These findings suggest low to moderate-certainty evidence showing a survival benefit without harm of ivermectin for treatment against covid-19. Low certainty evidence on improvement and deterioration support the possibility of clinical benefit with ivermectin. Low certainty evidence also suggest it could be a useful prophylaxis. Overall, therefore, the evidence suggests that early use of ivermectin may reduce morbidity and mortality from covid-19, based on reductions in covid-19 infections when ivermectin was used as post-exposure prophylaxis, more favourable point estimates for mild to moderate disease compared with severe disease for death due to any cause, and on the evidence demonstrating reductions in the number of patients deteriorating.
The evidence on severe adverse events in this review was graded as low certainty, partly because there were too few events to reach statistical significance. However, evidence from a recent systematic review of ivermectin use among people with parasitic infections suggests that ivermectin administered at the usual doses (0.2mg/kg or 0.4mg/kg) is safe and could be safe at higher doses.7,112 A recent World Health Organization document on ivermectin use for scabies found that adverse events with ivermectin were primarily minor and transient.21
We decided to restrict the included studies to the highest level of evidence, i.e. RCTs, despite the use of observational evidence being potentially used in times of emergency,113 and the numerous observational studies on ivermectin for covid-19. We included pre-print and unpublished data from completed but not yet published trials due to the urgency related to evidence synthesis in the context of a global pandemic.114 Whilst there is the potential for selective reporting of outcomes and publication bias, we have factored in these considerations in interpreting results and forming conclusions. We adhered to PRISMA guidelines and the WHO statement on developing global norms for sharing data and results during public health emergencies.114
There are a number of limitations with this review. Several of the studies contributing data did not provide full descriptions of methods, so assessing risk of bias was challenging. Where descriptions of study methods were sparse or unclear, we attempted to contact authors to clarify methods, but lack of information led us to downgrade findings in several instances. Overall interpretation of findings was hampered due to variability in the participants recruited, treatment regimen and in the care offered to those in control groups. We have tried to take this variation into account through subgroup and sensitivity analyses, nevertheless dosing and treatment regimens and the use of ivermectin with other components of “standard care” require further research. We did not include laboratory outcome measures, such as viral clearance. The latter, as well as other biochemical outcomes have been reported in several studies and reviews and tend to favour ivermectin.10,50,101,105 Several trials reported continuous data, such as length of hospital stay, as medians and interquartile ranges, therefore, we were unable to include these data in meta-analysis. As we did not undertake in our protocol to perform narrative evidence synthesis, and as these data tended to favour ivermectin, the certainty of the effects of ivermectin on these continuous outcomes may be underestimated.
To date, three other reviews of ivermectin use for covid-19 have been published9,10,115 but only one has been peer-reviewed.9 We applied AMSTAR 2,116 a critical appraisal tool for systematic reviews of healthcare interventions, to the two non-peered systematic reviews10,115 and both were judged to be of low quality (Table 4). However, there was also a suggestion that ivermectin may reduce risk of death in treatment of covid-19 in these reviews.
In addition to these reviews, the findings of several controlled observational studies are consistent with existing evidence and suggest improved outcomes with ivermectin treatment.49,52,54 Similarly, with respect to ivermectin prophylaxis of frontline workers and those at risk, controlled observational studies from Bangladesh and Argentina (the latter which involved 1195 health care workers) have shown apparent reductions in covid-19 transmission with ivermectin prophylaxis.42,48
Clarifying ivermectin safety in pregnancy is a key question in patient acceptability for pregnant women contracting covid-19. One source5 found little evidence of increased risk of abnormal pregnancies but similarly weak evidence of absence of risk. For (pre-exposure) prophylaxis in pregnancy, where vaccines may be contraindicated, the alternative of hydroxychloroquine has been advocated.117,118 In addition to safety and relative efficacy, different risk-benefit judgments may be presented for prophylaxis (pre- and post-exposure), and for treatment, with pregnancy a high-risk status for covid-19.
RCTs in this review did not specifically examine use of ivermectin in the elderly, though this is a known high-risk group for severe covid-19. In the setting of care homes, it is also notorious for rapid contagion. A standard indication for ivermectin in the elderly is scabies. We identified two recent reports suggesting that ivermectin may be efficacious as prevention and treatment of covid-19 in this age group.44,119
There is also evidence emerging from countries where ivermectin has been implemented. For example, Peru had a very high death toll from covid-19 early on in the pandemic.120 Based on observational evidence, the Peruvian government approved ivermectin for use against covid-19 in May 2020.120 After implementation, death rates in eight states reduced by 64–91% over a two-month period.120 Another analysis of Peruvian data from 24 states with early ivermectin deployment has reported a drop in excess deaths of 59% at 30 + days and of 75% at 45 + days.121 However, factors such as change in behaviour, social distancing, and face-mask use could have played a role in this reduction.
Other considerations related to the use of ivermectin treatment in the covid-19 pandemic include people's values and preferences, equity implications, acceptability and feasibility.122 None of the identified reviews specifically discussed these criteria in relation to ivermectin. However, in health care decision-making, evidence on effectiveness is seldom taken in isolation without considering these factors. Ultimately, if ivermectin is to be more widespread in its implementation, then some considerations are needed related to these decision-making criteria specified in the GRADE-DECIDE framework.122
Ivermectin may be equitable, acceptable and feasible global intervention against covid-19. There are numerous emerging ongoing clinical trials assessing ivermectin for covid-19. The trade-off with policy and potential implementation based on evidence synthesis reviews and/or RCTs will vary considerably from country to country. Certain South American countries, Indian states, and more recently Slovakia and other countries in Europe, have implemented its use for covid-19.121,123−126 Despite ivermectin being a low-cost medication in many countries globally, the apparent shortage of economic evaluations indicates that economic evidence on ivermectin for treatment and prophylaxis of SARS-CoV-2 is currently lacking. This may impact more on LMICs that are potentially waiting for guidance from organizations like the WHO.
Given the evidence of efficacy, safety, low cost and current death rates, ivermectin may potentially have an impact on health and economic outcomes of the pandemic across many countries. Ivermectin is not a new and experimental drug with safety concerns. It is a WHO ‘Essential Medicine’ used in several different indications. Health professionals should consider its use against Covid-19 in both treatment and prophylaxis.