Patients and physicians worldwide are facing tremendous health care hazards that are caused by the ongoing severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) pandemic. Remdesivir ...(GS-5734) is the first approved treatment for severe coronavirus disease 2019 (COVID-19). It is a novel nucleoside analog with a broad antiviral activity spectrum among RNA viruses, including ebolavirus (EBOV) and the respiratory pathogens Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV, and SARS-CoV-2. First described in 2016, the drug was derived from an antiviral library of small molecules intended to target emerging pathogenic RNA viruses.
, remdesivir showed therapeutic and prophylactic effects in animal models of EBOV, MERS-CoV, SARS-CoV, and SARS-CoV-2 infection. However, the substance failed in a clinical trial on ebolavirus disease (EVD), where it was inferior to investigational monoclonal antibodies in an interim analysis. As there was no placebo control in this study, no conclusions on its efficacy in EVD can be made. In contrast, data from a placebo-controlled trial show beneficial effects for patients with COVID-19. Remdesivir reduces the time to recovery of hospitalized patients who require supplemental oxygen and may have a positive impact on mortality outcomes while having a favorable safety profile. Although this is an important milestone in the fight against COVID-19, approval of this drug will not be sufficient to solve the public health issues caused by the ongoing pandemic. Further scientific efforts are needed to evaluate the full potential of nucleoside analogs as treatment or prophylaxis of viral respiratory infections and to develop effective antivirals that are orally bioavailable.
The ongoing SARS‐CoV‐2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of ...broadly active antiviral drugs and compounds that are known to inhibit viral replication of related viruses, several advances could be made in the development of treatment strategies against COVID‐19. The nucleoside analog remdesivir, which is known for its potent in vitro activity against Ebolavirus and other RNA viruses, was recently shown to reduce the time to recovery in patients with severe COVID‐19. It is to date the only approved antiviral for treating COVID‐19. Here, we provide a mechanism and evidence‐based comparative review of remdesivir and other repurposed drugs with proven in vitro activity against SARS‐CoV‐2.
This comprehensive review discusses preclinical and clinical outcomes of remdesivir and other repurposed antiviral drugs against SARS‐CoV‐2.
Abstract
Background
The role of molnupiravir for coronavirus disease 2019 (COVID-19) treatment is unclear.
Methods
We conducted a systematic review until 1 November 2022 searching for randomized ...controlled trials (RCTs) involving COVID-19 patients comparing molnupiravir ±standard of care (SoC) versus SoC and/or placebo. Data were pooled in random-effects meta-analyses. Certainty of evidence was assessed according to the Grading of Recommendations, Assessment, Development and Evaluations approach.
Results
Nine RCTs were identified, eight investigated outpatients (29 254 participants) and one inpatients (304 participants). Compared with placebo/SoC, molnupiravir does not reduce mortality risk ratio (RR) 0.27, 95% CI 0.07–1.02, high-certainty evidence and probably does not reduce the risk for ‘hospitalization or death’ (RR 0.81, 95% CI 0.55–1.20, moderate-certainty evidence) by Day 28 in COVID-19 outpatients. We are uncertain whether molnupiravir increases symptom resolution by Day 14 (RR 1.20, 95% CI 1.02–1.41, very-low-certainty evidence) but it may make no difference by Day 28 (RR 1.05, 95% CI 0.92–1.19, low-certainty evidence). In inpatients, molnupiravir may increase mortality by Day 28 compared with placebo (RR 3.78, 95% CI 0.50–28.82, low-certainty evidence). There is little to no difference in serious adverse and adverse events during the study period in COVID-19 inpatients/outpatients treated with molnupiravir compared with placebo/SoC (moderate- to high-certainty evidence).
Conclusions
In a predominantly immunized population of COVID-19 outpatients, molnupiravir has no effect on mortality, probably none on ‘hospitalization or death’ and effects on symptom resolution are uncertain. Molnupiravir was safe during the study period in outpatients although a potential increase in inpatient mortality requires careful monitoring in ongoing clinical research. Our analysis does not support routine use of molnupiravir for COVID-19 treatment in immunocompetent individuals.
This network meta-analysis (NMA) assessed the efficacy of remdesivir in hospitalized patients with COVID-19 requiring supplemental oxygen. Randomized controlled trials of hospitalized patients with ...COVID-19, where patients were receiving supplemental oxygen at baseline and at least one arm received treatment with remdesivir, were identified. Outcomes included mortality, recovery, and no longer requiring supplemental oxygen. NMAs were performed for low-flow oxygen (LFO
); high-flow oxygen (HFO
), including NIV (non-invasive ventilation); or oxygen at any flow (AnyO
) at early (day 14/15) and late (day 28/29) time points. Six studies were included (N = 5245 patients) in the NMA. Remdesivir lowered early and late mortality among AnyO
patients (risk ratio (RR) 0.52, 95% credible interval (CrI) 0.34-0.79; RR 0.81, 95%CrI 0.69-0.95) and LFO
patients (RR 0.21, 95%CrI 0.09-0.46; RR 0.24, 95%CrI 0.11-0.48); no improvement was observed among HFO
patients. Improved early and late recovery was observed among LFO
patients (RR 1.22, 95%CrI 1.09-1.38; RR 1.17, 95%CrI 1.09-1.28). Remdesivir also lowered the requirement for oxygen support among all patient subgroups. Among hospitalized patients with COVID-19 requiring supplemental oxygen at baseline, use of remdesivir compared to best supportive care is likely to improve the risk of mortality, recovery and need for oxygen support in AnyO
and LFO
patients.
Resistance against commonly used antibiotics has emerged in all bacterial pathogens. In fact, there is no antibiotic currently in clinical use against which resistance has not been reported. In ...particular, rapidly increasing urbanization in developing nations are sites of major concern. Additionally, the widespread practice by physicians to prescribe antibiotics in cases of viral infections puts selective pressure on antibiotics that still remain effective and it will only be a matter of time before resistance develops on a large scale. The biosynthesis pathway of the bacterial cell wall is well studied and a validated target for the development of antibacterial agents. Cell wall biosynthesis involves two major processes; 1) the biosynthesis of cell wall teichoic acids and 2) the biosynthesis of peptidoglycan. Key molecules in these pathways, including enzymes and precursor molecules are attractive targets for the development of novel antibacterial agents. In this review, we will focus on the major class of natural antibacterial compounds that target the peptidoglycan precursor molecule Lipid II; namely the glycopeptides, including the novel generation of lipoglycopeptides. We will discuss their mechanism-of-action and clinical applications. Further, we will briefly discuss additional peptides that target Lipid II such as the lantibiotic nisin and defensins. We will highlight recent developments and future perspectives. Keywords: antimicrobial peptides, Lipid II, bacterial cell wall, antibiotics
Innate immunity triggers responsible for viral control or hyperinflammation in COVID‐19 are largely unknown. Here we show that the SARS‐CoV‐2 spike protein (S‐protein) primes inflammasome formation ...and release of mature interleukin‐1β (IL‐1β) in macrophages derived from COVID‐19 patients but not in macrophages from healthy SARS‐CoV‐2 naïve individuals. Furthermore, longitudinal analyses reveal robust S‐protein‐driven inflammasome activation in macrophages isolated from convalescent COVID‐19 patients, which correlates with distinct epigenetic and gene expression signatures suggesting innate immune memory after recovery from COVID‐19. Importantly, we show that S‐protein‐driven IL‐1β secretion from patient‐derived macrophages requires non‐specific monocyte pre‐activation in vivo to trigger NLRP3‐inflammasome signaling. Our findings reveal that SARS‐CoV‐2 infection causes profound and long‐lived reprogramming of macrophages resulting in augmented immunogenicity of the SARS‐CoV‐2 S‐protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling.
SYNOPSIS
SARS‐CoV‐2 infection leads to hyperinflammatory syndromes in a subset of patients. We show that human primary macrophages require genome‐wide transcriptional modifications for pro‐inflammatory signaling upon stimulation with the SARS‐CoV‐2 surface glycoprotein (S‐protein).
The SARS‐CoV‐2 spike protein drives NRLP3 inflammasome activation in COVID‐19 patient derived macrophages.
Macrophages from SARS‐CoV‐2 naïve individuals fail to process and subsequently secrete IL‐1β upon stimulation with the S‐protein.
The S‐protein is a pathogen‐associated molecular pattern (PAMP) requiring macrophage pre‐activation for NLRP3 inflammasome formation.
Inflammasome activation and IL‐1β signaling represent attractive targets for pharmacological interventions in severe COVID‐19.
SARS‐CoV‐2 infection leads to hyperinflammatory syndromes in a subset of patients. We show that human primary macrophages require genome‐wide transcriptional modifications for pro‐inflammatory signaling upon stimulation with the SARS‐CoV‐2 surface glycoprotein (S‐protein).
Monoclonal antibodies (mAbs) are laboratory-produced molecules derived from the B cells of an infected host. They are being investigated as potential prophylaxis to prevent coronavirus disease 2019 ...(COVID-19).
To assess the effects of SARS-CoV-2-neutralising mAbs, including mAb fragments, to prevent infection with SARS-CoV-2 causing COVID-19; and to maintain the currency of the evidence, using a living systematic review approach.
We searched the Cochrane COVID-19 Study Register, MEDLINE, Embase, and three other databases on 27 April 2022. We checked references, searched citations, and contacted study authors to identify additional studies.
We included randomised controlled trials (RCTs) that evaluated SARS-CoV-2-neutralising mAbs, including mAb fragments, alone or combined, versus an active comparator, placebo, or no intervention, for pre-exposure prophylaxis (PrEP) and postexposure prophylaxis (PEP) of COVID-19. We excluded studies of SARS-CoV-2-neutralising mAbs to treat COVID-19, as these are part of another review.
Two review authors independently assessed search results, extracted data, and assessed risk of bias using Cochrane RoB 2. Prioritised outcomes were infection with SARS-CoV-2, development of clinical COVID-19 symptoms, all-cause mortality, admission to hospital, quality of life, adverse events (AEs), and serious adverse events (SAEs). We rated the certainty of evidence using GRADE.
We included four RCTs of 9749 participants who were previously uninfected and unvaccinated at baseline. Median age was 42 to 76 years. Around 20% to 77.5% of participants in the PrEP studies and 35% to 100% in the PEP studies had at least one risk factor for severe COVID-19. At baseline, 72.8% to 82.2% were SARS-CoV-2 antibody seronegative. We identified four ongoing studies, and two studies awaiting classification. Pre-exposure prophylaxis Tixagevimab/cilgavimab versus placebo One study evaluated tixagevimab/cilgavimab versus placebo in participants exposed to SARS-CoV-2 wild-type, Alpha, Beta, and Delta variant. About 39.3% of participants were censored for efficacy due to unblinding and 13.8% due to vaccination. Within six months, tixagevimab/cilgavimab probably decreases infection with SARS-CoV-2 (risk ratio (RR) 0.45, 95% confidence interval (CI) 0.29 to 0.70; 4685 participants; moderate-certainty evidence), decreases development of clinical COVID-19 symptoms (RR 0.18, 95% CI 0.09 to 0.35; 5172 participants; high-certainty evidence), and may decrease admission to hospital (RR 0.03, 95% CI 0 to 0.59; 5197 participants; low-certainty evidence). Tixagevimab/cilgavimab may result in little to no difference on mortality within six months, all-grade AEs, and SAEs (low-certainty evidence). Quality of life was not reported. Casirivimab/imdevimab versus placebo One study evaluated casirivimab/imdevimab versus placebo in participants who may have been exposed to SARS-CoV-2 wild-type, Alpha, and Delta variant. About 36.5% of participants opted for SARS-CoV-2 vaccination and had a mean of 66.1 days between last dose of intervention and vaccination. Within six months, casirivimab/imdevimab may decrease infection with SARS-CoV-2 (RR 0.01, 95% CI 0 to 0.14; 825 seronegative participants; low-certainty evidence) and may decrease development of clinical COVID-19 symptoms (RR 0.02, 95% CI 0 to 0.27; 969 participants; low-certainty evidence). We are uncertain whether casirivimab/imdevimab affects mortality regardless of the SARS-CoV-2 antibody serostatus. Casirivimab/imdevimab may increase all-grade AEs slightly (RR 1.14, 95% CI 0.98 to 1.31; 969 participants; low-certainty evidence). The evidence is very uncertain about the effects on grade 3 to 4 AEs and SAEs within six months. Admission to hospital and quality of life were not reported. Postexposure prophylaxis Bamlanivimab versus placebo One study evaluated bamlanivimab versus placebo in participants who may have been exposed to SARS-CoV-2 wild-type. Bamlanivimab probably decreases infection with SARS-CoV-2 versus placebo by day 29 (RR 0.76, 95% CI 0.59 to 0.98; 966 participants; moderate-certainty evidence), may result in little to no difference on all-cause mortality by day 60 (R 0.83, 95% CI 0.25 to 2.70; 966 participants; low-certainty evidence), may increase all-grade AEs by week eight (RR 1.12, 95% CI 0.86 to 1.46; 966 participants; low-certainty evidence), and may increase slightly SAEs (RR 1.46, 95% CI 0.73 to 2.91; 966 participants; low-certainty evidence). Development of clinical COVID-19 symptoms, admission to hospital within 30 days, and quality of life were not reported. Casirivimab/imdevimab versus placebo One study evaluated casirivimab/imdevimab versus placebo in participants who may have been exposed to SARS-CoV-2 wild-type, Alpha, and potentially, but less likely to Delta variant. Within 30 days, casirivimab/imdevimab decreases infection with SARS-CoV-2 (RR 0.34, 95% CI 0.23 to 0.48; 1505 participants; high-certainty evidence), development of clinical COVID-19 symptoms (broad-term definition) (RR 0.19, 95% CI 0.10 to 0.35; 1505 participants; high-certainty evidence), may result in little to no difference on mortality (RR 3.00, 95% CI 0.12 to 73.43; 1505 participants; low-certainty evidence), and may result in little to no difference in admission to hospital. Casirivimab/imdevimab may slightly decrease grade 3 to 4 AEs (RR 0.50, 95% CI 0.24 to 1.02; 2617 participants; low-certainty evidence), decreases all-grade AEs (RR 0.70, 95% CI 0.61 to 0.80; 2617 participants; high-certainty evidence), and may result in little to no difference on SAEs in participants regardless of SARS-CoV-2 antibody serostatus. Quality of life was not reported.
For PrEP, there is a decrease in development of clinical COVID-19 symptoms (high certainty), infection with SARS-CoV-2 (moderate certainty), and admission to hospital (low certainty) with tixagevimab/cilgavimab. There is low certainty of a decrease in infection with SARS-CoV-2, and development of clinical COVID-19 symptoms; and a higher rate for all-grade AEs with casirivimab/imdevimab. For PEP, there is moderate certainty of a decrease in infection with SARS-CoV-2 and low certainty for a higher rate for all-grade AEs with bamlanivimab. There is high certainty of a decrease in infection with SARS-CoV-2, development of clinical COVID-19 symptoms, and a higher rate for all-grade AEs with casirivimab/imdevimab. Although there is high-to-moderate certainty evidence for some outcomes, it is insufficient to draw meaningful conclusions. These findings only apply to people unvaccinated against COVID-19. They are only applicable to the variants prevailing during the study and not other variants (e.g. Omicron). In vitro, tixagevimab/cilgavimab is effective against Omicron, but there are no clinical data. Bamlanivimab and casirivimab/imdevimab are ineffective against Omicron in vitro. Further studies are needed and publication of four ongoing studies may resolve the uncertainties.
One of the purposes of outpatient treatment for COVID-19 patients is to prevent severe disease courses and hospitalization. There is a need for evidence-based recommendations to be applied in primary ...care and specialized outpatient settings.BACKGROUNDOne of the purposes of outpatient treatment for COVID-19 patients is to prevent severe disease courses and hospitalization. There is a need for evidence-based recommendations to be applied in primary care and specialized outpatient settings.This guideline was developed on the basis of publications that were retrieved by a systematic search for randomized controlled trials in the Cochrane COVID-19 trial registry. The quality of evidence was assessed with GRADE, and structured consensus generation was carried out with MAGICapp.METHODSThis guideline was developed on the basis of publications that were retrieved by a systematic search for randomized controlled trials in the Cochrane COVID-19 trial registry. The quality of evidence was assessed with GRADE, and structured consensus generation was carried out with MAGICapp.Unvaccinated COVID-19 outpatients with at least one risk factor for a severe disease course may be treated in the early phase of the disease with sotrovimab, remdesivir, or nirmatrelvir/ritonavir. Molnupiravir may also be used for such patients if no other clinically appropriate treatment options are available. Immunosuppressed persons with COVID-19 who are at high risk, and whose response to vaccination is expected to be reduced, ought to be treated with sotrovimab. It should be noted, however, that the clinical efficacy of sotrovimab against infections with the omicron subtype BA.2 is uncertain at the currently used dose, as the drug has displayed reduced activity against this subtype in vitro. COVID-19 patients at risk of a severe course may be offered budesonide inhalation, according to an off-label recommendation of the German College of General Practitioners and Family Physicians (other medical societies do not recommend either for or against this treatment). Thrombo - embolism prophylaxis with low-molecular-weight heparin may be given to elderly patients or those with a pre-existing illness. No recommendation is made concerning fluvoxamine or colchicine. Acetylsalicylic acid, azithromycin, ivermectin, systemic steroids, and vitamin D should not be used for the outpatient treatment of COVID-19.RESULTSUnvaccinated COVID-19 outpatients with at least one risk factor for a severe disease course may be treated in the early phase of the disease with sotrovimab, remdesivir, or nirmatrelvir/ritonavir. Molnupiravir may also be used for such patients if no other clinically appropriate treatment options are available. Immunosuppressed persons with COVID-19 who are at high risk, and whose response to vaccination is expected to be reduced, ought to be treated with sotrovimab. It should be noted, however, that the clinical efficacy of sotrovimab against infections with the omicron subtype BA.2 is uncertain at the currently used dose, as the drug has displayed reduced activity against this subtype in vitro. COVID-19 patients at risk of a severe course may be offered budesonide inhalation, according to an off-label recommendation of the German College of General Practitioners and Family Physicians (other medical societies do not recommend either for or against this treatment). Thrombo - embolism prophylaxis with low-molecular-weight heparin may be given to elderly patients or those with a pre-existing illness. No recommendation is made concerning fluvoxamine or colchicine. Acetylsalicylic acid, azithromycin, ivermectin, systemic steroids, and vitamin D should not be used for the outpatient treatment of COVID-19.Drug treatment is now available for outpatients with COVID-19 in the early phase. Nearly all of the relevant trials have been conducted in unvaccinated subjects; this needs to be kept in mind in patient selection.CONCLUSIONDrug treatment is now available for outpatients with COVID-19 in the early phase. Nearly all of the relevant trials have been conducted in unvaccinated subjects; this needs to be kept in mind in patient selection.
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