BACKGROUND: Molnupiravir and nirmatrelvir-ritonavir are orally administered pharmacotherapies for mild to moderate COVID-19. However, the effectiveness of these drugs among very old (≥80 years), hospitalised patients remains unclear, limiting the risk-benefit assessment of these antivirals in this specific group. This study investigates the effectiveness of these antivirals in reducing mortality among this group of hospitalised patients with COVID-19.
METHODS: Using a territory-wide public healthcare database in Hong Kong, a target trial emulation study was conducted with data from 13 642 eligible participants for the molnupiravir trial and 9553 for the nirmatrelvir-ritonavir trial. The primary outcome was all-cause mortality. Immortal time and confounding bias was minimised using cloning-censoring-weighting approach. Mortality odds ratios were estimated by pooled logistic regression after adjusting confounding biases by stabilised inverse probability weights.
RESULTS: Both molnupiravir (HR: 0.895, 95% CI: 0.826-0.970) and nirmatrelvir-ritonavir (HR: 0.804, 95% CI: 0.678-0.955) demonstrated moderate mortality risk reduction among oldest-old hospitalised patients. No significant interaction was observed between oral antiviral treatment and vaccination status. The 28-day risk of mortality was lower in initiators than non-initiators for both molnupiravir (risk difference: -1.09%, 95% CI: -2.29, 0.11) and nirmatrelvir-ritonavir (risk difference: -1.71%, 95% CI: -3.30, -0.16) trials. The effectiveness of these medications was observed regardless of the patients\' prior vaccination status.
CONCLUSIONS: Molnupiravir and nirmatrelvir-ritonavir are moderately effective in reducing mortality risk among hospitalised oldest-old patients with COVID-19, regardless of their vaccination status.

BACKGROUND: Trimodulin (human polyvalent immunoglobulin [Ig] M ~ 23%, IgA ~ 21%, IgG ~ 56% preparation) has previously been associated with a lower mortality rate in a subpopulation of patients with severe community-acquired pneumonia on invasive mechanical ventilation (IMV) and with clear signs of inflammation. The hypothesis for the ESsCOVID trial was that trimodulin may prevent inflammation-driven progression of severe coronavirus disease 2019 (COVID-19) to critical disease or even death.
METHODS: Adults with severe COVID-19 were randomised to receive intravenous infusions of trimodulin or placebo for 5 consecutive days in addition to standard of care. The primary efficacy endpoint was a composite of clinical deterioration (Days 6-29) and 28-day all-cause mortality (Days 1-29).
RESULTS: One-hundred-and-sixty-six patients received trimodulin (n = 84) or placebo (n = 82). Thirty-three patients died, nine during the treatment phase. Overall, 84.9% and 76.5% of patients completed treatment and follow-up, respectively. The primary efficacy endpoint was reported in 33.3% of patients on trimodulin and 34.1% of patients on placebo (P = 0.912). No differences were observed in the proportion of patients recovered on Day 29, days of invasive mechanical ventilation, or intensive care unit-free days. Rates of treatment-emergent adverse events were comparable. A post hoc analysis was conducted in patients with early systemic inflammation by excluding those with high CRP (> 150 mg/L) and/or D-dimer (≥ 3 mg/L) and/or low platelet counts (< 130 × 109/L) at baseline. Forty-seven patients in the trimodulin group and 49 in the placebo group met these criteria. A difference of 15.5 percentage points in clinical deterioration and mortality was observed in favour of trimodulin (95% confidence interval: -4.46, 34.78; P = 0.096).
CONCLUSIONS: Although there was no difference in the primary outcome in the overall population, observations in a subgroup of patients with early systemic inflammation suggest that trimodulin may have potential in this setting that warrants further investigation. ESSCOVID WAS REGISTERED PROSPECTIVELY AT CLINICALTRIALS.GOV ON OCTOBER 6, 2020.: NCT04576728.

OBJECTIVE: In this study, we aim to explore the efficacy of paxlovid on reducing mortality of COVID-19 patients in clinical setting, especially whether paxlovid modifies the risk of death in these severe and critical patients.
METHODS: Our retrospective cohort study was conducted on the medical records of patients, consecutively admitted for COVID-19 to five hospitals in Chongqing, China from Dec 8, 2022 to Jan 20, 2023. Based on whether patients received paxlovid during their hospitalization, patients were grouped as paxlovid group and non-paxlovid group. We used 1:1 ratio propensity score matching (PSM) in our study to adjust for confounding factors and differences between groups. Statistical analysis were performed by SPSS 23.0. The differences in 28-day mortality between these two groups and its influencing factors were the main results we focused on.
RESULTS: There were 1018 patients included in our study cohort. With 1:1 ratio PSM, each of the paxlovid group and non-paxlovid group included 237 patients. The results showed that patients using paxlovid have a lower 28-day mortality in overall population either before PSM (OR 0.594, 95% CI 0.385-0.917, p = 0.019) or after PSM (OR 0.458, 95% CI 0.272-0.774, p = 0.003) with multivariable adjusted logistic regression models. Meanwhile, in severe subgroup, it showed similar findings.With paxlovid treatment, it showed a significantly lower 28-day mortality in severe subgroup both before PSM (28% vs.41%, p = 0.008) and after PSM (19% vs.32%, p = 0.007).
CONCLUSIONS: Paxlovid can significantly reduce the risk of 28-day mortality in overall population and severe subgroup patients.This study distinguished the severe subgroup patients with COVID-19 who benefit more from paxlovid treatment.

OBJECTIVE: To explore the differences in Traditional Chinese Medicine (TCM) diagnosis and treatment rules for coronavirus disease 2019 (COVID-19) between Northern and Southern China based on the real-world data from 982 COVID-19 patients.
METHODS: All consecutive cases of COVID-19 admitted to the TCM department of designated COVID-19 hospitals in eight provinces and cities were retrospectively analyzed. Patients were divided into a Northern and a Southern group according to the location of the admitting hospital. The symptoms, syndrome elements, syndrome distribution and herbal treatments were analyzed. The core prescriptions were extracted using the multiscale backbone-based network comparison algorithm (msbNC).
RESULTS: The distribution of syndrome elements showed that dampness was common in Northern and Southern China, wind and heat were more often present in the South, while fire toxin and spleen deficiency were more often encountered in the North. The distribution of syndromes showed that the South was dominated by heat dampness accumulating in the lung (55.69%), while the North was dominated by dampness-toxin stagnating in the lung (44.90%).The results of core prescription mining showed that dispelling dampness, dispersing wind, clearing heat and strengthening spleen were the common treatment methods in Northern and Southern China. For mild cases, Jinyinhua (Flos Lonicerae) and Lianqiao (Fructus Forsythiae Suspensae) were often used in the South to clear heat and relieve exterior symptoms, while Chaihu (Radix Bupleuri Chinensis) and Huangqin (Radix Scutellariae Baicalensis) were often used in the North to relieve muscles by expelling heat. For moderate cases, Chaihu (Radix Bupleuri Chinensis), Qinghao (Herba Artemisiae Annuae), and Shigao (Gypsum Fibrosum) were often used to clear heat of Tri-jiao Channel and stomach in the South, while Fuling (Poria), Chenpi (Pericarpium Citri Reticulatae), and Dangshen (Radix Codonopsis) were often used to invigorate spleen and remove dampness in the North. For severe cases, spleen invigoration and dampness removal as well as relaxing the bowels and discharging heat were often used in the North.
CONCLUSIONS: There were certain North-South differences in terms of symptoms, syndrome elements and syndrome distribution of COVID-19, as well as differences in core prescriptions during different periods of the disease. The regional differences in the rules of TCM diagnosis and treatment for COVID-19 should be further considered in the process of optimization and revision of relevant treatment guidance.

High-dose inhaled Nitric Oxide (iNO) has been shown to have anti-inflammatory, vasodilator, and antimicrobial properties, resulting in improved arterial oxygenation as well as a beneficial therapeutic effect on lower respiratory tract infections. This study evaluated the safety and efficacy of 150-ppm intermittent iNO administered with a novel iNO-generator, for treating adults hospitalised for viral pneumonia. In this prospective, open-label, multicenter study, subjects aged 18-80, diagnosed with viral pneumonia received either standard supportive treatment alone (Control-Group) or combined with iNO for 40 min, 4 times per day up to 7 days (Treatment-Group). Out of 40 recruited subjects, 35 were included in the intention-to-treat population (34 with COVID-19). Adverse Events rate was similar between the groups (56.3% vs. 42.1%; respectively). No treatment-related adverse events were reported, while 2 serious adverse events were accounted for by underlying pre-existing conditions. Among the Treatment-Group, oxygen support duration was reduced by 2.7 days (Hazard Ratio = 2.8; p = 0.0339), a greater number of subjects reached oxygen saturation ≥ 93% within hospitalisation period (Hazard Ratio = 5.4; p = 0.049), and a trend for earlier discharge was demonstrated. Intermittent 150-ppm iNO-treatment is well-tolerated, safe, and beneficial compared to usual care for spontaneously breathing hospitalised adults diagnosed with COVID-19 viral pneumonia.

In recent years especially during COVID-19, the increased usage of antiviral drugs has led to increased interest in monitoring their presence in wastewater worldwide. In this study, it was examined the occurrence, fate and environmental risks of favipiravir which is used for COVID-19 treatment in two wastewater treatment plants (WWTPs) with different treatment processes in Istanbul, Turkey. Favipiravir was measured in WWTPs influent samples, effluent samples and sludge samples with maximum concentrations of 97 μg/L, 64.11 μg/L and 182.47 μg/g, respectively. Favipiravir had removal efficiency below 55 % for both WWTPs. Mass balance analysis showed that favipiravir removal in WWTPs mainly attributed to biodegradation/biotransformation. Statistical analysis revealed a significant correlation between favipiravir concentration and COVID-19 incidence in Istanbul. The microbial distribution analysis indicated that comparison of collected COVID-19 pandemic sludge and post-pandemic period sludge samples, a noteworthy reduction in the Chloroflexi and Actinobacteriota phyla at the phylum level was observed. Environmental risk assessment using risk quotients ranged from 168 to 704, indicating that the presence of this antiviral drug posed significant ecological risks to aquatic organisms. The study concluded that WWTPs were releasing antiviral drugs into the environment, thereby posing risks to both the aquatic ecosystem and public health. The results of this study demonstrate the persistence of favipiravir in WWTPs and offer crucial supporting data for further research into the advancement of wastewater treatment technology. Also, this study shows wastewater based monitoring is supplementary and early warning system for determining the occurrence of antiviral drugs.

BACKGROUND: Evidence on ivermectin as a treatment for Covid-19 is controversial. A Cochrane review concluded that the efficacy and safety of ivermectin is uncertain (evidence up to April 2022) and WHO recommended its use only in the setting of clinical trials. This study aimed to assess the efficacy and safety of oral ivermectin in hospitalized patients with mild to moderate Covid-19.
UNASSIGNED: A double-blind, randomized placebo-controlled clinical trial was conducted among RT-PCR-confirmed, adults, hospitalised within the first four days of symptoms. Patients received oral ivermectin 24 mg or placebo daily for five days. RT-PCR was repeated on days five and ten. Clinical progression was monitored using the World Health Organization Clinical Progression Scale. Serum ivermectin levels were measured on days three, five, and seven. The primary outcome was the difference in the viral load between day zero and ten in the two groups.
RESULTS: Out of 1699 patients screened, 249 underwent randomization and 127 received ivermectin, and 122 placebo. D10 median viral load for E gene (IQR) was 2,000 copies/mL (100 - 20,500) with ivermectin (n = 80) and 4,100 copies/mL (1,000-65,600) with placebo (n = 81, p = 0.028), per protocol analysis. The difference in Log viral load between day zero and ten between ivermectin and placebo was 3.72 and 2.97 respectively (p = 0.022). There was no significant difference in the WHO clinical progression scale or the adverse effects. Ivermectin blood levels taken before or with meals were not significantly different. Only 7 and 17 patients achieved blood levels above 160ng/ML and 100ng/ML respectively and they did not achieve a significantly lower viral load.
CONCLUSIONS: Although ivermectin resulted in statistically significant lower viral load in patients with mild to moderate Covid-19, it had no significant effect on clinical symptoms.
BACKGROUND: SLCTR/2021/020, Sri Lanka Clinical Trials Registry. 19/07/2021.

BACKGROUND: The efficacy, effectiveness, and safety of the approved nirmatrelvir/ritonavir regimen for treatment of laboratory-confirmed mild/moderately severe COVID-19 remains unclear.
METHODS: We systematically identified randomized controlled trials (RCTs) and real-world studies (RWS; observational studies) of the efficacy/effectiveness and/or safety of the approved nirmatrelvir/ritonavir regimen for COVID-19. We pooled appropriate data (adjusted estimates for RWS) using an inverse variance, random-effects model. We calculated statistical heterogeneity using the I 2 statistic. Results are presented as relative risk (RR) with associated 95% CI. We further assessed risk of bias/study quality and conducted trial sequential analysis of the evidence from RCTs.
RESULTS: We included 4 RCTs (4,070 persons) and 16 RWS (1,925,047 persons) of adults (aged ≥18 years). One and 3 RCTs were of low and unclear risk of bias, respectively. The RWS were of good quality. Nirmatrelvir/ritonavir significantly decreased COVID-19 hospitalization compared with placebo/no treatment (RR = 0.17; 95% CI, 0.10-0.31; I 2 = 77.2%; 2 RCTs, 3,542 persons), but there was no significant difference for decrease of worsening severity (RR = 0.82; 95% CI, 0.66-1.01; I 2 = 47.5%; 3 RCTs, 1,824 persons), viral clearance (RR = 1.19; 95% CI, 0.93-1.51; I 2 = 82%; 2 RCTs, 528 persons), adverse events (RR = 1.41; 95% CI, 0.92-2.14; I 2 = 70.6%; 4 RCTs, 4,070 persons), serious adverse events (RR = 0.82; 95% CI, 0.41-1.62; I 2 = 0%; 3 RCTs, 3,806 persons), and all-cause mortality (RR = 0.27; 95% CI, 0.04-1.70; I 2 = 49.9%; 3 RCTs, 3,806 persons), although trial sequential analysis suggested that the current total sample sizes for these outcomes were not large enough for conclusions to be drawn. Real-world studies also showed significantly decreased COVID-19 hospitalization (RR = 0.48; 95% CI, 0.37-0.60; I 2 = 95.0%; 11 RWS, 1,421,398 persons) and all-cause mortality (RR = 0.24; 95% CI, 0.14-0.34; I 2 = 65%; 7 RWS, 286,131 persons) for nirmatrelvir/ritonavir compared with no treatment.
CONCLUSIONS: Nirmatrelvir/ritonavir appears to be promising for preventing hospitalization and potentially decreasing all-cause mortality for persons with mild/moderately severe COVID-19, but the evidence is weak. More studies are needed.

Although real-world studies have found that remdesivir is effective in preventing poor prognosis, more information is needed on the optimal timing of remdesivir administration in high-risk coronavirus disease 2019 (COVID-19) patients in the Omicron era. From February 2022 to January 2023, a single-center retrospective study was performed in Korea. We compared the clinical characteristics and treatment outcomes between early (remdesivir treatment within 0-3 days from symptom onset) and late (≥ 4 days from symptom onset) treatment groups of patients who received remdesivir monotherapy. Of 284 patients, 225 were classified into the early treatment group and 59 were classified into the late treatment group. The early treatment group had a lower rate of 28-day progression to severe disease than the late treatment group (1.4% vs 7.4%, P = .03). Delaying remdesivir treatment ≥ 4 days from symptom onset (adjusted odds ratio [aOR], 6.17; 95% CI, 1.18-32.44; P = .03) and Charlson comorbidity index ≥ 3 (aOR, 9.62; 95% CI, 1.65-56.10; P = .01) were independent risk factors for 28-day progression to severe disease. Our results suggest that early administration of remdesivir could be associated with better prognosis in COVID-19 patients with the Omicron variant, and within 3 days from symptom onset seems to be the appropriate timing.

There is limited evidence about the use of medications among pregnant women with COVID-19, as well as risk factors for hospitalization due to COVID-19 in pregnancy. We aimed to describe the use of medications among SARS-CoV-2-positive pregnant women at the time around infection and identify predictors for hospitalization due to COVID-19 in two hospitals in Brazil. This is a hospital record-based study among pregnant women with positive SARS-CoV-2 tests between March 2020 and August 2022 from two Brazilian hospitals. Characteristics of sociodemographic, obstetrical, and COVID-19 symptoms were extracted retrospectively. The prevalence use of medications was based on self-reported use, and this was administered at the hospital. Logistic regression was used to estimate predictors of hospitalization due to COVID-19. There were 278 pregnant women included in the study, of which 41 (14.7%) required hospitalization due to COVID-19. The remaining 237 (85.3%) had mild symptoms or were asymptomatic. Most of the women had the infection in the third trimester (n = 149; 53.6%). The most prevalent medications used across all trimesters were analgesics (2.4% to 20.0%), antibacterials (15.0% to 23.1%), and corticosteroids (7.2% to 10.4%). Pre- or gestational hypertensive disorder (odds ratio (OR) 4.94, 95% confidence interval (CI) 1.65, 14.87) and having at least one dose of vaccine against SARS-CoV-2 (OR 0.13, 95% CI 0.04, 0.39) were associated with hospitalization due to COVID-19. Analgesics, antibacterials, and corticosteroids were the most frequently used medications among pregnant women with COVID-19. Women with hypertensive disorders have almost a five-fold increased risk of hospitalization due to COVID-19. Vaccination was the strongest protective factor for severe COVID-19. The COVID-19 vaccination among pregnant women should be promoted, and pregnant women diagnosed with COVID-19 who have hypertensive disorders should be closely monitored.