Is ivermectin effective for COVID-19?


The authors conclusion: Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use of ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.

Key messages

  • We found no evidence to support the use of ivermectin for treating or preventing COVID-19 infection, but the evidence base is limited.
    Evaluation of ivermectin is continuing in 31 ongoing studies, and we will update this review with their results when they become available.

    What is ivermectin?
    Ivermectin is a medicine used to treat parasites such as intestinal parasites in animals and scabies in humans. It is cheap and is widely used in regions of the world where parasitic infestations are common. It has few unwanted effects.

    Tests in the laboratory show ivermectin can slow the reproduction of the COVID-19 (SARS-CoV-2) virus but such effects would need major doses in humans. Medical regulators have not approved ivermectin for COVID-19. It should only be used as part of well-designed studies (called randomized controlled trials) evaluating potential effects.

    What did we want to find out?
    We wanted to know if ivermectin reduces death, illness, and length of infection in people with COVID-19, or is useful in prevention of the disease. We included studies comparing the medicine to placebo (dummy treatment), no treatment, usual care, or treatments for COVID-19 that are known to work to some extent, such as remdesivir or dexamethasone. We excluded studies that compared ivermectin to other drugs that do not work, such as hydroxychloroquine, or that are not known to be effective against COVID-19.

    We evaluated the effects of ivermectin in infected people on:
    – people dying;
    – whether people’s COVID-19 symptoms got better or worse;
    – unwanted effects;
    – hospital admission or time in hospital;
    – viral clearance.

    For prevention, we sought the effect on preventing COVID-19 and SARS-CoV-2 infection.

    What did we do?
    We searched for randomized controlled trials that investigated ivermectin to prevent or treat COVID-19 in humans. People being treated with ivermectin had to have laboratory-test confirmed COVID-19 and be receiving treatment in hospital or as outpatients.
    We compared and summarized the results of the studies and rated our confidence in the evidence, based on common criteria as to how reliable the evidence is.

    What did we find?

    We found 14 studies with 1678 participants that investigated ivermectin compared to no treatment, placebo, or usual care.
    For treatment, there were nine studies of people with moderate COVID-19 in hospital and four of outpatients with mild COVID-19. The studies used different doses of ivermectin and different durations of treatment.
    One study investigated ivermectin to prevent COVID-19.
    We also found 31 ongoing studies, and there are 18 studies still requiring clarification from the authors or not yet published.

    Main results
    Treating people in hospital with COVID-19
    We don’t know whether ivermectin compared with placebo or usual care, 28 days after treatment:
    – leads to more or fewer deaths (2 studies, 185 people);
    – worsens or improves patients’ condition assessed by need for ventilation (2 studies, 185 people) or oxygen (1 study, 45 people);
    – increases or reduces unwanted events (1 study, 152 people).
    Seven days after treatment, we don’t know if ivermectin:
    – increases or reduces negative COVID-19 tests (2 studies, 159 people).

    Ivermectin compared to placebo or usual care may make little or no difference to improving patients’ condition 28 days after treatment (1 study, 73 people) or to length of hospital stay (1 study, 45 people).

    Treating outpatients with COVID-19
    We don’t know whether ivermectin compared with placebo or usual care:
    – leads to more or fewer deaths 28 days after treatment (2 studies, 422 people);
    – worsens or improves patients’ condition 14 days after treatment assessed by need for ventilation (1 study, 398 people);
    – increases or reduces negative COVID-19 tests seven days after treatment (1 study, 24 people).

    Ivermectin compared to placebo or usual care may make little or no difference to improving outpatients’ condition 14 days after treatment (1 study, 398 people) or to the number of unwanted events 28 days after treatment (2 studies, 422 people).

    No studies looked at hospital admissions in outpatients.
    Preventing COVID-19
    We don’t know whether ivermectin leads to more or fewer deaths compared with no drug (1 study, 304 people); no participant died 28 days after the drug. This study reported results for development of COVID-19 symptoms (but not confirmed SARS-CoV-2 infection) and unwanted events, but in a way that we could not include in our analyses. This study did not look at hospital admissions.

    What are the limitations of the evidence?
    Our confidence in the evidence is very low because we could only include 14 studies with few participants and few events, such as deaths or need for ventilation. The methods differed between studies, and they did not report everything we were interested in, such as quality of life.

    How up to date is this evidence?
    The evidence is up to date to 26 May 2021.

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

Authors 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.

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.


The evidence base for ivermectin against COVID-19

To date, the efficacy of ivermectin in COVID-19 has been supported by the following:

  1. Since 2012, multiple in vitro studies have demonstrated that Ivermectin inhibits the replication of many viruses, including influenza, Zika, Dengue, and others.

  2. Ivermectin inhibits SARS-CoV-2 replication and binding to host tissue through several observed and proposed mechanisms.

  3. Ivermectin has potent anti-inflammatory properties with in vitro data demonstrating profound inhibition of both cytokine production and transcription of nuclear factor-κB (NF-κB), the most potent mediator of inflammation.

  4. Ivermectin significantly diminishes viral load and protects against organ damage in multiple animal models when infected with SARS-CoV-2 or similar coronaviruses.,

  5. Ivermectin prevents transmission and development of COVID-19 disease in those exposed to infected patients.

  6. Ivermectin hastens recovery and prevents deterioration in patients with mild to moderate disease treated early after symptoms.,,,

  7. Ivermectin hastens recovery and avoidance of ICU admission and death in hospitalized patients.,,,

  8. Ivermectin reduces mortality in critically ill patients with COVID-19.,,

  9. Ivermectin leads to temporally associated reductions in case fatality rates in regions after ivermectin distribution campaigns.

  10. The safety, availability, and cost of ivermectin are nearly unparalleled given its low incidence of important drug interactions along with only mild and rare side effects observed in almost 40 years of use and billions of doses administered.

  11. The World Health Organization has long included ivermectin on its “List of Essential Medicines.”

 

A summary of the statistically significant results from the above controlled trials are as follows:

Controlled trials in the prophylaxis of COVID-19 (8 studies)

  1. All 8 available controlled trial results show statistically significant reductions in transmission.

  2. Three RCTs with large statistically significant reductions in transmission rates, N = 774 patients.

  3. Five OCTs with large statistically significant reductions in transmission rates, N = 2052 patients.,

 

Controlled trials in the treatment of COVID-19 (19 studies)

  1. Five RCTs with statistically significant impacts in time to recovery or hospital length of stay.,,,,

  2. One RCT with a near statistically significant decrease in time to recovery, P = 0.07, N = 130.

  3. One RCT with a large, statistically significant reduction in the rate of deterioration or hospitalization, N = 363.

  4. Two RCTs with a statistically significant decrease in viral load, days of anosmia, and cough, N = 85.,

  5. Three RCTs with large, statistically significant reductions in mortality (N = 695).,,

  6. One RCT with a near statistically significant reduction in mortality, P = 0.052 (N = 140).

  7. Three OCTs with large, statistically significant reductions in mortality (N = 1688).,,

Safety of ivermectin

Numerous studies report low rates of adverse events, with the majority mild, transient, and largely attributed to the body’s inflammatory response to the death of the parasites and include itching, rash, swollen lymph nodes, joint paints, fever, and headache. In a study that combined results from trials including more than 50,000 patients, serious events occurred in less than 1% and largely associated with administration in Loa loa. Furthermore, according to the pharmaceutical reference standard Lexicomp, the only medications contraindicated for use with ivermectin are the concurrent administration of antituberculosis and cholera vaccines while the anticoagulant warfarin would require dose monitoring. Another special caution is that immunosuppressed or organ transplant patients who are on calcineurin inhibitors, such as tacrolimus or cyclosporine, or the immunosuppressant sirolimus should have close monitoring of drug levels when on ivermectin given that interactions exist that can affect these levels. A longer list of drug interactions can be found on the drugs.com database, with nearly all interactions leading to a possibility of either increased or decreased blood levels of ivermectin. Given studies showing tolerance and lack of adverse effects in human subjects given escalating high doses of ivermectin, toxicity is unlikely, although a reduced efficacy because of decreased levels may be a concern.

Concerns of safety in the setting of liver disease are unfounded given that, to the best of our knowledge, only 2 cases of liver injury have ever been reported in association with ivermectin, with both cases rapidly resolved without need for treatment., Furthermore, no dose adjustments are required in patients with liver disease. Some have described ivermectin as potentially neurotoxic, yet one study performed a search of a global pharmaceutical database and found only 28 cases among almost 4 billion doses with serious neurological adverse events, such as ataxia, altered consciousness, seizure, or tremor. Potential explanations included the effects of concomitantly administered drugs that increase absorption past the blood–brain barrier or polymorphisms in the mdr-1 gene. However, the total number of reported cases suggests that such events are exceedingly rare. Finally, ivermectin has been used safely in pregnant women, children, and infants.

 

 

Is ivermectin effective for COVID-19?


The authors conclusion: Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use of ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.

Key messages

  • We found no evidence to support the use of ivermectin for treating or preventing COVID-19 infection, but the evidence base is limited.
    Evaluation of ivermectin is continuing in 31 ongoing studies, and we will update this review with their results when they become available.

    What is ivermectin?
    Ivermectin is a medicine used to treat parasites such as intestinal parasites in animals and scabies in humans. It is cheap and is widely used in regions of the world where parasitic infestations are common. It has few unwanted effects.

    Tests in the laboratory show ivermectin can slow the reproduction of the COVID-19 (SARS-CoV-2) virus but such effects would need major doses in humans. Medical regulators have not approved ivermectin for COVID-19. It should only be used as part of well-designed studies (called randomized controlled trials) evaluating potential effects.

    What did we want to find out?
    We wanted to know if ivermectin reduces death, illness, and length of infection in people with COVID-19, or is useful in prevention of the disease. We included studies comparing the medicine to placebo (dummy treatment), no treatment, usual care, or treatments for COVID-19 that are known to work to some extent, such as remdesivir or dexamethasone. We excluded studies that compared ivermectin to other drugs that do not work, such as hydroxychloroquine, or that are not known to be effective against COVID-19.

    We evaluated the effects of ivermectin in infected people on:
    – people dying;
    – whether people’s COVID-19 symptoms got better or worse;
    – unwanted effects;
    – hospital admission or time in hospital;
    – viral clearance.

    For prevention, we sought the effect on preventing COVID-19 and SARS-CoV-2 infection.

    What did we do?
    We searched for randomized controlled trials that investigated ivermectin to prevent or treat COVID-19 in humans. People being treated with ivermectin had to have laboratory-test confirmed COVID-19 and be receiving treatment in hospital or as outpatients.
    We compared and summarized the results of the studies and rated our confidence in the evidence, based on common criteria as to how reliable the evidence is.

    What did we find?

    We found 14 studies with 1678 participants that investigated ivermectin compared to no treatment, placebo, or usual care.
    For treatment, there were nine studies of people with moderate COVID-19 in hospital and four of outpatients with mild COVID-19. The studies used different doses of ivermectin and different durations of treatment.
    One study investigated ivermectin to prevent COVID-19.
    We also found 31 ongoing studies, and there are 18 studies still requiring clarification from the authors or not yet published.

    Main results
    Treating people in hospital with COVID-19
    We don’t know whether ivermectin compared with placebo or usual care, 28 days after treatment:
    – leads to more or fewer deaths (2 studies, 185 people);
    – worsens or improves patients’ condition assessed by need for ventilation (2 studies, 185 people) or oxygen (1 study, 45 people);
    – increases or reduces unwanted events (1 study, 152 people).
    Seven days after treatment, we don’t know if ivermectin:
    – increases or reduces negative COVID-19 tests (2 studies, 159 people).

    Ivermectin compared to placebo or usual care may make little or no difference to improving patients’ condition 28 days after treatment (1 study, 73 people) or to length of hospital stay (1 study, 45 people).

    Treating outpatients with COVID-19
    We don’t know whether ivermectin compared with placebo or usual care:
    – leads to more or fewer deaths 28 days after treatment (2 studies, 422 people);
    – worsens or improves patients’ condition 14 days after treatment assessed by need for ventilation (1 study, 398 people);
    – increases or reduces negative COVID-19 tests seven days after treatment (1 study, 24 people).

    Ivermectin compared to placebo or usual care may make little or no difference to improving outpatients’ condition 14 days after treatment (1 study, 398 people) or to the number of unwanted events 28 days after treatment (2 studies, 422 people).

    No studies looked at hospital admissions in outpatients.
    Preventing COVID-19
    We don’t know whether ivermectin leads to more or fewer deaths compared with no drug (1 study, 304 people); no participant died 28 days after the drug. This study reported results for development of COVID-19 symptoms (but not confirmed SARS-CoV-2 infection) and unwanted events, but in a way that we could not include in our analyses. This study did not look at hospital admissions.

    What are the limitations of the evidence?
    Our confidence in the evidence is very low because we could only include 14 studies with few participants and few events, such as deaths or need for ventilation. The methods differed between studies, and they did not report everything we were interested in, such as quality of life.

    How up to date is this evidence?
    The evidence is up to date to 26 May 2021.