Ivermectin may reduce mortality risk in mild-to-moderate COVID-19 patients by an average of 62%, according to a meta-analysis in American Journal of Therapeutics. The findings will reignite the sometimes angry ongoing debate between those who believe that the repurposed anti-parasitic should be given emergency regulatory clearance worldwide and those who have rejected the evidence as too scanty, writes MedicalBrief.
The debate between the two camps will be sharpened by another meta-analysis, published in Clinical Infectious Diseases That found that in comparison to standard of care or placebo, Ivermectin “did not reduce all-cause mortality”. It concluded that the drug “is not a viable option to treat COVID-19 patients”.
The FLCC study suggests that risk of death among hospitalised patients treated with Ivermectin was 2.3%, compared to 7.8% for those who were not. The team said that there may be no benefit for COVID-19 patients in need of mechanical ventilation.
The meta-analysis of 18 randomised controlled treatment trials was conducted by scientists prominent in the avowedly pro-Ivermectin Front Line COVID-19 Critical Care Alliance (FLCCC). The authors concluded that Ivermectin in COVID-19 was linked to large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance.
Given that “numerous controlled prophylaxis trials have reported significantly reduced risks of contracting COVID-19 with the regular use of Ivermectin” and that there were many examples of Ivermectin distribution campaigns leading “to rapid population-wide decreases in morbidity and mortality”, the authors concluded that “an oral agent effective in all phases of COVID-19 has been identified”.
In a statement, FLCC said that the study, “peer reviewed by medical experts that included three US government senior scientists … the research is the most comprehensive review of the available data taken from clinical, in vitro, animal, and real-world studies”.
“We did the work that the medical authorities failed to do, we conducted the most comprehensive review of the available data on Ivermectin,” said Dr Pierre Kory, president and chief medical officer of the FLCCC. “We applied the gold standard to qualify the data reviewed before concluding that Ivermectin can end this pandemic.”
“A focus of the manuscript was on the 27 controlled trials available in January 2021, 15 of which were randomised controlled trials (RCTs), the preferred trial of the World Health Organization, US National Institutes of Health, and the European Medicines Agency. Consistent with numerous meta-analyses of ivermectin RCTs since published by expert panels from the UK, Italy, Spain, and Japan, they found large, statistically significant reduction in mortality, time to recovery and viral clearance in COVID-19 patients treated with Ivermectin.
“To evaluate the efficacy of ivermectin in preventing COVID-19, 3 RCT's and 5 observational controlled trial's including almost 2,500 patients all reported that Ivermectin significantly reduces the risk of contracting COVID-19 when used regularly.
“Many regions around the world now recognise that Ivermectin is a powerful prophylaxis and treatment for COVID-19. South Africa, Zimbabwe, Slovakia, Czech Republic, Mexico, and now, India, have approved the drug for use by medical professionals. The results as seen in this latest study demonstrate that the Ivermectin distribution campaigns repeatedly led to rapid population-wide decreases in morbidity and mortality.
“Our latest research shows, once again, that when the totality of the evidence is examined, there is no doubt that ivermectin is highly effective as a safe prophylaxis and treatment for COVID-19,” said Dr Paul E Marik, founding member of the FLCCC and Chief, Pulmonary and Critical Care Medicine at Eastern Virginia Medical School. “We can no longer rely on many of the larger health authorities to make an honest examination of the medical and scientific evidence. So, we are calling on regional public health authorities and medical professionals around the world to demand that ivermectin be included in their standard of care right away so we can end this pandemic once and for all.”
Ivermectin usage in South Africa
AfriForum this week sent a formal PAIA application to the Ministerial Advisory Committee on COVID-19 (MAC) and the SA Health Products Regulatory Authority (SAHPRA) to obtain documents and information relating to their review of Ivermectin for the prevention and treatment of COVID-19, with the intention of making Ivermectin more easily available.
In a statement, AfriForum and the I Can Make a Difference group of doctors said that they had earlier requested the MAC, SAHPRA, the National Essential Medicine List Committee (NEMLC) and the Infectious Diseases Society of South Africa (IDSSA) to provide their review documents on Ivermectin.
“This step was taken after Prof Helen Rees, chairperson of SAHPRA, indicated that these four institutions independently reviewed the available data on Ivermectin … The NEMLC referred AfriForum and I Can Make a Difference to the webpage of the Department of Health, where only an outdated ivermectin review document from January is available. The IDSSA indicated that the institution does not have such a document.
Barend Uys, Head of Research at AfriForum said that the SA authorities’ Ivermectin recommendations are based on outdated information. “The implementation of prevention and early treatment of COVID-19 with a combination of repurposed medicines can reduce pressure on hospitals and save lives. Everything points to the fact that the authorities’ current recommendation on ivermectin is based on outdated information.
“If the review of ivermectin was conducted independently by the four institutions, surely the documents relating to that must be available and can be provided on request? The question must be asked whether the public is deliberately misled or if those in leadership positions do not know what is happening,” said Uys.
This threatened Afriforum PAIA application follows a settlement agreement in April 2021 between four groups that had gone to court to contest the ban on the medicine with SAHPRA and the Department of Health, with the government bodies agreeing to pay the litigants almost R2m in costs. It was estimated that the legal costs of the two respondents were of a similar order.
The SA Health Products Regulatory Authority (SAHPRA) settlement agreement opened the way for the compounding of and access to the drug. In terms of the agreement, the Pretoria High Court ruled that any registered pharmacist or medical practitioner might compound and sell compounded medicine that contained Ivermectin as an active ingredient.
"Registered medical practitioners who are entitled to prescribe medicines in schedule 3 of the act, may, in their professional discretion, prescribe Ivermectin to be compounded into a medicine that contains Ivermectin as an active ingredient for the treatment of their patients, on condition that the medicine is compounded by the holder of a licence," the order read.
The settlement effectively provided another avenue to access the drug other than applying to use it through the SAHPRA compassionate programme. Judge Cassim Sardiwalla also ordered SAHPRA to report every three months on developments around the availability of Ivermectin for the treatment of COVID-19.
International regulatory positions on Ivermectin
The US Food & Drug Administration ((FDA) says it has not reviewed data to support the use of Ivermectin in COVID-19 patients, but that research is underway. It warns that it has received multiple reports of patients who have required medical support and been hospitalised after self-medicating with Ivermectin that had been approved for use as an anti-parasitic drug in animals.
The WHO says “current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive. Until more data is available, WHO recommends that the drug only be used within clinical trials.”
In a statement in April SAHPRA reiterated that “to date, there is insufficient scientific evidence on the efficacy of Ivermectin for the prevention or treatment of COVID-19. We wish to assure the public that SAHPRA has been and will continue to monitor emerging data regarding the use of Ivermectin for the treatment of COVID-19.”
FLCC Study details
Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19
Authors: Pierre Kory, Gianfranco Umberto Meduri, Joseph Varon, Jose Iglesias, Paul Marik
Published in American Journal of Therapeutics May/June 2021
After COVID-19 emerged in the US, 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 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.
A large majority of randomised 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.
Meta-analyses based on 18 randomised 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.
Second Study details
Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials</strong>
Authors: Yuani M Roman, MD, MPH, Paula Alejandra Burela, BSc, Vinay Pasupuleti, MD, PhD, Alejandro Piscoya, MD, Jose E Vidal, MD, PhD, Adrian V Hernandez, MD, PhD
Published in Clinical Infectious Diseases on 28 June 2021
We systematically assessed benefits and harms of the use of ivermectin (IVM) in COVID-19 patients.
Published and preprint randomized controlled trials (RCTs) assessing IVM effects on COVID-19 adult patients were searched until March 22, 2021 in five engines. Primary outcomes were all-cause mortality, length of stay (LOS), and adverse events (AE). Secondary outcomes included viral clearance and severe AEs. Risk of bias (RoB) was evaluated using Cochrane RoB 2·0 tool. Inverse variance random effect meta-analyses were performed. with quality of evidence (QoE) evaluated using GRADE methodology.
Ten RCTs (n=1173) were included. Controls were standard of care [SOC] in five RCTs and placebo in five RCTs. COVID-19 disease severity was mild in 8 RCTs, moderate in one RCT, and mild and moderate in one RCT. IVM did not reduce all-cause mortality vs. controls (RR 0.37, 95%CI 0.12 to 1.13, very low QoE) or LOS vs. controls (MD 0.72 days, 95%CI −0.86 to 2.29, very low QoE). AEs, severe AE and viral clearance were similar between IVM and controls (all outcomes: low QoE). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality in three RCTs at high RoB was reduced with IVM.
In comparison to SOC or placebo, IVM did not reduce all-cause mortality, length of stay or viral clearance in RCTs in COVID-19 patients with mostly mild disease. IVM did not have an effect on AEs or severe AEs. IVM is not a viable option to treat COVID-19 patients.
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