Wednesday, December 30, 2020

Naughty Or Nice

Inside a London supermarket

Treatment updates

Head louse, a target of ivermectin

Ivermectin: I poo-poo’d this antiparasitic drug months ago saying it had been tried only in test tubes and its chief promoter looked like a charlatan. Now that the drug has gained traction on the COVID-19 fringes I thought I’d go back to it. Pierre Kory, the guy who plugged it as a “wonder drug” in front of a notorious Senate panel in early December, is another charlatanoid, with his vitamins and ivermectin-laced protocol and his hyping ivermectin as “a global solution to the pandemic.” Would that it were! Dr. Kory has shifted his allegiance from hydroxychloroquine to ivermectin but he’s still singing the same tune. Ivermectin does have some antiviral effect in test tubes, but at levels higher than it is possible to reach in people. At least now several studies have been undertaken in COVID-19 patients. Two, in Florida and Bangladesh are retrospective rubbish. A third, also from Bangladesh, very small but methodologically better, found that patients cleared the virus slightly faster on ivermectin than on placebo, but did no better clinically. Another study, in Baghdad, supposedly randomized but very small and lacking either placebo controls or peer review, suggested some clinical improvement in patients given two doses of ivermectin alongside the tetracycline antibiotic doxycycline. Yet another trial is currently recruiting patients with severe COVID-19 pneumonia in Colombia, maybe that one will help settle the question.

Azithromycin (Z-Pak): I never understood how come this antibiotic got so widely considered of value in COVID-19. A new negative report from the RECOVERY trial should put that myth to rest.

REGN-COV2: A trial of Regeneron’s monoclonal antibody cocktail in outpatients has now been published, and the results are promising. In patients so early in their illness that they hadn’t yet developed any of their own antibodies, the viral load in their noses dropped markedly and only 6% needed medical attention within a month, as compared with 15% in a placebo group. 

Bamlanivimab (LY-CoV555): Lilly’s monoclonal antibody has flunked out definitively in COVID-19 patients hospitalized with pneumonia, confirming mediocre interim results. Maybe, like REGN-COV2, it’ll work better in outpatients.

A box of Lilly's monoclonal antibody on a pharmacy shelf in Georgia

Antibodies, anybody? Here we were thinking you had to be named Donald or Rudy to get your hands on the Lilly and Regeneron products. Amazingly, the opposite seems to be true: these valuable drugs are going unused. Nearly 300,000 doses have been shipped from federal stockpiles to American hospitals, but 80% of them are languishing on pharmacy shelves. One barrier to their use is logistical. Both drugs need to be administered, early in the course of disease, using a multihour intravenous infusion, in hospital-level environments with staff and equipment to handle possible severe reactions (though those reactions actually aren’t materializing). Another and probably more important barrier is a self-fulfilling prophecy – if patients and doctors all think you have to be rich or famous to get your hands on them, nobody tries!

The latest twist: AstraZeneca has come up with a long-acting antibody injection that they think could protect against infection for 6-12 months. A Phase 3 trial started up this month in people who’ve been exposed to COVID-19. (I’d be a bit concerned this drug might interfere with the response to a vaccine.)

Two ferrets

Dimeric lipopeptides: Remember that anti-COVID nose spray that had me all excited a month ago? The one that worked in ferrets? There’s no hint anyone’s started studying it in human beings. 

Baricitinib (Olumiant): This “JAK inhibitor” seems to slightly boost the modest efficacy of remdesivir in advanced COVID-19. But those are just the patients who should already be getting a much cheaper and more readily available drug, corticosteroids such as dexamethasone, which unlike barictinib have been shown to decrease death rates. A National Institutes of Health panel suggests baricitinib be considered only in patients who for one reason or another can’t be given steroids.

Remdesivir (Veklury): Intravenous remdesivir somewhat shortens the hospital stay of COVID-19 patients, but since antiviral drugs always work better the earlier they’re begun, it would make sense to try administering it before the patient becomes sick enough to need hospitalization. A phase 3 trial in outpatients has been underway for more thantwo months, no news yet. But wouldn’t an inhaled formulation rather than an intravenous infusion be exciting? A Phase 1/2/3 trial of just such a formulation has been started, in patients within 4 days of their positive swab. It’s still recruiting subjects, so we won’t see results for at least a few weeks.

Natural protection: We know now that SARS-CoV-2 antibodies fade away following infection, falling below the level of detectability after 2 months in 28% of people with mild cases. Putting that together with the fact that being exposed to SARS-CoV-2 protects you for at least 6 months, it is clear that the non-antibody-based parts of the immune system are particularly important in warding off COVID-19, as some have hypothesized, and that the absence of detectable antibodies doesn’t mean a COVID-19 survivors isn’t immune.

Foodstuffs: It’s easy to cure yourself of COVID-19. All have to do is eat a bat. A live one. (Eye of newt, anyone?)


Vaccine updates

Vaccination booth on Rome’s Piazza del Popolo, artist’s rendition

Sputnik V: The final results of the Russian Phase 3 trial have been announced in a press release: 78 cases of COVID-19 among 22,714 volunteers, 91.4% efficacy overall, and 100% in preventing severe disease (20 cases, all in the placebo group). A full report in “a leading medical journal” has been promised, so we will finally learn as yet unknown data crucial for countries’ decisions whether to authorize this vaccine, such as how old the volunteers were. My skepticism level remains high. 

Sinopharm: For the first time Phase 3 results from a Chinese vaccine. Sort of. A brief press release in Chinese supposedly says only that it’s 79% effective.

Pfizer: I said in my last post it was unthinkable for pressure from Trump to make Pfizer renege on its promised supplies of vaccine to the European Union and others. But I may have been wrong. Thank heavens the European calendar has been moved forward , with the EMA approving the vaccine a week earlier than planned. Pfizer’s Phase 3 trial has now been properly published, and looks good. It works as well in the obese as in the skinny, as well in the elderly as in the young (94% at 65-91 [N=3848], 95.6% under 55), and it works in blacks (N = 1502) and the chronically ill (N = 3934). It also seems to give at least 50% protection after the first dose. Pfizer hasn’t demonstrated it blocks asymptomatic infection, but according to one medical source they’re on the case, using a clever trick: in periodic blood draws of all Phase 3 subjects Pfizer is measuring not just total anti-SARS-CoV-2 antibodies but all sorts of subtypes. If the blood of a vaccinated person contains antibodies only against the spike protein, the ones induced by vaccination, then the person was never infected with the novel coronavirus. If they additionally have antibodies to other coronavirus proteins, they were infected. That should give a good idea whether the vaccine will block transmission as well as disease.

Moderna: The FDA has approved their vaccine for emergency use, and the European Medications Agency is expected to follow. Overall efficacy was about the same as for the Pfizer vaccine, including among chronically ill (N = 3102) and black (N = 1369) vaccinees, with some advantages. The Moderna vaccine is shippable at ordinary freezer temperatures, storable for a month in a doctor’s fridge, and protects overwhelmingly against severe disease. Another plus is that protection was 92.1% just two weeks after the first dose, nearly as good as after both doses. So it might be possible to postpone the booster shot, or even to use a one-dose regimen to cover more people fast. Moderna performed SARS-CoV-2 nasal swabs on their volunteers before each dose, and vaccine recipients were one-third as likely to come up positive on the second swab, implying the vaccine can largely prevent asymptomatic infection, breaking the chain of transmission. 

On the down side, Moderna’s vaccine gives worse flu-like reactions than Pfizer’s, and works a little less well in the elderly (95.6% effective at ages 18 to 64, 86.4% at 65 and older). Unfortunately for those of us in Europe and elsewhere outside North America, it will be months before any doses get beyond the US and Canada ­– and very few have even been promised.

AstraZeneca: The UK has approved the home-grown “Oxford” vaccine for emergency use, and plans to start vaccinating a million people a week shortly after New Year’s. Though how they intend to persuade people to take a jab that’s 60% effective when the competition hits 95% is beyond me.

Warped Speed: After downsizing their promises from 300 million to 40 million doses by New Year’s, Operation Warp Speed actually had shipped only 11.4 million doses around the US as of December 28th, 2 weeks after the vaccine campaign began, and only 2.1 million doses had definitely made it into arms – probably an underestimate, but even double that figure would fall far short. For comparison, when a single case of smallpox appeared in New York City in 1947, the health authorities managed to vaccinate 5 million people in two weeks.

European vaccination campaigns: On December 25th a first convoy of Pfizer trucks set off from the factory in Belgium, carrying doses to France, Germany, Spain, Italy, Belgium, Luxembourg, Holland, and Switzerland for a December 27th “Vaccine Day.” On Christmas the first doses reached the Spallanzani infectious disease hospital in Rome and were distributed around the country. But there were only 10,000 doses total for Italy, making the kickoff purely symbolic. France and Germany started mass vaccinations immediately, though the first batches will be smallerthan they had hoped – only enough to vaccinate 5% of the population by the end of January.

DHL will have flown 625,000 doses to Italy by the time you read this, but the vaccination campaign will only really start around January 15thFirst will come front line health care personnel – a couple of my officemates already have appointments – and nursing home residents/staff. Private physicians such as myself will probably get our vaccines in March, and it will likely be April before they get to anyone in the general population: people over 80, then those 60-79, the chronically ill, and essential workers. Rather than retrofitting the many public spaces that have been sitting vacant since March, authorities have their hearts set on building 1500 flower-shaped vaccine centers ex-novo on piazzas and in front of hospitals, to be manned by medical trainees or unemployed doctors and nurses. Once the inevitable polemics calm down, the vaccine centers should start springing up around Italy like so many mushrooms. You can already watch a nice pro-vaccination spot that uses the primrose – traditionally the first flower of spring – to symbolize the country’s return to life after this year-long winter. 

Italian subway car, 2020

Unfortunately neither the spot nor the virologists I’ve seen plugging the vaccine have been warning people that it may put them out of commission for a day or two with flu-like symptoms. Tactfully avoiding mention of those side effects will undoubtedly backfire, swelling the ranks of the no-vaxxers. On both sides of the pond their number has been shrinking lately, as the 95% efficacy rate sinks in and people are seen getting shots on TV. By now 73% of Americansand 77% of Italians say they’ll get vaccinated. But in Rome’s Lazio region only 70% of National Health Service docs have signed up for their jab. The head of the medical society calls it an “excellent percentage.” I say it’s terrible. 

Everything about the Pfizer vaccine is complicated, starting with the nightmarish cold chain (the company promisesit’s working on a more manageable formulation). Believe it or not, some batches of Pfizer vaccine had to be returned to the manufacturer because they had been transported too cold (at -92º C instead of -70º C). Then there’s the need to dilute the 5-dose vial doses, to be precise at drawing vaccine into the syringe, to discard unused doses after six hours. But I didn’t know until now that, at least according to one non-medical source, “Once the package reaches the hospital, the staff only has 90 seconds to unpack the boxes, check to make sure all the vials are intact, and put them into the ultra-cold freezers.” Who’s going to train the thousands and thousands of staff? Who will monitor adherence to protocol? This stuff is difficult enough even in the best-organized countries. In Germany several health care workers landed in the hospital because the person who vaccinated them screwed up the dosage. The Germans may also have to toss 1000 doses in the trash because of cold chain lapses. I tremble for my beloved but chaotic Italy…

Vaccinating placebo recipients: I’ve seen two good articles going into detail on this sticky issue. One is freely available but the other, even better, is unfortunately difficult for non-physicians to access. Pfizer is continuing to stonewall its placebo recipients, saying it will “unblind” them – tell them they received placebo – only when their turn for vaccination comes up according to age or work status. Moderna is being more menschlich, trying to offer vaccine right now to everybody in their placebo group, but they’re getting pushback from the FDA.

Side effects: A handful of people vaccinated with the Pfizer vaccine, and now one who received the Moderna version, have had anaphylactic allergic reactions. Most of them had had that kind of severe reaction in the past to medications or foods, but at least one had no known allergies. This is a somewhat higher rate than the 1 in a million usually reported with vaccines, which is somewhat worrisome. But mainly it underlines the need to observe everybody for 15 minutes after vaccination, to observe people with histories of anaphylaxis for a half hour, and have emergency supplies of adrenalin and other rescue meds on hand. Both vaccines contain polyethylene glycol, believed to be a potential culprit. 

Eight Moderna or Pfizer Phase 3 volunteers (out of 73,000) developed Bell’s palsy – facial paralysis – during the course of the trials, with all except one in the vaccine group. This suggests a link and is plausible, since other vaccines have been tied to various neurological syndromes.

Warped Speed: After downsizing their promises from 300 million to 40 million doses by New Year’s, Operation Warp Speed actually had shipped out only 11.4 million doses as of December 28th, and had only documented 2.1 millionthat had made it into arms. That is probably an underestimate, but even double that figure would be far short of predictions. For comparison, when a single case of smallpox appeared in New York City in 1947, the health authorities managed to vaccinate 5 million people in two weeks.

The purloined Pfizer: I said last time Australians are allowed to buy their way to the front of the vaccine line. Turns out American doctors with concierge practices are holding strong, so far, against pressure from the many wealthy patients who want to do the same. Italy are so afraid doses will be stolen and expatriated that they plan to use the military to distribute vaccines, and to keep storehouses’ locations secret. The French seem nervous too… but the first pilfered vaccines I’ve heard about are in my hometown, New York City, where ParCare clinics serving ultra-Orthodox Jews got hold of 2300 doses for its doctors and nurses, and then proceeded to advertise: “the vaccines will be made available on a first come first serve basis.” They publicly vaccinated at least one rabbi, as well as the ParCare CEO (who implausibly claimed “health worker” status).


A nastier, more aggressive coronavirus?

London street, Christmas 2020

A newly mutated strain of SARS-CoV-2, formally known as VOC 202012/01 – let’s call it VOC for short – has been detected in a large percentage of recent COVID-19 cases in the UK. Prime Minister Boris Johnson says the reason for his country’s terrible second wave is that this variant is particularly contagious, with the media and foreign governments taking his claims extremely seriously. 

Are they right? SARS-CoV-2, like all viruses, is mutating all the time, and variants are constantly replacing each other, so a change in dominant viral strain doesn’t necessarily mean much. Other mutated strains called 20A.EU1 and D614G, prevalent in Europe and  the Americas respectively, were similarly thought for a while to be faster-multiplying and more contagious than the original virus. That already makes me – and not only me – start out skeptical.

Here’s a conspiracy theory for you, take it or leave it. Many Brits think that Johnson knew he had to impose an unpopular lockdown over Christmas, feared the political consequences, and decided to blame the decision on the variant virus. If so, he doesn’t seem to have bargained for the effect: turning Britain overnight into a virtual pariah state, its citizens trapped inside its borders.

Johnson offered no evidence initially, but on December 23rd appeared a non-peer-reviewed preprint offering scientific backing for the claim that VOC is 56% more transmissible than other SARS-CoV-2 strains. I understand from this article that the variant is particularly infectious in a testtube, that an increasing proportion of COVID-19 cases in southern England are being caused by VOC, that people with VOC may tend to have a higher viral load, and that the variant is not more likely to lead to hospitalization or death. But beyond that the authors’ modelling approach is too complex for me.  They say it enables them to exclude 4 explanations for the VOC takeover: VOC does not spread more easily to children, does not reinfect COVID-19 survivors, does not become infectious sooner after exposure, and its geographic pattern is not accounted for by differences in socializing. They propose that the best fit to the data is a model assuming increased transmissibility. 

I am really not equipped to evaluate the models in this paper, and I haven’t managed to find any comments from people who are. But I do know that the English are being incredibly sloppy about masking and distancing, which surely goes far toward explaining the rapid recent spread of infection, without invoking the arrival of new variants. I know about the sloppiness not just because that’s what I hear from friends, not just because of pictures like the ones at the top of this section, but because those very same preprint authors have published a paper that said, “Despite similarities in policy, the second lockdown in England had a smaller impact on behaviour than did the second lockdown in Wales, resulting in more deaths and hospitalisations than we originally projected.”


A kinder, gentler coronavirus?

In the generally depressing landscape of Coronaland, one thing is said to be changing for the better: death rates among hospitalized patients. Crude 30-day death rates of COVID-19 patients in intensive care units are, in fact, now 60-70% lower than they were in March-April. 

But there’s less here than meets the eye, because the drop is largely accounted for by changing demographics. Early in the pandemic patients were overwhelmingly elderly and chronically ill, and either never made it to the hospital at all or arrived in desperate straits. These days they’re more likely to go to the Emergency Room in good time and, especially, are much younger – in Italy the average age of new cases is now about 48 as versus 65 or more in the spring. Age is the most important determinant of what happens when you get infected with SARS-CoV-2. For example:

If you adjust statistically for age and chronic medical conditions, it turns out mortality has fallen by only about 20%, whether measured overall or among hospitalized patients, intensive care unit patients, or intubated patients on respirators.

Any improvement is better than none, of course, so we should try to understand why. In addition to the all-important sea change toward younger, healthier patients, several other explanations have been proposed.

Are mutations making the coronavirus less deadly or less transmissible? No evidence in favor of this one (see previous section).  

Is treatment getting better? Not much, at least not lately. The biggest drop in mortality rates was between March, when hospital physicians didn’t know a damn thing about treating COVID-19, and May-June when they had caught on to proning, non-invasive breathing aids, heparin, and corticosteroids, and began to have access to remdesivir. The new monoclonal antibody products might improve things eventually but have had no impact yet.

Are medical staff less overwhelmed? This may well be a factor. In the spring hospitals in Italy and New York were overwhelmed by the level of care needed for the sickest COVID-19 patients – one fulltime ICU nurse per patient, ICU stays lasting weeks instead of the usual days. With the current surge some fear that high patient loads, overwork, and burnout will take their toll. In South Dakota, for example, the death rate among hospitalized patients has been risingdramatically. 

Are infections lighter to start with? Studies in Italy and Detroit suggest the viral load of your average COVID-19 patient may have fallen, possibly due to distancing measures and widespread masking. This theoretically ought to make the disease milder on the average, but as a more-or-less Italian I’m skeptical. Here the pandemic’s second wave has been reaping victims in droves despite universal masking.


Mad scientist department

In 1983 the French virologist Luc Montagnier identified the Human Immunodeficiency Virus, which causes AIDS, winning him the 2008 Nobel Prize. Then, to quote a blogger, he lost it. In 2009 he wrote two research papers claiming that he had detected electromagnetic signals from bacterial DNA, and hinting he could reconstruct the bacterium’s DNA from them. He published those papers, without peer review, in a brand-new journal whose editorial board he chaired. Then came flirtation with homeopathy, wild theories about autism (could it be cured with antibiotics?), and advocacy of papaya extract to treat everything from Parkinson’s disease to cancer. Now Montagnier has plunged into COVID-19 pandemonium with claims that the virus was created in a laboratory, that it incorporated genetic materialfrom HIV, and that the Pfizer and Moderna products should be considered not vaccines but gene therapy



And, for an Italian variant,