COVID-19 Therapeutics Research Articles

Providing COVID-19 Therapeutics and Clinical Guidance in Skilled Nursing Facilities

Providing COVID-19 Therapeutics and Clinical Guidance in Skilled Nursing Facilities

Novel insights into minipuberty and GnRH: Implications on neurodevelopment, cognition, and COVID-19 therapeutics.

In humans, the first 1000 days of life are pivotal for brain and organism development. Shortly after birth, gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus are activated, a phenomenon known as minipuberty. This phenomenon, observed in all mammals studied, influences the postnatal development of the hypothalamic-pituitary-gonadal (HPG) axis and reproductive function. This review will put into perspective the results of recent studies showing that the impact of minipuberty extends beyond reproductive function, influencing sensory and cognitive maturation. Studies in mice have revealed the role of nitric oxide (NO) in regulating minipuberty amplitude, with NO deficiency linked to cognitive and olfactory deficits. Additionally, findings indicate that cognitive and sensory defects in adulthood in a mouse model of Down syndrome are associated with an age-dependent decline of GnRH production, whose origin can be traced back to minipuberty, and point to the potential therapeutic role of pulsatile GnRH administration in cognitive disorders. Furthermore, this review delves into the repercussions of COVID-19 on GnRH production, emphasizing potential consequences for neurodevelopment and cognitive function in infected individuals. Notably, GnRH neurons appear susceptible to SARS-CoV-2 infection, raising concerns about potential long-term effects on brain development and function. In conclusion, the intricate interplay between GnRH neurons, GnRH release, and the activity of various extrahypothalamic brain circuits reveals an unexpected role for these neuroendocrine neurons in the development and maintenance of sensory and cognitive functions, supplementing their established function in reproduction. Therapeutic interventions targeting the HPG axis, such as inhaled NO therapy in infancy and pulsatile GnRH administration in adults, emerge as promising approaches for addressing neurodevelopmental cognitive disorders and pathological aging.

Inhalation of ACE2-expressing lung exosomes provides prophylactic protection against SARS-CoV-2

Continued emergence of SARS-CoV-2 variants of concern that are capable of escaping vaccine-induced immunity highlights the urgency of developing new COVID-19 therapeutics. An essential mechanism for SARS-CoV-2 infection begins with the viral spike protein binding to the human ACE2. Consequently, inhibiting this interaction becomes a highly promising therapeutic strategy against COVID-19. Herein, we demonstrate that ACE2-expressing human lung spheroid cells (LSC)-derived exosomes (LSC-Exo) could function as a prophylactic agent to bind and neutralize SARS-CoV-2, protecting the host against SARS-CoV-2 infection. Inhalation of LSC-Exo facilitates its deposition and biodistribution throughout the whole lung in a female mouse model. We show that LSC-Exo blocks the interaction of SARS-CoV-2 with host cells in vitro and in vivo by neutralizing the virus. LSC-Exo treatment protects hamsters from SARS-CoV-2-induced disease and reduced viral loads. Furthermore, LSC-Exo intercepts the entry of multiple SARS-CoV-2 variant pseudoviruses in female mice and shows comparable or equal potency against the wild-type strain, demonstrating that LSC-Exo may act as a broad-spectrum protectant against existing and emerging virus variants.

Mitoquinone mesylate as post-exposure prophylaxis against SARS-CoV-2 infection in humans: an exploratory single center pragmatic open label non-randomized pilot clinical trial with matched controls

An ongoing important need exists to rapidly develop novel therapeutics for COVID-19 that will retain antiviral efficacy in the setting of rapidly evolving SARS-CoV-2 variants and potential future development of resistance of SARS-COV-2 to remdesivir and protease inhibitors. To date, there is no FDA-approved treatment for post-exposure prophylaxis against SAR-CoV-2. We have shown that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has antiviral activity against SARS-CoV-2 invitro and in SARS-CoV-2 infected K18-hACE2 mice. In this exploratory, pragmatic open label clinical trial (ClinicalTrials.gov identifier NCT05381454), we studied whether Mito-MES is an effective post-exposure prophylaxis treatment in people who had high-grade unmasked exposures to SARS-CoV-2 within 5 days prior to study entry. Participants were enrolled in real-world setting in Los Angeles, United States between May 1 and December 1, 2022 and were assigned to either mito-MES 20mg daily for 14 days (n=40) or no mito-MES (controls) (n=40). The primary endpoint was development of SARS-CoV-2 infection based on 4 COVID-19 diagnostic tests [rapid antigen tests (RATs) or PCR] performed during the study period (14 days post exposure). Out of 40 (23 females; 57.5%) study participants who took Mito-MES, 12 (30%) developed SARS-CoV-2 infection compared to 30 of the 40 controls (75%) (difference-45.0%, 95% confidence intervals (CI):-64.5%,-25.5%). Out of 40 (19 females; 47.5%) study participants in the control group, 30 (75.0%) had at least one positive COVID-19 diagnostic test and 23 (57.5%) were symptomatic. With regards to key secondary outcomes, among symptomatic SARS-CoV-2 infections, the median duration of viral symptoms was lower in the Mito-MES group (median 3.0, 95% CI 2.75, 3.25) compared to the control group (median 5.0, 95% CI 4.0, 7.0). None of the study participants was hospitalized or required oxygen therapy. Mito-MES was well tolerated and no serious side effect was reported in any study participant. This work describes antiviral activity of mito-MES in humans. Mito-MES was well tolerated in our study population and attenuated transmission of SARS-CoV-2 infection. Given established safety of Mito-MES in humans, our results suggest that randomized control clinical trials of Mito-MES as post-exposure prophylaxis against SARS-CoV-2 infection are warranted. This work was supported in part by National Institutes of Health grant R01AG059501 (TK), National Institutes of Health grant R01AG059502 04S1 (TK), NIH/National Center for Advancing Translational Sciences (NCATS) UCLA CTSI Grant Number UL1TR001881 and California HIV/AIDS Research Program grant OS17-LA-002 (TK).

A Dual Pharmacological Strategy against COVID-19: The Therapeutic Potential of Metformin and Atorvastatin.

Metformin (MET) and atorvastatin (ATO) are promising treatments for COVID-19. This review explores the potential of MET and ATO, commonly prescribed for diabetes and dyslipidemia, respectively, as versatile medicines against SARS-CoV-2. Due to their immunomodulatory and antiviral capabilities, as well as their cost-effectiveness and ubiquitous availability, they are highly suitable options for treating the virus. MET's effect extends beyond managing blood sugar, impacting pathways that can potentially decrease the severity and fatality rates linked with COVID-19. It can partially block mitochondrial complex I and stimulate AMPK, which indicates that it can be used more widely in managing viral infections. ATO, however, impacts cholesterol metabolism, a crucial element of the viral replicative cycle, and demonstrates anti-inflammatory characteristics that could modulate intense immune reactions in individuals with COVID-19. Retrospective investigations and clinical trials show decreased hospitalizations, severity, and mortality rates in patients receiving these medications. Nevertheless, the journey from observing something to applying it in a therapeutic setting is intricate, and the inherent diversity of the data necessitates carefully executed, forward-looking clinical trials. This review highlights the requirement for efficacious, easily obtainable, and secure COVID-19 therapeutics and identifies MET and ATO as promising treatments in this worldwide health emergency.

Development of Mouse Hepatitis Virus Chimeric Reporter Viruses Expressing the 3CLpro Proteases of Human Coronaviruses HKU1 and OC43 Reveals Susceptibility to Inactivation by Natural Inhibitors Baicalin and Baicalein

The recent emergence of SARS-CoV-2 in 2019 has highlighted the necessity of antiviral therapeutics for current and future emerging coronaviruses. Recently, the traditional herbal medicines baicalein, baicalin, and andrographolide have shown inhibition against the main protease of SARS-CoV-2. This provides a promising new direction for COVID-19 therapeutics, but it remains unknown whether these three substances inhibit other human coronaviruses. In this study, we describe the development of novel chimeric mouse hepatitis virus (MHV) reporters that express firefly luciferase (FFL) and the 3CLpro proteases of human coronaviruses HKU1 and OC43. These chimeric viruses were used to determine if the phytochemicals baicalein, baicalin, and andrographolide are inhibitory against human coronavirus strains HKU1 and OC43. Our data show that both baicalein and baicalin exhibit inhibition towards the chimeric MHV strains. However, andrographolide induces cytotoxicity and failed to demonstrate selective toxicity towards the viruses. This study reports the development and use of a safe replicating reporter platform to investigate potential coronavirus 3CLpro inhibitors against common-cold human coronavirus strains HKU1 and OC43.

Neutralization of SARS-CoV-2 and Intranasal Protection of Mice with a nanoCLAMP Antibody Mimetic.

Intranasal treatment, combined with vaccination, has the potential to slow mutational evolution of viruses by reducing transmission and replication. Here, we illustrate the development of a SARS-CoV-2 receptor-binding domain (RBD) nanoCLAMP and demonstrate its potential as an intranasally administered therapeutic. A multi-epitope nanoCLAMP was made by fusing a pM affinity single-domain nanoCLAMP (P2710) to alternate epitope-binding nanoCLAMP, P2609. The resulting multimerized nanoCLAMP P2712 had sub-pM affinity for the Wuhan and South African (B.1.351) RBD (KD < 1 pM) and decreasing affinity for the Delta (B.1.617.2) and Omicron (B.1.1.529) variants (86 pM and 19.7 nM, respectively). P2712 potently inhibited the ACE2:RBD interaction, suggesting its utility as a therapeutic. With an IC50 = 0.4 ± 0.1 nM obtained from neutralization experiments using pseudoviral particles, nanoCLAMP P2712 protected K18-hACE2 mice from SARS-CoV-2 infection, reduced viral loads in the lungs and brains, and reduced associated upregulation of inflammatory cytokines and chemokines. Together, our findings warrant further investigation into the development of nanoCLAMPs as effective intranasally delivered COVID-19 therapeutics.

Discovery and development of COVID-19 vaccines and therapeutics: nonclinical perspectives.

The development and regulatory review of BNT162b2, a COVID-19 vaccine, and PaxlovidTM (nirmatrelvir tablets/ritonavir tablets), a COVID-19 therapeutic, are benchmarks for accelerated innovation during a global pandemic. Rapid choice of the SARS-CoV-2 spike protein and main protease (Mpro) as targets for the vaccine and therapeutic, respectively, leveraged the available knowledge of the biology of SARS-CoV-2 and related viruses. The nonclinical immunogenicity and safety of BNT162b2 was rigorously assessed. Likewise, a comprehensive nonclinical safety assessment was conducted for the therapeutic candidates, lufotrelvir (PF-07304814) and nirmatrelvir (PF-07321332). The development and regulatory review of BNT162b2 and Paxlovid was enabled through close collaboration of the pharmaceutical industry with regulatory agencies and public health organizations. This experience highlights approaches that could be adopted for pandemic preparedness including risk-based investment strategies, conduct of activities in parallel that normally are conducted sequentially, quick kill decisions, simultaneous evaluation of multiple candidates, and use of flexible, established vaccine platforms.

Validity of Routine Health Data To Identify Safety Outcomes of Interest For Covid-19 Vaccines and Therapeutics in the Context of the Emerging Pandemic: A Comprehensive Literature Review.

Regulatory guidance encourages transparent reporting of information on the quality and validity of electronic health record data being used to generate real-world benefit-risk evidence for vaccines and therapeutics. We aimed to provide an overview of the availability of validated diagnostic algorithms for selected safety endpoints for Coronavirus disease 2019 (COVID-19) vaccines and therapeutics in the context of the emerging pandemic prior to December 2020. We reviewed the literature up to December 2020 to identify validation studies for various safety events of interest, including myocardial infarction, arrhythmia, myocarditis, acute cardiac injury, vasculitis/vasculopathy, venous thromboembolism, stroke, respiratory distress syndrome (RDS), pneumonitis, cytokine release syndrome (CRS), multiple organ dysfunction syndrome, and renal failure. We included studies published between 2015 and 2020 that were considered high quality assessed with QUADAS and that reported positive predictive values (PPVs). Out of 43 identified studies, we found that diagnostic algorithms for cardiovascular outcomes were supported by the highest number of validation studies (n=17). Accurate algorithms are available for myocardial infarction (median PPV 80%; IQR 22%), arrhythmia (PPV range >70%), venous thromboembolism (median PPV: 73%) and ischaemic stroke (PPV range ≥85%). We found a lack of validation studies for less common respiratory and cardiac safety outcomes of interest (eg, pneumonitis and myocarditis), as well as for COVID-specific complications (CRS, RDS). There is a need for better understanding of barriers to conducting validation studies, including data governance restrictions. Regulatory guidance should promote embedding validation within real-world EHR research used for decision-making.

TRIPS Waiver Decision for Equitable Access to Medical Countermeasures in the Pandemic: COVID-19 Diagnostics and Therapeutics

TRIPS Waiver Decision for Equitable Access to Medical Countermeasures in the Pandemic: COVID-19 Diagnostics and Therapeutics

Engaging communities in therapeutics clinical research during pandemics: Experiences and lessons from the ACTIV COVID-19 therapeutics research initiative

Abstract This manuscript addresses a critical topic: navigating complexities of conducting clinical trials during a pandemic. Central to this discussion is engaging communities to ensure diverse participation. The manuscript elucidates deliberate strategies employed to recruit minority communities with poor social drivers of health for participation in COVID-19 trials. The paper adopts a descriptive approach, eschewing analysis of data-driven efficacy of these efforts, and instead provides a comprehensive account of strategies utilized. The Accelerate COVID-19 Treatment Interventions and Vaccines (ACTIV) public–private partnership launched early in the COVID-19 pandemic to develop clinical trials to advance SARS-CoV-2 treatments. In this paper, ACTIV investigators share challenges in conducting research during an evolving pandemic and approaches selected to engage communities when traditional strategies were infeasible. Lessons from this experience include importance of community representatives’ involvement early in study design and implementation and integration of well-developed public outreach and communication strategies with trial launch. Centralization and coordination of outreach will allow for efficient use of resources and the sharing of best practices. Insights gleaned from the ACTIV program, as outlined in this paper, shed light on effective strategies for involving communities in treatment trials amidst rapidly evolving public health emergencies. This underscores critical importance of community engagement initiatives well in advance of the pandemic.

Identification of lead inhibitors for 3CLpro of SARS-CoV-2 target using machine learning based virtual screening, ADMET analysis, molecular docking and molecular dynamics simulations.

The SARS-CoV-2 3CLpro is a critical target for COVID-19 therapeutics due to its role in viral replication. We employed a screening pipeline to identify novel inhibitors by combining machine learning classification with similarity checks of approved medications. A voting classifier, integrating three machine learning classifiers, was used to filter a large database (∼10 million compounds) for potential inhibitors. This ensemble-based machine learning technique enhances overall performance and robustness compared to individual classifiers. From the screening, three compounds M1, M2 and M3 were selected for further analysis. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis compared these candidates to nirmatrelvir and azvudine. Molecular docking followed by 200 ns MD simulations showed that only M1 (6-[2,4-bis(dimethylamino)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carbonyl]-1H-pyrimidine-2,4-dione) remained stable. For azvudine and M1, the estimated median lethal doses are 1000 and 550 mg kg-1, respectively, with maximum tolerated doses of 0.289 and 0.614 log mg per kg per day. The predicted inhibitory activity of M1 is 7.35, similar to that of nirmatrelvir. The binding free energy based on Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) of M1 is -18.86 ± 4.38 kcal mol-1, indicating strong binding interactions. These findings suggest that M1 merits further investigation as a potential SARS-CoV-2 treatment.

Australia and New Zealand consensus position statement: use of COVID-19 therapeutics in patients with haematological malignancies.

Despite widespread vaccination rates, we are living with high transmission rates of SARS-CoV-2. Although overall hospitalisation rates are falling, the risk of serious infection remains high for patients who are immunocompromised because of haematological malignancies. In light of the ongoing pandemic and the development of multiple agents for treatment, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 management in patients with haematological disorders. It is our recommendation that both patients with haematological malignancies and treating specialists be educated regarding the preventive and treatment options available and that patients continue to receive adequate vaccinations, keeping in mind the suboptimal vaccine responses that occur in haematology patients, in particular, those with B-cell malignancies and on B-cell-targeting or depleting therapy. Patients with haematological malignancies should receive treatment for COVID-19 in accordance with the severity of their symptoms, but even mild infections should prompt early treatment with antiviral agents. The issue of de-isolation following COVID-19 infection and optimal time to treatment for haematological malignancies is discussed but remains an area with evolving data. This position statement is to be used in conjunction with advice from infectious disease, respiratory and intensive care specialists, and current guidelines from the National COVID-19 Clinical Evidence Taskforce and the New Zealand Ministry of Health and Cancer Agency Te Aho o Te Kahu COVID-19 Guidelines.

Using TransR to enhance drug repurposing knowledge graph for COVID-19 and its complications

MotivationThe COVID-19 pandemic has been spreading globally for four years, yet specific drugs that effectively suppress the virus remain elusive. Furthermore, the emergence of complications associated with COVID-19 presents significant challenges, making the development of therapeutics for COVID-19 and its complications an urgent task. However, traditional drug development processes are time-consuming. Drug repurposing, which involves identifying new therapeutic applications for existing drugs, presents a viable alternative. ResultIn this study, we construct a knowledge graph by retrieving information on genes, drugs, and diseases from databases such as DRUGBANK and GNBR. Next, we employ the TransR knowledge representation learning approach to embed entities and relationships into the knowledge graph. Subsequently, we train the knowledge graph using a graph neural network model based on TransR scoring. This trained knowledge graph is then utilized to predict drugs for the treatment of COVID-19 and its complications. Based on experimental results, we have identified 15 drugs out of the top 30 with the highest success rates associated with treating COVID-19 and its complications. Notably, out of these 15 drugs, 10 specifically aimed at treating COVID-19, such as Torcetrapib and Tocopherol, has not been previously identified in the knowledge graph. This finding highlights the potential of our model in aiding healthcare professionals in drug development and research related to this disease.

Confidence score: a data-driven measure for inclusive systematic reviews considering unpublished preprints.

COVID-19, since its emergence in December 2019, has globally impacted research. Over 360000 COVID-19-related manuscripts have been published on PubMed and preprint servers like medRxiv and bioRxiv, with preprints comprising about 15% of all manuscripts. Yet, the role and impact of preprints on COVID-19 research and evidence synthesis remain uncertain. We propose a novel data-driven method for assigning weights to individual preprints in systematic reviews and meta-analyses. This weight termed the "confidence score" is obtained using the survival cure model, also known as the survival mixture model, which takes into account the time elapsed between posting and publication of a preprint, as well as metadata such as the number of first 2-week citations, sample size, and study type. Using 146 preprints on COVID-19 therapeutics posted from the beginning of the pandemic through April 30, 2021, we validated the confidence scores, showing an area under the curve of 0.95 (95% CI, 0.92-0.98). Through a use case on the effectiveness of hydroxychloroquine, we demonstrated how these scores can be incorporated practically into meta-analyses to properly weigh preprints. It is important to note that our method does not aim to replace existing measures of study quality but rather serves as a supplementary measure that overcomes some limitations of current approaches. Our proposed confidence score has the potential to improve systematic reviews of evidence related to COVID-19 and other clinical conditions by providing a data-driven approach to including unpublished manuscripts.

Disparate viral pandemics from COVID19 to monkeypox and beyond: a simple, effective and universal therapeutic approach hiding in plain sight.

The field of antiviral therapeutics is fixated on COVID19 and rightly so as the fatalities at the height of the pandemic in the United States were almost 1,000,000 in a twelve month period spanning parts of 2020/2021.A coronavirus called SARS-CoV2 is the causative virus. Development of a vaccine through molecular biology approaches with mRNA as the inducer of virus spike protein has played a major role in driving down mortality and morbidity. Antivirals have been of marginal value in established infections at the level of hospitalization. Thus, the current focus is on early symptomatic infection of about the first five days. The Pfizer drug paxlovid which is composed of nirmatrelvir, a peptidomimetic protease inhibitor of SARS-CoV2 Mpro enzyme, and ritonavir to retard degradation of nirmatrelvir, is the current FDA recommended treatment of early COVID19. There is no evidence of broad antiviral activity of paxlovid against other diverse viruses such as the influenza virus, poxviruses, as well as a host of respiratory viruses. Although type I interferons (IFNs) are effective against SARS-CoV2 in cell cultures and in early COVID19 infections, they have not been broadly recommended as therapeutics for COVID19. We have developed stable peptidomimetics of both types I and II IFNs based on our noncanonical model of IFN signaling involving the C-terminus of the IFNs. We have also identified two members of intracellular checkpoint inhibitors called suppressors of cytokine signaling (SOCS), SOCS1 and SOCS3 (SOCS1/3), and shown that they are virus induced intrinsic virulence proteins with activity against IFN signaling enzymes JAK2 and TYK2. We developed a peptidomimetic antagonist, based on JAK2 activation loop, against SOCS1/3 and showed that it synergizes with the IFN mimetics for potent broad spectrum antiviral activity without the toxicity of intact IFN molecules. IFN mimetics and the SOCS1/3 antagonist should have an advantage over currently used antivirals in terms of safety and potency against a broad spectrum of viruses.

Advancement of Computational Design Drug Delivery System in COVID-19: Current Updates and Future Crosstalk- A Critical update.

Positive strides have been achieved in developing vaccines to combat the coronavirus-2019 infection (COVID-19) pandemic. Still, the outline of variations, particularly the most current delta divergent, has posed significant health encounters for people. Therefore, developing strong treatment strategies, such as an anti-COVID-19 medicine plan, may help deal with the pandemic more effectively. During the COVID-19 pandemic, some drug design techniques were effectively used to develop and substantiate relevant critical medications. Extensive research, both experimental and computational, has been dedicated to comprehending and characterizing the devastating COVID-19 disease. The urgency of the situation has led to the publication of over 130,000 COVID-19-related research papers in peer-reviewed journals and preprint servers. A significant focus of these efforts has been the identification of novel drug candidates and the repurposing of existing drugs to combat the virus. Many projects have utilized computational or computer-aided approaches to facilitate their studies. In this overview, we will explore the key computational methods and their applications in the discovery of small-molecule therapeutics for COVID-19, as reported in the research literature. We believe that the true effectiveness of computational tools lies in their ability to provide actionable and experimentally testable hypotheses, which in turn facilitate the discovery of new drugs and combinations thereof. Additionally, we recognize that open science and the rapid sharing of research findings are vital in expediting the development of much-needed therapeutics for COVID-19.

Risk of Severe Sars-Cov-2 Infections in COVID-19 Vaccinated Individuals with Hematologic Malignancies (SAVE HEM): A Nationwide Cohort Study in the Netherlands

Introduction COVID-19 vaccination protects against a severe course of COVID-19. Nevertheless, individuals with hematologic malignancies (HM) remain at increased risk of COVID-19-related morbidity and mortality compared to the general population. However, these relative risks are unknown for individuals with specific hematologic cancers and treatments. We aimed to quantify the risk of severe COVID-19 among individuals with HM who had completed primary COVID-19 vaccination (i.e., two-dose generally, but three-dose in patients with a malignancy history). Therefore, we compared COVID-19 outcomes to those in individuals with no malignancy (NM) and individuals with solid malignancies (SM) who had completed primary COVID-19 vaccination. Thanks to unique centrally registered data on cancer care (Netherlands Cancer Registry, NCR), we were able to stratify risk for different hematologic malignancies. Methods We conducted a nationwide cohort study including all inhabitants of the Netherlands registered in the Personal Records Database on January 1, 2020, (n = 17 407 585) through linkage of data on cancer care, COVID-19 vaccination, SARS-CoV-2 testing, COVID-19-related hospitalization, and mortality. We used data from January 1, 2010, to December 31, 2022. We included individuals who completed primary COVID-19 vaccination at age 18 years or older and were SARS-CoV-2-infected more than two weeks later. Severe disease was defined as a SARS-CoV-2 infection resulting in hospital admission or death. We fitted generalized estimating equations and calculated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the associations between an HM history and severe COVID-19, relative to a history with NM and SM. In addition, we calculated aORs for associations between malignancy history and COVID-19-related hospital admission, ICU admission, and mortality. Odds ratios were adjusted for age and sex as potential confounders. We conducted stratified analyses by type of hematologic malignancy and incidence period of SARS-CoV-2 infection. For technical reasons, we calculated aORs using a random sample of 350 000 SARS-CoV-2-infected individuals from the NM group. Results We included 8 210 individuals with HM, 350 000 individuals with NM, and 37 752 individuals with SM. We observed 8 552, 364 530, and 38 432 SARS-CoV-2 infections in individuals with HM, NM, and SM, respectively. Severe COVID-19 was recorded in 817, 2 834 and 1 412 cases, respectively. Individuals with HM were at higher risk of severe COVID-19 compared to individuals with NM and SM (aOR [95% CI] for HM vs. NM 4.6 [4.2-5.0]; for HM vs. SM 3.3 [3.0-3.7]) (Figure 1). Patients with HM were at increased risk for COVID-19-related hospitalization (aOR [95% CI] for HM vs. NM 4.6 [4.3-5.1]; for HM vs. SM 3.4 [3.1-3.7]), for COVID-19-related ICU admission (aOR [95% CI] for HM vs. NM 6.5 [5.0-8.4]; for HM vs. SM 6.3 [4.6-8.6]), and for COVID-19-related mortality (aOR [95% CI] for HM vs. NM 1.7 [0.9-3.0]; for HM vs. SM 1.9 [1.0-3.7]). Within the group of HM, those with a diagnosis of acute lymphatic leukemia/lymphoblastic lymphoma or acute myeloid leukemia were at the highest risk of severe COVID-19 compared to individuals with NM, while those with myeloproliferative malignancies or cutaneous lymphomas had the lowest risk (Figure 1). Stratified analyses by incidence period of SARS-CoV-2 infection demonstrated that the aORs for severe COVID-19 remained increased over time, comparing individuals with HM to those with NM. Adjustments for other confounders, such as socio-economic status, and stratified analyses by incidence year of malignancy, immunosuppressive treatment, and number of booster vaccinations are currently being performed. Conclusions Despite intensified COVID-19 vaccination, individuals with HM remain at increased risk for a severe course of COVID-19 compared to both individuals with NM and SM. However, the degree of vulnerability within the hematologic population depends on type of malignancy and this should be taken into account when offering additional booster vaccinations or scarce COVID-19 therapeutics, such as protease inhibitors or antibody-based therapy.

2273. Azithromycin Use Before and During COVID- 19 and Impact of Implementing Evidence-based Guidelines

Abstract Background Early in the COVID-19 pandemic, results from small uncontrolled studies led to azithromycin being proposed as an effective treatment in patients with COVID-19. Numerous subsequent randomized controlled trials and observational studies have failed to demonstrate azithromycin’s effectiveness in COVID-19. The magnitude of azithromycin overuse, particularly for COVID-19 remains undocumented. We sought to quantify the use of azithromycin before and during the COVID-19 pandemic in a national healthcare system where specific evidence-based guidelines were rapidly implemented for judicious use of various suggested COVID-19 treatments. Methods The study was conducted at Hamad Medical Corporation in Qatar, which was the single provider of inpatient care for COVID-19 in Qatar. Evidence-based guidelines were implemented in Qatar for use of azithromycin in June 2020. For our study, all azithromycin prescriptions between 2019-2022 were retrieved from the electronic medical records. Number of azithromycin courses prescribed, and rate/100,000 population were calculated and compared over time. A course was defined as any azithromycin prescription with no gap of &amp;gt; 10 days. A course was deemed related to COVID-19 if written within -3 to +10 days of a positive SARS-CoV-2 PCR. A one-way repeated measured analysis of variance was conducted to evaluate the null hypothesis that there was no change in azithromycin use before and during COVID-19. Results During the study period, a total of 203,806 azithromycin courses were prescribed for 166,062 individuals. Overall number of courses increased in the first 2 quarters of 2020 (average 12,857/quarter in 2019 to average of 19,297 in Q1-Q2 of 2020) and then dropped precipitously to 9,881/quarter over the next 6 quarters. COVID-19 related azithromycin courses peaked in 2020-Q2 (13,691) and dropped subsequently to 2,836 for 2020-Q3, 1,410 for 2020-Q4; 5,465 for 2021-Q1, and 4,288 for 2021-Q2. Stringent evidence-based guidelines implemented in June 2020 for use of various COVID-19 therapeutics coincided with the rapid drop in azithromycin use for COVID-19. Conclusion While azithromycin prescriptions increased immediately after the COVID-19 pandemic, a rapid decline was observed immediately after implementing evidence-based guidelines Disclosures Adeel A. Butt, MBBS, MS, Gilead Sciences: Grant/Research Support|Merck and Company: Grant/Research Support

COVID-19 therapeutics: stewardship in England and considerations for antimicrobial resistance.

The COVID-19 pandemic saw unprecedented resources and funds driven into research for the development, and subsequent rapid distribution, of vaccines, diagnostics and directly acting antivirals (DAAs). DAAs have undeniably prevented progression and life-threatening conditions in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, there are concerns of antimicrobial resistance (AMR), antiviral resistance specifically, for DAAs. To preserve activity of DAAs for COVID-19 therapy, as well as detect possible mutations conferring resistance, antimicrobial stewardship and surveillance were rapidly implemented in England. This paper expands on the ubiquitous ongoing public health activities carried out in England, including epidemiologic, virologic and genomic surveillance, to support the stewardship of DAAs and assess the deployment, safety, effectiveness and resistance potential of these novel and repurposed therapeutics.