Monday, September 13, 2021

Déjà Moo

 

This post focuses chiefly on the hot topics of ivermectin and boosters, with one major detour about Italy and two minor ones about the UK. Thanks to blogger John Earl for my title.

 

Treatment news



Many of those hydroxychloroquine studies are still ongoing, though the drug was proven useless long ago.

Rule, Britannia: Incredible – the Brits have found a new treatment for COVID-19!!! Here’s how the BBC put it on August 20, “A new Covid treatment - that uses a pair of laboratory-made antibodies to attack the virus - has been approved for use in the UK.” What they’re talking about is . . . . Regeneron’s Regen-Cov. Yes, the same Regen-Cov that reported its first positive results a year ago, was given to Donald Trump last October, received authorization for emergency use in the United States in November 2020 and in Europe in February 2021, reduces the need for hospitalization by 70% in high-risk outpatients, and is (along with other similar products) the absolute best treatment we have for COVID-19. But hey, in the UK it's a novelty. 

UK authorities are said to have dragged their feet over this approval because of the price. Why waste $1000 to save someone who’s already old or sick? Little COVID-19 news shocks me nowadays, but this penny wise pound foolishness succeeded. 

Incidentally, the UK approved remdesivir in May 2020, at a price to the the government of $2,340 for a 5-day treatment course. Remdesivir shortens hospitalizations by a few days but doesn’t as far as we know save lives. Monoclonal antibodies do.

Natural immunity: I hadn’t seen new data for ages about how long COVID-19 prevents reinfection. Now a large Israeli study says people who were sick early this year are less likely to get infected than people vaccinated with Pfizer around the same time; even those who were sick more than a year ago still had some protection (which could be further boosted by giving them a dose of vaccine).

Baricitimib: A large randomized placebo-controlled trial in hospitalized COVID-19 patients who had laboratory evidence of inflammation has now been published and says . . . maybe, verging on probably. When the drug was added to standard care, which usually meant steroids and sometimes remdesivir, there was no significant improvement in the researchers’ compound chief outcome of disease progression (27.8% vs. 30.5%) but there was an improvement in one of its components. Since that component happened to be overall mortality, which was about 40% lower in the baricitimib group, there’s reason to be optimistic. When an outcome isn’t preassigned as the main one, though, improvements should be taken with a grain of salt.  

Proning: For some years ICUs have tried to keep intubated patients face down, to achieve better oxygen levels. In the spring of 2020 some hospitalists thought “proning” might help COVID-19 patients too, and it was soon found to raise their oxygen levels. But nobody had demonstrated that it did any good against solid clinical outcomes until now. More than 1000 hospitalized patients receiving high-flow oxygen therapy were randomized to either lie on their stomachs as much as they could tolerate – averaging 5 hours a day – or to follow standard hospital practice. (Pregnant women and the very obese were excluded.) Significantly fewer proned patients wound up intubated or dead 28 days later, 39.5% compared with 46.1%, a 14.5% improvement that’s about as good as what’s found for the much-touted tocilizumab. I find it satisfying that such a primitive intervention could save lives.

S309: An monoclonal antibody too new to have a sexy chemical name is claimed to be capable of neutralizing all current SARS-CoV-2 variants and perhaps most to come. The original research report is very dense, and I don’t pretend to understand it completely or even to be sure it covers the Delta variant, which is already knocked out by our current monoclonal antibody products. Yes, a broadly effective monoclonal antibody therapy would be welcome, but a universal mRNA vaccine would be even better.

Small interfering RNA: So-called siRNA consists in RNA fragments capable of attacking areas of a virus’s own RNA molecules. This technology, new to me, apparently yielded several drugs active against SARS and MERS. Scientists proposed applying it to SARS-CoV-2 as far back as April 2020, and an Australian group has now reported promising preclinical results. Their drug worked in mice with COVID-19, which is encouraging, but mice ain’t men. One thing I don’t understand is why the researchers suggest their drug be used early on, when they’ve engineered it to target the lung, which gets involved late in the disease.

AT-527: A new oral antiviral from a small company. In a Phase 2 trial, hospitalized COVID-19 patients taking the drug had 80% less virus in their noses a week later compared with patients on placebo. Nice, but it doesn’t necessarily mean patients given the drug will die less or get better faster. Future trials in an outpatient setting seem more likely to succeed, given both that antivirals generally work better when given earlier and that the only antiviral that’s done anything to help hospitalized patients, remdesivir, didn’t do much.

 

Vaccine news

Pfizer ad coming soon?


Pfizer: You’ve all heard the big news: full approval from the US Food and Drug Administration after 9 months of emergency use authorization. Hopefully this will trim down America’s vaccine refusers to the hard core, since many of the uncertain say they’d reconsider if the vaccine were no longer “experimental.” 

It is already opening the door to vaccine mandates. The US armed forces instantly added Pfizer to the long list of vaccines already required of all military personnel (the military can’t require any vaccine that’s not FDA-approved). New York’s Board of Education followed suit, with many more likely to come along, dragging private companies in their wake. I wonder about police, fire departments, and correctional facilities, with their crazy low vaccination rates

Americans can expect ads to start popping up soon on their TV screens. I generally detest straight-to-consumer drug advertising, but I’m totally cool with glossy “sunset/couples-hot-tub commercials” if they’ll get shots into arms. 

One of those large-scale Israeli studies compared Pfizer side effects and complications over six weeks to the much greater risks from COVID-19 itself. Their most interesting finding was an increased risk of herpes zoster (shingles). This is surprising not because vaccination can trigger it – many stressors do – but because being sick with COVID-19, much more of a stressor, doesn’t. (Incidentally, they found a risk of myocarditis somewhat higher than previously thought, not 10 per million doses but 30. Still far less than the risk of COVID-19 to the heart.)

Speaking of side effects, we now have some reassurance about Guillain-Barré Syndrome: out of 579 Israelis with a history of GBS who were vaccinated with Pfizer, the vaccine triggered an episode in only one, and it was treated successfully. So having had GBS is not necessarily a contraindication to vaccination.

Viral vector vaccines: More than 40 million doses of Johnson & Johnson and AstraZeneca may be sitting unused on Italian pharmacy shelves at the end of September. Hopefully they’ll get donated to COVAX, but the government has to act fast, before the doses expire. Since the last proper shipment of AstraZeneca was on July 8th I had thought maybe the European Union had abandoned it altogether. But no, it’s ordering piles more, though Denmark, Norway, Austria, and multiple Italian regions have long since nixed this product altogether and Germany trusts it so little that it is going to offer an mRNA booster to everyone who was fully vaccinated with AstraZeneca. Incidentally, a handful of recurrences of the rare and obscure “capillary leak syndrome” (definition of obscure: I never heard of it before) have been seen in Europe shortly after Johnson & Johnson vaccination, adding to the short list of contraindications.  Good news: some 20 million doses of Johnson & Johnson that were produced in South Africa but scandalously shipped to Europe are now being returned to the African continent.

Sinovac: A Brazilian study I’ve mentioned as a preprint, finding Sinovac’s Coronavac vaccine cut Gamma-variant COVID-19 in people over 70 by only 47%, has now been published in The Lancet without the results looking any the better for it. The vaccine worked best in the youngest old, and was only 33% effective in people over 80. Another study in Brazil showed  unfortunately that Coronavac is considerably less effective than AstraZeneca, which as we know is in turn considerably less effective than the mRNA vaccines. An observational study in Chile, published almost simultaneously, found Coronac to be 66% effective, including over age 60, but unfortunately the researchers adjusted all their results for age and did not report subcategories of the over-60 group, making it impossible to judge effectiveness in older people. And we already know that Coronavac, like other vaccines, is less effective against Deltathan against other strains – though how much less the Chinese aren’t saying.

ZyCov-D: The Indian scientists who developed this DNA vaccine claim it’s 67% effective against clinical COVID-19. Not in the same class as the mRNA vaccines, and it requires at least 3 doses to kick in, but being cheap to make, easy to store, and easy to administer (needleless) this vaccine may be extremely useful in the developing world.

 

Wax, wane, boost? 


The story of COVID-19 vaccine boosters has been a roller-coaster ride. Almost as soon as the vaccination campaign began, both Moderna and Pfizer started planting the notion of yearly booster shots aimed at variants, with an eye on the bottom line. In April the Pfizer CEO went even further, suggesting we might need boosters as early as 6 months after our second shot. 

Bourla’s warnings were bolstered in July by terrifying reports in the Israeli press, supposedly based on leaked government data, that Pfizer administered in January had already worn off. After 6 months the vaccines were said to be only 16% protective against infection overall (as per the above chart), and older people were said to be only 55%shielded against severe infection. That meant me. It sounded like all us bubbas and alter-kakers who had been blessed with early vaccination should hurry to demand another dose.

But on August 25th instead of vague hints we received some actual data, in the form of the preprint of a million-person Israeli study (click on "preliminary report" in this article), and they’re much less dire. During July’s Delta surge, people over 60 who completed their vaccination in May were 75% protected against any infection, those vaccinated back in January 57% -– a falloff, yes, but by no means precipitous. Against severe COVID-19, protection was nearly unchanged: 91% and 86% respectively. 

Note that the Pfizer vaccine is substantially less effective against Delta even soon after vaccination. Estimates vary wildly, but protection is likely around 60%, so the effect of waning immunity is hopelessly confounded by the effect of the Delta dominance that hit just around that time. For me that means the Israel figures don’t in themselves justify a mad dash to get third doses. The heads of the FDA and the CDC seem to be thinking along the same lines in calling for the booster campaign to be postponed, just two days after Anthony Fauci had endorsed it.

Other studies of mRNA vaccines have found protection levels after 5-6 months of 74% in the UK, against infection, and 66% among American health care workers. In these studies as well, it’s impossible to sort out waning effectiveness from the relative resistance of Delta to vaccines. – in Qatar, for example, overall effectiveness against Delta was only 56% from Pfizer, though it was 86% from Moderna. But in Qatar as elsewhere, including in yet another CDC study, even Pfizer was still 90% effective against severe disease.

All vaccines lose effectiveness over time, but AstraZeneca seems to wear off somewhat more slowly than Pfizer, though headlines claiming they become equal are misleading. Here’s the actual data:


Are boosters the answer? We’ve known for months that 3rd Pfizer doses boosted antibody levels, but yet another large Israeli study now provides encouraging data on real-world effectiveness: people over 60 who completed their Pfizer series in Jan-Feb 2021 and received a booster shot in early August were 10 times less likely to test positive for SARS-CoV-2 (Delta variant) than those vaccinated in the same period who hadn’t yet had a booster. The effect started quickly and peaked after 12 days. The authors of the preprint calculate that the third shot hoisted the effectiveness of the vaccine against Delta back to around the 95% it had against the wild strain in Phase 3 trials. 

This report has nudged me back in the direction of the pro-booster camp, and to thinking that a simple third dose of Pfizer is so effective that there’s no need to insist on Moderna for your third shot. But there’s not great urgency, and I think it makes sense to limit boosters to people at high risk, the elderly and the chronically ill, until more progress has been made in vaccinating the global South. And I do keep hoping that a universal COVID-19 vaccine will come through, capable of preventing not only the Delta variant but the even worse ones surely yet to come.

How about reports that 60% of Israelis hospitalized with COVID-19 are fully vaccinated? Should we worry? Nope. Think of it this way: if 100% of Israelis had been vaccinated, then 100% of people in the hospital would be vaccinated too. (Incidentally most hospitalized Israelis are very old, frail, and sick, often coming from nursing homes. And despite waning immunity and Delta, unvaccinated Israelis are six to eight times more likely to get severely ill.)

I think it’s particularly important for people who originally received AstraZeneca or Johnson & Johnson, less effective to start with, to get boosters. The question is, which product to boost with? So far the strongest data we have are for the AstraZeneca-Pfizer combo, which sends anti-spike antibody levels sky high and lifts AstraZeneca’s effectiveness nearly to the pre-Delta Pfizer level. But now Johnson & Johnson are reporting that a second dose of their same vaccine, given 6 months after the first one, increases antibody levels 9-fold. A Johnson & Johnson booster would boost the company’s profits, but my instinct is to go instead for an mRNA second dose, as I’ve been advising friends and patients. As I’ve mentioned, Germany intends to give all viral vector vaccinees an mRNA booster, regardless of when they were vaccinated.

One thing is clear, though: between the heightened transmissibility of the Delta variant and the waning of vaccine protection over time, older people who were vaccinated early should take extra precautions until they can get a booster. My husband and I flew double-masked to and from our beach paradise in Turkey. I’m also changing my policy in the office. For months I had been examining vaccinated patients with both of us barefaced, but now the party is sadly over, masks all around until I get a third shot. 

 

You are not a horse. You are not a cow. Seriously, y'all. Stop it – tweet from the FDA





I went ivermectin shopping online


I’ve written several times about ivermectin, the antiparasitic that’s been portrayed as a preventive and treatment for COVID-19. It’s been dubbed “the new hydroxychloroquine”: equally ineffective, and hyped by the same players, from Fox News to the Brazilian government to the head of the Tokyo Medical Association.

Ivermectin is great for treating certain human parasites, from scabies to river blindness. Similarly, hydroxychloroquine is essential for treating lupus and other autoimmune disorders. And both drugs seemed from laboratory studies to have potential for treating COVID-19. Unfortunately when tested in actual patients both have flunked. As I’ve reported before, ivermectin proved useless when tested in properly done clinical trials in Colombia and Argentina, while the paper most cited in its favor got yanked by the journal for data fabrication.

Ivermectin is safe when taken properly, but very dangerous when taken in doses and forms intended for large animals such as horses and cows – which is sadly happening widely in the US at the moment.

American ivermectin aficionados have been around since the word go – a prominent one, the charlatanoid Pierre Kory, has testified twice to the Senate Homeland Security and Governmental Affairs Committee, on Ron Johnson’s invitation, in May and December 2020.



You can see a small surge in sales following December’s publicity, but it’s only late this summer that the ivermectin craze has caught on big… and the giant surge at the right end of this graph does not include sales through the internet, at animal feed stores, or through vets, all of which are soaring to the point that pharmacies, feed stores, and warehouses (both brick-and-mortar and online) have been stripped bare of anything containing it, down to deworming pastes for horses and shampoos for head lice. Poison hotlines from Alabama to Oregon are having to field calls from or about people who swallowed or injected doses meant for cattle, leading to everything from diarrhea to incontinence, hallucinations, coma, and death.

The big question is, why now? The answer is in part the “American’s Frontline Doctors” group. The same guys you met last November, touting conspiracy theories that go way beyond Q-Anon – extraterrestial DNA and demonic sperm, anybody? They turn out to still be around and shifting from theory to practice, peddling ivermectin to innocent marks at $90 for a “consultation” and as much as $700 for the drug itself (that’s what goes to pharmacies, presumably including a kickback). There’s reason to think that this group of medical nutcases is what’s behind the ivermectin rage on social media. Several judges have forced hospitals to give ivermectin to inpatients who present prescriptions from outside doctors, though not all those orders have held up in higher courts. I didn’t find the original rulings totally shocking, since doctors are allowed to prescribe medications off-label, until I learned that many prescriptions came not from patients’ personal doctors but from “Frontline Doctors.”

Even more dangerously, rightwing media personalities from Laura Ingraham on are now fueling the fire. Ivermectin, like hydroxychloroquine before it and many other earlier snake-oils, should perhaps be considered more a political story than a scientific one, dangerously so in the gun-crazed and hyper-polarized US. Here researchers who find the “wrong” results have received not only disturbing emails (“Are you a reembodied NAZI Josef Mengele?”) but concrete threats to themselves and their families.

 

Close your eyes and think of England?

Face masks are obligatory on the London Tube

The classic advice to English brides facing the challenge of coitus is currently being flipped on its head: close your eyes, take off your facemask, and nuts to England. The UK’s life-as-normalists seem to be winning out, with masks and distancing fading away. Might that possibly have anything to do with the dire current state of their epidemic?



 

Stick out your arm and think of Italy

Face masks are obligatory on the Rome Metro


Italy’s vaccination campaign is now neck and neck with the UK, and it’s based overwhelmingly on the highly effective mRNA vaccines. As you see, they’re good about masks too… and, not surprisingly, they’re having much less of a Delta surge.



Italy is doing a lot better than the US in terms of both vaccination rates and the state of the pandemic. As of September 12th, 87% of Italians over 60, but only 78% of Americans over 65, were fully vaccinated (note the different denominators). And 81% of Italians over 12 and 74% of the entire population were at least partially vaccinated – compared with 75% and 64% of Americans. 

One way Italy has been encouraging vaccination is by making Green Passes (vaccination or recent COVID-19 or negative swab) obligatory to access everything from restaurants to long-distance trains. Just last night my husband and I had the mild thrill of having our QR codes scanned for the very first time, to see a dance performance. When recent demonstrations against the Green Pass managed to turn out only a few dozen people, hard-core activists decided to go for violence instead of popularity, putting together stashes of knives and brass knuckles for next time around, until the cops broke up the plot.

In October all employees will need Green Passes if they want to work in person. Teachers already have to show theirs at the gate, and vaccine refusers foot the bill for their own triweekly antigen swabs, as well they should. Hopefully vaccination will soon become mandatory for teachers. It already is for health care workers, and since August hardcore novaxers (fewer than 3% of doctors and nurses, but in some regions 10-12% of nonprofessional staff) are starting to be suspended without pay.

Between high vaccine coverage, the Green Pass, and unwavering adherence to masking and distancing, Italy has kept the pandemic in check even in the era of the hyper-contagious Delta variant. Yes, infections (graph above) and deaths have gone up a bit recently:



But there’s no comparison to the American horror show:






In one way, though, Italy is similar to the US: roughly speaking, where vaccination rates are low, case rates are high. If you believe in science, that’s no surprise at all.

Vaccination rates (left), weekly case numbers (right)


 

Lone Star striptease

A run-of-the-mill mask demo


For once, a flamboyant mask demonstrator who’s on the side of the angels:
















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