Bach Tran Nguyen (1), Julie Bertrand (1), Akosua A. Agyeman (2), Shengyuan Zhang (2), Ly-Mee Yu (3), Victoria Harris (3), Paul Little (4), Judith Breuer (2), David M Lowe (5, 6), Joseph F. Standing (2,7)*, Jérémie Guedj (1)* on behalf of the PANORAMIC study group
(1) Université Paris Cité, INSERM, IAME, F-75018, Paris, France, (2) Infection, Immunity and Inflammation, Great Ormond Street Institute of Child Health, University College London, London, UK, (3) Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK, (4) Primary Care Research Centre, University of Southampton, Southampton, UK, (5) Institute for Immunity and Transplantation, University College London, London, UK, (6) Department of Clinical Immunology, Royal Free London NHS Foundation Trust, London, UK, (7) Department of Pharmacy, Great Ormond Street Hospital for Children NHS Trust, London, UK. *Co-last authors
Introduction: Mathematical models play a crucial role in providing better insights on SARS-CoV-2 dynamics, allowing the prediction of clinical efficacy for antiviral treatments including molnupiravir[1,2]. Acting by inducing lethal mutations in the virus genome during replication, molnupiravir has been approved by the FDA-US, but only for Emergency Use of treating mild to moderate SARS-CoV-2 infection and its clinical benefits remain uncertain in clinical studies[3]. Results from PANORAMIC trial show that 5-day molnupiravir is associated with shorter times to symptom resolution and lower viral loads but also to increased mutagenesis[4], non-negligible rates of detectable virus on Day D5 and significantly higher viral persistence on D14[5]. Longer treatment courses may be required but the associated risk of generating highly mutated viruses has to be mitigated.
Objectives: (i) to disentangle host immune and drug effect by simultaneously fitting viral loads, antibody levels and proportions of transition mutations, (ii) to evaluate longer treatment courses.
Methods: We analysed self-collected nasopharyngeal swabs and dry blood spots returned by post from 324 and 253 participants respectively in the Usual care and Molnupiravir arms. Sampling in intensive and less intensive cohorts was conducted on days D1, D5 and D14, with additional swabs on D2 to D6 and D7 for intensive sampling [5]. We fitted virologic data using a corrected target cell-limited model with refractory cells, described antibody levels with a Gompertz equation and tested antibody effect on different viral kinetics parameters. The time course of transition mutation proportion was characterised using a logit-linear function.
Molnupiravir concentrations were derived following exponential growth and decline, given a half-life of 6 hours[6]. Drug efficacy was then tested on the proportion of infectious virus, the viral production rate from infected cells, and the proportion of transition mutations (directly or via an effect compartment). Next, we investigated the impact of transition mutation proportion on the proportion of infectious virus or the viral production rate from infected cells. Lastly, for treatment durations varying between 5 and 14 days, we focused on the following metrics: time to first undetectable viral load, time to sustained response, rates of viral rebound (defined as at least 1 viral load within 14 days post-treatment completion >3 log10copies/mL, with an increase >1.0 log10copies/mL compared to treatment completion), AUC of the transition mutation loads from treatment initiation to sustained negative PCR. Non-linear mixed-effect modelling approach was used to fit data from all individuals simultaneously using SAEM algorithm in Monolix for estimation and Simulx for simulation (version 2021R2, https://lixoft.com/products/monolix/).
Results: A viral dynamic model with refractory cells well reproduced viral kinetics. The model also described well the trajectories of anti-S antibodies, which increased viral elimination from infected cells with an EC90=1.7*104 IU/mL and Emax= 98%. Molnupiravir inhibited viral production from infected cells by 65% directly, and via boosting the proportion of transition mutations. Simulations showed a difference of only 1 day in times to first and to sustained negative PCR between 5-day molnupiravir and control group, respectively without improving viral rebound rates.
Longer administration of molnupiravir for at least 10 days may shorten by 5 days the times to first and to sustained negative PCR. Compared to a 5-day regimen, viral rebound rates are lowered by 1% and 2% for 10 and 14-day administration respectively, corresponding to a reduction by 17% and 20% in AUC of transition mutation loads over time from treatment initiation to sustained negative PCR.
Conclusions: Our model explains the viral rebound observed in untreated and treated patients with molnupiravir via cells refractory to SARS-CoV-2 infection. Simulations suggest that current 5-day duration may be insufficient, requiring longer administration with a trade-off at 10 days, associated with shorter times to viral clearance and reduced viral rebound rates, while minimising molnupiravir-induced transition mutations.
References:
[1] Gonçalves A, Bertrand J, Ke R, Comets E, de Lamballerie X, Malvy D, et al. Timing of Antiviral Treatment Initiation is Critical to Reduce SARS-CoV-2 Viral Load. CPT Pharmacometrics Syst Pharmacol. 2020;9: 509–514. doi:10.1002/psp4.12543.
[2] Gonçalves A, Maisonnasse P, Donati F, Albert M, Behillil S, Contreras V, et al. SARS-CoV-2 viral dynamics in non-human primates. PLoS Comput Biol. 2021;17: e1008785. doi:10.1371/journal.pcbi.1008785.
[3] Malin JJ, Weibel S, Gruell H, Kreuzberger N, Stegemann M, Skoetz N. Efficacy and safety of molnupiravir for the treatment of SARS-CoV-2 infection: a systematic review and meta-analysis. J Antimicrob Chemother. 2023;78: 1586–1598. doi:10.1093/jac/dkad132.
[4] Butler CC, Hobbs FDR, Gbinigie OA, Rahman NM, Hayward G, Richards DB, et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet. 2023;401: 281–293. doi:10.1016/S0140-6736(22)02597-1.
[5] Standing JF, Buggiotti L, Guerra-Assuncao JA, Woodall M, Ellis S, Agyeman AA, et al. Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients. Nat Commun. 2024;15: 1652. doi:10.1038/s41467-024-45641-0.
[6] Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, et al. Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2. Antimicrob Agents Chemother. 2021;65: e02428-20, AAC.02428-20. doi:10.1128/AAC.02428-20.
Reference: PAGE 32 (2024) Abstr 11044 [www.page-meeting.org/?abstract=11044]
Poster: Drug/Disease Modelling - Other Topics