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

New England Journal of Medicine, Journal Year: 2022, Volume and Issue: 387(9), P. 790 - 798

Published: Aug. 24, 2022

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 effectiveness preventing disease 2019 (Covid-19) outcomes from B.1.1.529 (omicron) are limited.We obtained data for all members Clalit Health Services who were 40 years age or older at start study period and assessed as being eligible to receive therapy during omicron surge. A Cox proportional-hazards regression model time-dependent covariates was used estimate association treatment hospitalization death due Covid-19, adjustment sociodemographic factors, coexisting conditions, previous SARS-CoV-2 immunity status.A total 109,254 met eligibility criteria, whom 3902 (4%) received period. Among 65 older, rate Covid-19 14.7 cases per 100,000 person-days among treated compared 58.9 untreated (adjusted hazard ratio, 0.27; 95% confidence interval [CI], 0.15 0.49). adjusted ratio 0.21 (95% CI, 0.05 0.82). 64 age, 15.2 15.8 0.74; 0.35 1.58). 1.32 0.16 10.75).Among rates significantly lower those than did not. No evidence benefit found younger adults.

Language: Английский

---

Nirmatrelvir Plus Ritonavir: First Approval

Drugs, Journal Year: 2022, Volume and Issue: 82(5), P. 585 - 591

Published: March 19, 2022

Nirmatrelvir plus ritonavir (Paxlovid™; Pfizer) is a co-packaged combination of nirmatrelvir and tablets, intended for co-administration developed the treatment post-exposure prophylaxis coronavirus disease 2019 (COVID-19). peptidomimetic inhibitor severe acute respiratory syndrome 2 (SARS-CoV-2) main protease, while human immunodeficiency virus type 1 (HIV-1) protease CYP3A inhibitor. received its first conditional authorization in December 2021 United Kingdom, COVID-19 adults who do not require supplemental oxygen are at increased risk progression to COVID-19. In January 2022, EU use same indication. authorized emergency USA. This article summarizes milestones development leading authorizations approval

Language: Английский

---

Real-world effectiveness of early molnupiravir or nirmatrelvir–ritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's omicron BA.2 wave: a retrospective cohort study

The Lancet Infectious Diseases, Journal Year: 2022, Volume and Issue: 22(12), P. 1681 - 1693

Published: Aug. 24, 2022

Language: Английский

---

Monoclonal antibody therapies against SARS-CoV-2

The Lancet Infectious Diseases, Journal Year: 2022, Volume and Issue: 22(11), P. e311 - e326

Published: July 5, 2022

Language: Английский

---

A Detailed Overview of SARS-CoV-2 Omicron: Its Sub-Variants, Mutations and Pathophysiology, Clinical Characteristics, Immunological Landscape, Immune Escape, and Therapies

Viruses, Journal Year: 2023, Volume and Issue: 15(1), P. 167 - 167

Published: Jan. 5, 2023

The COVID-19 pandemic has created significant concern for everyone. Recent data from many worldwide reports suggest that most infections are caused by the Omicron variant and its sub-lineages, dominating all previously emerged variants. numerous mutations in Omicron’s viral genome sub-lineages attribute it a larger amount of fitness, owing to alteration transmission pathophysiology virus. With rapid change structure, sub-variants, namely BA.1, BA.2, BA.3, BA.4, BA.5, dominate community with an ability escape neutralization efficiency induced prior vaccination or infections. Similarly, several recombinant sub-variants Omicron, XBB, XBD, XBF, etc., have emerged, which better understanding. This review mainly entails changes due having higher number mutations. binding affinity, cellular entry, disease severity, infection rates, importantly, immune evading potential them discussed this review. A comparative analysis Delta other variants evolved before gives readers in-depth understanding landscape infection. Furthermore, discusses range abilities possessed approved antiviral therapeutic molecules neutralizing antibodies functional against sub-variants. evolution is causing infections, but broader aspect their not been explored. Thus, scientific should adopt elucidative approach obtain clear idea about recently including variants, so effective vaccines drugs can be achieved. This, turn, will lead drop cases and, finally, end pandemic.

Language: Английский

---

Omicron: What Makes the Latest SARS-CoV-2 Variant of Concern So Concerning?

Journal of Virology, Journal Year: 2022, Volume and Issue: 96(6)

Published: Feb. 28, 2022

Emerging strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent disease 2019 (COVID-19) pandemic, that show increased transmission fitness and/or immune evasion are classified as "variants concern" (VOCs). Recently, a SARS-CoV-2 variant first identified in November 2021 South Africa has been recognized fifth VOC, termed "Omicron." What makes this VOC so alarming is high number changes, especially viral Spike protein, and accumulating evidence for efficiency escape from neutralizing antibodies. In an amazingly short time, Omicron outcompeted previously dominating Delta VOC. However, it seems overall less pathogenic than other VOCs. Here, we provide overview mutations genome resulting changes proteins compared to discuss their potential functional consequences.

Language: Английский

---

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

Journal of Biological Chemistry, Journal Year: 2022, Volume and Issue: 298(6), P. 101972 - 101972

Published: April 22, 2022

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

Language: Английский

---

The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir

mBio, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 10, 2023

The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for treatment of COVID-19. potential 3CLpro-inhibitors to select drug-resistant variants needs be established. Therefore, was passaged vitro presence increasing concentrations ALG-097161, probe compound designed context 3CLpro drug discovery program. We identified combination amino acid substitutions (L50F E166A L167F) that associated with >20× increase 50% effective concentration (EC50) values nirmatrelvir (PF-07321332), PF-00835231, ensitrelvir. While two single (E166A provide low-level resistance inhibitors biochemical assay, triple mutant results highest levels (6× 72×). All are significant loss enzymatic activity, suggesting reduction fitness. Structural biology analysis indicates different reduce number inhibitor/enzyme interactions while binding substrate maintained. These observations will important interpretation development clinical setting. IMPORTANCE Paxlovid first oral antiviral approved infection. Antiviral treatments often viruses. In order guide use novel antivirals, it essential understand risk characterize changes genes proteins. this work, we describe time pathway allows develop against vitro. characteristics may predictive situation. our work management COVID-19 next-generation inhibitors.

Language: Английский

---

The P132H mutation in the main protease of Omicron SARS-CoV-2 decreases thermal stability without compromising catalysis or small-molecule drug inhibition

Cell Research, Journal Year: 2022, Volume and Issue: 32(5), P. 498 - 500

Published: March 15, 2022

Language: Английский

---

Molecular characteristics, immune evasion, and impact of SARS-CoV-2 variants

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 28, 2022

Abstract The persistent COVID-19 pandemic since 2020 has brought an enormous public health burden to the global society and is accompanied by various evolution of virus genome. consistently emerging SARS-CoV-2 variants harboring critical mutations impact molecular characteristics viral proteins display heterogeneous behaviors in immune evasion, transmissibility, clinical manifestation during infection, which differ each strain endow them with distinguished features populational spread. Several variants, identified as Variants Concern (VOC) World Health Organization, challenged efforts on control due rapid worldwide spread enhanced evasion from current antibodies vaccines. Moreover, recent Omicron variant even exacerbated anxiety continuous pandemic. Its significant medical treatment disease highlights necessity combinatory investigation mutational pattern influence dynamics against immunity, would greatly facilitate drug vaccine development benefit policymaking. Hence this review, we summarized characteristics, impacts focused parallel comparison different profile, transmissibility tropism alteration, effectiveness, manifestations, order provide a comprehensive landscape for research.

Language: Английский

---