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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
@NickAnderegg
Jul 19, 2024 • 12 tweets • 5 min read • Read on X
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An interesting re-analysis was published today: "Remdesivir treatment does not reduce viral titers in patients with COVID-19"

Basically, remdesivir has no impact on *viral load* in acute COVID!

Here's a summary of the findings—and controversy—for a general audience!

1/12 Remdesivir treatment does not reduce viral titers in patients with COVID-19 "ABSTRACT The relationship (or lack thereof) between the clinical activity of remdesivir and its ability to reduce viral titers in patients with COVID-19 has not been fully delineated. There is a misconception that remdesivir was FDA-approved for COVID-19 due to its ability to reduce viral titers. Here, we analyze all clinical studies of remedesivir in COVID-19 that quantifed SARS-CoV-2 titers. As of 28 June 2024, we show there is no significant decrease in SARS-CoV-2 viral titers in patients treted with remd...
Initially, remdesivir received emergency FDA approval because in one NIH-sponsored trial, the remdesivir group recovered quicker than the control group. That's ALL.

It was trialed because it does seem to be a great drug in cell cultures in the lab!

2/
"Remdesivir (RDV) was the first FDA-approved treatment for COVID-19 based on results from the NIH-sponsored ACTT-1 trial demonstrating shorter time to recovery in patients with severe COVID-19 treated with remdesivir compared to placebo (10 vs 15 days, respectively) (1). While RDV demonstrated benefit in ACTT-1, its efficacy and clinical benefit have been marginal-to-ineffective in other contexts, making its FDA approval controversial. Several subsequent randomized controlled trials (RCTs) found no benefit with RDV treatment compared to placebo or the standard of care (SOC) (2-4), incl...
"Marginal clinical benefit with RDV treatment calls into question whether there is a relationship between the mechanism of viral load inhibition with RDV treatment and corresponding clinical outcomes. RDV is a prodrug of an ATP-analogue (GS-443902) that exhibits broad-spectrum antiviral activity (5). GS-443902 exhibits low Km for SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and cell-based assays have demonstrated low nanomolar EC50 values in SARS-CoV-2 infected cells treated with remdesivir (68)(9). Cells infected with SARS-CoV-2 and treated with remdesivir in vitro also show dose-de...
It SEEMED like it would be a great drug, because it does exactly what we want *in cell cultures*. Unfortunately, even in animal models, it seemingly had issues.

In particular, viral load was lower in fluid from the lungs, but not in nose, throat, or rectal swabs.

3/ "The preclinical pharmacodynamics of remdesivir have been extensively well-validated; it thus stands to reason that the observed decreases in viral load should translate in the clinic. If remdesivir demonstrates clinical benefit, it would stand to reason that there is a concomitant decrease in viral load associated with remdesivir treatment. However, this was not the case. Limited pharmacodynamic activity of RDV in humans was foreshadowed by the weak reductions in viral titers observed in rhesus macaque models of COVID-19 (11). Treatment with RDV lead to statistically significant decr...
In humans, no study has shown a statistically significant decrease in viral load as a result of remdesivir treatment!

Only two studies looked at changes in viral load under remdesivir treatment and both found NO significant differences compared to controls.

4/ "In humans, RDV has failed to demonstrate statistically significant reductions in viral titers compared to placebo control groups. [...] However, only two studies have documented the changes in viral titers associated with RDV treatment: (i) Wang et al. Lancet (2020), who published the first double-blind RCT of remdesivir versus placebo-treated patients hospitalized with severe COVID-19 and (ii) Killingley et al. Nature Medicine (2022), who published the results of the SARS-CoV-2 challenge study in healthy human volunteers. In the study by Wang and colleagues, viral titers were measur...
Apparently, one of the studies is criticized for having a small sample size... but that makes it much more likely that they'll have a false POSITIVE result, especially when it seemed to be so effective in preclinical research!

5/ "While critiqued for its low sample size, this study demonstrates: (i) there is no patently obvious clinical benefit with RDV treatment, thus necessitating a larger sample size to detect group differences and (ii) the clinical dose of 200 mg loading followed by 100 mg maintenance for 10 days does not produce a pharmacodynamic benefit."
In a challenge trial in 2022 (dear researchers: NO SC2 CHALLENGE TRIALS, WTF?), they provided remdesivir as a prophylactic against severe COVID, but the data suggested it might not be needed.

Thus, they discontinued administration for the rest of the participants.

6/ "In the study by Killingley et al., healthy human volunteers ages (18-29) were intranasally challenged with SARS-CoV-2 with the goal of characterizing the replica- tion kinetics of SARS-CoV-2 early in the pandemic (13). Participants were inoculated intranasally with a pipette at 10 TCID50 of SARS-CoV-2/(GBR/484861/2020). The original protocol indicated that all participants were to receive RDV treatment as a precaution to mitigate the risk of COVID-19 progression. As a result, the first 10 participants were preemptively given RDV after two consecutive quantifiable viral detections and ...
This change in protocol created a quasi-experiment, which is the focus here!

So, even in a study where participants were exposed to a standardized quantity of virus, no differences in viral load were found between the treated-with-remdesivir group and the no-remdesivir group.
7/ "Interestingly, this situation inadvertently enables one to compare the effects of RDV treatment versus no treatment in young, healthy participants with a standardized baseline viral titer challenge. Viral titers were measured by qPCR in nasal and throat swabs for the duration of the 28-day study (RDV N = 6; no RDV N = 12). No statistically significant differences in viral titers were observed in nasal or throat swabs between groups following SARS-CoV-2 challenge as measured by focus forming assay" Figure 1 "(C) Area under the curve for SARS-CoV-2 nasal viral titers measured...
Boiling it down:

- It shows a certain level of viral inhibition in the lab
- Some studies have found it may have an impact on OUTCOMES
- But it DOESN'T have an impact on the viral load

The issue seems to be that the dose in the body can't get high enough!

8/ "The studies by Wang et al. and Killingley et al. demonstrate no correlation between RDV treatment and decrease in viral titers compared to untreated controls. This finding highlights the discordance between RDV's mechanism of action and purported clinical benefit and re-emphasizes the controversial basis of RDV's FDA approval. Our finding once again calls attention to a central predicament of RDV's design: the inability to increase the dose to augment the weak pharmacodynamic activity observed in the clinic due to extensive hepatic metabolism (14-17). Finally, in a post-pandemic world...
HOWEVER! Meta-analyses have noted SOME sort of SMALL impact on mortality, for SOME patients, e.g.:

-
-
-

Maybe especially immunocompromised:
-

So what's up?
9/pubmed.ncbi.nlm.nih.gov/35598856/
pubmed.ncbi.nlm.nih.gov/36828006/
pubmed.ncbi.nlm.nih.gov/35512728/
pubmed.ncbi.nlm.nih.gov/38105461/
IMO, I think the most likely answer is that some sort of latent viral reactivation is playing a role here (e.g.: ).

Remdesivir does seem to be a good antiviral in vitro, so if it has an impact on some other virus, it could skew the clinical outcomes!

10/
That means a lot more research is needed on the specific factors that lead to severe acute outcomes (and LC!), allowing specific diagnostics, allowing specific treatments.

No clinical trial can be successful if unidentified underlying issues aren't being addressed!

11/
For the record, this is very different from my first draft of this thread.

After I realized it was written by *current* grad/med students, I rewrote it as an actual critique, instead of my usual incisive schtick

Paper:

12/12journals.asm.org/doi/10.1128/aa…

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More from @NickAnderegg

Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jun 30
Can I say something? I have a BA in psych, a BPhil in linguistics, and went to grad school for cognitive psych. My research, including an undergrad fellowship, was on the cognitive relationship between written and spoken language…

Audiobooks are NO DIFFERENT than reading print.
In the last hour, there have been a dozen replies from people nitpicking the first tweet

The topic of discussion is "do audiobooks 'count' as reading?," and the answer is "Audiobooks are NO DIFFERENT than reading print."

Maybe read the thread before arguing with it? lmfao
And for all those people with indignant responses who want to nitpick every detail, the fact that so many people hold THIS exact view—that audiobooks are somehow “cheating”—is the ENTIRE point. It leads to people who would benefit from audiobooks depriving themselves the medium
Read 4 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Feb 1
Many people are asking for recommendations about what storage media to buy, so here's a buying guide from an experienced data hoarder (me)

The MOST IMPORTANT thing to know is that SOLID-STATE MEDIA IS NOT DURABLE. Flash drives, SSDs, SD cards, etc. are NOT long-term storage.

1/
That's not to say that it's impossible to use solid-state media for long-term storage. It's just that anything with durability guarantees gets prohibitively expensive quickly. Spinning hard drives—as well as DVDs and Blu-ray discs!—are your friend.

2/
- The way data is stored in solid-state media makes it much more susceptible to bit rot than other media.
- In a spinning hard drive, the moving parts are the most common point of failure.
- When you burn a DVD, that shit is fairly permanent.

3/
Read 42 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jan 9
I wish people would understand that insurance underwriters have armies of actuaries calculating risks, and if an insurance company drops you, it's because things have changed in such a way that insuring you will take more out of the financial pool than you're putting in

1/
It sucks, but it's a direct result of the fact that humans are widely inhabiting locations that are rapidly becoming impossible to inhabit safely. If you can't find insurance for your home, it means there's a high likelihood you'll need to move soon anyway.

2/
You get insurance so that you can replace all of your stuff in the event of a disaster. When the insurance company effectively says "the risk of disaster is so high that insuring you would almost certainly cause us to lose a lot of money," it ALSO means your life is in danger

3/
Read 7 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jan 5
So here’s the thing about some of the subtle neuro damage related to SARS-CoV-2 infection that I think a lot of people miss: some of the known deficits are correlated with things like impulsiveness and poor emotional control, so we might expect to see deficits there are well

1/
Consider how impatient people seem to be on the road in the last couple years relative to the 2010s, and I think we have a perfect example of where this is LIKELY already manifesting.

2/
This impact is particularly insidious for the person experiencing it, because poor impulse control, by definition, doesn’t really come on gradually. My biggest concern is how interactions under these circumstances will play out if this impact continues to become more common

3/
Read 15 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jan 3
Let's review some major points in the Nukit controversy, since some people are unclear:

- Someone criticized someone's use of Nukit lanterns.
- Nukit attacked the critic because, as noted, this is how they market
- Nukit now demands "mediation" with the community (how??)

1/ @marigoldglitter: "these tools should be used for people who must be in public despite the dangers, not for white men who want to eat in restaurants and maintain the status quo. if this is what you're gonna use these for, give them to a disabled person who can't go to the doctor b/c of risk." Nukit: ""White man" in this case is buying those products from non-white small businesses who are focused on providing the community with effective, tested mitigations at far, far lower costs than anyone else." OP: "Like why are you coming at me with this aggressive...
Nukit: "If you are in the US, and would like to purchase Far-UVC products, we cannot help you at this time. We tried to resolve the issues there, but the US COVID-Aware community was uninterested in mediation or intercession. As a result of that disinterest, a great deal of harm was done. When stock is finished, we will not be selling our products to the Us anymore. If you are in the US and want Nukit products, would like 333 million Americans, many disabled or immune compromised, to be able to access the most affordable Far-UVC on the market, kindly address the people who made it unsa...
So let's look at this a bit more critically. Here is the "evidence" Nukit provided that the didn't say anything racist. First of all, these aren't the comments in question, but it's worth a look anyway.

2/ Ok, I get that "evidence," "citations," and "personal accountability" are going to be called racist, but since people insist on just spewing lie after lie without any pushback- here's what actually happened. @marigoldglitter- a white woman attacked a Nukit customer who was supporting us by showing our products. This is something we rely on to fund research and donations. If our customers do not do this, that money goes to paid advertising. So yes, attacking our customers is attacking our company and directly harming marginalized folks who receive our products. ...
Seems to be framed this way because Nukit knows it's not an adequate explanation, so they're acting like anyone who criticizes them is in the wrong. --- A bigoted comment is a bigoted comment, even if it's not directed at someone who might be personally offended. Of course, Nukit didn't include the comments people actually call racist! --- Nukit is explicitly saying here that they view any criticism as an "attack," because criticisms can potentially hurt their business goals. Fundamentally, Nukit is angry that this usage of their products are being criticized. --- After Nuki...
Let's be clear about what happened here: Someone lamented the unequal access to protective measures and criticized someone who seems to be using a certain device to *maintain the status quo*, and the manufacturer of the device found it unacceptable.

3/
Read 16 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Oct 9, 2024
NEW STUDY! This exploratory study identifies a SPECIFIC PHENOTYPE OF LONG COVID that appears related to NEUROMUSCULAR DISTURBANCE rather than lung damage—and they've termed it Complex Ventilatory Dysfunction!

Breakdown of the paper (thread written for a general audience!)...

1/ Published Oct 7, 2024: "A new phenotype of patients with post-COVID-19 condition is characterised by a pattern of complex ventilatory dysfunction, neuromuscular disturbance and fatigue symptoms" Abstract: Background Patients with post-COVID-19 condition frequently suffer from chronic dyspnoea. The causes and mechanism for dyspnoea in these patients without evidence of structural lung disease are unclear. ... Results ... A pattern of reduced forced vital capacity (FVC), but normal total lung capacity (TLC), termed complex ventilatory dysfunction ... was observed and occurred mo...
Broadly speaking, there are two groups of acute covid outcomes involving dyspnea (shortness of breath) as a long-term symptom:

- Severe cases that may have physical lung damage
- "Mild" cases that now have ME/CFS-like features, but who have no evidence of lung damage!

2/ "Current evidence suggests that cellular damage, a robust innate immune response with inflammatory cytokine production and a procoagulant state induced by SARS-CoV-2 infection are factors potentially contributing to post-COVID-19 sequelae such as dyspnoea, fatigue, and cognitive and mental disturbances... Dyspnoea has been well characterised as a major clinical symptom of post-COVID condition after severe and critical COVID-19 and is correlated with impaired lung function in terms of pulmonary restriction, and with reduced diffusion capacity as a possible consequence of pulmonary remod...
In this study, they explored this distinction further and identified a distinct subset of patients with a pattern of breathing abnormality that they have termed complex ventilatory dysfunction (CVD).

So how did they arrive at this conclusion? Let's dig in!

3/16 "We hypothesise that patients suffering from post-COVID-19 condition who have fatigue and exertional intolerance also have a reduction in respiratory muscle strength, causing a dysfunctional breathing pattern which is distinct from typical pulmonary sequelae after COVID-19 such as obstruction, restriction or impaired diffusion capacity. Based on clinical observations, we describe a new breathing abnormality termed complex ventilatory dysfunction (CVD), defined as total lung capacity (TLC) - forced vital capacity (FVC) >10% predicted value and absence of restriction (TLC ≥ lower limit o...
Read 16 tweets

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