The evidence from 20 randomized controlled trials(1–20), with 4140 participants suggests that Ivermectin does not improve mortality [RR 0.65, 95% CI 0.39, 1.09], progression to mechanical ventilation [RR 0.74, 95% CI 0.53, 1.04] or viral clearance in patients by day 7 with COVID-19 infection [RR 1.31, 95% I 0.95, 1.81]. At the doses used in these trials (median dose is 12 mg once daily orally) it does not have any major adverse events [RR 1.00, 95% CI 0.60, 1.67]. Multiple studies on Ivermectin in Covid-19 have been methodologically unsound with many retracted from peer reviewed literature, further clouding the data(21,22). A stratified analysis of all-cause mortality in studies with low risk of bias showed no benefit with Ivermectin [RR 0.85, 95% CI 0.48, 1.50]
Currently, its use may distract from use of other therapies for which there is better evidence. Indiscriminate use might also reduce its availability for other conditions where its benefit is established, such as parasitic infections. Taking this into account, we recommend against use of ivermectin outside of a randomized controlled trial.
Date of latest search: September 26th 2022
Date of completion & presentation to the Expert Working Group:
Date of planned review:
Evidence Synthesis Team: Harshdeep Acharya, Audrin Lenin,Jane Miracline John, Jisha Sara John, Sherly Shulamite, Richard Kirubakaran, Priscilla Rupali and Bhagteshwar Singh.
Explanations:
a. Downgraded by one level for serious imprecision, due to small absolute number of events, and CIs include important potential benefit and important potential harm.
b. Downgraded by one level for serious risk of bias. Due to Galan 2021 and Niaee 2021 having high risk of bias, and Gonzalez 2021 , Ravikirti 2021 , Abd Elsalam and Shahbaznejad 2021 having some concerns for risk of bias.
c. Downgraded by one level for serious risk of bias, due to Abd Elsalam , Galan 2021, Ravikirti 2021Shahbaznejad and I-tech trial having some concerns for risk of bias.
d. Downgraded by two levels for very serious risk of bias, due to Ahmed 2020 and Bukhari 2021 having high risk of bias and Bieber having some concerns for risk of bias for this outcome.
e. Downgraded by one level for serious inconsistency, due to substantial heterogeneity (I-squared=64%) and visually some trials having point effect estimates very far from those of other trials.
f. Downgraded by one level for serious imprecision, due to CIs overlapping no effect and inability to exclude important benefit.
g. Downgraded by one level for serious risk of bias., due to Chaccour 2021, Chachar 2021, Rocha et. al etc having high risk of bias (accounts for 15% weightage).
h. Downgraded by one level for serious imprecision, due to CIs overlapping including important potential benefit and important potential harm.
i. Downgraded by one level for serious risk of bias, due to Gonzalez 2021 having high risk of bias
j. Downgraded by one level for serious imprecision, due to CIs including important potential benefit and important potential harm.
Ivermectin has been shown to inhibit the replication of SARS CoV2 in vitro; it binds and destabilises the viral protein and prevents it from entering the nucleus (24). However, the drug dosages used in these laboratory studies far exceed those that have been used for other conditions (25). Drug doses and levels required to achieve therapeutic effects in COVID-19 infection in humans based on these studies may be safe, but this has not been studied in clinical trials (26). An additional potential effect may be in modulating the immune system, though this is yet to be studied thoroughly in humans (27).
Although Ivermectin is generally well tolerated, adverse effects like dizziness, tachycardia, postural hypotension, diarrhoea, arthralgia, facial and peripheral oedema have been reported even with single doses as used in parasitic diseases (28). Encephalopathy with permanent disability has been reported when ivermectin has been used in the treatment of onchocerciasis or other parasitic diseases (28). It is predominantly metabolized in the liver (CYP3A4), which may lead to drug-drug interactions.
Due to lack of conclusive evidence from trials, World Health Organization recommends use of ivermectin only in clinical trials (29). Use continues widely, including self-medication, especially in low- and middle-income countries due to easy availability and low cost of the drug (30). Multiple trials on Ivermectin on covid-19 were retracted due to questionable methodology and lack of reliable data. (21,22)
This review aims to provide a summary of the available evidence from randomised clinical trials of ivermectin for treatment of acute COVID-19, for any dose or duration, so the Expert Working Group can provide a recommendation to guide clinicians and researchers regarding the appropriate use of this drug.
We used Cochrane rapid review methods. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Epistemonikos, and the COVID‐19‐specific resource www.covid‐nma.com, for studies of any publication status and in any language published from March 2020 up to 07th June 2022. We also reviewed reference lists of systematic reviews and included studies. We contacted researchers to identify unpublished and ongoing studies.
We included randomized controlled trials (RCTs) testing ivermectin treatment of any dose or duration in people with acute COVID‐19, whether suspected or confirmed. Trials were included if the intervention arm did not combine ivermectin with another experimental drug, and if the comparator arm did not include ivermectin (this could involve use of placebo, standard care, or other potentially active drugs). We excluded trials that did not report any outcomes that could provide usable data for the review, those which were quasi-randomized and those lacking a comparator arm.
We planned to extract data for the following outcomes, pre-defined by the Expert Working Group:
- Critical (primary for this review):
- Mortality (all-cause) – at 28-30 days, or in-hospital
- Progression to:
- Oxygen therapy
- Ventilation: non-invasive or invasive
- Critical or Intensive care (any reason) - Duration of hospitalization
- Need for hospitalization (for out-patients)
- Adverse events: all and serious
- Important (secondary):
- Time to clinical improvement
- Time to negative PCR for SARS-CoV-2
- Negative PCR for SARS-CoV-2 by day 7 post-enrolment
- Complications of COVID-19:
- Thrombotic events
- Pulmonary function/fibrosis
- Long covid/ post-covid sequalae
- Secondary infections
Two reviewers independently assessed eligibility of search results. One reviewer extracted data from each included study and assessed risk of bias using the Cochrane Risk of bias (RoB) v2.0 tool. Data and RoB assessments were checked against a Cochrane systematic review team’s extractions and assessments (we used a consensus approach). In case of any discrepancies, the whole RoB assessment was scrutinised by the whole team for this review, to reach consensus.
We used RevMan 5.4 to perform meta‐analysis using a random‐effects model for outcomes where pooling of effect estimates was appropriate. We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CIs). We planned to explore heterogeneity in the effect on mortality using subgroup analysis comparing between trials, based on COVID-19 illness severity of participants included and risk of bias. We used the I2 statistic to measure residual heterogeneity. We used GRADE methodology to assess the certainty in the evidence and documented this in a ‘Summary of findings’ table using GradeProGDT.
We included 20 trials involving 4140 participants, all of whom were adults, and 2122 of whom received ivermectin (1–20). Of these 11 studies are included in the previous recommendation and 9 new studies were added to update the evidence (21,22) While updating the evidence, we excluded 1 study (22) which was present in the previous analysis as it was retracted due to unreliable methodology. There were two trials each from, India, Iran, Pakistan, Brazil, and Mexico; one trial each was reported from Bangladesh, Colombia, Nigeria, Egypt, Israel, Italy, Argentina, Spain, Thailand, and Malaysia. Eleven were in hospitalized patients, four recruited out-patients only, one recruited both, and three did not report care setting. Disease severity, prevalence of comorbidities, and use of co‐interventions varied substantially between trials. The ‘Summary of characteristics of included trials’ table provides further details about the trials.
We found potential risks of bias across all domains; 12 of the 20 trials were at high risk of bias overall for at least one outcome. Risk of bias for each domain per trial is displayed alongside the Forest plots below. Studies excluded at full-text review are listed in the References section, with the reason provided in brackets (21,22,31–40).
The following comparisons were investigated in the trials. We compared outcomes for arms randomised to ivermectin vs. outcomes in arms with placebo, standard care, or agents considered inactive or ineffective against COVID-19. Where multiple arms contained ivermectin without another experimental agent, we combined results in those arms into a single ivermectin arm, but we did not double-count controls. Where another experimental agent undergoing investigation was combined with ivermectin, that trial arm was excluded from the analysis (e.g., doxycycline).
- Ten trials (3–5,8,9,11,14,17,18,20) compared ivermectin vs. placebo (2358 participants)
- Six [18;22-23;25-26;29] compared ivermectin vs. standard care (1244 participants)
- One (1) compared ivermectin vs. placebo vs. a combination of ivermectin & doxycycline in three arms (72 participants; 24 participants in ivermectin & doxycycline arm excluded)
- One (5) compared ivermectin vs. placebo vs. hydroxychloroquine in three arms (106 participants)
- One (2) compared ivermectin vs. lopinavir/ritonavir (62 participants)
- One (4) compared ivermectin vs. chloroquine or hydroxychloroquine (168 participants)
All-Cause-Mortality: Low certainty evidence from 9 RCTs (6,8,10,12,15,19,20) with 3052 participants shows that ivermectin may result in little to no difference in mortality [RR 0.65, 95%CI 0.39,1.09]. As the studies have some concerns and high risk of biases, a stratified analysis of the data was done based on ‘Risk of bias’. The trials (8,20) with Low risk of bias showed no difference in mortality in patients receiving Ivermectin vs no Ivermectin [RR 0.85, 95%CI 0.48,1.50]
Progression to mechanical ventilation: Low certainty evidence from 8 trials (6,11,12,15,16) with 3263 participants showed that Ivermectin may have little to no effect in the progression to mechanical ventilation [RR 0.74, 95%CI 0.53,1.04]. 5 of the 8 included studies have some concerns.
Negative PCR by day 7: Very low certainty evidence from 7 trials (1,3,11,13,17,20) with 828 participants for viral clearance at day 7 [RR 1.31, 95%CI 0.95,1.81] gives no impression of Ivermectin’s effect on viral clearance at Day 7. Of the 7 trials, 3 of them where of High Risk of bias, 3 of them had some concerns and only 1 trial with low risk of bias and had only 19% weightage. (Look at the forest plot).
Adverse events: Low certainty evidence from 10 RCTs (4,5,8,9,13,14,16,18–20) with 3187 participants shows that Ivermectin results in no significant adverse events RR 1.00, [95%CI 0.79,1.25].
Serious adverse events: Low certainty evidence from 4 RCTs (7,8,19,20) with 2352 participants shows that Ivermectin results in no significant serious adverse events [RR 1.00, 95%CI 0.60,1.67].
One trial reported a higher risk of discontinuation of ivermectin vs. placebo due to an adverse event (RR 2.97; 95% CI 1.10 to 8.02; 1 trial (8); 398 participants).
95% confidence intervals for pooled effect estimates for all of the following outcomes not included in the summary of findings table included potential benefit and potential harm from ivermectin: need for critical or intensive care (2 trials (6,11); 283 participants); discharge from hospital by day 10 post-enrolment (1 trial (11); 115 participants); deterioration by 2 points on 8-point clinical ordinal scale (1 trial (8); 398 participants); lack of fever on day 7 (1 trial (1); 36 participants); lack of symptoms on day 7 (1 trial (5); 50 participants); and thrombotic events (1 trial (7); 106 participants). We were unable to pool data for time to clinical improvement as they were not reported in a way that was amenable to meta-analysis (3 trials (4,8,9); 149 participants).
No comparative data could be extracted for risk of progression to oxygen therapy; need for hospitalisation in outpatients; or post-acute COVID-19 pulmonary function/fibrosis or other sequelae; or secondary infections.
Lack of uniform criteria for COVID-19 severity, substantial overlap, and lack of clear reporting of severity in the included trials prevented a meaningful subgroup analysis by severity.
Furthermore, a lack of within trial comparison prevented subgroup analysis by age, duration of symptoms or dose of ivermectin. In addition, data of safety and efficacy in specific subgroups such as pregnancy, children, liver, and kidney disease were not available in the trials included in the rapid review.
CQ: Chloroquine; ECOG: Eastern Cooperative Oncology Group score; HCQ: Hydroxychloroquine; Lpv/Rtn: Lopinavir/Ritonavir; NEWS: National early warning score; RCT: Randomized control trial; RTPCR: Reverse transcription polymerase chain reaction; SoC: Standard of care
1. Mortality, stratified by risk of bias
2. Progression to mechanical ventilation
3. Negative PCR for SARS-CoV-2 by day 7
4. Adverse events
5. Serious adverse events
The Antiviral Expert Working Group met on 13th June 2021 to consider Favipiravir as a treatment for COVID-19. Conflict of interest declarations were reviewed by the Steering Committee; none were found to be relevant to Favipiravir.
A summary and then more detailed explanations of the Expert Working Group's judgements follow.
Problem
The COVID-19 pandemic in India with more than 44 million cases and over 0.53 million deaths has significantly impacted and stressed the health structure of the country. During the inception of the pandemic,with a shortage of intensive care unit beds, oxygen and trained personnel the country was facing a major health crisis. This had prompted many irrational and experimental treatment interventions like Favipiravir in all severity of patients across the country in patients hospitalized in COVID-19 without clear indication or evidence in which subgroup of population or disease severity the drug is effective for. Currently the drug is not used popularly for the treatment of covid-19. The group judged the problem to be of utmost priority.
Desirable effects
The panel agreed that the evidence suggests that Favipiravir doesn’t have a clinically significant effect on mortality, time to negative PCR, reducing progression of disease, or preventing critical or intensive care admissions. There is no significant effect in reducing the duration of hosptalisatin , time to clinical improvement or time to viral clearance.
Undesirable effects
The pooled data did not suggest any increase in serious or other adverse events, or adverse events leading to discontinuation when Favipiravir was added to usual care or with active comparators. However, the panel felt that hyperuricemia is a well-known adverse effect of favipiravir which is self-limiting in most cases and caution should be advised for use in renal failure and gout.
Certainty of evidence
Using GRADE methodology, the evidence synthesis team rated the certainty of evidence as very low for all-cause mortality, duration of hospitalization, progression to respiratory failure, progression to oxygen therapy, progression to invasive mechanical ventilation, any adverse events and serious adverse events. The certainty of evidence was high for duration of hospitalization and moderate for adverse events-hyperuricemia. The expert working group agreed with these judgements and rated the overall certainty as very low.
Values
The EWG felt that all the outcomes including those of mortality, progression to respiratory failure, oxygen therapy or mechanical ventilation, critical or intensive care for any reason, duration of hospitalisation and outcomes related to adverse events were expressed variably in the studies. However, there is probably no important uncertainty or variability on how people would value the main outcomes.
Balance of effects
The expert working group felt that the balance of effects does not favor either the intervention or the comparison. The panel felt that there is no convincing evidence to prove the benefit of this intervention, since there were different comparators and varying severity of disease across all studies. The intervention was also found to be not efficacious as per the sensitivity analysis where results were similar when we compared after splitting into 2 categories -SOC + active comparator (another antiviral) vs together.
Resources required
The group felt that the costs were small. The erratic supply chain had led to an increased demand for this drug during the initial phase of the second wave of the pandemic despite its uncertain clinical benefits until the drug was removed from the ministry of health guidelines for COVID-19 on June 7th 2021. The group includes clinicians in different types of Indian hospitals who have a good idea of drug and hospitalization costs.
Certainty of evidence of required resources
No studies reporting this were reviewed by the group but the clinicians in the group were aware of the cost and hence felt that there was high certainty of evidence for required resources to implement this intervention.
Cost effectiveness
The panel discussed that even though there was no research evidence that evaluated cost of Favipiravir in an Indian context, it favors the comparison, as this intervention was not of clinical benefit and conferred a cost for implementation and would always be in addition to the standard care.
Equity
At this point in time this intervention would increase equity if found efficacious as it would prevent admission into hospital. However as of now due to the lack of efficacy unnecessary adding of this drug would incur an additional cost and hence reduce equity.
Acceptability
The group felt that this intervention is likely to have wide acceptance by all the relevant stakeholders (policymakers, patients and clinicians) if efficacious as it is an oral drug that is probably quite safe, but taking evidence and cost into account a well-informed clinician would be unlikely to use it.
Feasibility
This is a feasible intervention if found efficacious as it is easy to deliver and available easily over the counter in the country.
Currently the evidence to support using Favipiravir for the treatment of COVID-19 in any patient group is lacking, as the certainty of the evidence to date is very low. Regarding adverse effects, there is evidence to suggest that there is definite hyperuricemia when given as a treatment for COVID-19 and the benefits (or the lack thereof) right now do not outweigh the risk. It is contraindicated in pregnancy based on data from animal studies showing teratogenicity thus caution should be exercised when prescribing for patients of reproductive age. Favipiravir is an oral drug, making it suitable as an outpatient or inpatient treatment. The dose is 1800 mg twice daily on the first day, followed by 800mg twice daily up to day 14. Previously there were only 200mg and 400mg doses available making the pill burden quite high which might affect treatment adherence, however 800mg tablets are now available. A two week treatment course costs around Rs.3600. If further evidence emerges showing Favipiravir is effective and safe for the treatment of COVID-19, it should be straightforward to implement this treatment into existing protocols.
Our conditional recommendation against the use of Favipiravir applies to all subgroups of patients with COVID-19. The group considered all trials of Favipiravir and found no subgroups where there was benefit in clinically meaningful endpoints whether evaluated by category of severity or by co-morbidities. There are very limited data available assessing its use in patients with liver or kidney disease.
Although the evidence for discontinuation of the drug because of the undesirable effects reported with widespread use such as hyperuricemia, liver dysfunction and chest pain has so far been low, this needs careful monitoring as the potential for drug-related harm cannot be ruled out.
There is currently no evidence to support the use of Favipiravir in any patient group for COVID-19 treatment. There is a need for conduct of well-structured, adequately powered randomized controlled trials with a low risk of bias to address the following:
- Does use of Favipiravir in different subgroups of disease severity or in different special populations (children, immunosuppressed, co-morbid conditions) keep patients from getting admitted into hospital?
- What dose of Favipiravir is safe and efficacious for the treatment of COVID-19?
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