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Epiabm is an open-source software package for epidemiological agent-based modelling, re-implementing the well-known CovidSim model from the MRC Centre for Global Infectious Disease Analysis at Imperial College London. It has been developed as part of the first-year training programme in the EPSRC SABS:R3 Centre for Doctoral Training at the University of Oxford. The model builds an age-stratified, spatially heterogeneous population and offers a modular approach to configure and run epidemic scenarios, allowing for a broad scope of investigative and comparative studies. Two simulation backends are provided: a pedagogical Python backend (with full functionality) and a high performance C++ backend for use with larger population simulations. Both are highly modular, and include a comprehensive testing suite (including 100% coverage on unit tests alongside a range of functional and integration tests), as well as complete online documentation for ease of understanding and extensibility. Epiabm is publicly available through GitHub at github.com/SABS-R3-Epidemiology/epiabm.

Background: Baloxavir marboxil is an oral, single-dose, cap-dependent endonuclease inhibitor that reduces the duration of influenza symptoms and rapidly stops viral shedding. We developed a susceptible, exposed, infected, recovered (SEIR) model to inform a cost-effectiveness model (CEM) of baloxavir versus oseltamivir or no antiviral treatment in the UK. Research design and methods: The SEIR model estimated the attack rates among otherwise healthy and high-risk individuals in seasonal and pandemic settings. The CEM assumed that a proportion of infected patients would receive antiviral treatment. Results were reported at the population level (per 10,000 at risk of infection). Results: The SEIR model estimated greater reductions in infections with baloxavir. In a seasonal setting, baloxavir provided incremental cost-effectiveness ratios (ICERs) of £1884 per quality-adjusted life-year (QALY) gained versus oseltamivir and a dominant cost-effectiveness position versus no antiviral treatment in the total population; ICERs of £2574/QALY versus oseltamivir and £128/QALY versus no antiviral treatment were seen in the high-risk population. Baloxavir was also cost-effective versus oseltamivir or no antiviral treatment and reduced population-level health system occupancy concerns during a pandemic. Conclusion: Baloxavir treatment resulted in the fewest influenza cases and was cost-effective versus oseltamivir or no antiviral treatment from a UK National Health Service perspective. Plain Language Summary: Baloxavir marboxil ('baloxavir') is a prescription medicine for people who become ill with influenza (or 'the flu') that can reduce how long flu symptoms last and the likelihood of complications from the flu that may require going to the hospital. Baloxavir can also reduce the amount and duration of virus shed by infected individuals thus potentially slow or stop the flu from spreading to healthy people. We studied differences in reducing predicted flu infections between baloxavir and another flu treatment, known as oseltamivir, or no flu treatment at all. Treatment with baloxavir resulted in fewer flu infections in the UK population than oseltamivir or no treatment. We then studied how these differences might affect costs between baloxavir and oseltamivir or no treatment at a population level in the UK. Overall, in the majority of scenarios explored in the model, baloxavir was cost-effective as an antiviral treatment for people with the flu in the UK. [ABSTRACT FROM AUTHOR]

To aid understanding of the effect of antiviral treatment on population-level influenza transmission, we used a novel pharmacokinetic-viral kinetic transmission model to test the correlation between nasal viral load and infectiousness, and to evaluate the impact that timing of treatment with the antivirals oseltamivir or baloxavir has on influenza transmission. The model was run under three candidate profiles whereby infectiousness was assumed to be proportional to viral titer on a natural-scale, log-scale, or dose-response model. Viral kinetic profiles in the presence and absence of antiviral treatment were compared for each individual (N = 1000 simulated individuals); subsequently, viral transmission mitigation was calculated. The predicted transmission mitigation was greater with earlier administration of antiviral treatment, and with baloxavir versus oseltamivir. When treatment was initiated 12-24 hours post symptom onset, the predicted transmission mitigation was 39.9-56.4% for baloxavir and 26.6-38.3% for oseltamivir depending on the infectiousness profile. When treatment was initiated 36-48 hours post symptom onset, the predicted transmission mitigation decreased to 0.8-28.3% for baloxavir and 0.8-19.9% for oseltamivir. Model estimates were compared with clinical data from the BLOCKSTONE post-exposure prophylaxis study, which indicated the log-scale model for infectiousness best fit the observed data and that baloxavir affords greater reductions in secondary case rates compared with neuraminidase inhibitors. These findings suggest a role for baloxavir and oseltamivir in reducing influenza transmission when treatment is initiated within 48 hours of symptom onset in the index patient.

Antiviral treatments against hepatitis B virus (HBV) suppress viral replication but do not eradicate the virus, and need therefore to be taken lifelong to avoid relapse. Mathematical models can be useful to support the development of curative anti‐HBV agents; however, they mostly focus on short‐term HBV DNA data and neglect the complex host‐pathogen interaction. This work aimed to characterize the effect of treatment with lamivudine and/or pegylated interferon (Peg‐IFN) in 1,300 patients (hepatitis B envelope antigen (HBeAg)–positive and HBeAg‐negative) treated for 1 year. A mathematical model was developed incorporating two populations of infected cells, namely I1, with a high transcriptional activity, that progressively evolve into I2, at a rate δtr, representing cells with integrated HBV DNA that have a lower transcriptional activity. Parameters of the model were estimated in patients treated with lamivudine or Peg‐IFN alone (N = 894), and the model was then validated in patients treated with lamivudine plus Peg‐IFN (N = 436) to predict the virological response after a year of combination treatment. Lamivudine had a larger effect in blocking viral production than Peg‐IFN (99.4–99.9% vs. 91.8–95.1%); however, Peg‐IFN had a significant immunomodulatory effect, leading to an enhancement of the loss rates of I1 (×1.7 in HBeAg‐positive patients), I2 (> ×7 irrespective of HBeAg status), and δtr (×4.6 and ×2.0 in HBeAg‐positive and HBeAg‐negative patients, respectively). Using this model, we were able to describe the synergy of the different effects occurring during treatment with combination and predicted an effect of 99.99% on blocking viral production. This framework can therefore support the optimization of combination therapy with new anti‐HBV agents. [ABSTRACT FROM AUTHOR]

To aid understanding of the effect of antiviral treatment on population-level influenza transmission, we used a novel pharmacokinetic–viral kinetic transmission model to test the correlation between nasal viral load and infectiousness, and to evaluate the impact that timing of treatment with the antivirals oseltamivir or baloxavir has on influenza transmission. The model was run under three candidate profiles whereby infectiousness was assumed to be proportional to viral titer on a natural-scale, log-scale, or dose–response model. Viral kinetic profiles in the presence and absence of antiviral treatment were compared for each individual (N = 1000 simulated individuals); subsequently, viral transmission mitigation was calculated. The predicted transmission mitigation was greater with earlier administration of antiviral treatment, and with baloxavir versus oseltamivir. When treatment was initiated 12–24 hours post symptom onset, the predicted transmission mitigation was 39.9–56.4% for baloxavir and 26.6–38.3% for oseltamivir depending on the infectiousness profile. When treatment was initiated 36–48 hours post symptom onset, the predicted transmission mitigation decreased to 0.8–28.3% for baloxavir and 0.8–19.9% for oseltamivir. Model estimates were compared with clinical data from the BLOCKSTONE post-exposure prophylaxis study, which indicated the log-scale model for infectiousness best fit the observed data and that baloxavir affords greater reductions in secondary case rates compared with neuraminidase inhibitors. These findings suggest a role for baloxavir and oseltamivir in reducing influenza transmission when treatment is initiated within 48 hours of symptom onset in the index patient. Author summary: The relationship between the amount of influenza virus shed when a person is infected and how infectious that person is as a result is yet to be established. Understanding this relationship is important for controlling the spread of influenza virus in a population. Here, we tested three models that describe this relationship to investigate how the timing and type of antiviral treatment would be expected to affect the transmission of influenza virus. We compared our simulated data with those from a clinical trial of an antiviral (baloxavir marboxil; BLOCKSTONE post-exposure prophylaxis study) to identify which of the three models best describes the relationship between influenza viral shedding and the infectiousness of a person. We found that two of the three models accurately describe this relationship, and that administration of antiviral treatment within 48 hours of symptom onset would be expected to reduce onward influenza transmission. [ABSTRACT FROM AUTHOR]

During infectious disease outbreaks, inference of summary statistics characterizing transmission is essential for planning interventions. An important metric is the time-dependent reproduction number (Rt), which represents the expected number of secondary cases generated by each infected individual over the course of their infectious period. The value of Rt varies during an outbreak due to factors such as varying population immunity and changes to interventions, including those that affect individuals' contact networks. While it is possible to estimate a single population-wide Rt, this may belie differences in transmission between subgroups within the population. Here, we explore the effects of this heterogeneity on Rt estimates. Specifically, we consider two groups of infected hosts: those infected outside the local population (imported cases), and those infected locally (local cases). We use a Bayesian approach to estimate Rt, made available for others to use via an online tool, that accounts for differences in the onwards transmission risk from individuals in these groups. Using COVID-19 data from different regions worldwide, we show that different assumptions about the relative transmission risk between imported and local cases affect Rt estimates significantly, with implications for interventions. This highlights the need to collect data during outbreaks describing heterogeneities in transmission between different infected hosts, and to account for these heterogeneities in methods used to estimate Rt. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'. [ABSTRACT FROM AUTHOR]

Aims: To optimise the dosing regimen of oseltamivir for immunocompromised (IC) paediatric patients (<18 years) with influenza, we used an extrapolation approach alongside clinical data. Methods: Efficacy was extrapolated from adult IC patients to paediatric IC patients by leveraging existing efficacy, safety, pharmacokinetic (PK)/pharmacodynamic (PD), and disease‐progression models of oseltamivir and oseltamivir carboxylate (OC). Data of IC paediatric patients from two studies (NV25719 and NV20234) were included in the population PK (n = 30), PK/PD analysis (n = 22) and disease modelling approach (n = 36). Simulations were performed to identify the optimal dosing regimen. Results: Clearance of oseltamivir (CL) and OC (CLM) were similar in IC and otherwise‐healthy (OwH) patients <10 years, but decreased by 44.4% (95% CI: 26.8–62.0) and 49.1% (95% CI: 34.5–63.8), respectively, in IC patients aged 10–17 years versus OwH patients. There were no notable exposure–response relationships for any of the virologic PD analyses. Thus, no additional benefit was seen with oseltamivir carboxylate exposures higher than achieved with the conventional dose (75 mg twice daily, age‐ and weight‐adjusted for children <13 years). The disease model illustrated that doses above the conventional oseltamivir dose had limited impact on viral kinetics in IC paediatric patients and a prolonged treatment duration of 10 days was favoured to limit potential viral rebound. Conclusion: An oseltamivir dosage recommendation (conventional dose, twice daily for 10 days) was established in IC paediatric patients with influenza, based on extrapolation of efficacy from IC adults, leveraging population PK, PK/PD, and disease modelling, whilst taking resistance and safety data into account. [ABSTRACT FROM AUTHOR]

Prompt antiviral treatment has the potential to reduce influenza virus transmission to close contacts, but rigorous data on the magnitude of treatment effects on transmission are limited. Animal model data indicate that rapid reductions in viral replication after antiviral treatment reduce the risk of transmission. Observational and clinical trial data with oseltamivir and other neuraminidase inhibitors indicate that prompt treatment of household index patients seems to reduce the risk of illness in contacts, although the magnitude of the reported effects has varied widely across studies. In addition, the potential risk of transmitting drug-resistant variants exists with all approved classes of influenza antivirals. A controlled trial examining baloxavir treatment efficacy to reduce transmission, including the risk of transmitting virus with reduced baloxavir susceptibility, is currently in progress. If reduced transmission risk is confirmed, modeling studies indicate that early treatment could have major epidemiologic benefits in seasonal and pandemic influenza. [ABSTRACT FROM AUTHOR]

The pharmacokinetics (PK) of RO7049389, a new hepatitis B virus (HBV) core protein allosteric modulator of class I, and of its active metabolite M5 were studied in fasted and fed conditions after single and multiple once‐a‐day and twice‐a‐day doses in healthy subjects and patients with HBV. The nonlinearity of the pharmacokinetics, the large variability, the small sample size per dose arms, the higher plasma exposure in Asians, and the heterogeneity in patient baseline characteristics seen in phase I studies made the ethnic sensitivity assessment and the selection of the recommended phase II dose difficult. A population PK model, simultaneously modeling RO7049389 and M5, was developed to characterize the complex PK, quantify ethnicity (i.e., Asian vs. non‐Asian) and gender effects on the PK of RO7049389 and M5, and infer the quantity of RO7049389 in liver relative to plasma. Exposures in the liver are of particular importance for dose selection since the liver is the site of action of the compound. The model described and reproduced the population PK profiles as well as the between‐subject variability of RO7049389 and its metabolite. It could show that the PK is similar between healthy subjects and in HBV patients, once the ethnicity and gender effects are accounted for. The model predicts that, despite a large difference in the plasma exposure of RO7049389 between Asians and non‐Asians, the exposure in the liver is comparable, allowing the use of the same dose to treat Asian and non‐Asian patients. This model provides a valuable basis to develop this new anti‐HBV drug and to define optimal dosing. [ABSTRACT FROM AUTHOR]

Aim: Pharmacologic effects were analysed to determine a dose recommendation for oseltamivir in immunocompromised (IC) adults with influenza. Methods: Quantitative clinical pharmacology methods were applied to data from 160 adult IC patients (aged 18‐78 years) from two studies (NV20234, 150 patients; NV25118, 10 patients) who received oseltamivir 75‐200 mg twice daily for up to 10 days. An established population‐pharmacokinetic (PK) model with additional effects on oseltamivir and oseltamivir carboxylate (OC) clearance described the PK characteristics of oseltamivir in IC patients versus otherwise healthy (OwH) patients from previous clinical trials. Estimated PK parameters were used to evaluate exposure‐response relationships for virologic endpoints (time to cessation of viral shedding, viral load measures and treatment‐emergent resistance). A drug‐disease model characterized the viral kinetics of influenza accounting for the effect of OC on viral production. Results: Oseltamivir clearance was 32.5% lower (95% confidence interval [CI], 26.1‐38.8) and OC clearance was 33.7% lower (95% CI, 23.2‐44.1) in IC versus OwH patients. No notable exposure‐response relationships were identified for exposures higher than those achieved after conventional dose oseltamivir 75 mg, which appeared to be close to the maximum effect of oseltamivir. Simulations of the drug‐disease model predicted that initiating treatment within 48 hours of symptom onset had maximum impact, and a treatment duration of 10 days was favourable over 3‐5 days to limit viral rebound. Conclusions: Our findings support the use of conventional‐dose oseltamivir 75 mg twice daily for 10 days in the treatment of IC adult patients with influenza. [ABSTRACT FROM AUTHOR]

Hepatitis B virus RNA (HBV RNA)–containing particles are encapsidated pre‐genomic RNA (pgRNA) detectable in chronically infected patients in addition to virions (HBV DNA) that have been suggested as a marker of the treatment efficacy. This makes promising the use of core protein allosteric modulators, such as RG7907, which disrupt the nucleocapsid assembly and profoundly reduce HBV RNA. Here, we developed a multiscale model of HBV extending the standard viral dynamic models to analyse the kinetics of HBV DNA and HBV RNA in 35 patients treated with RG7907 for 28 days. We compare the predictions with those obtained in patients treated with the nucleotide analog tenofovir. RG7907 blocked 99.3% of pgRNA encapsidation (range: 92.1%–99.9%) which led to a decline of both HBV DNA and HBV RNA. As a consequence of its mode of action, the first phase of decline of HBV RNA was rapid, uncovering the clearance of viral particles with half‐life of 45 min. In contrast, HBV DNA decline was predicted to be less rapid, due to the continuous secretion of already formed viral capsids (t1/2 = 17 ± 6 h). After few days, both markers declined at the same rate, which was attributed to the loss of infected cells (t1/2 ≅ 6 ± 0.8 days). By blocking efficiently RNA reverse transcription but not its encapsidation, nucleotide analog in contrast was predicted to lead to a transient accumulation of HBV RNA both intracellularly and extracellularly. The model brings a conceptual framework for understanding the differences between HBV DNA and HBV RNA dynamics. Integration of HBV RNA in viral dynamic models may be helpful to better quantify the treatment effect, especially in viral‐suppressed patients where HBV DNA is no longer detectable. [ABSTRACT FROM AUTHOR]

Clinical Development Phases I ‐ III Regulatory, Quality, Manufacturing Mericitabine is the prodrug of RO4995855, a selective inhibitor of the hepatitis C virus (HCV) NS5B polymerase. This study assessed the effect of renal impairment on RO4995855 pharmacokinetics. In this open ‐ label study, HCV ‐ negative volunteers (18 – 75 years) with normal renal function (NRF: creatinine clearance [CLCR] >80 mL/min, n = 10) or stable renal impairment (mild: CLCR 50 – 80 mL/min, n = 10; moderate: CLCR 30 – 49 mL/min, n = 10) received oral mericitabine 1000 mg twice daily (BID) (500 mg BID for moderate renal impairment) for 5 days. Primary outcome measures were renal clearance, maximum plasma concentration (Cmax), and area under the concentration ‐ time curve (0 – 12 h) (AUC0 – 12) for RO4995855. Renal clearance decreased as renal function decreased. Relative to subjects with NRF, the geometric mean ratios (GMR) for AUC0 – 12 and Cmax in mild renal impairment subjects were 1.45 (90% confidence interval [CI], 1.26 – 1.66) and 1.14 (1.02 – 1.28), respectively. For moderate renal impairment subjects, the dose ‐ normalized GMR for AUC0 – 12 and Cmax relative to NRF subjects were 2.51 (90% CI, 2.19 – 2.88) and 1.76 (1.56 – 1.97), respectively. Renal clearance of RO4995855 declined in subjects with mild/moderate renal impairment following mericitabine. Dose adjustment of mericitabine may be required in patients with moderate renal impairment. [ABSTRACT FROM AUTHOR]

In particular, our model predicts that HBV RNA dynamics is highly dependent on parameters that also determine RNA/DNA ratio at baseline. Keywords: HBV; HBV cure; HBV RNA; nucleosidic analogs; viral dynamics EN HBV HBV cure HBV RNA nucleosidic analogs viral dynamics 689 690 2 03/12/21 20210401 NES 210401 We thank Dahari and colleagues for our comments on our study on HBV RNA dynamics in CpAM and NA-treated patients1 and we provide elements of discussion below. [Extracted from the article]

The uncertainty associated with parameter estimations is essential for population model building, evaluation, and simulation. Summarized by the standard error (SE), its estimation is sometimes questionable. Herein, we evaluate SEs provided by different non linear mixed-effect estimation methods associated with their estimation performances. Methods based on maximum likelihood (FO and FOCE in NONMEMTM, nlme in SplusTM, and SAEM in MONOLIX) and Bayesian theory (WinBUGS) were evaluated on datasets obtained by simulations of a one-compartment PK model using 9 different designs. Bootstrap techniques were applied to FO, FOCE, and nlme. We compared SE estimations, parameter estimations, convergence, and computation time. Regarding SE estimations, methods provided concordant results for fixed effects. On random effects, SAEM and WinBUGS, tended respectively to under or over-estimate them. With sparse data, FO provided biased estimations of SE and discordant results between bootstrapped and original datasets. Regarding parameter estimations, FO showed a systematic bias on fixed and random effects. WinBUGS provided biased estimations, but only with sparse data. SAEM and WinBUGS converged systematically while FOCE failed in half of the cases. Applying bootstrap with FOCE yielded CPU times too large for routine application and bootstrap with nlme resulted in frequent crashes. In conclusion, FO provided bias on parameter estimations and on SE estimations of random effects. Methods like FOCE provided unbiased results but convergence was the biggest issue. Bootstrap did not improve SEs for FOCE methods, except when confidence interval of random effects is needed. WinBUGS gave consistent results but required long computation times. SAEM was in-between, showing few under-estimated SE but unbiased parameter estimations. [ABSTRACT FROM AUTHOR]