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.

Grant Number: 5R21AI174041-02
NIH Institute/Center: NIH
Principal Investigator: ADEEL BUTT