Viral dynamics at the individual and population levels: impact for antiviral treatment optimization – TheraCoV

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originat-ed in Wuhan, China, has become pandemic and a major concern all over the world. By March 22, 2020, this virus has a?ected more than 320,000 people worldwide and caused more than 14,000 deaths. Despite the unprecedented mobilization of the clinical and scientific community, the de-velopment and large scale implementation of vaccines or antiviral drug will take months. To readi-ly propose a first line of defense and combat the virus in hospitalized patients, WHO relies on al-ready existing drugs (“repurposed”) that are immediately available in large quantities and have a good safety profile. In coordination with other European institutions, France will implement on March 23 a randomized clinical trial in hospitalized patients (“DisCoVery”) comparing the efficacy of lopinavir/ritonavir (HIV protease inhibitors), remdesivir (Ebola nucleotide analogue), hy-droxychloroquine and IFN-ß1a. Given the very limited knowledge of the viral, immune and phar-macological factors that may impact treatment outcome, the clinical efficacy of these strategies is largely unknown and could be limited. In order to tease out the determinants of viral dynamics in patients and to demonstrate the effect (or the lack of effect) of these drugs, we propose to char-acterize in detail viral and immune dynamics of SARS-CoV-2. We will rely on data from un-treated patients of the cohort “French Covid” as well as from patients of DiCoVery to provide basic parameters of host-pathogen interaction in vivo, such as virus half-life, immune markers associated with viral clearance, mutation rate. Furthermore, by analyz-ing the effect of drug concentration on changes in viral load over time, we will determine target concentrations of each drug candidate that, in concert with the immune response, maximize viral suppression. This approach will therefore make possible to rapidly evaluate the relevance of cur-rent and future treatments as well as to tailor dosing strategies (dose, duration, combination) ac-cording to patient’s characteristics.
Our approach also aims to study the impact of viral dynamics on the patient-patient transmission. We will analyze the rate of infection in a cohort of index cases and their contacts to determine the association between viral load and the risk of transmission. By analyzing the impact of within-host parameters on disease transmission, we will be able to predict the effects of pre- or post-exposure prophylaxis in at-risk individuals to limit or even suppress viral replication (healthcare personal, high contact cases with co-morbidities), as is currently discussed with hydroxychloroquine.
Finally we will evaluate the benefit of expanded treatment strategies not only at the individual but also at the population level. Current epidemiological models used to inform policy makers do not integrate intra-host dynamics as a core driver of infectivity, and hence cannot predict the impact of larger antiviral strategies. Here, we propose to extend the existing epidemiological models to account for the interplay between the within host and the between-host dynamics. Finally we will evaluate the cost-effectiveness of a larger implementation of antiviral strategies.
It is now clear that we cannot let the epidemic develop in France, and antiviral treatments will be a pillar of our combat against this virus. By combining the largest COVID-19 datasets in France and a unique consortium of clinicians, mathematical modellers and evolutionary biologists, our consor-tium has the capability to unravel the mechanisms of the virological response and to propose practical and readily available antiviral strategies to contain the epidemics.