The impact of ivermectin on COVID-19 outcomes: a systematic review and meta-analysis

Abstract

Background:

The COVID-19 pandemic, resulting in approximately seven million deaths globally, underscores the urgency for effective treatments. Ivermectin, among several repurposed drugs, garnered interest due to its antiviral properties. However, conflicting evidence from observational studies and randomized controlled trials raised questions about its efficacy and safety.

Method:

This systematic review and meta-analysis followed MOOSE and PRISMA guidelines. Comprehensive searches were conducted in databases including Scopus, Embase, PubMed, and Web of Science up to April 2024. Data were extracted independently by two reviewers and analyzed using Comprehensive Meta-Analysis V3 software.

Results:

Across 33 studies encompassing 15,376 participants, ivermectin showed no significant impact on critical outcomes such as mortality [risk ratio (RR) 0.911, 95% confidence intervals (CI) 0.732–1.135], mechanical ventilation (RR 0.727, 95% CI 0.521–1.016), polymerase chain reaction conversion (RR 1.024, 95% CI 0.936–1.120), ICU admissions (RR 0.712, 95% CI 0.274–1.850), or hospitalization rates (RR 0.735, 95% CI 0.464–1.165) compared to controls. However, it significantly reduced time to symptom alleviation (standardized mean difference −0.302, 95% CI −0.587 to −0.018) and sustained symptom relief (RR 0.897, 95% CI 0.873–0.921). Adverse event (AE) rates were similar between the ivermectin and control groups (RR 0.896, 95% CI 0.797–1.007). Meta-regression indicated older age and diabetes as predictors of AEs.

Conclusion:

Despite its observed benefits in symptom management, ivermectin did not significantly influence critical clinical outcomes in COVID-19 patients. These findings highlight the importance of continued research to identify effective treatments for COVID-19, emphasizing the need for high-quality studies with robust methodology to inform clinical practice and public health policy effectively.

Introduction

Globally, the COVID-19 epidemic has claimed the lives of an astounding seven million people[1]. Early January 2020, the International Committee on Taxonomy of Viruses officially designated the novel coronavirus, which had been found in late 2019, as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)^[2,3]. Viral pneumonia, which is frequently exacerbated by potentially fatal morbidities such cardiomyopathies, is the main cause of death in COVID-19 patients[1].

Several medicines were repurposed for the treatment of COVID-19 in the search for therapeutic treatments, and these drugs were effective at different phases of the disease. These drugs include dexamethasone[4], tocilizumab[5], sarilumab[6], remdesivir[7], molnupiravir[8], and nirmatrelvir/ritonavir[9]. An antiparasitic medication that has garnered interest is ivermectin, which blocks the chloride channels of helminthic parasites and has demonstrated clinical effectiveness in treating ectoparasitic infections, onchocerciasis, and strongyloidiasis[10]. Ivermectin has been extensively investigated in vitro for its antiviral properties against a range of viral diseases, including SARS-CoV, yellow fever virus, Chikungunya virus, West Nile virus, human immunodeficiency virus, dengue virus, Zika virus, Hendra virus, Semliki Forest virus, Sindbis virus, and avian influenza virus[11]. Given its previous success against respiratory viruses, ivermectin was rigorously tested during the pandemic and demonstrated potent activity against SARS-CoV-2 in Vero-hSLAM cell cultures[12]. Ivermectin demonstrates antiviral efficacy against several RNA viruses by its interaction with distinct protein-binding sites, which in turn stops viral reproduction, as demonstrated by numerous in vitro experiments[13].

However, contradictory findings from observational studies have sparked a global discussion about ivermectin’s impact on COVID-19 patients^[14-17]. Several randomized controlled trials (RCTs) reporting positive findings for ivermectin were later found to have a high risk of bias^[18,19]. Further, in 2021 two RCTs from Argentina and Colombia revealed that ivermectin had no discernible impact on hospitalization rates and symptom resolution in COVID-19 patients^[20,21]. Two recent studies have conclusively demonstrated that ivermectin is not effective in treating COVID-19, with no significant differences in efficacy or safety compared to placebo. These studies also found that ivermectin did not reduce hospital admissions or improve outcomes; therefore, it should not be further used to treat SARS-CoV-2 infection^[22,23].

The goal of this meta-analysis and comprehensive review is to assess how ivermectin affects different COVID-19 patient outcomes, including mortality, adverse effects, and ICU admission. Updating a previous meta-analysis from August 2023, this study seeks to provide a more comprehensive assessment of determined outcomes[24]. Given the potential utility of ivermectin against viruses in the MERS-CoV and SARS-CoV classes, further investigation is warranted despite numerous negative reports. Additionally, this study includes a meta-regression analysis to examine the impact of age and comorbidities on the determined outcomes.

Method

Search strategy and protocol

Following the recommendations provided by MOOSE, AMSTAR (Assessing the methodological quality of systematic reviews) Guideline and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)[25], the current systematic review and meta-analysis was carried out. The protocol was registered on PROSPERO (…).

Several databases, including Scopus, Embase, PubMed and Web of Science, were used to conduct a thorough search for data from the databases’ creation until April 2024. Terms like “Ivermectin,” “COVID-19,” and its synonyms were used during the literature search. The language used throughout the procedure was only English. During the literature search procedure, Endnote 20 bibliographic data were examined to eliminate duplicate articles. Likewise, the search was not restricted by study type, date, or location. An extensive search strategy has been provided in Supplementary Digital Content (available at: http://links.lww.com/MS9/A644).

Eligibility criteria and screening

The following criteria were used for included studies: observational studies, such as cohorts, prospective studies, and randomized control trials (RCTs) involving the COVID-19 population; studies involving the use of ivermectin as an intervention among the COVID-19 population; and studies comparing the effects of ivermectin with a control group to determine efficacy and safety.

Conference papers, reviews, editorials, case reports, case series, and animal research are among the studies that are not included. By reading the study titles and abstracts, two reviewers independently performed screening. Afterward, complete text review of the shortlisted studies was conducted. A third reviewer was consulted in order to reach mutual consensus to settle any disagreements that arose during the process.

Data extraction

Data from the included studies, including the last name of the authors, the year of publication, the type of study, demographic information (age, sex, sample size), the intervention (ivermectin dosage), the length of follow-up, comorbidities [diabetes, hypertension [HTN], coronary heart disease (CHD)], and outcome data [mortality, adverse events (AE), length of hospitalization], were extracted independently by two reviewers. Throughout the process, disagreements were settled by mutual consensus.

Data analysis and quality assessment

The data analysis was undertaken by a single independent reviewer utilizing the comprehensive meta-analysis V3 software. For dichotomous and continuous outcomes, the risk ratio (RR) and standardized mean difference (SMD) were employed, with 95% confidence intervals (CI). A forest plot was devised for PCR negative, all-cause mortality, mechanical ventilation requirement, ICU admission, hospitalization, adverse effects, and skin rash. Meta-regression was executed separately, and scatterplots were formulated to investigate the impact of mean age, CHD, and HTN. Heterogeneity between the analyzed studies was considered substantial when I² surpassed 50%, for which point leave-one-out analysis was performed. An independent reviewer utilized the Newcastle Ottawa scale and the Cochrane Collaboration assessment for risk of bias to evaluate the quality of the included observational studies and RCTs, as depicted in the Supplementary Digital Content (available at: http://links.lww.com/MS9/A644). RCTs were categorized as low risk, high risk, or uncertain risk based on biases in selection, detection, reporting, and attrition. Publication bias among the analyzed studies was addressed using a funnel plot and the Eggers regression intercept was employed to evaluate the studies, as illustrated in the Supplementary Digital Content (available at: http://links.lww.com/MS9/A644).

Results

Study selection

The initial comprehensive search across various databases including PubMed, Scopus and ScienceDirect yielded 2344 articles. After removing 537 duplicates, 1807 unique articles remained for additional evaluation. Following the screening of titles and abstracts, 87 articles were identified as potentially relevant for inclusion, and therefore were subjected to a rigorous full-text review. Consequently, 33 studies were selected for the systematic review and meta-analysis after meeting the predetermined inclusion and exclusion criteria^{[13,20-23,26-55]}. (Fig. 1)

Figure 1.

PRISMA flow diagram showing the study selection process, including records identified, screened, assessed for eligibility, and included in the analysis, with reasons for exclusions.

Baseline characteristics

33 studies were included, with a total sample size of 15,376 participants across various countries, including the UK, Japan, Thailand, Egypt, China, Bangladesh, Mexico, Israel, the USA, Nigeria, Italy, Spain, Argentina, Turkey, India, Brazil, and Iran. Patients identified by WHO criteria as suffering from mild to moderate COVID-19 were included in the study. The included studies average participant age ranged from 26 to 62.5 years. The sex ratio showed a considerable representation of female participants, ranging from 21.3% to 67.8%. All studies confirmed COVID-19 via laboratory testing. Hospitalization rates varied significantly, with some studies including only outpatients while others focused solely on hospitalized individuals. The presence of comorbid conditions such as cardiovascular disease (CVD) or CHD, HTN and diabetes mellitus (DM) was reported variably across studies. In studies reporting these comorbidities, the prevalence ranged from 1.1% to 59% for CVD/CHD, 0% to 59% for DM, and 0% to 75.3% for HTN. Ivermectin dosing regimens varied, with most studies administering doses ranging from 0.2 mg/kg to 600 μg/kg, either as single doses or daily for up to 7 days. Control groups typically received placebo or standard of care. Follow-up durations ranged from 5 to 365 days, assessing outcomes such as time to recovery, viral clearance, symptom resolution, hospitalization, mortality, AEs, and serious adverse events (SAE). Funding sources included government bodies, academic institutions, and industry sponsors, with some studies not disclosing their funding sources. Baseline characteristics of included studies are given in Table 1.

Table 1.

Baseline characteristics of included studies.

Study authors (year)	Country (sample size)	IVM doseand duration	Control group	COVID-19 severity by WHO classification	Patient age, mean (SD) or median (IQR), y	Laboratory-confirmed COVID-19	Hospitalized	Female Sex	CVD or CHD	DM	HTN	Presenting symptoms	Evaluated outcomes	Duration of follow-up, days
Hayward G2024	UK(n = 8811)	300–400 μg/kg, taken as one dose daily for 3 days [18 mg daily (6 × 3 mg tablets) for weight 45–64 kg, 24 mg daily (8 × 3 mg tablets) for weight 65–84 kg, and 30 mg daily (10 × 3 mg tablets) for weight ≥84 kg]	Usual care	Mild to moderate	51.2 (13.0)	100%	1.60%	58%	NA	NA	NA	Fever, difficulty in breathing, headaches, and weakness	Time to recovery,hospitalization/death, symptoms at 3/6/12 month	365
Mikamo H 2024	Japan and Thailand (N = 325)	0.3–0.4 mg/kg for 3 days	Standard of care	Mild	41.5 (13.5)	100%	0%	51.40%	NA	5.50%	10.50%	Rhinorrhoea, fever, cough, poor feeding, and cold extremities.	Viral clearance, clinical recovery, safety	28
Aref et al, 2021	Egypt (N = 114)	Ivermectin mucoadhesive nanosuspension intranasal spray	NA	Mild	45.1 ± 18.9	100%	0%	52%	NA	NA	NA	Myalgia, headache, smell and taste disturbances, and cough, with dry cough	Clinical improvement, viral clearance, lab parameters	7
Abbas 2022	China (n = 202)	300 μg/kg/day for 5 days	Placebo	Mild	IVM: 38.33 (6.84) Control: 37.33 (5.84)	100%	100	55.4	0	0	0	Fatigue, headache, chest pain, dyspnea (shortness of breath), cough, olfactory dysfunction, myalgia and gustatory dysfunction	All-cause mortality rate, symptoms resolved, SAEs, hospitalization due to progression	21
Abd-Elsalamet 2021	Egypt, 2020 (n = 164)	12 mg/day IVM with standard care	Standard care only	Mildly to moderately	IVM: 42.38 (16.02) Control: 39.38 (16.92)	100	100	50	NA	16.5	19.5	Fever, cough, shortness of breath, sore throat, and myalgia	MV requirement, all-cause mortality rate, LOS	30
Ahmed 2021	Bangladesh (n = 48)	12 mg once daily for 5 days	Placebo	Mild	42 (NR)	100	100	54	0	0	0	Myalgia, headache, smell and taste disturbances, cough, with dry cough	Remission of symptoms, LOS, SAEs, oxygen requirement,	14
Angkasekwinai 2022	Thailand (n = 447)	400–600 μg/kg, once daily for 2 days	Placebo	Mild in 11.6%, moderate in 88.4%	39.5 (12.1)	100	7.4	56.8	1.8	6.9	11.2	Fever, cough, fatigue, shortness of breath, myalgia, headache, sore throat, diarrhea, and loss of taste or smell.	All-cause mortality rate, AEs, Symptoms resolved, SAEs	28
Babalola 2022	Nigeria (n = 62)	Given every 84 h, twice a week for 2 weeks + SOC: A1: 6 mg; A2: 12 mg	Placebo + SOC	Asymptomatic or mild/moderate symptoms	44.1 (14.7)	100	NA	30.6	NA	3.2	14.5	Fever, cough, dyspnea, fatigue, and myalgia.	All-cause mortality rate, duration taken for negative, AEs, SAEs	42
Beltrán-Gonzalez 2021	Mexico (n = 106)	12 or 18 mg, according to patient weight	Placebo	Severe in 100%	53 (16.9)	100	100	37.8	NA	33.9	32.1	Fever, cough, shortness of breath, fatigue, myalgia, headache, sore throat, loss of taste or smell, and gastrointestinal symptoms (nausea, vomiting, diarrhea)	All-cause mortality rate, clinical recovery, LOS, AEs, respiratory deterioration	28
Biber 2022	Israel (=89)	Ivermectin 0.2 mg/kg for 3 day	Placebo	Mild to moderate, not requiring O2 and asymptomatic cases	35 (28–47) (IQR)	100	0	21.3	NA	NA	NA	Fever, cough, shortness of breath, fatigue, myalgia.	PCR negative conversion, AEs, Hospitalization due to progression, SAEs	21
Bramante 2022	USA (n = 1323)	390–470 μg/kg/day, for 3 days	Placebo	Mild in 100%	46 ([IQR] 37–55	100	0	56	22.8	1.6	NA	Cough, shortness of breath, fever, fatigue, loss of taste or smell, muscle or body aches, sore throat, congestion or runny nose, nausea or vomiting, diarrhea	Hypoxemia, emergency department visit, hospitalization, mortality	14
Bukhari 2021	Pakistan (n = 86)	Single dose: 12 mg	SOC	Mild in most patients (percentage unclear)	39 (42)	100	100	15	5.8	12	14	Fever, cough, dyspnea, gasping and chronic disease	Time to viral clearance, AEs	28
Buonfrate 2022	Italy (n = 93)	Single dose A1: 600 μg/ kg; A2: 1200 μg/kg	Placebo	Mild in 83.9%, moderate in 16.1%	47 (31–58)	100	100	41.9	23.4	4.7	NA	Cough, pyrexia, fatigue, myalgia, headache, anosmia, infective rhinitis	Viral clearance, hospitalization due to progression, mean durations of symptoms, mean reduction in viral load, SAEs	14
Chaccour 2021	Spain (n = 24)	Single dose 400 μg/kg	Placebo	Mild in 100%	26 (19–36)	100	0	50	0	0	0	Fever, cough, sore throat and symptoms in general	All-causemortality rate, AEs, PCR at day 7	28
Elshafie 2022	Egypt (n = 206)	36 mg on day 1, 3, 6	Placebo	Moderate to severe	59 (16)	35.4	100	46.6	9.7	27.7	38.3	Fever, cough, fatigue, headache, sore throat, runny nose, muscle or body aches, diarrhea, nausea or vomiting	All-cause mortality rate, AEs, time or number of recoveries	90
Krolewiecki 2021	Argentina (n = 45)	0.6 mg/kg once daily for 5 day	SOC	Mild in 87%, moderate in 13%	41 (12)	100	100	44	NA	16	13	Fever, cough, shortness of breath, fatigue, and other respiratory symptoms associated	Viral load at day 5, IVM plasma level	30
Kishoria 2020	India (n = 32)	12 mg + SOC	SOC	Asymptomatic/ Mild patients in 100%	38	100	100	28.1	NA	NA	NA	Fever, cough, fatigue, sore throat, shortness of breath, and less common symptoms	PCR negative conversion, Discharged from hospital	6
Lim 2022	Malaysia (n = 490)	0.4 mg/kg body weight daily for 5 days + SOC	SOC	Mild in 34.1%, moderate in 65.9%	62.5 (8.7)	100	0	54.5	11.6	53.5	75.3	Cough, fever, and runny nose	All-cause mortality rate, LOS, symptoms resolved, Admission to ICU, MV requirement, progress to more severe disease	28
López-Medina 2021	Colombia (n = 398)	300 μg/kg once daily for 5 d	Placebo	Mild in 100%	37 (29–48)	100	1	78	1.7	6	13	Myalgia, headache, smell and taste disturbances	All-cause mortality rate, time to complete resolution, AEs, SAEs, escalation of care	21
Manomaipiboon 2022	Thailand (n = 72)	12 mg/day, for 5 days	SOC	Mild to moderate	48.57 (14.8)	100	100	62.5	2.8	23.6	40.3	Cough, dyspnea, smell disturbances, runny nose, sore throat, headache, muscle pain, and malaise	PCR negative conversion, symptoms resolved, mean durations of symptoms	28
Mirahmadizadeh2022	Iran (n = 391)	3 mg for 2 days, cumulative dose of 24 mg	Placebo	Mild in 100%	39 (17)	100	0	49	1.1	5	6.9	Fever, cough, and sore throat	All-cause mortality rate, symptoms resolved, MV requirement, hospitalization due to progression, AEs, SAEs, Mean durations of symptoms
Mohan 2021	India (n = 157)	A1: Ivermectin 12 mg (single dose); A2: Ivermectin 24 mg (single dose)	Placebo	Mild in 64%, moderate in 36%	35.3 (10.4)	100	100	11.2	0.8	8.8	11.2	Fever, cough, breathlessness, sore throat, fatigue, headache, myalgia, nausea/vomiting, loss of taste/smell and chest pain	PCR negative conversion, Progress to more severe disease, discharged from hospital, AEs, SAEs	14
Naggie 2022	USA (n = 1591)	Ivermectin 400 μg/kg for 3 days	Placebo	Mild-to moderate	48 (12)	100	0	59	NA	59	26	Fatigue, dyspnea, fever, cough, nausea, vomiting, diarrhea, body aches, chills, headache, sore throat, nasal symptoms, and loss of sense of taste or smell	All-cause mortality rate, admission to ICU, MV requirement,	28
Naggie 2023	USA (n = 1206)	Ivermectin 600 μg/kg for 6 days	Placebo	Mild-to moderate	IVM: 47 (38–58) Control:48 (39–58)	100	0	59.1	3.9	9	26.3	Fever, cough, nausea, vomiting, diarrhea, body aches, chills, headache, sore throat, nasal symptoms, and loss of sense of taste or smell.	Time to sustained recovery, All-cause hospitalization rate, All-cause mortality rat	28
Okumuş 2021	Turkey (n = 60)	0.2 mg/kg for 5 days + SOC	SOC	Severe pneumonia	IVM: 58.17 (11.52) Control: 66.23 (13.31)	100	100	33.3	23.3	31.6	45	Fever, cough, sore throat, dyspnea, headache, weakness, myalgia, diarrhea and nausea/vomiting	All-cause mortality rate, PCR negative conversion, clinical improvement, AEs, SAEs	5
Podder 2020	Bangladesh (n = 62	Single dose: 200 μg/kg	SOC	Mild in 81%, moderate in 19%	39 (12)	100	NA	29	NA	NA	NA	Fever, cough, shortness of breath, sore throat, anosmia, dysgeusia, diarrhea, myalgia, fatigue, headache, and rhinorrhea	Time to full recovery, viral clearance	10
Ravikirti 2021	India (n = 115)	12 mg/day for 2 days	Placebo	Mild in 79%, moderate in 21%	53 (15)	100	100	28	11	36	35	Fever, breathlessness, or hypoxia	All-cause mortality rate, admission to ICU, MV requirement, viral clearance at day 6	10
Reis 2022	Brazil (n = 679)	Ivermectin: 400 μg/kg of body weight once daily for 3 days + SOC	Placebo + SOC	Mild-to moderate	49 (38–57)	100	0	58.2	1.8	12.9	8.4	Fever, cough, and sore throat	MV requirement, AEs, hospitalization due to progression, viral clearance	21
Rezai 2022	Iran (n = 1158)	0.4 mg/kg/day for 3 days + SOC	Placebo + SOC	Moderate in 53.9%, severe in 46.1%	44.9 (5–96)	100	52.6	50	7.7	20.1	18.7	Fever, body pain, cough, dyspnea, dry cough	Clinical improvement, recovery, LOS, ICU admission, MV requirement, AEs, mortality	7
Rocha 2022	Mexico (n = 56)	12 mg/day for 3 days + SOC	Placebo + SOC	Asymptomatic and mild	IVM: 40.4 (15.2) Control:36.4 (13)	100	100	67.8	3/30: 1/26	2/30: 1/26	4/30 1/26	Fever, cough, muscular pain, fatigue, shortness of breath, headache, diarrhea, palpitations, expectoration, hypogeusia/ageusia, hyposmia/anosmia and back pain	PCR negative conversion, symptoms resolved, progress to more severe disease, AEs	14
Shahbaznejad 2021	Iran (n = 69)	0.2 mg/kg + SOC	SOC	Moderate in 55%, severe in 45%	46.4 (22.5)	64	100	47.8	NA	NA	NA	Fever, chills, sore throat, cough, dyspnea, loss of appetite, abdominal pain, dizziness, insomnia, itching, joint pain, joint swelling, headache, nausea, vomiting, diarrhea, malaise, conjunctivitis, tachycardia, wheezing, rhonchi, retraction, hypotension, and rash	Duration of hospital stay, overall clinical improvement	10
Vallejos 2021	Argentina (n = 501)	IVM: BW < 80 kg: 12 mg at inclusion and another 12 mg after 24 h; 80 kg < BW < 110 kg:18 mg at inclusion and another 18 mg after 24 h; 110 kg < BW: 24 mg at inclusion and another 24 mg after 24 h + SOC	Placebo + SOC	Mild in 100%	42.5 (15.5)	100	0	47.3	2.6	9.6	23.6	Fever, cough, sore throat, headache, muscle aches, fatigue, shortness of breath, and loss of taste and smell	All-cause mortality rate, PCR negative conversion, MV requirement, hospitalization due to progression, AEs, SAEs	30
Wada 2023	Japan (n = 221)	200 μg/kg	Placebo	Asymptomatic or mild/moderate symptoms	47.7 (15.0)	100	0	35.4	NA	13.7	NA	Fever, cough, fatigue, headache, sore throat, runny nose, muscle or body aches, diarrhea, nausea, or vomiting	Time to a negative, All-cause mortality rate, MV requirement, hospitalization due to progression, AEs	45

All-cause mortality

Across 15 studies, the RR of all-cause mortality between the ivermectin group and the control group was 0.911 (95% CI 0.732, 1.135; I² = 0%; P = 0.406). This indicates that patients receiving ivermectin and those in the control group did not vary statistically significantly in terms of all-cause mortality. The heterogeneity among these studies was low (I² = 0%), indicating a consistent effect across the different studies included in the meta-analysis (Fig. 2). It should be noted that several studies, including those by Ahmed (2021), Angkasekwinai (2022), Babalola (2022), Biber (2022), Bukhari (2021), Buonfrate (2022), Chaccour (2021), Krolewiecki (2021), Manomaipiboon (2022), Mirahmadizadeh (2022), Mohan (2021), Podder (2020), Rocha (2022), Shahbaznejad (2021), and Wada (2023), were not included in this analysis because there were no deaths reported in either the ivermectin or control groups in these studies.

Figure 2.

Forest plot showing the pooled risk ratio for all-cause mortality among COVID-19 patients treated with ivermectin versus control groups.

Mechanical ventilation requirement

Across 13 studies, the RR for the requirement of mechanical ventilation between the ivermectin group and the control group was 0.727 (95% CI 0.521–1.016; I² = 0%; P = 0.062). Although this indicates a trend toward a reduction in the need for mechanical ventilation in the ivermectin group, the difference did not reach statistical significance. The heterogeneity among these studies was low (I² = 0%), suggesting a consistent effect across the different studies included in this analysis (Fig. 3).

Figure 3.

Forest plot showing the pooled risk ratio for the requirement of mechanical ventilation in COVID-19 patients treated with ivermectin versus control groups.

PCR negative conversion

Across 15 studies, the RR for PCR negative conversion between the ivermectin group and the control group was 1.024 (95% CI 0.936–1.120; I² = 57.968; P = 0.607). This demonstrates no statistically significant difference in PCR negative conversion between patients treated with ivermectin and those in the control group. However, there was moderate heterogeneity among these studies (I² = 57.968) (Fig. 4). To further explore this heterogeneity, a leave-one-out analysis was conducted. The resulting forest plot from this analysis is provided in Supplementary Digital Content (available at: http://links.lww.com/MS9/A644).

Figure 4.

Forest plot showing the pooled risk ratio for PCR negative conversion among COVID-19 patients treated with ivermectin versus control groups.

Sustained alleviation of all symptoms

Across 3 studies, the RR for sustained alleviation of all symptoms between the ivermectin group and the control group was 0.897 (95% CI 0.873–0.921; I² = 0%; P < 0.0001). This indicates a statistically significant reduction in the sustained alleviation of all symptoms among patients treated with ivermectin compared to those in the control group (Fig. 5).

Figure 5.

Forest plot showing the pooled risk ratio for sustained alleviation of symptoms in COVID-19 patients treated with ivermectin versus control groups.

ICU admission

Across four studies, the RR for ICU admission between the ivermectin group and the control group was 0.712 (95% CI 0.274–1.850; I² = 54.397%; P = 0.486). Despite the possibility that the ivermectin group may have fewer ICU admissions as a result, however statistical nonsignificant (Fig. 6). To address heterogeneity, a leave-one-out analysis was conducted, and the resulting plot is included in Supplementary Digital Content (available at: http://links.lww.com/MS9/A644).

Figure 6.

Forest plot showing the pooled risk ratio for ICU admission among COVID-19 patients treated with ivermectin versus control groups.

Hospitalization

Across seven studies, the RR for hospitalization between the ivermectin group and the control group was 0.735 (95% CI 0.464–1.165; I² = 67.696; P = 0.190). This indicates no statistically significant difference in hospitalization rates between patients treated with ivermectin and those in the control group (Fig. 7). To explore heterogeneity, a leave-one-out analysis was conducted, and the resulting plot is included in Supplementary Digital Content (available at: http://links.lww.com/MS9/A644).

Figure 7.

Forest plot showing the pooled risk ratio for hospitalization among COVID-19 patients treated with ivermectin versus control groups.

Time to alleviation of all symptoms

Across five studies, the SMD for time to alleviation of all symptoms between the ivermectin group and the control group was −0.302 (95% CI −0.587 to −0.018; I² = 94.157%; P = 0.037). Comparing individuals receiving ivermectin to those in the control group, this shows a statistically significant decrease in the time to alleviation of all symptoms (Fig. 8). To address heterogeneity, a leave-one-out analysis was conducted, and the resulting plot is included in Supplementary Digital Content (available at: http://links.lww.com/MS9/A644).

Figure 8.

Forest plot showing the pooled risk ratio for time to alleviation of all symptoms in COVID-19 patients treated with ivermectin versus control groups.

Adverse events

An analysis of 18 studies revealed an RR of 0.896 (95% CI 0.797–1.007; I² = 55.846; P = 0.066) for AEs between the ivermectin and control groups. This indicates a nonsignificant trend toward fewer AEs in the ivermectin group (Fig. 9). A leave-one-out analysis was performed due to moderate heterogeneity, with the resulting plot available in Supplementary Digital Content (available at: http://links.lww.com/MS9/A644). Examination of 8 studies showed an RR of 1.187 (95% CI 0.627–2.250; I² = 0%; P = 0.598) for skin rash between the two groups, suggesting no significant difference in occurrence (Fig. 10). Similarly, analysis of three studies yielded an RR of 1.618 (95% CI 0.323–8.110; I² = 0%; P = 0.559) for pneumonia, indicating no significant difference in incidence between the groups (Fig. 11). Additionally, evaluation of three studies produced an RR of 0.656 (95% CI 0.260–1.650; I² = 4.153; P = 0.370) for nausea, also demonstrating no significant difference in incidence between ivermectin-treated patients and the control group (Fig. 12).

Figure 9.

Forest plot showing the pooled risk ratio for adverse events in COVID-19 patients treated with ivermectin versus control groups.

Figure 10.

Forest plot showing the pooled risk ratio for skin rash in COVID-19 patients treated with ivermectin versus control groups.

Figure 11.

Forest plot showing the pooled risk ratio for pneumonia in COVID-19 patients treated with ivermectin versus control groups.

Figure 12.

Forest plot showing the pooled risk ratio for nausea in COVID-19 patients treated with ivermectin versus control groups.

Publication bias

Funnel plots were created for the primary outcome measures, which encompassed all-cause mortality, AEs, PCR negative conversion, and mechanical ventilation requirement. The all-cause mortality funnel plot exhibited minor asymmetry, potentially suggesting publication bias. To examine this further, Egger’s regression intercept was computed, yielding a nonsignificant result (intercept −0.459, P = 0.10), which indicated no substantial publication bias for this outcome (Fig. 13). The PCR negative conversion funnel plot also showed slight asymmetry. However, the Egger’s regression intercept for this measure was also nonsignificant (intercept 0.21, P = 0.35), implying no considerable publication bias (Fig. 14). Similarly, the AEs funnel plot demonstrated minor asymmetry, but the Egger’s regression intercept was not statistically significant (intercept 0.617, P = 0.12), suggesting no notable publication bias for this outcome (Fig. 15). In contrast, the mechanical ventilation requirement funnel plot showed a more symmetrical distribution of studies, indicating a lower probability of bias for this outcome (Fig. 16).

Figure 13.

Funnel plot showing the assessment of potential publication bias for all-cause mortality among the included studies.

Figure 14.

Funnel plot showing the assessment of potential publication bias for PCR negative conversion among the included studies.

Figure 15.

Funnel plot showing the assessment of potential publication bias for adverse events among the included studies, plotting standard error versus effect size.

Figure 16.

Funnel plot showing the assessment of potential publication bias for mechanical ventilation requirement among the included studies, plotting standard error versus effect size.

Meta-regression analysis

To investigate possible sources of heterogeneity for different outcomes, meta-regression analyses were carried out by examining the impact of mean age, CHD, DM, and HTN. For all-cause mortality, the coefficients were 0.04 (P = 0.14) for mean age, −0.0059 (P = 0.86) for CHD, −0.087 (P = 0.07) for DM, and 0.029 (P = 0.33) for HTN. For mechanical ventilation requirement, the coefficients were 0.06 (P = 0.34) for mean age, 0.01 (P = 0.82) for CHD, −0.09 (P = 0.15) for DM, and 0.03 (P = 0.30) for HTN. For PCR negative conversion, the coefficients were −0.01 (P = 0.66) for mean age, 0.05 (P = 0.14) for CHD, −0.02 (P = 0.42) for DM, and 0.01 (P = 0.46) for HTN. For AEs, the coefficients were −0.048 (P = 0.0014) for mean age, −0.054 (P = 0.037) for CHD, 0.058 (P = 0.006) for DM, and −0.0003 (P = 0.97) for HTN. The results indicate that older age and DM were significant predictors of AEs, with CHD also showing a significant impact. However, none of these factors significantly predicted mechanical ventilation requirement, all-cause mortality, or PCR negative conversion, suggesting that while demographic and clinical characteristics can influence specific outcomes like AEs, they do not necessarily predict more critical outcomes such as mortality or the requirement for mechanical ventilation. Scatters plots of regression results are included in Supplementary Digital Content (available at: http://links.lww.com/MS9/A644).

Discussion

COVID-19 remains a significant global health challenge despite extensive vaccination efforts[56]. While vaccinations have mitigated the disease’s impact, numerous clinical trials continue worldwide to identify the most effective treatments^[57,58]. This systematic review and meta-analysis explore the use of ivermectin for COVID-19 patients, incorporating data up to April 2024. With numerous studies published annually, there is substantial interest from the scientific community and significant investments from institutions and authorities in researching this potential treatment^[59-61]. Data up to 2022 were provided by earlier systematic reviews and meta-analyses, focusing on limited outcome variables. Including data up to April 2024 allows for a more current and comprehensive analysis, reflecting the most recent research developments. Therefore, a comprehensive study examining a broader range of outcomes is crucial. This systematic review and meta-analysis address this gap by considering multiple outcomes and employing meta-regression to evaluate additional variables that may predict these outcomes.

The analysis showed that ivermectin had significant impact on a few outcomes but not on others. Notably, when comparing the ivermectin to the control group, there was a notable decrease in the amount of time to alleviation of all symptoms. Additionally, sustained alleviation of all symptoms was significantly reduced for patients treated with ivermectin. However, several other outcomes showed no significant differences between the ivermectin and control groups. These included all-cause mortality, the requirement for mechanical ventilation, PCR negative conversion rates, ICU admissions, and hospitalization rates. Additionally, the analysis showed that there was no difference between the two groups in the frequency of particular AEs such skin rashes, pneumonia, and nausea. While there was a trend toward fewer adverse events in the ivermectin group, this did not reach statistical significance. Meta-regression analyses revealed that older age and diabetes were significant predictors of AEs, but these factors did not significantly predict more critical outcomes such as all-cause mortality, the requirement for mechanical ventilation, or PCR negative conversion. Overall, while ivermectin showed some significant benefits in symptom alleviation, it did not significantly affect other key clinical outcomes.

Despite not being recommended in the latest COVID-19 guidelines, self-medication was common during the pandemic, with ivermectin frequently utilized, as shown in recent research^[62,63]. Factors contributing to this trend may include media misinformation, rejection of scientific evidence, limited health-care access, and perceptions of ivermectin’s affordability and safety[64]. Some health organizations incorporated ivermectin into their COVID-19 protocols[65]. Sales inquiries indicated significant distribution of ivermectin by pharmaceutical firms. Studies have shown ivermectin’s potential antiviral effects against various RNA viruses, including Zika^[66,67]. One key antiviral mechanism involves the inhibition of the importin α/β1 heterodimer, which is essential for viral protein nuclear transport and replication^[68-70]. Another mechanism, previously identified but not fully elucidated, involves ivermectin functioning as an ionophore agent. Ivermectin’s potential therapeutic role in COVID-19 has garnered significant interest due to its proposed mechanisms of action, although these remain largely speculative. One hypothesis posits that ivermectin inhibits viral replication by blocking the transport of viral proteins into the host cell nucleus via the importin-α/β1 pathway, potentially aiding the immune response against SARS-CoV-2. Ivermectin may also enhance antiviral immunity by modulating host cell processes and suppressing inflammatory pathways, potentially reducing the severity of cytokine storms in severe COVID-19 cases. Another mechanism involves ivermectin binding to viral RNA-dependent RNA polymerase, possibly inhibiting viral replication directly. Additionally, it might destabilize viral particles by influencing host cellular proteins.

A study conducted by Plasek et al. investigated various adjuvant and treatment options for COVID-19 patients[71]. Their findings revealed that prophylactic-dose anticoagulation treatment was beneficial compared to full-dose anticoagulation. Vitamin D supplementation, however, did not show any appreciable advantages in terms of lowering hospital mortality. Furthermore, analysis showed that neither Isoprinosine nor ivermectin significantly reduced hospital mortality. Studies have also investigated other drugs such as niclosamide, an antiparasitic medication, which displayed promising anti-inflammatory properties in inflammatory airway diseases like cystic fibrosis, COVID-19, and asthma^[72,73]. In experiments with mouse models, niclosamide demonstrated a reduction in eosinophilic infiltration, mucus content, and cell death[72]. Furthermore, in vitro studies revealed that niclosamide inhibited interleukin release in airway epithelial cell lines. These beneficial effects were associated with niclosamide’ s ability to inhibit the Ca²⁺-activated Cl⁻ channels ANO1 and ANO6, as well as reduce intracellular Ca²⁺ levels^[74,75]. Ivermectin, on the other hand, did not show comparable results, indicating that niclosamide may be useful in treating inflammatory airway disorders in addition to its well-known antiviral properties.

The rationale behind the COVID-19 pandemic ivermectin use has been clarified by a number of studies. According to these research, ivermectin was taken as a preventative by more than half of the individuals[76]. In Chincha, regional leaders endorsed ivermectin as prophylactic therapy despite the absence of scientific evidence, citing its reported plasma half-life of 12–66 hours[64]. However, another study found that ivermectin did not significantly prevent hospitalizations in COVID-19 patients[20]. Conversely, around two-thirds of the participants who used ivermectin did so to alleviate COVID-19 symptoms, despite the lack of conclusive clinical evidence supporting its efficacy^[18,77]. These techniques may have created a false sense of security among the Chincha community, perhaps contributing to increased COVID-19 transmission and hospitalizations.

The field of infectious disease management, including COVID-19, has been profoundly influenced by recent breakthroughs in vaccine technology and therapeutic approaches. The rapid development and efficacy of mRNA vaccines have revolutionized pandemic response strategies, demonstrating their potential applicability to various infectious diseases[78]. Concurrently, novel techniques such as nano-vaccines show promise in enhancing vaccine effectiveness, offering superior immune responses with reduced side effects[79]. Comprehensive COVID-19 treatment and prevention strategies necessitate a thorough understanding of both humoral and cellular immune components, as recent findings underscore their distinct yet complementary roles in protective immunity[80]. The immunomodulatory impact of vitamin D on COVID-19 patients further emphasizes the importance of investigating supplementary therapies to support vaccine and drug-based interventions[81]. MicroRNAs have also emerged as potential therapeutic targets, providing new perspectives on leveraging molecular biology to combat COVID-19 and other viral infections[82]. However, treatments like convalescent plasma therapy require careful evaluation, particularly given the emergence of SARS-CoV-2 variants that may affect therapeutic efficacy and increase associated risks[83]. Additionally, the wider implications of zoonotic diseases in a changing climate highlight the need for a multidisciplinary approach to infectious disease control, taking into account both environmental and biological factors[84]. These evolving insights underscore the dynamic nature of COVID-19 treatment and prevention, emphasizing the crucial role of ongoing research in refining therapeutic and public health strategies.

The limitations of our study include a limited number of RCTs. Further trials of high quality with varied dosages are necessary to enhance the robustness of our findings. Additionally, more RCTs with longer follow-up durations are required, as our study only involved follow-up data up to 1 year. Another limitation is the lack of dosage analysis in our study due to an insufficient number of trials available for analysis. Future studies should prioritize investigating different dosages, as dosage not only affects the efficacy but also the safety of the drug. Presently, studies have predominantly focused on the efficacy of drugs without adequately reporting appropriate trials.

The strengths of our study are multifaceted. First, we have incorporated literature up to 2024, ensuring that our analysis encompasses the most recent research developments in the field. Additionally, we have included a wide range of outcome variables, mitigating the biases and limitations present in previous systematic reviews. By including diverse outcome measures, we provide a comprehensive understanding of the effects of the interventions under consideration. Moreover, our utilization of meta-regression analysis enables us to dissect the data further and identify variables that independently affect the outcomes, irrespective of the interventions employed. This approach is crucial for future studies as it facilitates the control of these variables when drawing conclusions and making recommendations. Overall, the comprehensive nature of our study and the rigorous analytical techniques employed enhance the validity and applicability of our findings in informing clinical practice and guiding future research endeavors.

This meta-analysis offers crucial insights for public health in the search for effective COVID-19 treatments. Although ivermectin alleviated symptoms, it did not significantly improve critical clinical outcomes like mortality, ICU admissions, or ventilator use. Thus, ivermectin may help manage mild cases but is not suitable as a primary treatment for severe COVID-19. The findings highlight the necessity for careful use and the importance of prioritizing proven interventions, such as vaccines and antiviral drugs, in public health strategies.

These findings support public health policies promoting ongoing evaluation of repurposed medications through extensive RCTs to better assess their effectiveness and safety. Considering the potential for misinformation about treatments like ivermectin, it is essential for public health authorities to deliver clear, evidence-based guidelines to ensure health-care providers and the public access accurate, current information. The study underscores the need for a balanced approach that combines accessible treatments with established public health measures to tackle the ongoing COVID-19 challenges. This meta-analysis emphasizes the critical need for extensive, high-quality RCTs to verify ivermectin’s efficacy in COVID-19 treatment. The current analysis included studies with limitations such as small participant numbers, varied treatment approaches, and diverse patient groups, potentially affecting result reliability. Future studies should focus on robust research methods, incorporating well-defined participant selection criteria, consistent dosing protocols, and precise outcome assessments. Additionally, large-scale RCTs are necessary to minimize biases present in observational studies and smaller trials, allowing accurate identification of ivermectin’s potential benefits and risks. These investigations should include diverse populations across different regions to account for variations in health-care systems, COVID-19 variants, and treatment availability. By adhering to stringent research principles, upcoming trials can provide more conclusive evidence regarding ivermectin’s efficacy in treating COVID-19, ultimately informing public health strategies and clinical practices with greater certainty.

Conclusion

To sum up, our comprehensive evaluation and meta-analysis offer significant understanding about the application of ivermectin for COVID-19 patients, incorporating data up to April 2024. Despite the extensive vaccination efforts, COVID-19 remains a significant global health challenge, necessitating effective treatment options. Our analysis included 33 studies involving 15,376 participants across various countries, covering a wide range of outcomes such as PCR negative conversion all-cause mortality, AEs and mechanical ventilation requirement. While ivermectin showed significant benefits in symptom alleviation and sustained symptom relief, it did not significantly affect other key clinical outcomes such as mortality, mechanical ventilation requirement, or hospitalization rates. Our study’s strengths lie in its incorporation of recent literature, comprehensive inclusion of outcome variables, and utilization of meta-regression analysis to identify independent predictors of outcomes. However, limitations include the need for more high-quality trials with varied dosages and longer follow-up durations. Overall, our findings contribute to the ongoing efforts to identify effective treatments for COVID-19 and inform future research and clinical practice.

Ethical approval

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Consent

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Sources of funding

The authors received no extramural funding for the study.

Author contribution

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Conflicts of interest disclosure

The authors declare no potential conflicts of interest concerning the research, authorship, and/or publication of this article.

Research registration unique identifying number (UIN)

PROSPERO (CRD42024555182).

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All authors take responsibility for the work, access to data and decision to publish.

Availability of data and materials

Data available within the article. The authors confirm that the data supporting the findings of this study are available within the article.

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