In which authors (including Carlos Chaccour) argue for the usefulness of pre- or post-exposure prophylactic antiviral treatment due to new variants, even with ongoing vaccination.
Abstract
As of March 2021, no antiviral drug regimen has proved effective against SARS-CoV-2 infection. 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. Emerging Variants of Concern (VOCs), e.g. B1.1.7, B.1.351, and B.1.1.248, however, are characterized by higher transmissibility (R0).
Here we model and simulate the effect of altered R0 on viral load profiles, and its impact on antiviral therapy. As a hypothetical case study, we simulated treatment with ivermectin 600µg/kg for 3 days initiated at different time points around the infection. Simulated mutations range from 1.25 to 2-fold greater infectivity, but also include putative co-adapted variants with lower transmissibility (0.75-fold).
Antiviral efficacy was correlated with R0, making highly transmissible VOCs more sensitive to antiviral therapy. Viral exposure was reduced by 42% compared to 22% in wild type if treatment was started on inoculation. Less transmissible variants appear less susceptible.
Our findings suggest there may be a role for pre- or post-exposure prophylactic antiviral treatment in areas with presence of highly transmissible variants. Furthermore, clinical trials with borderline efficacious results should consider identifying VOCs and examine their impact in post-hoc analysis.
Some excerpts from the paper
... we used a pharmacometric model to simulate treatment with ivermectin (IVM). We selected IVM as it is a drug with well described pharmacokinetics but so far only little documented benefit in SARS-CoV-2 infections.
...
Early treatment of SARS-CoV-2 infections achieved the greatest effect on total exposure and peak load, as previously noted8,11,12. Importantly, emerging highly transmissible VOCs appear to be more susceptible to antiviral treatment. The authors would like to stress that ivermectin was used as a placeholder to study the effects on altered within-host infectivity in lieu of other drug repurposing candidates, not as an endorsement for use in patients infected with a VOC esp. while evidence for its clinical efficacy is still emerging 13 . The drug, however, is the subject of ongoing trials which could benefit from our findings, and its pharmacokinetic characteristics are well defined14.
...
Given that many trials have included subjects during a time when the now discovered VOCs had already been circulating, 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 uncover significant effects against certain variants even when no effect was seen on trial level. If successful, this would open up additional avenues for early treatment or prophylaxis that could complement vaccine campaigns in areas of high VOC prevalence, esp. as long as these are still suffering from production shortages and supply chain problems.
[-] TehCaster | 3 points | Apr 21 2021 01:22:03
In which authors (including Carlos Chaccour) argue for the usefulness of pre- or post-exposure prophylactic antiviral treatment due to new variants, even with ongoing vaccination.
Abstract
As of March 2021, no antiviral drug regimen has proved effective against SARS-CoV-2 infection. 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. Emerging Variants of Concern (VOCs), e.g. B1.1.7, B.1.351, and B.1.1.248, however, are characterized by higher transmissibility (R0).
Here we model and simulate the effect of altered R0 on viral load profiles, and its impact on antiviral therapy. As a hypothetical case study, we simulated treatment with ivermectin 600µg/kg for 3 days initiated at different time points around the infection. Simulated mutations range from 1.25 to 2-fold greater infectivity, but also include putative co-adapted variants with lower transmissibility (0.75-fold).
Antiviral efficacy was correlated with R0, making highly transmissible VOCs more sensitive to antiviral therapy. Viral exposure was reduced by 42% compared to 22% in wild type if treatment was started on inoculation. Less transmissible variants appear less susceptible.
Our findings suggest there may be a role for pre- or post-exposure prophylactic antiviral treatment in areas with presence of highly transmissible variants. Furthermore, clinical trials with borderline efficacious results should consider identifying VOCs and examine their impact in post-hoc analysis.
Some excerpts from the paper
... we used a pharmacometric model to simulate treatment with ivermectin (IVM). We selected IVM as it is a drug with well described pharmacokinetics but so far only little documented benefit in SARS-CoV-2 infections.
...
Early treatment of SARS-CoV-2 infections achieved the greatest effect on total exposure and peak load, as previously noted8,11,12. Importantly, emerging highly transmissible VOCs appear to be more susceptible to antiviral treatment. The authors would like to stress that ivermectin was used as a placeholder to study the effects on altered within-host infectivity in lieu of other drug repurposing candidates, not as an endorsement for use in patients infected with a VOC esp. while evidence for its clinical efficacy is still emerging 13 . The drug, however, is the subject of ongoing trials which could benefit from our findings, and its pharmacokinetic characteristics are well defined14.
...
Given that many trials have included subjects during a time when the now discovered VOCs had already been circulating, 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 uncover significant effects against certain variants even when no effect was seen on trial level. If successful, this would open up additional avenues for early treatment or prophylaxis that could complement vaccine campaigns in areas of high VOC prevalence, esp. as long as these are still suffering from production shortages and supply chain problems.
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