Antiviral effect of high-dose Ivermectin in adults with COVID-19: A proof-of-concept randomized trial

Lancet eClinical Medicine ^ | 07/16/2021 | Alejandro Krolewiecki, Adrián Lifschitz Matías Moragas Marina Travacio Ricardo Valentini Daniel F.

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Abstract

Background

There are limited antiviral options for the treatment of patients with COVID-19. Ivermectin (IVM), a macrocyclic lactone with a wide anti-parasitary spectrum, has shown potent activity against SARS-CoV-2 in vitro. This study aimed at assessing the antiviral effect of IVM on viral load of respiratory secretions and its relationship with drug concentrations in plasma.

Methods

Proof-of-concept, pilot, randomized, controlled, outcome-assessor blinded trial to evaluate antiviral activity of high-dose IVM in 45 COVID-19 hospitalized patients randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care in 4 hospitals in Argentina. Eligible patients were adults with RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. The primary endpoint was the difference in viral load in respiratory secretions between baseline and day-5, by quantitative RT-PCR. Concentrations of IVM in plasma were measured. Study registered at ClinicalTrials.gov: NCT04381884.

Findings

45 participants were recruited (30 to IVM and 15 controls) between May 18 and September 9, 2020. There was no difference in viral load reduction between groups but a significant difference was found in patients with higher median plasma IVM levels (72% IQR 59–77) versus untreated controls (42% IQR 31–73) (p = 0·004). Mean ivermectin plasma concentration levels correlated with viral decay rate (r: 0·47, p = 0·02). Adverse events were similar between groups. No differences in clinical evolution at day-7 and day-30 between groups were observed.

Interpretation

A concentration dependent antiviral activity of oral high-dose IVM was identified at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19.

Research in context

Evidence before this study

The potential role of ivermectin against SARS-CoV-2 was first reported in April 2020 when an Australian group published in-vitro results. Since then, multiple opinion papers and a few studies tried to understand the meaning of those results and utility of ivermectin in COVID-19. Mostly observational reports suggest a potential activity that needs confirmation through randomized controlled trials.

Added value of this study

Our study contributes evidence of the antiviral activity of ivermectin against SARS-CoV-2 in patients with COVID-19 through a randomized, controlled, outcome-assessor blinded clinical trial with innovative analyses that include the use of quantitative viral load determinations and measurement of ivermectin plasma levels, which allow an in-depth interpretation of the data and the identification of ivermectin systemic concentrations needed for a significant antiviral effect. The use of an untreated control group highlights the need for controlled trials and on the viral load dynamics in the natural history of COVID-19. Finally, we also add further information on the safety of high dose ivermectin.

Implications of all the available evidence

A concentration dependent antiviral effect of ivermectin in COVID-19 was identified, with significant reductions in SARS-CoV-2 viral load in respiratory secretions among patients achieving high systemic ivermectin concentration compared to untreated controls. These results, that did not show toxicity related to the use of high dose ivermectin, provide evidence of the antiviral effect and support the design of trials to investigate the clinical implications of our findings. Further exploration of the factors involved in the oral bioavailability of ivermectin are also warranted.

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Ending the pandemic will take a multifactorial approach including vaccines and treatments

By 'vaccines', you speaking about immunity issues without using the word 'immunity'. Why is that? Shouldn't immunity be the focus instead of a genetic therapy? After all, we are trying to achieve 'herd immunity' still, aren't we?

Do you think naturally immunized survivors (CoVID / SARS-1) should be the gold standard instead of a 'jab' that creates variants of the disease, and reinfection, apparently?