Systematic review and patient-level meta-analysis of SARS-CoV-2 viral dynamics to model response to antiviral therapies

Gastine, Silke; Pang, Juanita; Boshier, Florencia A.T.; Carter, Simon J.; Lonsdale, Derrick; Cortina‐Borja, Mario; Hung, Ivan; Breuer, Judith; Kloprogge, Frank; Standing, Joseph F.

doi:10.1101/2020.08.20.20178699

Cited by 10 publications

(26 citation statements)

References 71 publications

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“…A major caveat to our findings is that our cohort is paediatric, for which both the clinical picture and outcome of SARS-CoV-2 infections are known to differ from adults. Notwithstanding, similar patterns of clinical and virological response to remdesivir have been described in adults (3,10,46,59) . Moreover, both clinical and viral sequence data from the use of repurposed drugs to treat other severe RNA viral infections has shown similarities in adults and children (12,50,55) .…”

Section: Discussionsupporting

confidence: 61%

Remdesivir induced viral RNA and subgenomic RNA suppression, and evolution of viral variants in SARS-CoV-2 infected patients

Pang

Penner

et al. 2020

Preprint

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While changes in SARS-CoV-2 viral load over time have been documented, detailed information on the impact of remdesivir and how it might alter intra-host viral evolution is limited. Sequential viral loads and deep sequencing of SARS-CoV-2 recovered from the upper respiratory tract of hospitalised children revealed that remdesivir treatment suppressed viral RNA levels in one patient but not in a second infected with an identical strain. Evidence of drug resistance to explain this difference was not found. Reduced levels of subgenomic (sg) RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication that is independent of viral RNA levels. Haplotype reconstruction uncovered persistent SARS-CoV-2 variant genotypes in four patients. We conclude that these are likely to have arisen from within-host evolution, and not co-transmission, although superinfection cannot be excluded in one case. Sample-to-sample heterogeneity in the abundances of variant genotypes is best explained by the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalisation is well described in serious lung infections caused by influenza and Mycobacterium tuberculosis and has been associated with poor drug penetration, suboptimal treatment and drug resistance. Our data provide evidence that remdesivir is able to suppress SARS-CoV-2 replication in vivo but that its efficacy may be compromised by factors reducing penetration into the lung. Based on data from influenza and Mycobacterium tuberculosis lung infections we conclude that early use of remdesivir combined with other agents should now be evaluated.Summary SentenceDeep sequencing of longitudinal samples from SARS-CoV-2 infected paediatric patients identifies evidence of remdesivir-associated inhibition of viral replication in vivo and uncovers evidence of within host evolution of distinct viral genotypes.

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Section: Discussionsupporting

confidence: 61%

Remdesivir induced viral RNA and subgenomic RNA suppression, and evolution of viral variants in SARS-CoV-2 infected patients

Pang

Penner

et al. 2020

Preprint

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“…The simulated time to peak in viral load is in qualitative agreement with clinical observations, which suggest that SARS‐CoV‐2 achieves peak viral loads relatively quickly, roughly coinciding with symptom onset, 38 and with an estimated incubation period of about 4–7 days 39 . Simulated viral loads in the nominal unit test are qualitatively comparable to those typically observed in nasopharyngeal swab samples in patients with COVID‐19, as reported in a recent meta‐analysis of over 2,200 samples in 315 patients by Gastine et al 40 . Moreover, peak viral loads are in agreement with data that have been shown to range between 8 log 10 and 11 log 10 RNA molecules/mL 40–42 in severe hospitalized cases.…”

Section: Resultssupporting

confidence: 85%

“…Simulated viral loads in the nominal unit test are qualitatively comparable to those typically observed in nasopharyngeal swab samples in patients with COVID‐19, as reported in a recent meta‐analysis of over 2,200 samples in 315 patients by Gastine et al 40 . Moreover, peak viral loads are in agreement with data that have been shown to range between 8 log 10 and 11 log 10 RNA molecules/mL 40–42 in severe hospitalized cases.…”

Section: Resultssupporting

confidence: 83%

“…( e ) Damaged AT1 cells scaled to the maximum of nominal case of 4.45 million damaged AT1 cells and ( f ) Damaged AT2 cells scaled to the maximum of nominal case of 5.16 million damaged AT2 cells. Median and maximal viral load measurements of nasopharyngeal swab samples from patients with coronavirus disease 2019 (COVID‐19) from Gastine et al 40 . are depicted with green dashed lines.…”

Section: Resultsmentioning

confidence: 99%

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A Prototype QSP Model of the Immune Response to SARS‐CoV‐2 for Community Development

Dai

Rao

Sher

et al. 2020

CPT Pharmacom & Syst Pharma

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic requires the rapid development of efficacious treatments for patients with life-threatening coronavirus disease (COVID-19). Quantitative Systems Pharmacology (QSP) models are mathematical representations of pathophysiology for simulating and predicting the effects of existing or putative therapies. The application of model-based approaches, including QSP, have accelerated the development of some novel therapeutics. Nevertheless, the development of disease-scale mechanistic models can be a slow process, often taking years to be validated and considered mature. Furthermore, emerging data may make any QSP model quickly obsolete. We present a prototype QSP model to facilitate further development by the scientific community. The model accounts for the interactions between viral dynamics, the major host immune response mediators, and tissue damage and regeneration. The immune response is determined by viral activation of innate and adaptive immune processes that regulate viral clearance and cell damage. The prototype model captures two physiologically relevant outcomes following infection: a 'healthy' immune response that appropriately defends against the virus, and an uncontrolled alveolar inflammatory response that is characteristic of acute respiratory distress syndrome. We aim to significantly shorten the typical QSP model development and validation timeline by encouraging community use, testing, and refinement of this prototype model. It is our expectation that the model will be further advanced in an open science approach; i.e. by multiple contributions towards a validated quantitative platform in an open forum, with the ultimate goal of informing and accelerating the development of safe and effective treatment options for patients.

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“…A major caveat to our findings is that of our cohort pediatric, for which both the clinical picture and outcome of SARS‐CoV‐2 infections are known to differ from adults. Notwithstanding, similar patterns of clinical and virological response to remdesivir have been described in adults 2,7,46 . Moreover, both clinical and viral sequence data from the use of repurposed drugs to treat other severe RNA viral infections have shown similarities in adults and children 10,38 .…”

Section: Discussionmentioning

confidence: 81%

Evolution of viral variants in remdesivir‐treated and untreated SARS‐CoV‐2‐infected pediatrics patients

Boshier

Pang

Penner

et al. 2021

Journal of Medical Virology

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Detailed information on intrahost viral evolution in SARS‐CoV‐2 with and without treatment is limited. Sequential viral loads and deep sequencing of SARS‐CoV‐2 from the upper respiratory tract of nine hospitalized children, three of whom were treated with remdesivir, revealed that remdesivir treatment suppressed viral load in one patient but not in a second infected with an identical strain without any evidence of drug resistance found. Reduced levels of subgenomic RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication. Haplotype reconstruction uncovered persistent SARS‐CoV‐2 variant genotypes in four patients. These likely arose from within‐host evolution, although superinfection cannot be excluded in one case. Although our dataset is small, observed sample‐to‐sample heterogeneity in variant frequencies across four of nine patients suggests the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalization could compromise the penetration of remdesivir into the lung, limiting the drugs in vivo efficacy, as has been observed in other lung infections.

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Systematic review and patient-level meta-analysis of SARS-CoV-2 viral dynamics to model response to antiviral therapies

Cited by 10 publications

References 71 publications

Remdesivir induced viral RNA and subgenomic RNA suppression, and evolution of viral variants in SARS-CoV-2 infected patients

Remdesivir induced viral RNA and subgenomic RNA suppression, and evolution of viral variants in SARS-CoV-2 infected patients

A Prototype QSP Model of the Immune Response to SARS‐CoV‐2 for Community Development

Evolution of viral variants in remdesivir‐treated and untreated SARS‐CoV‐2‐infected pediatrics patients

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