Ivermectin and the Hendra virus

lessons from COVID-19

The coronavirus (COVID-19) pandemic has resulted in some surprising discoveries. One is that ivermectin (yes, that ivermectin, the anthelminthic drug) is a broad-spectrum antiviral agent, inhibiting a wide variety of viruses.

Ivermectin is antiviral

It's been known for awhile in research circles (e.g., in virology labs) that ivermectin has antiviral properties. However, it hasn't been used clinically (i.e., in patients with naturally occurring disease) as an antiviral agent until now.

Based on laboratory confirmation that ivermectin inhibits SARS-CoV-2 (the novel coronavirus that causes COVID-19), doctors in many different countries have been using ivermectin in the treatment and prevention of COVID. More on that in a bit.

It turns out that ivermectin inhibits a wide variety of viruses, including Hendra virus (HeV). Here is a list of some of the viruses known to be inhibited by ivermectin, at least in the laboratory:

This list covers several different viral groups, making ivermectin a broad-spectrum antiviral agent.

How it works

The way ivermectin inhibits viral activity within a cell is complex โ€” because viral replication is a complex process. In essence, ivermectin blocks the virus from entering the cell's nucleus and disabling a key component of the cell's antiviral response. In other words, ivermectin blocks one of the critical steps involved in virus replication.

A note of caution before we go on: the molecule blocked by ivermectin โ€” called importin alpha, or IMP๐›‚ โ€” is a nuclear transporter protein that aids the transport ('import') of molecules from the cytoplasm of the cell into the nucleus. However, IMP๐›‚ is involved in a variety of normal cell functions, including antiviral responses. So, although many different viruses 'hijack' this transporter protein for their own purposes, it is not a good idea to persistenty or permanently block IMP๐›‚ in order to block virus replication. To do so would block normal cell functions as well โ€” including the ability to mount an antiviral response.

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Model of IMPษ‘โ€ฒs role in nuclear transport of host and viral proteins, and mechanism of inhibition by ivermectin. A. Normal function. B. Viral hijacking. C. Inhibition by ivermectin.
 
Abbreviations: IBB, IMP๐›ƒ-binding region of IMP๐›‚; IMP๐›‚, importin alpha; IMP๐›ƒ1, importin beta-1; NE, nuclear envelope; NF๐œฟB, nuclear factor kappa B; NPC, nuclear pore complex, NS5, a specific viral protein.
 
Note: Not all viruses use or rely exclusively on IMP๐›‚, so ivermectin is not effective against all viruses, just against those that rely on IMP๐›‚ for their replication, such as those listed above.

 

Here is where dosage is key โ€” not just the amount of ivermectin given, but how often the dose is repeated and for how long.

Dosage

We don't yet know the optimal dosage of ivermectin as an antiviral agent. Its clinical use in this regard is still very new, and much is yet to be learned. However, we can begin to make some tentative deductions.

As of January 2021, there were almost 70 clinical trials underway worldwide on the safety and effectiveness of ivermectin for the treatment or prevention of COVID-19 in humans. (Most have been completed, but some are still ongoing.)

The striking thing to me is that many of those trials used ivermectin dosages that are the same as what we use in horses as an anthelminthic agent: 0.2 mg/kg (200 ยตg/kg) bodyweight. This dosage is also used for anthelminthic treatment in humans, which is probably why it was chosen in numerous studies: it is known to be well tolerated in humans.

Higher dosages (up to 0.6 mg/kg, or 600 ยตg/kg, bodyweight) are used in humans for certain parasitic diseases, and these higher dosages have been used in a few of the COVID trials and in at least one current treatment protocol (see below).

Some trials used a single oral dose of ivermectin; others repeated the dose daily for up to 7 days, or gave 2 doses spaced at least 2 days apart (e.g., on Days 1 and 3). The optimal dosing regimen remains to be determined, but in none of these trials was dosing repeated for more than 7 days in a row.

Perhaps the most comprehensive review to date was published by the Front Line COVID-19 Critical Care Alliance (FLCCC), a group of critical-care physicians. The current FLCCC guidelines recommend the following:

Prevention (prophylaxis) in high-risk individuals

* ivermectin, 0.2 mg/kg per dose โ€” first dose today, second dose 48 hours later (i.e., on day 1 and day 3) following known exposure

examples include a household member becoming COVID-positive, or having prolonged exposure to a COVID-positive patient while not wearing a mask

* if the risk is ongoing, take one dose every 2 weeks

This preventive protocol also includes supplemental vitamin D3, vitamin C, quercetin, melatonin, and zinc. It does not rely on ivermectin alone.

Early treatment

* ivermectin (0.2 mg/kg) per dose โ€” one dose per day for at least 2 days after the onset of cold- or flu-like symptoms

* continue daily until recovery (maximum of 5 days)

This early treatment protocol also includes supplemental vitamin D3, vitamin C, melatonin, zinc, and aspirin. It does not rely on ivermectin alone.

Treatment for hospitalised patients

* ivermectin (0.4โ€“0.6 mg/kg) per dose โ€” one dose daily for 5 days or until recovery

(Note that this dose rate is 2โ€“3 times higher than the one used for prevention and for early treatment of patients with mild to moderate COVID.)

The FLCCC considers ivermectin to be a core medication for the treatment of COVID-19 in hospitalised patients and they advise giving it on admission to hospital. Even so, it is used in combination with numerous other medications and supplements.

FLCCC

screen shot from FLCCC home page, 12 July 2021.

 

What does this mean for viral infections in horses?

This research raises a lot of questions for me. An obvious one is whether ivermectin might be useful in the treatment of serious viral infections in horses for which we don't currently have very good or cost-effective treatments, such as the neurologic form of equine herpesvirus type 1 (EHV-1), Murray Valley encephalitis virus, Kunjin virus (Australian strain of West Nile virus), and, of course, HeV. It is possible that horses with Ross River virus infection might also benefit, although I have not found definitive evidence that ivermectin blocks this particular virus.

If nothing else, ivermectin is anti-inflammatory by virtue of being a potent inhibitor of NFkB.

Given the potential for HeV to spread to other horses and to humans, it is reasonable to ask whether we should even be attempting to treat HeV infection in horses. I would answer that with an emphatic yes! It's not the politically correct answer, but it's a medically sound one.

As I discuss in the multi-part article on HeV in horses, HeV infection is not universally fatal in horses; some infected horses recover โ€” and others don't even become ill when infected with HeV. Furthermore, experimental studies have shown that HeV is not highly contagious.

In the first experiment of a 3-part disease transmission study using flying-foxes, horses, and cats, 8 flying-foxes were inoculated with HeV and housed in contact with 3 uninfected flying-foxes and 2 uninfected horses.
 
None of the flying-foxes or horses became ill, although 6 of 8 inoculated bats developed antibodies against HeV, and 2 of 6 had vascular (blood vessel) lesions on postmortem examination which contained viral antigen. The in-contact bats and horses did not develop HeV antibodies, indicating that they had not been infected with HeV.
 
In the second experiment, 4 horses were inoculated with HeV by subcutaneous injection and intranasal inoculation, and housed in contact with 3 uninfected horses and 6 uninfected cats.
 
Three inoculated horses became ill, but the fourth horse did not, despite being inoculated with HeV. The in-contact horses and cats did not become infected.
 
In a third experiment, 12 cats were inoculated with HeV and housed in contact with 3 uninfected horses. One horse became ill, but the other 2 horses did not.
 
In this study, transmission from flying-foxes to horses could not be proven and neither could transmission from horses to horses or horses to cats. "Under the experimental conditions of the study, HeV is not highly contagious."
 
A similarly low rate of person-to-person transmission is reported for the closely related Nipah virus (NiV) in people, who can be directly infected with NiV from contact with bat excretions. In one study, only 35 of the 2,494 people who came in contact with a NiV patient (1.4%) probably acquired NiV through person-to-person transmission. Spouses of NiV patients were infected more often (14%) than other close family members (1.3%) or unrelated contacts (0.9%).

 

Yes, let's isolate any suspect case while awaiting HeV test results. And let's take all appropriate precautions with personal protective equipment to ensure that we don't become infected ourselves or spread the virus when handling these horses. But let's also treat these sick horses while we're waiting!

Where is the harm in administering a single oral dose of ivermectin โ€” properly suited up, of course โ€” while we wait on the HeV test results?

And even if the test comes back positive for HeV, where's the harm in continuing to treat the horse symptomatically and with ivermectin, guided by what we've learned from the human clinical trials of ivermectin for the treatment and prevention of COVID?

This approach could also be extended to exposed but still-healthy horses on the same or neighbouring farm, and even to the humans handling the ill horse.

As to that, a monoclonal antibody-based HeV treatment for humans cleared the first hurdle โ€” safety in healthy human volunteers โ€” in early 2020. The next step is to complete a clinical trial that documents its effectiveness for the treatment and prevention of HeV infection in humans exposed to HeV. "The antibody has been available in Queensland since 2010 for the treatment of HeV infection in people. Since then, it has been used on compassionate grounds in 13 people in Queensland."

Just one note of caution about using ivermectin in horses to prevent HeV infection. Although it may turn out to be a worthwhile preventive strategy in still-healthy horses exposed to a HeV-infected horse, it is not a wise long-term strategy.

Quite apart from the fact that ivermectin blocks a normal and necessary nuclear transporter protein, ivermectin is still one of the most important anthelminthic drugs we have for horses. Overuse speeds the development of drug resistance in parasites, not just to ivermectin but to all other drugs in its class (abamectin, moxidectin, etc.).

If you are choosing not to vaccinate your horse against HeV, then save the ivermectin for situations in which there is a fairly high degree of risk that your horse has been exposed to HeV, whether from a sick horse or directly from flying-foxes. And then use it only for the period of high risk.

Until we have some data that is specific to horses, the FLCCC guidelines for preventing COVID-19 in humans are a good place to start:

Because we need ivermectin to remain a highly effective anthelminthic drug in horses, it would be better to resolve the risk of HeV infection so that ongoing treatment with ivermectin is unnecessary. Rather than continuing with ivermectin every 1โ€“2 weeks,* as currently recommended for COVID-19 in high-risk people, do whatever is needed in the situation to prevent further exposure to HeV.

* Why "1โ€“2 weeks" in horses when the FLCCC guidelines for humans advise "2 weeks"? This dosing interval is my current suggestion, based on the principle of "an abundance of caution"; it is likely to change as we learn more. In the meantime, here are the facts that have guided my thinking: The incubation period for HeV in horses under conditions of natural infection is reported to be 5 to 16 days. Although ivermectin may be detectable in the horse's system for up to 3 weeks after a single oral dose, about 90% is eliminated within the first 4 days.

***

More on ivermectin and COVID-19

The FLCCC recommendations are based on the following conclusions derived from existing scientific data:

1. Since 2012, multiple in vitro studies have demonstrated that ivermectin inhibits the replication of many viruses, including influenza, Zika, Dengue, and others.

2. Ivermectin inhibits SARS-CoV-2 replication and binding to host tissue via several observed and proposed mechanisms.

3. Ivermectin has potent anti-inflammatory properties with in vitro data demonstrating profound inhibition of both cytokine production and transcription of nuclear factor-ฮบB (NF-ฮบB), the most potent mediator of inflammation.

4. Ivermectin significantly diminishes viral load and protects against organ damage in multiple animal models when infected with SARS-CoV-2 or similar coronaviruses.

5. Ivermectin prevents transmission and development of COVID-19 disease in those exposed to infected patients.

6. Ivermectin hastens recovery and prevents deterioration in patients with mild to moderate disease treated early after symptoms.

7. Ivermectin hastens recovery and avoidance of ICU admission and death in hospitalized patients.

8. Ivermectin reduces mortality in critically ill patients with COVID-19.

9. Ivermectin leads to striking reductions in case-fatality rates in regions with widespread use.

10. The safety, availability, and cost of ivermectin is nearly unparalleled, given its near nil drug interactions, along with only mild and rare side effects observed in almost 40 years of use and billions of doses administered.

11. The World Health Organization has long included ivermectin on its โ€œList of Essential Medicinesโ€.

[Source, including references]

 

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ยฉ Christine M. King, 2021. All rights reserved.
First published 04 July 2021.
Last updated 14 July 2021.