The year 2019 saw the reemergence of a new strain of virus that had hitherto made its mark on a limited population. Said to have originated from a species of bat, the virus was identified in Wuhan town of China before it made its mark globally. The SARS -COVID virus is a positive-sense single-stranded RNA virus that spreads through air droplets, close contact, and contaminated surfaces. Once inside, through contact with the ACE2 receptors, and starts its destructive action. Starting from conditions of flu, it may progress into severe pneumonia symptoms, ultimately leading to multiple organ failure followed by death.
The impact of Covid-19
The impact of Covid-19 has been felt globally, with up to 274,628,461 cases recorded worldwide and 5,358,978 deaths among them. The US has been most affected by this. A total of 52,253,811 cases have been recorded in the States, with the death number crossing 80, 0000. 68% of these deaths took place in a hospital setting. 147,351 of these cases were between ages 50-64. The economic impact of the situation was bad. There was a -2.4% change in GDP due to the pandemic. Due to travel restrictions, the travel and tourism industry recorded a loss of $51.5 billion with a 1.4% decrease in hotel occupancy. Children represented 17.3% of the total cases, with males being affected more than females irrespective of age.
Treatment options for Covid
As of now, there is no complete cure for the situation. Antiviral pills, though promising, are still under lab research. Dexamethasone, Monoclonal Antibodies like Tocilizumab, and Anticoagulants are secondary medications approved by the FDA for taking care of complications induced by the virus rather than the main virus itself. Vaccines like Johnson and Johnson, Moderna, and BioNtech help the body develop immunity to the virus and, in some cases, act as a prophylaxis against it. Some vaccines use pieces of the pathogen to create an immune response, while some use genetic material to provide cells with the instructions to make the antigen. But there is a chance of a repeat infection. Stronger, better options are required to cure the virus and prevent its recurrence effectively.
What about Ivermectin?
Ivermectin created a stir in the medical community in the initial phases of the pandemic when treatment options were still in the making and the panic regarding the unavailability of options was growing in intensity day by day. A lot of half-correct theories were passed around regarding its effectiveness. Panic and desperate lack of alternatives with indiscriminate prescriptions lead to it getting out of stock and available illegally at black market prices. This worsened the situation and made some people resort to the medication’s veterinary forms, leading to further complications and casualties. The situation escalated to the point of governments declaring it a controlled substance and strictly moderating its use that has prevailed till this day. One question was in everyone’s minds then and continues till date. “Is Ivermectin a possible treatment option for Covid-19?”. To answer this question, it is important to understand in detail Ivermectin and its action on the virus and the human body. As per the FDA, Ivermectin is not approved for humans to treat or prevent Covid 19.
A word about Ivermectin
Ivermectin was discovered in Japan by two scientists, Satoshi Omura and William Campbell. The search was on at that time for an effective anthelmintic or antiparasitic medication. Ivermectin fitted the criteria going as far as proving itself a broad-spectrum antiparasitic for ectoparasites, mites, and scabies. It was approved for veterinary use in 1981. By 1988, it was modified and approved for human use and one of the first medications to work effectively against Strongyloidiasis. By 2018, it was the 420th most prescribed medication in the United States, with the WHO declaring it an essential medication, and the FDA approved its use for parasitic infections.
A detailed description
Ivermectin is used for a variety of parasitic arthropods like mites and scabies, and more popularly, lice. Usually, two doses of the medications are sufficient to kill the active insects while destroying the eggs in the second dose. The medication also effectively treats other parasitic conditions like Lymphatic filariasis and Onchocerciasis. The WHO has approved Ivermectin for Strongyloidiasis or river blindness, a common infection in African countries with mixed prognosis. Ivermectin is effective on its own for a variety of parasitic conditions. Sometimes, it is used in combination with other drugs like Albendazole for Whipworms and gnathostomiasis. It works by interfering with the nerve and muscle functions of the parasites and hyperpolarizing their cell membranes. This paralyzes or kills them, after which they are removed from the body. Its role in Covid is different from its other pathophysiologies.
Does Ivermectin work on the Sars-Covid virus?
Researchers have formulated a number of ways in which Ivermectin works on the SARS-Covid virus. As discussed earlier, the SARS virus enters the body through contaminated droplets. For this purpose, it uses its spike proteins that bind themselves to the ace two receptors located on the nasal, lungs, and gastrointestinal tract. The cell surface protease and lysosomal protease help in its fusion into the lysosomal membranes and entry inside the human body. Once inside, it starts multiplying at a fast rate and initiating a cytokinetic storm. This eventually paralyzes the immune system and leads to multiple points of inflammation within the body.
A detailed explanation
Ivermectin attaches itself to the spike proteins of the virus and forms a protective shield around it. This impairs its ability to fuse with the ACE receptor and thus forms an important role in preventing its entry into the body. It is important for the virus to replicate for survival inside the human body. Ivermectin alters the virus’s NCP (nucleocapsid protein) by selectively inhibiting the host protein on which the virus attaches itself after its entry into the body. Altering the NCP prevents the virus from replicating and surviving. This helps in preventing the propagation and spread of the infection. Apart from preventing replication, Ivermectin binds to metal cations like zinc and forms lipid-soluble complexes facilitating their transport inside the cell membrane of the virus. This leads to dysregulation of osmosis and direct cytotoxic effects altogether, killing the virus off.
Thrombosis or blood clot is an important complication created by the Sars Covid virus. Apart from the other damage, these blood clots risk obstructing the heart in the form of emboli and resulting in a heart attack or stroke. Its CD147-mediated action on the RBS prevents the virus from adhering itself to them and damaging them. Additionally, it forms a synergistic reaction with other medications used for Covid treatment. It has been known to form successful combinations with compounds like Zinc, Doxycycline, and Hydroxychloroquine to effectively fight against the virus.
Why has WHO not approved it yet?
Despite its effectiveness, the WHO has not approved Ivermectin for treatment against the virus. According to the WHO, the current evidence on the role of the medication in Covid positive patients is inconclusive. In response to the increased international attention over Ivermectin, a guideline development group consisting of an independent, international team of experts was formed consisting of health experts, ethicists, and clinical care partners in multiple specialties. Pooled data from 16 randomized trials were collected by these experts and surveyed. A total of 16 trials, including both inpatients and outpatients, were included in the trials. They found that these trial data were very small and had methodological limitations, including a small number of events. This made it an uncertain decision whether Ivermectin was effective in reducing mortality or reducing the need for mechanical ventilation or hospital admission.
A sneak peek into some of these trials
A double-blind, randomized clinical trial was held in Cali, Columbia, to determine the efficacy of Ivermectin for Covid-19. 476 adult patients diagnosed Covid positive with mild disease and symptoms were enrolled for the study. Patients were randomized to receive Ivermectin 300 microgram/body weight for five days or a placebo. Adverse effects and serious adverse events were collected during the study. Among the 400 patients finalized for the study, 395 subjects completed the trial. The median time to resolution of symptoms was ten days in the Ivermectin group compared to 12 days in the placebo group. By day 21, 82% in the Ivermectin group and 79% in the placebo group had resolved symptoms. Headache was the most common side effect reported by 104 subjects in the Ivermectin group and 111 subjects in the placebo group. Two patients in each group suffered multiple organ failures. The overall findings did not show any significant effect of Ivermectin for Covid positive patients with mild symptoms. The 5-day course of Ivermectin did not significantly improve the symptoms in comparison to placebo.
On the other hand, 22 other randomized clinical trials identified by PAHO showed variable end results because of heterogeneity in the subjects receiving it. The co-interventions received in place of Ivermectin were variable, ranging from placebo to no intervention to other treatment methods. The end results suggested that Ivermectin had the potential to work in favor of Covid positive patients, but a lot more trials were required to reach a conclusive result.
What went wrong?
Apart from the small size of the trials and their undefined outcome measures, other things made the panel deem them to have ‘methodological limitations’. Firstly, all of these trials used different doses and schedules of Ivermectin instead of adhering to one dose. Secondly, some of these trials were open-label studies in which neither the subjects nor the participants were blinded to treatment arms making the results somewhat biased. Thirdly, the concomitant medications used in the trials alongside the medication made it difficult to understand the exact efficacy or safety of the intended drug. Additionally, the severity of Covid-19 in the study participants was not well described.
Most importantly, the WHO has a problem with the required dose of Ivermectin for the treatment of Covid cases. Usually, 5uM of Ivermectin is required for inhibiting the virus for around 48 hours. This is much higher than the approved dose of the medication for the treatment of parasitic conditions (200µg/kg). According to the WHO, the recommended dose was too high to be considered within safety measures. Even if the virus was treated by Ivermectin successfully, the complications arising from overuse or side-effects of the drug would be far greater than those ensuing due to the virus itself.
All is not lost. The WHO has not banned Ivermectin completely, and it has merely been recommended for the drug to be used only in clinical trials. The FLCCC (Front Line Covid 19 Critical Care Alliance) despite the resistance from WHO, has determined that Ivermectin can be considered the gold standard for reducing the risk of infection on regular use. All of these lead to two end thoughts. First, there is mixed opinion in the medical field regarding the safety and efficacy of Ivermectin. The medical communities need to come to a combined conclusion regarding the final verdict about Ivermectin as a treatment option for Covid. Second, more trials following a common set of parameters are required to understand the pros and cons associated with the drug.