Discussion
We have argued that the selectivity of anti-viral therapy can be
significantly enhanced by exploiting matching of the drug based on its
purported mechanism of action with the viral cell cycle dynamics.Table 2 summarizes the association of the mechanism of action
of currently tested repurposed molecules for COVID-19 with the specific
rate constants. It is interesting to note that of these drugs, those
drugs that target the conversion rate constant alone, such as those that
target viral proteolysis, RNA dependent RNA polymerase, and those that
act nonspecifically such as ivermectin, cyclosporine and nitrozoxanide
are least likely to result in meaningful efficacy based on the model
described in this manuscript. This is supported by weight of evidence
(clinical trial or white paper based arguments) that has been generated
so far on remdesivir [7, 8], protease inhibitors [20], and
ivermectin [21], that either indicates that the effects are likely
to be negligible to modest at best.
Our simulations demonstrated some important themes for consideration of
combination treatments targeting the SARS-CoV-2 cell cycle. In general,
antivirals should be initiated as early in the course of infection as
possible to maximize impact on viral load AUC, duration of viral
shedding and number of epithelial cells infected. This was a common
theme across the scenarios and endpoints evaluated. Indeed, beginning
treatment beyond 3 days after peak viral load is unlikely to have any
meaningful impact on endpoints that may correlate with patient symptoms
according to our simulations, but benefit for later intervention may
persist beyond for clinical and public health endpoints associated with
duration of viral shedding. As prolonged viral shedding phenotypes are
described for influenza [22] and COVID-19 [23], we performed
sensitivity analyses with c and δ. We observed in prolonged viral
shedder phenotypes that cessation of viral shedding benefit persists for
therapeutics that promote virion kill (c), infected cell death (δ) and
inhibit virion release (ρ). Such interventions would be preferred to
address so-called SARS-CoV-2 super spreaders [24, 25].
To illustrate the potential benefit of combinations of repurposed drugs,
example combinations were drawn from the current trial literature
(Table 3 ).
We assumed modest effect (0.333 log10 effect, 53.6% inhibition, 1.15
fold increase) for each target. Single target interventions were
selected as β, δ, ρ, c; two target intervention was selected as δρ;
three target interventions were selected as δρc and βδρ; four target
interventions was selected as βδρc. Figure 4 shows the output
of these simulations at different intervention times. Supplemental
Figure3 and
Figure 4A shows the predicted impact on viral and infected
epithelial cell kinetics assuming intervention three days before peak
viral load. For the single interventions (top row) β, δ, ρ, c, no single
intervention is sufficient to halt viral growth, but each blunts the
peak and may shift the timing of peak viral load. However, a meaningful
(> 2 log10) improvement in epithelial cells infected is
expected. The combination interventions (bottom row) δρ, βδρ, cδρ, βδρc
follow. The two-target intervention, δρ, shows a similar “blunting and
delaying” quality on viral load as the single-target interventions, but
better overall suppression of viral load and epithelial cell infection.
In contrast, the three- and four-target interventions halt viral growth
and (nearly) abolish epithelial cell infection. As a reminder, each
element of each intervention is assumed to have a modest effect, so the
results shown for the multiple-target combinations express their
cooperative/synergistic effect on viral load and infected epithelial
cells.
Figure 4B shows the predicted impact on viral and infected
epithelial cell kinetics assuming intervention at peak viral load. As
above, the single interventions have modest effect on viral load, with δ
identified as ideal for reducing duration of viral shedding and c
identified as ideal for reducing viral load AUC (Table 1 ). A
three log10 reduction in uninfected epithelial cells is expected. The
three- and four-target interventions somewhat improve duration of viral
shedding, but the biggest gain is observed in a one log10 improvement in
uninfected epithelial cells, with β identified as ideal for reducing
infected epithelial cells (Table 1 ).
Figure 4C shows the predicted impact on viral and infected
epithelial cell kinetics assuming intervention three days before peak
viral load. Some modest gains are possible for duration of viral
shedding, with δ identified as ideal for reducing duration of viral
shedding and c identified as ideal for reducing viral load AUC
(Table 1 ). Very little improvement in infected epithelial cells
is predicted, reinforcing the primary finding of this work and others
that early intervention is critical. Here, we explicitly report the
effect on host cell damage, which has been underappreciated in prior
efforts.
Table 1 captures the primary results of this simulation study,
reporting that interventions targeting the host-cell “factories” forde novo virions are broadly effective in reducing the magnitude
of viral load and infected epithelial cells and reducing the duration of
viral shedding. Mechanisms that promote infected cell death (δ) and/or
reduce copies of virions per infection (ρ) achieve this goal.
Simulations results suggest interchangeability of these effects, with
the noted exception of reducing duration of viral shedding where δ is
superior to ρ. Interchangeability suggests additive effects, from
simplistic anergy/additivity/synergy perspective, but also offers an
opportunity to combine two low-potency agents, each targeting one
mechanism, to boost the overall potency of the combination. Within the
host cells, simply delaying the viral replication machinery (k) is not a
good strategy.
Outside or on the border of host cells, Table 1reports differing strategies that depend on the objective of the
intervention. Mechanisms that remove circulating virus (c) are broadly
effective in reducing the viral load AUC and infected epithelial cells
and reducing the duration of viral shedding. Mechanisms that prevent
viral entry and infection of host cells (β) are only effective prior to
peak viral load or if only focused on sparing host cell infection. Put
simply, killing virus (c) both removes virus and prevents infection.
Vaccines and antibodies fall into the category of removing circulating
virus (c), and are predicted to have strong effects even at low potency
if administered early (or before, in the case of vaccines) in the course
of infection.
Given that the full time course is rarely measured in clinical
evaluations with the exception of PEP studies, viral load AUC is a
largely insensitive endpoint to evaluate potential therapeutic
interventions. This is because of their dependence on the
pre-intervention viral load values. For a therapeutic intervention to
work in this regard, it needs to exhibit a rapid pharmacological onset
(e.g., loading dose, direct rather than indirect pharmacology) and needs
to be effective at clearing the virus. Treatments targeting c (killing
of released virions) were the most effective, meaning that interventions
like convalescent plasma, or investigational antibodies would be
anticipated to be most likely to impact total viral load meaningfully.
Of the therapies being investigated, remdesivir was recently shown in
hospitalized adults with moderate disease to provide a 31% faster time
to recovery than those who received placebo (p<0.001) [8],
but no virologic information was reported. However, in the study by Wang
et al. [7], remdesivir had no meaningful effect on viral load.
Remdesivir is thought to play a role in the incorporation into new viral
RNA, leading to the inability of the viral polymerase to add new RNA.
In the absence of key mechanistic information, we assumed that
remdesivir reduces the production of new virions by halting replication
of its genome, and thus its effect is proximally associated with ρ. It
is possible that remdesivir may show meaningful efficacy if studied in
more early infection phase. Future data on remdesivir in early onset
mild patients with COVID-19, combined with suitable therapeutics will
likely inform on the benefits of early intervention for this molecule.
Duration of viral shedding is less time sensitive to perturbation than
viral load AUC and epithelial cells infected and is also influenced by a
broader array of pharmacological interventions in the SARS-CoV2 cell
cycle. Unlike both epithelial cells and viral load AUC, treatments
targeting δ (death of infected cells) were the most effective against
duration of viral shedding. The concept of early intervention with
combination treatments targeting δ was validated in the clinic recently,
where an open label, prospective, randomized early treatment study
(median 5 days, [IQR 3-7 days] since symptom onset) showed triple
combination of ribavirin, lopinavir/ritonavir, interferon (which all
target δ) reduced viral shedding by 5 days sooner versus Lop/r alone
[9]. Such findings may translate into meaningful benefits for
patients and society, as duration of viral shedding may impact duration
of hospital stay or isolation for an individual, and risk of
transmission to others and the associated costs from a public health
perspective [17].
The SARS-CoV-2 cell cycle provides some foundational basis for the
selection of existing treatments with pharmacological plausibility
within a set of combination regimens. To maximize sparing of epithelial
cells and potential consequences of downstream cytotoxicity and
pulmonary inflammation, a treatment regimen should include treatment(s)
that maximize pharmacology on β (inhibition of new epithelial cell
infection) like camostat, chloroquine and hydroxychloroquine, or
influence rho as evidenced via remdesivir. To reduce duration of viral
shedding, treatment regimens should include components that effectively
reduce δ (death of infected cells) such as ribavirin,
lopinavir/ritonavir and/or interferon. Interventions like convalescent
plasma, or investigational antibodies such as RGN-COV2 and other
investigational antibody treatments targeting c (killing of released
virions) have the most significant promise in rapidly reducing viral
load and will be a welcome addition to the combination armamentarium.