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Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19.

ABSTRACT:

Background

After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials.

Areas of uncertainty

The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses.

Data sources

Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns.

Therapeutic advances

A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large "natural experiments" occurred in regions that initiated "ivermectin distribution" campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns.

Conclusions

Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.

SUBMITTER: Kory P

PROVIDER: S-EPMC8088823 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ivermectin has received particular attention as a potential treatment for COVID-19. However, the evidence to support its clinical efficacy is controversial. We undertook a new systematic review of ivermectin for the treatment and prophylaxis of COVID-19, including new primary studies, outcomes other than mortality, and grading the quality of the available evidence following the Cochrane guidance for methodology. We searched electronic databases, repository databases, and clinical trial registries (up to June 2021). The measure of treatment effect was risk difference (RD) with 95% confidence intervals (CIs). The GRADE system was used to assess the certainty of the evidence. The review includes 11 RCTs (2436 participants). The certainty of the available evidence was quite low or very low due to risk of bias, inconsistency, and imprecision. When the analysis was limited to patients with baseline mild or moderate disease (8 reports, 1283 patients), there were no differences in mortality between ivermectin and control groups (low level of certainty); in patients with baseline severe diseases (3 reports, 304 patients), the use of ivermectin significantly decreased mortality compared to the controls (RD -0.17; 95% CIs, -0.24/-0.10; p = 0.00001; low level of certainty). In terms of disease progression (to severe pneumonia, admission to intensive care unit, and/or mechanical ventilation), the results were much the same. At day 14, the rate of patients with a negative RT-PCR test was 21% higher (from 5 to 36% higher) for ivermectin recipients than it was for the controls (low quality of evidence). Three studies (736 subjects) indicated that prophylaxis with ivermectin increased the likelihood of preventing COVID-19 compared to controls (low quality of evidence). Serious adverse events were rarely reported. There is limited evidence for the benefit of ivermectin for COVID-19 treatment and prophylaxis, and most of this evidence is of low quality. Further evidence is needed to fine-tune potential indications and optimal treatment protocols for ivermectin as a treatment for COVID-19.

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Project description:The COVID-19 pandemic has been characterized by a lack of clear evidence to guide healthcare professionals, the public and policymakers. The resulting uncertainty, coupled with changing guidelines as additional evidence became available, added to the stress and anxiety reported by decision-makers. Research results are key to providing evidence to guide healthcare decisions. Important questions have arisen about whether various interventions are safe and effective. The evidence found guides those making treatment decisions, and influences those selecting interventions for further evaluation in research studies. As the COVID-19 pandemic intensified, the effectiveness and safety of many pharmaceuticals was queried. Ivermectin will be used to explore the ethics of how healthcare evidence must be critically appraised, even, or especially, during a pandemic. This drug is alleged to be effective in treating COVID-19, with various studies and systematic reviews finding supportive evidence. Some of these have now been linked to concerns about fraud or poor research reporting. This article will focus on the scientific literature and how apparently fraudulent studies were published and influenced treatment decisions, on-going research and public health guidelines. Research evidence is critical during emergencies like pandemics, but urgency should not overtake ethical responsibilities to critically appraise (or evaluate) studies as they become available. These responsibilities apply in various ways to editors, peer-reviewers, news media reporters, and those making treatment decisions, including clinicians, policymakers and the general public. While research article authors have the primary ethical responsibility to reject fraudulent or inaccurate claims, the readers of health research must carefully evaluate all publications. To detect and reject fraudulent healthcare claims, readers need critical appraisal skills that match their level of engagement with those articles. The core principles of critical appraisal will be described in the article, and how they can be adapted for different types of readers. Exemplar tools that develop critical appraisal skills will be noted, with reviews of ivermectin's efficacy explored as examples. As stakeholders in healthcare evidence are increasingly able to identify well-conducted and ethical research they will simultaneously be able to spot and reject fraudulent reports and prevent them from influencing healthcare decisions.