October 05, 2023

VIEW TRANSCRIPT

Clinical Reports

Long-term Cardiovascular, Cerebrovascular, and Other Thrombotic Complications in Coronavirus Disease 2019 Survivors: A Retrospective Cohort Study
Growing evidence suggests that some coronavirus disease 2019 (COVID-19) survivors experience a wide range of long-term postacute sequelae. Researchers examined the postacute risk and burden of new-incident cardiovascular, cerebrovascular, and other thrombotic complications after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a highly vaccinated multiethnic Southeast Asian population, during Delta predominance. This cohort study used national testing and healthcare claims databases in Singapore to build a cohort of individuals who had a positive SARS-CoV-2 test between 1 September and 30 November 2021 when Delta predominated community transmission. Concurrently, we constructed a test-negative control group by enrolling individuals between 13 April 2020 and 31 December 2022 with no evidence of SARS-CoV-2 infection. Participants in both groups were followed up for a median of 300 days. We estimated risks of new-incident cardiovascular, cerebrovascular, and other thrombotic complications using doubly robust competing-risks survival analysis. Risks were reported using 2 measures: hazard ratio (HR) and excess burden (EB) with 95% confidence intervals. Researchers included 106 012 infected cases and 1 684 085 test-negative controls. Compared with the control group, individuals with COVID-19 exhibited increased risk (HR, 1.157 [1.069–1.252]) and excess burden (EB, 0.70 [.53–.88]) of new-incident cardiovascular and cerebrovascular complications. Risks decreased in a graded fashion for fully vaccinated (HR, 1.11 [1.02–1.22]) and boosted (HR, 1.10 [.92–1.32]) individuals. Conversely, risks and burdens of subsequent cardiovascular/cerebrovascular complications increased for hospitalized and severe COVID-19 cases (compared to nonhospitalized cases). Increased risks and excess burdens of new-incident cardiovascular/cerebrovascular complications were reported among infected individuals; risks can be attenuated with vaccination and boosting.
SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels
Patients with coronavirus disease 2019 (COVID-19) present increased risk for ischemic cardiovascular complications up to 1 year after infection. Although the systemic inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques remains unknown. Here researchers report that SARS-CoV-2 viral RNA is detectable and replicates in coronary lesions taken at autopsy from severe COVID-19 cases. SARS-CoV-2 targeted plaque macrophages and exhibited a stronger tropism for arterial lesions than adjacent perivascular fat, correlating with macrophage infiltration levels. SARS-CoV-2 entry was increased in cholesterol-loaded primary macrophages and dependent, in part, on neuropilin-1. SARS-CoV-2 induced a robust inflammatory response in cultured macrophages and human atherosclerotic vascular explants with secretion of cytokines known to trigger cardiovascular events. Our data establish that SARS-CoV-2 infects coronary vessels, inducing plaque inflammation that could trigger acute cardiovascular complications and increase the long-term cardiovascular risk.

Antiviral Therapeutics and Vaccines

FDA Authorizes Updated Novavax COVID-19 Vaccine Formulated to Better Protect Against Currently Circulating Variants
Today, the U.S. Food and Drug Administration amended the emergency use authorization (EUA) of the Novavax COVID-19 Vaccine, Adjuvanted for use in individuals 12 years of age and older to include the 2023-2024 formula. Individuals 12 years of age and older previously vaccinated with a COVID-19 vaccine (and who have not already been vaccinated with a recently updated mRNA COVID-19 vaccine) are eligible to receive one dose and unvaccinated individuals receive two doses. The updated vaccine addresses currently circulating variants to provide better protection against serious consequences of COVID-19, including hospitalization and death. Consistent with the totality of the evidence and input from the FDA’s expert advisors, the Novavax COVID-19 Vaccine, Adjuvanted, a monovalent vaccine, has been updated to include the spike protein from the SARS-CoV-2 omicron variant lineage XBB.1.5 (2023-2024 formula).
Effectiveness of Maternal mRNA COVID-19 Vaccination During Pregnancy Against COVID-19–Associated Hospitalizations in Infants Aged <6 Months During SARS-CoV-2 Omicron Predominance — 20 States, March 9, 2022–May 31, 2023
Infants aged <6 months are not eligible for COVID-19 vaccination and are at risk for COVID-19–associated complications. Maternal vaccination received during pregnancy could protect infants from COVID-19–related hospitalization. During the period of recent SARS-CoV-2 Omicron predominance, maternal receipt of an mRNA COVID-19 vaccine during pregnancy reduced the likelihood of COVID-19-related hospitalizations and serious complications among infants aged <6 months. Expectant mothers should remain current with COVID-19 vaccination to protect themselves and their infants from hospitalization and severe outcomes associated with COVID-19.
COVID-19 Vaccination Recommendations and Practices for Women of Reproductive Age by Health Care Providers — Fall DocStyles Survey, United States, 2022
COVID-19 vaccination is recommended for all persons ≥6 months of age. Pregnant women are at increased risk for severe COVID-19 compared with other reproductive-aged women. Health care provider (HCP) recommendations are important for increasing vaccination coverage. Although most (82.9%) surveyed HCPs recommended that women of reproductive age stay up to date with COVID-19 vaccines, only 54.7% offered or administered the vaccine in their practice. HCPs were more likely to offer or administer COVID-19 vaccination on-site to pregnant patients if they also offered or administered influenza (adjusted prevalence ratio [aPR] = 5.5) and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines (aPR = 2.3). Encouraging HCPs to recommend, offer, and administer COVID-19 vaccines along with influenza or Tdap vaccines might help reinforce vaccine confidence and increase coverage among women of reproductive age, including pregnant women.
Molnupiravir for intra-household prevention of COVID-19: The MOVe-AHEAD randomized, placebo-controlled trial
MOVe-AHEAD was a randomized, controlled, double-blind, phase 3 trial comparing molnupiravir (800 mg twice daily for 5 days) with placebo. Eligible participants were adult, unvaccinated, asymptomatic household contacts of patients with laboratory-confirmed COVID-19. The primary efficacy endpoint was the incidence of COVID-19 through day 14 in modified intention-to-treat (MITT) participants (those who received ≥1 dose of study intervention) without detectable SARS-CoV-2 at baseline, termed the MITT-VN population. Superiority of molnupiravir was prespecified as a stratified one-sided p-value of <0.0249 for the treatment difference in this endpoint. The MITT population comprised 763 participants randomized to molnupiravir and 764 to placebo; 83.6% had anti-SARS-CoV-2 antibodies at baseline. In the MITT-VN population, COVID-19 rates through day 14 were 6.5% with molnupiravir and 8.5% with placebo (one-sided p-value: 0.0848). In the molnupiravir arm, 25/35 of confirmed COVID-19 events (71.4%) occurred after completion of treatment (versus 17/49 [34.7%] for placebo). Adverse event rates were low and similar between molnupiravir and placebo. Molnupiravir was well-tolerated but did not meet the prespecified superiority criterion, possibly influenced in part by the high pre-existing immunity in the trial population.
Efficacy of Gabapentin For Post–COVID-19 Olfactory Dysfunction
In this double-blinded, placebo-controlled pilot randomized clinical trial (RCT), the rate of response as determined by the Clinical Global Rating of Improvement (CGI) after an 8-week fixed-dose phase was 44.4% and 46.2% for the gabapentin and placebo treatment groups, respectively. Changes in odor identification and olfaction-related quality of life were not significantly different between the 2 treatment groups. The lack of a statistically significant or clinically important effect of oral gabapentin suggests that it should not be considered as a potential therapeutic agent for COVID-19–induced OD.

Epidemiology

The New Normal: Delayed Peak SARS-CoV-2 Viral Loads Relative to Symptom Onset and Implications for COVID-19 Testing Programs
Early in the COVID-19 pandemic, peak viral loads coincided with symptom onset. Researchers hypothesized that in a highly immune population, symptom onset might occur earlier in infection, coinciding with lower viral loads. Study authors assessed SARS-CoV-2 and influenza A viral loads relative to symptom duration in symptomatic adults (>16y) presenting for testing in Georgia (4/2022-4/2023; Omicron variant predominant). Participants provided symptom duration and recent testing history. Nasal swabs were tested by Xpert Xpress SARS-CoV-2/Flu/RSV assay and Ct values recorded. Nucleoprotein concentrations in SARS-CoV-2 PCR-positive samples were measured by Single Molecule Array. To estimate hypothetical antigen rapid diagnostic test (Ag RDT) sensitivity on each day after symptom onset, percentages of individuals with Ct value <30 or <25 were calculated. Of 348 newly-diagnosed SARS-CoV-2 PCR-positive individuals (65.5% women, median 39.2y), 317/348 (91.1%) had a history of vaccination, natural infection, or both. By both Ct value and antigen concentration measurements, median viral loads rose from the day of symptom onset and peaked on the fourth/fifth day. Ag RDT sensitivity estimates were 30.0-60.0% on the first day, 59.2-74.8% on the third day, and 80.0-93.3% on the fourth day of symptoms. In 74 influenza A PCR-positive individuals (55.4% women; median 35.0y), median influenza viral loads peaked on the second day of symptoms. In a highly immune adult population, median SARS-CoV-2 viral loads peaked around the fourth day of symptoms. Influenza A viral loads peaked soon after symptom onset. These findings have implications for ongoing use of Ag RDTs for COVID-19 and influenza.
Viral kinetics of sequential SARS-CoV-2 infections
The impact of a prior SARS-CoV-2 infection on the progression of subsequent infections has been unclear. Using a convenience sample of 94,812 longitudinal RT-qPCR measurements from anterior nares and oropharyngeal swabs, researchers identified 71 individuals with two well-sampled SARS-CoV-2 infections between March 11th, 2020, and July 28th, 2022. Researchers compared the SARS-CoV-2 viral kinetics of first vs. second infections in this group, adjusting for viral variant, vaccination status, and age. Relative to first infections, second infections usually featured a faster clearance time. Furthermore, a person’s relative (rank-order) viral clearance time, compared to others infected with the same variant, was roughly conserved across first and second infections, so that individuals who had a relatively fast clearance time in their first infection also tended to have a relatively fast clearance time in their second infection (Spearman correlation coefficient: 0.30, 95% credible interval (0.12, 0.46)). These findings provide evidence that, like vaccination, immunity from a prior SARS-CoV-2 infection shortens the duration of subsequent acute SARS-CoV-2 infections principally by reducing viral clearance time. Additionally, there appears to be an inherent element of the immune response, or some other host factor, that shapes a person’s relative ability to clear SARS-CoV-2 infection that persists across sequential infections.
Antiviral efficacy of molnupiravir versus ritonavir-boosted nirmatrelvir in patients with early symptomatic COVID-19 (PLATCOV): an open-label, phase 2, randomised, controlled, adaptive trial
Molnupiravir and ritonavir-boosted nirmatrelvir are the two leading oral COVID-19 antiviral treatments, but their antiviral activities in patients have not been compared directly. The aim of this ongoing platform trial is to compare different antiviral treatments using the rate of viral clearance as the measure of antiviral effect. PLATCOV is an open-label, multicentre, phase 2, randomised, controlled, adaptive pharmacometric platform trial running in Thailand, Brazil, Pakistan, and Laos. The component of the trial reported here was conducted in the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. We recruited low-risk adult patients aged 18–50 years with early symptomatic COVID-19 (<4 days of symptoms). Eligible patients were randomly assigned using block randomisation via a centralised web app to one of seven treatment groups: molnupiravir, ritonavir-boosted nirmatrelvir, casirivimab–imdevimab, tixagevimab–cilgavimab, favipiravir, fluoxetine, or no study drug. The no study drug group comprised a minimum proportion of 20% of patients at all times, with uniform randomisation ratios applied across the active treatment groups. Results for the concurrently randomised molnupiravir, ritonavir-boosted nirmatrelvir, and no study drug groups are reported here. The primary endpoint was the rate of oropharyngeal viral clearance assessed in a modified intention-to-treat population, defined as patients with more than 2 days of follow-up. Safety was assessed in all participants who took at least one dose of the medication. The viral clearance rate was derived under a Bayesian hierarchical linear model fitted to the log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 1 week (18 measurements). Treatment groups with a probability of more than 0·9 that viral clearance was accelerated by more than 20% compared with no drug entered a non-inferiority comparison (with a 10% non-inferiority margin) compared with the platform's current most effective drug. Between June 6, 2022, and Feb 23, 2023, 209 patients in Thailand were enrolled and concurrently randomly assigned to molnupiravir (n=65), ritonavir-boosted nirmatrelvir (n=59), or no study drug (n=85). 129 (62%) of the patients were female and 80 (38%) were male. Relative to the no study drug group, the rates of viral clearance were 37% (95% credible interval 16–65) faster with molnupiravir and 84% (54–119) faster with ritonavir-boosted nirmatrelvir. In the non-inferiority comparison, viral clearance was 25% (10–38) slower with molnupiravir than ritonavir-boosted nirmatrelvir. Molnupiravir was removed from the study platform when it reached the prespecified inferiority margin of 10% compared with ritonavir-boosted nirmatrelvir. Median estimated viral clearance half-lives were 8·5 h (IQR 6·7–10·1) with ritonavir-boosted nirmatrelvir, 11·6 h (8·6–15·4) with molnupiravir, and 15·5 h (11·9–21·2) with no study drug. Viral rebound occurred more frequently following nirmatrelvir (six [10%] of 58) compared with the no study drug (one [1%] of 84; p=0·018) or the molnupiravir (one [2%] of 65; p=0·051) groups. Persistent infections following molnupiravir had more viral mutations (three of nine patients had an increased number of single nucleotide polymorphisms in samples collected at 7 or more days compared with those at baseline) than after nirmatrelvir (zero of three) or no study drug (zero of 18). There were no adverse events of grade 3 or worse, or serious adverse events in any of the reported treatment groups. Both molnupiravir and ritonavir-boosted nirmatrelvir accelerate oropharyngeal SARS-CoV-2 viral clearance in patients with COVID-19, but the antiviral effect of ritonavir-boosted nirmatrelvir was substantially greater. Measurement of oropharyngeal viral clearance rates provides a rapid and well tolerated approach to the assessment and comparison of antiviral drugs in patients with COVID-19. It should be evaluated in other acute viral respiratory infections.
Optimal Duration of Systemic Corticosteroids in Coronavirus Disease 2019 Treatment: A Systematic Review and Meta-analysis
Corticosteroids confer a survival benefit in individuals hospitalized with coronavirus disease 2019 (COVID-19) who require oxygen. This meta-analysis seeks to determine the duration of corticosteroids needed to optimize this mortality benefit. Electronic databases were searched to 9 March 2022, for studies reporting corticosteroid versus no corticosteroid treatment in hospitalized COVID-19 patients. We estimated the effect of corticosteroids on mortality by random-effects meta-analyses. Subgroup analyses and meta-analyses were conducted to assess the optimal duration of corticosteroid treatment while adjusting for the severity of disease, age, duration of symptoms, and proportion of control group given steroids. Researchers identified 27 eligible studies consisting of 13 404 hospitalized COVID-19 patients. Seven randomized controlled trials and 20 observational studies were included in the meta-analysis of mortality, which suggested a protective association with corticosteroid therapy (risk ratio [RR], 0.71 [95% confidence interval {CI}, .58–.87]). Pooled analysis of 18 studies showed the greatest survival benefit for a treatment duration up to 6 days (RR, 0.54 [95% CI, .39–.74]). Survival benefit was 0.65 (95% CI, .51–.83) up to 7 days, and no additional survival benefit was observed beyond 7 days of treatment (RR, 0.64 [95% CI, .44–.93]). The survival benefit was not confounded by severity of disease, age, duration of symptoms, or proportion of control group given steroids. In this meta-analysis, optimal duration of corticosteroid treatment for hospitalized COVID-19 patients was up to 6 days, with no additional survival benefit with >7 days of treatment.