Modelling the effectiveness of antiviral treatment strategies to prevent household transmission of acute respiratory viruses DOI Creative Commons
Hind Zaaraoui,

Clarisse Schumer,

Xavier Duval

et al.

PLoS Computational Biology, Journal Year: 2024, Volume and Issue: 20(12), P. e1012573 - e1012573

Published: Dec. 5, 2024

Households are a major driver of transmission acute respiratory viruses, such as SARS-CoV-2 or Influenza. Until now antiviral treatments have mostly been used curative treatment in symptomatic individuals. During an outbreak, more aggressive strategies involving pre- post-exposure prophylaxis (PrEP PEP) could be employed to further reduce the risk severe disease but also prevent household contacts. In order understand effectiveness and factors that may modulate them, we developed multi-scale model follows infection at both individual-level (viral dynamics) population-level (transmission households. Using simulation study explored different strategies, evaluating their on reducing virological burden households for range virus characteristics (e.g., secondary attack rate—SAR, time peak viral load). We found when index case can identified treated before symptom onset, reduced by > 75% most SAR values load, with minimal benefit treat additionally While initiated after onset does not transmission, it still household, proxy subsequent outside household. optimal involve contacts PEP, efficacy 50% load occurs 30-50% otherwise. all considered cases, were ranging 20-60%, larger sizes. This highlights opportunity drug-based interventions during outbreak minimize burden.

Language: Английский

Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance DOI Creative Commons
Tin Phan, Ruy M. Ribeiro,

Gregory E. Edelstein

et al.

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 4, 2025

ABSTRACT In a subset of SARS-CoV-2-infected individuals treated with the antiviral nirmatrelvir-ritonavir, virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used mathematical model to describe longitudinal viral load dynamics 51 20 whom rebounded. Target cell preservation, either by robust innate immune response or initiation N-R near time symptom onset, coupled incomplete clearance, appears be main factor leading rebound. Moreover, occurrence is likely influenced treatment relative progression infection, earlier treatments higher chance A comparison an untreated cohort suggests that early nirmatrelvir-ritonavir may associated delay in onset adaptive response. Nevertheless, our demonstrates extending course 10-day regimen greatly diminish people mild-to-moderate COVID-19 and who at high risk severe disease. Altogether, results suggest some individuals, standard 5-day starting around completely eliminate virus. Thus, after ends, can if effective has fully developed. These findings on role target preservation clearance also offer possible explanation for other SARS-CoV-2. IMPORTANCE Nirmatrelvir-ritonavir initial reduction followed once stopped. show timing influence stops growth preserves cells but lead full adequately developed, remaining Our provide insights into help develop better strategies minimize possibility.

Language: Английский

Citations

2
A unifying model to explain frequent SARS-CoV-2 rebound after nirmatrelvir treatment and limited prophylactic efficacy DOI Creative Commons
Shadisadat Esmaeili, Katherine Owens,

Jessica Wagoner

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 28, 2024

Abstract In a pivotal trial (EPIC-HR), 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic SARS-CoV-2 infection (within three days symptoms onset), decreased hospitalization and death by 89.1% nasal viral load 0.87 log relative to placebo in high-risk individuals. Yet, nirmatrelvir/ritonavir failed as post-exposure prophylaxis trial, frequent rebound has been observed subsequent cohorts. We develop mathematical model capturing viral-immune dynamics nirmatrelvir pharmacokinetics that recapitulates loads from this another clinical (PLATCOV). Our results suggest nirmatrelvir’s vivo potency is significantly lower than vitro assays predict. According our model, maximally potent agent would reduce the approximately 3.5 logs at 5 days. The identifies earlier initiation shorter treatment duration are key predictors post-treatment rebound. Extension 10 for Omicron variant vaccinated individuals, rather increasing dose or dosing frequency, predicted incidence significantly.

Language: Английский

Citations

9
A mathematical model for the within-host (re)infection dynamics of SARS-CoV-2 DOI Creative Commons
Lea Schuh,

Peter V. Markov,

Vladimir M. Veliov

et al.

Mathematical Biosciences, Journal Year: 2024, Volume and Issue: 371, P. 109178 - 109178

Published: March 13, 2024

Interactions between SARS-CoV-2 and the immune system during infection are complex. However, understanding within-host dynamics is of enormous importance for clinical public health outcomes. Current mathematical models focus on describing acute phase. Thereby they ignore important long-term post-acute effects. We present a model, which not only describes phase, but extends current approaches by also recapitulating clinically observed effects, such as recovery number susceptible epithelial cells to an initial pre-infection homeostatic level, permanent full clearance within individual, waning, formation capacity levels after infection. Finally, we used our model its description explore reinfection scenarios differentiating distinct variant-specific properties reinfecting virus. Together, model's ability describe provides more realistic key outcomes allows application in scenarios.

Language: Английский

Citations

7
A unifying model to explain high nirmatrelvir therapeutic efficacy against SARS-CoV-2, despite low post-exposure prophylaxis efficacy and frequent viral rebound DOI Creative Commons
Shadisadat Esmaeili, Katherine Owens,

Jessica Wagoner

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 24, 2023

Abstract In a pivotal trial (EPIC-HR), 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic SARS-CoV-2 infection (within three days symptoms onset), decreased hospitalization and death by 89.1% nasal viral load 0.87 log relative to placebo in high-risk individuals. Yet, nirmatrelvir/ritonavir failed as post-exposure prophylaxis trial, frequent rebound has been observed subsequent cohorts. We developed mathematical model capturing viral-immune dynamics nirmatrelvir pharmacokinetics that recapitulated loads from this another clinical (PLATCOV). Our results suggest nirmatrelvir’s vivo potency is significantly lower than vitro assays predict. According our model, maximally potent agent would reduce the approximately 3.5 logs at 5 days. The identifies earlier initiation shorter treatment duration are key predictors post-treatment rebound. Extension 10 for Omicron variant vaccinated individuals, rather increasing dose or dosing frequency, predicted incidence significantly.

Language: Английский

Citations

4
Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance DOI Creative Commons
Tin Phan, Ruy M. Ribeiro,

Gregory E. Edelstein

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 16, 2024

Abstract In a subset of SARS-CoV-2 infected individuals treated with the oral antiviral nirmatrelvir-ritonavir, virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used mathematical model to describe longitudinal viral load dynamics 51 20 whom rebounded. Target cell preservation, either by robust innate immune response or initiation nirmatrelvir-ritonavir near time symptom onset, coupled incomplete clearance, appear be main factors leading rebound. Moreover, occurrence is likely influenced treatment relative progression infection, earlier treatments higher chance Finally, our demonstrates that extending course treatment, in particular 10-day regimen, may greatly diminish risk for people mild-to-moderate COVID-19 and who at high severe disease. Altogether, results suggest some individuals, standard 5-day starting around onset completely eliminate virus. Thus, after ends, can if an effective adaptive has fully developed. These findings on role target preservation clearance also offer possible explanation other SARS-CoV-2. Importance Nirmatrelvir-ritonavir initial reduction followed once stopped. show timing influence stops growth preserves cells but lead full adequately developed, remaining Our provide insights into help develop better strategies minimize possibility.

Language: Английский

Citations

1
SARS-CoV-2: An Update on the Biological Interplay with the Human Host DOI Creative Commons
Giuseppe Lippi, Fabián Sanchis‐Gomar, Camilla Mattiuzzi

et al.

COVID, Journal Year: 2023, Volume and Issue: 3(10), P. 1586 - 1600

Published: Oct. 10, 2023

Coronavirus Disease 2019 (COVID-19) is an infectious respiratory illness caused by severe acute syndrome coronavirus 2 (SARS-CoV-2). The disease, first identified in the Chinese city of Wuhan November 2019, has since spread worldwide, latest human pandemic and officially infected over 800 million people nearly seven deaths to date. Although SARS-CoV-2 belongs large family coronaviruses, it some unique biological characteristics its interplay with host. Therefore, this narrative review aims provide up-to-date overview structure virus, incubation shedding host, infectivity evolution time, as well main mechanisms for invading host cells replicating within. We also proffer that ongoing epidemiological surveillance newly emerged variants must always be accompanied studies aimed at deciphering new advantageous traits may contribute increasing virulence pathogenicity, such most appropriate strategies establishing a (relatively) safe coexistence can implemented.

Language: Английский

Citations

3
Ensemble modeling of SARS-CoV-2 immune dynamics in immunologically naïve rhesus macaques predicts that potent, early innate immune responses drive viral elimination DOI Creative Commons
Catherine Byrne, Joshua T. Schiffer

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 7, 2024

Introduction An unprecedented breadth of longitudinal viral and multi-scale immunological data has been gathered during SARS-CoV-2 infection. However, due to the high complexity, non-linearity, multi-dimensionality, mixed anatomic sampling, possible autocorrelation available immune data, it is challenging identify components innate adaptive response that drive elimination. Novel mathematical models analytical approaches are required synthesize contemporaneously cytokine, transcriptomic, flow cytometry, antibody response, load into a coherent story control, ultimately discriminate drivers mild versus severe Methods We investigated dataset describing innate, specific T cell, responses in lung early late stages infection immunologically naïve rhesus macaques. used multi-model inference ensemble modeling from ecology weather forecasting compare combine various competing models. Results discussion Model outputs suggest plays crucial role controlling infection, while CD4+ cells correspond later elimination, anti-spike IgG antibodies do not impact dynamics. Among numerous genes potentially contributing we identified IFI27 as most closely linked decline. A 90% knockdown our validated model resulted ~10-fold increase peak Our approach provides novel methodological framework for future analyses similar complex, non-linear multi-component immunologic sets.

Language: Английский

Citations

0
Meeting Report of the 37th International Conference on Antiviral Research in Gold Coast, Australia, May 20–24, 2024, organized by the International Society for Antiviral Research DOI
Stephen R. Welch, John P. Bilello, Kara Carter

et al.

Antiviral Research, Journal Year: 2024, Volume and Issue: 232, P. 106037 - 106037

Published: Nov. 13, 2024

Language: Английский

Citations

0
Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2 DOI Creative Commons
Shadisadat Esmaeili, Katherine Owens, Joseph F. Standing

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral levels three separate trials. We used mathematical models to simulate these trials closely recapitulated their virologic outcomes. Model simulations suggest lower potency against pre-omicron variants than omicron. estimate vitro assays underestimate vivo 7-8 fold omicron variants. Our model suggests because polymerase chain reaction detects molnupiravir mutated variants, the true reduction non-mutated underestimated ∼0.5 log 10 two conducted while dominated. Viral area under curve estimates differ significantly between RNA. results reinforce past work suggesting are unreliable for estimating drug endpoints respiratory virus clinical should be catered mechanism of action.

Language: Английский

Citations

0
Within-host dynamics of antiviral treatment with remdesivir for SARS-CoV-2 infection DOI Creative Commons
Lea Schuh, Peter V. Markov, Ioanna Voulgaridi

et al.

Journal of The Royal Society Interface, Journal Year: 2024, Volume and Issue: 21(220)

Published: Nov. 1, 2024

The effectiveness of antiviral treatment with remdesivir against COVID-19 has been investigated in clinical trials suggesting earlier recovery. However, this effect seems to be rather modest. In study, we tracked the course SARS-CoV-2 infections 369 individuals across a spectrum illness severities, including both untreated and who received remdesivir. Moreover, using process-based mathematical model, quantified analysed within-host infection dynamics total 88 individuals, which 69 were 19 antiviral-treated individuals. For found that those hospitalized exhibit lower levels early immune response higher cumulative viral loads than not. treated died on average later after symptom onset survived, underscoring importance medical intervention for severe COVID-19. Finally, our model estimates limited activity Our results provide valuable insights into during suggest need alternative regimens.

Language: Английский

Citations

0