Novel modelling approaches to predict the role of antivirals in reducing influenza transmission

Asher, Jason; Lemenuel‐Diot, Annabelle; Clay, Matthew; Durham, David P.; Mier-y-Terán-Romero, Luis; Arguello, Carlos J; Jolivet, Sebastien; Wong, Diana Y; Kuhlbusch, Klaus; Clinch, Barry; Charoin, Jean-Eric

doi:10.1371/journal.pcbi.1010797

Cited by 8 publications

(4 citation statements)

References 21 publications

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“…Finally, we used a phenomenological approach to fit the functional forms of the shedding and symptom score data, rather than developing a mechanistic model to explain underlying virus replication and cell infection dynamics [58][59][60][61]. This choice was motivated by data availability: fitting an appropriate and identifiable mechanistic model for influenza virus infection requires information on viral load and various immune cell populations that were not captured in this study.…”

Section: Discussionmentioning

confidence: 99%

Influenza virus shedding and symptoms: Dynamics and implications from a multi-season household transmission study

Morris,

Nguyen,

Grijalva

et al. 2024

Preprint

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Isolation of symptomatic infectious persons can reduce influenza transmission. However, virus shedding that occurs without symptoms will be unaffected by such measures. Identifying effective isolation strategies for influenza requires understanding the interplay between individual virus shedding and symptom presentation. From 2017–2020, we conducted a case-ascertained household transmission study using influenza real-time reverse transcription quantitative PCR (RT-qPCR) testing of nasal swabs and daily symptom diary reporting for up to 7 days after enrollment (≤14 days after index onset). We assumed real-time RT-qPCR cycle threshold (Ct) values were indicators of quantitative virus shedding and used symptom diaries to create a score that tracked influenza-like-illness (ILI) symptoms (fever, cough, or sore throat). We fit phenomenological nonlinear mixed-effects models stratified by age and vaccination status and estimated two quantities influencing isolation effectiveness: shedding before symptom onset and shedding that might occur once isolation ends. We considered different isolation end points (including 24 hours after fever resolution or 4 days after symptom onset) and assumptions about the infectiousness of Ct shedding trajectories. Of the 116 household contacts with ≥2 positive tests for longitudinal analyses, 105 (91%) experienced ≥1 ILI symptom. On average, children <5 years experienced greater peak shedding, longer durations of shedding, and elevated ILI symptom scores compared with other age groups. Most individuals (63/105) shed <10% of their total shed virus before symptom onset, and shedding after isolation varied substantially across individuals, isolation end points, and infectiousness assumptions. Our results can inform strategies to reduce transmission from symptomatic individuals infected with influenza.

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Section: Discussionmentioning

confidence: 99%

Influenza virus shedding and symptoms: Dynamics and implications from a multi-season household transmission study

Morris,

Nguyen,

Grijalva

et al. 2024

Preprint

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show abstract

“…In addition, this reduction was maintained in the subgroup of index cases aged < 12 years. Other modeling studies indicate that early treatment BXM could lead to substantial reductions in community transmission of influenza viruses and reduce its well‐recognized impacts [ 31 , 32 ]. The more rapid reduction in infectious virus titers associated with BXM compared to OTV treatment may explain BXM's greater reduction in secondary household transmission than observed with OTV.…”

Section: Discussionmentioning

confidence: 99%

Comparative Effectiveness of Baloxavir Marboxil and Oseltamivir Treatment in Reducing Household Transmission of Influenza: A Post Hoc Analysis of the BLOCKSTONE Trial

Ikematsu,

Baba,

Saito

et al. 2024

Influenza Resp Viruses

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BackgroundThe transmission of influenza virus in households, especially by children, is a major route of infection. Prior studies suggest that timely antiviral treatment of ill cases may reduce infection in household contacts. The aim of the study was to compare the effects of oseltamivir (OTV) and baloxavir marboxil (BXM) treatment of index cases on the secondary attack rate (SAR) of influenza within household.MethodsA post hoc analysis was done in BLOCKSTONE trial—a placebo‐controlled, double‐blinded post‐exposure prophylaxis of BXM. Data were derived from the laboratory‐confirmed index cases' household contacts who received placebo in the trial and also from household members who did not participate in the trial but completed illness questionnaires. To assess the SAR of household members, multivariate analyses adjusted for factors including age, vaccination status, and household size were performed and compared between contacts of index cases treated with BXM or OTV.ResultsIn total, 185 index cases (116 treated with BXM and 69 treated with OTV) and 410 household contacts (201 from trial, 209 by questionnaire) were included. The Poisson regression modeling showed that the SAR in household contacts of index cases treated with BXM and OTV was 10.8% and 18.5%, respectively; the adjusted relative reduction in SAR was 41.8% (95% confidence interval: 1.0%–65.7%, p = 0.0456) greater with BXM than OTV. Similar reductions were found in contacts from the trial and those included by questionnaire.ConclusionBXM treatment of index cases appeared to result in a greater reduction in secondary household transmission than OTV treatment.

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“…The same pattern is seen in infections, such as HIV or hepatitis C, which can progress from acute to chronic, where the decline does not necessarily lead to the elimination of the virus. The viral load frequently correlates with a person's infectiousness and, thus, the probability of viral transmission [1][2][3][4][5][6][7][8]. Understanding the viral dynamics throughout the course of infection, including prior to the viral peak, is critical to understanding viral transmission [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

How robust are estimates of key parameters in standard viral dynamic models?

Zitzmann,

Ke,

Ribeiro

et al. 2024

PLoS Comput Biol

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Mathematical models of viral infection have been developed, fitted to data, and provide insight into disease pathogenesis for multiple agents that cause chronic infection, including HIV, hepatitis C, and B virus. However, for agents that cause acute infections or during the acute stage of agents that cause chronic infections, viral load data are often collected after symptoms develop, usually around or after the peak viral load. Consequently, we frequently lack data in the initial phase of viral growth, i.e., when pre-symptomatic transmission events occur. Missing data may make estimating the time of infection, the infectious period, and parameters in viral dynamic models, such as the cell infection rate, difficult. However, having extra information, such as the average time to peak viral load, may improve the robustness of the estimation. Here, we evaluated the robustness of estimates of key model parameters when viral load data prior to the viral load peak is missing, when we know the values of some parameters and/or the time from infection to peak viral load. Although estimates of the time of infection are sensitive to the quality and amount of available data, particularly pre-peak, other parameters important in understanding disease pathogenesis, such as the loss rate of infected cells, are less sensitive. Viral infectivity and the viral production rate are key parameters affecting the robustness of data fits. Fixing their values to literature values can help estimate the remaining model parameters when pre-peak data is missing or limited. We find a lack of data in the pre-peak growth phase underestimates the time to peak viral load by several days, leading to a shorter predicted growth phase. On the other hand, knowing the time of infection (e.g., from epidemiological data) and fixing it results in good estimates of dynamical parameters even in the absence of early data. While we provide ways to approximate model parameters in the absence of early viral load data, our results also suggest that these data, when available, are needed to estimate model parameters more precisely.

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Novel modelling approaches to predict the role of antivirals in reducing influenza transmission

Cited by 8 publications

References 21 publications

Influenza virus shedding and symptoms: Dynamics and implications from a multi-season household transmission study

Influenza virus shedding and symptoms: Dynamics and implications from a multi-season household transmission study

Comparative Effectiveness of Baloxavir Marboxil and Oseltamivir Treatment in Reducing Household Transmission of Influenza: A Post Hoc Analysis of the BLOCKSTONE Trial

How robust are estimates of key parameters in standard viral dynamic models?

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