Efficacy and safety of antiviral treatment for COVID-19 from evidence in studies of SARS-CoV-2 and other acute viral infections: a systematic review and meta-analysis

Liu, Wei; Zhou, Pengxiang; Chen, Ken; Ye, Zhikang; Liu, Fang; Li, Xiaotong; He, Na; Wu, Ziyang; Zhang, Qi; Gong, Xuepeng; Tang, Qiyu; Du, Xin; Ying, Yingqiu; Xu, Xiangyu; Zhang, Yahui; Liu, Jinyu; Li, Yun; Shen, Ning; Couban, Rachel; Ibrahim, Quazi; Guyatt, Gordon; Zhai, Suodi

doi:10.1503/cmaj.200647

Cited by 74 publications

(71 citation statements)

References 45 publications

(88 reference statements)

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“…Another cases serie collected in China confirm that half of patients suffered digestive adverse effect and 7/10 patients showed hypokalemia [ 68 , 69 ]. Two recent meta-analyses [ 74 , 75 ] evaluating efficacy and safety of the most frequently used therapies for COVID-19 show as most of the AEs rate were comparable across the intervention and control groups. Conversely, LPV/r alone showed trend to more diarrhea events, while the combination of LPV/r, ribavirin and corticosteroids reduced incidence of diarrhea significantly.…”

Section: Clinical Studiesmentioning

confidence: 99%

Lopinavir/ritonavir: Repurposing an old drug for HIV infection in COVID-19 treatment

et al. 2021

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Section: Clinical Studiesmentioning

confidence: 99%

Lopinavir/ritonavir: Repurposing an old drug for HIV infection in COVID-19 treatment

et al. 2021

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“…There has been considerable controversy about the effects of hydroxychloroquine, which inhibits SARS-CoV-2 replication in vitro 5 , but fails clinically to clear SARS-CoV-2 and to improve Covid-2, at least in hospitalized patients [6][7][8][9] . Hydroxychloroquine is a prototypic lysosomotropic agent, meaning that, due to its lipophilicity (at neutral pH) and low TPSA, it attains the cytoplasm and then enriches in the acidic environment of lysosomes because it is protonated and hence trapped within the lysosomal lumen.…”

Section: Lysosomotropic Versus Non-lysosomotropic Sars-cov-2 Antiviramentioning

confidence: 99%

On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2

et al. 2020

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The current epidemic of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) calls for the development of inhibitors of viral replication. Here, we performed a bioinformatic analysis of published and purported SARS-CoV-2 antivirals including imatinib mesylate that we found to suppress SARS-CoV-2 replication on Vero E6 cells and that, according to the published literature on other coronaviruses is likely to act ontarget, as a tyrosine kinase inhibitor. We identified a cluster of SARS-CoV-2 antivirals with characteristics of lysosomotropic agents, meaning that they are lipophilic weak bases capable of penetrating into cells. These agents include cepharentine, chloroquine, chlorpromazine, clemastine, cloperastine, emetine, hydroxychloroquine, haloperidol, ML240, PB28, ponatinib, siramesine, and zotatifin (eFT226) all of which are likely to inhibit SARS-CoV-2 replication by non-specific (off-target) effects, meaning that they probably do not act on their 'official' pharmacological targets, but rather interfere with viral replication through non-specific effects on acidophilic organelles including autophagosomes, endosomes, and lysosomes. Imatinib mesylate did not fall into this cluster. In conclusion, we propose a tentative classification of SARS-CoV-2 antivirals into specific (on-target) versus non-specific (off-target) agents based on their physicochemical characteristics.

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“…However, they did not report on specific adverse events. Other systematic reviews found an increase in the risk of diarrhoea and nausea and/or vomiting with lopinavir-ritonavir 37,38 and hydroxychloroquine, [38][39][40] increase in arrhythmias and QTc interval prolongation with hydroxychloroquine alone, [40][41][42] or combined with a macrolide, 43,44 and no significant increase in renal failure with remdesivir. 45…”

Section: Strengths and Limitations Of This Reviewmentioning

confidence: 99%

Adverse effects of remdesivir, hydroxychloroquine, and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomized trials

Izcovich

Siemieniuk

Bartoszko

et al. 2020

Preprint

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IntroductionIn an attempt to improve outcomes for patients with coronavirus disease 19 (COVID-19), several drugs, such as remdesivir, hydroxychloroquine (with or without azithromycin), and lopinavir/ritonavir, have been evaluated for treatment. While much attention focuses on potential benefits of these drugs, this must be weighed against their adverse effects.MethodsWe searched 32 databases in multiple languages from 1 December 2019 to 27 October 2020. We included randomized trials if they compared any of the drugs of interest to placebo or standard care, or against each other. A related world health organization (WHO) guideline panel selected the interventions to address and identified possible adverse effects that might be important to patients. Pairs of reviewers independently extracted data and assessed risk of bias. We analyzed data using a fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the GRADE approach.ResultsWe included 16 randomized trials which enrolled 8226 patients. Compared to standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury (risk difference [RD] 8 fewer per 1000, 95% confidence interval (CI): 27 fewer to 21 more) or cognitive dysfunction/delirium (RD 3 more per 1000, 95% CI: 12 fewer to 19 more). Low certainty evidence suggests that hydroxychloroquine may increase the risk of serious cardiac toxicity (RD 10 more per 1000, 95% CI: 0 more to 30 more) and cognitive dysfunction/delirium (RD 33 more per 1000, 95% CI: 18 fewer to 84 more), whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI: 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI: 23 more to 110 more) compared to standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea (RD 168 more per 1000, 95% CI: 58 more to 330 more) and nausea and/or vomiting (RD 160 more per 1000, 95% CI: 100 more to 210 more) compared to standard care or placebo.ConclusionHydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Remdesivir may have no effect on risk of acute kidney injury or cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.

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Efficacy and safety of antiviral treatment for COVID-19 from evidence in studies of SARS-CoV-2 and other acute viral infections: a systematic review and meta-analysis

Cited by 74 publications

References 45 publications

Lopinavir/ritonavir: Repurposing an old drug for HIV infection in COVID-19 treatment

Lopinavir/ritonavir: Repurposing an old drug for HIV infection in COVID-19 treatment

On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2

Adverse effects of remdesivir, hydroxychloroquine, and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomized trials

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