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

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088823/

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines

Background:

Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials.

Areas of uncertainty:

We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection.

Data sources:

We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion.

Therapeutic Advances:

Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19–0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian–Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff–Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%–91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for “need for mechanical ventilation,” whereas effect estimates for “improvement” and “deterioration” clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty.

Conclusions: Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/

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Ivermectin prophylaxis versus no ivermectin prophylaxis

Three studies involving 738 participants evaluated ivermectin for COVID-19 prophylaxis among health care workers and COVID-19 contacts. Meta-analysis of these 3 trials, assessing 738 participants, found that ivermectin prophylaxis among health care workers and COVID-19 contacts probably reduces the risk of COVID-19 infection by an average of 86% (79%–91%) (3 trials, 738 participants; aRR 0.14, 95% CI 0.09–0.21; 5.0% vs. 29.6% contracted COVID-19, respectively; low-certainty evidence; downgraded due to study design limitations and few included trials) (Figure ​(Figure15).15). In 2 trials involving 538 participants, no severe adverse events were recorded (SoF Table ​Table44).

Given the evidence of efficacy, safety, low cost, and current death rates, ivermectin is likely to have an impact on health and economic outcomes of the pandemic across many countries. Ivermectin is not a new and experimental drug with an unknown safety profile. It is a WHO “Essential Medicine” already used in several different indications, in colossal cumulative volumes. Corticosteroids have become an accepted standard of care in COVID-19, based on a single RCT of dexamethasone.1 If a single RCT is sufficient for the adoption of dexamethasone, then a fortiori the evidence of 2 dozen RCTs supports the adoption of ivermectin.

Ivermectin is likely to be an equitable, acceptable, and feasible global intervention against COVID-19. Health professionals should strongly consider its use, in both treatment and prophylaxis.

A COVID-19 prophylaxis? Lower incidence associated with prophylactic administration of ivermectin

3. Results and discussion

Our study compared the incidence of COVID-19 among countries with different PCT campaigns and those countries in which PCT is non-existent. It is perhaps obvious that the latter group is by far the largest. It should also not be surprising that this set of samples had a rather large variability (Fig. 1 ). However, in spite of this, the difference between nations that deploy PCT using ivermectin and those that do not use any PCT turned out to be highly significant (adjusted significance P < 0.01). These initial results were obtained on 15 April 2020 and because at that time SARS-CoV-2 was still being detected in new countries on an almost daily basis, we chose to monitor the situation and observe whether this correlation would over time become less significant. We updated our calculations and added additional newly affected countries several times throughout the month of May 2020 and noticed that the observed association between ivermectin MDA and lower COVID-19 incidence actually grew strictly stronger over time. By 5 June 2020, the adjusted significance had improved to P < 0.001, actually reported by IBM SPSS Statistics as 0.000. It has remained at that level since.

As we have stated, the sizes of the three samples (PCT with ivermectin, other PCT and no PCT) vary greatly. Another important aspect to consider is the fact that many of the ivermectin campaigns are unsurprisingly administered in African countries as the underlying parasitic infections are particularly common in these nations. As such, it is important to look at the subset of African countries separately as well. Fig. 2 shows a boxplot similar to Fig. 1 but containing only the African countries in the data set. It should not be surprising that the largest difference between the two analyses can be seen in the ‘No PCT’ group as this group contained the most non-African countries. The much smaller number of nations on the African continent and associated island groups allows us to enumerate the individual countries and to visualise them in a violin plot. Fig. 3 quite clearly visualises the strong correlation between PCT with ivermectin and lower incidence of COVID-19. This relationship is statistically significant (P = 0.017), making it only slightly less significant in Africa than among the worldwide data set.

As COVID-19 is such a new disease, none of the existing MDA campaigns are targeted at controlling its spread. Nor is there any documented prophylactic use of the deployed drugs against SARS-CoV-2 infection. However, there is a very strong negative correlation between the use of PCT—especially involving ivermectin—and COVID-19 proliferation. This, paired with ivermectin's proven inhibitory effect on SARS-CoV-2 replication in vitro, leads us to the hypothesis that the drug may have a—likely indirect—prophylactic effect and thereby reduce the spread of the disease.

It might be interesting to note that the percentage of the overall population that received PCT using ivermectin mostly ranged from 30–90%, yet there was no significant difference in the resulting incidence of COVID-19. Even the lower treatment coverages achieved the same reductions resulting from MDA reaching nearly the entire population. The reasons for this fact are so far unexplained. There was also no detectable advantage to any one administration timeframe or interval. While individual dosages generally varied between 150 μg and 200 μg per kilogram of body weight, there seemed to be no notable difference in COVID-19 incidence among recipients of different dosages either. It must therefore be assumed that any pathway connecting ivermectin administration and lower COVID-19 incidence is achieved by administration of the drug in relatively low doses far below potentially dangerous levels considered elsewhere as potentially effective for COVID-19 treatment [19]. This becomes less surprising once we consider the relatively short half-life of ivermectin [20], meaning that the added effect of any higher dose would not be prolonged. Instead, we hypothesise that there is an as of yet unknown pathway that can be triggered with lower, proven safe doses….

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698683/

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…The fact that PCT without ivermectin also showed a strong negative—albeit not statistically significant—correlation with COVID-19 incidence suggests that other drugs used in MDA campaigns might include additional candidates for the treatment and/or prevention of COVID-19. It is, however, important to note that many of the analysed countries that only administered these other drugs in 2018 actually have used ivermectin in previous or following years. Hence, a residual effect of an ivermectin-induced pathway cannot be ruled out, although the exact nature of such a pathway would still need to be discovered. This speculation would gain further strength if experimental analysis could prove that SARS-CoV-2 replication remains inhibited after serum levels of ivermectin decline.

It is important to note that the hypothesis that ivermectin might have a prophylactic effect against SARS-CoV-2 is merely based on a rather strong correlation. On the other hand, this correlation has grown increasingly stronger in the worldwide data set earlier this year and then been independently replicated within the African data set later in the summer. Both remain highly significant, suggesting that there may be a causal connection, which is also suggested by other recent findings reported in literature. We therefore hope that this communication may serve as an invitation to further investigate and consider ivermectin as a potential prophylactic against COVID-19. In addition to the obvious advantages of a potential prophylactic, more refined results could hopefully also deter the public from further dangerous self-medication with ivermectin that has sometimes included veterinary-grade products that contain additional ingredients [21]. In this sense, even negative results might be very valuable to the health community and to society at large.

Prophylactic Role of Ivermectin in Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers

Monitoring Editor: Alexander Muacevic and John R Adler

Priyamadhaba Behera,1 Binod K Patro,1 Biswa M Padhy,2 Prasanta R Mohapatra,3 Shakti K Bal,3 Pradnya D Chandanshive,1 Rashmi R Mohanty,4 SR Ravikumar,1 Arvind Singh,1 Sudipta R Singh,5 Siva Santosh Kumar Pentapati,1 Jyolsna Nair,1 and Gitanjali Batmanbanecorresponding author6

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Abstract

Introduction

Healthcare workers (HCWs) are vulnerable to getting infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Preventing HCWs from getting infected is a priority to maintain healthcare services. The therapeutic and preventive role of ivermectin in coronavirus disease 2019 (COVID-19) is being investigated. Based on promising results of in vitro studies of oral ivermectin, this study was conducted with the aim to demonstrate the prophylactic role of oral ivermectin in preventing SARS-CoV-2 infection among HCWs at the All India Institute of Medical Sciences (AIIMS) Bhubaneswar.

Methods

A prospective cohort study was conducted at AIIMS Bhubaneswar, which has been providing both COVID and non-COVID care since March 2020. All employees and students of the institute who provided written informed consent participated in the study. The uptake of two doses of oral ivermectin (300 μg/kg/dose at a gap of 72 hours) was considered as exposure. The primary outcome of the study was COVID-19 infection in the following month of ivermectin consumption, diagnosed as per Government of India testing criteria (real-time reverse transcriptase polymerase chain reaction [RT-PCR]) guidelines. The log-binomial model was used to estimate adjusted relative risk (ARR), and the Kaplan-Meier failure plot was used to estimate the probability of COVID-19 infection with follow-up time.

Results

Of 3892 employees, 3532 (90.8%) participated in the study. The ivermectin uptake was 62.5% and 5.3% for two doses and single dose, respectively. Participants who took ivermectin prophylaxis had a lower risk of getting symptoms suggestive of SARS-CoV-2 infection (6% vs 15%). HCWs who had taken two doses of oral ivermectin had a significantly lower risk of contracting COVID-19 infection during the following month (ARR 0.17; 95% CI, 0.12-0.23). Females had a lower risk of contracting COVID-19 than males (ARR 0.70; 95% CI, 0.52-0.93). The absolute risk reduction of SARS-CoV-2 infection was 9.7%. Only 1.8% of the participants reported adverse events, which were mild and self-limiting.

Conclusion

Two doses of oral ivermectin (300 μg/kg/dose given 72 hours apart) as chemoprophylaxis among HCWs reduced the risk of COVID-19 infection by 83% in the following month. Safe, effective, and low-cost chemoprophylaxis has relevance in the containment of pandemic alongside vaccine.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698683/

>>14564666

Forget that vaccine=Toxin

Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity Score-Matched Retrospective Cohort Study

Ivermectin has a 19-hour plasma half-life, an enterohepatic cycle and its active metabolites can remain in the blood for up to 72 hours. Its excretion is 99% hepatic and only 1% is excreted in the urine. If we give successive doses of ivermectin on days one, four and seven, the drug accumulation in blood is minimal [8-9]. Ivermectin is very lipophilic and its concentration in some tissues is high; active levels in the lungs reach almost three times higher than in the blood and are detectable in fat tissue for at least seven days [10].

Kaplan-Meier risk analysis showed that the prevention with ivermectin occurred after the second dose was received on day eight. This finding could suggest that to achieve a preventive dose of ivermectin in the tissues, a second dose is needed (Figure 2).

This is consistent with the study results conducted in India by Behera and colleagues, which evaluated 91 healthcare workers exposed to patients with COVID-19 who received preventive ivermectin at 0.3 mg/kg on days one and four and were followed for one month. They compared this group with another group of 67 health workers that were not administered ivermectin. A 73% decrease risk in COVID-19 infection was observed in the ivermectin group versus the placebo group (OR = 0.26, 95% CI [0.14, 0.47]). COVID-19 infections in the group that received the two doses of ivermectin were not severe in any case and there were no cases of death. They reported a third group of 17 people who only took ivermectin on day one, in whom the preventive effect was not observed [11].

Chahla and colleagues, in Tucuman, Argentina, conducted a 1:1 randomized controlled study in healthcare workers for four weeks with a two-week follow-up after completion of the study. They compared a group that was administered PrEP with ivermectin PO 12mg weekly plus Iota-Carrageenan 6 nasal sprays daily, versus a control group that did not receive any medication. In the “Ivermectin-Carrageenan” group, four out of the 117 participants (3.4%) were infected with COVID-19, and in the control group 25 out of the 117 participants (21.4%) were infected. The difference between the two groups was statistically significant (p-value <0.05). The odds ratio (OR) was 0.13, this value transformed into relative risk (RR) becomes 84% less risk of contagion of SARS-CoV-2 in the “Ivermectin-Carrageenan” group in comparison with the control group. In the ivermectin group four patients had a mild infection and in the control group, in 15 patients the infection was mild, in seven moderate and in three severe [12].

In our study, the hazard ratio (HR) of 0.26 was achieved in the ivermectin group, which translates into a 74% lower risk of contagion with SARS-CoV-2. This risk result is similar to Behera et al., but 10 points less than the Chahla et al. study [11-12]. This additional difference could be attributed to the use of Iota-Carrageenan.

In the present study, when comparing healthcare personnel who presented COVID-19 infection, the progression of the disease, the appearance of complications, the need for hospitalization and the occurrence of death, the difference between both groups was not statistically significant (Table 2). These findings could be due to: 1. their average young age of 35 years old, where patients tend to have fewer complications with COVID-19 infections; 2. the study could be underpowered for the secondary outcomes; 3. the patients of both groups were offered early treatment with ivermectin, which diminishes the progression of SARS-CoV-2 infection, as seen in previous studies [6]….

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698683/

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…Since this is not a randomized study and the selection of groups was based on adherence, it does not allow us to clear certain confounding factors, such as the fact that the ivermectin group could be made up of healthcare personnel more concerned with prevention in general, including greater personal protection measures and more careful use of the PPE, reducing the risks of contracting SARS-CoV-2. To analyze this argument, we followed up the same participants of the ivermectin group (Figure 4) that passed from the weekly dose to a monthly dose PO 0.4 mg/kg and were followed for 56 days (eight weeks). During these 56 days, most of the healthcare workers progressively discontinued ivermectin of their own will, for nonspecific reasons (Figure 3). When the ivermectin group was compared to the control group, there was no statistically significant difference regarding new cases of COVID-19 infections. This finding makes the first argument unlikely.

Another element that may raise doubts could be the possibility that some participants in the control group used ivermectin on their own or another preventive drug. We consider that this probability is very low, since the hospital management widely provided the medicine to the health personnel of both medical centers and free of charge.

Hydroxychloroquine Prophylaxis against Coronavirus Disease-19: Practice Outcomes among Health-Care Workers

Conclusions This clinical study did not detect a reduction in SARS CoV-2 transmission with prophylactic administration of 400 mg/HCQ in HCW’s. All participants who did contract SARSCoV-2 were either asymptomatic or had mild disease courses with full recoveries. All adverse events were self-limiting and no serious cardiovascular events were reported with use of HCQ. In the absence of robust data, it seems premature to recommend HCQ as a prophylactic panacea for COVID-19.

https://www.medrxiv.org/content/10.1101/2021.08.02.21260750v1

https://twitter.com/ianbremmer/status/1436810414122229762

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All participants who did contract SARSCoV-2 were either asymptomatic or had mild disease courses with full recoveries

oh, that's a +

Or just wait until you are symptomatic and take it.

That works too.

https://twitter.com/TheBembridge/status/1436718670496079878

Correlation between Non-Polio Acute Flaccid Paralysis Rates with Pulse Polio Frequency in India

The last case of polio from India was reported in 2011. That year, the non-polio acute flaccid paralysis (NPAFP) rate in India was 13.35/100,000, where the expected rate is 1⁻2/100,000. A previous study of data from 2000 to 2010 has detailed the NPAFP rate in a state correlated with the pulse polio rounds conducted there, and the strongest correlation with the NPAFP rate was found when the number of doses from the previous 4 years were used. However, a simple association being found with regression analysis does not prove a causal relationship. After publication of those findings, as the threat of polio had lessened, the number of rounds of OPV administration was brought down. The present study has been done to look at data till the end of 2017, to see if the incidence of NPAFP declined with this reduction in polio immunization rounds. We used polio surveillance data acquired by the Government of India from 2000⁻2017. Correlation of the NAFP rate to the number of polio rounds in the state was examined, and the cumulative effect of polio doses administered in previous years was sought. NPAFP rate correlated with the OPV pulse polio rounds in that year (R = 0.46; p < 0.001), and the NPAFP rate started to decrease from 2012 when the number of pulse polio rounds had decreased. NPAFP rates in the states of Uttar Pradesh (UP) and Bihar were the highest in the country. Looking at the high-NPAFP states of UP and Bihar, we found that the correlation coefficient was strongest when doses used over 5 years was considered (R = 0.76; p < 0.001). The response to the reduction in OPV rounds (de-challenging) adds credence to the assumption that OPV was responsible for the change in the NPAFP rate. Now that India has been polio-free for over 6 years, we propose that we may be able to reduce NPAFP by further reducing pulse polio rounds.

https://pubmed.ncbi.nlm.nih.gov/30111741/