The association between the use of ivermectin and mortality in patients with COVID-19: a meta-analysis

Kow, Chia Siang; Merchant, Hamid A.; Mustafa, Zia Ul; Hasan, Syed Shahzad

doi:10.1007/s43440-021-00245-z

Cited by 37 publications

(48 citation statements)

References 13 publications

(20 reference statements)

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“…High-quality RCTs and systematic reviews are necessary to evaluate efficacy of IVM in COVID-19.Threesystematic reviews on the effect of IVM on clinical outcomes were published [11][12][13]. Padhy et al only included three small observational studies [11].…”

Section: Introductionmentioning

confidence: 99%

“…Siemieniuk et al conducted a living systematic review of all treatments for COVID-19, but details were scarce and quality of evidence was very low [12]. Finally, Kow et al evaluated six RCTs, five of them from Asia and none from Latin America [13]. In addition to published studies, other systematic reviews or narrative reviews of the effects of IVM have been only disseminated as pre-prints [14][15][16] or only presented on websites [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials

Roman

Burela

Pasupuleti³

et al. 2021

Preprint

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Background: We systematically assessed benefits and harms of the use of ivermectin (IVM) in COVID-19 patients. Methods: Published and preprint randomized controlled trials (RCTs) assessing IVM effects on COVID-19 adult patients were searched until March 15, 2021 in five engines. Primary outcomes were all-cause mortality, length of stay (LOS), and adverse events (AE). Secondary outcomes included viral clearance and severe AEs. We evaluated risk of bias (RoB) using the Cochrane RoB 2.0 tool. Inverse variance random effect meta-analyses were performed with quality of evidence (QoE) evaluated using GRADE methodology. Subgroup analyses by severity of disease and RoB, and sensitivity analyses by time of follow-up were conducted. Results: Ten RCTs (n=1173) were included. Controls were standard of care [SOC] in five RCTs and placebo in five RCTs. RCTs sample size ranged from 24 to 398 patients, mean age from 26 to 56 years-old, and severity of COVID-19 disease was mild in 8 RCTs, moderate in one RCT, and mild and moderate in one RCT. IVM did not reduce all-cause mortality vs. controls (RR 1.11, 95%CI 0.16-7.65, very low QoE). IVM did not reduce LOS vs. controls (MD 0.72 days, 95%CI -0.86 to 2.29, very low QoE). AEs, severe AE and viral clearance were similar between IVM and controls (low QoE for these three outcomes). Subgroup analyses by severity of COVID-19 disease or RoB were consistent with main analyses. Sensitivity analyses excluding RCTs with follow up <21 days showed no difference in all-cause mortality but diminished heterogeneity (I2=0%). Conclusions: In comparison to SOC or placebo, IVM did not reduce all-cause mortality, length of stay or viral clearance in RCTs in COVID-19 patients with mostly mild disease. IVM did not have effect on AEs or SAEs. IVM is not a viable option to treat COVID-19 patients.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials

Roman

Burela

Pasupuleti³

et al. 2021

Preprint

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“…These theoretical predictions could guide the possibility of deriving formulations or analogues that can be administered to achieve relevant therapeutic concentrations, as it has been suggested necessary to do in the particular case of ivermectin [5] , [69] . It is important to say that these predictions based on theoretical models are not without interest as they show the possible structural distortion that ivermectin homologues induce in both cellular and viral sites, which in some way may be a reflection of the remarkable and controversial clinical benefits noted very recently by different groups worldwide [70] , [71] . The novel approach of ENM-based models showed a possible multidirectional activity of ivermectin, and an orientation towards cellular structures (AVM-B1a), and also towards viral proteins (AVM-B1b) associated with COVID-19, because homologues can generate changes at the distribution level of the initial quasi-rigid regions in this proteins, what could affect biological activity.…”

Section: Resultsmentioning

confidence: 99%

Structural deformability induced in proteins of potential interest associated with COVID-19 by binding of homologues present in ivermectin: Comparative study based in elastic networks models

González

Hurtado-León

Lossada

et al. 2021

Journal of Molecular Liquids

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The COVID-19 pandemic has accelerated the study of the potential of multi-target drugs (MTDs). The mixture of homologues called ivermectin (avermectin-B1a + avermectin-B1b) has been shown to be a MTD with potential antiviral activity against SARS-CoV-2 in vitro . However, there are few reports on the effect of each homologue on the flexibility and stiffness of proteins associated with COVID-19, described as ivermectin targets. We observed that each homologue was stably bound to identified proteinsthe proteins studied and were able to induce detectable changes with Elastic Network Models (ENMs). The perturbations induced by each homologue were characteristic of each compound and, in turn, were represented by a disruption of native intramolecular networks (interactions between residues). The homologues were able to slightly modify the conformation and stability of the connection points between the Cα atoms of the residues that make up the structural network of proteins (nodes), compared to free proteins. Each homologue was able to modified differently the distribution of quasi-rigid regions of the proteins, which could theoretically alter their biological activities. These results could provide a biophysical-computational view of the potential MTD mechanism that has been reported for ivermectin.

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“…Ivermectin has an in vitro anti-COVID-19 effect 3 and also certain clinical trials suggested a beneficial effect of ivermectin on COVID-19 disease outcome 4 . However, in a recent small double blind, randomized control trial in Colombia, five days of ivermectin, at a 10 times the recommended dose, did not reduce the duration of symptoms of mild COVID-19 disease compared to placebo 5 .…”

mentioning

confidence: 99%

“…La ivermectina tiene un efecto anti-COVID-19 in vitro 3 y también ciertos ensayos clínicos sugirieron un efecto beneficioso de la ivermectina sobre el resultado de la enfermedad COVID-19 4 . Sin embargo, en un reciente ensayo controlado aleatorizado, doble ciego, realizado en Colombia, cinco días de ivermectina, a una dosis 10 veces mayor que la recomendada, no redujo la duración de los síntomas de la enfermedad leve COVID-19 en comparación con el placebo 5 .…”

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COVID-19: The African Enigma

Colebunders

2021

Colomb Med

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To the editor Related article: https://colombiamedica.univalle.edu.co/...iew/4613 We read with interest the paper by Guerrero et al “COVID-19: The Ivermectin African Enigma” . In an ecological study they compared COVID-19 related mortality and infection rates between APOC (African Programme for Onchocerciasis Control) and non-APOC countries. After adjusting for Human Development Index (HDI) and number of performed test, COVID-19 mortality and infection rate were respectively 28% and 8% lower in non-APOC countries compared to APOC countries. The authors suggested that this difference may be related to the community directed treatment with ivermectin (CDTI) programs established in APOC countries. We agree that it remains to be explained why a lower COVID-19 mortality is observed in many APOC countries compared to other parts of the world. However, we do not believe that this is related to CDTI programs. Indeed, in APOC countries ivermectin is distributed only once (most countries) or twice a year 2. Moreover, April 1st 2020, because of the COVID-19 pandemic, CDTI programs were interrupted and were only recently restarted. Ivermectin has an in vitro anti-COVID-19 effect and also certain clinical trials suggested a beneficial effect of ivermectin on COVID-19 disease outcome. However, in a recent small double blind, randomized control trial in Colombia, five days of ivermectin, at a 10 times the recommended dose, did not reduce the duration of symptoms of mild COVID-19 disease compared to placebo. Given the half-life of ivermectin, approximately 18h, it is unlikely that CDTI, only one dose of ivermectin once or twice a year, may be able to reduce COVID-19 related mortality. Many factors could explain the lower COVID-19 mortality in APOC countries. One of them could be exposure to parasitic infections and the immune response induced by these infections. For example, for P. falciparum, a parasitic infection highly prevalent in APOC countries, it has been hypothesised that the immunological memory against P. falciparum merozoites primes SARS-CoV-2 infected cells for early phagocytosis and therefore may protect persons with a recent P. falciparum infection against severe COVID-19 disease. Helminth infections, such as onchocerciasis, may down regulate immune responses and potentially inactivate the inflammatory signalling pathways that may induce acute respiratory distress syndrome (ARDS), one of the causes of death in COVID-19 infected persons

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The association between the use of ivermectin and mortality in patients with COVID-19: a meta-analysis

Cited by 37 publications

References 13 publications

Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials

Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials

Structural deformability induced in proteins of potential interest associated with COVID-19 by binding of homologues present in ivermectin: Comparative study based in elastic networks models

COVID-19: The African Enigma

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