Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

Krolewiecki, Alejandro; Lifschitz, Adrián; Moragas, Matías; Travacio, Marina; Valentini, Ricardo; Alonso, Daniel F.; Solari, Hernán G.; Tinelli, Marcelo A.; Cimino, Rubén O.; Álvarez, Luis Ignacio Ortega; Fleitas, Pedro Emanuel; Ceballos, Laura; Golemba, Marcelo Darío; Fernández, F. M. Vega; Oliveira, Diego Fernández de; Astudillo, Germán Osvaldo; Baeck, Inés; Farina, Javier; Cardama, Georgina Alexandra; Mangano, Andrea; Spitzer, Eduardo; Gold, Silvia; Lanusse, Carlos

doi:10.1016/j.eclinm.2021.100959

Cited by 76 publications

(83 citation statements)

References 33 publications

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“…Overall, 115 studies with 77,128 patients reported the number of patients requiring mechanical ventilation during the study period. We included ACEIs/ARBs, ammonium chloride, azithromycin, bamlanivimab, baricitinib plus remdesivir, bromhexine, budesonide, camostat mesilate, canakinumab, chloroquine, colchicine, convalescent plasma, dexamethasone, doxycycline, favipiravir, hydroxychloroquine, hydroxychloroquine plus azithromycin, hydroxychloroquine plus favipiravir, imatinib, INM005, interferon beta, intravenous immunoglobulin, ivermectin, lopinavir/ritonavir, methylprednisolone, recombinant human GCSF, remdesivir, sarilumab, sofosbuvir plus daclatasvir, sulodexide, tocilizumab, tofacitinib, vitamin D3 and SOC as treatment nodes in the NMA, for which observations came from 84 studies ( 3 , 6 , 22 – 26 , 28 – 31 , 35 , 42 , 43 , 46 , 47 , 50 , 53 , 55 , 57 – 61 , 63 , 64 , 66 , 67 , 71 , 73 – 77 , 79 , 80 , 82 , 83 , 85 – 87 , 89 , 92 – 94 , 96 – 100 , 102 , 105 – 107 , 109 , 111 – 118 , 120 – 124 , 126 , 128 – 132 , 134 , 135 , 139 , 140 , 145 , 151 , 152 , 154 – 156 ). About one-third (26/84) of the included studies were evaluated as low risk ( Supplementary Table 6 ).…”

Section: Resultsmentioning

confidence: 99%

Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

Zhang

Jin

Wen

et al. 2021

Front. Public Health

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Background: We provided a comprehensive evaluation of efficacy of available treatments for coronavirus disease 2019 (COVID-19).Methods: We searched for candidate COVID-19 studies in WHO COVID-19 Global Research Database up to August 19, 2021. Randomized controlled trials for suspected or confirmed COVID-19 patients published on peer-reviewed journals were included, regardless of demographic characteristics. Outcome measures included mortality, mechanical ventilation, hospital discharge and viral clearance. Bayesian network meta-analysis with fixed effects was conducted to estimate the effect sizes using posterior means and 95% equal-tailed credible intervals (CrIs). Odds ratio (OR) was used as the summary measure for treatment effect. Bayesian hierarchical models were used to estimate effect sizes of treatments grouped by the treatment classifications.Results: We identified 222 eligible studies with a total of 102,950 patients. Compared with the standard of care, imatinib, intravenous immunoglobulin and tocilizumab led to lower risk of death; baricitinib plus remdesivir, colchicine, dexamethasone, recombinant human granulocyte colony stimulating factor and tocilizumab indicated lower occurrence of mechanical ventilation; tofacitinib, sarilumab, remdesivir, tocilizumab and baricitinib plus remdesivir increased the hospital discharge rate; convalescent plasma, ivermectin, ivermectin plus doxycycline, hydroxychloroquine, nitazoxanide and proxalutamide resulted in better viral clearance. From the treatment class level, we found that the use of antineoplastic agents was associated with fewer mortality cases, immunostimulants could reduce the risk of mechanical ventilation and immunosuppressants led to higher discharge rates.Conclusions: This network meta-analysis identified superiority of several COVID-19 treatments over the standard of care in terms of mortality, mechanical ventilation, hospital discharge and viral clearance. Tocilizumab showed its superiority compared with SOC on preventing severe outcomes such as death and mechanical ventilation as well as increasing the discharge rate, which might be an appropriate treatment for patients with severe or mild/moderate illness. We also found the clinical efficacy of antineoplastic agents, immunostimulants and immunosuppressants with respect to the endpoints of mortality, mechanical ventilation and discharge, which provides valuable information for the discovery of potential COVID-19 treatments.

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Section: Resultsmentioning

confidence: 99%

Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

Zhang

Jin

Wen

et al. 2021

Front. Public Health

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“…Although no differences between treated and control patients were observed in SARS-CoV-2 viral load, a concentration-dependent antiviral activity was noticed after five days of IVM treatment. A relationship was identified between high IVM plasma concentrations (>160 ng/mL) and significant increases of SARS-CoV-2 viral decay rates in respiratory secretions [7].…”

Section: Introductionmentioning

confidence: 97%

“…However, a question remains whether these high concentrations can be effectively achieved clinically at safe doses. Recently, we reported the results of a proof-ofconcept randomized clinical trial in hospitalized COVID-19 patients receiving high oral doses of IVM (0.6 mg/kg/day) [7]. Although no differences between treated and control patients were observed in SARS-CoV-2 viral load, a concentration-dependent antiviral activity was noticed after five days of IVM treatment.…”

Section: Introductionmentioning

confidence: 99%

Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients

Segatori

Garona

Caligiuri

et al. 2021

Viruses

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Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations.

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“…However, one doubleblind randomized controlled trial found no significant difference in duration of symptoms (10 versus 12 days) in adults with mild COVID-19 treated with ivermectin versus placebo (Lopez-Medina et al, 2021). More recently, a randomized trial of hospitalized COVID-19 patients revealed that an oral highdose ivermectin regimen was well-tolerated and led to antiviral activity that was dependent on plasma concentration of the drug (Krolewiecki et al, 2021). A recent meta-analysis of 15 trials indicated moderate-certainty evidence that large reductions in COVID-19 mortality are possible with ivermectin treatment (versus control)early therapy may also decrease progression to severe disease (Bryant et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Combination Treatment With Remdesivir and Ivermectin Exerts Highly Synergistic and Potent Antiviral Activity Against Murine Coronavirus Infection

Tan

Chu

et al. 2021

Front. Cell. Infect. Microbiol.

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The recent COVID-19 pandemic has highlighted the urgency to develop effective antiviral therapies against the disease. Murine hepatitis virus (MHV) is a coronavirus that infects mice and shares some sequence identity to SARS-CoV-2. Both viruses belong to the Betacoronavirus genus, and MHV thus serves as a useful and safe surrogate model for SARS-CoV-2 infections. Clinical trials have indicated that remdesivir is a potentially promising antiviral drug against COVID-19. Using an in vitro model of MHV infection of RAW264.7 macrophages, the safety and efficacy of monotherapy of remdesivir, chloroquine, ivermectin, and doxycycline were investigated. Of the four drugs tested, remdesivir monotherapy exerted the strongest inhibition of live virus and viral RNA replication of about 2-log10 and 1-log10, respectively (at 6 µM). Ivermectin treatment showed the highest selectivity index. Combination drug therapy was also evaluated using remdesivir (6 µM) together with chloroquine (15 µM), ivermectin (2 µM) or doxycycline (15 µM) – above their IC50 values and at high macrophage cell viability of over 95%. The combination of remdesivir and ivermectin exhibited highly potent synergism by achieving significant reductions of about 7-log10 of live virus and 2.5-log10 of viral RNA in infected macrophages. This combination also resulted in the lowest cytokine levels of IL-6, TNF-α, and leukemia inhibitory factor. The next best synergistic combination was remdesivir with doxycycline, which decreased levels of live virus by ~3-log10 and viral RNA by ~1.5-log10. These results warrant further studies to explore the mechanisms of action of the combination therapy, as well as future in vivo experiments and clinical trials for the treatment of SARS-CoV-2 infection.

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Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

Cited by 76 publications

References 33 publications

Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients

Combination Treatment With Remdesivir and Ivermectin Exerts Highly Synergistic and Potent Antiviral Activity Against Murine Coronavirus Infection

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