Whither Ivermectin?

DESPITE the bad press that Ivermectin has received recently due to cases of overdose, we should form an educated opinion of it by looking at the whole spectrum of scientific facts and hard empirical evidence.

It is, after all, a Nobel Prize-winning drug with a wide margin of safety and decades of safety data.

This is especially important when the drug may have the potential to provide a safety bridge to full vaccination (but not vaccine substitution in any measure) and have our backs even in the presence of Covid-19 variants.

First, we should clarify that the following discussion is all about human-grade Ivermectin. The animal-grade version is not for humans and its effects are largely unknown.

Even then, human-grade Ivermectin is strictly not for self-medication without proper guidance from the health authorities.

We do not intend to give support to either proponents or opponents of Ivermectin here, but wish to invite both sides to look at the issue in a detailed and balanced way, backed by science.

After all, we are not out of the woods yet as far as the pandemic is concerned, and the science behind Ivermectin may hold valuable knowledge in facing this and future pandemics.

SARS-CoV-2 is not the first virus to draw scientists' attention to this drug. Close to five decades' worth of scientific literature documents its potent effects on a broad range of RNA and DNA viruses such as Zika, dengue, yellow fever, West Nile, Human immunodeficiency Virus Type 1 and many others.

Recent research significantly expands understanding of the link between this humble dewormer and various viral infections, including SARS-CoV-2.

Ivermectin, primarily discovered for its deworming function, acts on parasites' neural and muscle cells by hyperpolarising them, interrupting proper function and causing paralysis and death.

Though the drug is safe for humans in therapeutic doses (FDA approved) of 150-200 microgrammes per kg body weight, and even higher doses in various protocol regimes.

However, if Ivermectin crosses the blood-brain barrier, it may cause brain damage.

In other words, it is not to be consumed by those with a compromised blood-brain barrier; for example, meningitis patients, children below two years old or who weigh below 15kg, and pregnant or breastfeeding women due to danger to the child.

Furthermore, people with impaired liver or kidney function should also be cautious with Ivermectin. However, many people might be unaware of their liver or kidney malfunction, which underscores once again the fact that Ivermectin is strictly not for self-medication.

Research has found that Ivermectin's beneficial functions do not stop at paralysing worms and here, the science gets exciting.

Although Ivermectin does not kill the virus directly, its several mechanisms inhibit viral replication and may be best described as having a virostatic effect, that is, it inhibits the growth or replication of viruses.

First, Ivermectin is found to inhibit SARS-CoV-2's ability to suppress the host's cellular defensive mechanisms.

As a result, the cell can recognise the viral intrusion and ramp up not only its own defence but inform neighbouring cells to do the same.

Furthermore, Ivermectin shows relatively high binding efficacy to SARS-CoV-2's essential protein for viral replication inside the host's cells.

By blocking this, Ivermectin halts the replication of SARS-CoV-2 viral RNA, rendering newly -formed copies of the virus hollow and useless.

Additionally, computer models that examined molecular docking capabilities have revealed that Ivermectin efficiently binds to viral proteins as well as human cell receptors. Sandwiched between the two, IVermectin can prevent viral entry into human cells.

Ivermectin also appears to have potent anti-inflammatory action. On top of all that, it possibly reduces blood-vessel clotting observed in SARS-CoV-2 patients.

The Ivermectin module can also bind with the viral spike protein, and therefore reduce blood clotting in SARS-CoV-2 infections.

The above scientific rationale has made Ivermectin one of the most looked-into potential repurposed drugs for Covid-19 management at all stages, from prophylaxis/preventive healthcare to critical care.

The two most recent, comprehensive and robust systematic reviews on the efficacy and safety of Ivermectin therapy against Covid-19, which held the included studies to the highest level of evidence, were published in June.

Both came to similar conclusions that Ivermectin was associated with reduced risk of mortality and progression to severe disease in Covid-19 management.

One study also found that Ivermectin prophylaxis reduced Covid-19 infection by an average of 86% but graded this finding as low-certainty due to underlying study design limitations and fewer included trials.

There were too few adverse events reported which were not clearly associated with the use of Ivermectin and also minor and transitory in nature.

However, another recent review published in July in Cochrane Library, a database highly regarded in the medical field, found no evidence of Ivermectin benefits in Covid-19 treatment.

One important variable that might explain these contradictory results between the studies is dosage and protocol.

Indeed, the majority of the studies included in the Cochrane review, in contrast with other reviews, used very low doses of Ivermectin – close to therapeutic levels.

It is already generally understood in the medical field that even if Ivermectin is to have a beneficial effect in Covid-19 treatment outcomes, it can be achieved mostly at higher than therapeutic doses.

Future research should be geared towards ascertaining the effect of Ivermectin doses.

In light of the above scientific rationale and empirical evidence, the fact that Malaysia's authorities at last initiated their own Ivermectin clinical trial is a highly positive development – although it could have been done earlier.

However, the authorities should also consider immediate initiation of clinical trials for those in very early stages of the disease (perhaps those in quarantine centres) and not only for the critically ill like in their current study.

This is because the use of Ivermectin as an early treatment for those who have no immunity against Covid-19, be it natural or vaccine-induced, has the greatest potential to effectively flatten the curve without economic collapse.

In other words, it could form a safe bridge to the time of full vaccination.

Furthermore, given the current public pressure for Ivermectin treatment and anecdotal evidence of its ongoing unauthorised use, volunteer recruitment could be expedited.

Should the study show positive results, the strategy is clear: massive and quick testing and early Ivermectin treatment for those with no immunity against Covid-19.

This is similar to what Peru's authorities did in May last year, in one of the largest documented case studies on population-wide use of Ivermectin for Covid-19 treatment with apparent success.

Importantly, note that most of Ivermectin's identified mechanisms of action on SARS-CoV-2 are not impacted by the presence of variants.

Therefore, this drug may have potential to have us covered if current vaccines start losing their efficacy in the face of new variants.

Meanwhile, it is worrying that anecdotal evidence suggests ongoing unauthorised sale and re-sale of Ivermectin in Malaysia.

The lives of Malaysians are in double jeopardy due to concerns over the drug's authenticity and its use without proper medical guidance in terms of dosage, protocol or contraindications, and supervision.

Hopefully, our health authorities can come up with some swift and definitive action on all of the above.

Rais Hussin and Margarita Peredaryenko are part of the research team at EMIR Research, an independent think tank focused on strategic policy recommendations based on rigorous research.