TREATMENT, EFFICACY-ADVERSE EVENTS AND DRUG RESISTENCE

Brian E. McGarry et al.

Monoclonal Antibody and Oral Antiviral Treatment of SARS-CoV-2 Infection in US Nursing Homes

JAMA, July 2023; doi:10.1001/jama.2023.12945

Abstract

Nursing home residents are at elevated risk for severe infection from SARS-CoV-2,1 making them a priority for antiviral treatment.2 Although oral antiviral use has been found to be greater in nursing homes than the community,3 overall use among nursing home residents has been low and may not be commensurate with residents’ elevated risk. Furthermore, multiple barriers to antiviral use exist in nursing homes, including treatment access, frequently changing authorizations and recommendations on the use of monoclonal antibodies (mAbs), patient and physician preferences, unfamiliarity with these medications, and treatment costs.4,5 We examined the use of COVID-19 antiviral treatments within US nursing homes and the facility characteristics associated with use.

Methods

The primary data source was the Centers for Disease Control and Prevention National Healthcare Safety Network (NHSN) Nursing Home COVID-19 database, which contains information regarding the number of residents treated with monoclonal antibodies (eg, bebtelovimab; complete list in the eAppendix in Supplement 1) and oral antivirals (nirmatrelvir-ritonavir and molnupiravir), as well as new resident COVID-19 weekly cases. All Medicare-certified nursing homes were required to submit information to NHSN. Facility characteristics were obtained from LTCFocus, the Centers for Medicare & Medicaid Services (CMS) Payroll-Based Journal, the CMS Nursing Home Compare database, and the CMS Physician Compare databases (eAppendix in Supplement 1).

We examined trends from May 31, 2021, through December 25, 2022, in the total number of oral antivirals and monoclonal antibodies (hereafter referred to as “treatments”) administered, confirmed new resident COVID-19 cases, treatment rates (ie, treatments divided by new cases), and the cumulative share of nursing homes that reported ever using treatments. Data from 106 facilities were omitted due to low data quality. Facility-level treatment rates were capped at 100%, and a 6-week moving average was used to estimate weekly rates. We used multivariable linear probability regression models (with county fixed effects) to estimate the relationship between facility characteristics and whether the nursing home reported ever (vs never) using treatments among facilities with at least 1 COVID-19 case, adjusted for variables in the Table (eAppendix in Supplement 1). Per Harvard policy, institutional review board approval and written informed consent were not required for publicly available data. Analyses were performed with Stata version 16. Statistical significance was determined by 95% CIs that did not include 0.

Results

During the study period, there were 763 340 resident cases of COVID-19 and 136 066 residents treated for COVID-19 among 15 092 nursing homes, equating to an overall oral antiviral or monoclonal antibody treatment rate of 17.8% (95% CI, 17.4%-18.3%) (Figure, A). The moving average treatment rate peaked at 32.7% (95% CI, 30.5%-34.8%) on November 28, 2021, coinciding with a decrease in new resident COVID-19 cases. During the last 6 weeks of the study, the mean treatment rate was 24.5% (95% CI, 23.2%-25.7%). Oral antiviral treatments replaced monoclonal antibodies as the dominant treatment in 2022; nirmatrelvir-ritonavir constituted 61.1% of all treatments in 2022, and molnupiravir constituted 18.2% (Figure, B). The share of facilities ever using a treatment increased steadily, but by the end of 2022, 41.0% of facilities still had not reported any use.

After adjustment, larger bed size, higher overall quality rating, greater direct care hours per resident-day, having an affiliated geriatrician, higher staff and resident vaccination rates, and greater mean resident age and acuity were positively associated with treatment use. Being for-profit and having higher shares of non-White race and Medicaid residents were significantly associated with lower probability of treatment use (Table).

Discussion

Despite their high risk, only 1 in 4 nursing home residents with COVID-19 had been treated with evidence-based antiviral treatments by the end of 2022.6 Overall treatment rates tracked closely with recent government estimates.3 Over 40% of nursing homes reported never administering any oral antiviral or monoclonal antibody treatment in the 19-month study window. Lower treatment rates in for-profit facilities and those with higher shares of Medicaid and non-White residents suggest that structural barriers may be contributing to underuse and disparities.

Jay A Pandit et al.

The Coronavirus Disease 2019 Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences in Participants Treated With Nirmatrelvir Plus Ritonavir Versus Untreated Controls Get access Arrow

CID, February 2023 ; doi.org/10.1093/cid/ciad102

Abstract

Background

The uptake of nirmatrelvir plus ritonavir (NPR) in patients with coronavirus disease 2019 (COVID-19) has been limited by concerns around the rebound phenomenon despite the scarcity of evidence around its epidemiology. The purpose of this study was to prospectively compare the epidemiology of rebound in NPR-treated and untreated participants with acute COVID-19 infection.

Methods

We designed a prospective, observational study in which participants who tested positive for COVID-19 and were clinically eligible for NPR were recruited to be evaluated for either viral or symptom clearance and rebound. Participants were assigned to the treatment or control group based on their decision to take NPR. Following initial diagnosis, both groups were provided 12 rapid antigen tests and asked to test on a regular schedule for 16 days and answer symptom surveys. Viral rebound based on test results and COVID-19 symptom rebound based on patient-reported symptoms were evaluated.

Results

Viral rebound incidence was 14.2% in the NPR treatment group (n = 127) and 9.3% in the control group (n = 43). Symptom rebound incidence was higher in the treatment group (18.9%) compared to controls (7.0%). There were no notable differences in viral rebound by age, gender, preexisting conditions, or major symptom groups during the acute phase or at the 1-month interval.

Conclusions

This preliminary report suggests that rebound after clearance of test positivity or symptom resolution is higher than previously reported. However, notably we observed a similar rate of rebound in both the NPR treatment and control groups. Large studies with diverse participants and extended follow-up are needed to better understand the rebound phenomena.

William A Werbel et al.

Your Outpatient has Coronavirus Disease 2019: What Are the Treatment Options in the Current Severe Acute Respiratory Syndrome Coronavirus 2 Variant Climate?

CID, March 2023; doi.org/10.1093/cid/ciad178

Abstract

Mutations accumulated by novel Severe Acute Respiratory Syndrome Coronavirus 2 Omicron sublineages contribute to evasion of previously effective monoclonal antibodies for treatment or prevention of Coronavirus Disease 2019 (COVID-19). Other authorized or approved antiviral drugs such as nirmatrelvir/ritonavir, remdesivir, and molnupiravir are, however, predicted to maintain activity against these sublineages and are key tools to reduce severe COVID-19 outcomes in vulnerable populations. A stepwise approach may be taken to target the appropriate antiviral drug to the appropriate patient, beginning with identifying whether a patient is at high risk for hospitalization or other complications of COVID-19. Among higher risk individuals, patient profile (including factors such as age, organ function, and comedications) and antiviral drug access inform suitable antiviral drug selection. When applied in targeted fashion, these therapies serve as a complement to vital ongoing nonpharmaceutical interventions and vaccination strategies that reduce morbidity and maximize protection against COVID-19.

Qian-Fang Meng et al.

Inhalation delivery of dexamethasone with iSEND nanoparticles attenuates the COVID-19 cytokine storm in mice and nonhuman primates

Science, June 2023 ; doi/10.1126/sciadv.adg3277

Abstract

Dexamethasone (DEX) is the first drug to show life-saving efficacy in patients with severe coronavirus disease 2019 (COVID-19), while DEX is associated with serious adverse effects. Here, we report an inhaled, Self-immunoregulatory, Extracellular Nanovesicle-based Delivery (iSEND) system by engineering neutrophil nanovesicles with cholesterols to deliver DEX for enhanced treatment of COVID-19. Relying on surface chemokine and cytokine receptors, the iSEND showed improved targeting to macrophages and neutralized broad-spectrum cytokines. The nanoDEX, made by encapsulating DEX with the iSEND, efficiently promoted the anti-inflammation effect of DEX in an acute pneumonia mouse model and suppressed DEX-induced bone density reduction in an osteoporosis rat model. Relative to an intravenous administration of DEX at 0.1 milligram per kilogram, a 10-fold lower dose of nanoDEX administered by inhalation produced even better effects against lung inflammation and injury in severe acute respiratory syndrome coronavirus 2–challenged nonhuman primates. Our work presents a safe and robust inhalation delivery platform for COVID-19 and other respiratory diseases.

Dean Follmann

Examining protective effects of SARS-CoV-2 neutralizing antibodies after vaccination or monoclonal antibody administration

Nature, June 2023; doi.org/10.1038/s41467-023-39292-w

Abstract

While new vaccines for SARS-CoV-2 are authorized based on neutralizing antibody (nAb) titer against emerging variants of concern, an analogous pathway does not exist for preventative monoclonal antibodies. In this work, nAb titers were assessed as correlates of protection against COVID-19 in the casirivimab + imdevimab monoclonal antibody (mAb) prevention trial (ClinicalTrials.gov #NCT4452318) and in the mRNA-1273 vaccine trial (ClinicalTrials.gov #NCT04470427). In the mAb trial, protective efficacy of 92% (95% confidence interval (CI): 84%, 98%) is associated with a nAb titer of 1000 IU50/ml, with lower efficacy at lower nAb titers. In the vaccine trial, protective efficacies of 93% [95% CI: 91%, 95%] and 97% (95% CI: 95%, 98%) are associated with nAb titers of 100 and 1000 IU50/ml, respectively. These data quantitate a nAb titer correlate of protection for mAbs benchmarked alongside vaccine induced nAb titers and support nAb titer as a surrogate endpoint for authorizing new mAbs.

Cécile Hérate et al.

Sotrovimab retains activity against SARS-CoV-2 omicron variant BQ.1.1 in a non-human primate model

Cell, May 2023 ; doi.org/10.1016/j.heliyon.2023.e16664

Abstract

The SARS-CoV2 Omicron variants have acquired new Spike mutations leading to escape from the most of the currently available monoclonal antibody treatments reducing the options for patients suffering from severe Covid-19. Recently, both in vitro and in vivo data have suggested that Sotrovimab could retain partial activity against recent omicron sub-lineage such as BA.5 variants, including BQ.1.1. Here we report full efficacy of Sotrovimab against BQ.1.1 viral replication as measure by RT-qPCR in a non-human primate challengemodel.

Rosie Kwon et al

Effectiveness of famotidine on the risk of poor prognosis in patients with COVID-19: A nationwide cohort study in Korea

Cell, May 2023 ; doi.org/10.1016/j.heliyon.2023.e16171

Abstract

Famotidine has been proposed as a promising candidate for the treatment of coronavirus disease 2019 (COVID-19). However, there is limited research on the association of famotidine with the poor prognosis of COVID-19.

Methods

The Korean nationwide cohort included 6,556 patients who tested positive on RT-PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The poor COVID-19-related outcomes were defined on the basis of having encountered the composite outcome of high oxygen therapy, intensive care unit admission, administration of mechanical ventilation, or death. In addition, we performed exposure-driven propensity score matching for no H2-blocker use versus current famotidine use, and other H2-blocker use versus current famotidine use.

Results

4,785 (73.0%) patients did not use a H2-blocker, 393 (6.0%) patients were currently used famotidine, and 1,292 (19.7%) patients currently used H2-blocker other than famotidine. In multivariable analysis after matching (no H2-blocker use versus current famotidine use), there was no significant association between current famotidine use and composite outcomes (adjusted odd ratios [aOR]: 1.30, 95% confidence interval [CI]: 0.55–3.06). On the other hand, another matched cohort (other H2-blocker use versus current famotidine use), demonstrated a positive association between current famotidine use and composite outcomes (aOR: 3.56, 95% CI: 1.03–12.28)

Conclusions

Our study results did not support the potential of famotidine as a therapeutic agent for COVID-19. A rather unexpected result could be observed in the comparisons between current famotidine use and other H2-blocker use; it was observed that current famotidine use increased the risk of poor COVID-19 related outcomes. Further studies are needed to clearly prove the causal relationship with several H2-blockers, including famotidine.

Samuel M Brown et al.

Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial

The Lancet, June 2023 ; doi.org/10.1016/S2213-2600(23)00147-9

Abstract

There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure.

Methods

TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2–4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49–76 days, (3) at home and off oxygen for 1–48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761.

Findings

Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46–66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80–1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77–1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94–2·08; p=0·10).

Interpretation

Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy.

Sheriza N Baksh et al.

Symptom Duration and Resolution With Early Outpatient Treatment of Convalescent Plasma for Coronavirus Disease 2019: A Randomized Trial

Academic.oup, January 2023; doi.org/10.1093/infdis/jiad023

Abstract

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) reduces hospitalizations among outpatients treated early after symptom onset. It is unknown whether CCP reduces time to symptom resolution among outpatients.

Methods

We evaluated symptom resolution at day 14 by trial arm using an adjusted subdistribution hazard model, with hospitalization as a competing risk. We also assessed the prevalence of symptom clusters at day 14 between treatments. Clusters were defined based on biologic clustering, impact on ability to work, and an algorithm.

Results

Among 1070 outpatients followed up after transfusion, 381 of 538 (70.8%) receiving CCP and 381 of 532 (71.6%) receiving control plasma were still symptomatic (P = .78) at day 14. Associations between CCP and symptom resolution by day 14 did not differ significantly from those in controls after adjustment for baseline characteristics (adjusted subdistribution hazard ratio, 0.99; P = .62). The most common cluster consisted of cough, fatigue, shortness of breath, and headache and was found in 308 (57.2%) and 325 (61.1%) of CCP and control plasma recipients, respectively (P = .16).

Conclusions

In this trial of outpatients with early COVID-19, CCP was not associated with faster resolution of symptoms compared with control. Overall, there were no differences by treatment in the prevalence of each symptom or symptom clusters at day 14.

Rosie Kwon et al.

Effectiveness of famotidine on the risk of poor prognosis in patients with COVID-19: A nationwide cohort study in Korea

Cell, May 2023 ; doi.org/10.1016/j.heliyon.2023.e16171

Abstract

Methods

Results

Conclusions

Cécile Hérate et al.

Sotrovimab retains activity against SARS-CoV-2 omicron variant BQ.1.1 in a non-human primate model

Cell, May 2023; doi.org/10.1016/j.heliyon.2023.e16664

Abstract

Evan M Bloch et al.

Guidance on the Use of Convalescent Plasma to Treat Immunocompromised Patients With Coronavirus Disease 2019

CID, February 2023; doi.org/10.1093/cid/ciad066

Abstract

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) is a safe and effective treatment for COVID-19 in immunocompromised (IC) patients. IC patients have a higher risk of persistent infection, severe disease, and death from COVID-19. Despite the continued clinical use of CCP to treat IC patients, the optimal dose, frequency/schedule, and duration of CCP treatment has yet to be determined, and related best practices guidelines are lacking. A group of individuals with expertise spanning infectious diseases, virology and transfusion medicine was assembled to render an expert opinion statement pertaining to the use of CCP for IC patients. For optimal effect, CCP should be recently and locally collected to match circulating variant. CCP should be considered for the treatment of IC patients with acute and protracted COVID-19; dosage depends on clinical setting (acute vs protracted COVID-19). CCP containing high-titer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, retains activity against circulating SARS-CoV-2 variants, which have otherwise rendered monoclonal antibodies ineffective.

Sheriza N Baksh et al

Symptom Duration and Resolution With Early Outpatient Treatment of Convalescent Plasma for Coronavirus Disease 2019: A Randomized Trial

Academic.oup, January 2023; doi.org/10.1093/infdis/jiad023

Abstract

Methods

Results

Conclusions

Rosie Kwon et al

Effectiveness of famotidine on the risk of poor prognosis in patients with COVID-19: A nationwide cohort study in Korea

Cell, May 2023; doi.org/10.1016/j.heliyon.2023.e16171

Abstract

Methods

Results

Conclusions

CécileHérate et al.

Sotrovimab retains activity against SARS-CoV-2 omicron variant BQ.1.1 in a non-human primate model

Cell, May 2023; doi.org/10.1016/j.heliyon.2023.e16664

Abstract

ÁlvaroAvezum et al.

Rivaroxaban to prevent major clinical outcomes in non-hospitalised patients with COVID-19: the CARE – COALITION VIII randomised clinical trial

The Lancet, May 2023; doi.org/10.1016/j.eclinm.2023.102004

Abstract

COVID-19 progression is associated with an increased risk of arterial and venous thrombosis. Randomised trials have demonstrated that anticoagulants reduce the risk of thromboembolism in hospitalised patients with COVID-19, but a benefit of routine anticoagulation has not been demonstrated in the outpatient setting.

Methods

We conducted a randomised, open-label, controlled, multicentre study, evaluating the use of rivaroxaban in mild or moderate COVID-19 patients. Adults ≥18 years old, with probable or confirmed SARS-CoV-2 infection, presenting within ≤7 days from symptom onset with no clear indication for hospitalization, plus at least 2 risk factors for complication, were randomised 1:1 either to rivaroxaban 10 mg OD for 14 days or to routine care. The primary efficacy endpoint was the composite of venous thromboembolic events, need of mechanical ventilation, acute myocardial infarction, stroke, acute limb ischemia, or death due to COVID-19 during the first 30 days. ClinicalTrials.gov: NCT04757857.

Findings

Enrollment was prematurely stopped due to sustained reduction in new COVID-19 cases. From September 29th, 2020, through May 23rd, 2022, 660 patients were randomised (median age 61 [Q1-Q3 47–69], 55.7% women). There was no significant difference between rivaroxaban and control in the primary efficacy endpoint (4.3% [14/327] vs 5.8% [19/330], RR 0.74; 95% CI: 0.38–1.46). There was no major bleeding in the control group and 1 in the rivaroxaban group.

Interpretation

On light of these findings no decision can be made about the utility of rivaroxaban to improve outcomes in outpatients with COVID-19. Metanalyses data provide no evidence of a benefit of anticoagulant prophylaxis in outpatients with COVID-19. These findings were the result of an underpowered study, therefore should be interpreted with caution.

David T. W. Lui, et al

Analysis of All-Cause Hospitalization and Death Among Nonhospitalized Patients With Type 2 Diabetes and SARS-CoV-2 Infection Treated With Molnupiravir or Nirmatrelvir-Ritonavir During the Omicron Wave in Hong Kong

JAMA, May 2023; doi:10.1001/jamanetworkopen.2023.14393

Abstract

Importance Diabetes and COVID-19 are both global pandemics, and type 2 diabetes is a common comorbidity in patients with acute COVID-19 and is proven to be a key determinant of COVID-19 prognosis. Molnupiravir and nirmatrelvir-ritonavir are oral antiviral medications recently approved for nonhospitalized patients with mild to moderate COVID-19, following demonstration of their efficacies in reducing adverse outcomes of the disease; it is crucial to clarify whether both oral antiviral medications are efficacious in a population consisting exclusively of patients with type 2 diabetes.

Objective To evaluate the effectiveness of molnupiravir and nirmatrelvir-ritonavir in a contemporary population-based cohort comprising exclusively nonhospitalized patients with type 2 diabetes and SARS-CoV-2 infection.

Design, Setting, and Participants This retrospective cohort study was performed using population-based electronic medical record data for patients in Hong Kong with type 2 diabetes and confirmed SARS-CoV-2 infection between February 26 and October 23, 2022. Each patient was followed up until death, outcome event, crossover of oral antiviral treatment, or end of the observational period (October 30, 2022), whichever came first. Outpatient oral antiviral users were divided into molnupiravir and nirmatrelvir-ritonavir treatment groups, respectively, and nontreated control participants were matched through 1:1 propensity score matching. Data analysis was performed on March 22, 2023.

Exposures Molnupiravir (800 mg twice daily for 5 days) or nirmatrelvir-ritonavir (300 mg nirmatrelvir and 100 mg ritonavir twice daily for 5 days, or 150 mg nirmatrelvir and 100 mg ritonavir for patients with an estimated glomerular filtration rate of 30-59 mL/min per 1.73 m2).

Main Outcomes and Measures The primary outcome was a composite of all-cause mortality and/or hospitalization. The secondary outcome was in-hospital disease progression. Hazard ratios (HRs) were estimated with Cox regression.

Results This study identified 22 098 patients with type 2 diabetes and COVID-19. A total of 3390 patients received molnupiravir and 2877 received nirmatrelvir-ritonavir in the community setting. After application of exclusion criteria followed by 1:1 propensity score matching, this study comprised 2 groups. One group included 921 molnupiravir users (487 men [52.9%]), with a mean (SD) age of 76.7 (10.8) years, and 921 control participants (482 men [52.3%]), with a mean (SD) age of 76.6 (11.7) years. The other group included 793 nirmatrelvir-ritonavir users (401 men [50.6%]), with a mean (SD) age of 71.7 (11.5) years, and 793 control participants (395 men [49.8%]), with a mean (SD) age of 71.9 (11.6) years. At a median follow-up of 102 days (IQR, 56-225 days), molnupiravir use was associated with a lower risk of all-cause mortality and/or hospitalization (HR, 0.71 [95% CI, 0.64-0.79]; P < .001) and in-hospital disease progression (HR, 0.49 [95% CI, 0.35-0.69]; P < .001) compared with nonuse. At a median follow-up of 85 days (IQR, 56-216 days), nirmatrelvir-ritonavir use was associated with a lower risk of all-cause mortality and/or hospitalization (HR, 0.71 [95% CI, 0.63-0.80]; P < .001) and a nonsignificantly lower risk of in-hospital disease progression (HR, 0.92 [95% CI, 0.59-1.44]; P = .73) compared with nonuse.

Conclusions and Relevance These findings suggest that both molnupiravir and nirmatrelvir-ritonavir oral antiviral medications were associated with a lower risk of all-cause mortality and hospitalization among patients with COVID-19 and type 2 diabetes. Further studies in specific populations, such as individuals in residential care homes and individuals with chronic kidney disease, are suggested.

Yan Leyfman et al

Extracellular vesicles: A promising therapy against SARS-CoV-2 infection

Cell, May 2023; doi.org/10.1016/j.ymthe.2023.03.033

Abstract

Severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) has infected over 650 million people and claimed the lives of nearly 7 million since the start of the pandemic. While SARS-CoV-2 is becoming endemic with several preventative therapies, an effective treatment against severe disease remains unavailable. Immunocompromised patients remain vulnerable given the limited efficacy of vaccinations and are at risk of respiratory failure, organ failure, and septic shock if infected.1 The development of therapeutics to combat the progression and severity of SARS-CoV-2 infection presents an opportunity to explore innovative approaches to treating viral diseases. Novel therapeutic strategies aim to target the host response to hyper-inflammation and prevent the cytokine storm that is often associated with severe COVID-19 cases.2

In recent years, researchers have focused on intracellular secreted factors, such as extracellular vesicles (EVs), to improve and build upon the knowledge gained from cell-based research and spearhead the use as potential therapeutic agents for various diseases, including SARS-CoV-2. EVs are small membranous structures secreted by the cell membrane or the cell’s internal recycling pathways and have emerged as a promising therapeutic strategy due to their involvement in a range of biological processes, including cell signaling, immune response, and disease progression. The objective of this analysis is to examine the potential efficacy of EV-based therapies in the treatment of SARS-CoV-2 severity, with a particular emphasis on their common mechanisms and suitability for future therapeutic use in human patients.

The ongoing COVID-19 pandemic caused by SARS-CoV-2 highlights the critical need for effective therapies to mitigate disease progression and reduce severity. EV-based therapeutics have shown the capacity to attenuate the hyper-inflammatory response caused by SARS-CoV-2 and promote repair of damaged lung tissue in preclinical models, with similar results when translated into SARS-CoV-2 patients. In addition, EVs may harbor therapeutic applications to tackle the prolonged symptoms of infection (long COVID) that are associated with prolonged overactivation and exhaustion of immune cells.28 The overview presented in this work highlights the innovative use of EVs as a promising approach to address severe SARS-CoV-2 infections. Recent progress in clinical trials has also laid the groundwork for the development of effective EV-based therapies for a broad range of viral infections.

Jonathan Daniel Ip et al.

Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance

eBioMedicine, April 2023; doi.org/10.1016/j.ebiom.2023.104559

Abstract

Nirmatrelvir-ritonavir (Paxlovid) and ensitrelvir are 3-chymotrypsin-like cysteine protease (3CLpro) inhibitors which have been approved for the treatment of COVID-19 in 2021 and 2022, respectively. Previous studies have identified 3CLpro mutations that are associated with reduced susceptibility to these antivirals. The aim of the current study was to estimate the global prevalence of 3CLpro inhibitor-resistant SARS-CoV-2 strains.

Methods

We compiled a list of 3CLpro mutations which have been associated with nirmatrelvir or ensitrelvir resistance based on either viral replication or 3CLpro activity assays, and determined their prevalence among 13.4 million sequences deposited in GISAID as of December 14, 2022, about 1 year after the approval of nirmatrelvir-ritonavir. We analyzed the prevalence for different time periods, SARS-CoV-2 lineages and geographical locations.

Findings

Overall, 0.5% (67,095/13,446,588) of the sequences contained at least one mutation that was shown to affect the inhibitory activity of nirmatrelvir or ensitrelvir on viral replication or 3CLpro activity. We did not observe any increasing trend of resistance after the widespread clinical use of nirmatrelvir-ritonavir. G15S (2070 per million) and T21I (1386 per million) were the most prevalent mutations, and these mutations were dominant in some SARS-CoV-2 lineages. E166V and S144E, previously shown to affect the inhibitory activity of nirmatrelvir on viral replication or protease activity by > 100-folds, were found in <1 per million sequences.

Interpretation

Our data suggest that 3CLpro inhibitor resistance is currently rare. However, continuous global genotypic and phenotypic surveillance would be crucial in the early detection of resistant mutants.

Tian-Tian Li et al.

Human mesenchymal stem cell therapy in severe COVID-19 patients: 2-year follow-up results of a randomized, double-blind, placebo-controlled trial

Lancet, May 2023; doi.org/10.1016/j.ebiom.2023.104600

Abstract

Long-term effects of human mesenchymal stem cell (MSC) treatment on COVID-19 patients have not been fully characterized. The aim of this study was to evaluate the safety and efficacy of a MSC treatment administered to severe COVID-19 patients enrolled in our previous randomized, double-blind, placebo-controlled clinical trial (NCT 04288102).

Methods

A total of 100 patients experiencing severe COVID-19 received either MSC treatment (n = 65, 4 × 107 cells per infusion) or a placebo (n = 35) combined with standard of care on days 0, 3, and 6. Patients were subsequently evaluated 18 and 24 months after treatment to evaluate the long-term safety and efficacy of the MSC treatment. Outcomes measured included: 6-min walking distance (6-MWD), lung imaging, quality of life according to the Short Form 36 questionnaire (SF-36), COVID-19-related symptoms, titers of SARS-CoV-2 neutralizing antibodies, tumor markers, and MSC-related adverse events (AEs).

Findings

Two years after treatment, a marginally smaller proportion of patients had a 6-MWD below the lower limit of the normal range in the MSC group than in the placebo group (OR = 0.19, 95% CI: 0.04–0.80, Fisher's exact test, p = 0.015). At month 18, the general health score from the SF-36 was higher in the MSC group than in the placebo group (50.00 vs. 35.00, 95% CI: 0.00–20.00, Wilcoxon rank sum test, p = 0.018). Total severity score of lung imaging and the titer of neutralizing antibodies were similar between the two groups at months 18 and 24. There was no difference in AEs or tumor markers at the 2-year follow-up between the two groups.

Interpretation

Long-term safety was observed for the COVID-19 patients who received MSC treatment. However, efficacy of MSC treatment was not significantly sustained through the end of the 2-year follow-up period.

Juan Ignacio MoránBlanco et al.

Antihistamines as an early treatment for Covid-19

Cell, April 2023; doi.org/10.1016/j.heliyon.2023.e15772

Abstract

Infection with SARs-COV-2 results in COVID-19 disease.

Between March 2020 and August 2021, 468 COVID-19 patients confirmed by PCR or antigen test, in Yepes, Spain, received early treatment with antihistamines, adding azithromycin in selected cases. The primary endpoint is the hospitalization rate of COVID-19 patients, and the secondary endpoints are ICU admission and mortality rates. All endpoints are compared with the official Spanish rates during the time period of the study.

There were 20 hospital admissions (hospitalization rate 4,3%), 5 ICU admissions (ICU admission rate 1,1%) and 3 deaths (fatality rate of 0,6%). No patients in the study required follow up treatment, which suggest they did not develop long COVID. Results from this retrospective trail indicate that early treatment of SARS-COV-2 positive patients with antihistamines may reduce the odds of hospitalization (OR: 0.490, CI: 0.313–0.767, p-value: 0.001). Randomized controlled clinical trials are needed to further evaluate the effects of early antihistamine treatment of SARS-CoV-2 patients to prevent hospitalization, ICU admission, mortality and long-covid.

NaliniAmbrose et al.

Neutralizing Monoclonal Antibody Use and COVID-19 Infection Outcomes

JAMA, April 2023; doi:10.1001/jamanetworkopen.2023.9694

Abstract

Importance Evidence on the effectiveness and safety of COVID-19 therapies across a diverse population with varied risk factors is needed to inform clinical practice.

Objective To assess the safety of neutralizing monoclonal antibodies (nMAbs) for the treatment of COVID-19 and their association with adverse outcomes.

Design, Setting, and Participants This retrospective cohort study included 167 183 patients from a consortium of 4 health care systems based in California, Minnesota, Texas, and Utah. The study included nonhospitalized patients 12 years and older with a positive COVID-19 laboratory test collected between November 9, 2020, and January 31, 2022, who met at least 1 emergency use authorization criterion for risk of a poor outcome.

Exposure FournMAb products (bamlanivimab, bamlanivimab-etesevimab, casirivimab-imdevimab, and sotrovimab) administered in the outpatient setting.

Main Outcomes and Measures Clinical and SARS-CoV-2 genomic sequence data and propensity-adjusted marginal structural models were used to assess the association between treatment with nMAbs and 4 outcomes: all-cause emergency department (ED) visits, hospitalization, death, and a composite of hospitalization or death within 14 days and 30 days of the index date (defined as the date of the first positive COVID-19 test or the date of referral). Patient index dates were categorized into 4 variant epochs: pre-Delta (November 9, 2020, to June 30, 2021), Delta (July 1 to November 30, 2021), Delta and Omicron BA.1 (December 1 to 31, 2021), and Omicron BA.1 (January 1 to 31, 2022).

Conclusions and Relevance In this study, nMAb treatment for COVID-19 was safe and associated with reductions in ED visits, hospitalization, and death, although it was not associated with reduced risk of hospitalization during the Omicron BA.1 epoch. These findings suggest that targeted risk stratification strategies may help optimize future nMAb treatment decisions.

HatasuKobayashi et al.

Oxidative DNA Damage by N4-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir

Academic, December 2022; doi.org/10.1093/infdis/jiac477

Abstract

Molnupiravir is an antiviral agent recently used for treating coronavirus disease 2019 (COVID-19). Here, we demonstrate that N4-hydroxycytidine (NHC), a molnupiravir metabolite, treated with cytidine deaminase (CDA) induced Cu(II)-mediated oxidative DNA damage in isolated DNA. A colorimetric assay revealed hydroxylamine generation from CDA-treated NHC. The site specificity of DNA damage also suggested involvement of hydroxylamine in the damage. Furthermore, Cu(I) and H2O2 play an important role in the DNA damage. We propose oxidative DNA damage via CDA-mediated metabolism as a possible mutagenic mechanism of NHC, highlighting the need for careful risk assessment of molnupiravir use in therapies for viral diseases, including COVID-19.

Bosco Hon-Ming Ma et al.

Clinical Outcomes Following Treatment for COVID-19 With Nirmatrelvir/Ritonavir and Molnupiravir Among Patients Living in Nursing Homes

JAMA, April 2023; doi:10.1001/jamanetworkopen.2023.10887

Abstract

Importance Older patients living in nursing homes are at very high risk of mortality after getting COVID-19.

Objective

To evaluate outcomes following oral antiviral treatment for COVID-19 among nonhospitalized older patients living in nursing homes.

Design, Setting, and Participants

This is a territory-wide, retrospective cohort study conducted between February 16 and March 31, 2022, with the last follow-up date on April 25, 2022. Participants were patients with COVID-19 living in nursing homes in Hong Kong. Data analysis was performed from May to June 2022.

Exposures

Molnupiravir, nirmatrelvir/ritonavir, or no oral antiviral treatment.

Main Outcomes and Measures

The primary outcome was hospitalization for COVID-19, and the secondary outcome was risk of inpatient disease progression (ie, admission to intensive care unit, use of invasive mechanical ventilation, and/or death).

Conclusions and Relevance

In this retrospective cohort study, the use of oral antivirals to treat COVID-19 was associated with a reduced risk of hospitalization and inpatient disease progression among patients living in nursing homes. The findings of this study of nursing home residents could be reasonably extrapolated to other frail older patients living in the community.

Hiroshi Mukae et al.

Efficacy and Safety of Ensitrelvir in Patients With Mild-to-Moderate Coronavirus Disease 2019: The Phase 2b Part of a Randomized, Placebo-Controlled, Phase 2/3 Study

CID, December 2022; doi.org/10.1093/cid/ciac933

Abstract

This phase 2b part of a randomized phase 2/3 study assessed the efficacy and safety of ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron epidemic.

Methods

Patients were randomized (1:1:1) to orally receive ensitrelvirfumaric acid 125 mg (375 mg on day 1) or 250 mg (750 mg on day 1) or placebo once daily for 5 days. The co-primary endpoints were the change from baseline in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer on day 4 and time-weighted average change from baseline up to 120 hours in the total score of predefined 12 COVID-19 symptoms. Safety was assessed through adverse events.

Results

A total of 341 patients (ensitrelvir 125-mg group: 114; ensitrelvir 250-mg group: 116; and placebo group: 111; male: 53.5–64.9%; mean age: 35.3–37.3 years) were included in the efficacy analyses. The change from baseline in SARS-CoV-2 titer on day 4 was significantly greater with both ensitrelvir doses than with placebo (differences from placebo: −0.41 log10 50% tissue-culture infectious dose/mL; P < .0001 for both). The total score of the 12 COVID-19 symptoms did not show a significant difference between the ensitrelvir groups and placebo group. The time-weighted average change from baseline up to 120 hours was significantly greater with ensitrelvir versus placebo in several subtotal scores, including acute symptoms and respiratory symptoms. Mostadverseeventsweremild in severity.

Conclusions

Ensitrelvir treatment demonstrated a favorable antiviral efficacy and potential clinical benefit with an acceptable safety profile

Ahmad Mourad et al.

Dexamethasone for Inpatients With COVID-19 in a National Cohort

JAMA, April 2023; doi:10.1001/jamanetworkopen.2023.8516

Abstract

Importance Limited effective therapeutics are available to hospitalized patients with COVID-19. Clinical trials and observational studies have shown varying effects of systemic corticosteroids, including dexamethasone, in hospitalized patients with COVID-19, with limited descriptions of important patient subgroups.

Objective To examine the clinical use of dexamethasone for hospitalized patients with COVID-19 respiratory illness and to explore the heterogeneity of treatment outcomes across different subgroups.

Design, Setting, and Participants This is a retrospective, propensity score–weighted cohort study of adult patients hospitalized for at least 48 hours for COVID-19 respiratory illness between July 1, 2020, and October 31, 2021, at a large health care network of 156 hospitals across the US. Data analysis was performed from March 2022 to February 2023.

Exposures Systemic dexamethasone administered within 48 hours of either admission or escalation in oxygen support.

Main Outcomes and Measures All-cause in-hospital mortality or discharge to hospice.

Conclusions and Relevance In this national multicenter cohort study of inpatients with COVID-19, early administration of dexamethasone was associated with significantly reduced odds of mortality or discharge to hospice in those requiring supplemental oxygen or MV and/or ECMO but not in those requiring no supplemental oxygen or NIPPV. These results support the continued use of systemic dexamethasone in patients hospitalized with COVID-19.

Seyed Arad Moghadasi et al.

Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors

Science, March 2023; doi/10.1126/sciadv.ade8778

Abstract

Vaccines and drugs have helped reduce disease severity and blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ongoing virus transmission, continuous evolution, and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease [Mpro; 3C-like protease (3CLpro)] of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different resistance mutation profile. Importantly, phylogenetic analyses indicate that several of these resistant variants have pre-existed the introduction of these drugs into the human population and are capable of spreading. These results encourage the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy.

Patricia Fanlo et al.

Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19

A Randomized Phase 2/3 Clinical Trial

JAMA, April 2023; doi:10.1001/jamanetworkopen.2023.7243

Abstract

Importance COVID-19 pneumonia is often associated with hyperinflammation. The efficacy and safety of anakinra in treating patients with severe COVID-19 pneumonia and hyperinflammation are still unclear.

Objective To assess the efficacy and safety of anakinra vs standard of care alone for patients with severe COVID-19 pneumonia and hyperinflammation.

Design, Setting, and Participants The Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to COVID-19 (ANA-COVID-GEAS) was a multicenter, randomized, open-label, 2-group, phase 2/3 clinical trial conducted at 12 hospitals in Spain between May 8, 2020, and March 1, 2021, with a follow-up of 1 month. Participants were adult patients with severe COVID-19 pneumonia and hyperinflammation. Hyperinflammation was defined as interleukin-6 greater than 40 pg/mL, ferritin greater than 500 ng/mL, C-reactive protein greater than 3 mg/dL (rationale, ≥5 upper normal limit), and/or lactate dehydrogenase greater than 300 U/L. Severe pneumonia was considered if at least 1 of the following conditions was met: ambient air oxygen saturation 94% or less measured with a pulse oximeter, ratio of partial pressure O2 to fraction of inspired O2 of 300 or less, and/or a ratio of O2 saturation measured with pulse oximeter to fraction of inspired O2 of 350 or less. Data analysis was performed from April to October 2021.

Interventions Usual standard of care plus anakinra (anakinra group) or usual standard of care alone (SoC group). Anakinrawas given at a dose of 100 mg 4 times a day intravenously.

Main Outcomes and Measures The primary outcome was the proportion of patients not requiring mechanical ventilation up to 15 days after treatment initiation, assessed on an intention-to-treat basis.

Results A total of 179 patients (123 men [69.9%]; mean [SD] age, 60.5 [11.5] years) were randomly assigned to the anakinra group (92 patients) or to the SoC group (87 patients). The proportion of patients not requiring mechanical ventilation up to day 15 was not significantly different between groups (64 of 83 patients [77.1%] in the anakinra group vs 67 of 78 patients [85.9%] in the SoC group; risk ratio [RR], 0.90; 95% CI, 0.77-1.04; P = .16). Anakinra did not result in any difference in time to mechanical ventilation (hazard ratio, 1.72; 95% CI, 0.82-3.62; P = .14). There was no significant difference between groups in the proportion of patients not requiring invasive mechanical ventilation up to day 15 (RR, 0.99; 95% CI, 0.88-1.11; P > .99).

Conclusions and Relevance In this randomized clinical trial, anakinra did not prevent the need for mechanical ventilation or reduce mortality risk compared with standard of care alone among hospitalized patients with severe COVID-19 pneumonia.

Seyed Arad Moghadasi et al

Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors

Science, March 2023; doi/10.1126/sciadv.ade8778

Abstract

Israel S. Maia et al.

Antivirals for adult patients hospitalised with SARS-CoV-2 infection: a randomised, phase II/III, multicentre, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX – REVOLUTIOn trial

The Lancet, march 2023; doi.org/10.1016/j.lana.2023.100466

Abstract

Repurposed drugs for treatment of new onset disease may be an effective therapeutic shortcut. We aimed to evaluate the efficacy of repurposed antivirals compared to placebo in lowering SARS-CoV2 viral load of COVID-19 patients.

Methods

REVOLUTIOn is a randomised, parallel, blinded, multistage, superiority and placebo controlled randomised trial conducted in 35 centres in Brazil. We include patients aged 18 years or older admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, symptoms onset 9 days or less and SpO2 94% or lower at room air were eligible. All participants were randomly allocated to receive either atazanavir, daclatasvir or sofosbuvir/daclatasvir or placebo for 10 days. The primary outcome was the decay rate (slope) of the SARS-CoV-2 viral load logarithm assessed in the modified intention to-treat population. This trial was registered with ClinicalTrials.gov, number NCT04468087.

Interpretation

No significant reduction in viral load was observed from the use of atazanavir, daclatasvir or sofosbuvir/daclatasvir compared to placebo in hospitalised COVID-19 patients who need oxygen support with symptoms onset 9 days or less.

Thais G. Moreira et al.

Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19

PNAS, March 2023; https://doi.org/10.1073/pnas.2220272120

Abstract

T cells are present in early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and play a major role in disease outcome and long-lasting immunity. Nasal administration of a fully human anti-CD3 monoclonal antibody (Foralumab) reduced lung inflammation as well as serum IL-6 and C-reactive protein in moderate cases of COVID-19. Using serum proteomics and RNA-sequencing, we investigated the immune changes in patients treated with nasal Foralumab. In a randomized trial, mild to moderate COVID-19 outpatients received nasal Foralumab (100 μg/d) given for 10 consecutive days and were compared to patients that did not receive Foralumab. We found that naïve-like T cells were increased in Foralumab-treated subjects and NGK7+ effector T cells were reduced. CCL5, IL32, CST7, GZMH, GZMB, GZMA, PRF1, and CCL4 gene expression were downregulated in T cells and CASP1 was downregulated in T cells, monocytes, and B cells in subjects treated with Foralumab. In addition to the downregulation of effector features, an increase in TGFB1 gene expression in cell types with known effector function was observed in Foralumab-treated subjects. We also found increased expression of GTP-binding gene GIMAP7 in subjects treated with Foralumab. Rho/ROCK1, a downstream pathway of GTPasessignaling was downregulated in Foralumab-treated individuals. TGFB1, GIMAP7, and NKG7 transcriptomic changes observed in Foralumab-treated COVID-19 subjects were also observed in healthy volunteers, MS subjects, and mice treated with nasal anti-CD3. Our findings demonstrate that nasal Foralumab modulates the inflammatory response in COVID-19 and provides a novel avenue to treat the disease.

Emily Harris et al.

Nasally Administered Monoclonal Antibody for COVID-19

JAMA, March 2023; doi:10.1001/jama.2023.4000

Abstract

Treating people with mild to moderate COVID-19 infections nasally with foralumab, an anti-CD3 monoclonal antibody, decreases the expression of genes involved in the inflammatory T-cell response, according to a randomized trial. Patients with COVID-19 who received foralumab for 10 days also had higher levels of brain-derived neurotrophic factor, which is linked with recovery from COVID-19, than those who did not receive the drug, the researchers reported in PNAS.

Moreover, participants with multiple sclerosis and healthy participants experienced identical changes in gene expression as those with COVID-19 after treatment with foralumab. “[N]ot only does our study suggest that this new monoclonal antibody drug is safe and can modulate the immune system without major side effects, but it can also decrease inflammation in multiple realms, so it may be useful for treating other diseases,” study investigator Thais Moreira, PhD, said in a statement.

Vincent Labbé

Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia - The ANTICOVID Randomized Clinical Trial

JAMA, March 2023; doi:10.1001/jamainternmed.2023.0456

Abstract

Importance Given the high risk of thrombosis and anticoagulation-related bleeding in patients with hypoxemic COVID-19 pneumonia, identifying the lowest effective dose of anticoagulation therapy for these patients is imperative.

Objectives To determine whether therapeutic anticoagulation (TA) or high-dose prophylactic anticoagulation (HD-PA) decreases mortality and/or disease duration compared with standard-dose prophylactic anticoagulation (SD-PA), and whether TA outperforms HD-PA; and to compare the net clinical outcomes among the 3 strategies.

Design, Settings, and Participants The ANTICOVID randomized clinical open-label trial included patients with hypoxemic COVID-19 pneumonia requiring supplemental oxygen and having no initial thrombosis on chest computer tomography with pulmonary angiogram at 23 health centers in France from April 14 to December 13, 2021. Of 339 patients randomized, 334 were included in the primary analysis—114 patients in the SD-PA group, 110 in the HD-PA, and 110 in the TA. At randomization, 90% of the patients were in the intensive care unit. Data analyses were performed from April 13, 2022, to January 3, 2023.

Interventions Patients were randomly assigned (1:1:1) to receive either SD-PA, HD-PA, or TA with low-molecular-weight or unfractionated heparin for 14 days.

Main Outcomes and Measures A hierarchical criterion of all-cause mortality followed by time to clinical improvement at day 28. Main secondary outcome was net clinical outcome at day 28 (composite of thrombosis, major bleeding, and all-cause death).

Conclusions and Relevance This randomized clinical trial found that compared with SD-PA, neither HD-PA nor TA use improved the primary hierarchical outcome of all-cause mortality or time to clinical improvement in patients with hypoxemic COVID-19 pneumonia; however, HD-PA resulted in significantly better net clinical outcome by decreasing the risk of de novo thrombosis.

Joseph A Lewnard et al.

Effectiveness of nirmatrelvir–ritonavir in preventing hospital admissions and deaths in people with COVID-19: a cohort study in a large US health-care system

The Lancet, March 2023; doi.org/10.1016/S1473-3099(23)00118-4

Abstract

In the USA, oral nirmatrelvir–ritonavir is authorised for use in patients aged 12 years or older with mild-to-moderate COVID-19 who are at risk of progression to severe disease and hospitalisation. We aimed to establish the effectiveness of nirmatrelvir–ritonavir in preventing hospital admissions and death in people with COVID-19 in an outpatient prescribing context in the USA.

Methods

In this matched observational outpatient cohort study in the Kaiser Permanente Southern California (CA, USA) health-care system, data were extracted from electronic health records of non-hospitalised patients aged 12 years or older who received a positive SARS-CoV-2 PCR test result (their index test) between April 8 and Oct 7, 2022, and had not received another positive test result within the preceding 90 days. We compared outcomes between people who received nirmatrelvir–ritonavir and those who did not receive nirmatrelvir–ritonavir by matching cases by date, age, sex, clinical status (including care received, the presence or absence of acute COVID-19 symptoms at testing, and time from symptom onset to testing), vaccination history, comorbidities, health-care seeking during the previous year, and BMI. Our primary endpoint was the estimated effectiveness of nirmatrelvir–ritonavir in preventing hospital admissions or death within 30 days of a positive test for SARS-CoV-2.

Interpretation

In a setting with high levels of COVID-19 vaccine uptake, nirmatrelvir–ritonavir effectively reduced the risk of hospital admission or death within 30 days of a positive outpatient SARS-CoV-2 test.

DjillaliAnnane et al.

Intravenous ravulizumab in mechanically ventilated patients hospitalised with severe COVID-19: a phase 3, multicentre, open-label, randomised controlled trial

The Lancet, March 2023; doi.org/10.1016/S2213-2600(23)00082-6

Abstract

The complement pathway is a potential target for the treatment of severe COVID-19. We evaluated the safety and efficacy of ravulizumab, a terminal complement C5 inhibitor, in patients hospitalised with severe COVID-19 requiring invasive or non-invasive mechanical ventilation.

Methods

This phase 3, multicentre, open-label, randomised controlled trial (ALXN1210-COV-305) enrolled adult patients (aged ≥18 years) from 31 hospitals in France, Japan, Spain, the UK, and the USA. Eligible patients had a confirmed diagnosis of SARS-CoV-2 that required hospitalisation and either invasive or non-invasive mechanical ventilation, with severe pneumonia, acute lung injury, or acute respiratory distress syndrome confirmed by CT scan or x-ray. We randomly assigned participants (2:1) to receive intravenous ravulizumab plus best supportive care (BSC) or BSC alone using a web-based interactive response system. Randomisation was in permuted blocks of six with stratification by intubation status. Bodyweight-based intravenous doses of ravulizumab were administered on days 1, 5, 10, and 15. The primary efficacy endpoint was survival based on all-cause mortality at day 29 in the intention-to-treat (ITT) population. Safety endpoints were analysed in all randomly assigned patients in the ravulizumab plus BSC group who received at least one dose of ravulizumab, and in all randomly assigned patients in the BSC group. The trial is registered with ClinicalTrials.gov, NCT04369469, and was terminated at interim analysis due to futility.

Interpretation

Addition of ravulizumab to BSC did not improve survival or other secondary outcomes. Safety findings were consistent with the known safety profile of ravulizumab in its approved indications. Despite the lack of efficacy, the study adds value for future research into complement therapeutics in critical illnesses by showing that C5 inhibition can be accomplished in severely ill patients.

Andrea Alemany et al.

Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trial

eClinical Medicine, March 2023; doi.org/10.1016/j.eclinm.2023.101898

Abstract

Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection.

Methods

We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141.

Interpretation

Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19.

MihirKhunte et al.

Projected COVID-19 Mortality Reduction From Paxlovid Rollout

JAMA, March 2023; doi:10.1001/jamahealthforum.2023.0046

Abstract

Introduction

COVID-19 was the third leading cause of death in the US in 2022, and following FDA approval of Paxlovid (nirmatrelvir-ritonavir), the test-to-treat initiative became a cornerstone of the US pandemic response.1 Paxlovid treatment requires testing and initiating medication within 5 days of symptom onset. However, the population-level impact of Paxlovid rollout has not been estimated.2 The purpose of this study is to project simulated effects of Paxlovid rollout on hospitalizations and mortality and to quantify the number of COVID-19 tests and Paxlovid courses required for different levels of mortality reduction during a surge comparable to the 2022 winter Omicron wave (WOW) (December 15, 2021, to March 15, 2022).

Results

We estimated that 78% of US cases that will require hospitalization are detected within 5 days of symptom onset, and that uptake of Paxlovid is 5% among eligible infected individuals. Given Paxlovid effectiveness of 67% against hospitalization and 81% against mortality, this corresponds to relative percentage reductions of COVID-19 hospitalization by 2.7% and mortality by 3.2% (Figure).

In sensitivity analyses (Table, models 2-3), COVID-19 hospitalization reductions varied between 0.5% and 7.5% and mortality reductions between 0.6% and 7.5%. However, in nursing homes, with higher uptake, we estimate hospitalization and mortality reductions at 7.7% and 9.3% (model 4). If Paxlovid uptake among eligible populations increases to 40% (model 7), we project a 21% reduction in hospitalization and 25% reduction in mortality. If Paxlovid uptake increases to 80% (model 8), we project a 42% reduction in hospitalization and 51% reduction in mortality.

At 5% Paxlovid uptake (model 1), the required number of symptomatic tests and Paxlovid courses needed during the WOW would have been 4.8 million and 2.5 million, respectively, averting 2.7% of hospitalizations and 3.2% of deaths. At 80% Paxlovid uptake (model 8), the required number of symptomatic tests and Paxlovid courses would have been 75.3 million and 39.8 million, respectively, averting 41.8% of hospitalizations and 50.5% of deaths.

Discussion

In this study, we estimated that had current Paxlovid uptake been achieved in January 2022, 4.8 thousand deaths would have been averted during the WOW. Our estimates suggest that 0.7 to 75.3 million symptomatic tests and 0.4 to 39.8 million courses of Paxlovid are needed for a future Omicron-like wave.

There are limitations to this work. Our parameterization is limited by a dearth of data on Paxlovid uptake. Also, relevant parameters are likely to continue shifting over time due to reduced prescribing restrictions or potential resistance.

Ilaria Mastrorosa et al.

Sarilumab plus standard of care vs standard of care for the treatment of severe COVID-19: a phase 3, randomized, open-labeled, multi-center study (ESCAPE study)

The Lancet, march 2023; doi.org/10.1016/j.eclinm.2023.101895

Abstract

Background

Among interleukin-6 inhibitors suggested for use in COVID-19, there are few robust evidences for the efficacy of sarilumab. Herein, we evaluated the efficacy and safety of sarilumab in severe COVID-19.

Interpretation

The efficacy of sarilumab in severe COVID-19 was not demonstrated both in the overall and in the stratified for severity analysis population. Exploratory analyses suggested that subsets of patients with lower CRP values or lower lymphocyte counts might have had benefit with sarilumab treatment, but this finding would require replication in other studies. The relatively low rate of concomitant corticosteroid use, could partially explain our results.

Xin Wang et al.

Network-based drug repurposing for the treatment of COVID-19 patients in different clinical stages

Cell, February 2023; doi.org/10.1016/j.heliyon.2023.e14059

Abstract

In the severe acute respiratory coronavirus disease 2019 (COVID-19) pandemic, there is an urgent need to develop effective treatments. Through a network-based drug repurposing approach, several effective drug candidates are identified for treating COVID-19 patients in different clinical stages. The proposed approach takes advantage of computational prediction methods by integrating publicly available clinical transcriptome and experimental data. We identify 51 drugs that regulate proteins interacted with SARS-CoV-2 protein through biological pathways against COVID-19, some of which have been experimented in clinical trials. Among the repurposed drug candidates, lovastatin leads to differential gene expression in clinical transcriptome for mild COVID-19 patients, and estradiolcypionate mainly regulates hormone-related biological functions to treat severe COVID-19 patients. Multi-target mechanisms of drug candidates are also explored. Erlotinib targets the viral protein interacted with cytokine and cytokine receptors to affect SARS-CoV-2 attachment and invasion. Lovastatin and testosterone block the angiotensin system to suppress the SARS-CoV-2 infection. In summary, our study has identified effective drug candidates against COVID-19 for patients in different clinical stages and provides comprehensive understanding of potential drug mechanisms.

Soumya G. Remeshet al.

Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps

Cell, February 2023; doi.org/10.1016/j.str.2023.01.009

Abstract

The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor-binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-RBD and prevent viral entry into host cells (“receptor traps”). Here we determine cryo-EM structures of our receptor traps in complex with stabilized Spike ectodomain. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high-affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high-affinity (0.53–4.2 nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron and Delta pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.

Kirsten Bibbins-Domingo,Preeti N. Malani

At a Higher Dose and Longer Duration, Ivermectin Still Not Effective Against COVID-19

JAMA, February 2023; doi:10.1001/jama.2023.1922

Abstract

ACochrane meta-analysis of 11 eligible trials examining the efficacy of ivermectin for the treatment of COVID-19 published through April 2022 concluded that ivermectin has no beneficial effect for people with COVID-19.1 Since May 2022, an additional 3 large randomized clinical trials including several thousand participants have been published, each reaching a similar conclusion.

Today JAMA publishes a new trial of ivermectin treatment for mild to moderate COVID-19 that addresses the possibility that the existing literature may have missed the efficacy of ivermectin because the previously tested dose (approximately 400 μg/kg daily for 3 days) was insufficient.5 At a higher treatment dose (600 μg/kg daily) and longer treatment duration (6 days), Naggie and colleagues again conclude that ivermectin is not beneficial for the treatment of COVID-19.

At the doses and durations tested in these studies, ivermectin does not appear to be associated with serious adverse effects. However, a generally well-tolerated therapy that lacks efficacy can still be dangerous, particularly if it results in patients forgoing other interventions with proven efficacy, such as evidence-based COVID-19 treatments6 or vaccination against SARS-CoV-2. Ivermectin has been used throughout the pandemic.7 Although the current prevalence of ivermectin use in the US and globally is difficult to determine, reports in the lay media as well as our own experience as clinicians suggest that use of ivermectin for COVID-19 has not fully abated, fueled in part by real or perceived lack of access to effective therapies, continued confusion or misinformation, and active disinformation about ivermectin’s efficacy, including by physicians.8

Scientists will continue to produce knowledge on the effectiveness of interventions for the prevention and treatment of COVID-19.9 JAMA will continue to vet this science and help disseminate the highest-quality work to clinicians, patients, and the general public. But closing the knowledge gap is, on its own, not sufficient, and more must be done in partnership with others to address the misinformation that continues as we embark on the fourth year of the COVID-19 pandemic.

Susanna Naggie et al.

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19 - A Randomized Clinical Trial

JAMA, February 2023; doi:10.1001/jama.2023.1650

Abstract

Importance It is unknown whether ivermectin, with a maximum targeted dose of 600 μg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate COVID-19.

Objective To evaluate the effectiveness of ivermectin at a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo, for the treatment of early mild to moderate COVID-19.

Design, Setting, and Participants The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial was designed to evaluate repurposed therapies among outpatients with mild to moderate COVID-19. A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93 sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022.

Interventions Participants were randomly assigned to receive ivermectin, with a maximum targeted dose of 600 μg/kg (n = 602) daily, or placebo (n = 604) for 6 days.

Main Outcomes and Measures The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28.

Conclusions and Relevance Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo did not improve time to sustained recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.

Alain Amstutz et al.

Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials

The Lancet, February 2023; doi.org/10.1016/S2213-2600(22)00528-8

Abstract

Background

Interpretation of the evidence from randomised controlled trials (RCTs) of remdesivir in patients treated in hospital for COVID-19 is conflicting. We aimed to assess the benefits and harms of remdesivir compared with placebo or usual care in these patients, and whether treatment effects differed between prespecified patient subgroups.

Interpretation

This individual patient data meta-analysis showed that remdesivir reduced mortality in patients hospitalised with COVID-19 who required no or conventional oxygen support, but was underpowered to evaluate patients who were ventilated when receiving remdesivir. The effect size of remdesivir in patients with more respiratory support or acquired immunity and the cost-effectiveness of remdesivir remain to be further elucidated

Andre C Kalil

Remdesivir saves lives. Were 3 years needed to learn that?

The Lancet, February 2023; doi.org/10.1016/S2213-2600(23)00036-X

Abstract

In The Lancet Respiratory Medicine, Alain Amstutz and colleagues1 address a 3-year-old controversy: does remdesivir reduce mortality in patients hospitalised for COVID-19?

Remdesivir is a viral RNA polymerase inhibitor that was evaluated in patients hospitalised for COVID-19 in February, 2020, in the National Institutes of Health (NIH) Adaptive COVID-19 Treatment Trial (ACTT-1)2—a federally funded, placebo-controlled, double-blind, randomised stratified trial that enrolled 1062 patients and was completed in 59 days. ACTT-1 showed a significantly shorter time to recovery with remdesivir than with placebo (5 days shorter overall, and 7 days shorter for the sickest patients), 50% faster improvement in clinical status, 30% lower progression to non-invasive ventilation, 43% lower progression to invasive mechanical ventilation, and 45% reduction in mortality at 14 days—all prespecified endpoints with significant results.2 In April, 2020, the ACTT-1 data safety monitoring board recommended to stop the trial because of the significant benefits of remdesivir, and all patients receiving placebo were offered remdesivir on the basis of unanimous ethical justification.

The results of ACTT-1 were straightforward: remdesivir was associated with faster time to recovery, shorter length of hospital stay, decreased progression to mechanical ventilation, and lower mortality, all of which are patient-centered outcomes fully relevant to clinical care. At that time, the amendment of major medical guidelines in accordance with the results of ACTT-1 would have been expected in order to immediately benefit patients hospitalised for COVID-19. However, both the Infectious Diseases Society of America (IDSA)3 and NIH4 guidelines recommended remdesivir only for patients on supplemental oxygen. These recommendations were made even though the 95% CIs of all respiratory support subgroups overlapped and treatment heterogeneity (interaction) was absent, which indicated that the benefits of remdesivir were similar among subgroups. The WHO guidelines did not recommend treatment with remdesivir at all, and a recommendation against its use in patients hospitalised with COVID-19 was subsequently made5 on the basis of the interim results of the open-label Solidarity trial.6 The final results7 of the Solidarity trial showed that treatment with remdesivir led to significant hospital mortality reduction in patients with or without supplemental oxygen (rate ratio 0·86 [95% CI 0·76–0·98]) and significantly lower progression to mechanical ventilation or death (0·84 [0·75–0·93]).

The individual patient data meta-analysis by Amstutz and colleagues1 featured prespecified analyses according to group allocation, standardised outcome definitions, and adverse events stratified by organ systems. The study evaluated data from a total of 10 480 patients in eight randomised controlled trials and concluded that remdesivir significantly reduces mortality in patients hospitalised with COVID-19 with or without supplemental oxygen (adjusted odds ratio [aOR] 0·80 [95% CI 0·70–0·93]). A further significant reduction is also seen in the progression to mechanical ventilation or death with remdesivir (0·63 [0·48–0·83]). A conclusion could not be reached for patients receiving ventilation owing to a lack of statistical power. In terms of patient safety, the meta-analysis showed that—both overall and by organ system—grade 3 or 4 adverse events and serious adverse events were not increased with remdesivir. Notably, these results confirm the findings of ACTT-1 that were reported in April, 2020.2 Additionally, it should not be surprising that if remdesivir significantly reduced mortality in patients receiving supplemental oxygen,2 patients given remdesivir earlier in the course of COVID-19 should also benefit: such findings were shown by the Solidarity trial7 and this meta-analysis1 (significantly better survival and lower progression to mechanical ventilation or death in hospitalised patients with or without supplemental oxygen); by multiple large, real-world, comparative effectiveness studies from different countries8, 9, 10, 11 (significantly better survival and clinical recovery in hospitalised patients without supplemental oxygen); and by the PINETREE trial12 (significantly lower progression to hospitalisation or death in outpatients at high risk without supplemental oxygen).

In summary, this individual patient data meta-analysis1 adds relevant scientific evidence and supports both the lower progression to mechanical ventilation and the significant survival benefits of remdesivir for patients hospitalised for COVID-19 with or without supplemental oxygen. The study suggests individualising approaches to remdesivir treatment for patients on mechanical ventilation, a practical example being continuing remdesivir in order to combat progressive respiratory failure due to persistent SARS-CoV-2 viral replication. Prioritising underpowered subgroup results instead of powered overall results helped to prevent the NIH and IDSA guidelines from recommending remdesivir to patients hospitalised for COVID-19 without supplemental oxygen for nearly 2 years, and prioritising the interim results of a high risk of bias trial6 over the complete and beneficial results of a low risk of bias trial2 helped to prevent the WHO guidelines from recommending remdesivir to any patients for almost 3 years. In the context of a deadly pandemic, it would have been beneficial for these panels to have erred on the side of inclusiveness and benefit rather than focusing on subgroup and interim results as evidence of no benefit, particularly in light of the robust and positive prespecified overall outcome findings of a placebo-controlled, double-blind, randomised stratified trial2 with a reassuring patient safety profile (no difference in adverse events between remdesivir and placebo) and the strong biological and clinical plausibility that antiviral benefit would extend to patients in the earlier stages of COVID-19 (before requiring supplemental oxygen). Regrettably, the delays in recommendation of remdesivir for patients—even after the initial remdesivir shortage was resolved—adversely shaped antimicrobial policy in hospitals around the world, preventing patients from receiving timely remdesivir. How many more lives could have been saved had remdesivir been recommended more broadly and made more readily available? All of us—the scientific community, public health agencies, professional societies, journal editors, and guideline committees—must learn from these mistakes to provide more reliable scientific recommendations to directly benefit the individual care of patients globally, and to advocate for equitable access to safe and life-saving antiviral therapies such as remdesivir in low-income and middle-income countries.

Najjar-Debbiny R. et al.

Effectiveness of Molnupiravir in High-Risk Patients: A Propensity Score Matched Analysis

CID, September 2022; doi.org/10.1093/cid/ciac781

Abstract

Background

Molnupiravir was granted emergency use authorization for the treatment of mild to moderate coronavirus disease 2019 (COVID-19). In this study, we used population-based real-world data to evaluate the effectiveness of molnupiravir.

Methods

The database of the largest healthcare provider in Israel was used to identify all adults with first-ever positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) performed in the community during January–February 2022, who were at high risk for severe COVID-19, and had no contraindications for molnupiravir use. Patients were included regardless of SARS-CoV-2 vaccination status. A total of 2661 patients who received molnupiravir were propensity score matched with 2661 patients who have not received molnupiravir (control group). Patients were followed through 10 March 2022 for up to 28 days for the first occurrence of the composite severe COVID-19 or COVID-19-specific mortality.

Results

The composite outcome occurred in 50 patients in the molnupiravir group and 60 patients in the control group. Molnupiravir was associated with a nonsignificant reduced risk of the composite outcome: hazard ratio, 0.83 (95% confidence interval, .57–1.21). However, subgroup analyses showed that molnupiravir was associated with a significant decrease in the risk of the composite outcome in older patients 0.54 (0.34–0.86), in females 0.41 (0.22–0.77), and in patients with inadequate COVID-19 vaccination 0.45 (0.25–0.82). The results were similar when each component of the composite outcome was examined separately.

Conclusions

This study suggests that in the era of Omicron and in real-life setting, molnupiravir might be effective in reducing the risk of severe COVID-19 and COVID-19-related mortality, particularly in specific subgroups.

Chauvin C. et al.

Tocilizumab treated convalescent COVID-19 patients retain the cross-neutralization potential against SARS-CoV-2 variants

Cell; doi.org/10.1016/j.isci.2023.106124

Abstract

While tocilizumab treatment in severe and critical COVID-19 patients has proven its efficacy at clinical level, there is little evidence supporting the effect of short-term use of IL-6 receptor blocking therapy on the B cell sub-populations and the cross-neutralization of SARS-CoV-2 variants in convalescent COVID-19 patients. We performed immunological profiling of 69 tocilizumab-treated and non-treated convalescent COVID-19 patients in total. We observed that SARS-CoV-2-specific IgG1 titers depended on disease severity but not on tocilizumab-treatment. The plasma of both treated and non-treated patients infected with the ancestral variant exhibit strong neutralizing activity against the ancestral virus, Alpha, Beta, and Delta variants of SARS-CoV-2, while the Gamma and Omicron virus were less sensitive to seroneutralization. Overall, we observed that, despite the clinical benefits of short-term tocilizumab therapy in modifying the cytokine storm associated with COVID-19 infections, there were no modifications in the robustness of B-cell and IgG responses to Spike antigens.

Langford B.J. et al.

Antimicrobial resistance in patients with COVID-19: a systematic review and meta-analysis

The Lancet, January 2023; doi.org/10.1016/S2666-5247(22)00355-X

Abstract

Background

Frequent use of antibiotics in patients with COVID-19 threatens to exacerbate antimicrobial resistance. We aimed to establish the prevalence and predictors of bacterial infections and antimicrobial resistance in patients with COVID-19.

Methods

We did a systematic review and meta-analysis of studies of bacterial co-infections (identified within ≤48 h of presentation) and secondary infections (>48 h after presentation) in outpatients or hospitalised patients with COVID-19. We searched the WHO COVID-19 Research Database to identify cohort studies, case series, case-control trials, and randomised controlled trials with populations of at least 50 patients published in any language between Jan 1, 2019, and Dec 1, 2021. Reviews, editorials, letters, pre-prints, and conference proceedings were excluded, as were studies in which bacterial infection was not microbiologically confirmed (or confirmed via nasopharyngeal swab only). We screened titles and abstracts of papers identified by our search, and then assessed the full text of potentially relevant articles. We reported the pooled prevalence of bacterial infections and antimicrobial resistance by doing a random-effects meta-analysis and meta-regression. Our primary outcomes were the prevalence of bacterial co-infection and secondary infection, and the prevalence of antibiotic-resistant pathogens among patients with laboratory-confirmed COVID-19 and bacterial infections. The study protocol was registered with PROSPERO (CRD42021297344).

Findings

We included 148 studies of 362 976 patients, which were done between December, 2019, and May, 2021. The prevalence of bacterial co-infection was 5·3% (95% CI 3·8–7·4), whereas the prevalence of secondary bacterial infection was 18·4% (14·0–23·7). 42 (28%) studies included comprehensive data for the prevalence of antimicrobial resistance among bacterial infections. Among people with bacterial infections, the proportion of infections that were resistant to antimicrobials was 60·8% (95% CI 38·6–79·3), and the proportion of isolates that were resistant was 37·5% (26·9–49·5). Heterogeneity in the reported prevalence of antimicrobial resistance in organisms was substantial (I2=95%).

Interpretation

Although infrequently assessed, antimicrobial resistance is highly prevalent in patients with COVID-19 and bacterial infections. Future research and surveillance assessing the effect of COVID-19 on antimicrobial resistance at the patient and population level are urgently needed.

Reis G. et al.

Early Treatment with Pegylated Interferon Lambda for Covid-19

NEJM, February 2023; DOI: 10.1056/NEJMoa2209760

Abstract

BACKGROUND

The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear.

METHODS

We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 μg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization.

RESULTS

A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19–related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups.

CONCLUSIONS

Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo.

Chen J. et al.

Functional nucleic acids as potent therapeutics against SARS-CoV-2 infection

Cell, January 2023; doi.org/10.1016/j.xcrp.2023.101249

Abstract

The COVID-19 pandemic has posed a severe threat to human life and the global economy. Although conventional treatments, including vaccines, antibodies, and small-molecule inhibitors, have been broadly developed, they usually fall behind the constant mutation of SARS-CoV-2, due to the long screening process and high production cost. Functional nucleic acid (FNA)-based therapeutics are a newly emerging promising means against COVID-19, considering their timely adaption to different mutants and easy design for broad-spectrum virus inhibition. In this review, we survey typical FNA-related therapeutics against SARS-CoV-2 infection, including aptamers, aptamer-integrated DNA frameworks, functional RNA, and CRISPR-Cas technology. We first introduce the pathogenesis, transmission, and evolution of SARS-CoV-2, then analyze the existing therapeutic and prophylactic strategies, including their pros and cons. Subsequently, the FNAs are recommended as potent alternative therapeutics from their screening process and controllable engineering to effective neutralization. Finally, we put forward the remaining challenges of the existing field and sketch out the future development directions.

MichihitoSasaki et al.

S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters

Science, November 2022; doi/10.1126/scitranslmed.abq4064

Abstract

In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Oral antiviral medication demands not only high antiviral activity but also target specificity, favorable oral bioavailability, and high metabolic stability. Although a large number of compounds have been identified as potential inhibitors of SARS-CoV-2 infection in vitro, few have proven to be effective in vivo. Here, we show that oral administration of S-217622 (ensitrelvir), an inhibitor of SARS-CoV-2 main protease (Mpro; also known as 3C-like protease), decreases viral load and ameliorates disease severity in SARS-CoV-2–infected hamsters. S-217622 inhibited viral proliferation at low nanomolar to submicromolar concentrations in cells. Oral administration of S-217622 demonstrated favorable pharmacokinetic properties and accelerated recovery from acute SARS-CoV-2 infection in hamster recipients. Moreover, S-217622 exerted antiviral activity against SARS-CoV-2 variants of concern, including the highly pathogenic Delta variant and the recently emerged Omicron BA.5 and BA.2.75 variants. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase 3 clinical trial (clinical trial registration no. jRCT2031210350), has remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.

McCarthy MW et al.

Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19 A Randomized Clinical Trial

JAMA, January 2023; doi:10.1001/jama.2022.24100

Abstract

Importance: The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear.

Objective: To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US.

Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.

Senefeld JW et al.

COVID-19 Convalescent Plasma for the Treatment of Immunocompromised Patients: A Systematic Review and Meta-analysis

JAMA, January 2023; doi:10.1001/jamanetworkopen.2022.50647

Abstract

Importance Patients who are immunocompromised have increased risk for morbidity and mortality associated with coronavirus disease 2019 (COVID-19) because they less frequently mount antibody responses to vaccines. Although neutralizing anti-spike monoclonal-antibody treatment has been widely used to treat COVID-19, evolutions of SARS-CoV-2 have been associated with monoclonal antibody-resistant SARS-CoV-2 variants and greater virulence and transmissibility of SARS-CoV-2. Thus, the therapeutic use of COVID-19 convalescent plasma has increased on the presumption that such plasma contains potentially therapeutic antibodies to SARS-CoV-2 that can be passively transferred to the plasma recipient.

Objective: To assess the growing number of reports of clinical experiences of patients with COVID-19 who are immunocompromised and treated with specific neutralizing antibodies via COVID-19 convalescent plasma transfusion.

Data Sources: On August 12, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma use in patients who are immunocompromised.

Study Selection: Randomized clinical trials, matched cohort studies, and case report or series on COVID-19 convalescent plasma use in patients who are immunocompromised were included. The electronic search yielded 462 unique records, of which 199 were considered for full-text screening.

Data Extraction and Synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 3 independent reviewers in duplicate and pooled.

Main Outcomes and Meaures: The prespecified end point was all-cause mortality after COVID-19 convalescent plasma transfusion; exploratory subgroup analyses were performed based on putative factors associated with the potential mortality benefit of convalescent plasma.

Results: This systematic review and meta-analysis included 3 randomized clinical trials enrolling 1487 participants and 5 controlled studies. Additionally, 125 case series or reports enrolling 265 participants and 13 uncontrolled large case series enrolling 358 participants were included. Separate meta-analyses, using models both stratified and pooled by study type (ie, randomized clinical trials and matched cohort studies), demonstrated that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for the amalgam of both randomized clinical trials and matched cohort studies (risk ratio [RR], 0.63 [95% CI, 0.50-0.79]).

Conclusions and Relevance: These findings suggest that transfusion of COVID-19 convalescent plasma is associated with mortality benefit for patients who are immunocompromised and have COVID-19.

ZhujunCao et al.

VV116 versus Nirmatrelvir–Ritonavir for Oral Treatment of Covid-19

NEJM, December 2022; DOI: 10.1056/NEJMoa2208822

Abstract

BACKGROUND

Nirmatrelvir–ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

METHODS

We conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir–ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19–related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of >1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir–ritonavir).

RESULTS

A total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir–ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir–ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir–ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19–related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir–ritonavir group (67.4% vs. 77.3%).

CONCLUSIONS

Among adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir–ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns.

IrfanUllah et al.

The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice

Cell, December 2022; doi.org/10.1016/j.xcrm.2022.100893

Abstract

COVID-19 convalescent plasmas (CCPs) are chosen for plasma therapy based on neutralizing titers and anti-Spike immunoglobulin levels. However, CCP characteristics that promote SARS-CoV-2 control are complex and incompletely defined. Using an in vivo imaging approach, we demonstrate that CCPs with low neutralizing (ID50 ≤ 1:250), but moderate to high Fc-effector activity, in contrast to those with poor Fc function, delay mortality and/or improve survival of SARS-CoV-2-challenged K18-hACE2 mice. The impact of innate immune cells on CCP efficacy depended on their residual neutralizing activity. Fractionation of a selected CCP revealed that IgG and Ig(M + A) were required during therapy, but the IgG fraction alone sufficed during prophylaxis. Finally, despite reduced neutralization, ancestral SARS-CoV-2-elicited CCPs significantly delayed Delta and Beta-induced mortality suggesting that Fc-effector functions contribute to immunity against VOCs. Thus, Fc activity of CCPs provide a second line of defense when neutralization is compromised and can serve as an important criterion for CCP selection.

Pan D.Z. et al.

Remdesivir improves biomarkers associated with disease severity in COVID-19 patients treated in an outpatient setting

Nature, January 2023; doi.org/10.1038/s43856-022-00232-2

Abstract

Background

Remdesivir (RDV) is an intravenous antiviral with activity against SARS-CoV-2 for treatment of hospitalized COVID-19 patients with moderate-to-severe disease. Biomarkers associated with clinical outcomes have been identified for COVID-19, but few evaluated in context of antiviral treatment. Here, we assessed baseline (day 1, prior to first RDV dose) biomarkers and the impact of RDV treatment on longitudinal biomarker readouts.

Methods

Recently, RDV was evaluated in high-risk, non-hospitalized patients with confirmed SARS-CoV-2 infection and was highly effective at preventing disease progression. The randomized, double-blind, placebo-controlled Phase 3 study included 562 participants who received at least 1 dose of study drug, of which 312 consented for longitudinal biomarker assessments at baseline, day 3, and day 14. We assessed sixteen baseline biomarkers and the impact of RDV treatment on longitudinal biomarker readouts.

Results

Six well-known, inflammation-associated biomarkers are elevated at baseline in participants meeting the primary endpoint of hospitalization or death by day 28. Moreover, in comparison to placebo, biomarkers in RDV-treated participants show accelerated improvement, including reduction of soluble angiopoietin-2, D-dimer, and neutrophil-to-lymphocyte ratio, as well as an increase in lymphocyte counts.

Conclusions

Overall, the findings in this study suggest that RDV treatment may accelerate the improvement of multiple biomarkers of COVID-19 severity, which are associated with better clinical outcomes during infection. These findings have implications for better understanding the activity of antiviral treatments in COVID-19.

Suran M.

VA Finds Nirmatrelvir Associated With Lower Risk of Long COVID

JAMA, December 2022; doi:10.1001/jama.2022.20051

Abstract

The antiviral therapy nirmatrelvir, 1 of the medications used in Paxlovid, may mitigate the development of long COVID conditions, according to an observational study by the US Department of Veterans Affairs (VA). The study was posted to the preprint server medRxiv in early November and had not yet been peer-reviewed.

In the study of medical records from veterans who tested positive for SARS-CoV-2, about 9200 patients took oral nirmatrelvir within 5 days of their diagnosis while about 47 000 did not receive antiviral or antibody treatment during the first 30 days of infection. All patients had at least 1 risk factor for developing severe COVID-19. None were hospitalized on the day they tested positive, and all survived for at least 30 days.

About 3 months after diagnosis, patients who received nirmatrelvir were 26% less likely to develop long COVID conditions such as blood clots, fatigue, heart disease, kidney disease, liver disease, muscle pain, neurocognitive impairment, and shortness of breath. Such conditions occurred less often among these patients regardless of their vaccination status and prior history of SARS-CoV-2 infection. Nirmatrelvir use was also associated with a 30% and 48% reduction in postacute hospitalization and death, respectively. However, the drug wasn’t associated with a lower risk of new-onset diabetes or cough.

Anita Slomski

Angiotensin Receptor Blockers Not Effective Against COVID-19

JAMA, December 2022; doi:10.1001/jama.2022.20053

Abstract

Apragmatic randomized clinical trial demonstrated that angiotensin receptor blockers (ARBs), widely used as an antihypertensive and used to treat individuals with a high risk of heart disease, did not improve clinical outcomes among people hospitalized with COVID-19. Because SARS-CoV-2 enters host cells by binding to angiotensin-converting enzyme 2 (ACE-2) receptors, the investigators evaluated whether modulation of the renin-angiotensin system with ARBs might reduce disease severity.

The trial was conducted at 17 hospitals in Australia and India from May 2020 through November 2021. it included 787 patients whose average age was 49 years and who were naive to ARBs.

The primary end point was COVID-19 disease severity using a modified World Health Organization (WHO) Clinical Progression Scale.

After 14 days of treatment, there was no meaningful difference in illness severity between the 2 groups, so the trial was stopped for futility.

The trial cohort had milder disease than anticipated; nearly 75% of the participants returned home by day 7 and nearly all were home by day 14. ARBs may have a different effect among patients with more severe disease or at a higher dose, according to the investigators.

They concluded that although ARBs did not provide benefit in the treatment of COVID-19, the drugs are safe to use in patients with the infection. The results were reported in The BMJ.

Butler C.C. et al.

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial

Lancet, December 2022, doi.org/10.1016/S0140-6736(22)02597-1

Abstract

The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population.

Interpretation

Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community.

Pooja Yadav, Papia Chowdhury

Effectivity of Repurposed Drugs Against SARS-CoV-2 Infections, A Hope for COVID 19: Inhibitor Modelling studies by Docking and Molecular Dynamics

Cell; December 2022; doi.org/10.1016/j.heliyon.2022.e12327

Abstract

In the present study, the authors have done a comparative study on the efficacy of some currently used repurposed drugs: Oseltamivir (O), Favipiravir (F) and Hydroxychloroquine (H) in individual and in their combinational mode against CoV-2 infections. The ADME analysis has helped us to identify the inhibitory possibility of the tested drugs towards receptor 3CLpro protein of SARS-CoV-2. Various thermodynamical parameters obtained from Molecular Docking, Molecular dynamics (MD) and MMPBSA simulations like binding affinity, potential energy (Epot), RMSD, RMSF, SASA energy, interaction energies, Gibbs free energy (ΔGbind) etc. also helped us to verify the effectivity of mentioned drugs against CoV-2 protease.

Chokkalingam A.P. et al.

Association of Remdesivir Treatment With Mortality Among Hospitalized Adults With COVID-19 in the United States

JAMA, December 2022; doi:10.1001/jamanetworkopen.2022.44505

Abstract

Importance SARS-CoV-2, which causes COVID-19, poses considerable morbidity and mortality risks. Studies using data collected during routine clinical practice can supplement randomized clinical trials to provide needed evidence, especially during a global pandemic, and can yield markedly larger sample sizes to assess outcomes for important patient subgroups.

Objective To evaluate the association of remdesivir treatment with inpatient mortality among patients with COVID-19 outside of the clinical trial setting.

Design, Setting, and Participants A retrospective cohort study in US hospitals using health insurance claims data linked to hospital chargemaster data from December 1, 2018, to May 3, 2021, was conducted among 24 856 adults hospitalized between May 1, 2020, and May 3, 2021, with newly diagnosed COVID-19 who received remdesivir and 24 856 propensity score–matched control patients.

Exposure Remdesivir treatment.

Main Outcomes and Measures All-cause inpatient mortality within 28 days of the start of remdesivir treatment for the remdesivir-exposed group or the matched index date for the control group.

Conclusions and Relevance In this retrospective cohort study using health insurance claims and hospital chargemaster data, remdesivir treatment was associated with a significantly reduced inpatient mortality overall among patients hospitalized with COVID-19. Results of this analysis using data collected during routine clinical practice and state-of-the-art methods complement results from randomized clinical trials. Future areas of research include assessing the association of remdesivir treatment with inpatient mortality during the circulation of different variants and relative to time from symptom onset.

I’ah Donovan-Banfield et al.

Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial

Nature, November 2022; doi.org/10.1038/s41467-022-34839-9

Abstract

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatmentemergent adaptations.

Hansen K.S. et al.

High-dose coenzyme Q10 therapy versus placebo in patients with post COVID-19 condition: A randomized, phase 2, crossover trial

The Lancet, November 2022; doi.org/10.1016/j.lanepe.2022.100539

Abstract

Background

Post COVID-19 condition (PCC) is defined as symptoms lasting more than 12 weeks after developing COVID-19. Evidence of mitochondrial dysfunction has been reported in peripheral blood mononuclear cells obtained from patients with COVID-19. We hypothesized that PCC is caused by prolonged mitochondrial dysfunction. Given that coenzyme Q10 (CoQ10) can improve mitochondrial function, we examined whether high-dose CoQ10 can reduce the number and/or severity of PCC-related symptoms.

Interpretation

Based on self-reported data, CoQ10 treatment does not appear to significantly reduce the number or severity of PCC-related symptoms when compared to placebo. However, we observed a significantspontaneous improvement on both scores regardless of treatment during 20 weeks observation.

Takeshita M et al

Potent SARS-CoV-2 neutralizing antibodies with therapeutic effects in two animal models

Cell, November 2022; doi.org/10.1016/j.isci.2022.105596

Abstract

The use of therapeutic neutralizing antibodies against SARS-CoV-2 infection has been highly effective. However, there remain few practical antibodies against viruses that are acquiring mutations. In this study, we created 494 monoclonal antibodies from COVID-19–convalescent patients, and identified antibodies that exhibited comparable neutralizing ability to clinically used antibodies in the neutralization assay using pseudovirus and authentic virus including variants of concerns.

Zarębska-Michaluk D, Flisiak R.

Early oral antiviral use in patients hospitalised with COVID-19

The Lancet, August 2022, doi.org/10.1016/S1473-3099(22)00522-9

Abstract

Nearly 2 years after the emergence of SARS-CoV-2, two oral antiviral drugs, molnupiravir and nirmatrelvir–ritonavir, which reduce the risk of COVID-19 progression and death in patients at high risk, were approved for emergency use.

In summary, the results of Wong and colleagues’ study, conducted in a real-world setting, support the early use of oral antiviral drugs in patients with mild-to-moderate COVID-19 who are at high risk, regardless of whether they are in outpatient or inpatient care.

Saoussen Ben Abdallah et al.

Twice daily oral zinc in the treatment of patients with Coronavirus Disease-19 A randomized double-blind controlled trial

CID, November 2022; doi.org/10.1093/cid/ciac807

Abstract

BACKGROUND

Zinc supplementation has been considered one of the potential therapies for coronavirus disease-19 (COVID-19). We aimed to examine zinc efficacy in adult patients with COVID-19 infection.

METHODS

We conducted a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Patients tested positive for COVID-19 without end organ failure were randomized to oral zinc (n = 231) or matching placebo (n = 239) for 15 days. The primary combined outcome was death due to COVID-19 or ICU admission within 30 days after randomization. Secondary outcomes included length of hospital stay for inpatients and duration of COVID-19 symptoms with COVID-19 related hospitalization for outpatients.

INTERPRETATION

Our results showed that in COVID-19 patients, oral zinc can decrease 30-day death and ICU admission rate and can shorten symptoms duration.

Saye H Khoo et al.

Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial Lancet Infectious Diseases, October 2022; doi.org/10.1016/S1473-3099(22)00644-2

Abstract

Background

The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19.

Methods

This randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus

We found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive.

Chandiwana N. et al.

Safety and efficacy of four drug regimens versus standard-of-care for the treatment of symptomatic outpatients with COVID-19: A randomised, open-label, multi-arm, phase 2 clinical trial

eBioMedicine, November 2022 ;doi.org/10.1016/j.ebiom.2022.104322

Abstract

Background

This exploratory study investigated four repurposed anti-infective drug regimens in outpatients with COVID-19.

Methods

This phase 2, single centre, randomised, open-label, clinical trial was conducted in South Africa between 3rd September 2020 and 23rd August 2021. Symptomatic outpatients aged 18–65 years, with RT-PCR confirmed SARS-CoV-2 infection were computer randomised (1:1:1:1:1) to standard-of-care (SOC) with paracetamol, or SOC plus artesunate-amodiaquine (ASAQ), pyronaridine-artesunate (PA), favipiravir plus nitazoxanide (FPV + NTZ), or sofosbuvir-daclatasvir (SOF-DCV). The primary endpoint was the incidence of viral clearance, i.e., the proportion of patients with a negative SARS-CoV-2 RT-PCR on day 7, compared to SOC using a log-binomial model in the modified intention-to-treat (mITT) population.

Interpretation

There was no statistical difference in viral clearance for any regimen compared to SOC. All treatments were well tolerated.

Schwartz KL et al.

Real-world effectiveness of nirmatrelvir/ritonavir use for COVID-19: A population-based cohort study in Ontario, Canada

MedRxiv,November 2022; doi.org/10.1101/2022.11.03.22281881

Abstract

Background: Our objective was to evaluate the real world effectiveness of nirmatrelvir/ritonavir to prevent severe COVID-19 while Omicron and its subvariants predominate.

Methods: We conducted a population based cohort study in Ontario, Canada including all residents >17 years of age who tested positive for SARS-CoV-2 by PCR between 4 April and 31 August 2022. We compared nirmatrelvir/ritonavir treated patients to unexposed patients and measured the primary outcome of hospitalization or death from COVID-19, and a secondary outcome of death 1-30 days.

Xie Y et al.

Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19

MedRxiv, November 2022; doi.org/10.1101/2022.11.03.22281783

Abstract

Long Covid – the disease encompassing the post-acute sequelae of SARS-CoV-2 (PASC) —affects

millions of people around the world. Prevention of PASC is an urgent public health priority. In this work, we aimed to examine whether treatment with nirmatrelvir in the acute phase of COVID-19 is associated with reduced risk of postacute sequelae. We used the healthcare databases of the US Department of Veterans Affairs to identify users of the health system who had a SARS-CoV-2 positive test between March 01, 2022 and June 30, 2022, were not hospitalized on the day of the positive test, had at least 1 risk factor for progression to severe COVID-19 illness and survived the first 30 days after SARS-CoV-2 diagnosis. We identify those who were treated with oral nirmatrelvir within 5 days after the positive test (n=9217) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection (control group, n= 47,123).. In sum, our results show that in people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe COVID-19 illness, treatment with nirmatrelvir within 5 days of a positive SARS-CoV-2 test was associated with reduced risk of PASC regardless of vaccination status and history of prior infection. The totality of findings suggests that treatment with nirmatrelvir during the acute phase of COVID-19 reduces the risk of post-acute adverse health outcomes.

Bereczki I et al.

Semisynthetic teicoplanin derivatives with dual antimicrobial activity against SARS-CoV-2 and multiresistant bacteria

Nature, September 2022; doi.org/10.1038/s41598-022-20182-y

Abstract

Here the authors report the synthesis and biological evaluation of seven derivatives of teicoplanin bearing hydrophobic or superbasic side chain. They identified three perfluoralkyl and one monoguanidine analog of teicoplanin as dual inhibitors of Gram-positive bacteria and SARS-CoV-2.

McMahon J.H. et al.

Favipiravir in COVID-19 sintomatico precoce, uno studio randomizzato controllato con placebo

Eclinm, October 2022; doi.org/10.1016/j.eclinm.2022.101703

Abstract

Favipiravir inhibits SARS-CoV-2 viral replication in vitro with evidence of clinical benefit in open label trials. Placebo controlled studies of people with early symptomatic COVID-19 with regular assessments of SARS-CoV-2 viral load can determine if it has an antiviral effect and improves clinical outcomes.

Naggie S. et al.

Effect of Ivermectin vs placebo on time to sustained recovery in outpatients wwith mild to moderate COVID-19. A randomized clinical trial

JAMA, October 2022; doi:10.1001/jama.2022.18590

Abstract

The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown.

O.P.O. Nevalainen et al.

Effect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial

Nature Communications, October 2022 ; doi.org/10.1038/s41467-022-33825-5

Abstract

The study reports the first long-term follow-up of a randomized trial (NCT04978259) addressing the effects of remdesivir on recovery (primary outcome) and other patient-important outcomes one year after hospitalization resulting from COVID-19.

N. Murakami et al.

Therapeutic advances in COVID-19

Nature Reviews Nephrology, October 2022; doi.org/10.1038/s41581-022-00642-4

Abstract

Patients with acute and chronic kidney disease were under-represented in many of the COVID-19 clinical trials, and outcomes in this population might differ from those reported in the general population. The authors examine the clinical evidence for the therapies through a kidney medicine lens.The emergence of novel variants has further complicated the interpretation of much of the available evidence, particularly for antibody therapies.

J. Kim et al.

Rapid generation of circulating and mucosal decoy human ACE2 using mRNA nanotherapeutics for the potential treatment of SARS-CoV-2

Advanced Science, October 2022; doi.org/10.1002/advs.202202556

Abstract

In this study a synthetic mRNA is engineered to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. The proof of principle study shows that mRNA-based nanotherapeutics can be potentially deployed to neutralize SARS-CoV-2 and open new treatment opportunities for coronavirus disease 2019 (COVID-19).

S.H. Khoo et al.

Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial

The Lancet Infectious Diseases, October 2022; doi.org/10.1016/S1473-3099(22)00644-2

Abstract

The authors aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19.The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults.

A. Faridzadeh et al.

The role of melatoninas an adjuvant in the treatment of COVID-19: A systematic review

Heliyon, October2022; doi: 10.1016/j.heliyon.2022.e10906

Abstract

Melatoninisknownas an anti-oxidant, anti-inflammatory, and immunomodulatory agent whose anti-viralproperties, cost-effectiveness, and relativelyfew side effects make it a potentialadjuvant in the treatment of COVID-19. In thissystematic review the authorsintendto summarize the clinical studies on the effects of melatonin on COVID-19 patients.

J.W. Eikelboom et al.

Colchicine and the combination of rivaroxaban and aspirin in patientshospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial

Lancet Respiratory Medicine, October2022; doi: 10.1016/S2213-2600(22)00298-3

Abstract

The Anti-Coronavirus Therapies (ACT) inpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with the combination of rivaroxaban and aspirin for prevention of diseaseprogression in patientshospitalised with COVID-19.

R.L. Miller et al.

Impact of SARS-CoV-2 lockdown on expansion of HIV transmission clusters among key populations: aretrospectivephylogeneticanalysis

The Lancet Regional Health – Americas, September 2022;doi.org/10.1016/j.lana.2022.100369

Abstract

Public health measuresdesigned to reduce SARS-CoV-2 transmission led to reduced access to care andprevention services for people living with or at risk of acquiring HIV, particularlyduring the initialintroduction of extensiverestrictions. Thisreduction in access mayhavecontributed to increases in HIV transmission not out-weighed by decreases in transmission occurringas a result of reduced contact rates promoted by the same public health measures.

E. Laplantine et al.

The FDA-approved drug Auranofin has a dual inhibitory effect on SARS-CoV-2 entry and NF-κB signaling

iScience, October2022;doi.org/10.1016/j.isci.2022.105066

Abstract

Patients with severe COVID-19 show an altered immune response that fails to control the viral spread and suffer from exacerbated inflammatory response, which eventually can lead to death. A major challenge is to develop an effective treatment for COVID-19. NF-κB is a major player in innate immunity and inflammatory process. The authors show that Auranofin prevents post-translational modifications of NF-κB effectors and their recruitment into activating complexes in response to SARS-CoV-2 infection or cytokine stimulation.

L. Pires et al.

Translational feasibility and efficacy of nasal photodynamic disinfection of SARS-CoV-2

Nature Scientific Reports, August 2022; doi.org/10.1038/s41598-022-18513-0

Abstract

The lack of therapeutic options to fight Covid-19 has contributed to the current global pandemic. Despite the emergence of effective vaccines, development of broad-spectrum antiviral treatment remains a significant challenge, in which antimicrobial photodynamic therapy (aPDT) may play a role, especially at early stages of infection. This study is the first demonstration based on quantitative clinical viral infectivity measurements that MB-aPDT is a safe, easily delivered and effective front-line technique that can reduce local SARS-CoV-2 viral load.

B. Yu et al.

The First Chinese Oral Anti-COVID-19 Drug Azvudine Launched

The Innovation, September 2022; doi.org/10.1016/j.xinn.2022.100321

Abstract

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) at the end of 2019, thousands of SARS-CoV-2 mutations have been increasingly observed. The development of novel antivirals capable of treating SARS-CoV-2 infections has been a central focus of current research. To cope with the current novel coronavirus pneumonia (COVID-19) epidemic, the National Medical Products Administration (NMPA) granted conditional authorization for Azvudine developed by us to be used to treat COVID-19 on July 25, 2022, being the first domestic oral antiviral agent approved in China. Most antivirals target the polymerases and proteases that are essential for SARS-CoV-2 replication. Particularly, modified nucleosides show great promise for antiviral therapies. As a broad-spectrum antiviral agent, Azvudine may provide hopes to treat patients with HIV/HBV and HIV/HCV coinfections. The authors believe that Azvudine could cope with the current COVID-19 epidemic and is potentially to be used to treat future coronavirus infections as well as other coronavirus-related diseases.

S. Ganatra et al.

Oral Nirmatrelvir and Ritonavir in Non-hospitalized Vaccinated Patients with Covid-19

Clinical Infectious Diseases, August 2022; doi.org/10.1093/cid/ciac673

Abstract

Treatment of coronavirus disease-2019 (Covid-19) with nirmatrelvir plus ritonavir (NMV-r) in high-risk non-hospitalized unvaccinated patients reduced the risk of progression to severe disease. However, the potential benefits of NMV-r among vaccinated patients are unclear.

The authors conducted a comparative retrospective cohort study using the TriNetX research network. Cohorts were developed based on the use of NMV-r within five days of diagnosis. The primary composite outcome was all-cause emergency room (ER) visit, hospitalization, or death at a 30-days follow-up. Secondary outcomes included individual components of primary outcomes, multisystem symptoms, Covid-19 associated complications, and diagnostic test utilization.

Treatment with NMV-r in non-hospitalized vaccinated patients with Covid-19 was associated with a reduced likelihood of emergency room visits, hospitalization, or death. Complications and overall resource utilization were also decreased.

R. Arbel et al.

Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge

N Engl J Med, September 2022; doi: 10.1056/NEJMoa2204919

Abstract

Background: The oral protease inhibitor nirmatrelvir has shown substantial efficacy in high-risk, unvaccinated patients infected with the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data regarding the effectiveness of nirmatrelvir in preventing severe coronavirus disease 2019 (Covid-19) outcomes from the B.1.1.529 (omicron) variant are limited.

Results: A total of 109,254 patients met the eligibility criteria, of whom 3902 (4%) received nirmatrelvir during the study period. Among patients 65 years of age or older, the rate of hospitalization due to Covid-19 was 14.7 cases per 100,000 person-days among treated patients as compared with 58.9 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.27; 95% confidence interval [CI], 0.15 to 0.49). The adjusted hazard ratio for death due to Covid-19 was 0.21 (95% CI, 0.05 to 0.82). Among patients 40 to 64 years of age, the rate of hospitalization due to Covid-19 was 15.2 cases per 100,000 person-days among treated patients and 15.8 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.74; 95% CI, 0.35 to 1.58). The adjusted hazard ratio for death due to Covid-19 was 1.32 (95% CI, 0.16 to 10.75).

Conclusions: Among patients 65 years of age or older, the rates of hospitalization and death due to Covid-19 were significantly lower among those who received nirmatrelvir than among those who did not. No evidence of benefit was found in younger adults.

S. Hakki et al.

Onset and window of SARS-CoV-2 infectiousness and temporal correlation with symptom onset: a prospective, longitudinal, community cohort study

Lancet Respir Med, August 2022; doi: 10.1016/S2213-2600(22)00226-0

Abstract

Background: Knowledge of the window of SARS-CoV-2 infectiousness is crucial in developing policies to curb transmission. Mathematical modelling based on scarce empirical evidence and key assumptions has driven isolation and testing policy, but real-world data are needed. We aimed to characterise infectiousness across the full course of infection in a real-world community setting.

Methods: The Assessment of Transmission and Contagiousness of COVID-19 in Contacts (ATACCC) study was a UK prospective, longitudinal, community cohort of contacts of newly diagnosed, PCR-confirmed SARS-CoV-2 index cases. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and agree to self-swabbing of the upper respiratory tract. The primary objective was to define the window of SARS-CoV-2 infectiousness and its temporal correlation with symptom onset. We quantified viral RNA load by RT-PCR and infectious viral shedding by enumerating cultivable virus daily across the course of infection. Participants completed a daily diary to track the emergence of symptoms. Outcomes were assessed with empirical data and a phenomenological Bayesian hierarchical model.

Findings: Between Sept 13, 2020, and March 31, 2021, we enrolled 393 contacts from 327 households (the SARS-CoV-2 pre-alpha and alpha variant waves); and between May 24, 2021, and Oct 28, 2021, we enrolled 345 contacts from 215 households (the delta variant wave). 173 of these 738 contacts were PCR positive for more than one timepoint, 57 of which were at the start of infection and comprised the final study population. The onset and end of infectious viral shedding were captured in 42 cases and the median duration of infectiousness was 5 (IQR 3-7) days. Although 24 (63%) of 38 cases had PCR-detectable virus before symptom onset, only seven (20%) of 35 shed infectious virus presymptomatically. Symptom onset was a median of 3 days before both peak viral RNA and peak infectious viral load (viral RNA IQR 3-5 days, n=38; plaque-forming units IQR 3-6 days, n=35). Notably, 22 (65%) of 34 cases and eight (24%) of 34 cases continued to shed infectious virus 5 days and 7 days post-symptom onset, respectively (survival probabilities 67% and 35%). Correlation of lateral flow device (LFD) results with infectious viral shedding was poor during the viral growth phase (sensitivity 67% [95% CI 59-75]), but high during the decline phase (92% [86-96]). Infectious virus kinetic modelling suggested that the initial rate of viral replication determines the course of infection and infectiousness.

Interpretation: Less than a quarter of COVID-19 cases shed infectious virus before symptom onset; under a crude 5-day self-isolation period from symptom onset, two-thirds of cases released into the community would still be infectious, but with reduced infectious viral shedding. Our findings support a role for LFDs to safely accelerate deisolation but not for early diagnosis, unless used daily. These high-resolution, community-based data provide evidence to inform infection control guidance.

K. G. Barnett et al.

Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19: Interim Analysis

New England J Medicine, July 2022; doi.org/10.1056/EVIDoa2200145

Abstract

Background

Sabizabulin is an oral, novel microtubule disruptor that has dual antiviral and anti-inflammatory activities in preclinical models.

Methods

A randomized, multicenter placebo-controlled phase 3 clinical trial was conducted with hospitalized patients with moderate to severe Covid-19 who were at high risk for acute respiratory distress syndrome (ARDS) and death. Patients were randomly assigned (2:1) to 9 mg of oral sabizabulin or placebo daily (up to 21 days). The primary end point was all-cause mortality up to day 60. Key secondary end points were days in the intensive care unit (ICU), days on mechanical ventilation, and days in the hospital.

Results

A total of 204 patients were randomly assigned to treatment: 134 to sabizabulin and 70 to placebo. Baseline characteristics were similar. Sabizabulin superiority was demonstrated by a planned interim analysis for the first 150 randomized patients. Sabizabulin treatment resulted in a 24.9 percentage point absolute reduction and a 55.2% relative reduction in deaths compared with placebo (odds ratio, 3.23; 95% CI confidence interval, 1.45 to 7.22; P=0.0042). The mortality rate was 20.2% (19 of 94) for sabizabulin versus 45.1% (23 of 51) for placebo. For the key secondary end points, sabizabulin treatment resulted in a 43% relative reduction in ICU days (P=0.0013), a 49% relative reduction in days on mechanical ventilation (P=0.0013), and a 26% relative reduction in days in the hospital (P=0.0277) versus placebo. Adverse and serious adverse events were lower in the sabizabulin group compared with the placebo group.

Conclusions

Sabizabulin treatment resulted in a 24.9% absolute reduction in deaths compared with placebo in hospitalized patients with moderate to severe Covid-19 at high risk for ARDS and death, with a lower incidence of adverse and serious adverse events compared with placebo.

S. Salim et al.

Time to Stop Using Ineffective Covid-19 Drugs

New England J Medicine, August 2022; doi: 10.1056/NEJMe2209017

Abastract

In practicing evidence-based medicine, physicians use the best evidence currently available on safety and efficacy in making decisions on treatment choices for their patients. During the Covid-19 pandemic, some of the early treatment trials were rushed, leading to studies that were badly conducted or had too few patients. As a result, initial evidence of the efficacy of some Covid-19 treatments could not be replicated, but these drugs were already in widespread use by then, and some clinicians have been reluctant to change to proven efficacious alternatives. Ivermectin and fluvoxamine, in particular, are still widely prescribed, even though evidence has been steadily accumulating to indicate that both treatments at acceptable doses are not effective for Covid-19.

A. Martner et al.

Transient and durable T cell reactivity after COVID-19

Proc Natl Acad Sci USA, July 2022; doi: 10.1073/pnas.2203659119

Abstract

This study analyzed whole blood samples (n = 56) retrieved from 30 patients at 1 to 21 (median 9) mo after verified COVID-19 to determine the polarity and duration of antigen-specific T cell reactivity against severe acute respiratory syndrome coronavirus 2-derived antigens. Multimeric peptides spanning the entire nucleocapsid protein triggered strikingly synchronous formation of interleukin (IL)-4, IL-12, IL-13, and IL-17 ex vivo until ∼70 d after confirmed infection, whereafter this reactivity was no longer inducible. In contrast, levels of nucleocapsid-induced IL-2 and interferon-γ remained stable and highly correlated at 3 to 21 mo after infection. Similar cytokine dynamics were observed in unvaccinated, convalescent patients using whole-blood samples stimulated with peptides spanning the N-terminal portion of the spike 1 protein. These results unravel two phases of T cell reactivity following natural COVID-19: an early, synchronous response indicating transient presence of multipolar, antigen-specific T helper (T_H) cells followed by an equally synchronous and durable T_H1-like reactivity reflecting long-lasting T cell memory.

J.S. Driouich et al.

Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2

EBioMedicine, August 2022; doi: 10.1016/j.ebiom.2022.104148

Abstract

Background: To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy.

Methods: In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2.

Findings: First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC₅₀.

Interpretation: These preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19.

ACTIV-3–Therapeutics for Inpatients with COVID-19 (TICO) Study Group

Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial

The Lancet Respiratory Medicine, July 2022; doi.org/10.1016/S2213-2600(22)00215-6

Abstract

Background Tixagevimab–cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab–cilgavimab versus placebo, in patients receiving remdesivir and other standard care. Methods In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg–cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab–cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing. Findings From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab–cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab–cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97–1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97–1·34]; p=0·13). Mortality was lower in the tixagevimab– cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50–0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab–cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68–1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab–cilgavimab group and 38 (5%) in the placebo group. Interpretation Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab–cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower.

M. Masia et al.

Robust long-term immunity to SARS-CoV-2 in patients recovered from severe COVID-19 after interleukin-6 blockade

eBioMedicine, July 2022; doi.org/10.1016/j.ebiom.2022.104153

Abstract

Background Whether interleukin-6 (IL-6) blockade in patients with COVID-19 will affect the protective immunity against SARS-CoV-2 has become an important concern for anti-IL-6 therapy. We aimed to investigate the effects of IL-6 blockade on long-term immunity to SARS-CoV-2. Methods Prospective, longitudinal cohort study conducted in patients hospitalized for severe or critical COVID-19 with laboratory confirmed SARS-CoV-2 infection. We assessed humoral (anti-S1 domain of the spike [S], anti-nucleocapsid [N], anti-trimeric spike [TrimericS] IgG, and neutralizing antibodies [Nab]) and T-cell (interferon-g release assay [IGRA]) responses and evaluated the incidence of reinfections over one year after infection in patients undergoing IL-6 blockade with tocilizumab and compared them with untreated subjects.

Findings From 150 adults admitted with confirmed SARS-CoV-2 infection, 78 were 1:1 propensity score-matched. Patients receiving anti-IL6 therapy showed a shorter time to S-IgG seropositivity and stronger S-IgG and N-IgG antibody responses. Among unvaccinated subjects one year after infection, median (Q1-Q3) levels of TrimericS-IgG (295 vs 121 BAU/mL; p = 0.011) and Nab (74.7 vs 41.0 %IH; p = 0.012) were higher in those undergoing anti-IL6 therapy, and a greater proportion of them had Nab (80.6% vs 57.7%; p = 0.028). T-cell immunity was also better in those treated with anti-IL6, with higher median (Q1-Q3) interferon-g responses (1760 [7023992] vs 542 [351716] mIU/mL; p = 0.013) and more patients showing positive T-cell responses in the IGRA one year after infection. Patients treated with anti-IL6 had fewer reinfections during follow-up and responded to vaccination with robust increase in both antibody and T-cell immunity. Interpretation IL-6 blockade in patients with severe COVID-19 does not have deleterious effects on long-term immunity to SARS-CoV-2. The magnitude of both antibody and T-cell responses was stronger than the observed in non-anti-cytokine-treated patients with no increase in the risk of reinfections.

D. Focosi et al.

Monoclonal antibody therapies against SARS-CoV-2

The Lancet Infectious Diseases, July 2022; doi.org/10.1016/S1473-3099(22)00311-5

Abstract

Monoclonal antibodies (mAbs) targeting the spike protein of SARS-CoV-2 have been widely used in the ongoing COVID-19 pandemic. In this paper, we review the properties of mAbs and their effect as therapeutics in the pandemic, including structural classification, outcomes in clinical trials that led to the authorisation of mAbs, and baseline and treatment-emergent immune escape. We show how the omicron (B.1.1.529) variant of concern has reset treatment strategies so far, discuss future developments that could lead to improved outcomes, and report the intrinsic limitations of using mAbs as therapeutic agents.

S.E. Greasley et al.

Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants

J. Biol. Chem., April 2022; doi.org/10.1016/j.jbc.2022.101972

Abstract

The COVID-19 pandemic continues to be a public health threat with emerging variants of SARS-CoV-2. Nirmatrelvir (PF-07321332) is a reversible, covalent inhibitor targeting the main protease (Mpro) of SARS-CoV-2 and the active protease inhibitor in PAXLOVID (nirmatrelvir tablets and ritonavir tablets). However, the efficacy of nirmatrelvir is underdetermined against evolving SARS-CoV-2 variants. Here, we evaluated the in vitro catalytic activity and potency of nirmatrelvir against the Mpro of prevalent variants of concern (VOCs) or variants of interest (VOIs): Alpha (α, B.1.1.7), Beta (β, B.1.351), Delta (δ, B1.617.2), Gamma (γ, P.1), Lambda (λ, B.1.1.1.37/C37), Omicron (ο, B.1.1.529), as well as the original Washington or wildtype strain. These VOCs/VOIs carry prevalent mutations at varying frequencies in the Mpro specifically for α, β, γ (K90R), λ (G15S), and ο (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the mutant Mpros demonstrates that they are catalytically comparable to wildtype. We found that nirmatrelvir has similar potency against each mutant Mpro including P132H that is observed in the Omicron variant with a Ki of 0.635 nM as compared to a Ki of 0.933 nM for wildtype. The molecular basis for these observations were provided by solution-phase structural dynamics and structural determination of nirmatrelvir bound to the ο, λ, and β Mpro at 1.63 to 2.09 Å resolution. These in vitro data suggest that PAXLOVID has the potential to maintain plasma concentrations of nirmatrelvir many-fold times higher than the amount required to stop the SARSCoV-2 VOC/VOI, including Omicron, from replicating in cells.

D. Iaconis et al.

Characterization of raloxifene as a potential pharmacological agent against SARS-CoV-2 and its variants

Nature, Cell Death and Disease, May 2022; doi.org/10.1038/s41419-022-04961-z

Abstract

The new coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic, which so far has caused over 6 million deaths in 2 years, despite new vaccines and antiviral medications. Drug repurposing, an approach for the potential application of existing pharmaceutical products to new therapeutic indications, could be an effective strategy to obtain quick answers to medical emergencies. Following a virtual screening campaign on the most relevant viral proteins, we identified the drug raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a new potential agent to treat mild-to-moderate COVID-19 patients. In this paper we report a comprehensive pharmacological characterization of raloxifene in relevant in vitro models of COVID-19, specifically in Vero E6 and Calu-3 cell lines infected with SARS-CoV-2. A large panel of the most common SARS-CoV-2 variants isolated in Europe, United Kingdom, Brazil, South Africa and India was tested to demonstrate the drug’s ability in contrasting the viral cytopathic effect (CPE). Literature data support a beneficial effect by raloxifene against the viral infection due to its ability to interact with viral proteins and activate protective estrogen receptor-mediated mechanisms in the host cells. Mechanistic studies here reported confirm the significant affinity of raloxifene for the Spike protein, as predicted by in silico studies, and show that the drug treatment does not directly affect Spike/ACE2 interaction or viral internalization in infected cell lines. Interestingly, raloxifene can counteract Spike-mediated ADAM17 activation in human pulmonary cells, thus providing new insights on its mechanism of action. A clinical study in mild to moderate COVID-19 patients (NCT05172050) has been recently completed. Our contribution to evaluate raloxifene results on SARS-CoV-2 variants, and the interpretation of the mechanisms of action will be key elements to better understand the trial results, and to design new clinical studies aiming to evaluate the potential development of raloxifene in this indication.

H. Montgomery et al.

Efficacy and safety of intramuscular administration of tixagevimab–cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind,placebo-controlled trial

Lancet, Respir. Med., June 2022; doi.org/10.1016/ S2213-2600(22)00180-1

Abstract

Background Early intramuscular administration of SARS-CoV-2-neutralising monoclonal antibody combination, tixagevimab–cilgavimab, to non-hospitalised adults with mild to moderate COVID-19 has potential to prevent disease progression. We aimed to evaluate the safety and efficacy of tixagevimab–cilgavimab in preventing progression to severe COVID-19 or death.

Methods TACKLE is an ongoing, phase 3, randomised, double-blind, placebo-controlled study conducted at 95 sites in the USA, Latin America, Europe, and Japan. Eligible participants were non-hospitalised adults aged 18 years or older with a laboratory-confirmed SARS-CoV-2 infection (determined by RT-PCR or an antigen test) from any respiratory tract specimen collected 3 days or less before enrolment and who had not received a COVID-19 vaccination. A WHO Clinical Progression Scale score from more than 1 to less than 4 was required for inclusion and participants had to receive the study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever. Participants were randomly assigned (1:1) to receive either a single tixagevimab–cilgavimab 600 mg dose (two consecutive 3 mL intramuscular injections, one each of 300 mg tixagevimab and 300 mg cilgavimab) or placebo. Randomisation was stratified (using central blocked randomisation with randomly varying block sizes) by time from symptom onset, and high-risk versus low-risk of progression to severe COVID-19. Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments. The primary endpoints were severe COVID-19 or death from any cause through to day 29, and safety. This study is registered with ClinicalTrials.gov, NCT04723394.

Findings Between Jan 28, 2021, and July 22, 2021, 1014 participants were enrolled, of whom 910 were randomly assigned to a treatment group (456 to receive tixagevimab–cilgavimab and 454 to receive placebo). The mean age of participants was 46·1 years (SD 15·2). Severe COVID-19 or death occurred in 18 (4%) of 407 participants in the tixagevimab–cilgavimab group versus 37 (9%) of 415 participants in the placebo group (relative risk reduction 50·5% [95% CI 14·6–71·3]; p=0·0096). The absolute risk reduction was 4·5% (95% CI 1·1–8·0; p<0·0001). Adverse events occurred in 132 (29%) of 452 participants in the tixagevimab–cilgavimab group and 163 (36%) of 451 participants in the placebo group, and were mostly of mild or moderate severity. There were three COVID-19-reported deaths in the tixagevimab–cilgavimab group and six in the placebo group.

Interpretation A single intramuscular tixagevimab–cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab–cilgavimab might lead to more favourable outcomes.

M.G. Johnson et al.

Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19: A Randomized, Placebo-Controlled Trial

Annals of Internal Medicine, June 2022; doi.org/10.7326/M22-0729

Abstract

In the MOVe-OUT trial, molnupiravir showed a clinically meaningful reduction in the risk for hospitalization or death in adults with mild to moderate COVID-19 and risk factors for progression to severe disease.

Objective:

To identify other potential clinical benefits of molnupiravir versus placebo.

Design:

Secondary analysis of the randomized, double-blind, placebo-controlled phase 3 component of MOVe-OUT. (ClinicalTrials.gov: NCT04575597)

Setting:

107 sites globally.

Participants:

1433 nonhospitalized adults aged 18 years or older with mild to moderate COVID-19.

Intervention:

Molnupiravir, 800 mg, or placebo every 12 hours for 5 days.

Measurements:

Changes from baseline in C-reactive protein (CRP) concentration and oxygen saturation (Spo₂), need for respiratory interventions (including invasive mechanical ventilation), and need for medical services in all randomly assigned participants through day 29, and need for respiratory interventions and time to discharge in the subgroup of participants who were hospitalized after randomization.

Results:

Participants receiving molnupiravir showed faster normalization of CRP and Spo₂, with improvements observed on day 3 of therapy, compared with placebo. Molnupiravir-treated participants had a decreased need for respiratory interventions versus placebo-treated participants (relative risk reduction [RRR], 34.3% [95% CI, 4.3% to 54.9%]), with similar findings in participants who were hospitalized after randomization (RRR, 21.3% [CI, 0.2% to 38.0%]). Hospitalized participants who received molnupiravir were discharged a median of 3 days before those who received placebo. Acute care visits (7.2% vs. 10.6%; RRR, 32.1% [CI, 4.4% to 51.7%]) and COVID-19–related acute care visits (6.6% vs. 10.0%; RRR, 33.8% [CI, 5.6% to 53.6%]) were less frequent in molnupiravir- versus placebo-treated participants.

Limitations:

Some analyses were performed post hoc. Longer-term benefits of molnupiravir therapy were not evaluated. Participants were not immunized against SARS-CoV-2.

Conclusion:

The findings suggest there are additional important clinical benefits of molnupiravir beyond reduction in hospitalization or death.

S. Miersch et al.

Ultrapotent and broad neutralization of SARS-CoV-2 variants by modular, tetravalent, bi-paratopic antibodies

Cell Reports, May 2022; doi.org/10.1016/j.celrep.2022.110905

Abstract

Neutralizing antibodies (nAbs) that target the SARS-CoV-2 spike protein have received emergency use approval for treatment of COVID-19. However, with the emergence of variants of concern, there is a need for new treatment options. We report a format that enables modular assembly of bi-paratopic tetravalent nAbs with antigen-binding sites from two distinct nAbs. The tetravalent nAb purifies in high yield and exhibits biophysical characteristics that are comparable to those of clinically used therapeutic antibodies. The tetravalent nAb binds to the spike protein trimer at least 100-fold more tightly than bivalent IgGs (apparent KD < 1 pM) and neutralizes a broad array of SARS-CoV-2 pseudoviruses, chimeric viruses, and authentic viral variants with high potency. Together, these results establish the tetravalent diabody-Fc-Fab as a robust, modular platform for rapid production of drug-grade nAbs with potencies and breadth of coverage that greatly exceed those of conventional bivalent IgGs.

T. Cheuk-Fung Yip et al.

Impact of the Use of Oral Antiviral Agents on the Risk of Hospitalisation in Community COVID-19 Patients

The Lancet, May 2022; doi.org/10.2139/ssrn.4112160

Abstract

Background We examined the effectiveness of molnupiravir and nirmatrelvir/ritonavir in reducing hospitalisation and deaths in a real-world cohort of non-hospitalised COVID-19 patients.
Methods This was a territory-wide retrospective cohort study in Hong Kong. Non-hospitalised COVID-19 patients who attended designated outpatient clinics between 16 February and 31 March 2021 were identified. Patients who were hospitalised on the day of the first appointment at clinic or used both oral antivirals were excluded. The primary endpoint was hospitalisation. The secondary endpoint was a composite of intensive care unit admission, invasive mechanical ventilation use, and/or death. Patients’ clinical characteristics were balanced using propensity score weighting.

Findings Of 93,883 patients, 83,154 (88·6%), 5,808 (6·2%), and 4,921 (5·2%) were oral antiviral non-users, molnupiravir users, and nirmatrelvir/ritonavir users respectively. Compared to non-users, oral antiviral users were older and had more comorbidities, lower complete vaccination rate, and more hospitalisations in the previous year. Molnupiravir users were older, and had more comorbidities, lower complete vaccination rate, and more hospitalisations in the previous year than nirmatrelvir/ritonavir users. At a median follow-up of 30 days, 1,931 (2·1%) patients were admitted to hospital and 225 (0·2%) patients developed the secondary endpoint. After propensity score weighting, nirmatrelvir/ritonavir use (weighted hazard ratio 0·79, 95% CI 0·65-0·95, P =0·011) but not molnupiravir use (weighted hazard ratio 1·17, 95% CI 0·99-1·39, P =0·062) was associated with a reduced risk of hospitalisation than non-users. The use of molnupiravir or nirmatrelvir/ritonavir was not associated with a lower risk of the secondary endpoint as compared to non-users. In the subgroup of patients aged ≥60 years or aged <60 years with comorbidities, nirmatrelvir/ritonavir use but not molnupiravir use was associated with a reduced risk of hospitalisation than non-users.

Interpretation The use of nirmatrelvir/ritonavir but not molnupiravir was associated with a reduced risk of hospitalisation in real-world non-hospitalised COVID-19 patients.

Benedetti et al.

Can Cytokine Blocking Prevent Depression in COVID-19 Survivors?

J Neuroimmune Pharmacol., January 2021; doi: 10.1007/s11481-020-09966-z

Abstract

Current insight on inflammation in psychiatry suggests that infection-triggered perturbation of immune homeostasis could foster psychopathology (Miller and Raison 2016). High rates of psychiatric disorders have been reported during and after coronavirus infection (Rogers et al. 2020). We also observed a psychopathological impact of COVID-19, with emergent depression and post-traumatic stress disorder (PTSD) after COVID-19 associated to systemic inflammation index (SII) during the acute illness (Mazza et al. 2020): 31% of patients self-rated in the psychopathological range for depression and 28% for PTSD, one month after hospital discharge, complete viral clearance and clinical recovery.

Studies revealed persistent low-grade inflammation in mood disorders, and pointed at interleukin (IL)-1β and IL-6 as inflammatory cytokines implicated in major depression and its detrimental outcomes(Arteaga-Henríquez et al. 2019). Severe COVID-19 induces a ‘cytokine storm’ involving massive release of IL-1β and IL-6. Pharmacological blockade of both cytokines was explored and we reported benefits on hyper-inflammation and progression to respiratory failure with high-dose anakinra (Cavalli et al. 2020), a recombinant version of the human IL-1β receptor antagonist, and less clear effects with tocilizumab (Campochiaro et al. 2020), a monoclonal antibody targeting the IL-6 receptor. Given the central role of IL-1 and IL-6 in depression, we hypothesize that depressive symptoms should be lower in COVID-19 survivors treated with cytokine-blocking agents.

K. Gupta et al.

Rapid Relapse of Symptomatic SARS-CoV-2 Infection Following Early Suppression with

Nirmatrelvir/Ritonavir

Research Square, April 2022; doi.org/10.21203/rs.3.rs-1588371/v1

Abstract

Initiation of NM/R treatment on Day 0 in a 71-year-old vaccinated and boosted male resulted in rapid resolution of COVID-19 symptoms followed one week later by the development of typical cold symptoms. SARS-CoV-2 viral load fluctuated in parallel with symptoms, with two distinct peaks on Day 1 and Day 9 of illness. No other respiratory pathogens were identified. Viral samples demonstrated sequence identity for the omicron subvariant BA.1 on Days 1, 7, and 11. Our findings suggest that viral replication and COVID-19 symptoms may recur after very early treatment with NM/R before natural immunity is sufficient to fully clear SARS-CoV-2.

WHO Solidarity Trial Consortium

Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses

The Lancet, May 2022; doi.org/10.1016/S0140-6736(22)00519-0

Abstract

Background

The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-β1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date.

Methods

Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948.

Findings

Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82–1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89–1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76–0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46–1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76–0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77–1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75–0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings.

Interpretation

Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both).

K. Westendorf et al.

LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

BioRxiv, March 2022; doi: 10.1101/2021.04.30.442182

Abstract

SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization when administered early during COVID-19 disease. However, the emergence of variants of concern has negatively impacted the therapeutic use of some authorized mAbs. Using a high throughput B-cell screening pipeline, we isolated a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody called LY-CoV1404 (also known as bebtelovimab). LY-CoV1404 potently neutralizes authentic SARS-CoV-2 virus, including the prototype, B.1.1.7, B.1.351 and B.1.617.2). In pseudovirus neutralization studies, LY-CoV1404 retains potent neutralizing activity against numerous variants including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant and retains binding to spike proteins with a variety of underlying RBD mutations including K417N, L452R, E484K, and N501Y. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved with the exception of N439 and N501. Notably, the binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The breadth of reactivity to amino acid substitutions present among current VOC together with broad and potent neutralizing activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants causing COVID-19.

In brief: LY-CoV1404 is a potent SARS-CoV-2-binding antibody that neutralizes all known variants of concern and whose epitope is rarely mutated.

Highlights: LY-CoV1404 potently neutralizes SARS-CoV-2 authentic virus and known variants of concern including the B.1.1.529 (Omicron), the BA.2 Omicron subvariant, and B.1.617.2 (Delta) variantsNo loss of potency against currently circulating variantsBinding epitope on RBD of SARS-CoV-2 is rarely mutated in GISAID databaseBreadth of neutralizing activity and potency supports clinical development.

R. Libster et al.

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

N Engl J Med. February 2021; doi: 10.1056/NEJMoa2033700

Abstract

BACKGROUND

Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness.

METHODS

We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible.

RESULTS

A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed.

CONCLUSIONS

Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19.

Therapeutics and COVID-19 – Living guideline April 2022

WHO, April 2022; www.who.int/publications

The WHO Therapeutics and COVID-19: living guideline contains the Organization’s most up-to-date recommendations for the use of therapeutics in the treatment of COVID-19. The latest version of this living guideline is available in pdf format (via the ‘Download’ button) and via an online platform, and is updated regularly as new evidence emerges.

This tenth version of the WHO living guideline now contains 17 recommendations, including two new recommendations regarding nirmatrelvir-ritonavir. No further updates to the previous existing recommendations were made in this latest version.

C. L. Todd et al.

Fluvoxamine for Outpatient Management of COVID-19 to Prevent HospitalizationA Systematic Review and Meta-analysis

JAMA Netw. Open, April 2022; doi:10.1001/jamanetworkopen.2022.6269

Abstract

Importance Widely available and affordable options for the outpatient management of COVID-19 are needed, particularly for therapies that prevent hospitalization.

Objective To perform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19.

Data Sources World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov.

Study Selection Studies with completed outpatient trials with available results that compared fluvoxamine with placebo were included.

Data Extraction and Synthesis The PRISMA 2020 guidelines were followed and study details in terms of inclusion criteria, trial demographics, and the prespecified outcome of all-cause hospitalization were extracted. Risk of bias was assessed by the Cochrane Risk of Bias 2 tool and a bayesian random effects meta-analysis with different estimates of prior probability was conducted: a weakly neutral prior (50% chance of efficacy with 95% CI for risk ratio [RR] between 0.5 and 2.0) and a moderately optimistic prior (85% chance of efficacy). A frequentist random-effects meta-analysis was conducted as a senstivity analysis, and the results were contextualized by estimating the probability of any association (RR ≤ 1) and moderate association (RR ≤ 0.9) with reduced hospitalization.

Main Outcomes and Measures All-cause hospitalization.

Results This systematic review and meta-analysis of 3 randomized clinical trials and included 2196 participants. The RRs for hospitalization were 0.78 (95% CI, 0.58-1.08) for the bayesian weakly neutral prior, 0.73 (95% CI, 0.53-1.01) for the bayesian moderately optimistic prior, and 0.75 (95% CI, 0.58-0.97) for the frequentist analysis. Depending on the scenario, the probability of any association with reduced hospitalization ranged from 94.1% to 98.6%, and the probability of moderate association ranged from 81.6% to 91.8%.

Conclusions and Relevance In this systematic review and meta-analysis of data from 3 trials, under a variety of assumptions, fluvoxamine showed a high probability of being associated with reduced hospitalization in outpatients with COVID-19. Ongoing randomized trials are important to evaluate alternative doses, explore the effectiveness in vaccinated patients, and provide further refinement to these estimates. Meanwhile, fluvoxamine could be recommended as a management option, particularly in resource-limited settings or for individuals without access to SARS-CoV-2 monoclonal antibody therapy or direct antivirals.

M. Cosentino et al.

Early outpatient treatment of Covid-19: a retrospective analysis of 392 cases in Italy

MedRxiv, April 2022; doi.org/10.1101/2022.04.04.22273356

Abstract

Introduction: The pandemic of severe acute respiratory syndrome (SARS)-coronavirus-2 (CoV-2) disease 2019 (COVID-19) was declared in march 2020. Knowledge of COVID-19 pathophysiology soon provided a strong rationale for the early use of anti-inflammatory, antiplatelet and anticoagulant drugs, however the evidence was only slowly and partially incorporated into institutional guidelines. Unmet needs of COVID-19 outpatients were soon taken care of by networks of physicians and researchers, using pharmacotherapeutic approaches based on the best available experiences.

Methods: Observational retrospective study investigating characteristics, management and outcomes in COVID-19 patients taken care of in Italy by physicians volunteering within the IppocrateOrg Association, one of the main international assistance networks, between 1^st november 2020 and 31^st march 2021.

Results: Ten doctors took part in the study and provided data about 392 consecutive COVID-19 patients. Patients’ mean age was 48,5 years (range: 0,5-97). They were 51,3% females and were taken care of when in COVID-19 stage 0 (15,6%), 1 (50,0%), 2a (28,8%), 2b (5,6%). Many patients were overweight (26%) or obese (11,5%), with chronic comorbidities (34,9%), mainly cardiovascular (23%) and metabolic (13,3%). Drugs most frequently prescribed included: vitamins and supplements (98,7%), aspirin (66,1%), antibiotics (62%), glucocorticoids (41,8%), hydroxychloroquine (29,6%), enoxaparin (28,6%), colchicine (8,9%), oxygen therapy (6,9%), ivermectin (2,8%). Hospitalization occurred in 5,8% of total cases, mainly in patients taken care of when in stage 2b (27,3%). Altogether, 390 patients (99,6%) recovered, one patient (0,2%) was lost at follow up, and one patient (0,2%) died after hospitalization. One doctor reported one grade 1 adverse drug reaction (ADR) (transient or mild discomfort), and 3 doctors reported in total 8 grade 2 ADR (mild to moderate limitation in activity).

Conclusions: This is the first study describing attitudes and behaviors of physicians caring for COVID-19 outpatients, and the effectiveness and safety of COVID-19 early treatment in the real world. COVID-19 lethality in our cohort was 0,2%, while the overall COVID-19 lethality in Italy in the same period was between 3% and 3,8%. The use of individual drugs and drug combinations described in this study appears therefore effective and safe, as indicated by the few and mild ADR reported. Present evidence should be carefully considered by physicians caring for COVID-19 patients as well as by political decision makers managing the current global crisis.

Alfano G. et al.

Awaiting a cure for COVID-19: therapeutic approach in patients with different severity levels of COVID-19

Le Infezioni in Medicina, 2022; doi: 10.53854/liim-3001-2

Abstract

COVID-19 is an unpredictable infectious disease caused by SARS-CoV-2. The development of effective anti-COVID-19 vaccines has enormously minimized the risk of severe illness in most immunocompetent patients. However, unvaccinated patients and non-responders to the COVID-19 vaccine are at risk of shortand long-term consequences. In these patients, the outcome of COVID-19 relies on an interplay of multiple factors including age, immunocompetence, comorbidities, inflammatory response triggered by the virus as well as the virulence of SARS-CoV-2 variants. Generally, COVID-19 is asymptomatic or mildly symptomatic in young people, but it may manifest with respiratory insufficiency requiring mechanical ventilation in certain susceptible groups of patients. Furthermore, severe SARS-CoV-2 infection induces multiorgan failure syndrome by affecting liver, kidney heart and nervous system. Since December 2019, multiple drugs have been tested to treat COVID-19, but only a few have been proven effective to mitigate the course of the disease that continues to cause death and comorbidity worldwide. Current treatment of COVID-19 patients is essentialSUMMARY ly based on the administration of supportive oxygen therapy and the use of specific drugs such as steroids, anticoagulants, antivirals, anti-SARS-CoV-2 antibodies and immunomodulators. However, the rapid spread of new variants and the release of new data coming from the numerous ongoing clinical trials have created the conditions for maintaining a continuous updating of the therapeutic management of COVID-19 patients. Furthermore, we believe that a well-established therapeutic strategy along with the continuum of medical care for all patients with COVID-19 is pivotal to improving disease outcomes and restoring healthcare care fragmentation caused by the pandemic. This narrative review, focusing on the therapeutic management of COVID-19 patients, aimed to provide an overview of current therapies for (i) asymptomatic or mildly/moderate symptomatic patients, (ii) hospitalized patients requiring low-flow oxygen, (iii) highflow oxygen and (iv) mechanical ventilation. Keywords: COVID-19, SARS-CoV-2, therapy, ventilation, steroid, anticoagulant, tocilizumab, convalescent-plasma, monoclonal antibody, antiviral.

A. Jayk Bernal et al.

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

New England J of Medicine, February 2022; doi: 10.1056/NEJMoa2116044

Abstract

Background: New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29.

Results: A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, -6.8 percentage points; 95% confidence interval [CI], -11.3 to -2.4; P = 0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, -3.0 percentage points; 95% CI, -5.9 to -0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group.

Conclusions: Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.).

V. Belleudi et al.

Drug Prescriptions in the Outpatient Management of COVID-19: Evidence-Based Recommendations Versus Real Practice

Front. Pharmacol., March 2022; https://doi.org/10.3389/fphar.2022.825479

Abstract

Background: Evidence-based recommendations for outpatient management of COVID-19 were published by the Italian Medicines Agency (AIFA) to limit the use of off-label treatments. The aim of this study is to measure the use of outpatient drug treatments in a COVID-19-positive population, taking into account the Italian regulatory agency’s advices.

Methods: A descriptive observational study was conducted. All patients testing positive for COVID-19 residing in Lazio region, Italy, with diagnosis date between March 2020 and May 2021 were selected, and outpatient medicine prescription patterns were identified.

Results: Independent of AIFA recommendations, the use of drug therapy in the management of outpatient COVID-19 cases was frequent (about one-third of the cases). The most used drug therapy was antibiotics, specifically azithromycin, despite the negative recommendation of AIFA, while the use of corticosteroids increased after the positive recommendation of regulatory agency for the use in subjects with severe COVID-19 disease. The use of hydroxychloroquine was limited to the early pandemic period where evidence on its potential benefit was controversial. Antithrombotics were widely used in outpatient settings, even if their use was recommended for hospitalized patients.

Conclusion: In this study, we show a frequent use of drug therapy in the management of outpatient cases of COVID-19, mainly attributable to antibiotics use. Our research highlights the discrepancy between recommendations for care and clinical practice and the need for strategies to bridge gaps in evidence-informed decision-making.

D. J. Sullivan et al.

Early Outpatient Treatment for Covid-19 with Convalescent Plasma

The New England J of Medicine, March 2022; doi: 10.1056/NEJMoa2119657

Abstract

BACKGROUND

Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain.

METHODS

In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19–related hospitalization within 28 days after transfusion.

RESULTS

Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P=0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized.

CONCLUSIONS

In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460. opens in new tab.)

Franck Touret et al.

In vitro evaluation of therapeutic antibodies against a SARS‑CoV‑2 Omicron B.1.1.529 isolate

Nature, https://www.nature.com/articles/s41598-022-08559-5.pdf

CONTENUTO E COMMENTO: In questo studio è stato analizzato il potere neutralizzante di otto anticorpi monoclonali attualmente utilizzati contro la variante Omicron. E’ stato osservato che sei di questi anticorpi hanno perso la loro capacità di neutralizzazione. Degli anticorpi che mantengono attività neutralizzante, Sotrovimab/Vir-7831 mostra una lieve riduzione, Cilgavimab/AZD1061 da solo mostra una notevole riduzione nell'efficacia, con conseguente perdita significativa di attività di Evusheld (Tixagevimab-Cilgavimab ) in cui Tixagevimab non conserva attività significativa contro Omicron.

Duvignaud A et al

Inhaled ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE)

CMI, https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(22)00108-2/fulltext

CONTENUTO E COMMENTO : Trial clinico randomizzato open-label su 217 pazienti con COVID-19 non ospedalizzati, trattati con ciclesonide (steroide) per via inalatoria con endpoint primario il peggioramento clinico entro il giorno 14 dalla diagnosi. Si conclude per una insufficiente evidenza di beneficio degli steroidi inalatori in COVID-19.

Puskarich MA et al

Efficacy of Losartan in Hospitalized Patients With COVID-19–Induced Lung Injury A Randomized Clinical Trial

JAMA, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2790162

CONTENUTO E COMMENTO : Trial clinico randomizzato controllato con placebo eseguito in 13 centri degli USA nel periodo aprile 2020 – febbraio 2021 su 205 pazienti ospedalizzati con polmonite da SARS-CoV-2 e trattati con il sartano losartan o con placebo in aggiunta alla terapia standard per COVID-19 : non si osserva un miglioramento degli scambi gassosi (paO2/FiO2) a 7 giorni nei trattati con losartan, che dunque non appare utile nel trattamento di COVID-19.

Sydney B. Ross et al.

COVID-SAFER: Deprescribing Guidance for Nirmatrelvir-ritonavir Drug Interactions in Older Adults

Medrxiv.org, https://www.medrxiv.org/content/10.1101/2022.03.01.22271254v1.full.pdf

CONTENUTO E COMMENTO : Questo studio analizza le interazioni farmacologiche tra nirmatrelvir-ritonavir, potente CYP3A4 inibitore, e i farmaci potenzialmente inappropriati (PIM) assunti dalla popolazione anziana, ad alto rischio di gravi complicanze da COVID-19.

Di 5698 partecipanti, il 68% stava assumendo un farmaco che potenzialmente avrebbe interagito con nirmatrelvir-ritonavir, e di questi il 21% assumevano almeno un PIM. Con questa analisi viene sottolineata l’importanza di effettuare azioni di deprescribing negli anziani che assumono numerosi farmaci, per aumentare la proporzione di paziente che possono, in caso di infezione da Sars-CoV2, assumere nirmatrelvir-ritonavir senza interazioni.

Rebecca Rockett et al.

Resistance Mutations in SARS-CoV-2 Delta Variant after Sotrovimab Use

NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMc2120219?articleTools=true

CONTENUTO E COMMENTO: Tra i primi 100 pazienti che hanno ricevuto sotrovimab, un anticorpo monoclonale diretto contro SARS-CoV-2, in un centro in Australia, in 8 pazienti il tampone molecolare rimaneva persistentemente positivo. Gli isolati ottenuti da 4 pazienti hanno mostrato una mutazione associata alla resistenza a sotrovimab nel dominio del recettore e le colture sono risultate positive a 2-3 settimane dopo il trattamento.

Nicola K Wills et al.

Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis

Medrxiv.org, https://www.medrxiv.org/content/10.1101/2022.03.05.22271947v1.full.pdf

CONTENUTO E COMMENTO: Metanalisi su 11 trial clinic randomizzati per un totale di 5873 pazienti con COVID19 trattati con terapia anticoagulante a dosaggio profilattico o aumentato (intermedio o terapeutico): la terapia anticoagulante a dosaggio aumentato non ha dimostrato alcun effetto significativo sulla mortalità a breve termine ed era invece associata ad un aumento del rischio di sanguinamento. La riduzione del rischio di tromboembolia venosa osservata e la possibile tendenza alla riduzione della mortalità nei pazienti ospedalizzati non in ICU richiedono ulteriori studi.

Emi Takashita et al.

Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2

NEJM, https://www.nejm.org/doi/pdf/10.1056/NEJMc2201933?articleTools=true

CONTENUTO E COMMNENTO: Valutazione dell'attività in vitro degli anticorpi monoclonali e degli antivirali nei confronti della variante Omicron/BA.2.

Le suscettibilità di Omicron/BA.2 a remdesivir, molnupiravir e nirmatrelvir è confermata, mentre è stata osservata un'attività variabile degli anticorpi monoclonali, in particolare S309 (precursore di sotrovimab) ha dimostrato una ridotta attività neutralizzante nei confronti di Omicron/BA.2.

Shytaj I L et al

The FDA-Approved Drug Cobicistat Synergizes with Remdesivir To Inhibit SARS-CoV-2 Replication In Vitro and Decreases Viral Titers and Disease Progression in Syrian Hamsters

Virology, https://journals.asm.org/doi/full/10.1128/mbio.03705-21

CONTENUTO E COMMENTO: Secondo lo studio, il cobicistat (questo e' il nome del farmaco) potrebbe inibire la moltiplicazione del virus SARS-CoV-2 con un meccanismo diverso da quello dei farmaci ad ora utilizzati, ovvero bloccandone la fusione alle cellule bersaglio. Inoltre, lo studio dimostra che il cobicistat puó attenuare la progressione della malattia nel modello animale di criceto, potenziando in tal senso anche l´effetto di un altro farmaco anti-COVID, ovvero il remdesivir.

Finora i tentativi di usare farmaci antiretrovirali contro il SARS-CoV-2 non avevano portato risultati significativi. Come spiegano gli autori dello studio, uno dei motivi principali sono i dosaggi necessari per ottenere un effetto inibitorio contro la replicazione del virus. Lo studio infatti dimostra che il cobicistat inibisce efficacemente la moltiplicazione del virus SARS-CoV-2 a livelli circa quattro volte superiori a quelli somministrati nelle sperimentazioni cliniche iniziali.

L´aspetto più importante dello studio è la dimostrazione che un composto che coadiuva l´azione di altri farmaci possa anche avere un effetto antivirale in vivo. Questo doppio effetto consente di testare una vasta gamma di combinazioni farmacologiche per arrivare ad un cocktail ottimale che possa inibire completamente la replicazione del virus.

Albuquerque AM et al

Mortality Rates Among Hospitalized Patients With COVID-19 Infection Treated With Tocilizumab and CorticosteroidsA Bayesian Reanalysis of a Previous Meta-analysis

JAMA Network Open, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2789444

CONTENUTO E COMMENTO : Re-analisi di una metanalisi su 15 trial clinic randomizzati, per un totale di 5339 pazienti ospedalizzati e trattati con tocilizumab e steroidi per COVID-19: il beneficio del tocilizumab sulla mortalità, già dimostrato in una metanalisi precedente, sarebbe confermato per i pazienti trattati con ossigenoterapia convenzionale o ventilazione non invasiva, ma non per i pazienti sottoposti a ventilazione meccanica invasiva. Il ruolo di tocilizumab nel trattamento di COVID-19 merita ulteriore studio.

Broman N et al

Early administration of tocilizumab in hospitalized COVID-19 patients with elevated inflammatory markers; COVIDSTORM – A prospective, randomized, single center, open label study

Clinical Microbiology and Infection, https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(22)00104-5/fulltext

CONTENUTO E COMMENTO : Studio prospettico randomizzato monocentrico open-label su soli 57 pazienti, in cui sono stati inclusi adulti ospedalizzati per ipossiemia e COVID-19, con almeno due marker infiammatori elevati fra PCR, ferritina, D-dimero e interleukina-6: l’aggiunta di tocilizumab alla terapia standard è associata in questa casistica a una migliore condizione clinica (scala WHO) a 28 giorni e a una minore durata di ospedalizzazione.

Lim SCL et al

Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities The I-TECH Randomized Clinical Trial

JAMA, https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2789362

CONTENUTO E COMMENTO : Trial clinico su 490 pazienti adulti di età superiore a 50 anni condotto in Malesia, in cui si somministrava l’antiparassitario ivermectina oppure un placebo, oltre alle terapie standard, nella prima settimana dall’esordio di COVID-19 lieve-moderata : l’ivermectina non riduce significativamente il rischio di progressione verso la malattia grave e dunque non appare indicata come trattamento nelle fasi precoci di COVID-19.

Komagamine J et al

Evaluation of Antimicrobial Drug Use and Concurrent Infections During Hospitalization of Patients With COVID-19 in Japan

JAMA, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2789175

CONTENUTO E COMMENTO : Studio retrospettivo cross-sectional condotto in Giappone su oltre 1000 pazienti ricoverati per COVID-19 in un centro privo di Rianimazione. La metà dei pazienti aveva polmonite, solo 1.7% ha ricevuto antibiotici durante l’ospedalizzazione. Le sovrainfezioni batteriche sono state solo 7, in meno dell’1% dei ricoverati in questo gruppo di pazienti.

Steven Chee Loon Lim et al.

Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities The I-TECH Randomized Clinical Trial

JAMA Intern Med, https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2789362

CONTENUTO E COMMENTO: Trial clinico randomizzato condotto su pazienti affetti da COVID19 ad alto rischio di progressione verso la malattia severa trattati con l’aggiunta di ivermectina per 5 giorni somministrata per via orale durante la prima settimana di malattia.

I risultati hanno mostrato che l’aggiunta di ivermectina allo standard of care non era associata a unariduzione del rischio di sviluppare una malattia grave.

Pertanto i risultati dello studio non supportanol'utilizzo di ivermectina per i pazienti con COVID-19.

Jennifer Hammond et al.

Oral Nirmatrelvir for High-Risk,Nonhospitalized Adults with Covid-19

The New England Journal of Medicine, https://www.nejm.org/doi/pdf/10.1056/NEJMoa2118542?articleTools=true

CONTENUTO E COMMENTO: Trial di fase 2-3 in doppio cieco, randomizzato e controllato in cui adulti sintomatici, non vaccinati e non ospedalizzati, ad alto rischio di progressione verso una forma grave di Covid-19 sono stati assegnati in rapporto 1:1 a ricevere 300 mg di nirmatrelvir per via orale (inibitore della proteasi principale Mpro con una potente attività in vitro contro i coronavirus umani), più 100 mg di ritonavir o placebo.

I risultati hanno mostrato che il trattamento di adulti con COVID-19 sintomatici con nirmatrelvirpiù ritonavir è associato ad unariduzione del rischio di progressione a COVID-19 severo dell’89% rispetto al gruppotrattato con placebo, con un buonprofilo di sicurezza.

RECOVERY Collaborative group

Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

The Lancet,

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00163-5/fulltext

CONTENUTO E COMMENTO : Studio randomizzato, controllato, open-label condotto sulla piattaforma RECOVERY, in 127 ospedali in UK su pazienti ospedalizzati per COVID-19 tra settembre 2020 e maggio 2021. L’obiettivo dello studio era quello di valutare l’efficacia di casirivimab e imdevimab, due anticorpi monoclonali che legano due differenti siti del receptor binding domain della proteina spike di SARS-CoV-2, nel ridurre la mortalità a 28 giorni.

I ridultati dimostrano che l’utilizzo di anticorpi monoclonali casirivimab e imdevimab nei pazienti ospedalizzati con COVID-19 riduce la mortalità a 28 giorni solo nei pazienti sieronegativi ma non in quelli sieropositivi, ovvero soltanto in coloro che non avevano precedentemente montato una propria risposta immunitaria.

Cairns DM et al

Efficacy of Niclosamide vs Placebo in SARS-CoV-2 Respiratory Viral Clearance, Viral Shedding, and Duration of Symptoms Among Patients With Mild to Moderate COVID-19A Phase 2 Randomized Clinical Trial

JAMA Netw Open, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2788857

CONTENUTO E COMMENTO : Trial clinico randomizzato controllato con placebo condotto su pazienti con COVID-19 lieve-moderato con l’obiettivo di valutare se l’utilizzo di niclosamide (un antielmintico orale con potente attività anti-SARS-CoV-2 in vitro) sia efficace nel ridurre lo shedding virale e la durata dei sintomi. Il trial è stato interrotto precocemente ad aprile 2021 per la drammatica riduzione dei casi di COVID-19 in Massachusetts, arruolando soltanto 73 partecipanti. Non è stata dimostrata nessuna differenza statisticamente significativa tra i due gruppi nella clearance virale a livello orofaringeo a 3 giorni né nella durata dei sintomi COVID-19 relati.

Behr CR et al

Anti–SARS-CoV-2 Monoclonal Antibody Distribution to High-risk Medicare Beneficiaries, 2020-2021

JAMA, https://jamanetwork.com/journals/jama/fullarticle/2788904?widget=personalizedcontent&previousarticle=2788849

CONTENUTO E COMMENTO : Studio della allocazione delle terapia con anticorpi monoclonali contro SARS-CoV-2 in quasi 2 milioni di adulti con COVID-19 negli USA. Si osserva che per lo più le terapie erano destinate a pazienti a minor rischio, possibilmente a causa della difficoltà per i pazienti a rischio maggiore di malattia grave di ricevere diagnosi e prescrizione nei tempi adeguati.

Frank L. van de Veerdonk et al.

A guide to immunotherapy for COVID-19

Nature Medicine, https://www.nature.com/articles/s41591-021-01643-9.pdf

CONTENUTO E COMMENTO: La disfunzione immunitaria è una componente importante della fisiopatologia del COVID-19. Una vasta letteratura ha riportato l'effetto di terapie immunitarie in pazienti con COVID-19, con alcuni notevoli successi come l'uso di steroidi o le terapie anti-citochine.

Attraverso questa revisione delle strategie di immunoterapia nei pazienti con COVID-19, viene fornita una panoramica delle evidenze finora pubblicate, viene discussa una stratificazione del paziente e proposto un algoritmo per guidare l'utilizzo dell’immunoterapia nella pratica clinica.

The ITAC (INSIGHT 013) Study Group

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

The Lancet, https://www.thelancet.com/action/showPdf?pii=S0140-6736%2822%2900101-5

CONTENUTO E COMMENTO: Trial clinico randomizzato di fase 3, doppio cieco, controllato con placebo, in cui i pazienti ricoverati con COVID-19, sintomatici per un massimo di 12 giorni e senza end-organ failure, sono stati assegnati in modo casuale (1:1) a ricevere immunoglobuline iperimmuni per via endovenosa (hIVIG) o placebo, oltre al remdesivir. Lo studio non ha evidenziato efficacia nel trattamento con hIVIG per i pazienti ricoverati con COVID-19 senza end-organ failure.

O’Brien MP et al

Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection A Randomized Clinical Trial

JAMA, https://jamanetwork.com/journals/jama/fullarticle/2788256

CONTENUTO E COMMENTO : Trial clinico randomizzato controllato in doppio-cieco di fase 3 con l’biettivo di valutare l’effetto della somministrazione sottocutanea della combinazione di anticorpi monoclonali casirivimab e imdevimab nel prevenire la progressione dell’infezione da SARS-CoV-2 dalla forma asintomatica alla malattia sintomatica. Studio condotto in USA, Romania e Moldavia tra luglio 2020 e marzo 2021.

Lo studio dimostra che la somministrazione sottocutanea di casirivimab e imdevimab nei pazienti asintomatici con infezione da SARS-CoV-2 riduce significativamente il rischio di sviluppare malattia sintomatica e la durata dei sintomi sviluppati.

Questo studio ha il vantaggio di indagare la somministrazione di anticorpi monoclonali per via sottocutanea, di più facile applicabilità rispetto all’infusione endovenosa, facilità che ne consentirebbe una maggiore diffusione anche a livello territoriale. D’altro canto lo studio è stato condotto in un arco temporale in cui non era ancora diffusa la variante omicron, contro cui casirivimab e imdevimab sembrano aver perso potere neutralizzante ed efficacia, come emerso da recenti studi di laboratorio.

Jayk Bernal A et al

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2116044?query=featured_coronavirus

CONTENUTO E COMMENTO: Trial clinico di fase 3 su 1433 pazienti con infezione da SARS-CoV-2, non ospedalizzati ma sintomatici, trattati con l’antivirale molnupiravir contro placebo per 5 giorni, iniziando il trattamento entro 5 giorni dall’esordio dei sintomi : si osserva una riduzione del rischio di ospedalizzazione. Esclusi i vaccinati e le persone con storia di infezione pregressa da SARS-CoV-2. Pur tenendo conto del fatto che si tratti di uno studio condotto sui non vaccinati, ridurre l’ospedalizzazione significa ridurre la pressione sui sistemi sanitari, il che rende i trattamenti domiciliari come molnupiravir molto promettenti.