Current outbreaks of COVID-19 are threatening the health care systems of several countries around the world. Control measures, based on isolation, contact tracing, and quarantine, can decrease and delay the burden buy effexor of the ongoing epidemic. With respect to the ongoing COVID-19 epidemic, recent modeling work shows that these interventions may be inadequate to control local outbreaks, even when perfect isolation is assumed. The effect of infectiousness prior to symptom onset combined with asymptomatic infectees further complicates the use of contact tracing. We aim to study whether antivirals, which decrease the viral load and reduce infectiousness, could be integrated into control measures in order to augment the feasibility of controlling the epidemic.

Methods
Using a simulation-based model of viral transmission, we tested the efficacy of different intervention measures to control local COVID-19 outbreaks. For individuals that were identified through contact tracing, we evaluate two procedures: monitoring individuals for symptoms onset and testing of individuals. Additionally, we investigate the implementation of an antiviral compound combined with the contact tracing process.

Results
For an infectious disease in which asymptomatic and presymptomatic infections are plausible, an intervention measure based on contact tracing performs better when combined with testing instead of monitoring, provided that the test is able to detect infections during the incubation period. Antiviral drugs, in combination with contact tracing, quarantine, and isolation, result in a significant decrease of the final size and the peak incidence, and increase the probability that the outbreak will fade out.

Conclusion
In all tested scenarios, the model highlights the benefits of control measures based on the testing of traced individuals. In addition, the administration of an antiviral drug, together with quarantine, isolation, and contact tracing, is shown to decrease the spread of the epidemic. This control measure could be an effective strategy to control local and re-emerging outbreaks of COVID-19.

Peer Review reports
Background
The use of invasive non-pharmaceutical interventions (i.e. full city lockdown (Wuhan), school closures, cutting inter-city travel and intra-city mobility) was able to bring the epidemic under control in China [1, 2], but these measures are associated with profound societal and economic disruptions. We investigate the use of contact tracing and isolation in combination with an antiviral compound to control local outbreaks of COVID-19, to avoid such invasive social measures, and to preemptively reduce the burden of the epidemic. Even when perfect isolation is in place, this may not be sufficient to contain a local COVID-19 outbreak [3], due to presymptomatic transmission [4, 5]. Therefore, in the absence of a vaccine, an antiviral drug in addition to isolation could be used to contain the current COVID-19 epidemic. There are currently no potent and selective antivirals available against coronaviruses. The development of such potent and safe drugs typically takes 10 years or longer. However, there are a number of drugs that either directly target a viral enzyme (such as the viral RNA-dependent RNA polymerase, e.g., remdesivir and favipiravir) or that have been developed for non-viral indications, but that exert at least some claritin australia level of antiviral activity (the so-called repurposed drugs). We here assume that an antiviral drug will reduce the viral load of an infected individual with COVID-19. For our modeling experiments, we considered the experimental drug remdesivir, for which viral load data were available to inform our model. Remdesivir is an investigational, broad-spectrum antiviral agent that was developed for the treatment of Ebola virus infections. It is a nucleotide analog that inhibits the viral RNA-dependent RNA polymerase and has activity against a wide range of RNA viruses [6]. It is also active against SARS-CoV and MERS-CoV, which can be explained by similarities in the active site of the polymerase of these viruses. Based on this promising activity against other coronaviruses, remdesivir was recently shown to also inhibit SARS-CoV-2 in vitro [7]. As a consequence, this drug is currently under evaluation against COVID-19 in various clinical trials, and based on preliminary efficacy data, the drug was granted emergency use designation for severe COVID-19 patients by the FDA on 1 May 2020. For the aforementioned reasons, we chose to inform our model with data on the control of MERS-CoV viral load by remdesivir in a translational murine model [8]. This animal model was specifically developed to better approximate the pharmacokinetics and drug exposure profile in humans. Therefore, the measure of viral titers in lung tissue at different time points in this murine model serves as a reasonable proxy for viral dynamics upon compound exposure in the controlled setting of a viral challenge. To this end, we calibrate the model to represent the viral load decrease thereof.

In this manuscript, we first present the effect of isolation, considering both home quarantine (for individuals that are part of a contact trace network and for infected individuals with mild symptoms) and hospital isolation (for severe cases). We argue that when an individual is quarantined at home, this will only result in a partial reduction of contacts, since contacts with household members remain and other breaks of isolation can occur. To compensate for this imperfect isolation, we consider the use of an antiviral compound. We test these different control measures in a simulation study that aims at representing, given the available information, the current COVID-19 epidemic. Many countries are already beyond the point where local containment alone will suffice. However, we do expect that the methodology we propose will be key to avoid a second peak, especially given the limited depletion of susceptibles.

Methods
Epidemiological dynamics
The disease dynamics are depicted in the left panel of Fig. 1. The possible transitions between epidemic classes are described by the arrows.


Disease dynamics. Possible transitions among the different epidemic compartments

Full size image
Individuals are initially susceptible (S), and once infected, they enter the exposed class (E). The infection can be asymptomatic (Ia) if individuals do not show symptoms during their infectious periods or symptomatic. Symptomatic individuals, after a presymptomatic period (Ip), can show mild (Im) or severe symptoms (Is). When diagnosed, symptomatic individuals are hospitalized (H) or are confined in home quarantine (Q), based on the severity of symptoms. We assumed that hospitalized individuals are immediately isolated. Asymptomatic individuals, however, are assumed to not be diagnosed. Ultimately, all infectives are assumed to either recover from infection or die (R). Isolation and quarantine start at the time of diagnosis. Isolation is assumed to be perfect; therefore, individuals can no longer transmit the disease. The quarantined individuals, instead, can still make contacts, although at a decreased rate.




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