Timing of Antiviral Treatment Initiation is Critical to Reduce SARS‐CoV‐2 Viral Load

Gonçalves, Antônio José; Bertrand, Julie; Ke, Ruian; Comets, Emmanuelle; Lamballerie, Xavier de; Malvy, Denis; Pizzorno, Andrés; Terrier, B.; Rosa‐Calatrava, Manuel; Mentré, France; Smith, Patrick F.; Perelson, Alan S.; Guedj, Jérémie

doi:10.1002/psp4.12543

Cited by 191 publications

(289 citation statements)

References 33 publications

(50 reference statements)

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“…Because repurposed drugs are designed primarily for other, typically unrelated targets, they may display suboptimal efficacies against their newly intended targets. Indeed, a recent analysis of SARS-CoV-2 dynamics in 13 patients treated with different repurposed drugs found that the drug efficacies were in the range of 20–70% and were far below the minimum of 80% that would be required for effective treatment after the onset of symptoms [ 58 ]. Increasing drug levels to achieve desired efficacies is likely to be limited by toxicities.…”

Section: Discussionmentioning

confidence: 99%

“…Given a desired efficacy of the combination, arising from considerations, for instance, of achieving a desired decline in viral load [ 58 ], optimal drug dosages can be estimated that would maximize synergy while ensuring efficacy, as has been demonstrated in other settings [ 40 , 43 , 52 , 54 , 71 ]. Our model provides a framework that can be readily applied to predict these optimal dosages.…”

Section: Discussionmentioning

confidence: 99%

“…The infected cell death rate and the virion clearance rate constants have been chosen to apply to SARS-CoV-2 infections. These have been set to 0.53 d -1 and 10 d -1 in earlier studies [ 58 ]. The virion production rate per infected cell was set to zero mimicking pseudo-typed virus infection.…”

Section: Methodsmentioning

confidence: 99%

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Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection

2020

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The entry of SARS-CoV-2 into target cells requires the activation of its surface spike protein, S, by host proteases. The host serine protease TMPRSS2 and cysteine proteases Cathepsin B/L can activate S, making two independent entry pathways accessible to SARS-CoV-2. Blocking the proteases prevents SARS-CoV-2 entry in vitro. This blockade may be achieved in vivo through ‘repurposing’ drugs, a potential treatment option for COVID-19 that is now in clinical trials. Here, we found, surprisingly, that drugs targeting the two pathways, although independent, could display strong synergy in blocking virus entry. We predicted this synergy first using a mathematical model of SARS-CoV-2 entry and dynamics in vitro. The model considered the two pathways explicitly, let the entry efficiency through a pathway depend on the corresponding protease expression level, which varied across cells, and let inhibitors compromise the efficiency in a dose-dependent manner. The synergy predicted was novel and arose from effects of the drugs at both the single cell and the cell population levels. Validating our predictions, available in vitro data on SARS-CoV-2 and SARS-CoV entry displayed this synergy. Further, analysing the data using our model, we estimated the relative usage of the two pathways and found it to vary widely across cell lines, suggesting that targeting both pathways in vivo may be important and synergistic given the broad tissue tropism of SARS-CoV-2. Our findings provide insights into SARS-CoV-2 entry into target cells and may help improve the deployability of drug combinations targeting host proteases required for the entry.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection

2020

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“…5 Some have elevated levels of interleukin (IL)-6, which can suppress hepatic cytochromes, including cytochrome P450 (CYP) 3A4, with elevation of exposures for its many substrates. 6 The natural history of the disease may impact efficacy; direct antivirals may be more effective in the early stages of the disease, 7 whereas treatment intended to modify the host immune response may need to be used only in late disease. The impact of disease appears to vary between populations, for example, men appear to be at greater risk of dying from COVID-19 than women; 8 might there be differences in exposure-response to therapies due to gender or other factors?…”

mentioning

confidence: 99%

A Real‐World Evidence Framework for Optimizing Dosing in All Patients With COVID‐19

Peck

Weiner²,

Cook

et al. 2020

Clin Pharma and Therapeutics

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Potential treatments for coronavirus disease 2019 (COVID-19) are being investigated at unprecedented speed, and successful treatments will rapidly be used in tens or hundreds of thousands of patients. To ensure safe and effective use in all those patents it is essential also to develop, at unprecedented speed, a means to provide frequently updated, optimal dosing information for all patient subgroups. Success will require immediate collaboration between drug developers, academics, and regulators.

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“…However, to date, these analyses have been population dynamics models of SARS-CoV-2 infection and transmission or correlative analyses of COVID-19 comorbidities and treatment response. Simple viral dynamics models have been also developed and used to predict the SARS-CoV-2 response to anti-viral drugs 18,19 . All these models, however, do not explicitly consider the biological or physiological mechanisms underlying disease progression or the time-course of response to various therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

In silico dynamics of COVID-19 phenotypes for optimizing clinical management

Voutouri

Nikmaneshi

Hardin

et al. 2020

Preprint

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Understanding the underlying mechanisms of COVID-19 progression and the impact of various pharmaceutical interventions is crucial for the clinical management of the disease. We developed a comprehensive mathematical framework based on the known mechanisms of the SARS-CoV-2 virus infection, incorporating the renin-angiotensin system and ACE2, which the virus exploits for cellular entry, key elements of the innate and adaptive immune responses, the role of inflammatory cytokines and the coagulation cascade for thrombus formation. The model predicts the evolution of viral load, immune cells, cytokines, thrombosis, and oxygen saturation based on patient baseline condition and the presence of co-morbidities. Model predictions were validated with clinical data from healthy people and COVID-19 patients, and the results were used to gain insight into identified risk factors of disease progression including older age, co-morbidities such as obesity, diabetes, and hypertension, and dysregulated immune response 1,2. We then simulated treatment with various drug classes to identify optimal therapeutic protocols. We found that the outcome of any treatment depends on the sustained response rate of activated CD8+ T cells and sufficient control of the innate immune response. Furthermore, the best treatment –or combination of treatments – depends on the pre-infection health status of the patient. Our mathematical framework provides important insight into SARS-CoV-2 pathogenesis and could be used as the basis for personalized, optimal management of COVID-19.

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Timing of Antiviral Treatment Initiation is Critical to Reduce SARS‐CoV‐2 Viral Load

Cited by 191 publications

References 33 publications

Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection

Targeting TMPRSS2 and Cathepsin B/L together may be synergistic against SARS-CoV-2 infection

A Real‐World Evidence Framework for Optimizing Dosing in All Patients With COVID‐19

In silico dynamics of COVID-19 phenotypes for optimizing clinical management

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