Oral Antivirals against COVID-19 and Clinical Outcomes in High Risk Populations

COVID-19 has led to over 350 million reported cases and over 5.6 million resulting deaths globally, and nearly 72 million cases and >900,000 deaths in the US. Highly effective vaccines are now available and are the first line of defense. However, immunity wanes off over time and breakthrough infections in fully vaccinated persons have been reported, particularly with the newer variants. In December 2021, two novel oral antiviral agents, Nirmatrelvir/ritonavir (NMV/r) and Molnupiravir (MPV), were granted Emergency Use Authorization (EUA) by the FDA for treatment of early symptomatic patients with mild to moderate COVID-19 at high risk of progression to severe disease. These authorizations were granted based on limited published data, and critical questions about their comparative effectiveness, effectiveness in the real-world settings, and effectiveness in specific high-risk sub-populations remain to be answered. There is an urgent need to understand the real-world effectiveness of these drugs, especially in the high-risk and vulnerable populations, as well as longer term clinical outcomes in treated patients. Such knowledge is essential for the patients, providers, payors, and policymakers, to ensure that they are used only in the appropriate populations and situations based on strong clinical evidence. To address these critical gaps in knowledge, we propose the following hypotheses: Hypothesis 1: Treatment with NMV/r or MPV will be associated with a significant reduction in COVID-19 related hospitalization and 30-day all-cause mortality in older persons, those with a high comorbidity burden, and in socially vulnerable persons. Hypothesis 2: We hypothesize that NMV/r and MPV treatment will be associated with a significant reduction in subsequent hospital admissions, emergency department visits, and outpatient clinic visits over a 1-year period after recovery. Treatment will also be associated with a lower incidence of acute myocardial infarction, stroke, decline in renal function, and diabetes, compared with propensity-score matched untreated persons. We will use the Department of Veterans Affairs’ COVID-19 Shared Data Resource (VA ORDCOVID) which contains extensive demographic, clinical, pharmacologic, laboratory, vital signs and clinical outcomes information derived from multiple validated sources. We will compare those treated with NMV/r or MPV with propensity-score matched untreated controls, matched on demographics, clinical variables, severity of presenting illness, geographic location, time of treatment, vaccination status, time from completion of a full course of vaccination, and booster dose administration. The PI, Dr. Butt has extensive experience in creating and analysing large national databases and has published 45 papers on COVID-19 in journals including the New England Journal of Medicine, Annals of Internal Medicine, JAMA Internal Medicine, Journal of Clinical Investigation, Nature Medicine, and others. He already has IRB approval to study the epidemiology, natural history, and clinical outcomes of SARS-CoV-2 infection in the VA population.