Therapeutics for COVID-19

Nature Microbiology, Journal Year: 2023, Volume and Issue: 8(5), P. 771 - 786

Published: May 4, 2023

Vaccines and monoclonal antibody treatments to prevent severe coronavirus disease 2019 (COVID-19) illness were available within a year of the pandemic being declared but there remained an urgent need for therapeutics treat patients who not vaccinated, immunocompromised or whose vaccine immunity had waned. Initial results investigational therapies mixed. AT-527, repurposed nucleoside inhibitor hepatitis C virus, enabled viral load reduction in hospitalized cohort did reduce outpatients. The molnupiravir prevented death failed hospitalization. Nirmatrelvir, main protease (Mpro), co-dosed with pharmacokinetic booster ritonavir, reduced hospitalization death. Nirmatrelvir–ritonavir received Emergency Use Authorization United States at end 2021. Immunomodulatory drugs such as baricitinib, tocilizumab corticosteroid, which target host-driven COVID-19 symptoms, are also use. We highlight development challenges that remain anticoronavirals. Therapeutics their during reviewed, including future prospects

Language: Английский

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SARS-CoV-2 viral clearance and evolution varies by type and severity of immunodeficiency

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(731)

Published: Jan. 24, 2024

Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the immune defects that predispose an individual to persistent disease 2019 (COVID-19) remain incompletely understood. In this study, we performed detailed viro-immunologic analyses of a prospective cohort participants with COVID-19. The median times nasal viral RNA culture clearance in immunosuppression due hematologic malignancy or transplant (S-HT) were 72 40 days, respectively, both which significantly longer than rates autoimmunity B cell deficiency (S-A), nonsevere immunodeficiency, nonimmunocompromised groups ( P < 0.01). Participants who severely had greater SARS-CoV-2 evolution higher developing resistance against therapeutic monoclonal antibodies. Both S-HT S-A diminished SARS-CoV-2–specific humoral responses, whereas only group reduced T cell–mediated responses. This highlights varied COVID-19 across distinct immunosuppressive conditions suggests suppression responses results highest contributing infection.

Language: Английский

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SARS-CoV-2 Virologic Rebound With Nirmatrelvir–Ritonavir Therapy

Annals of Internal Medicine, Journal Year: 2023, Volume and Issue: 176(12), P. 1577 - 1585

Published: Nov. 13, 2023

Background: Data are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir−ritonavir (N-R) and virologic rebound (VR). Objective: To compare the frequency VR in patients without N-R for COVID-19. Design: Observational cohort study. Setting: Multicenter health care system Boston, Massachusetts. Participants: Ambulatory adults use N-R. Intervention: Receipt 5 days versus no therapy. Measurements: The primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after prior negative or 2 consecutive loads above 4.0 log10 copies/mL that were also at least 1.0 higher than load below copies/mL. Results: Compared untreated persons (n = 55), those taking 72) older, received more vaccinations, commonly had immunosuppression. Fifteen participants (20.8%) 1 (1.8%) who (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 points]; P 0.001). All result. In multivariable models, only associated (adjusted odds ratio, 10.02 [CI, 1.13 88.74]; 0.038). Virologic common among started therapy within symptom onset (26.3%) (0%) (P 0.030). Among receiving N-R, prolonged shedding replication-competent virus compared did not have (median, 14 vs. 3 days). Eight 16 (50% 25% 75%]) reported rebound; completely asymptomatic. No post-VR resistance mutations detected. Limitations: study design differences treated groups; used surrogate marker risk ongoing transmission. Conclusion: occurred approximately people often rebound, virus. Primary Funding Source: National Institutes Health.

Language: Английский

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Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19

Med, Journal Year: 2024, Volume and Issue: 5(1), P. 42 - 61.e23

Published: Jan. 1, 2024

BackgroundOral antiviral drugs with improved potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks rebound, drug-drug interactions, emerging resistance.MethodsOlgotrelvir (STI-1558) is designed as a next-generation targeting SARS-CoV-2 main protease (Mpro), an essential enzyme replication, human cathepsin L (CTSL), key entry into host cells.FindingsOlgotrelvir highly bioavailable oral prodrug that converted plasma its active form, AC1115. The dual mechanism action olgotrelvir AC1115 was confirmed by activity inhibition assays co-crystal structures Mpro CTSL. displayed inhibiting replication all tested variants cell culture systems. Olgotrelvir also inhibited viral cells using Spike-mediated pseudotypes In K18-hACE2 transgenic mouse model SARS-CoV-2-mediated disease, significantly reduced virus load lungs, prevented body weight loss, cytokine release lung pathologies. demonstrated potent against nirmatrelvir-resistant E166 mutants. showed enhanced bioavailability animal models humans significant exposure without ritonavir. phase I studies (ClinicalTrials.gov: NCT05364840 NCT05523739), favorable profile activity.ConclusionsOlgotrelvir inhibitor CTSL high standalone candidate COVID-19.FundingFunded Sorrento Therapeutics.

Language: Английский

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Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 4, 2025

ABSTRACT In a subset of SARS-CoV-2-infected individuals treated with the antiviral nirmatrelvir-ritonavir, virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used mathematical model to describe longitudinal viral load dynamics 51 20 whom rebounded. Target cell preservation, either by robust innate immune response or initiation N-R near time symptom onset, coupled incomplete clearance, appears be main factor leading rebound. Moreover, occurrence is likely influenced treatment relative progression infection, earlier treatments higher chance A comparison an untreated cohort suggests that early nirmatrelvir-ritonavir may associated delay in onset adaptive response. Nevertheless, our demonstrates extending course 10-day regimen greatly diminish people mild-to-moderate COVID-19 and who at high risk severe disease. Altogether, results suggest some individuals, standard 5-day starting around completely eliminate virus. Thus, after ends, can if effective has fully developed. These findings on role target preservation clearance also offer possible explanation for other SARS-CoV-2. IMPORTANCE Nirmatrelvir-ritonavir initial reduction followed once stopped. show timing influence stops growth preserves cells but lead full adequately developed, remaining Our provide insights into help develop better strategies minimize possibility.

Language: Английский

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Clinical course and management of COVID-19 in the era of widespread population immunity

Nature Reviews Microbiology, Journal Year: 2023, Volume and Issue: 22(2), P. 75 - 88

Published: Dec. 19, 2023

Language: Английский

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Treatments for COVID-19

Annual Review of Medicine, Journal Year: 2023, Volume and Issue: 75(1), P. 145 - 157

Published: Sept. 19, 2023

The treatment for COVID-19 has evolved rapidly since the start of pandemic and now consists mainly antiviral immunomodulatory agents. Antivirals, such as remdesivir nirmatrelvir-ritonavir, have proved to be most useful earlier in illness (e.g., outpatient therapy) less severe disease. Immunomodulatory therapies, dexamethasone interleukin-6 or Janus kinase inhibitors, are disease critical illness. role anti-SARS-CoV-2 monoclonal antibodies diminished because emergence viral variants that not anticipated susceptible these treatments, there still is a consensus on use convalescent plasma. been associated with increased rates venous thromboembolism, but antithrombotic therapy limited. Multiple investigational agents continue studied, which will alter current paradigms new data released.

Language: Английский

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Symptoms, Viral Loads, and Rebound Among COVID-19 Outpatients Treated With Nirmatrelvir/Ritonavir Compared With Propensity Score–Matched Untreated Individuals

Clinical Infectious Diseases, Journal Year: 2023, Volume and Issue: 78(5), P. 1175 - 1184

Published: Nov. 14, 2023

Abstract Background Nirmatrelvir/ritonavir (N/R) reduces severe outcomes from coronavirus disease 2019 (COVID-19); however, rebound after treatment has been reported. We compared symptom and viral dynamics in individuals with COVID-19 who completed N/R similar untreated individuals. Methods identified symptomatic participants tested acute respiratory syndrome 2–positive were eligible a household transmission study. Index cases ambulatory settings their households contacts enrolled. collected daily symptoms, medication use, specimens for quantitative polymerase chain reaction 10 days during March 2022—May 2023. Participants (treated) propensity score matched to participants. rebound, load (VL) average VL by status measured completion or 7 onset if untreated. Results Treated (n = 130) 241) had baseline characteristics. After completion, treated greater occurrence of (32% vs 20%; P .009) (27% 7%; &lt; .001). Average symptoms lower among without (1.0 1.6; .01) but not statistically (3.0 3.4; .5). VLs (0.9 2.6; (4.8 5.1; .7). Conclusions Individuals experienced fewer occured more often Providers should prescribe N/R, when indicated, communicate risk patients.

Language: Английский

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COVID-19 Rebound After VV116 vs Nirmatrelvir-Ritonavir Treatment

JAMA Network Open, Journal Year: 2024, Volume and Issue: 7(3), P. e241765 - e241765

Published: March 13, 2024

Importance With the widespread use of anti–SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment. Objective To compare COVID-19 a standard 5-day course antiviral treatment with VV116 vs nirmatrelvir-ritonavir. Design, Setting, and Participants This is single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients mild-to-moderate within 5 days SARS-CoV-2 infection were enrolled between December 20, 2022, January 19, 2023, randomly allocated to receive either or Interventions group received oral 600-mg tablets every 12 hours on day 1 300 mg 2 through 5. nirmatrelvir-ritonavir nirmatrelvir plus 100 ritonavir for days. followed up other until 28 week 60. Main Outcomes Measures The primary outcome was (VLR), defined as half-log increase RNA copies per milliliter compared completion. Secondary outcomes included reduction cycle threshold value 1.5 more, time VLR, symptom rebound, an more than points score secondary analyzed using full analysis set. Sensitivity analyses protocol Adverse events safety Results set 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] men) who (n = 165) 180). Viral occurred 33 (20.0%) 39 (21.7%) ( P .70). Symptom 41 160 (25.6%) 40 163 (24.5%) .82). whole-genome sequencing 24 cases same lineage at baseline each case. Conclusions Relevance In this COVID-19, both common Prolongation duration might be investigated reduce rebound. Trial Registration Chinese Clinical Registry Identifier: ChiCTR2200066811

Language: Английский

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Safety Profile and Clinical and Virological Outcomes of Nirmatrelvir-Ritonavir Treatment in Patients With Advanced Chronic Kidney Disease and Coronavirus Disease 2019

Clinical Infectious Diseases, Journal Year: 2023, Volume and Issue: 77(10), P. 1406 - 1412

Published: Aug. 2, 2023

Abstract Background Nirmatrelvir-ritonavir is currently not recommended in patients with an estimated glomerular filtration rate (eGFR) &lt;30 mL/minute/1.73 m2. Methods To determine the safety profile and clinical virological outcomes of nirmatrelvir-ritonavir use at a modified dosage adults chronic kidney disease (CKD), prospective, single-arm, interventional trial recruited eGFR m2 on dialysis. Primary included profile, adverse/serious adverse events, events leading to drug discontinuation. Disease symptoms, by serial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral polymerase chain reaction (PCR) tests, rapid antigen symptomatic rebound were also recorded. Results Fifty-nine (69.4%) 85 participants had stage 5 CKD Eighty (94.1%) completed full treatment course; 9.4% 5.9% serious these comparable between those &lt; or &gt;30 The load significantly decreased days 5, 15, 30 (P .001 for all), reduction was consistent subgroup Ten rebound, which transient asymptomatic. Conclusions Among CKD, dose well-tolerated therapy mild COVID-19 as it can effectively suppress SARS-CoV-2 favorable profile. Virological although low infectivity, may occur after treatment. should be considered including Clinical Trials Registration. Trials.gov; identifier: NCT05624840.

Language: Английский

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