Ivermectin for Prevention and Treatment of COVID-19 Infection

          Ivermectin for Prevention and Treatment of COVID-19 Infection

                                                 Dr. KS Dhillon

Ivermectin oral tablet is used to treat infections of parasites. These include parasitic infections of our intestinal tract, skin, and eyes. It is also available as a topical cream and topical lotion. Ivermectin oral tablet is available as the brand-name drug Stromectol. 

Ivermectin tablet works by binding to parts inside the parasite. It eventually paralyzes and kills off the parasite, and it also stops adult parasites from making larvae for some time. This results in the eradication of the parasitic infection. 

In recent years several groups have shown, in-vitro, that ivermectin has anti-viral activity against a broad range of viruses [1]. Due to its in vitro antiviral activity against a broad range of viruses, it has been used off-label for the treatment of some viral diseases. 

Several studies have reported antiviral effects of ivermectin on RNA viruses such as dengue, Zika, yellow fever, West Nile, Hendra, Newcastle, Venezuelan equine encephalitis, chikungunya, Semliki Forest, Sindbis, Avian influenza A, Porcine Reproductive and Respiratory Syndrome, Human immunodeficiency virus type 1, and severe acute respiratory syndrome coronavirus 2. There are also some studies that show antiviral effects of ivermectin against DNA viruses such as Equine herpes type 1, BK polyomavirus, pseudorabies, porcine circovirus 2, and bovine herpesvirus 1.

Ivermectin has been found to have antiviral action against the SARS-CoV-2 clinical isolate in vitro. A single dose of ivermectin is able to control viral replication within 24–48 hours by inhibiting IMPα/β1-mediated nuclear import of viral proteins [1].

Ivermectin has an established safety profile for human use [2,3,4] and is FDA-approved for several parasitic infections [2,4]. Recent reviews and meta-analyses indicate that high-dose ivermectin has comparable safety as the standard low-dose treatment [5]. There, however, is not enough evidence to make conclusions about the safety profile in pregnancy.

Many drugs with anti-inflammatory, antiviral, and immunomodulatory properties are currently used in the treatment of COVID-19. Unfortunately, none of them can provide a complete cure [6]. One of the drugs whose effectiveness has been and is being investigated in the treatment of  COVID-19 is ivermectin.

Up to February 2021, the Pan American Health Organization (PAHO) identified twenty-two ivermectin randomized clinical trials through a rapid review of current available literature [7]. In these studies, there is considerable heterogeneity in the population receiving ivermectin, with studies administering it to family contacts of confirmed COVID-19 cases as a prophylactic measure [8], other studies using ivermectin for treatment of mild and moderate disease [9], and even in patients who are hospitalized with severe disease [10]. 

Kim et al [11] recently published a systematic review and network meta-analysis that compared the efficacy and safety of pharmacological interventions for COVID-19 in hospitalized patients. The review included 110 studies (78 published and 38 unpublished) with 40 randomized clinical trials and 70 observational studies. Based on the observational data, they found that high-dose intravenous immunoglobulin, tocilizumab, and ivermectin were associated with a reduced mortality rate in critically ill patients. They also found that none of the analyzed drugs were significantly associated with increased non-cardiac serious adverse events compared to standard care.

Kow et al [12] carried out a meta-analysis to study the association between the use of ivermectin and mortality in patients with COVID-19. The study included 6 randomized controlled trials with a total of 658 patients who were randomized to receive ivermectin and 597 patients randomized in the control group who did not receive ivermectin. The meta-analysis showed significantly reduced odds of mortality with the use of ivermectin among patients with COVID-19 relative to non-use of ivermectin. The estimated effect of ivermectin indicated mortality benefits.

Rajter et al [13] carried out a study that showed that the use of Ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease. Their study included 280 patients, 173 treated were treated with ivermectin and 107 without ivermectin. Most patients in both groups also received hydroxychloroquine, azithromycin, or both. Univariate analysis showed lower mortality in the ivermectin group. Mortality also was lower among ivermectin-treated patients with severe pulmonary involvement. No significant differences were found in extubation rates or length of stay. After multivariate adjustment for confounders and mortality risks, the mortality difference remained significant. Mortality was significantly lower in the ivermectin group. 

Okumus et al [14] carried out a study to evaluate the effectiveness and safety of adding ivermectin to treatment in patients with severe COVID-19.

It was a prospective, randomized, controlled, single-blind phase 3 multicenter clinical trial to assess the effectiveness and safety of ivermectin use in the treatment of patients without mutation. All patients in the study had severe COVID19 pneumonia. Ivermectin 200 mcg/kg/day for 5 days in the form of a solution prepared for enteral use was given to the study group in addition to the reference treatment protocol of hydroxychloroquine, favipiravir, and azithromycin. Patients in the control group were given only reference treatment with 3 other drugs without ivermectin. The study showed that ivermectin provided an increase in clinical recovery, improvement in prognostic laboratory parameters, and a decrease in mortality rates even when used in patients with severe COVID-19. The authors were of the opinion that ivermectin should be considered as an alternative drug that can be used in the treatment of COVID-19 disease or as an additional option to existing protocols.

Shoumann et al [15] carried out a randomized clinical trial to study the use of ivermectin for chemoprophylaxis for covid-19 infection. This was a  prospective interventional randomized open label-controlled study. Two arms were designed according to the use of ivermectin. In the ivermectin arm, contacts of a patient with covid infection received ivermectin on the day of the diagnosis of their index case. The nonintervention group received no ivermectin. Both groups were followed up for two weeks to look for symptoms suggestive of COVID-19.

In the Ivermectin group, there were 203 contacts (to 52 index cases). In the nonintervention group, there were 101 contacts (to 24 index cases). Fifteen contacts (7.4%) developed COVID-19 in the ivermectin arm as compared to 59 (58.4%) in the nonintervention arm. The authors concluded that Ivermectin is suggested to be a promising, effective, and safe chemoprophylactic drug in the management of COVID-19.

Bryant et al [16] carried out a systematic review and meta-analysis to assess the efficacy of ivermectin treatment and/or prophylaxis among people with, or at high risk of covid-19 infection. They searched bibliographic databases up to February 2021. Their study included 21 RCTs involving 2741 participants. Meta-analysis of 13 trials found that ivermectin reduced the risk of death compared with no ivermectin. The evidence was of low to moderate certainty. Low-certainty evidence found that ivermectin prophylaxis reduced covid-19 infection by an average of 86%.

The systematic review and meta-analysis were done using rigorous Cochrane methods. Evidence was assessed using the GRADE approach which judges the certainty of the evidence.

The authors concluded that the apparent safety and low cost of the drug suggest that ivermectin could have an impact on the SARS-CoV-2 pandemic globally. Ivermectin is not a new and experimental drug with safety concerns; it is a WHO ‘essential medicine’ usually used for the treatment of other diseases.

López-Medina et al [17] carried out a randomized clinical trial to determine whether ivermectin is efficacious in the treatment for mild COVID-19. In this double-blind, randomized trial a total of 476 adult patients with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled

between July 15 and November 30, 2020, and followed up through December 21, 2020. The patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200).

The median time to resolution of symptoms was 10 days in the ivermectin group compared with 12 days in the placebo group. By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms. The authors concluded that among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. They said that their findings do not support the use of ivermectin for the treatment of mild COVID-19.

Despite the presence of several randomized clinical trials which show the effectiveness of Ivermectin in the treatment and prophylaxis of covid-19, WHO in its latest 2021 guidelines does not recommend the use of ivermectin for the treatment of covid-19 infections. According to WHO the current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive. WHO recommends that the drug only be used within clinical trials. The WHO panel did not look at the use of ivermectin to prevent COVID-19. 

WHO strongly recommends the use of systemic corticosteroids for severe or critically ill COVID-19 patients. WHO does not recommend the use of remdesivir, hydroxychloroquine, and lopinavir/ritonavir for treatment of covid-19.  WHO provides conditional recommendation for the use of low-dose anticoagulants in hospitalized covid-19 patients. 

The WHO decision was based on the following factors. Their panel found that for most key outcomes, including mortality, mechanical ventilation, hospital admission, duration of hospitalization, and viral clearance, the evidence was of very low certainty. The evidence was rated as very low certainty mainly because of very serious imprecision for most outcomes: the aggregate data had wide confidence intervals and/or very few events. There were also concerns related to the risk of bias for some outcomes, specifically lack of blinding, lack of trial pre-registration, and lack of outcome reporting for one trial that did not report mechanical ventilation despite pre-specifying it in their protocol (publication bias) [18].

There has been some criticism of the WHO analysis [19]. According to the critics, the WHO analysis contains many flaws [19]: 

• Of the 58 studies (29 RCTs) available in the literature, WHO only included 16 in their analysis.
• They excluded all 14 prophylaxis studies (4 RCTs).
• There was no protocol for data exclusion.
• Trials included in the original UNITAID search protocol were excluded.
• They excluded all epidemiological evidence, although WHO has considered such evidence in the past.
• They combine early treatment and late treatment studies and do not provide heterogeneity information. Early treatment is more successful, so pooling late treatment studies will obscure the effectiveness of early treatment. They chose not to do subgroup analysis by disease severity across trials, although treatment delay is clearly a critical factor in COVID-19 treatment, the analysis is easily done, and it is well known that the studies for ivermectin and many other treatments clearly show greater effectiveness for early treatment.
• WHO downgraded the quality of trials compared to the UNITAID systematic review team and a separate international expert guideline group that has long worked with the WHO.
• They disregarded their own guidelines that stipulate quality assessments should be upgraded when there is evidence of a large magnitude effect (which there is), and when there is evidence of a dose-response relationship (which there is). They claim there is no dose-response relationship, while the UNITAID systematic review team found a clear relationship.
• Their risk of bias assessments does not match the actual risk of bias in studies. There is a clear treatment delay-response relationship and very late stage treatment is not expected to be as effective as early treatment. Much higher quality studies were classified as high risk of bias.
• Although WHO's analysis is called a "living guideline", it is rarely updated and very out of date. As of May 14, 2021, four of the missing RCTs are known to WHO and labeled "RCTs pending data extraction" [COVID-NMA]. 
• A single person served as Methods Chair, member of the Guidance Support Collaboration Committee, and member of the Living Systematic Review/NMA team.
• Public statements from people involved in the WHO analysis suggest substantial bias. For example, a co-chair reportedly said that "the data available was sparse and likely based on chance". The data is comprehensive, and we estimate the probability that an ineffective treatment generated results as positive as observed to be 1 in 9 trillion (p = 0.00000000000011). The clinical team lead refers to their analysis of ivermectin as "fighting this overuse of unproven therapies ... without evidence of efficacy", despite the extensive evidence of efficacy from the 58 studies by 519 scientists with 18,776 patients. People involved may be more favorable to the late-stage treatment of COVID-19, for example, the co-chair recommended treating severe COVID-19 with remdesivir.

It is not true that there is no evidence for the use of ivermectin in the prevention and treatment of covid-19 infections. There is evidence but the evidence is apparently weak.

In conclusion, research related to ivermectin use in COVID-19 has several limitations but the evidence continues to grow [20,21]. The use of ivermectin for prophylaxis or treatment for COVID-19 should be done based on trustable evidence, without conflicts of interest, with proven safety and efficacy in patient-consented, ethically approved, randomized clinical trials [22]. There remains a need for large randomized clinical trials to prove the efficacy of ivermectin in the prevention and treatment of covid-19 infections.

Reference

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