Effects of antivirals on patients with COVID-19 breakthrough – BMC Infectious Diseases – BMC Infectious Diseases

Study design and participants

A retrospective cohort study was conducted at Nhan Dan Gia Dinh (NDGD) Hospital, a general tertiary hospital in Vietnam. Participant recruitment was taken by screening a sampling frame of patients under the management of NDGD Hospital from January 1, 2021, to January 31, 2022. We included patients who: (1) were 18 years old; (2) were fully vaccinated against COVID-19 before infection (received at least 2 doses, either homologous or heterologous, of the following vaccines: BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), AZD1222 (AstraZeneca), or BBIBP-CorV (Sinopharm), at least 2 weeks before getting first COVID-19); (3) had a confirmative diagnosis of COVID-19 (positive to either real-time polymerase chain reaction test or rapid antigen test with typical symptom(s) of COVID-19); and (4) agreed to participate. Patients were excluded if they: (1) were pregnant or breastfeeding; (2) were severely or critically ill before treatment (based on the clinical spectrum proposed by the NIH [13]); (3) were moderately or severely immunocompromised (immunosuppressive medications, moderate or severe primary immunodeficiency, advanced or untreated human immunodeficiency virus infection, active cancer treatment, or white blood cell count<4109/L); (4) were renally impaired (estimated glomerular filtration rate<30 mL/minutes/1.73 m2); or (5) were hepatically impaired (ChildPugh class B or C).

We followed the participants until March 31, 2022, or until they left the study. We reported this study in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement (Supplementary Checklist, available in the Supplementary File).

Two groups were investigated, of which patients were given: (1) standard of care (SoC, control group) or (2) standard of care plus antiviral (SoC+antiviral). In our study setting, SoC referred to treatment with appropriate medications (excluding antivirals) and supportive care that aligned with the guidelines of Vietnams Ministry of Health [14], WHO [11, 15], IDSA [12], and NIH [13]. Antivirals included remdesivir, molnupiravir, and favipiravir. Remdesivir was given by intravenous infusion to hospitalized patients, with 200mg on the first day and 100mg on the next 4 days. Molnupiravir was taken orally, with 800mg twice daily for 5 days. Favipiravir was also an oral antiviral with dosage of 1,600mg twice daily on the first day and 600mg twice daily on the next days (duration of 57 days).

The primary outcome was residual respiratory symptoms of COVID-19 breakthrough (including but not be limited to cough, dyspnea/shortness of breath/difficulty breathing, congestion, sore throat, loss of smell), measured in frequency. Based on our pilot data, the proposed timeframe cut-off to classify residual symptoms in COVID-19 breakthrough was 7 days. Thus, patients having respiratory symptoms after day 7 (from the day with first symptoms or diagnosis, whichever happened first) were counted towards the primary outcome. As these participants were under the management of NDGD Hospital, they were encouraged to self-report symptoms of COVID-19 every 12 days until resolution using MyCap platform [16]. For data collection, patients without self-reported records were contacted to retrieve the this outcome.

The secondary outcome was long COVID-19 [17,18,19], measured in frequency. This was diagnosed by specialized physicians in COVID-19 at NDGD Hospital using the guideline of the National Institute for Health and Care Excellence [19]. Following that, long COVID-19 includes ongoing symptomatic COVID-19 (signs and symptoms of COVID-19 from 4 weeks up to 12 weeks) and post-COVID-19 syndrome (signs and symptoms that develop during or after an infection consistent with COVID19, continue for more than 12 weeks and are not explained by an alternative diagnosis) [19]. We collected these data by screening patient health records for long COVID-19 diagnosis.

We calculated the sample size using the online website Power and Sample Size [20], with type I error rate () of 5%, power (1 - ) of 80%, and a sampling ratio of 1:1. Following the findings of Bergwerk et al., 31% of infected healthcare workers had residual symptoms 14 days after diagnosis [21]. Given that our study was conducted on the general population with a 7-day cut-off, we estimated the primary outcome could be found in at least 41% of the patients. For antivirals to be considered effective against COVID-19 breakthrough in low and middle-income countries like Vietnam, we expected a reduction of at least 50% in the primary outcome, resulting in a minimum sample size of 144 patients. Thus, we decided to recruit 150 patients.

Considering our study setting, the following factors were identified as potential confounders: gender (female/male), age (in years), weight (in kg), height (in cm), comorbidities, and concurrent medications. To avoid overadjustment bias, we excluded medications for comorbidities, keeping only those that were used for COVID-19 treatment.

We removed observations that were missing or lost to follow-up from analysis. We presented demographic and baseline data as mean with standard deviation for continuous variables or as frequency with percentage for categorical variables. Incidence rates (using Poisson regression) and odds ratio (OR, using logistic regression) were given with 95% confidence intervals (95% CI). As there were 3 nationally approved antivirals for COVID-19 in Vietnam during this study timeframe (remdesivir, molnupiravir, and favipiravir), effect estimates might be biased by favipiravir due to its lack of evidence. To test the robustness of our findings, we conducted a sensitivity analysis by removing observations with favipiravir use. Since antivirals were primarily recommended for high-risk patients, we also wanted to explore these medications effects on both outcomes with a priori subgroup analysis. The subgroups were pre-specified based on the following variables: gender (male/female), age (<65/ 65), comorbidities (yes/no), and corticosteroid use (yes/no). This subgroup analysis was considered exploratory to generate new hypotheses (if available), so we did not attempt to adjust for multiplicity. All statistical hypotheses were tested with a confidence level of 95%. We performed all analyses using R software (version 4.2.1, R Foundation for Statistical Computing, Vienna, Austria).

This study was approved by the Institutional Review Board of NDGD Hospital, Ho Chi Minh City, Vietnam, under approval number 85-2021/CN-HDDD. All recruited participants gave their informed consent.

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Effects of antivirals on patients with COVID-19 breakthrough - BMC Infectious Diseases - BMC Infectious Diseases