Results
Figure 2 reports the overview of treatment effects by
intervention time and disease metric. The major points from this
overview are:
- Outcome improves for every disease metric with earlier intervention.
This suggests that PrEP- and PEP provides the best opportunity for
repurposed drugs with (potentially) low potency to impact disease.
- Treatment initiated after viral peak have little to no impact on viral
load AUC. Treatments initiated 3 days after viral peak have no impact
on Epithelial Cells Infected. Treatments initiated after viral peak
still have potential to shorten the Duration of viral shedding.
- Combinations targeting multiple pathways can be as effective or more
effective as targeting single pathways with equivalent summed
treatment effects. The heterogeneity observed at each summed effect
level suggests that some combinations are less effective than others.
Figure 3 compares all 1 and 2 target treatments by treatment
initiation time (Peak -3, 0, +3 days), endpoint, and 1 and 2 log10
summed drug effect. Supplemental 2 reports results for all combinations.
All endpoints are improved with earlier intervention. The major points
from this presentation are:
- No endpoints are improved with single or combination treatments
targeting k except in the cases of early (Peak -3) intervention with
potent (2 log10 summed drug effect). That is, treatments onlydelaying the transition time between cell infection and
production of new virions are not generally effective.
- Viral load AUC is improved with single or combination treatments
targeting c; δ and ρ are interchangeable and modestly effective.
Single or combination treatments involving β are not effective at or
after viral peak.
- Duration of viral shedding is improved with single or combination
treatments targeting δ; ρ and c are interchangeable and modestly
effective. Single or combination treatments involving β are not
effective at or after viral peak.
- Epithelial Cells Infected is improved with single or combination
treatments targeting β or c and are interchangeable; δ and ρ are
interchangeable and modestly effective.
Table 1 provides a qualitative ranking of target choices by
metric of interest. Slowing transition, k, of infected epithelial cells
from eclipse, I1 , to productive, I2 , is not effective
relative to other target choices. Increasing turn-over, δ, and/or
decreasing productivity, ρ, of infected epithelial cells, I2 , is
predicted to have positive benefit for all metrics and should be
considered a “backbone” of proposed combinations. Broadly speaking,
targeting δ and ρ seek to disrupt the production machinery of
SARS-CoV-2. Increasing virion kill, c, to deplete extracellular virions,V , is predicted to have positive benefit for all metrics.
Inhibiting infection, β, is interchangeable with c for the Epithelial
Cells Infected metric, but not the viral load AUC and Duration of viral
shedding: c both removes virions and prevents infection but β only
prevents infection.
Supplemental Figure 3 and Figure 4 report the predicted impact viral and
infected epithelial cell kinetics assuming intervention six days before
and six days after peak viral load, respectively.