key: cord-0841124-9sr5b44k authors: Torneri, Andrea; Libin, Pieter Jules Karel; Vanderlocht, Joris; Vandamme, Anne-Mieke; Neyts, Johan; Hens, Niel title: A prospect on the use of antiviral drugs to control local outbreaks of COVID-19 date: 2020-03-20 journal: nan DOI: 10.1101/2020.03.19.20038182 sha: d37e4948cc2342320608f44affdda2cafee28a61 doc_id: 841124 cord_uid: 9sr5b44k Background: Current outbreaks of COVID-19 are threatening the health care systems of several countries around the world. Control measures, based on isolation and quarantine, have been shown to decrease and delay the burden of the ongoing epidemic. With respect to the ongoing COVID-19 epidemic, recent modelling work shows that this intervention technique may be inadequate to control local outbreaks, even when perfect isolation is assumed. Furthermore, the effect of infectiousness prior to symptom onset combined with a significant proportion of asymptomatic infectees further complicates the use of contact tracing. Antivirals, which decrease the viral load and reduce the infectiousness, could be integrated in the 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 for the control of COVID-19. For individuals that were identified through contact tracing, we evaluate two procedures: monitoring individuals for symptoms onset and testing of individuals. Moreover, we investigate the effect of a potent antiviral compound on the contact tracing process. Findings: The use of an antiviral drug, in combination with contact tracing, quarantine and isolation, results in a significant decrease of the final size, the peak incidence, and increases the probability that the outbreak will fade out. Interpretation: For an infectious disease in which presymptomatic infections are plausible, an intervention measure based on contact tracing performs better when realized together with testing instead of monitoring, provided that the test is able to detect infections during the incubation period. In addition, in all tested scenarios, the model highlights the benefits of the administration of an antiviral drug in addition to quarantine, isolation and contact tracing. The resulting control measure, could be an effective strategy to control local and re-emerging outbreaks of COVID-19. To control local outbreaks of COVID-19 we investigate the use of contact tracing and isolation in 1 combination with an antiviral compound. Even when perfect isolation is in place, it may not be we calibrate the model to represent the viral load decrease thereof. 23 In this manuscript we first present the effect of isolation, considering both home quarantine (for 24 individuals that are part of a contact trace network and for infected individuals with mild symptoms) 25 and hospital isolation (for severe cases). We argue that when an individual is quarantined at home, 26 this will only result in a partial reduction of contacts, accounting for contacts with household 27 members and other isolation imperfectness. To compensate for this imperfect isolation, we consider 28 the use of an antiviral compound. We test these different control measures in a simulation study 29 that aims at representing, given the available information, the current COVID-19 epidemic. When such contacts generated between susceptible and infectious people, these can result in an 42 infection event according to a Bernoulli probability value based on the time since infection. This 43 probability is computed, at a precise time point, as the product of two components: the infectious-44 ness measure, ν(t), which quantifies the level of infectiousness over time, and the total amount of 45 infectivity q, i.e. the number of infections over the contact rate [12] . The function ν(t) is defined 46 over the exposed and infectious period, or analogously over the incubation and symptomatic period, 47 along which it integrates to one. This function is scaled to have a similar shape among different 48 infectives, based on their lengths of exposed and infectious period. According to this framework, 49 an infectious individual makes effective contacts at a rate, r(t) given by: where λ is the contact rate. The mean number of effective contacts is an approximation of the 51 reproduction number. The two quantities are identical in an infinite and homogeneous population, 52 where the probability of making two effective contacts with the same person is zero. For the 53 considered population size, the probability of this event is extremely low. Therefore, throughout 54 the manuscript, we approximate the reproduction number with the mean number of secondary 55 cases. In the considered framework, isolation/quarantine is implemented by reducing the contact rate 57 λ at the time of diagnosis. To date, little is known about the difference in viral load among 58 severe and mild cases. Zhou et al. [19] indicate that in nasal and throat swabs the viral load is 59 higher in mild cases. However, virus was detected also in blood and stool sample [9] . Due to this 60 uncertainty, we assume that the same curve is defined for all the infected individuals. In this work, 61 we assume the population to be homogeneous, closed and finite population. The former assumption 62 was chosen because of the limited knowledge on the COVID-19 determinants as mentioned above. The two latter assumptions relate to the control measures currently in place, e.g. in Italy, aiming 64 at containing immigration and emigration in a country with an ongoing outbreak. 65 In Table 1 we report the parameters and distributions that were utilized in the simulation study. Where distributions are not reported, the parameters are assumed to be constant. In the last 67 column, when available, we report the references to the literature that justifies the choice of the 68 parameter value, or distribution, we use. throat swabs data [19] . The time to hospitalization is estimated from the data presented in [1] . We 77 assume that the time to hospitalization coincides with the time of diagnosis. At this time-point, 78 depending on the severity of the symptoms, individuals are isolated (severe cases) or quarantined 79 (mild cases). The population size is set to 500 to represent a localised outbreak of COVID-19. Furthermore, we assume that the contact tracing starts when individuals are diagnosed. We assume that traced-back individuals that test positive are isolated in the 16% of cases. The 88 quarantine will result in a decreased contact rate (i.e. imperfect isolation), λ q , while in case of perfect 89 isolation the contact rate is set to zero. Similarly, diagnosed individuals will also be quarantined: at home (mild symptoms), with a decreased contact rate λ q , or in the hospital (severe symptoms), 91 where we assume that perfect isolation is possible. We assume that 16% of infections is severe and 92 require hospitalisation [4] . 93 To compensate for imperfect isolation we investigate the use of antiviral compounds to reduce the 94 infectiousness of an infected individual. We assume that, once the antiviral compound has been 95 administered, the infectiousness measure will exponentially decay according to an inverse Malthusian 96 growth model (shown in Figure 2 ) [8] . The rate of this decay is set to represent the reduction in 97 viral load, due to Remdesevir, as reported in [11] for the MERS coronavirus. Figure 2 : Reduction of infectiousness. The blue and the orange lines describe the infectiousness measure, respectively, before (dashed blue) and after antiviral injection (solid yellow). The red arrows indicate the injection times. 98 4 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We assume the following parameters for the reduction of contacts because of home quarantine: λ q = 99 0.1λ, 0.25λ, 0.5λ and for the probability of tracing back a contact in history H i : η = 0.25, 0.5, 0.75 [6] . Scenarios: In all the considered scenarios we assume that individuals are isolated, or quarantined, 101 when diagnosed. Moreover, we assume that contact tracing starts at the time of diagnosis. IAS: Traced individuals are monitored for two weeks, and isolated/quarantined if they show symptoms during this period. This scenario is similar to the baseline scenario described by Hellewell et al. [5] with the exception that in our description only severe cases are isolated while the mild are home quarantined. This scenario reflects more realistically the current practice of containment. IBS: Traced individuals are isolated/quarantined, as soon as they test positive for SARS-COV-2. We assume that an individual that is infected tests positive 2 days after infection. Therefore, a traced individual is tested immediately when traced, and, if this test was negative, we test the individual again two days later. IBTBS: Diagnosed patient is immediately treated with the antiviral drug. Furthermore, traced individuals are isolated/quarantined and injected with the antiviral drug, as soon as they test positive for SARS-COV-2. We assume that an individual that is infected tests positive 2 days after infection. Therefore, a traced individual is tested immediately when traced, and, if this test was negative, we test the individual again two days later. For each scenario we run 5000 simulations. Among these, we compute the mean final size and the 103 cases at peak for the one in which at least the 10% of individuals have been infected. Doing this, 104 we only account for outbreaks that are most challenging to contain. 105 Quarantine, isolation and antiviral treatments lead, in different levels, to the mitigation of the 106 outbreak by reducing the final size as well as by reducing the number of cases at the peak of 107 the epidemic. The containment performance depends, among all the scenarios, on the probability 108 to successfully trace contacts and on the reduction in contact rate due to quarantine ( Figure 3 ). Isolation and quarantine lead to a substantial decrease in mean final size and peak incidence. When 110 performed prior to symptom onset their efficacy increases, which is important, as there is a positive 111 probability of presymptomatic infection [3] . The antiviral treatment is shown to have a substantial 112 impact and, together with quarantine and isolation, significantly reduces the mean final size, the 113 peak incidence and the number of outbreaks that are most challenging to contain. 114 We assume that we have sufficient antiviral drugs doses to treat all individuals that are encountered 115 via the contact tracing procedure. This is motivated by the fact that we consider an emerging 116 outbreak and the required number of doses will thus be limited. Furthermore, we assume that all the individuals will show symptoms, sooner or later, during their 118 infectious period, and therefore all infected individuals will be diagnosed. Due to the awareness of 119 COVID-19 given by media and government officials, individuals are more likely to act upon even 120 mild symptoms. This assumption is in line with the work of Hellewell et al. [5] . Moreover, we 121 assume that all infected individuals will eventually be diagnosed. While this is a limitation of our 122 5 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 20, 2020. study, we argue that in the scenarios where we aggressively trace and treat the contacts of individ-123 uals, we are more likely to find (and constrain) cases that would otherwise go undetected. In the hospital, we assume perfect isolation, meaning that infected individuals cannot spread the 126 infection. However, health care workers are at risk and they could be infected by infected individuals 127 in isolation [5] . In the IBS and IBTBS scenarios we assume that the traced individuals that test positive are 129 isolated in the 16% of cases, even before showing actual severe symptoms. This is a simplification; a 130 more realistic implementation would be to first quarantine cases and isolated them when the severe 131 symptoms onset. We expect that our implementation may only slightly affect the outcomes, without The ongoing epidemic of COVID-19 threatens the health system of many countries. Control strate-153 gies are fundamental measures that public health officials must implement to contain this epidemic. Isolation and quarantine can be of great importance, however, relying on their exclusive use could 155 fail to contain an ongoing outbreak. In addition, when several infected individuals need hospital 156 care, the number of cases at peak should be minimized as much as possible to avoid that regions 157 run out of hospital capacity. With this study we highlight the impact of a potential antiviral com-158 pound that reduces the viral load and, consequently, the infectiousness of infectives. We describe 159 the action of Remdesivir, however, the proposed investigation can be extended to other antivirals, 160 with the caveat that the efficacy of administering an antiviral compound, in addition to isolation 161 and quarantine, depends on the effectiveness of the respective drug. We show that the use of this 162 compound leads to a substantial reduction of the mean final size and the peak incidence. In ad-163 dition, the number of outbreaks that are most challenging to contain decreases when the antiviral 164 is administered to diagnosed and traced individuals. Therefore, the administration of an antiviral 165 drug, together with isolation and quarantine, is expected to have a major impact in the control of 166 local COVID-19 outbreaks. 167 We remain hopeful that the ongoing clinical trials will reveal an antiviral compound that can be Besides his employment at the Hasselt University, JV is employed at Bioqube Ventures. Bioqube Ventures was not involved in this work, nor does it prosper financially as a result of the current 188 study. The other authors declare that they have no competing interests. 189 7 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We report in Figure 4 and 5 the sensitivity analysis for the quarantine contact rate: λ q = 0.1λ, 0.5λ. The introduction of an antiviral compound substantially contributes in reducing the mean final size, 193 the peak incidence and the probability of a challenging outbreak in all the considered settings. This 194 decrease, compared to the scenario in which only isolation/quarantine is implemented, increases 195 when quarantine is less effective (left panels). In Figure 6 and 7, we vary the reproduction number 196 that is set, respectively, to R 0 = 2 and R 0 = 3. The effect of the antiviral drug, in addition to 197 isolation and quarantine, increases when the reproduction number increases. In case of R 0 = 3, (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Figure 6 : Mean final size distribution (left panel) and mean peak incidence for Scenario IAS (yellow), Scenario IBS (green) and Scenario IBTBS (blue) when the quarantine contact rate is λ q = 0.25λ, and R 0 = 2. In the left panel, for each scenario we report the probability that a simulation leads to a number of cases smaller than the 10% of the population (purple asterisks). In the right panel, together with the point estimates we report the 2.5% and 97.5 % percentiles. Figure 7 : Mean final size distribution (left panel) and mean peak incidence for Scenario IAS (yellow), Scenario IBS (green) and Scenario IBTBS (blue) when the quarantine contact rate is λ q = 0.25λ, and R 0 = 3. In the left panel, for each scenario we report the probability that a simulation leads to a number of cases smaller than the 10% of the population (purple asterisks). In the right panel, together with the point estimates we report the 2.5% and 97.5 % percentiles. 9 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 20, 2020. Figure 8 : Mean final size distribution (left panel) and mean peak incidence for Scenario IAS (yellow), Scenario IBS (green) and Scenario IBTBS (blue) when the quarantine contact rate is λ q = 0.25λ, R 0 = 2.5 and the test detect positively an infectious individual after 4 days since infection. In the left panel, for each scenario we report the probability that a simulation leads to a number of cases smaller than the 10% of the population (purple asterisks). In the right panel, together with the point estimates we report the 2.5% and 97.5 % percentiles. Incubation period of 2019 novel coronavirus (2019-ncov) infections among travellers from wuhan, china Has china faced only a herald wave of sars-cov-2? 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