Promising Pills, but Lengthening Shadows

 

Paxlovid pouring off the assembly line in Germany

Game-changing treatment news, Italy right and wrong, longings for normalcy, updates on vaccine hesitancy, lots on long COVID, and many flavors of crackpot.

 

Treatment news

Paxlovid: When Merck announced the first anti-covid pill a few weeks ago it was immediately hyped as a game-changer. But Pfizer’s new combination pill frankly blows molnipiravir out of the water. Its main ingredient is a novel antiviral, PF-07321332, tailor-made for SARS-CoV-2. But each pill also contains a low dose of an AIDS drug called ritonavir that lets PF-07321332 hang around longer and stronger in the body. According to Pfizer’s press releasedescribing a 1200-subject controlled Phase 3 trial, high-risk unvaccinated patients with mild-moderate COVID-19 given Paxlovid ran an 85% lower risk of hospitalization if they were treated within 5 days of getting sick, and an incredible 89% if treated within 3 days, without major side effects. All 10 deaths were in the placebo group. Compare those results with 70% for Regeneron’s monoclonal antibodies, and only 50% for molnupiravir. This is without any doubt the most exciting COVID-19 treatment news ever.

As soon as Paxlovid hit the news the nutcases started saying it was just ivermectin under another name. Do you remember when they said the exact same thing about molnupiravir? Guess they’re reduced to singing a one-note tune.

On the availability front, the US government will be stockpiling enough pills for 10 million courses of treatment, while the UK, South Korea, and Australia apparently have next dibs. The factories in Germany, and upcoming in Ireland, allow hope that the European Union may get its hands on some as well. Pfizer has even committed to share its licensing, which though the agreement is limited should allow the production of cheap generics. The company has already submitted an application to the FDA for Emergency Use Authorization, though only for the unvaccinated; trials in vaccinated subjects and for post-exposure prevention are still ongoing. However quickly the regulatory agencies get their asses in gear, Paxlovid won’t hit your local pharmacy before the New Year.

Molnupiravir: Since Merck’s anti-COVID-19 pill works by inducing mutations in the SARS-CoV-2 virus, some reputable virologists are worried that its widespread use could lead to the evolution of dangerous variants. There’s even fear that the drug could promote mutations in human cells, promoting birth defects or cancer. Others are less concerned, and I’m no expert, but these possibilities do leave me somewhat alarmed. At the very least they’re another reason to prefer the Pfizer drug, in addition to its being more effective. (Incidentally, Merck too will be sharing its license.)

The “MATH+ Protocol”: In February Pierre Kory and co-conspirators published an article claiming a huge reduction in death rates when hospitalized COVID-19 patients were given a cocktail that included high-dose vitamins, melatonin, testosterone antagonists, and the antiparasitics nitazoxanide and (natch) ivermectin. Now the article has been retracted after investigators showed the data had been grossly falsified, and that “Protocol” patients actually died at a higher rate. It is unusual to have such clear documentation of research fakery.

Fluvoxamine: I should have featured more prominently the Brazilian trial that found this antidepressant, which costs €11 in Italy, to reduce hospitalizations and deaths in high-risk outpatients by more than 30% – even more if you only analyze patients who actually took their pills.

 

Vaccine news

Pfizer: The BMJ has published a whistle-blower’s claims that bad practices in Pfizer’s Phase 3 trial cast doubts on its results, while experts such as Paul Offit have cast doubts on those doubts. I suspect the truth lies in the middle. There may well have been specimen handling errors and unsafely discarded needles, but I’d chalk that up to the department of shit happens, and doubt they compromised the scientific findings. Incidentally, the Phase 3 trial showing 91% efficacy in children ages 5 to 11 has now been published, with no surprises.

Novavax: Finally! A mere 8 months after we first saw Phase 3 results showing 90% efficacy, Novavax has finally begun applying for emergency use authorization. It’s already approached Australia, Canada, the UK, New Zealand, the EU, and the World Health Organization, with the FDA up next. Indonesia and the Philippines, which were hard hit after using less effective Chinese vaccines, have already approved it. Novavax could be a winner in the developing world. It’s easy to ship and store, and will apparently be priced as low as $3 per dose to poorer countries ($16 to $21in wealthy ones).

Covaxin (BBV152): The 24,000-person Phase 3 trial of this home-grown Indian vaccine has now been published in The Lancet, touting an overall efficacy of 78% against any COVID-19 and 93% against severe disease. But efficacy was only 66% in people over 60 or otherwise vulnerable, and only 65% against the Delta variant even in the young. 

Waning Johnson & Johnson: Waning mRNA vaccine efficacy over time is old news, but J&J turns out to be even worse. In a study among US veterans, its effectiveness began to drop just weeks after vaccination and by 6 months had reached an abysmal 13%. It did continue to lower death rates, by 58%.

Waning Pfizer and Moderna: That same veterans study found Pfizer’s protection against COVID-19 to fall to 43% at 6 months, and Moderna’s to 58%; as usual, effectiveness against death was much better, especially in younger people.

Pfizer and Moderna meet Delta: Still another study, this one from Qatar, confirms that the Moderna vaccine is better than Pfizer in preventing Delta variant disease (73% vs. 52%), but also that both are great at preventing severe disease and death (93% and 96%).

Spikevax and the bottom line: The US National Institutes of Health, having invested top scientists and $10 billion in taxpayer funds into developing Moderna’s COVID-19 vaccine, is making claims on sharing the patent. Yes, it’s the best vaccine around, but Moderna has fixed prices to match, and particularly resists giving discounts to poorer countries. So the patent dispute could greatly benefit the global South, especially if the NIH not only succeeds in wresting control over pricing but forces Moderna to share its formula and technology.

Patch it up: Japanese and Australian researchers came up with the patch vaccine concept last spring. Now the Australians have gone one step further, showing their product can prevent COVID-19 in mice, while other groupshave joined the hunt. If patches can be stored at room temperature and be self- administered, they would be ideal for poor countries with limited infrastructure. But only if – a big if given the sophisticated technology – they can be priced affordably. …Plus one Guardian article, while enthusing about the soon-to-begin preliminary human trials of one patch vaccine, left buried deep in the text that this vaccine “Will not be available until 2025 at the earliest.”

Universal vaccines: A study of UK healthcare workers has turned up a few individuals who seem to have aborted SARS-CoV-2 infections on the basis of pure T-cell immunity, without ever developing antibodies. The researchers think this phenomenon could be exploited to create pan-coronavirus vaccines covering all present and future variants. Similar attempts involving influenza have gone nowhere, and coronaviruses are particularly complicated viruses, so I’m not holding my breath.

 

Il Belcovid Paese

Down with Italy! Bravo Italy! Take your pick. 

Glass half empty 

Infections have been rising sharply here in the last few weeks, and several regions seem destined for heightened “Yellow” restrictions. Here’s what’s behind the surge, as I see it: 

1)    Screening to meet Green Pass requirements is detecting more asymptomatic cases (unfortunately this isn’t as large a component as we’d hope).

2)    Those Green Pass requirements aren’t succeeding in motivating the unvaccinated, with first doses now down to 18,000 a day from an early summer peak of 400,000.

3)    The authorities have foolishly loosened up on discotheque restrictions, so cases are bounding in young people. 

4)    Likewise they’ve largely scrapped capacity limits. 

5)    The borders have become too porous. Italy now allows unvaccinated European Union residents, including from countries with raging COVID-19 epidemics, to enter Italy based simply on a negative rapid test, even though those tests notoriously miss up to 50% of infections. It’s abandoned quarantines, and stopped requiring follow-up testing. Not to speak of the return of those damned cruise ships, historically petri dishes for the coronavirus.

6)    The elderly and the medically vulnerable, who were vaccinated early on, have lost much of their protection by now and many are still unboosted. 

7)    The Delta variant is a bitch.

Glass half full

The redder the color, the more cases per million in the last week. The greyed-out countries (Croatia, Russia, Turkey, and the UK) would all be deep burgundy.

Italy’s figures are far better than most – fewer cases per capita than any other European country except Spain – and severe cases have barely inched upward. (Germany, once a model country, now has 4 times as many cases per capita and twice as many deaths as Italy, due to low vaccine rates, laxity in checking Green Passes, devil-may-care youth, and some optional masking.) Some reasons the Italians are doing so well:

1)    The Italian authorities have largely resisted the temptation to reopen. 

2)    They’ve put thousands of unvaccinated healthcare workers on unpaid leave without flinching. 

3)    They’ve imposed and enforced Green Pass requirements (vaccination, recent disease, or a negative swab) not only to enter restaurants/shows/museums/movies/stadiums but also just to go to work. People have downloaded 124 million QR codes thus far. And they may soon remove the rapid test option, creating a vaccine mandate for any worker who has not recently recovered from COVID-19. 

4)    Masks are required in all public indoor spaces.

5)    Italians have been remarkably obedient about masking, usually with KN95s – many still wear masks outdoors too (photo above), even though they’re not required.

6)    Vaccine uptake is high: 87% of all Italians over 12 have had a dose, 85% are fully vaccinated, and only 7% are determined novaxers.

7)    Older or vulnerable Italians fully vaccinated 6 months ago are flocking to get boosters – I calculate 60% coverage already – and in December everyone 40 and up becomes eligible.

 

American exceptionalism rides again

Novax demonstration

Vaccine hesitancy has been dwindling all over the world – except in the United States, where it’s hardly budged. Here are the rates the Morning Consult international survey found back in July:

Below is the same survey during the second week of November. You can see that the number uncertain or unwilling fell from 48% to 37% in Russia, from 28% to 13% in France, and from 19% to 11% in Italy, but only slipped from 30% to 27% in the USA.

 

Normalcy

David Leonhardt being reassuring on CNN

Several people have asked what I think about of a recent New York Times column by David Leonhardt, “How Does This End? Thinking about Covid and normalcy,” so I guess I should comment on it here. What do I think of the rosy picture he paints? Not much, and here’s why:

- Leonhardt inappropriately extrapolates the low infection rates in places like SF to the rest of the country. The CDC would consider 10 weekly cases per 100,000 to be acceptable? The US is currently running 177 (Italy has now hit 91, which we consider terrible because a month ago it was 28).

- He wildly underestimates the importance of long COVID.

- He spins the position of his chief consultant, a prominent Bay Area physician, as “let’s make like it’s 2019,” when judging by what Dr. Wachter himself says he’s actually much more cautious. My sources on the ground from South Carolina to Alabama to Massachusetts to Michigan tell me that Americans are pretty much already making like it’s 2019.

- When I checked out his “studies show” link for “The flu and other viruses also cause mysterious, lasting problems for a small share of people, studies show,” I was very irritated to see that the article actually says nothing of the sort – see for yourself. 

After Leonhardt two important pandemic pleas have arrived. Anthony Fauci aimed his to the 50 million eligible Americans who still haven’t had any vaccine: Get your shots! Vaccinating more Americans is the only chance we have at reducing COVID-19 to an ordinary endemic disease during 2022. Zeynep Tufekci, even more boldly, aimed hers at the highest levels of government: rebuild the public health infrastructure and create a “sane, sensible health care system” like the ones in other developed countries. 

 

Just when I thought I’d seen it all

A crude Photoshopping job that got shared 180 times on Facebook

My last post featured Italian fake vaccine news – this time it’s America’s turn. A few old chestnuts in a recent poll: 24% of Americans think vaccines might contain microchips, 31% think they might make you sterile, 24% think they might give you COVID-19, 21% think they might alter your DNA. But there’s a seemingly endless supply of new ones…..

-       Vaccinated pilots have been dropping dead mid-flight (a total fabrication).

-       Covid vaccines contain antifreeze.

-       Vaccines are “a violation of the Nuremberg Code.”

-       “Give up Fox News. They did their own mandate. I switched over to Newsmax.”

-       “The Covid vaccine, particularly boosters, interrupt our natural anti-bodies.”

-       “If they know your stance against the shot that you aren't given good hospital care.”

-       Aiding and abetting mass murder through vaccination, for population control.

-       The Vaccine Mafia are targeting Black People with their experimental military technology disguised as a vaccine.

-       Vaccines are the “white man’s death plan.”

-       “Bill Gates had a video where he said if they do good vaccines they can cut down the world’s population by 10-15%” (quote from Dr. Stella Immanuel, she of demon sex/alien DNA fame).

-       People vaccinated against COVID-19 are legally no longer human. 

-       We are at war with Transhumanist fundamentalists.

-       Fantasy: COVID-19 vaccines contain “remnants of a murdered baby.” Reality: no COVID-19 vaccines include anything human. Drugs tested on cell lines that may have originated in aborted fetal tissue include not only all 3 COVID-19 vaccines used in the United States, but also Benadryl, Sudafed, Tylenol, Tums, Preparation H, albuterol, aspirin, ibuprofen, Pepto Bismol, Lipitor, Senokot, Maalox, Ex-Lax, Benadryl, Sudafed, Preparation H, Claritin, Prilosec, Zoloft, Humira, and even the RegenCov monoclonal antibody treatment that’s been embraced by abortion-is-murderists such as Florida Governor Ron DeSantis. Not to speak of vaccines against chickenpox, rubella, hepatitis A, polio, tuberculosis, rabies, shingles, and Ebola. 

 

Long haulers

We know a great deal about what happens after COVID-19 patients get discharged from the hospital, but surprisingly little about how long people treated at home remain ill. The best single study in the medium term, from the Mayo Clinic, found that 71% of adult outpatients with mild-to-moderate COVID-19 (median age 41) were still ill after 4 weeks. 

In the longer range, studies agree on discouraging figures. In a study of Irish outpatients, 58% were still unwell an average of 10 weeks out, and 31% had not returned to work. A group from Seattle found that 33% of outpatients with mild disease had persistent symptoms after 6 months. In a Swiss study of COVID-19 patients, of whom only 19% had been hospitalized, 55% were still fatigued after 6-8 months. A recent systematic review concluded that 54% of all COVID-19 survivors have persistent symptoms 6 months later. One multinational study that focussed on long COVID found that 78% of outpatients who hadn’t recovered after 4 weeks were still experiencing fatigue at 6 months, 55% said they couldn’t “think straight,” 84% had at least one symptom, and only one in 3 had returned to fulltime work. In the UK last April one third of everyone who had been diagnosed with COVID-19 12 or more weeks earlier reported persistent symptoms, 40% of them for a year or more. Single-institution studies have reported 48% to 81% of all COVID-19 survivors to have persistent symptoms after a year, and some patients have reached the 18-month markwithout improving much. 

These numbers are terrifying. Even just sticking to official figures, which are widely considered underestimates, 86 million people in the world have survived COVID-19 in the last 6 months. So we can say with some assurance that at least 50 million people are right now suffering from sequelae of their infections.

Long COVID can afflict children, but much less often. An early UK study said more than 10% of kids under 12 still had symptoms after 5 weeks, but that figure was soon revised downward to 7%. Generally speaking kids stay sick for less than a week, with just 3% still having symptoms after a month. Only one small study, from the Gemelli Hospital in Rome, gave higher percentages, saying that 46% of children were still distressed by symptoms several months after being diagnosed. But children with completely asymptomatic infections were said to have even higher rates, 51%, casting doubt on all their findings.

Looking for good news about long COVID, I find myself grasping at straws. Here’s one: fully vaccinated people with breakthrough COVID-19 are half as likely as the unvaccinated to develop long COVID. And another: we’re starting to understand “brain fog,” including both its clinical characteristics and the abnormal cerebral PET scans and technetium scans (Marc Jamoulle, The Permanente Journal, in press) seen in a few patients. I’m also a bit encouraged by the growing consensus that a hyperactive immune system is responsible, because understanding causes can sometimes lead to treatment. Many long-haulers have autoantibodies directed against their own cells, and those antibodies could directly cause certain symptoms. Researchers have also found persistently activated immune cells and high levels of pro-inflammatory cytokines/chemokines such as interleukin 6, interferon gamma, and CCL5/RANTES.

On the therapy front, however, we’re still at the word go, and published guidelines, while I’m glad they’re being created, have little concrete to offer. 

Corticosteroids are invaluable for treating autoimmune diseases such as lupus and for the treatment of severe acute COVID-19. They also seem to have helped a handful of Spanish and Indian long haulers, though they could be counterproductive if taken at length; a larger placebo-controlled trial is being performed in Madrid (María Ruiz-Ruigómez, personal communication). 

One other candidate drug aimed at the immune system is undergoing testing: leronlimab, a novel anticytokine antibody with some antiviral properties, produced by a company called CytoDyn. It seemed to help a few long COVID patients in preliminary results reported this June, but there’s no word since. The drug initially flunked out for treating hospitalized patients, but the company hasn't thrown in the sponge,

Finally, after COVID deniers we now have long COVID deniers who think patients are inventing or malingering, a category that includes much of the medical profession. A new article from France, published in the prestigious Journal of the American Medical Association, claims to demonstrate that long COVID doesn’t really exist. Why? Because the researchers found that believing you had had COVID-19 predicted long COVID symptoms better than having measurable SARS-CoV-2 antibodies. The research methodology expert F. Perry Wilson points out points out fatal flaws in this study, including both failure to take swab tests into consideration and dependence solely on SARS-CoV-2 antibodies to establish previous infection. Many infections will have been missed, because antibodies drop rapidly in outpatients and often zero out by 3 months. I wish JAMA had sent Dr. Wilson this article for peer review before publishing it. Partly because of the French naysayers and their like, many American long COVID patients have found it difficult or impossible to get the disability benefits they desperately need.

 

Dressed to kill

This ad earned the Australian activewear firm Lorna Jane, brainchild of Lorna Jane Clarkson, a $3.7 million fine.

Lorna Jane Clarkson