And this was known to be a problem a year ago and Merck kept pushing it forward despite its low efficacy and risk for driving mutation. Meanwhile Paxlovid is underprescribed despite its effectiveness.
As I understand it, part of the issue is that Paxlovid interacts with a large number of other medications. This is a problem because people at high risk of dying from Covid tend to have preexisting medical conditions, and thus are more likely to take medications that interact with Paxlovid.
Most of the interactions can be managed, but I think the message got out among primary care docs there are drug interactions and so they get scared to prescribe it. There are relatively few meds that are absolutely contraindicated, while there's a large list of meds that require some dose adjustment or holding the med for a few days. This is an issue with the ritonavir in the paxlovid, which has been extensively used in HIV treatment -- so, this isn't a new issue that we know nothing about.
And then I've heard from too many patients their doctor doesn't think they need it because they're not that sick, so it's not worth managing the drug interactions. Unfortunately, paxlovid needs to be started within five days of symptom onset, but most patients aren't going to be hospitalized within those first five days.
Given the lack of monoclonal antibodies, the potential mutagenic effect of molupiravir, and the less-than-steller impact of remdesivir... if I or someone I loved got covid, I'd be jumping on paxlovid since there aren't many other options right now.
The medical system in the US is optimized to get people in, bill them, and get them out; that's it. Managing drug interactions is a long tail process that requires critical thinking, which is not an incentiviced activity. Plenty of startups have failed thinking that they could succeed if their products resulted in improvements to quality of care.
Managing drug interactions for paxlovid isn't much more complicated than inputting meds into a web form and looking at the color of the box that pops up after. I think most providers can handle that if they know these tools exist and get past the reflex of "paxlovid has drug interactions, you don't want to take it."
Managing drug interactions is part of ordering medications, and if it's really taking that much time (i.e., the EHR isn't just doing all the work for you), then it'd result in a higher E&M code when it's billed out. Medication management, in some cases, can also be billed and reimbursed by the pharmacist.
So, totally agree that the US medical system is optimized for billing. I don't think those of us in the US should be ok with that, and I don't think it's an excuse in this case to not prescribe paxlovid to patients who want it and would qualify for it.
Sure, in the abstract it is straight forward, but you quickly run into data gaps when considering multiple medications. Particularly in the context of comorbidities.
Medical professionals are overwhelmed, so you can't hospitalize these patients to monitor their compliance. And this is, in the large, not a demographic you can trust for maximal patient compliance.
By the medical professional who is prescribing paxlovid. When I wrote "can be managed", I mean the health care provider tells the patient to either stop taking their other meds for 5-7 days, to reduce the dose, or to look out for symptoms and call them if they have certain issues. Not be hospitalized to watch for side effects. You can look for yourself at the list of common meds, and the ones that are absolutely contraindicated are relatively few:
https://www.covid19treatmentguidelines.nih.gov/therapies/ant...
One's ability to "trust" a patient isn't a factor here, and is, frankly, pretty condescending. The patient and provider have aligned interests, it's just a matter of ensuring the provider is making sure the patient understands what's going on. The provider should be doing that in all of their encounters, so that's nothing specific to paxlovid.
> One's ability to "trust" a patient isn't a factor here, and is, frankly, pretty condescending.
I suspect you haven't worked with elderly patients.
I help a relative manage his care. I keep having to hide the DayQuil so he doesn't take it alongside his arthritis medication and overdose on acetamenophin. He "knows" he's not supposed to, but it doesn't click when the pills are in his hand and his nose is running (because he took it for decades prior to the arthritis prescription and deeply-ingrained habits are not easily replaced). He definitely tells the doctor he understands, and the doctor believes him, but it's not like the doctor is in any way responsible for verifying that information.
Drug interactions are way past the maximum complexity capacity of the median patient at high risk for death by COVID.
I spent a decade working in a nursing home before becoming an epidemiologist, so definitely have worked with elderly patients. Not to mention my own experiences with elderly family members.
> but it's not like the doctor is in any way responsible for verifying that information.
Yeah, that's the exact point. Everybody does things that the doctor says they shouldn't, but that doesn't mean we withhold care as a result.
People stop antibiotics before the scripts are done. People smoke and drink too much, some even drink and drive. People don't take their blood pressure or cholesterol or even HIV meds as prescribed. Some people take half a pill because the pill they were prescribed is "too big" -- people are weird and do all kinds of things.
Paxlovid is no different. The provider can be checking drug interactions, making adjustments as needed and counseling the patient. That's their job. They can't babysit the patient all of the time. If it's clear the patient doesn't understand and can't care for themselves, then there are larger conversations to be had.
My point is that deciding not to prescribe a medication to a qualifying patient because it generally has too many drug interactions and patients can't be trusted with their health is not ok. Patients don't need to understand that ritonavir is a protease inhibitor that was incidentally found to inhibit cytochrome P450-3A4, which subsequently boosts the levels of many other medications. They just need to know to stop taking their cholesterol pill for the next week. That's all. Some, like your elderly relative, may not be able to follow that direction. But there are millions of high risk people who are able to do that, and shouldn't be denied care based on the assumption they're incompetent.
Didn't we restrict Sudafed because people can cook it into meth and change the painkiller regiment because of opioid addiction? I don't think the rule "we don't refrain from prescribing a drug because some users won't be able to use it responsibly" is universal.
Yes, there are levels of controlled substances based on, among other things, their abuse potential. That's not what we're talking about here because paxlovid is not a controlled substance.
If you're going to construct a new strawman argument, don't make up quotes that I never wrote. I also have a lot of thoughts about how controlled substance laws create problems and harm patients. But I'll stick to the main point of this thread: paxlovid drug interactions are easily checked and managed for the majority of patients, and should not be a reason for providers to reflexively deny prescription requests for it.
What if that someone you love is young and in good health? Paxlovid has some significant side effects and is only recommended for patients at high risk of severe COVID-19 due to advanced age or other risk factors.
I think this is where many providers get mixed up. It's for "mild-to-moderate" COVID-19 (i.e., "you're not sick enough yet" isn't at play, because then you have "mild" covid which is exactly what paxlovid is indicated for) who are at "high risk for progression to severe COVID-19."
According to the CDC, risk factors that make you at "high risk" include being over 50, having a mood disorder (including anxiety and depression), being obese or overweight, being physically inactive, being a current or former smoker, or having asthma:
https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/...
Most Americans would check one of those boxes, even the healthy and young among us. And some of those (e.g., "physically inactive") are pretty ill-defined that you could argue even more fit in that category. Just saying you're anxious about covid outcomes should qualify you for paxlovid because anxiety is a risk factor.
Many of the infectious disease doctors I work with think that paxlovid should be offered to virtually everybody because it seems to decrease your viral load (this could decrease the chance of onward transmission), there may be a decrease in risk of long covid, it may shorten your symptom duration, and there aren't many other treatment options if you get sicker. So, short of being on one of the medications that's absolutely contraindicated, their opinion is generally if you want paxlovid you should get it.
So if your doctor is saying you don't need it or don't qualify, and you want to take it, I would find a different doctor or use a telemedicine provider.
yeah people in my house hold are getting covid a couple of times a year and are constantly exposed to it at school and work and we are all vaccinated but dont take any other medications for covid.
There are renal dosing standards for paxlovid. So if you have not-great kidneys, they just give you a different dose. Covid can also cause kidney damage, and kidney issues are associated with worse outcomes from covid. So, it's all a bit of a double edged sword.
Similar to my two experiences with antibiotics. Relief after half a day, clear reversal of illness by the next, after that only lingering discomfort to heal from the damage caused.
When I was living in SE Asia, I had really bad stomach issues quite often. One time was worse than ever. Went to a local pharmacy and they gave me some pill. Took it and literally hours later, I was fine. I remember looking it up and it was something developed in the 60's that wasn't used in the US any longer... but wow, it worked like magic.
I was recently reading about a drug called ibogaine - which is apparently pretty effective at treating opioid addiction, but is illegal in the US. The drug is prescribed in New Zealand, and the studies I saw made it look like a miracle cure (for most but not all patients).
Infuriating that, in the midst of the opioid crisis, the government wouldn't even consider permitting safe and effective treatment.
You do a disservice to legalization efforts by ignoring the fact that you are discussing a powerful psychedelic. I am all for legalization efforts, but it is important to be clear and upfront about what we are talking about. Tangental to your point; I wonder if the US would currently be facing such an extreme and distressing methamphetamine epidemic if ephedra were still available (recognizing the obvious catch 22 here, as ephedrine is famously used in a variety of stimulant manufacture)
It has a very high rate of serious side effects, and the psychedelic affect makes it worse because already unreliable people (drug addicts) get even more unreliable.
No it doesn't. Everything I've read indicates it's pretty safe with minimal to no serious side effects. Other psychedelics are legal in the US even for recreational use (e.g. Salvia) - so I don't see what the relevance is.
If I google that phrase I get a case study of a man who died after injecting himself with "4 g of ibogaine and 2 g of an uncharacterized ‘booster’ that he bought on the Internet" [1]. On the other hand, there are treatment centers using ibogaine that have been open for decades worldwide. That source also mentions a clinic in the Netherlands that has used ibogaine for approximately 5,000 cases.
This paper [2] is a review of deaths associated with ibogaine known to the authors. They contacted different clinics around the world known to use ibogaine. They found 19 deaths over an 18 year period. 14 of these deaths had post-mortem data and 12 of the 14 had clear comorbidities that likely substantially contributed (e.g. also using heroin and meth, or having severe heart problems already).
You can find a number of papers[3], here is one for example, where no side effects are reported for ibogaine - "In two Phase 1 studies using very low doses, single 20 mg doses of ibogaine were well tolerated (N = 21), with no effect on vital signs and no adverse effects". And, here is the conclusion of that paper, just for fun - "A single ibogaine treatment reduced opioid withdrawal symptoms and achieved opioid cessation or sustained reduced use in dependent individuals as measured over 12 months".
Even if those were valid side effects, you'd still have to put them in context - being an opiod addict is likely much riskier than taking a one time dose of ibogaine in a clinical setting with a doctor's supervision. Net - ibogaine treatment is negative side effect.
The state of medical care in the US is such that the regulators have to be very conservative. This isn’t a sophisticated place with good access or integrated records for care in most cases.
If you’re a high risk patient like an addict, when you end up in the ER for whatever, they’re just going to cut off whatever medication you’re on, keep you from dying, and kick you out as soon as they aren’t liable.
My fever and muscle aches, which came on within about 12 hours, went away within about 24 hours after I started Paxlovid. However, I continued to have lingering congestion that didn't go away, and in fact continued for about three weeks after the Paxlovid course was done.
Still a big improvement, but it makes me wonder whether a longer course of Paxlovid might have cleared the symptoms more completely. I have read that there have been suggestions that the five day course still leaves a significant amount of virus in the body and that lengthening it has been considered, but the FDA has not done anything about it.
> I continued to have lingering congestion that didn't go away, and in fact continued for about three weeks after the Paxlovid course was done.
The immune system often reacts to viral fragments leftover from replication or destruction. Some viruses are (hypothesized to be?) adapted to this, e.g. delaying sneezing and coughing (or at least the deliberate exacerbation of it) until viral load and viral shedding can be higher. Viral fragments can linger much longer than the primary infection, and in the case of COVID-19 are hypothesized to be responsible for or at least part of the process of some long-COVID symptoms.
> The immune system often reacts to viral fragments leftover from replication or destruction.
Yes, agreed. But I have also read that studies of patients who took the 5-day course of Paxlovid showed that there were still significant numbers of "unassembled" viruses--i.e., the only reason they had not become full COVID viruses that could infect other cells was that Paxlovid was blocking the last stage of virus assembly--remaining at the end of the 5-day course, and once the Paxlovid stops, those unassembled viruses can now assemble themselves and cause further infection. This has been hypothesized to account not only for lingering symptoms but for recurrence of more severe symptoms in a significant number of patients.
The Quanta article is talking about something different from what I was describing.
What I was describing is a consequence of the way Paxlovid works: it doesn't "kill" the virus or get your immune system to kill it, it just stops the last step of virus assembly inside cells by inhibiting the enzyme, protease, that catalyzes that step. So while you are taking Paxlovid the virus can still go through all the stages of getting inside cells (the normal way, not the different way described in the Quanta article--each virus particle just infects one cell and does all of its replication there), replicating its RNA there, and expressing all of the proteins that form a complete virus particle along with the RNA; it just can't do the very last step, assembling all of those pieces into more complete virus particles, while the protease inhibitor from Paxlovid is present. But once you stop Paxlovid, the protease inhibitor goes away and all of those virus pieces can now assemble (each set of pieces inside a single cell) to become full virus particles that can infect more cells.
The issue might be that, how long do you have to keep taking Paxlovid before those partially complete viruses degrade enough to not be able to reassemble after you stop.
Yes, and I don't think anyone knows an exact answer to that question, but I think it's been established that the answer is "significantly longer than the current 5 days that a course of Paxlovid is for".
> You may have recovered quickly regardless. I never took paxlovid and my covid symptoms lasted 2 days and i recovered quickly.
Well, quite.
Of the four confirmed Covid cases we've had in our immediate family in the last 12 months, three of us took nothing stronger than standard painkillers and didn't even need to speak to a doctor; my OH spoke to our doctor and was given an inhaler to help with the cough.
“In an updated analysis of 1153 patients enrolled through December 2021, treatment with Paxlovid showed a nonsignificant 51% relative risk reduction in hospitalization or death. Among 721 vaccinated adults with at least 1 risk factor, treatment with Paxlovid showed a nonsignificant 57% relative risk reduction.”
"Nonsignificant" is the key word in that quote. Both times. (and in fact several other times in the linked article).
So, it's not a strong enough or consistent enough difference between treatment and placebo to be certain that it isn't just chance. (this could happen if for example if out of our 1000 data points, 2 people on placebo were hospitalised but only 1 on the treatment was hospitalised. That'd be "a 50% reduction in risk", but not be statistically significant since it could easily have just been random chance when we're talking about such a small difference).
Probably needs an even larger sample population to really nail down whether it's real or not. Seems suggestive that all the various reported tests showed (inconclusive) benefits when you'd expect an actually-ineffective treatment to show results varying randomly in both "effective" and "not-effective" directions, though that could certainly be positive reporting bias, especially since it's being run and reported by a company with a financial stake in the results.
There's not enough data to say whether or not the efficacy has dropped off. EPIC-SR is a different patient population, and Pfizer hasn't released data for the primary endpoint in EPIC-SR of symptom relief. For the secondary endpoint of hospitalization or death, they got about a 50% reduction, but it's not significant, because the numbers were 5 hospitalizations or deaths in the treatment group and 10 in the placebo group.
Ummm…the first interim analysis of 853 patients failed to show a difference.
Then the secondary analysis of another 1163 patients failed to show a difference AND the delta between the two arms was smaller than the first analysis.
Its trending towards no difference between arms.
And symptom relief has a huge subjective aspect to it since it based on a patient questionnaire.
If it shows no difference in hospitalization or death but some small effect on symptoms it has little value as a treatment. It going to end up like Tamiflu.
And i just checked clinicaltrials.gov, Pfizer terminated the trial.
Look, I'm sure you took a stats course so you know all of this, but it's not the number of patients that matters, it's the number of events in the endpoint. They got 5 on treatment and 10 on control. If they wanted p<.05 they would need to substantially enlarge the study. The good news is that among vaccinated, "standard risk" people, it's fairly rare to go to the hospital even without Paxlovid.
This study just isn't powered well enough to say for sure whether Paxlovid provides a hospitalization/death benefit or not for the standard risk group. It also doesn't really provide any good information about whether newer variants cause Paxlovid to work better or worse.
Not to mention the original paxlovid trial was for a 10 day course of treatment but it was decided when approving the EUA that a 5 day course would be used to help spread out the limited doses. Yet today it just sits on shelves unused and people are still getting less effective half courses, many going on to 'rebound' and not clear the virus completely.
What really bothers me with Ivermectin is that it used to be one of the cheapest and most available drugs yet it instantly became taboo to even talk about for in the context of covid.
Why a known, safe, cheap and readily available drug couldn’t be used off label in the context of an unprecedented (at least in terms of social restrictions measures) global pandemic will always remain a mystery.
Not to defend Ivermectin use, but your BMJ link advises against Ivermectin due to a lack of evidence one way or the other and the current analysis methods may be misleading either way, not because there is actual evidence of failure.
"These websites show pooled estimates suggesting significant benefits with ivermectin, which has resulted in confusion for clinicians, patients and even decision-makers. This is usually a problem when performing meta-analyses which are not based in rigorous systematic reviews, often leading to spread spurious or fallacious findings. Concluding, research related to ivermectin in COVID-19 has serious methodological limitations resulting in very low certainty of the evidence, and continues to grow. The use of ivermectin, among others repurposed drugs for prophylaxis or treatment for COVID-19, should be done based on trustable evidence, without conflicts of interest, with proven safety and efficacy in patient-consented, ethically approved, randomised clinical trials."
The obvious solution is to prescribe every medication when there's no evidence for or against it. Just take every medication that hasn't been proven not to work, and you'll be cured! Oh, wait...
Imagine it's 2020. There's no vaccine, you are immunocompromised, you caught COVID, and now you are dying.
If I'm dying, is it unethical for me to, with informed consent, try whatever drug I am interested in, regardless of origin, to save my life? Even if there is not evidence for or against such a drug? At that point, I don't care if it's mixing herbs grown on the seventh peak of the Himalayas, I think I should have the right to try whatever I damn well please. Even if Ivermectin is useless, at least my family won't get wrapped up in conspiracy theories that I was denied lifesaving treatment for political reasons.
Obviously, this is different than for people who have COVID and are not dying, but we used to emphasize personal responsibility for stupidity.
The thing is it isn’t 2020 and we have a lot more data to work with.
Also, medications both useful and not cause harm. Thus the default is to not use them unless there is some reason to believe they are actually useful or you’re conducting research. Yolo it is just a really really bad idea.
> Thus the default is to not use them unless there is some reason to believe they are actually useful or you’re conducting research. Yolo it is just a really really bad idea.
There actually was such a reason to believe:
2021, The Lancet: "Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial"[0]:
"[A] significant difference was found in patients with higher median plasma IVM levels (72% IQR 59–77) versus untreated controls (42% IQR 31–73) (p = 0·004)."
2021, The Japanese Journal of Antibiotics: "Global trends in clinical studies of ivermectin" (authored by 4 doctors, including Satoshi Ōmura, winner of the Nobel Prize in 2015 for his work on ivermectin)[1]:
"As of the 27th of February 2021, the results of 42 clinical studies worldwide have undergone meta-analysis and concluded that ivermectin is effective in the treatment and prevention of COVID-19. In the UK, a consensus-based recommendation by 75 healthcare professionals from 17 countries around the world has been carried out and submitted to the WHO to further encourage the issuance of guidelines for the use of ivermectin in the treatment and prevention of COVID-19."
2017, The Journal of Antibiotics: "Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations"[2]:
"Recent research has confounded the belief, held for most of the past 40 years, that ivermectin was devoid of any antiviral characteristics. Ivermectin has been found to potently inhibit replication of the yellow fever virus, with EC50 values in the sub-nanomolar range. It also inhibits replication in several other flaviviruses, including dengue, Japanese encephalitis and tick-borne encephalitis, probably by targeting non-structural 3 helicase activity. Ivermectin inhibits dengue viruses and interrupts virus replication, bestowing protection against infection with all distinct virus serotypes, and has unexplored potential as a dengue antiviral. Ivermectin has also been demonstrated to be a potent broad-spectrum specific inhibitor of importin α/β-mediated nuclear transport and demonstrates antiviral activity against several RNA viruses by blocking the nuclear trafficking of viral proteins. It has been shown to have potent antiviral action against HIV-1 and dengue viruses, both of which are dependent on the importin protein superfamily for several key cellular processes. Ivermectin may be of import in disrupting HIV-1 integrase in HIV-1 as well as NS-5 (non-structural protein 5) polymerase in dengue viruses."
There where several reviews mislead because: “ The hype around ivermectin is driven by some studies where the effect size for ivermectin is frankly not credible, and this has driven the conclusions in other reviews. The study with a huge effect has now been retracted as fake. Careful appraisal is the cornerstone of Cochrane’s work, and with such extreme public demands for a drug to work during the pandemic, it remains vital that we hold onto our scientific principles to guide care.” https://cidg.cochrane.org/news/new-cochrane-review-ivermecti...
“Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias. Ivermectin doses and treatment duration varied among included studies.“
“We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality”
“Authors' conclusions: Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.”
It’s easy to understand why people where mislead by a fake study, but in 2023 we just have better data and better treatments.
Ah good, another article from someone who thinks they are very smart and can have a necessary level of understanding by "reading up on the relevant stats and medicine" and seems to think the only difference between a seasoned immunologist and a joe blow is like a week of reading wikipedia?
We know that now, but in a major scientific misstep that I believe gives partial culpability to science for the widespread misbelief, is that first major study published in The Lancet showing hydroxychloroquine to be ineffective actually was full of statistical errors that were severe and it was retracted.
We now have better studies showing hydroxychloroquine to be ineffective, but the first study everyone went off of showing it to be useless... actually was bunk. And not just a little bunk, "A first-year statistics major could tell you about major flaws in the design of the analysis." This, of course, was a major help to conspiracies and confused doctors, as why would everyone be using such a flawed study to claim hydroxychloroquine is ineffective? I get why it would look political.
Is that satire or acknowledging the fact that Paxlovid isn't really that great at preventing adverse outcomes? Poe's Law applies again, it's quite impossible to tell, but then with satire you are not supposed to be able to tell.
The early studies were with Paxlovid in unvaccinated patients, where it worked pretty good. But by now everyone is vaccinated and/or has caught the pestilence several times over, and efficacy against severe disease and death is much less clear-cut. It still provides benefit in the elderly, but not in the rest of the population.
