Underuse of Antiviral Drugs to Prevent Progression to Severe COVID-19 — Veterans Health Administration, March–September 2022

Methods

Study Cohort and Patient Characteristics

Data on vaccination and SARS-CoV-2 infection and demographic and clinical data were obtained from the VA COVID-19 Shared Data Resource (7) and from electronic medical records (EMRs) and vital status in the Corporate Data Warehouse, respectively. The VA Joint Legacy Viewer interface, a web application that provides an integrated read-only view of EMR data from the VA, Department of Defense, and community partners^†,§ was used for chart review.

The first date of a documented positive SARS-CoV-2 test result was used to define infection after vaccination. Data were limited to infections documented from March 1, 2022 (when effective oral antivirals became widely available to treat outpatients with mild-to-moderate COVID-19) (5), through September 30, 2022. Patients with a diagnosis of solid organ transplantation, CLL, or plasma cell malignancies were initially identified by single use of International Classification of Diseases, Tenth Revision (ICD-10) codes during January 1, 2021–September 30, 2022. Use of immunosuppressive or antineoplastic drugs was ascertained 3–12 months before the date of infection (depending on the drug). Nonuse of oral (by outpatient pharmacy dispensing records) or intravenous antiviral drugs (by orders placed) was preliminarily ascertained from 5 days before (to identify treatment based on a non-VA test) to 28 days after the VA test. The electronic search for prescription of an antiviral was limited to nirmatrelvir/ritonavir, molnupiravir, and monoclonal antibodies, because pharmacy records preclude distinguishing between remdesivir use to treat versus prevent severe COVID-19 (5). Severe COVID-19 was defined as 1) death within 28 days after the positive test result, or 2) hospitalization with either use of dexamethasone or evidence of at least mild hypoxemia (minimum oxygen saturation <94% or any use of supplemental oxygen) (8).

Comorbidities were defined using ICD-10 codes per the Chronic Conditions Warehouse^¶ during the 12 months preceding initial vaccination.** Presence of comorbidities was summarized as a count (0–6) of six chronic conditions that have been associated with severe COVID-19 after vaccination (8,9). To improve representativeness of the high-risk VA population and to reduce the prevalence of missing data, the study was limited to patients who had documentation of either 2 doses of an mRNA COVID-19 vaccine or 1 dose of an adenoviral COVID-19 vaccine.

Sampling and Inclusion Criteria

The full cohort comprised 1,196 VA patients who received a vaccination for COVID-19; had an ICD-10 code indicating solid organ transplantation, CLL, or plasma cell malignancy; and had received a positive SARS-CoV-2 test result during March 1–September 30, 2022. A random sample of patients without EMR evidence of prescription of antiviral medication was then selected for detailed chart review. To obtain a random sample, a random number was assigned to each case, and cases were reviewed in sequential order beginning with the lowest assigned number until the target number of cases meeting criteria for inclusion was obtained.

After chart review, patients were included in the analysis of reasons for nonreceipt of antiviral medication if the patients met the following criteria: 1) confirmation of a diagnosis of solid organ transplantation, CLL, or plasma cell malignancy; 2) confirmation of no evidence of antiviral use at either a VA or non-VA facility; and 3) initial medical evaluation of mild-to-moderate COVID-19. Review proceeded until 110 cases meeting inclusion criteria were classified. A target of 100 cases was chosen to allow reasonable precision in estimating the frequency of a common event (for example, an outcome of 28% would have a 95% CI of 20%–36%) for a time-intensive process. The aim was to include similar numbers of cases of solid organ transplantation and hematologic malignancies (including numbers of patient with CLL or plasma cell malignancies).

Data Analysis

A member of the study team conducted chart review and classified each case using the following criteria: 1) antiviral was offered, and the patient declined treatment; or antiviral was not offered because of 2) symptom duration >5 days; 3) concern about drug interactions expressed by the provider; 4) administrative barriers or delays; or 5) not determined to be indicated because of mild or asymptomatic disease, with the option for antiviral treatment either rejected by the provider or not mentioned. Reference to a patient’s or provider’s concern for Paxlovid rebound (a phenomenon of temporary recurrence of symptoms shortly after completing a standard 5-day Paxlovid treatment) was also recorded.

Among cases that were reviewed but did not meet inclusion criteria for analysis, the proportion for which an antiviral was received for mild-to-moderate COVID-19 but was not discernible from the initial electronic screen of EMR (e.g., remdesivir given for 3 days, or an oral antiviral given in the emergency department or through a non-VA pharmacy) was determined, to better estimate under usage of antivirals. This activity was determined to be exempt from Institutional Review Board (IRB) oversight or a requirement for informed consent by the IRB of the VA Boston Healthcare System.^††