Effect of Ivermectin on COVID-19 Infection and Mortality

[nerd]

Now if you use liposomal delivery, you may increase the concentration of the drug inside cells, but potentially this may also increase adverse effects, so that your maximum safe dose becomes lower, because liposomal delivery has made the drug more potent.

That's what I suspected. But I was also thinking of a change in drug delivery from blood-related adverse effects to tissue-related efficacy. Again, this will depend on the cell type, I assume. But it's a cheap and easy method to try, I think.

It is also worth mentioning that in the paper you mentioned earlier, their model predicted that hydroxychloroquine would be the most potent antiviral for coronavirus, since figure 4 indicates the model predicts hydroxychloroquine reaches concentrations of 1000 times higher than the EC50. This in theory would make hydroxychloroquine an extremely potent antiviral.

I noticed the same. It's quite peculiar and it shows that antiviral efficacy might not be the best predictor for the decrease of mortality of a drug against SARS-CoV-2. However, we have to consider that antiviral efficacy is applicable only in the incubation phase primarily, and definitely not in hospitals. Many of the trials that tried to debunk HCQ as a treatment for COVID-19 used it during hospitalization or even later when patients were incubated. This was based on the false implicit assumption that a positive PCR would be a predictor for viral replication, when in fact, it only shows dead viral load in hospitalized patients. I'm still convinced that HCQ is a potent antiviral against SARS-CoV-2. But it lacks the other mechanisms of action of Ivermectin that become relevant during mid- and late-disease.

Here is what CovidAnalysis wrote in their meta-review of HCQ:

We analyze all studies for HCQ and COVID-19. 100% of the 29 early treatment studies report a positive effect (13 statistically significant in isolation) with an estimated reduction of 65% in the effect measured (death, hospitalization, etc.) using a random effects meta-analysis, RR 0.35 [0.25-0.50]. Late treatment is less successful, with only 72% of the 161 studies reporting a positive effect. Very late stage treatment is not effective and may be harmful, especially when using excessive dosages.

 

[nerd]

Do you know what viruses may underlie you own ME/CFS, @nerd? Have you been appropriately tested for the usual culprits (coxsackievirus B, echovirus, EBV, cytomegalovirus, HHV-6 and parvovirus B19)?

Unfortunately, I do not. I only have mixed results on EBV and Lyme, negative ones for HPV. My immunologist suspected residual gamma herpes activity. Residual viral activity is how I think CFS/ME could be generally defined pathologically.

Assuming it was any of the ones you mention, would you expect other antivirals to work? What's your take on why some PCRs are positive so often? Is this a larger topic to discuss in another post, so we don't get off-topic again?

 

[Hip]

it shows that antiviral efficacy might not be the best predictor for the decrease of mortality of a drug against SARS-CoV-2

Yes, in vitro studies can only measure the direct antiviral effects of a compound (ie, the compound's ability to prevent viral replication inside a cell, or prevent the virus entering a cell in the first place).

But in vitro studies cannot usually detect or measure whether a compound boosts the immune response against viruses, which also can help control a viral infection. That can only be measured by in vivo studies, either in humans or animals.

However, we have to consider that antiviral efficacy is applicable only in the incubation phase primarily, and definitely not in hospitals.

Antivirals in the general case should be helpful at any stage of the infection. When people get varicella zoster virus reactivation (singles) for example, antivirals are still effective.

However, with COVID, because there are some suggestions that coronavirus may cause an autoimmune attack on the immune system itself, perhaps once that attack is triggered, it may become a lot harder to clear the virus. So we might speculate that taking antivirals early, to try to prevent this autoimmunity from arising, may result in a better outcome.

I'm still convinced that HCQ is a potent antiviral against SARS-CoV-2.

Some have postulated that early use of hydroxychloroquine may provide some benefits which are not obtained once the patient is already quite severe and needs hospital treatment.

However, there was one interesting paper which examined the incidence of COVID in around 200k people who take HCQ daily as part of their routine medications. So these people are taking HCQ even before they catch coronavirus, so you cannot get any earlier than that. Yet the incidence of COVID in these patients was no lower than in the general population.

That suggests that even early use HCQ does not help. Although the patients in this study had autoimmune conditions already, which may possibly skew the study results.

I only have mixed results on EBV and Lyme, negative ones for HPV. My immunologist suspected residual gamma herpes activity. Residual viral activity is how I think CFS/ME could be generally defined pathologically.

Yes, this "residual viral activity" in the case of enteroviruses (like coxsackievirus B and echovirus) is nowadays an understood mechanism: it is known as a non-cytolytic enterovirus infection, which is actually an infection of naked viral RNA inside cells, rather than a normal lytic infection which involves the creation of viral particles which break out of cells by lysis.

There are some details about non-cytolytic enterovirus in this post.

Assuming it was any of the ones you mention, would you expect other antivirals to work? What's your take on why some PCRs are positive so often? I

If you are positive for enterovirus (coxsackievirus B or echovirus), then Dr John Chia, who is the leading expert on enterovirus ME/CFS, uses the herbal immunomodulator called oxymatrine to treat. Dr Chia says oxymatrine results in major improvements in about 30% of ME/CFS patients; but a survey on this forum suggests the success rate is lower, perhaps around 13%.

Nevertheless, it may be worth trying oxymatrine, as it is a reasonably cheap supplement available without prescription online.

Dr Chia also uses the antiviral Epivir off-label to treat enterovirus. The benefits of this are more mild than oxymatrine, however. In both cases, it takes about 6 weeks or so of treatment to see results. I tried both for my coxsackievirus B4 ME/CFS, but they did not work for me.

If you are positive for cytomegalovirus, HHV-6 and/or EBV, then Valcyte works for some patients. However, this drug is expensive, and it takes about a year or so to see benefits.



Dr Chia says only antibody tests that use the neutralization method are sensitive enough to detect the chronic enterovirus infections in ME/CFS. Antibody tests using the ELISA, IFA or CFT methods are not sufficiently sensitive, he finds. Though antibody tests using the neutralization are rare and hard to find (as this method is more laborious than ELISA etc).

IMD Lab in Germany provide individual antibody neutralization tests for CVB3, CVB4, CVB5 and EV6, EV30. These tests cost €34 each. The staff at IMD lab speak English. There is an IMD test offering CVB4, CVB5, EV6 and EV30 together (but not CVB3).

Or in the US, ARUP lab provide tests for coxsackievirus B and echovirus, costing around $200 each.

I was tested for coxsackievirus B1 to B6 in a lab in the Netherlands, but unfortunately that lab stopped offering neutralization tests.

Other testing labs are detailed in the coxsackievirus B and echovirus section of my ME/CFS roadmap document.

 

[Hip]

What's your take on why some PCRs are positive so often?

Dr John Chia spent years looking at different ways of testing for enterovirus in ME/CFS. He found that even the most sensitive PCR tests will only be positive for enterovirus around 30% of the time.

He says this shows that there is very little virus in the blood itself, because in ME/CFS, you have these low-level non-cytolytic infections present more in the tissues than the blood (tissues like the muscles, intestines and brain).

See the section "detection of non-cytolytic infections" for more info on Dr Chia's research.

 

[nerd]

But in vitro studies cannot usually detect or measure whether a compound boosts the immune response against viruses, which also can help control a viral infection. That can only be measured by in vivo studies, either in humans or animals.

Usually, it's both. First, they show that a certain pathological mechanism (like immune suppression) is interrupted by the agent. And then they use animals as a control of the in vitro model. Unfortunately, SARS-CoV-2 has a long list of mechanisms.

That suggests that even early use HCQ does not help. Although the patients in this study had autoimmune conditions already, which may possibly skew the study results.

Yes, I think this could be confounded by these conditions, even if it was adjusted for the common factors. If HCQ was still being considered, it definitely would be worth looking into why the RCTs show a different story. However, due to the relatively greater risks of HCQ, its prophylactic use would never find a way into guidelines. What MDs want is one drug for any phase of the disease. Ivermectin would meet this requirement. Most antivirals that are in pipelines do not. If they have benefits, then just like Remdesivir or HCQ, only in the early phase and not in hospitals.

IMD Lab in Germany provide individual antibody neutralization tests for CVB3, CVB4, CVB5 and EV6, EV30. These tests cost €34 each. The staff at IMD lab speak English. There is an IMD test offering CVB4, CVB5, EV6 and EV30 together (but not CVB3).

I know the lab since I'm from Germany, and I also know doctors who work with the lab. Thanks for the reference, I will try to get tested.

He says this shows that there is very little virus in the blood itself, because in ME/CFS, you have these low-level non-cytolytic infections present more in the tissues than the blood (tissues like the muscles, intestines and brain).

I think this is the case with any viral residues that affect CFS/ME, if cytolytic or latent-lytic.

 

[Hip]

I think this is the case with any viral residues that affect CFS/ME, if cytolytic or latent-lytic.

This seems to be the case: whether you have herpesvirus-associated ME/CFS or enterovirus-associated ME/CFS (or both), antibody levels are chronically high, but blood PCR is usually negative.

By contrast, if you perform enterovirus PCR on tissue biopsies taken from the muscles of enterovirus ME/CFS patients, then that is often positive. All the early British research on ME/CFS in the late 1980s and 1990s focused on testing muscle tissue.

Dr Chia in the US then extended the British research to show that stomach tissue biopsies also test positive for enterovirus.

The same research on muscle or stomach tissues of herpesvirus-associated ME/CFS has not been done, however. So the location of these chronic herpesvirus infections in ME/CFS is less clear.


But in the case of enterovirus, it seems likely that the high antibody levels are due to this chronic low-level infection in the muscles.

It must be said though that even healthy controls may have muscle infections with enterovirus, so on their own, these muscle infections will not necessarily lead to ME/CFS.

 

[Bronc]

The Journal of Antibiotics has carried a meta analysis explaining Ivermectin's Mechanism of Action Targeting Sars-Cov2. The following is from Trial Site News:

What’s the mechanism of action behind Ivermectin? A growing interest in this repurposed, FDA-approved drug has exploded since last year when TrialSite first started chronicling ivermectin-based studies. Now two researchers based in Italy provide more useful information. TrialSite has meticulously documented dozens of clinical trials involving this drug, and the authors survey a number of these studies in a quest to better address the mechanism of action via a review of the evidence of both in vitro and in vivo investigations. Thus a meta-analysis includes an extensive search and review in the PubMed database covering articles from January 1, 2008, all the way through January 30, 2021, based on syntax using MeSH Database terms (stromectol OR Ivermectin OR “dihydroavermectin”) OR (22 AND 23-dihydroavermectin B) AND (antiviral OR virus OR COVID-19 OR SARS-CoV-2). The two researchers manually reviewed all the content, filtering and prioritizing based on relevance and appropriateness. They conclude that there’s sufficient evidence for a broader investigation into the use of the drug targeting COVID-19.
Mechanism of Action Summary
According to this meta-analysis, the ivermectin’s influence against COVID-19 can be divided into four groups, including 1) a direct action on SARS-CoV-2 blocking the pathogen’s cell entry while acting on Importin (IMP) superfamily as well as serving as an Ionophore; 2) acts against host targets for viral replication including behaving like an antiviral while inhibiting viral replication and assembly but also acting on post-translational processing of viral polyproteins while acting against Karyopherin (KPNA/KPNB) receptors; 3) Act on host targets for inflammation which includes a number of specific actions; and 4) the drug apparently acts on other host targets from Plasmin and Annexin A2 to CD147 on the RBC to action on mitochondrial ATP under hypoxia on cardiac function. This study was published in the Journal of Antibiotics.

Conclusion
The researchers believe they have uncovered enough evidence in the investigation into ivermectin’s mechanism of action targeting SARS-CoV-2 to merit broader medical establishment attention given the ongoing COVID-19 pandemic, along with its evolving mutant variants.

Lead Research/Investigator
Dr. Asiya Kamber Zaidi, Member, Association “Naso Sano” Onlus, Umbria Regional Registry of volunteer activities, Corciano, Italy; Mahatma Gandhi Memorial Medical College, Indore, India
Dr. Puya Dehgani-Mobaraki, President, Association “Naso Sano” Onlus, Umbria Regional Registry of volunteer activities, Corciano, Italy

 

[Bronc]

Ivermectin and outcomes from Covid-19 pneumonia: A systematic review and meta-analysis of randomized clinical trial studies
https://onlinelibrary.wiley.com/doi/10.1002/rmv.2265

CONCLUSION
Our meta-analysis of randomized clinical trial studies indicates that ivermectin administration had an association with favourable outcomes of Covid-19, compromising of higher rate of negative RT-PCR test results, shorter time to negative RT-PCR test results, higher rate of symptoms alleviations, shorter time to symptoms alleviations, shorter time to hospital discharge, reduction in the severity and mortality rate from Covid-19. This study suggests that ivermectin may be the potential therapeutic agents for the managements of Covid-19 to give better outcomes for the patients. However, more randomized clinical trial studies are still necessary and encouraged to be done for confirming the results of our study. Finally, ivermectin should be considered as an essential drug for future Covid-19 therapy models.

 

[Bronc]

The American Journal of Therapeutics has just published a meta analysis on Ivermectin by UK researchers Dr. Tess Lawrie and Dr. Andrew Bryant:

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

https://covid19criticalcare.com/wp-...tin_for_Prevention_and_Treatment_of.98040.pdf

In their conclusion Bryant et al state:

"Given the evidence of efficacy, safety, low cost, and current death rates, ivermectin is likely to have an impact on health and economic outcomes of the pandemic across many countries. Ivermectin is not a new and experimental drug with an unknown safety profile. It is a WHO “Essential Medicine” already used in several different indications, in colossal cumulative volumes. Corticosteroids have become an accepted standard of care in COVID-19, based on a single RCT of dexamethasone.1 If a single RCT is sufficient for the adoption of dexamethasone, then a fortiori the evidence of 2 dozen RCTs supports the adoption of ivermectin. Ivermectin is likely to be an equitable, acceptable, and feasible global intervention against COVID-19. Health professionals should strongly consider its use, in both treatment and prophylaxis.''

 

[Learner1]

This seems to be the case: whether you have herpesvirus-associated ME/CFS or enterovirus-associated ME/CFS (or both), antibody levels are chronically high, but blood PCR is usually negative.

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