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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
@NickAnderegg
Jul 19 • 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
Jul 18
NEW study in the Journal of Hospital Infection has found that, even from a purely economic perspective, the LACK OF MITIGATIONS currently present in healthcare settings MAKES NO SENSE!

Of course, preventative measures save LIVES, too.

Here's a quick analysis...

1/16 Admission screening testing of patients and staff N95 masks are cost-effective in reducing COVID-19 hospital acquired infections "Findings: Compared to no admission screening testing and staff surgical masks, all scenarios were cost saving with health gains. Staff N95s + RAT admission screening of patients was the cheapest, saving A$78.4M [95%UI 44.4M-135.3M] and preventing 1,543 [1,070-2,146] deaths state-wide per annum. Both interventions were individually beneficial: staff N95s in isolation saved A$54.7M and 854 deaths state-wide per annum, while RAT admission screening of patients...
This study is out of Australia, where patients who acquire COVID after their admission to the hospital are 50% more likely to die within 90 days.

When over 10% of the patients in the hospital are there BECAUSE of hospital-acquired infections, the problem is obvious.

2/ "... Hospital-acquired COVID-19 infections occur when patients admitted for non-COVID-19 reasons acquire COVID-19 following exposure to staff, other patients or visitors, and infection prevention and control measures are insufficient to prevent transmission. As well as being a patient safety risk, hospital-acquired infections carry significant costs to the health system [2-4]. [...] In the state of Victoria, 15-25% of patients in hospital with COVID-19 between June 2022-June 2023 acquired their infection after admission, with 90-day mortality of 18.9% compared to 12.3% among matched pa...
They used an established agent-based model—a model which simulates the interactions of individuals in a community—calibrated to actual local data.

Of course, it took a lot of work to get the appropriate data, because data collection was—surprise, surprise!—terrible.

3/ "Data on outbreaks occurring in Victorian acute care settings was aggregated from multiple sources, consisting of the outbreak size (number of patient and staff diagnoses), outbreak duration, and the corresponding demographic composition of each setting that recorded an outbreak (number of admissions, age distribution of admissions, distribution of length of stay, and staff:patient ratios).... ... Each of the outbreaks contained complete information about number of patient diagnoses, outbreak duration and demographic composition, however ~75% of outbreaks recorded zero staff diagnoses...
Read 16 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jul 15
Because the "benefit of the doubt" is often brought up here, I want to make it clear that there is NO DOUBT that, if you willingly stopped masking, you made an empirically-harmful CHOICE.

Let's see what was known and when, starting with a commentary out of Italy in Aug 2021!

1/
"COVID-19: why not learn from the past?" DOI: 10.1007/s11684-021-0883-0
Obviously, different countries were going to take different approaches, but right out of the gate, much of the US/Euro response was based on empirically-unfounded dogma.

To begin with, many of the CRITICAL lessons from SARS were ignored by "opinion leaders."
2/
"What information was available about SARS in the scientific literature before the COVID-19 pandemic? Laboratory practices and medical treatment guidelines were published during and shortly after the 2003 SARS outbreak, regarding coronavirus identification by RT-PCR, epidemiology, and containment strategies. Clinical chemistry guidelines [22], diagnosis based on RT-PCR [23-26] and indications for therapeutic treatment were readily available from the experience with SARS. Although this knowledge was available well before the COVID-19 pandemic, much of it was "rediscovered" in...
"Similarly, the use of hyper-immune serum from recovered patients was indicated among the successful therapeutic interventions during the SARS outbreak [29] and was apparently rediscovered, as a new and innovative strategy, during the COVID-19 pandemic. Also the increased incidence of Kawasaki-like disease (or rather "syndrome" as this clinical presentation of the SARS-CoV-2 infection in children is now called), had been described during the SARS outbreak, and has occurred again during the COVID-19 pandemic [30], as should have been expected, given the much larger prevalence ...
And let's be clear... not a single person who said "vax and relax" had BOTH of these attributes:

- Was informed of the science
- Had your best interest in mind

The fact that a partially-immunized population creates *evolutionary pressure* was already well-known.

3/ "Lessons for the future: are we ready for the next battle? ... First, there exist spontaneous mutations that steadily improve the virus' capacity to infect and propagate among its human hosts, in a word, to evolve. Secondly, vaccines alone cannot guarantee safety against the outbreak of new variants in the future and may convey a false sense of protection in the population. This means that constant monitoring and alertness to this threat should go hand-in-hand with the enforcement of new measures to increase preparedness for timely interventions, in order to avert another pandemic. Fu...
Read 15 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jul 13
Potential prophylactic!? POTENTIAL COVID PROPHYLACTIC!

A review was published today on an immunostimulator called IMQ. Before reading, I decided I'd only cover it if it hit certain critical points; it hit them all REPEATEDLY.

Wow, wow, WOW. Here's a summary (for everybody)!
1/ Abstract from "Immune Stimulation with Imiquimod to Best Face SARS-CoV-2 Infection and Prevent Long COVID": "Nonetheless, a significant demographic, comprising around 20% to 30% of the adult population, remains unimmunized due to diverse factors. Furthermore, alongside those recovered from the infection, there is a subset of the population experiencing persistent symptoms referred to as Long COVID. ... This review delves into the advantages and constraints associated with employing imiquimod in human subjects to enhance the immune response during SARS-CoV-2 immunization. Res...
This isn't at all a new drug, but for whatever reason, it's been totally ignored by the covid literature (with the exception of a paper from 2020 that is also cited by the current review).

Inexplicably, NOBODY has looked at IMQ yet!

2/
Screenshot of PubMed search results showing only a single relevant result for IMQ in the COVID literature collection (out of five total results; four appear to be false hits).
"During the SARS-CoV-2 pandemic, some authors suggested the potential usefulness of IMQ as an immunostimulant to enhance individuals' immune readiness before exposure to the virus. However, there are no reported clinical studies or suggested application protocols for this specific purpose so far. Imiquimod (1-isobutyl-1H-imidazo [4,5-c]-quinolin-4-amine(C14H16N4)) is a synthetic imidazoquinoline with a molecular weight of 240.31 g•mol-1."
WARNING: Imiquimod has NOT been CLINICALLY EVALUATED in any way for SARS-CoV-2.

I'm excited about this paper because it matches my mental model of covid pathophysiology almost perfectly, but I'm not a doctor.

This thread is a conceptual explanation. THIS IS NOT ADVICE.

3/
Read 33 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jul 8
OOHHHH WOW! New preprint on the host immune response in Long Covid was just posted (few hours ago), and it's more significant than the 3-gene signature!

They found reactivation of viral herpes (EBV/CMV/HSV2) and CONFIRMED PERSISTENT SARS-CoV-2 INFECTIONS! Here's a summary...

1/ Preprint Title: "MENSA, a Media Enriched with Newly Synthesized Antibodies, to Identify SARS-CoV-2 Persistence and Latent Viral Reactivation in Long-COVID." Abstract: "Here, we use MENSA, Media Enriched with Newly Synthesized Antibodies, secreted exclusively from circulating human plasmablasts, to provide an immune snapshot that defines the underlying viral triggers. [...] Applying the same principles for long-COVID patients, MENSA is positive for SARS2 in 40% of PASC vs none of the COVID recovered (CR) patients without any sequelae demonstrating ongoing SARS2 viral inflamma...
IMO, this is a hugely important study, so I'm going to do my best to explain it in detail, in a way that everybody can understand!

The headline here is that a persistent/reactivated infection of (one or more of) SARS2, EBV, CMV, and/or HSV2 were found in 60% of LC patients!

2/ "In summary, MENSA is a novel immune diagnostic which captures unique signatures of the early-minted ASC in the blood to reveal the cause of illness. In chronic conditions such as PASC where serum antibody titers are high, MENSA is an independent matrix that identifies persistence of SARS2 viruses or antigens and can also recognize the reactivation of latent herpes viruses, such as EBV, CMV, and HSV2 in 60% of patients. This host immune snapshot reveals the fundamental drivers of viral persistence and reactivation in this chronic disease." That means 60% of LC patients have one o...
Simply put, they looked at the antibodies produced by "Antibody-Secreting Cells" (ASCs), a type of short-lived immune response cells!

The primary types of antibodies stay in the blood. In contrast, ASCs peak *shortly* after infection, then rapidly decline! (see screenshot)

3/ From "The Antibody-Secreting Cell Response to Infection: Kinetics and Clinical Applications" (2017): "In this review, we summarize previous studies that have used techniques to enumerate ASCs during infection. We describe the emergence, peak, and waning of these cells in peripheral blood during infection with a number of bacterial and viral pathogens, as well as malaria infection. We find that the timing of antigen-specific ASC appearance and disappearance is highly conserved across pathogens, with a peak response between day 7 and day 8 of illness and largely absent followi...
Read 28 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jul 7
GUESS WHAT?! A new study has shown SARS-CoV-2 infection is DISTINCT from common respiratory viruses!

Unequivocally, COVID is NOT "just a cold."

These findings are HUGELY significant, for multiple reasons! Here's a breakdown of the study (written for a general audience)...
1/16 SARS-CoV-2 infections—both symptomatic and asymptomatic—produce distinct host immune responses compared to human rhinovirus infections (the common cold), influenza virus infections, and RSV infections. That is, SARS-CoV-2 induces a set of changes in gene expression with significantly higher magnitude of change compared to other common respiratory viruses. For each of the four viruses, the column on the left shows differential gene expression (relative to controls) for symptomatic infections, while the column on the right shows differential gene expression for asymptomatic infections. Note...
The paper is fairly complicated, so I'm going to start with the high-level takeaways before explaining everything in more detail.

Overall, they found a 3-gene signature that distinguishes SARS-CoV-2 infections from common viral infections—long before PCR test positivity!

2/ A T-Cell-Derived 3-Gene Signature Distinguishes SARS-CoV-2 from Common Respiratory Viruses Abstract: ..., we performed a multi-cohort analysis with integrated bioinformatics and machine learning. We collected 3730 blood samples from both asymptomatic and symptomatic individuals infected with SARS-CoV-2, seasonal human coronavirus (sHCoVs), influenza virus (IFV), respiratory syncytial virus (RSV), or human rhinovirus (HRV) across 15 cohorts. First, we identified an enhanced cellular immune response but limited interferon activities in SARS-CoV-2 infection, especially in asymptomatic cases. Se...
Because the signature:

1. is SPECIFIC to SARS-CoV-2,
2. is an EARLY indicator of infection,
3. is a DISTINCT pattern from other infections, and
4. even accurately identifies Omicron infections,

this discovery may be useful as a diagnostic tool AND a direction for treatment!

3/ "The 3-gene signature offered two major improvements to SARS-CoV-2 infection triage: specificity and early diagnostic power. ...showed superior diagnostic performance only in SARS-CoV-2 ... achieved excellent diagnostic performance in Omicron patients ... showed exceptional performance to identify SARS-CoV-2 infection before detectable viral RNA on RT-PCR testing.... ... The bioinformatics methods, including DEGs and WGCNA, provided biological insights into the stable SARS-CoV-2 specific candidate genes. The machine learning approaches on these candidates offered a better extrapolation po...
Read 28 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jun 3
SIGNIFICANT new study has found a potential mechanism of ALS pathogenesis (with broader implications for other unexplained/idiopathic/"functional" neurological conditions?!)

This thread is pretty long, because I try to explain *everything* in a way anyone can understand!

1/many Endogenous Retroviruses are Dysregulated in ALS doi: 10.1016/j.isci.2024.110147 Amyotrophic Lateral Sclerosis (ALS) is a universally fatal neurodegenerative disease with no cure. Human endogenous retroviruses (HERVs) have been implicated in its pathogenesis but their relevance to ALS is not fully understood….. Using different methods of feature selection, including differential expression analysis and machine learning, we discovered that transcription of HERV-K loci 1q22 and 8p23.1 were significantly upregulated in the spinal cord of individuals with ALS. Additionally, we identified a subs...
The short summary is that an endogenous retrovirus (HERV-K) is highly expressed in the brain and spinal cord of ALS patients, and may lead to neuroinflammation which leads to neurodegeneration.

These next several tweets are the background needed to understand the results!

2/ Image
So, DNA… it's a *language* that encodes the instructions a cell uses to build proteins out of smaller molecules.

Like written language, different symbols are used to indicate when segments start and stop (i.e. capital letters, spaces, punctuation in human language).

3/ Visualization of gene structure from Wikipedia. The structure of a eukaryotic protein-coding gene. Regulatory sequence controls when and where expression occurs for the protein coding region (red). Promoter and enhancer regions (yellow) regulate the transcription of the gene into a pre-mRNA which is modified to remove introns (light grey) and add a 5' cap and poly-A tail (dark grey). The mRNA 5' and 3' untranslated regions (blue) regulate translation into the final protein product.
Read 37 tweets

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