Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe respiratory syndrome coronavirus 2 (SARS-CoV-2), cases worldwide have crossed the hundred million mark, with over 2.2 million deaths recorded.
The overwhelming demands of the pandemic on public health and healthcare systems have made it a matter of the utmost urgency to identify safe and effective antivirals that target this infection.
A team of researchers based in Peru and the U.S. recently examined the role of the anti-parasitic drug ivermectin in treating COVID-19. The team has released their findings on the medRxiv* preprint server.
The aim of the study
Ivermectin is a semisynthetic drug, used to treat helmintic infestations. Its mode of operation is via binding to glutamate-gated chloride ion channels, found in invertebrate nerve and muscle cells.
As part of the avermectins, ivermectin is extensively used to treat and control parasitic infestations in large animals, including tick infestations and scabies. It has also been used to prevent human filariasis and to treat scabies in humans. With a good safety profile at recommended dosages, and with FDA (U.S. Food and Drug Administration) approval, it became a mainstream drug in the treatment of COVID-19.
Earlier reports suggested that it had antiviral activity in both RNA and DNA viruses. This was followed by another study examining its pharmacokinetics, which concluded that even at tenfold the approved human dosage, the compound could not inhibit SARS-CoV-2 in lung tissue.
The current study aimed to review the range of studies that reported the clinical efficacy of ivermectin in the treatment of the illness.
The researchers included 12 qualitative and five quantitative studies, mostly preprints. These studies originated from all over the world, two being from the U.S., two from Spain, two from South America, one each from Iraq and Iran, and four from Bangladesh.
Altogether, there were around 7,400 participants, with a mean age of 47.5 years. About 60% were male. The treatment protocols for all included studies comprised ivermectin either alone or in combination with another anti-inflammatory, antibiotic or blood-thinning drug like azithromycin, hydroxychloroquine, dexamethasone, enoxaparin, aspirin or dicloxacillin.
The majority of patients had been diagnosed by reverse transcriptase-polymerase chain reaction (RT PCR), and were hospitalized, though one study included asymptomatic families.
Five randomized controlled trials (RCTs) had missing data on study outcomes, leading to a serious risk of bias. Four cohort studies also showed a high risk of bias.
In one analysis of four preprints, based on retrospective studies, there was no evidence of reduced mortality following ivermectin use. Patient recovery was also not affected.
The GRADE system was used to assess the quality of evidence, using mortality and recovery outcomes. The mortality outcome was evaluated in over 3,600 participants, while recovery was assessed in about 400 participants. The first was based on five retrospective studies, and the latter from three preprint retrospective studies.
In both analyses, the degree of certainty of evidence was low, with a high risk of bias.
What are the implications?
Ivermectin was not significantly associated with a lower mortality or higher recovery of patients in this meta-analysis. However, the majority of studies were preprints, allowing for later changes in the data on which these conclusions are based.
The basis of ivermectin use was because of a study published in Australia that reported this drug’s in vitro efficacy in Vero cells in culture. The clinical applicability of this finding is far from certain, but physicians rapidly began to use ivermectin in the treatment of hospitalized COVID-19 patients.
This was more likely in hard-hit countries such as Peru, where ivermectin became a first-line treatment and preventive against SARS-CoV-2 infection.
However, the safety and efficacy of this drug in preventing and treating this illness is not yet proven, especially because the studies were poorly designed. This has cast doubt on the accuracy of the effect measures. Even when the odds ratio showed a significant benefit for ivermectin use in terms of an 85% reduction in mortality, the certainty of evidence was conceded to be very low.
Thirdly, the dose effective in human SARS-CoV-2 infections is still unknown, with the study doses ranging from 120 uM/kg to 200 uM/kg per dose, and the route of administration varying from intramuscular to oral. Such high doses have not been approved for human use.
Finally, efficacy testing of ivermectin in humans must be based on a dose-response trial with a placebo control group. In the absence of such studies, the optimal high dosage of ivermectin remains unclear.
The heterogeneous study populations and methods may also grossly reduce the accuracy of the review’s findings. After adjusting for such differences, the researchers found that their assessment of biases and effect measure size was close to the actual results. The lack of certainty of evidence for the estimated effect, as shown by GRADE criteria, indicates a serious difference between the true and estimated effect.
More randomized clinical trials need to be included in a meta-analysis, with fewer biases. At the moment, there is no evidence that the use of ivermectin changes the clinical outcome of inpatients or outpatients.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.