Best Covid-19 news ever; signal the beginning of the end of the pandemic

Three just released British studies - for which I have no link because I'm in my Christmas break, not following the professional news so close; just got this from a newsletter sent to my mailbox but the actual article (presumably with links to the studies themselves) is behind a paywall I don't subscribe to - seem to confirm that Omicron causes milder illness than Delta.

Both Merck's and Pfizer's oral antivirals got authorized by the FDA. Merck's, which is less efficacious (30%) and with more side effects including birth defects, is more restricted, including high risks patients who can't have access to other accepted treatments. Pfizer's, which has higher efficacy of 88%-89% in avoiding hospitalizations and deaths in their studies and much fewer side effects, is authorized quite broadly, for any patient older than 12 and weighing more than 88 pounds, who is at high risk for developing severe Covid-19.

The latter is a HUGE game changer. The United States' government has purchased 10 million complete courses of treatment (several pills per day, for five days, taken at home) and it will be available in a few days. A positive PCR test and a doctor's prescription will be required. It will be free for the patients. It needs to be started within 5 days of the first symptoms.

Like I said many times, this treatment, Paxlovid, is equally efficacious for all variants of the SARS-CoV-2, present and future, because it hits the virus in a process that they all need to replicate, and is not subject to mutations.

I think these combined news, with the fact that milder Omicron is replacing deadly Delta (yesterday, 74% of all US infections were Omicron; in a few days this will be 100%), signals in my opinion the beginning of the end of the pandemic. Likely Omicron will run all over the country, will infect millions, and will act as a natural vaccine, counting towards herd immunity; those who will contract it and might be at risk from it, will get the oral antivirals.

The only obstacle in this rosy picture is that Pfizer doesn't have yet much production capacity for its brand new oral antiviral, and we have way more than 10 million people who might catch Omicron and still be at risk. Hopefully the production will increase in the next several month, Omicron will peak and fade relatively rapidly (because it spreads so fast), we may have a bumpy winter with overwhelmed hospitals, but Spring and Summer may bring life back to (almost) normal.

The FDA says that the two authorized antivirals are not to be used for prevention or post-exposure so they are not a substitute for vaccines. They are to be used for confirmed PCR-positive high risk patients. Still, if distributed widely enough to catch these cases, it will have a great positive impact in avoiding hospitalizations and death.

Finally, excellent news. Advanced science is about to bring an end to this pandemic. Once these antivirals are everywhere in a pharmacy near you (which may take several months to happen), Covid-19 will become a case of the sniffles, with minimal mortality and hopefully minimal morbidity.

 

I think the FDA approval of the Pfizer protease inhibitor is great news.

However, everyone who gets covid with more than very mild symptoms will want the pill. We will soon get 300,000+ new cases per day, could be 500,000 or more. Only 65,000 treatments will be available in the first week. That won't cover a lot of the new infections. The question is: How will it be determined who gets the treatment and who doesn't?

My view: People thinking that this drug will save the day of they get sick after Christmas and New Year parties will have to think again. While it is great that this drug will be available, it is not going to save the bacon in the early stages of the current omicron wave. People will behave irresponsibly, then get sick, and go to the hospital with the expectation to get a prescription of PAXLOVID. They will be sorely disappointed to hear that there are not enough doses.

My suggestion: Don't bet your life on this drug, at least not for another 1-2 months. Will people listen? Probably not.

 

Very true. The gatekeepers are supposed to be we, the doctors, because this drug requires a prescription and it is supposed to be only given to people who have at least one risk factor for severe Covid-19. But I'm telling you, for many doctors it will be hard to deny a patient the drug - he/she is your longstanding patient, he/she is scared, is begging for a prescription... what to do? How can you be sure that if you deny the prescription, there won't be a poor outcome, maybe not death, but organ damage? I'm actually happy in this regard that I'm a hospitalist, so, I'll only have to typically deal with sick people who do qualify. A pediatrician, or a family doctor taking care of a healthy young adult, will have an ethical dilemma in their hands if their patients ask for a prescription of Paxlovid and do not qualify. I'd hope that people will follow the FDA guidelines but I know that it won't happen every time (unless there are other mechanisms to ensure compliance). I'm also afraid that the bad guys will get hold of this. Just like you have online pill mills that deliver prescriptions of Viagra, we may see pill mills delivering prescriptions of Paxlovid for the people willing to pay top price for a prescription. Medical Boards will have to be attentive. As usual, when human beings feel threatened, they get selfish and they want a solution for themselves, and couldn't care less if the prescription they'll be getting will deny the drug to someone in dire need of it who then won't find it available. This could be a mess.

This said, I'm on vacation, enjoying my Christmas break, with my family out of town, and I did not look into whether or not there will be some sort of additional control, such as, the need to show evidence of a co-morbid condition that makes someone an elevated risk for severe Covid-19 before a prescription can be written. I haven't even read the FDA's EUA yet. I'm looking at this intermittently and from lay sources, mostly. While I do have VPN access to my hospital's intranet, I didn't even bring to my vacation the tablet from which I can have that access (which is vetted and encrypted). I brought my personal laptop and I don't mix pleasure with business. Access to the intranet from this laptop would be a violation of the conditions of use, because we don't want to increase hacking opportunities by allowing people to use their personal machines to log into the intranet, without them being brought to the IT Department for encryption, and I don't want my personal laptop to have the hassle of the encryption and the security steps they require.

So, I'm without my regular tools where I receive official notifications and memos from my hospital's Pharmacy and Therapeutics Committee, and the tools from where I have hospital-sponsored paid subscription to several scientific journals and trade publications, etc.

The bottom line is, at this time I'm as equipped as any of you for looking into this, instead of having an insider track. Rather than unfettered access to professional sources, I can only do what you all do: a Google search. So I don't know all the details yet.

But once production beefs up and the pills become widely available, then they will be a game changer, no doubt.

 

You should probably just stay home indefinitely with tightly locked doors.

 

So, something doesn't quite make sense to me: These anti-virals hit the virus where they need to replicate, as you stated. So why wouldn't you use them as a preventive? From a layman's prospective(which I acknowledge to be inferior to a scientific one), it makes common sense that it would seem to act as a natural preventive. If I had to take a stab at it from a layman's prospective, I think the FDA is largely saying that as a supply issue. If people viewed it as a preventive, the demand would be excessive to supply. But regardless of the FDA's statement, the overall impact of this anti-viral(by definition of its own name, anti-viral) is that it would eliminate the virus in a person's system.

Hell, I still remember early in the pandemic we were told that there was no way to tell(short of the PCR test) due to asymptomatic people. So wouldn't it stand to reason that most people have/had virus in their system? Yeah, I think the FDA's claim is not based on the science, but on the supply chain issue.

 

As planned by Bill Gates pandemic supposed to stop in 2022.
Everything goes by schedule.
Once QR codes are implemented, shadow government does not need to worry about anything.

 

I might be hard to grasp, but the world is not black and white. One can go out and enjoy life while still trying to minimize one's exposure to the virus.

 

Simple. These are short-acting drugs. You can't use them for prevention unless you took them every single day for months in a row, and then the risks of more severe side effects would be likely to be prohibitive. These are treatments (it's a five-day course), not preventative drugs. They weren't studied for prevention, and they weren't studied, safety-wise, for prolonged daily use. So, no, the FDA was not able to approve them for this indication. Yes, the FDA's indication is based on the current science. They can't take wild guesses and assume that daily use for months is safe. Because, you know, the moment you stop taking it and it gets out of your system, you're no longer protected since they aren't antibodies. They act on the live virus that is infecting you here and now. So for preventative use you'd have to take them constantly.

The supply issue resides on restricting them to people at risk. Yes, of course this part is true, because if we had enough for 350 million treatments instead of 10 million (and these 10 million will take months to be produced and delivered; the first batch until year end will have only 65,000), sure, anybody who caught Covid should have it, just like anybody who catches the flu can have widely available Tamiflu.

Do realize also that Pfizer's trials were on people at risk, so even from this perspective, the FDA indication is correct. But I'm sure that when the drug becomes more available the FDA will extend the indication to anybody who catches Covid-19. We're not there yet. Actually we are months or one year from that. Which is why we still need to be careful and still need to vaccinate (lousy protection against Omicron but at least some protection; we'll be gaining time until Paxlovid becomes more available).

There was a very recent study saying that 3 doses of an mRNA vaccine prevents Omicron, but likely just for 10 weeks (based on the pattern of fading neutralizing antibodies, which is known, and the threshold for Omicron neutralization which is way higher than for previous variants, so a booster would offer protection for a few months against the other variants but likely just 10 weeks against Omicron - do take it all with a grain of salt because it's theoretical and Omicron hasn't been around us for 10 weeks). Each week of production of Paxlovid will be precious, to avoid deaths.

 

When I visited my Daughter in British Columbia, Canada, couldn’t go to a restaurant without a QR code. Had paper proof of two Moderna shots, and several photo ID’s, however, unacceptable.

 

For some people life is enjoyable even in prison. You are apparently suggesting to accept that kind of enjoyment.

 

Yea, but some people do not understand who easy they can be fooled.

 

@AmericanNationalist and @CenterField,

I agree the use of these protease inhibitors as prophylactics would produce some serious side effects. One protease inhibitor (ritonavir) in the Pfizer drug is an old HIV protease inhibitor that was discontinued in therapeutic doses because of it’s side effects. Now it is only used in small amounts to act as a half life extender of other protease inhibitors. In this drug it’s likely very safe as a treatment regimen but would not be good for kidneys (especially diabetics and pre-diabetics kidneys). I believe they are using a lower dose on people with diagnosed kidney disease, Centerfield can correct me if I’m wrong on that.

I’m very happy this is an option for people at risk. Good news indeed.

 

And we're sure the pills are going to work miracles because . . .?

 

Well, we’ve been trying to come up with a vaccine to whip AIDS/HIV for decades with not much success. Protease inhibitors have turned HIV into an infection you can live with not die from. It’s likely the same scenario will play out here. Protease inhibitors will likely eclipse vaccines for Covid as well.

One of the protease inhibitors in the Pfizer drug is an old HIV inhibitor that has documented success (but some serious side effects). It’s being used in doses low enough to avoid serious side effects as a treatment along with an inhibitor designed for SARS1. In HIV treatment, protease inhibitors must be taken indefinitely so side effects are more of a concern. For Covid we only need a few days of use. I don’t expect miracles but especially with Omicron it’s certain to help. Which is good because monoclonal antibodies that have been working well won’t help much with Omicron.

 

Omicron being a weaker variant is the end of the pandemic. Time will likely tell that the next variant will be weaker still.

 

Correct.

Eli Lilly's and Regeneron's monoclonal antibodies won't be distributed any longer since now Omicron is the dominant variant and they are useless against it. There will be beefing up of the production of Sotrovimab, the one made by Vir and GSK, which remains active against Omicron.

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Paxlovid is active against Omicron, as expected. Yes, Paxlovid is a combination of nirmatrelvir and a low dose of ritonavir, the latter just intended to keep nirmatrelvir blood levels up for longer. The active one against the SARS-CoV-2 is nirmatrelvir.

Yes, prolonged use of ritonavir can lead to liver damage. Even for short-term use in low doses, caution should still be exercised for patients with pre-existing liver disease and it should not be given to people with advanced/severe liver disease..

The most common side effects of Paxlovid are impaired sense of taste, diarrhea, high blood pressure and muscle aches.

People with uncontrolled or drug-resistant HIV-1 should not use Paxlovid. It is also contra-indicated in patients with advanced renal disease.

There are numerous drug-drug interactions between Paxlovid and other medications a patient may be on, so your doctor will have to run a drug-drug interaction checker before prescribing it.

Paxlovid is packaged with two 150mg tablets of nirmatrelvir with one 100mg tablet of ritonavir for each oral administration. The three tablets are to be taken together, twice a day for five days. It needs to be started within 5 days of the first symptom of Covid-19, and it is only approved for PCR-confirmed cases, in patients 12 and older, heavier than 40kg (88 pountds), and with at least one condition that puts them at risk for severe Covid-19.

The above are the most important general facts.

Here are more details for those who crave them:

More specifically, nirmatrelvir binds to the catalytic cysteine (Cys145) residue of the cysteine protease enzyme called 3C-Like Protease (3CL-Pro) that is used by the SARS-CoV-2. So by binding to this residue, this drug inhibits the activity of this specific cysteine protease, which is an enzyme that cleaves the virus' polyproteins 1a and 1ab, a process that the virus needs to replicate. This enzyme does that, by catalyzing the hydrolysis of peptide chains. This process is common to all variants of the SARS-CoV-2, thus why this medication is equally active against all variants, present and future. This process is not subject to mutations. Without the ability to cleave its polyproteins 1a and 1ab (which would result in the formation of 14 structural proteins) the SARS-CoV-2 can not replicate (it can not make more copies of itself).

Ritonavir is a potent inhibitor of the CYP3A4 enzyme, which is part of the cytochrome P450 system. This is the system that degrades drugs in the liver, and the CYP3A4 is responsible for digesting nirmatrelvir, among other drugs. So by inhibiting this enzyme, ritonavir makes nirmatrelvir available for longer in the blood stream, and with higher plasma concentration. It pushes the half-life of nirmatrelvir to 6 hours (half-life is the time that it takes to digest/eliminate half the amount of a circulating drug after administration - about 5 half-lives are needed for complete elimination of a drug). So ritonavir keeps nirmatrelvir active until the next dose.

 

So possibly **** your liver up, or just get over the common cold as you used to normally do.

Got it.

 

Very good explanation. There is one caveat, though. While paxlovid target the cysteine in the catalytic site, which cannot be mutated, for covalent modification, it gains its high binding affinity from non-covalent interactions with other residues in the binding site, which CAN be mutated. Here is the paxlovid-bound SarsCov2 protease structure:



The cysteine modified by the CN group is on the left. There are lots of other intermolecular interactions, though, for example indicated by the dotted lines, such as hydrogen bonding, or hydrophobic interactions. Those CAN be changed by mutations of the protease, potentially weakening the affinity for the compound.

Not trying to be a negative nelly here, just pointing out the realities behind the science.

 

Awesome info. Thank you.

Thoughts on this?

Data from a new study suggests negative effectiveness

https://www.medrxiv.org/content/10.1101/2021.12.20.21267966v2.full

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That's concerning. If I'm reading that correctly, only Pfizer guarantees protection without possibility of increasing infection odds, and only for 30 days. After 90 days both, only increase the odds of infection.

I'm looking at the methods to see if there something there distorting these results:

Thanks, Zorro

 

Darn, yes, that could potentially become a problem. Thanks for pointing it out. Let's hope it doesn't.

 

Zorro, that's not what this study is showing. The way we use to calculate efficacy is like this:
100 subjects in the vaccine group, 100 subjects in the placebo group.
Say, 30 days after peak, 10 people got Covid in the placebo group, and 2 got it in the active group.
This means that the vaccine is 80% effective (not 90%). The 80% comes from the comparison between 10 and 2, not 100 and 90.
So if at 61-90 days the protection goes like this, 5 people catch it in each group, then the efficacy is 0%.

Now as time goes by, if the protection entirely disappears, what you'll see as people go about their business, is that the no-longer-protected people who got the vaccine start getting Covid. Their advantage has crumbled so they start to catch up to the other group. So it then happens that that group may have 10 infections and the other group 5 (the virus has already collected the low-hanging fruit for the other group) so now you have a negative 50%.

But it's not that the vaccine is MAKING people get infected or increasing the odds that they'll get infected. It's just because no longer being protected, those who had avoided the infection at the time when the vaccine was working, start getting Covid because the vaccine is no longer working.

Any vaccine that protects for a short period against a highly infectious disease will show something like this. But it's not the vaccine that is making people catch it. It's just that the vaccine is short-acting so it only protected people for a few months.

Those vertical lines are confidence intervals. What matters is the dot. So both the Pfizer and the Moderna only turned negative at 91-150, with Moderna performing a bit better.

Boosters appear to push it again to positive 54.6% against Omicron, in this study, and positive 75.5% in another one they quoted. There's been evidence that this protection, for Omicron, is supposed to last for only about 10 weeks.

Do notice as well that this is just antibodies. There is also cellular immunity.

The bottom line is:

Yes, protection from these vaccines against Omicron is short-lived (better with booster), but no, the vaccines won't make you catch Omicron or increase your odds of catching it..

 

Some of us listen.

I'm alive to listen because I listened about a wearing seatbelt (and shoulder belt)--January 5, 1973 when I got in an auto accident that totaled my car and would almost have certainly killed me. Our daughter was born on September 17 that year. Every day is a bonus. No sense throwing your life away on covid.