Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance

Journal of Virology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 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.

Язык: Английский

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A unifying model to explain frequent SARS-CoV-2 rebound after nirmatrelvir treatment and limited prophylactic efficacy

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июнь 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.

Язык: Английский

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A mathematical model for the within-host (re)infection dynamics of SARS-CoV-2

Mathematical Biosciences, Год журнала: 2024, Номер 371, С. 109178 - 109178

Опубликована: Март 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.

Язык: Английский

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Post-recovery viral shedding shapes wastewater-based epidemiological inferences

Communications Medicine, Год журнала: 2025, Номер 5(1)

Опубликована: Май 22, 2025

The prolonged viral shedding from the gastrointestinal tract is well documented for numerous pathogens, including SARS-CoV-2. However, impact of on epidemiological inferences using wastewater data not yet fully understood. To gain a better understanding this phenomenon at population level, we extended wastewater-based modeling framework that integrates dynamics, load in wastewater, case report data, and an epidemic model. Our results indicate as outbreak progresses, recovered individuals gradually becomes predominant, surpassing infectious population. This leads to dynamic relationship between model-inferred reported daily incidence over course outbreak. Sensitivity analyses duration rate reveal accounting can considerably advance prediction transmission peak timing. Furthermore, extensive toward conclusion wave may overshadow signals newly infected cases carrying emerging variants, which delay rapid recognition variants based load. These findings highlight necessity integrating post-recovery enhance accuracy utility analysis.

Язык: Английский

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A unifying model to explain high nirmatrelvir therapeutic efficacy against SARS-CoV-2, despite low post-exposure prophylaxis efficacy and frequent viral rebound

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 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.

Язык: Английский

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Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 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.

Язык: Английский

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SARS-CoV-2: An Update on the Biological Interplay with the Human Host

COVID, Год журнала: 2023, Номер 3(10), С. 1586 - 1600

Опубликована: Окт. 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.

Язык: Английский

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Ensemble modeling of SARS-CoV-2 immune dynamics in immunologically naïve rhesus macaques predicts that potent, early innate immune responses drive viral elimination

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Ноя. 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.

Язык: Английский

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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

Antiviral Research, Год журнала: 2024, Номер 232, С. 106037 - 106037

Опубликована: Ноя. 13, 2024

Язык: Английский

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Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 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.

Язык: Английский

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