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1.
Cad Saude Publica ; 38(7): e00001022, 2022.
Article in English | MEDLINE | ID: covidwho-1963142

ABSTRACT

Off-label use of azithromycin, hydroxychloroquine, and ivermectin (the "COVID kit") has been suggested for COVID-19 treatment in Brazil without clinical or scientific evidence of efficacy. These drugs have known adverse drug reactions (ADR). This study aimed to analyze if the sales of drugs in the "COVID kit" are correlated to the reported number of ADR after the COVID-19 pandemic began. Data was obtained from the Brazilian Health Regulatory Agency (Anvisa) website on reported sales and ADRs for azithromycin, hydroxychloroquine, and ivermectin for all Brazilian states. The period from March 2019 to February 2020 (before the pandemic) was compared to that from March 2020 to February 2021 (during the pandemic). Trend adjustment was performed for time series data and cross-correlation analysis to investigate correlation between sales and ADR within the same month (lag 0) and in the following months (lag 1 and lag 2). Spearman's correlation coefficient was used to assess the magnitude of the correlations. After the pandemic onset, sales of all investigated drugs increased significantly (69.75% for azithromycin, 10,856,481.39% for hydroxychloroquine, and 12,291,129.32% for ivermectin). ADR levels of all medications but azithromycin were zero before the pandemic, but increased after its onset. Cross-correlation analysis was significant in lag 1 for all drugs nationwide. Spearman's correlation was moderate for azithromycin and hydroxychloroquine but absent for ivermectin. Data must be interpreted cautiously since no active search for ADR was performed. Our results show that the increased and indiscriminate use of "COVID kit" during the pandemic correlates to an increased occurrence of ADRs.


Subject(s)
COVID-19 , Coronavirus Infections , Drug-Related Side Effects and Adverse Reactions , Pneumonia, Viral , Azithromycin/adverse effects , Brazil/epidemiology , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Drug-Related Side Effects and Adverse Reactions/epidemiology , Humans , Hydroxychloroquine/adverse effects , Ivermectin/adverse effects , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology
2.
Cochrane Database Syst Rev ; 6: CD015017, 2022 06 21.
Article in English | MEDLINE | ID: covidwho-1898514

ABSTRACT

BACKGROUND: Ivermectin, an antiparasitic agent, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in early stages of infection. Currently, evidence on ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. OBJECTIVES: To assess the efficacy and safety of ivermectin plus standard of care compared to standard of care plus/minus placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), WHO COVID-19 Global literature on coronavirus disease, and HTA database weekly to identify completed and ongoing trials without language restrictions to 16 December 2021. Additionally, we included trials with > 1000 participants up to April 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing ivermectin to standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity or treatment setting, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms.  For this review update, we reappraised eligible trials for research integrity: only RCTs prospectively registered in a trial registry according to WHO guidelines for clinical trial registration were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We assessed RCTs for bias, using the Cochrane RoB 2 tool. We used GRADE to rate the certainty of evidence for outcomes in the following settings and populations: 1) to treat inpatients with moderate-to-severe COVID-19, 2) to treat outpatients with mild COVID-19 (outcomes: mortality, clinical worsening or improvement, (serious) adverse events, quality of life, and viral clearance), and 3) to prevent SARS-CoV-2 infection (outcomes: SARS-CoV-2 infection, development of COVID-19 symptoms, admission to hospital, mortality, adverse events and quality of life). MAIN RESULTS: We excluded seven of the 14 trials included in the previous review version; six were not prospectively registered and one was non-randomized. This updated review includes 11 trials with 3409 participants investigating ivermectin plus standard of care compared to standard of care plus/minus placebo. No trial investigated ivermectin for prevention of infection or compared ivermectin to an intervention with proven efficacy. Five trials treated participants with moderate COVID-19 (inpatient settings); six treated mild COVID-19 (outpatient settings). Eight trials were double-blind and placebo-controlled, and three were open-label. We assessed around 50% of the trial results as low risk of bias. We identified 31 ongoing trials. In addition, there are 28 potentially eligible trials without publication of results, or with disparities in the reporting of the methods and results, held in 'awaiting classification' until the trial authors clarify questions upon request. Ivermectin for treating COVID-19 in inpatient settings with moderate-to-severe disease We are uncertain whether ivermectin plus standard of care compared to standard of care plus/minus placebo reduces or increases all-cause mortality at 28 days (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 3 trials, 230 participants; very low-certainty evidence); or clinical worsening, assessed by participants with new need for invasive mechanical ventilation or death at day 28 (RR 0.82, 95% CI 0.33 to 2.04; 2 trials, 118 participants; very low-certainty evidence); or serious adverse events during the trial period (RR 1.55, 95% CI 0.07 to 35.89; 2 trials, 197 participants; very low-certainty evidence). Ivermectin plus standard of care compared to standard of care plus placebo may have little or no effect on clinical improvement, assessed by the number of participants discharged alive at day 28 (RR 1.03, 95% CI 0.78 to 1.35; 1 trial, 73 participants; low-certainty evidence); on any adverse events during the trial period (RR 1.04, 95% CI 0.61 to 1.79; 3 trials, 228 participants; low-certainty evidence); and on viral clearance at 7 days (RR 1.12, 95% CI 0.80 to 1.58; 3 trials, 231 participants; low-certainty evidence). No trial investigated quality of life at any time point. Ivermectin for treating COVID-19 in outpatient settings with asymptomatic or mild disease Ivermectin plus standard of care compared to standard of care plus/minus placebo probably has little or no effect on all-cause mortality at day 28 (RR 0.77, 95% CI 0.47 to 1.25; 6 trials, 2860 participants; moderate-certainty evidence) and little or no effect on quality of life, measured with the PROMIS Global-10 scale (physical component mean difference (MD) 0.00, 95% CI -0.98 to 0.98; and mental component MD 0.00, 95% CI -1.08 to 1.08; 1358 participants; high-certainty evidence). Ivermectin may have little or no effect on clinical worsening, assessed by admission to hospital or death within 28 days (RR 1.09, 95% CI 0.20 to 6.02; 2 trials, 590 participants; low-certainty evidence); on clinical improvement, assessed by the number of participants with all initial symptoms resolved up to 14 days (RR 0.90, 95% CI 0.60 to 1.36; 2 trials, 478 participants; low-certainty evidence); on serious adverse events (RR 2.27, 95% CI 0.62 to 8.31; 5 trials, 1502 participants; low-certainty evidence); on any adverse events during the trial period (RR 1.24, 95% CI 0.87 to 1.76; 5 trials, 1502 participants; low-certainty evidence); and on viral clearance at day 7 compared to placebo (RR 1.01, 95% CI 0.69 to 1.48; 2 trials, 331 participants; low-certainty evidence). None of the trials reporting duration of symptoms were eligible for meta-analysis. AUTHORS' CONCLUSIONS: For outpatients, there is currently low- to high-certainty evidence that ivermectin has no beneficial effect for people with COVID-19. Based on the very low-certainty evidence for inpatients, we are still uncertain whether ivermectin prevents death or clinical worsening or increases serious adverse events, while there is low-certainty evidence that it has no beneficial effect regarding clinical improvement, viral clearance and adverse events. No evidence is available on ivermectin to prevent SARS-CoV-2 infection. In this update, certainty of evidence increased through higher quality trials including more participants. According to this review's living approach, we will continually update our search.


Subject(s)
COVID-19 , Humans , Ivermectin/adverse effects , Randomized Controlled Trials as Topic , Respiration, Artificial , SARS-CoV-2 , Severity of Illness Index
3.
J Dermatol ; 49(8): 769-774, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1816488

ABSTRACT

Despite poor evidence, the antiparasitic ivermectin has been advocated as a potential COVID-19 therapy. This has led to a rise in calls to poison-control centers by people self-medicating with ivermectin, which is sold over the counter for veterinary uses. We aimed to investigate the association between severe cutaneous adverse reactions (SCARs) and ivermectin. Postmarketing data from the FDA Adverse Event Reporting System (FAERS), gathered between 2014 and 2021, was employed to detect disproportional signals of SCARs following systemic ivermectin therapy. The reporting odds ratio (ROR) was used to quantify the strength of association, while adjusting for age, sex, and region. The search yielded 517 reports of systemic ivermectin (median age 54 years, 46.8% female), of which 25 (4.8%), 81 (15.7%), and 411 (79.5%) were classified as SCARs, nonsevere cutaneous adverse events (AEs), or noncutaneous AEs, respectively. The regional distribution differed between SCAR reports (32.0% from Africa and 12.0% from North America) compared with other AEs, which originated from North America in over half of cases. The most common SCARs were toxic epidermal necrolysis (seven cases), Stevens-Johnson syndrome (seven cases), and drug reaction with eosinophilia and systemic symptoms (four cases). Five SCAR cases (20.0%) resulted in death and 12 (48.0%) lead to hospitalization. There was a strong safety signal for any SCAR (adjusted ROR 3.34, 95% confidence interval [CI] 2.17-5.12) and toxidermias (adjusted ROR 7.08, 95% CI 4.23-11.84). This study suggests that ivermectin is associated with SCARs on rare occasions. Dermatologists should be aware of this given the increase in ivermectin misuse.


Subject(s)
COVID-19 , Stevens-Johnson Syndrome , Cicatrix , Female , Humans , Ivermectin/adverse effects , Male , Middle Aged , Pharmacovigilance
4.
N Engl J Med ; 386(18): 1721-1731, 2022 05 05.
Article in English | MEDLINE | ID: covidwho-1768965

ABSTRACT

BACKGROUND: The efficacy of ivermectin in preventing hospitalization or extended observation in an emergency setting among outpatients with acutely symptomatic coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unclear. METHODS: We conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2-positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 µg per kilogram of body weight) once daily for 3 days or placebo. (The trial also involved other interventions that are not reported here.) The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization. RESULTS: A total of 3515 patients were randomly assigned to receive ivermectin (679 patients), placebo (679), or another intervention (2157). Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16). Of the 211 primary-outcome events, 171 (81.0%) were hospital admissions. Findings were similar to the primary analysis in a modified intention-to-treat analysis that included only patients who received at least one dose of ivermectin or placebo (relative risk, 0.89; 95% Bayesian credible interval, 0.69 to 1.15) and in a per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen (relative risk, 0.94; 95% Bayesian credible interval, 0.67 to 1.35). There were no significant effects of ivermectin use on secondary outcomes or adverse events. CONCLUSIONS: Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19. (Funded by FastGrants and the Rainwater Charitable Foundation; TOGETHER ClinicalTrials.gov number, NCT04727424.).


Subject(s)
Anti-Infective Agents , COVID-19 , Ivermectin , Adult , Ambulatory Care , Anti-Infective Agents/adverse effects , Anti-Infective Agents/therapeutic use , Bayes Theorem , COVID-19/drug therapy , Double-Blind Method , Hospitalization , Humans , Ivermectin/adverse effects , Ivermectin/therapeutic use , SARS-CoV-2 , Treatment Outcome
5.
Clin Infect Dis ; 74(6): 1022-1029, 2022 03 23.
Article in English | MEDLINE | ID: covidwho-1701751

ABSTRACT

BACKGROUND: We systematically assessed benefits and harms of the use of ivermectin (IVM) in patients with coronavirus disease 2019 (COVID-19). METHODS: Published and preprint randomized controlled trials (RCTs) assessing the effects of IVM on adult patients with COVID-19 were searched until 22 March 2021 in 5 engines. Primary outcomes were all-cause mortality rate, length of hospital stay (LOS), and adverse events (AEs). Secondary outcomes included viral clearance and severe AEs (SAEs). The risk of bias (RoB) was evaluated using the Cochrane Risk of Bias 2.0 tool. Inverse variance random effect meta-analyses were performed, with quality of evidence (QoE) evaluated using GRADE methods. RESULTS: Ten RCTs (n = 1173) were included. The controls were the standard of care in 5 RCTs and placebo in 5. COVID-19 disease severity was mild in 8 RCTs, moderate in 1, and mild and moderate in 1. IVM did not reduce all-cause mortality rates compared with controls (relative risk [RR], 0.37 [95% confidence interval, .12-1.13]; very low QoE) or LOS compared with controls (mean difference, 0.72 days [95% confidence interval, -.86 to 2.29 days]; very low QoE). AEs, SAEs, and viral clearance were similar between IVM and control groups (low QoE for all outcomes). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality rates in 3 RCTs at high RoB were reduced with IVM. CONCLUSIONS: Compared with the standard of care or placebo, IVM did not reduce all-cause mortality, LOS, or viral clearance in RCTs in patients with mostly mild COVID-19. IVM did not have an effect on AEs or SAEs and is not a viable option to treat patients with COVID-19.


Subject(s)
COVID-19 , Adult , COVID-19/drug therapy , Humans , Immunization, Passive/adverse effects , Immunization, Passive/methods , Ivermectin/adverse effects , Randomized Controlled Trials as Topic , Respiration, Artificial
6.
JAMA Intern Med ; 182(4): 426-435, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1704290

ABSTRACT

Importance: Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19. Evidence-based data to recommend either for or against the use of ivermectin are needed. Objective: To determine the efficacy of ivermectin in preventing progression to severe disease among high-risk patients with COVID-19. Design, Setting, and Participants: The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was an open-label randomized clinical trial conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. Within the first week of patients' symptom onset, the study enrolled patients 50 years and older with laboratory-confirmed COVID-19, comorbidities, and mild to moderate disease. Interventions: Patients were randomized in a 1:1 ratio to receive either oral ivermectin, 0.4 mg/kg body weight daily for 5 days, plus standard of care (n = 241) or standard of care alone (n = 249). The standard of care consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging. Main Outcomes and Measures: The primary outcome was the proportion of patients who progressed to severe disease, defined as the hypoxic stage requiring supplemental oxygen to maintain pulse oximetry oxygen saturation of 95% or higher. Secondary outcomes of the trial included the rates of mechanical ventilation, intensive care unit admission, 28-day in-hospital mortality, and adverse events. Results: Among 490 patients included in the primary analysis (mean [SD] age, 62.5 [8.7] years; 267 women [54.5%]), 52 of 241 patients (21.6%) in the ivermectin group and 43 of 249 patients (17.3%) in the control group progressed to severe disease (relative risk [RR], 1.25; 95% CI, 0.87-1.80; P = .25). For all prespecified secondary outcomes, there were no significant differences between groups. Mechanical ventilation occurred in 4 (1.7%) vs 10 (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17), intensive care unit admission in 6 (2.4%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79), and 28-day in-hospital death in 3 (1.2%) vs 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09). The most common adverse event reported was diarrhea (14 [5.8%] in the ivermectin group and 4 [1.6%] in the control group). Conclusions and Relevance: In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04920942.


Subject(s)
COVID-19 , Ivermectin , Adult , Disease Progression , Female , Hospital Mortality , Humans , Ivermectin/adverse effects , Ivermectin/therapeutic use , Middle Aged , SARS-CoV-2 , Treatment Outcome
7.
Ther Innov Regul Sci ; 56(3): 382-385, 2022 05.
Article in English | MEDLINE | ID: covidwho-1682774

ABSTRACT

In treatment or prevention of COVID-19, ivermectin is not approved by the United States (US) Food and Drug Administration (FDA). Nonetheless, in the US, prescriptions of ivermectin by healthcare providers have increased > tenfold from 3589 per week pre-COVID-19 to 39,102. Ivermectin is FDA approved for animals to treat parasites and for humans to treat intestinal strongyloidiasis and onchocerciasis orally, and ectoparasites and skin conditions topically. It is not a benign drug, with reported side effects including cutaneous, gastrointestinal, and cardiovascular symptoms. The evidence to support ivermectin to treat or prevent COVID-19 includes some basic research and inconsistent clinical observations that contribute to the formulation of a hypothesis of efficacy in COVID-19. At present, data from peer-reviewed published randomized trials of sufficient size, dose, and duration to reliably test the hypothesis of the most plausible small to moderate benefits on clinically relevant endpoints are sparse. In addition to the US FDA, the US National Institutes of Health, World Health Organization, and European Medicines Agency have all advised against ivermectin for treatment or prevention of COVID-19 outside of randomized trials. For ivermectin in treatment or prevention of COVID-19, healthcare providers should reassure all patients that if sufficient evidence were to emerge, then this drug could be considered a therapeutic innovation and regulatory authorities would approve the drug. In the meanwhile, we strongly recommend a moratorium on the prescription of ivermectin for the treatment or prevention of COVID-19 except in randomized trials to provide the most reliable test of the hypothesis.


Subject(s)
COVID-19 , Ivermectin , Animals , COVID-19/drug therapy , Humans , Ivermectin/adverse effects , Ivermectin/therapeutic use , Prescriptions , SARS-CoV-2
8.
Eur J Med Res ; 27(1): 21, 2022 Feb 05.
Article in English | MEDLINE | ID: covidwho-1666676

ABSTRACT

The global COVID-19 pandemic has affected the world's population by causing changes in behavior, such as social distancing, masking, restricting people's movement, and evaluating existing medication as potential therapies. Many pre-existing medications such as tocilizumab, ivermectin, colchicine, interferon, and steroids have been evaluated for being repurposed to use for the treatment of COVID-19. None of these agents have been effective except for steroids and, to a lesser degree, tocilizumab. Ivermectin has been one of the suggested repurposed medications which exhibit an in vitro inhibitory activity on SARS-CoV-2 replication. The most recommended dose of ivermectin for the treatment of COVID-19 is 150-200 µg/kg twice daily. As ivermectin adoption for COVID-19 increased, the Food and Drug Administration (FDA) issued a warning on its use during the pandemic. However, the drug remains of interest to clinicians and has shown some promise in observational studies. This narrative reviews the toxicological profile and some potential therapeutic effects of ivermectin. Based on the current dose recommendation, ivermectin appears to be safe with minimum side effects. However, serious questions remain about the effectiveness of this drug in the treatment of patients with COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Ivermectin/adverse effects , Ivermectin/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Clinical Trials as Topic , Humans , Ivermectin/administration & dosage , Ivermectin/pharmacokinetics , Pre-Exposure Prophylaxis/methods
9.
J Infect Chemother ; 28(4): 548-553, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1587254

ABSTRACT

INTRODUCTION: COVID-19 patients have been reported to have digestive symptoms with poor outcome. Ivermectin, an antiparasitic drug, has been used in COVID-19 patients. The objective of this study was to evaluate whether ivermectin has effects on gastrointestinal complications and ventilator-free days in ventilated patients with COVID-19. METHODS: COVID-19 patients who were mechanically ventilated in the ICU were included in this study. The ventilated patients who received ivermectin within 3 days after admission were assigned to the Ivermectin group, and the others were assigned to the Control group. Patients in the Ivermectin group received ivermectin 200 µg/kg via nasal tube. The incidence of gastrointestinal complications and ventilator-free days within 4 weeks from admission were evaluated as clinical outcomes using a propensity score with the inverse probability weighting method. RESULTS: We included 88 patients in this study, of whom 39 patients were classified into the Ivermectin group, and 49 patients were classified into the Control group. The hazard ratio for gastrointestinal complications in the Ivermectin group as compared with the Control group was 0.221 (95% confidence interval [CI], 0.057 to 0.855; p = 0.029) in a Cox proportional-hazard regression model. The odds ratio for ventilator-free days as compared with the Control group was 1.920 (95% CI, 1.076 to 3.425; p = 0.027) in a proportional odds logistic regression model. CONCLUSIONS: Ivermectin improved gastrointestinal complications and the number of ventilator-free days in severe COVID-19 patients undergoing mechanical ventilation. Prevention of gastrointestinal symptoms by SARS-Cov-2 might be associated with COVID-19 outcome.


Subject(s)
COVID-19 , Gastrointestinal Diseases , COVID-19/complications , COVID-19/drug therapy , Gastrointestinal Diseases/drug therapy , Humans , Ivermectin/adverse effects , Propensity Score , Respiration, Artificial , SARS-CoV-2
12.
S Afr Med J ; 111(10): 934-937, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1478412

ABSTRACT

Some clinicians prescribe ivermectin for COVID-19 despite a lack of support from any credible South African professional body. They argue that when faced by clinical urgency, weak signals of efficacy should trigger action if harm is unlikely. Several recent reviews found an apparent mortality benefit by including studies at high risk of bias and with active rather than placebo controls. If these studies are discounted, the pooled mortality effect is no longer statistically significant, and evidence of benefit is very weak. Relying on this evidence could cause clinical harm if used to justify vaccine hesitancy. Clinicians remain responsible for ensuring that guidance they follow is both legitimate and reliable. In the ivermectin debate, evidence-based medicine (EBM) principles have largely been ignored under the guise thatin a pandemic the 'rules are different', probably to the detriment of vulnerable patients and certainly to the detriment of the profession's image. Medical schools and professional interest groups are responsible for transforming EBM from a taught but seldom-used tool into a process of lifelong learning, promoting a consistent call for evidence-based and unconflicted debate integral to clinical practice.


Subject(s)
COVID-19/drug therapy , Ivermectin/administration & dosage , Practice Patterns, Physicians'/standards , /psychology , COVID-19 Vaccines/administration & dosage , Evidence-Based Medicine/standards , Humans , Ivermectin/adverse effects , Research Design , South Africa
14.
Curr Res Transl Med ; 69(4): 103309, 2021 10.
Article in English | MEDLINE | ID: covidwho-1459004

ABSTRACT

PURPOSE OF THE STUDY: Currently no treatment has been proven to be efficacious for patients with early symptoms of COVID-19. Although most patients present mild or moderate symptoms, up to 5-10% may have a poor disease progression, so there is an urgent need for effective drugs, which can be administered even before the onset of severe symptoms, i.e. when the course of the disease is modifiable. Recently, promising results of several studies on oral ivermectin have been published, which has prompted us to conduct the present review of the scientific literature. METHODS: A narrative review has been carried out, focusing on the following four main topics: a) short-term efficacy in the treatment of the disease, b) long-term efficacy in the treatment of patients with post-acute symptoms of COVID-19, c) efficacy in the prophylaxis of the disease, and c) safety of ivermectin. RESULTS: The reviewed literature suggests that there seems to be sufficient evidence about the safety of oral ivermectin, as well as the efficacy of the drug in the early-treatment and the prophylaxis of COVID-19. CONCLUSIONS: In the view of the available evidence, the Frontline COVID-19 Critical Care Alliance (FLCCC) recommends the use of oral ivermectin for both prophylaxis and early-treatment of COVID-19. Further well-designed studies should be conducted in order to explore the efficacy and safety of invermectin at low and high doses, following different dosing schedules, in both, the short and long-term treatment.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Ivermectin/therapeutic use , SARS-CoV-2/drug effects , Antiviral Agents/adverse effects , COVID-19/prevention & control , Case-Control Studies , Dose-Response Relationship, Drug , Humans , Ivermectin/administration & dosage , Ivermectin/adverse effects , Ivermectin/pharmacology , Meta-Analysis as Topic , Multicenter Studies as Topic , Practice Guidelines as Topic , Protein Transport/drug effects , RNA Viruses/drug effects , Randomized Controlled Trials as Topic , Time Factors , Treatment Outcome
15.
QJM ; 114(10): 721-732, 2021 Dec 20.
Article in English | MEDLINE | ID: covidwho-1440648

ABSTRACT

BACKGROUND: Ivermectin became a popular choice for COVID-19 treatment among clinicians and the public following encouraging results from pre-print trials and in vitro studies. Early reviews recommended the use of ivermectin based largely on non-peer-reviewed evidence, which may not be robust. This systematic review and meta-analysis assessed the efficacy and safety of ivermectin for treating COVID-19 based on peer-reviewed randomized controlled trials (RCTs) and observational studies (OSs). METHODS: MEDLINE, EMBASE and PubMed were searched from 1 January 2020 to 1 September 2021 for relevant studies. Outcomes included time to viral clearance, duration of hospitalization, mortality, incidence of mechanical ventilation and incidence of adverse events. RoB2 and ROBINS-I were used to assess risk of bias. Random-effects meta-analyses were conducted. GRADE was used to evaluate quality of evidence. RESULTS: Three OSs and 14 RCTs were included in the review. Most RCTs were rated as having some concerns in regards to risk of bias, while OSs were mainly rated as having a moderate risk of bias. Based on meta-analysis of RCTs, the use of ivermectin was not associated with reduction in time to viral clearance, duration of hospitalization, incidence of mortality and incidence of mechanical ventilation. Ivermectin did not significantly increase incidence of adverse events. Meta-analysis of OSs agrees with findings from RCT studies. CONCLUSIONS: Based on very low to moderate quality of evidence, ivermectin was not efficacious at managing COVID-19. Its safety profile permits its use in trial settings to further clarify its role in COVID-19 treatment. PROTOCOL REGISTRATION: The review was prospectively registered in PROSPERO (CRD42021275302).


Subject(s)
COVID-19 , Ivermectin , Hospitalization , Humans , Ivermectin/adverse effects , Observational Studies as Topic , Respiration, Artificial , SARS-CoV-2
16.
BMJ Open ; 11(9): e050532, 2021 09 17.
Article in English | MEDLINE | ID: covidwho-1416673

ABSTRACT

INTRODUCTION: Ivermectin is a drug with antiviral properties and has been proposed as an alternative treatment for patients with COVID-19, in some countries; however, there is limited evidence to support its clinical use. Accordingly, the aim of this review and meta-analysis is to obtain superior evidence on the effectiveness and safety of ivermectin in treatment of COVID-19. METHODS AND ANALYSIS: We will search in the medical databases and International Clinical Trials Registry Platform databases for randomised clinical trials and quasi-randomised trials published from December 2019. The criteria for inclusion are that infection needs to be confirmed by a real-time PCR or serology test, and the effect of ivermectin has been compared with placebo, symptomatic treatment or no treatment. We will exclude observational studies and clinical trials that involved patients with symptoms suggestive of COVID-19, but without a laboratorial diagnosis. Outcomes of interest include mortality, time to symptom resolution, time of hospitalisation, frequency of invasive mechanical ventilation and extracorporeal membrane oxygenation, incidence of severe acute respiratory syndrome, admission to intensive care unit, viral load, PCR-negative status, percentage of infection after prophylactic use, and total incidence of adverse and side effects. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two reviewers will independently select the studies and assess their eligibility. Two other reviewers will independently extract data from each study. Meta-analysis will then be carried out using fixed-effects or random-effects model, using the mean difference for continuous outcomes and the relative risk for dichotomous outcomes. Bias risk will be assessed using the Cochrane risk-of-bias tool. The quality of evidence for each outcome will be assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. Review Manager V.5.3.5 will be used for synthesis and subgroup analysis. ETHICS AND DISSEMINATION: Owing to the nature of the review, ethical approval is not required. The results will be disseminated through peer-reviewed publications. PROSPERO REGISTRATION NUMBER: CRD42020197395.


Subject(s)
COVID-19 , Ivermectin , Humans , Ivermectin/adverse effects , Meta-Analysis as Topic , Review Literature as Topic , SARS-CoV-2 , Systematic Reviews as Topic , Treatment Outcome
17.
Adv Respir Med ; 89(4): 413-418, 2021.
Article in English | MEDLINE | ID: covidwho-1399544

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected almost every country in the world since De-cember 2019. Despite the efforts of the human race to combat the virus, we are still looking for an evidence-based permanent cure for the disease. Ivermectin has recently emerged as one of the therapies having a beneficial effect on COVID-19. Ivermectin, owing to its properties, continues to be a possible treatment against the COVID-19 disease. Already being a mainstream drug with minimal adverse effects, it garners valid consideration. It's use in hospitalized patients, randomized controlled trials, and observational studies has also supported its implementation. In this article, we have reviewed recent studies and explored the effectiveness of ivermectin in hospitalized COVID-19 patients.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Ivermectin/therapeutic use , Antiviral Agents/adverse effects , COVID-19/therapy , Humans , Ivermectin/adverse effects , Length of Stay/statistics & numerical data
18.
Trials ; 22(1): 591, 2021 Sep 06.
Article in English | MEDLINE | ID: covidwho-1398875

ABSTRACT

OBJECTIVES: The study objective is to quantify the effectiveness of ivermectin (subcutaneous/oral IVM) in the presence or absence of zinc (Zn) for clinical and radiological improvement in coronavirus disease 2019 (COVID-19) patients with moderate severity. TRIAL DESIGN: This quadruple-blinded, placebo-controlled randomized clinical trial will be a multiarmed multi-centered study with superiority framework. PARTICIPANTS: Quinquagenarian and sexagenarian patients with moderate COVID-19 symptoms and positive severe respiratory syndrome coronavirus -2 (SARS-CoV-2) PCR will be included. Participants with co-morbidities and pregnant women will be excluded. Patient recruitment will be done in Shaikh Zayed Medical Complex, Doctors Lounge and Ali Clinic in Lahore (Pakistan). INTERVENTION AND COMPARATOR: The registered patients will be allocated in 6 groups (30 participants each). Patients will be taking subcutaneous IVM at 200 µg/kg/48 h (Arm A) or subcutaneous IVM at 200 µg/kg/48 h and oral Zn 20mg/8 h (Arm B) or oral IVM at 0.2 mg/kg/day (Arm C) or oral IVM at 0.2 mg/kg/day and oral Zn 20mg/8 h (Arm D) or alone oral Zn 20mg/8 h (Arm E) or placebo alone (Arm X). Patients in all arms will receive standard care and respective placebo (empty capsule 8 hourly and/or subcutaneous normal saline 2ml/48 h). MAIN OUTCOMES: Primary endpoints will be duration of symptomatic phase and SARS-CoV-2 clearance along with high resolution CT (HRCT) chest score and clinical grade scale (CGS) on day 6. 30-day mortality will be documented as a secondary endpoint. SARS-CoV-2 clearance will be calculated by second PCR on day 7. HRCT chest score will be measured by the percentage and lung lobes involvement on day 6 with a maximum score of 25. CGS will be recorded on a seven-point scale; grade 1 (not hospitalized, no evidence of infection and resumption of normal activities), grade 2 (not hospitalized, but unable to resume normal activities), grade 3 (hospitalized, not requiring supplemental oxygen), grade 4 (hospitalized, requiring supplemental oxygen), grade 5 (hospitalized, requiring nasal high-flow oxygen therapy and/or noninvasive mechanical ventilation), grade 6 (hospitalized, requiring ECMO and/or invasive mechanical ventilation) and grade 7 (death). RANDOMISATION: A simple lottery method will be used to randomly allocate scrutinized patients in 1:1:1:1:1:1 ratio in 6 groups. BLINDING (MASKING): Patients, primary care physicians, outcome assessors and the data collection team will be blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 180 participants will be randomized into six arms with five investigational and one placebo group. TRIAL STATUS: Institutional Review Board Shaikh Zayed Post-Graduate Medical Complex, Lahore, Pakistan has approved the protocol (version 2.3) with ID SZMC/IRB/Internal0056/2020. The trial was approved on July 14, 2020, and enrolment started on July 30, 2020. The estimated completion date is October 30, 2021. TRIAL REGISTRATION: Clinical Trial has been retrospectively registered on www.clinicaltrials.gov with registration ID NCT04472585 dated July 16, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). With the intention of expediting dissemination of this trial, the conventional formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.


Subject(s)
COVID-19 , Ivermectin , Female , Humans , Ivermectin/adverse effects , Multicenter Studies as Topic , Pregnancy , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome , Zinc/adverse effects
19.
Int Immunopharmacol ; 99: 108004, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1333527

ABSTRACT

INTRODUCTION: SARS-CoV-2 replication in cell cultures has been shown to be inhibited by ivermectin. However, ivermectin's low aqueous solubility and bioavailabilityhinders its application in COVID-19 treatment. Also, it has been suggested that best outcomes for this medication can be achieved via direct administration to the lung. OBJECTIVES: This study aimed at evaluating the safety of a novel ivermectin inhalable formulation in rats as a pre-clinical step. METHODS: Hydroxy propyl-ß-cyclodextrin(HP-ß-CD) was used to formulate readily soluble ivermectin lyophilized powder. Adult male rats were used to test lung toxicity for ivermectin-HP-ß-CD formulations in doses of 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg for 3 successive days. RESULTS: The X-ray diffraction for lyophilized ivermectin-HP-ß-CD revealed its amorphous structure that increased drug aqueous solubility 127-fold and was rapidly dissolved within 5 s in saline.Pulmonary administration of ivermectin-HP-ß-CD in dosesof 0.2, 0.4 and 0.8 mg/kgshowed dose-dependent increase in levels of TNF-α, IL-6, IL-13 and ICAM-1 as well as gene expression of MCP-1, protein expression of PIII-NP and serum levels of SP-D paralleled by reduction in IL-10. Moreover, lungs treated with ivermectin (0.2 mg/kg) revealed mild histopathological alterations, while severe pulmonary damage was seen in rats treated with ivermectin at doses of 0.4 and 0.8 mg/kg. However, ivermectin-HP-ß-CD formulation administered in doses of 0.05 and 0.1 mg/kg revealed safety profiles. CONCLUSION: The safety of inhaledivermectin-HP-ß-CD formulation is dose-dependent. Nevertheless, use of low doses(0.05 and 0.1 mg/kg) could be considered as a possible therapeutic regimen in COVID-19 cases.


Subject(s)
Ivermectin/adverse effects , Lung/metabolism , Animals , COVID-19/drug therapy , Cytokines/metabolism , Intercellular Adhesion Molecule-1/metabolism , Ivermectin/chemistry , Lung/pathology , Male , Rats , Rats, Inbred WF , Receptors, CCR2 , Solubility
20.
Cochrane Database Syst Rev ; 7: CD015017, 2021 07 28.
Article in English | MEDLINE | ID: covidwho-1328590

ABSTRACT

BACKGROUND: Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. OBJECTIVES: To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms.  We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy. DATA COLLECTION AND ANALYSIS: We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse events, mortality, admission to hospital, and quality of life. MAIN RESULTS: We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias.  Ivermectin doses and treatment duration varied among included studies.  We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies. Ivermectin compared to placebo or standard of care for inpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low-certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. Ivermectin compared to placebo or standard of care for outpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low-certainty evidence) or non-IMV or high flow oxygen requirement (0 participants required non-IMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days. Ivermectin compared to no treatment for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days. AUTHORS' CONCLUSIONS: 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 ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.


Subject(s)
Antiparasitic Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Ivermectin/therapeutic use , Antiparasitic Agents/adverse effects , Antiviral Agents/adverse effects , COVID-19/mortality , COVID-19/prevention & control , COVID-19/virology , Cause of Death , Humans , Ivermectin/adverse effects , Placebos/therapeutic use , Post-Exposure Prophylaxis , Randomized Controlled Trials as Topic , Respiration, Artificial/statistics & numerical data , SARS-CoV-2/drug effects , Time Factors , Treatment Outcome
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