Early antiviral treatment to prevent viral persistence and inflammation as drivers of Long COVID: a proof-of-concept mechanistic trial

PROJECT SUMMARY/ABSTRACT In the months to years following an episode of COVID-19, SARS-CoV-2 RNA and protein can be detected in the blood and tissue of many people, and ongoing immune activation and inflammation have been shown to persist across the whole body. Both SARS-CoV-2 persistence and inflammation are associated with an increased likelihood of Long COVID, a chronic disease state set off by SARS-CoV-2 infection, and have been proposed as potential drivers of other post-acute sequelae, such as cardiovascular events. Thus, preventing SARS-CoV-2 persistence and its downstream effects may significantly reduce chronic illness and improve long-term health. The total viral burden (maximum nasal viral load, duration of infectious shedding) during the acute phase has also been tied to later development of Long COVID. We hypothesize that poorly controlled viral replication during the acute phase of COVID-19 results in a higher viral burden that drives a biological pathway resulting in (1) post-acute viral persistence and (2) a pathogenic inflammatory response, which together contribute to adverse clinical outcomes. If this is true, then targeting the virus early and in a sustained manner with a tissue-penetrant drug could prevent post-acute antigen persistence and inflammation, as well as their downstream consequences. To test this conceptual model, we will conduct a single-center, phase 2, home-based, randomized, controlled trial (1:1) of a 14-day course of the novel oral antiviral protease inhibitor EDP-235 (Enanta Pharmaceuticals) vs. placebo among 150 outpatients with acute COVID-19 enrolled within 5 days of symptom onset and followed for 180 days. During the acute phase, we will examine whether treatment versus placebo reduces the total viral burden over the first 30 days, as assessed by nasal antigen positivity, infectious viral shedding, and virologic rebound. The study's primary outcome - tissue persistence of SARS-CoV-2 - will be evaluated on gut biopsies collected via flexible sigmoidoscopy during the post-acute phase (90 days post-COVID), and will be assessed using a multiplex immunofluorescence and immunohistochemistry platform; blood-based measurements of SARS-CoV-2 spike and nucleocapsid antigen (single molecule arrays, Simoa) and activation/differentiation states of SARS-CoV-2-specific T cells (spectral flow cytometry) will also be used. Finally, we will assess the effect of early COVID-19 treatment on whole-body T cell activation and inflammation during the post-acute phase (90 days post-COVID) using blood-based measurements (proteomics, Simoa) and non-invasive PET/CT imaging with [18F]F-AraG, a radiotracer specific for T cell activation. To achieve these goals, we will leverage our established COVID-19 research infrastructure to study acute and post-acute COVID-19 which to date has supported 5 clinical trials and more than 75 collaborations on post-COVID biology. This will be among the first preventive therapeutic trials seeking to alter biological events during acute COVID-19 to reduce viral persistence and inflammation, both processes associated with post-acute chronic illness. If successful, it will be a foundation upon which a prevention agenda for chronic post-acute sequelae of viral infections can be built.