Charlotte Kern (1, 2), Verena Schöning (1), Carlos Chaccour (3,4,5) and Felix Hammann (1)
(1) Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland, (2) Graduate School for Health Sciences, University of Bern, Switzerland, (3) ISGlobal, Hospital ClÃnic - Universitat de Barcelona, Barcelona, Spain, (4) ClÃnica Universidad de Navarra, Pamplona, Spain (5) Ifakara Health Institute, Ifakara, United Republic of Tanzania
Introduction: As of May 2021, no antiviral drug regimen has proved effective against SARS-CoV-2. With the pandemic showing no signs of slowing down, and vaccine campaigns only starting to be rolled out, we appear to have few options other than non-pharmacological measures. This is particularly worrying as every new mutation increases the risk of vaccine escape. Emerging variants of concern (VOCs) such as the lineages B1.1.7, B.1.351, and P1, as well as variants of interest (VOI) like B.1.617 are characterized by higher transmissibility (R0), which could lead them to respond differently to antiviral drug therapy than wild type strains. [1-2] Here we investigate the effect of changes in within-host transmissibility on antiviral drug effect using modeling and simulation. We selected ivermectin (IVM) as an example drug for this case study as it has well described pharmacokinetics but so far only little proven effect against SARS-CoV-2. [3-4] IVM is not authorized for COVID-19 in the EU.
Objectives:
- Explore the effect of altered within-host transmissibility on peak viral load (as Ct: cycle threshold), duration of detectable viral load and total viral load (as AUC: area under curve)
- Investigate how altered within-host transmissibility impacts antiviral drug effect.
Methods: Viral loads were simulated from a target-cell limited model with acquired immune response around 10 days post inoculation (dpi). The effects of drug treatment are described by the inhibition of viral entry into susceptible cells, and by blocking viral production rate within infected cells. We assumed two pharmacodynamic effects: inhibition of nicotinic acetylcholine receptors (nAChR) and inhibition of RNA helicase. A detailed description of the model and its implementation are given in Kern et al. [5] Therapeutic effect was summarized by change in AUC, peak viral load, and duration.
Highly transmissible variants were set to 1.25-, 1.5-, and 2-fold increases in the within-host reproductive number R0 compared to wild type (R0 = 3.79). Hypothetical co-adaptation of variants (i.e. a less transmissible mutation) were set to a 0.75-fold decrease in R0.
Drug treatment was modeled according to Duthaler et al. [6] The dosing regimen was IVM 600 µg/kg qd for 3d. Simulations were carried out in GNU R (version 3.6.3), Monolix (version 2019R2), and deSolve (version 1.28). Source code is available at https://github.com/cptbern/sars2-viral-kinetics.
Results: Compared to wild type strains, increases in R0 resulted in higher peaks (Ctmin 25.2-27.4 vs. 28.4) which are also achieved earlier (2.1-3.7 vs. 5.4 dpi), similar durations above the Ct threshold of 35 (11.4-12.7 vs. 13.5 d), and increased AUC 152-402%. Co-adaptation resulted in positivity at 9.1 dpi, a duration of 15.1 d, a Ctmin of 29.6, and an AUC of 66%.
The effects of treatment with IVM 600 µg/kg qd for 3 d were sensitive to R0 as well as timing of treatment initiation. Exposure was reduced most strongly in highly-transmissible mutations with treatment started around inoculation (0 dpi). Duration was less sensitive, and Ctmin levels were unaffected.
Conclusions: In this analysis, antiviral efficacy is correlated with R0, suggesting that highly transmissible VOCs are more sensitive to antiviral treatments, especially when started around the time of inoculation. This would need to be confirmed in clinical trials first. However, given that many trials have included subjects during a time when VOCs had already been circulating, i.e. in late 2020, it could be worthwhile to revisit borderline efficacious drugs and screen patient samples for these mutant strains in order to perform subgroup analyses, focusing on responders vs. non-responders. This may reveal effects against VOCs despite inconclusive results on trial level.
From a clinical standpoint, the expected earlier time to positivity in RT-PCR would make it even more difficult to base the decision to treat on the availability of diagnostic reports that is already the case in wild type infections. It therefore remains unlikely that any antiviral drug will show satisfactory effects in the practical management of acute cases of COVID-19. However, if increased antiviral effect are demonstrated for any drug, this would open up additional avenues for early treatment or prophylaxis that could complement vaccine campaigns in areas of high VOC prevalence, especially as long as these are still suffering from production shortages and supply chain problems.
References:
[1] A Rambaut et al., 2020.
[2] H Tegally et al., medrXiv (2020).
[3] C Chaccour et al., EClinicalMedicine (2021).
[4] VD Schmith et al., Clin Pharmacol Ther 108 (4), 762 (2020).
[5] C Kern et al., Front Pharmacol 12, 625678 (2021).
[6] U Duthaler et al., Br J Clin Pharmacol 85 (3), 626 (2019).
Reference: PAGE 29 (2021) Abstr 9737 [www.page-meeting.org/?abstract=9737]
Poster: Drug/Disease Modelling - COVID-19