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Editor's Note: Open Forum Infectious Diseases issued an about the study by Hill et al., following the retraction of a key study included in the meta-analysis. Hill et al. will submit a revised version of their analysis, and the current paper will be retracted.

Proponents of ivermectin for COVID-19 have long been talking about an expected review and meta-analysis led by Andrew Hill, PhD, of the University of Liverpool.

These results were finally , and they're positive -- but they haven't escaped criticism, and most researchers still want results from a randomized controlled trial.

The review and meta-analysis was conducted as part of the International Ivermectin Project Team from December 2020 to May 2021. Ivermectin proponents said Hill was conducting the analysis for the WHO, but Hill recently told 麻豆传媒 the analysis was supported by Fort Worth, Texas-based Rainwater Charitable Foundation, and not WHO.

Hill and colleagues assessed 24 randomized trials totaling 3,328 patients that involved some type of control, whether it was standard of care or another therapy. Sample sizes ranged from 24 to 400 participants. Eight of the studies had been published, nine were preprints, six were unpublished results shared for the analysis, and one was reported on a trial registry website.

In the 11 trials (totaling 2,127 patients) that focused on moderate or severe infection, there was a 56% reduction in mortality (relative risk [RR] 0.44, 95% CI 0.25-0.77, P=0.004), with 3% of patients on ivermectin dying compared with 9% of controls.

But the researchers noted that the total number of deaths was small (128) and there was no difference between ivermectin and controls in the subgroup with severe disease. As for moderate disease, they reported a 70% improvement in survival with ivermectin (RR 0.30, 95% CI 0.15-0.58, P=0.0004).

Use of ivermectin was also associated with a reduction in time to recovery of 1.58 days compared with controls (95% CI -2.8 to -0.35, P=0.01) and with a shorter duration of hospitalization (-4.27 days, 95% CI -8.6 to -0.06, P=0.05).

However, the drug was not associated with a lower risk of hospitalization, though a sensitivity analysis that included any hospitalizations within 12 hours of taking the drug did show a reduction with ivermectin (RR 0.32, 95% CI 0.13-0.80, P=0.01).

Many studies included in the analysis were not peer reviewed, which was a limitation; additionally, studies varied widely in terms of dosage, treatment duration, and inclusion criteria. Studies also included a range of comparators, including hydroxychloroquine, lopinavir/ritonavir, standard of care, and placebo.

The authors concluded that their results "need to be validated in larger confirmatory trials" -- a fact that David Boulware, MD, MPH, of the University of Minnesota, who has been interested in evaluating ivermectin for COVID-19 outpatients, agreed with.

On Twitter, Boulware pointed out that there was no mention of patients receiving steroids, which could be a major confounder.

As for the outpatient findings, he noted that only two of seven trials showed a reduction in symptom duration, and that a small sample size didn't offer adequate analysis as to whether hospitalization risk was reduced by early treatment.

"Thus, there remains a need for phase 3 randomized clinical trials testing early ivermectin treatment to be completed in order to delineate what is the clinical benefit of early treatment? Quicker resolution of symptoms? Less hospitalization?" . "Personally, I would have liked to see more separation of outpatient vs hospitalized therapy, as blurring everything together is not particularly helpful."

"Of course, rolling out vaccination as quickly and widespread as possible would negate the need to use ivermectin as a treatment," . "So big picture, vaccines are the better solution."

Boulware noted that there are multiple ongoing phase III randomized controlled trials "which will provide definitive results," including the that's aiming to enroll about 1,500 patients in its ivermectin arm.

One Argentinian randomized controlled trial of 500 patients found that ivermectin didn't prevent hospitalization among outpatients with COVID-19.

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