effective. It seems common sense that clinicians should consider a longer course for Paxlovid. There is widespread ignorance among clinicians that "off label" prescribing is perfectly legal and rarely considered "outside community standards" if based on common sense.
Thank you for this interesting essay. The NIH a has a large budget to study Long Covid. Maybe they will asked Pfizer to help them run a prospective RCT to determine if and in whom Paxlovid reduces Long Covid? Such a study could do double duty, helping to clarify the incidence of Long Covid now.
Paxlovid was granted EUA based on a study conducted when delta predominated ending January 2022 to include a few subjects infected by the earliest omicron variants. Crucially, subjects were unvaccinated and had no evidence of prior infection. Thus, the study submitted by Pfizer for EUA was for conditions that no longer exist. As such, I fail to see how anyone would prescribe Paxlovid these days. There may be a weak justification for patient over 65 years, based on the Israeli study. Even so, the viral mutations make for a moving target that continually keep ongoing studies a step or two late for clinical application.
Like all drugs, Paxlovid is not benign. Before prescribing to anyone, I'd like to see convincing evidence of safety and efficacy for actual currently circulating variants. A study that supposedly demonstrates efficacy against "long covid" is so fraught with pitfalls that critical thinkers will remain incredulous. For starters, what is the definition of "long covid"? With 200 possible symptoms, the research team can easily get the result they want by p-hacking and other manipulations.
This comment isn’t related to the post, but I’m hoping Dr. Cifu reads and responds. Whenever I read about vaccines, there is always the conclusion that they are worthwhile, regardless of effectiveness in limiting transmission or infection rates, because “vaccines limit severity’. Is this currently true? It’s a stated reason why boosters were needed, but documentation that the boosters reduced severity beyond what was obtained with original dosage didn’t seem to be proven.
And now, there is a new variant XBB. Yet despite its recent appearance, the same vaccine claim is being made. From MSN today, “When it comes to evasion of vaccine protection, it’s important to recognize that vaccine protection is not all or none,” Dr. Adalja says. “Even with immune-evasive variants, vaccine protection against what matters most—severe disease—remains intact.” Is it true that a booster will reduce disease severity more effectively than if someone was vaccinated with the original dosage? Is the answer different for XBB versus Omicron? I’ve only seen the nursing home study, which didn’t seem to be persuasive.
Thanks for reading and commenting. You'll note in the post that I specifically mentioned the original vaccine. Getting vaccinated in late 2020 through the 1st half of 2021 was critical. Like all vaccines, not everyone vaccinated benefited but given we had no immunity to SARV CoV-2 and mortality was high (0.25-8% depending on population) the vaccine was critical and hugely beneficial. Now, I just don't know. With vaccine induced immunity and previous infections the vaccines has an effect but I think the absolute benefit in most people is small. I think, at this point November 2022, getting vaccinated depends on an individuals history, personal health, and approach to their own health care. Hope that helps.
Adam
Adam, Nicely done.
Perhaps obvious to all here, but probably deserving of calling out, is that I have yet to understand what "long covid" is, and how it is differentiated from "long post-viral something else". For that matter, it is often symptom-similar with CFS/fibromyalgia.
There are now 200 symptoms linked to "long covid". This reminds me of one of those medical school lessons -- if there are 200 drugs to treat a disease, all you know is that none of them work. If there are 200 symptoms, all you know is that you have not characterized whatever it is...disease or not.
The other really major issue to which you alluded is the "bad" coding in the EMR. Having done endless work on this over the years, that data is close to worthless for this kind of exploration. It is likely a larger confounder than you have underscored. What other codes were there for these same patients? Why those 12? Why not another 12? Who checked to see if the codes corresponded to the same thing in each patient (they often do not). Etc.
Still a good commentary. In my opinion, not harsh enough, though. I am spending considerable time doing damage control on the NYT article which people keep bringing/sending to me.
As others have mentioned, it is not nearly as worthless as the NEJM masking article (and the accompanying editorials) that were just published. A critique of that mess would be a good thing for this column. it breaks my heart that the NEJM (to which, at great struggle, I bought a lifetime subscription in medical school) has become an archetype of yellow journalism.
Great points on long COVID. It is a morass we will be sorting out for years.
I'll be honest. "peer reviewed" doesn't mean much anymore. Was the recent NEJM (are they a medical journal? Like Rolling Stones is about music? Or ESPN is about sports? yeah right) study on masking in Boston area schools peer reviewed? As I've said many times, "scientist" and "doctors" took a hit during the pandemic. With very few exceptions, they are all weak herd following sheep. However I respect almost all who write on this substack - whether I agree or not. The general populous of doctors? sheep. At least in the coastal elite cities. Worse than sheep, actively bought into the Big Pharma marketing team Sheep.
As for "left leaning journal" it's hard not to use them since they are the vast majority. I've been burned by NY Times too many times to even consider it a newspaper. I lean conservative, but I'm not a "right wing nut" by any measure. But after a while, the S/N ratio becomes too bothersome to even bother reading anything by them. "BUT WHAT ABOUT FOXNEWS, YOU NUTJOB??" some may ask. They too fall into the "don't really matter" category. Although they tend to be (a little) better. I now rely on non-corporate media. Matt Taibbi, Greenwald, Breaking Points etc. *That* is where I get my daily dose of news while the Democratic arm of the MSM and the Right wing arm of Fox battle it out. Let me put it bluntly, if NY Times as an entity was on fire, I wouldn't even cross the street to piss on it to put out the fire.
Tragic that we can't trust media nor now even journals. We once thought that media would hold the powerful accountable or at least explore the various aspects of their fact finding, but no longer.
I've been wondering about that. Has it always been like this with the media and we never knew? Kind of like "were there always pedophiles" and we just know about it more now do to mass communication?
But I feel like it's a newer phenomenon with the liberal well to do elites joining the ranks of newsroom. I mean Peter Jennings didn't even graduate HS or was just had a high school degree. And I feel like press was more gritty, more blue collar back in the days. But it could just be my bias (read hatred) about current media.
I think the advent of journalism schools has trained many in liberal ideology. That class can't readily identify with the masses or even understand them. And it seems few are really seeing an issue from various viewpoints.
It is true that sensationalism has created fears that we would not have been as concerned about in the past. The number of child abductions, etc are quite low yet parents are afraid of letting their kids free range.
Thanks Adam---- All good points-especially supporting my strong doubts that EMR ICD screening is a very poor way to detect Long COVID (better for pathologically document forms of PASC ie MACE, DM etc). Second it appears to me that PAXLOVID effectiveness is diminishing int he OMICRON era ( as morbidity plumets even in at risk patients ( the PANORAMA/molnupiravir study and others show that severe outcomes are dramatically diminishing in all groups except the most vulnerable) finally as recent 'pre print ' by Michael Mina suggests Paxlovid in a ciommunity setting -failed to protect (and was numerically inferior) for 1 viral clearance; relapse (both clinical and virologic) based on a non randomized pragmatic trial. Having said that I still use it in my high risk and in particular our immunocompromised patients.
Thanks for reading and responding Leonard.
--A
Thanks, Adam. This kind of posting is so helpful and should inform medical students and trainees about the tools used to review the medical literature critically.
I have a perception and question regarding paxlovid. So many reports regarding the clinical course of treated patients, including President Biden, with paxlovid show that "relapse" after initial clinical and virologic response to medication is possible, if not probable As physicians know, just because the package insert recommends a five day course, off label use of any drug is quite legal and common. As a pediatrician, the majority of drugs that I prescribed over my 40+ year career had to be "off label" because they were not studied or FDA-approved in children. It seems to me that an 8 to 10 day course of paxlovid should be studied for acute treatment and impact on long COVID in response to the obvious lack of durability of the five day course. It is not an expensive drug so cost to the patient should not be an issue. Why has this not be done? Have you considered this approach in your patients? If not, why not? Many thanks in advance for your insights.
I have wondered why the 5 day course was selected. Does anyone know about toxicity data in pre-clinical models?
The clinical design for FDA studies always involve a bit of arbitrariness. Five days is the course for oseltamavir (Tamil) for influenza whereas ten days has been the arbitrary duration of most antibiotics. Recent studies have shown that shorter courses of antibiotics are often effective. It seems common sense that clinicians should consider a longer course for Paxlovid. There is widespread ignorance among clinicians that "off label" prescribing is perfectly legal and rarely considered "outside community standards" if based on common sense.
Thank you for this interesting essay. The NIH a has a large budget to study Long Covid. Maybe they will asked Pfizer to help them run a prospective RCT to determine if and in whom Paxlovid reduces Long Covid? Such a study could do double duty, helping to clarify the incidence of Long Covid now.
Totally agree Paul. It would be a great use of the funding.