Real-world effectiveness of early remdesivir and sotrovimab in the highest-risk COVID-19 outpatients during the Omicron surge

Piccicacco et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkac256, Aug 2022

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Sotrovimab for COVID-19

44th treatment shown to reduce risk in August 2022, now with p = 0.00054 from 28 studies, recognized in 42 countries. Efficacy is variant dependent.

Lower risk for mortality, ICU, and hospitalization.

No treatment is 100% effective. Protocols combine treatments.

6,200+ studies for 180+ treatments. c19early.org

Retrospective high-risk outpatients in the USA, 82 treated with remdesivir, 88 with sotrovimab, and 90 control patients, showing significantly lower combined hospitalization/ER visits with both treatments in unadjusted results. The dominant variant was omicron B.1.1.529.

Efficacy is variant dependent. In Vitro studies predict lower efficacy for BA.11-3, BA.4, BA.54, XBB.1.9.3, XBB.1.5.24, XBB.2.9, CH.1.15, and no efficacy for BA.26, XBB, XBB.1.5, ХВВ.1.9.17, XBB.1.16, BQ.1.1.45, and CL.15. US EUA has been revoked.

Standard of Care (SOC) for COVID-19 in the study country, the USA, is very poor with very low average efficacy for approved treatments8. Only expensive, high-profit treatments were approved for early treatment. Low-cost treatments were excluded, reducing the probability of early treatment due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.

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Study covers remdesivir and sotrovimab.

risk of death, 66.4% lower, RR 0.34, p = 1.00, treatment 0 of 88 (0.0%), control 1 of 90 (1.1%), NNT 90, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 29.

risk of hospitalization, 34.9% lower, RR 0.65, p = 0.46, treatment 7 of 88 (8.0%), control 11 of 90 (12.2%), NNT 23, day 29.

risk of hospitalization/ER, 66.3% lower, RR 0.34, p = 0.01, treatment 7 of 88 (8.0%), control 21 of 90 (23.3%), NNT 6.5, odds ratio converted to relative risk, day 29.

risk of progression, 89.8% lower, RR 0.10, p = 0.009, treatment 1 of 88 (1.1%), control 10 of 90 (11.1%), NNT 10, ER visit, day 29.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. Liu et al., Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2, bioRxiv, doi:10.1101/2021.12.14.472719.biorxiv.org, doi.org.

2. Sheward et al., Variable loss of antibody potency against SARS-CoV-2 B.1.1.529 (Omicron), bioRxiv, doi:10.1101/2021.12.19.473354.biorxiv.org, doi.org.

3. VanBlargan et al., An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by several therapeutic monoclonal antibodies, bioRxiv, doi:10.1101/2021.12.15.472828.biorxiv.org, doi.org.

4. Haars et al., Prevalence of SARS-CoV-2 Omicron Sublineages and Spike Protein Mutations Conferring Resistance against Monoclonal Antibodies in a Swedish Cohort during 2022–2023, Microorganisms, doi:10.3390/microorganisms11102417.mdpi.com, doi.org.

5. Pochtovyi et al., In Vitro Efficacy of Antivirals and Monoclonal Antibodies against SARS-CoV-2 Omicron Lineages XBB.1.9.1, XBB.1.9.3, XBB.1.5, XBB.1.16, XBB.2.4, BQ.1.1.45, CH.1.1, and CL.1, Vaccines, doi:10.3390/vaccines11101533.mdpi.com, doi.org.

6. Zhou et al., SARS-CoV-2 Omicron BA.2 Variant Evades Neutralization by Therapeutic Monoclonal Antibodies, bioRxiv, doi:10.1101/2022.02.15.480166.biorxiv.org, doi.org.

7. Uraki et al., Antiviral efficacy against and replicative fitness of an XBB.1.9.1 clinical isolate, iScience, doi:10.1016/j.isci.2023.108147.sciencedirect.com, doi.org.

8. c19early.org, c19early.org/soc/usa.html.

Piccicacco et al., 1 Aug 2022, retrospective, USA, peer-reviewed, 7 authors, study period 27 December, 2021 - 4 February, 2022, average treatment delay 4.4 days. Contact: npiccicacco@tgh.org.

This Paper Sotrovimab All

Real-world effectiveness of early remdesivir and sotrovimab in the highest-risk COVID-19 outpatients during the Omicron surge

Nicholas Piccicacco, Kristen Zeitler, Austin Ing, Jose Montero, Jonathan Faughn, Suzane Silbert, Kami Kim

Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkac256

Background: Remdesivir and sotrovimab both have clinical trial data in the outpatient setting demonstrating reduction in the risk of hospitalizations and emergency department (ED) visits related to COVID-19. Objectives: To evaluate the effectiveness of remdesivir in comparison with sotrovimab and matched high-risk control patients in preventing COVID-19-related hospitalizations and ED visits during the Omicron B.1.1.529 surge. Patients and methods: This retrospective cohort study included outpatients positive for SARS-CoV-2, with nonsevere symptoms for ≤7 days and deemed high-risk for severe COVID-19 by an internal scoring matrix. Patients who received remdesivir or sotrovimab from 27/12/2021 to 04/02/2022 were included (n = 82 and n = 88, respectively). These were compared with a control cohort of high-risk COVID-19 outpatients who did not receive therapy (n = 90). The primary outcome was a composite of 29 day COVID-19-related hospitalizations and/or ED visits. Pre-specified secondary outcomes included components of the primary endpoint, 29 day all-cause mortality and serious adverse drug events. Results: Patients treated with remdesivir were significantly less likely to be hospitalized or visit the ED within 29 days from symptom onset (11% versus 23.3%; OR = 0.41, 95% CI = 0.17-0.95). Patients receiving sotrovimab were also less likely to be hospitalized or visit the ED (8% versus 23.3%; OR = 0.28, 95% CI = 0.11-0.71). There was no difference in the incidence of hospitalizations/ED visits between sotrovimab and remdesivir. Conclusions: Our highest-risk outpatients with Omicron-related COVID-19 who received early sotrovimab or remdesivir had significantly lower likelihoods of a hospitalization and/or ED visit.

Author contributions Concept and design: N.P., K.Z., A.I. and J.M. Acquisition, analysis or interpretation of data: N.P., K.Z., A.I. and J.M. Drafting of manuscript: N.P., A.I., K.Z., J.F. and S.S. Critical revision of the manuscript for important intellectual content: K.K. and J.M. Statistical analysis: N.P. and K.Z. Supplementary data Table S1 is available as Supplementary data at JAC Online.

References

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Andrews, Stowe, Kirsebom, Covid-19 vaccine effectiveness against the Omicron (B.1.1.529) variant, N Engl J Med, doi:10.1056/NEJMoa2119451

Bhimraj, Morgan, Shumaker, IDSA Guidelines on the Treatment and Management of Patients with COVID-19

Fda, FDA Takes Actions to Expand Use of Treatment for Outpatients With Mild-to-Moderate COVID-19

Gottlieb, Vaca, Paredes, Early remdesivir to prevent progression to severe Covid-19 in outpatients, N Engl J Med, doi:10.1056/NEJMoa2116846

Gupta, Gonzalez-Rojas, Juarez, Effect of sotrovimab on hospitalization or death among high-risk patients with mild to moderate COVID-19: a randomized clinical trial, JAMA, doi:10.1001/jama.2022.2832

Hui, Ho, Cheung, SARS-CoV-2 Omicron variant replication in human bronchus and lung ex vivo, Nature, doi:10.1038/s41586-022-04479-6

Iuliano, Brunkard, Boehmer, Trends in disease severity and health care utilization during the early Omicron variant period compared with previous SARS-CoV-2 high transmission periods -United States, December 2020-January 2022, MMWR Morb Mortal Wkly Rep, doi:10.15585/mmwr.mm7104e4

Lee, Wong, Chai, Efficacy of covid-19 vaccines in immunocompromised patients: systematic review and meta-analysis, BMJ, doi:10.1136/bmj-2021-068632

Peters, Rabinstein, Dubrock, Use of remdesivir in myasthenia gravis and COVID-19, Pharmacotherapy, doi:10.1002/phar.2524

Piccicacco, Zeitler, Montero, Effectiveness of severe acute respiratory syndrome coronavirus 2 monoclonal antibody infusions in high-risk outpatients, Open Forum Infect Dis, doi:10.1093/ofid/ofab292

Planas, Saunders, Maes, Considerable escape of SARS-CoV-2 Omicron to antibody neutralization, Nature, doi:10.1038/s41586-021-04389-z

Razonable, Ganesh, Bierle, Clinical prioritization of antispike monoclonal antibody treatment of mild to moderate Outpatient remdesivir versus sotrovimab for Omicron COVID-19, Mayo Clin Proc, doi:10.1016/j.mayocp.2021.11.017

Stolle, Nalamasu, Pergolizzi, Fact vs fallacy: the anti-vaccine discussion reloaded, Adv Ther, doi:10.1007/s12325-020-01502-y

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Yek, Warner, Wiltz, Risk factors for severe COVID-19 outcomes among persons aged ≥18 years who completed a primary COVID-19 vaccination series -465 health care facilities, United States, MMWR Morb Mortal Wkly Rep, doi:10.15585/mmwr.mm7101a4

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DOI record: { "DOI": "10.1093/jac/dkac256", "ISSN": [ "0305-7453", "1460-2091" ], "URL": "http://dx.doi.org/10.1093/jac/dkac256", "abstract": "Abstract\n \n Background\n Remdesivir and sotrovimab both have clinical trial data in the outpatient setting demonstrating reduction in the risk of hospitalizations and emergency department (ED) visits related to COVID-19.\n \n \n Objectives\n To evaluate the effectiveness of remdesivir in comparison with sotrovimab and matched high-risk control patients in preventing COVID-19-related hospitalizations and ED visits during the Omicron B.1.1.529 surge.\n \n \n Patients and methods\n This retrospective cohort study included outpatients positive for SARS-CoV-2, with non-severe symptoms for ≤7 days and deemed high-risk for severe COVID-19 by an internal scoring matrix. Patients who received remdesivir or sotrovimab from 27/12/2021 to 04/02/2022 were included (n = 82 and n = 88, respectively). These were compared with a control cohort of high-risk COVID-19 outpatients who did not receive therapy (n = 90). The primary outcome was a composite of 29 day COVID-19-related hospitalizations and/or ED visits. Pre-specified secondary outcomes included components of the primary endpoint, 29 day all-cause mortality and serious adverse drug events.\n \n \n Results\n Patients treated with remdesivir were significantly less likely to be hospitalized or visit the ED within 29 days from symptom onset (11% versus 23.3%; OR = 0.41, 95% CI = 0.17–0.95). Patients receiving sotrovimab were also less likely to be hospitalized or visit the ED (8% versus 23.3%; OR = 0.28, 95% CI = 0.11–0.71). There was no difference in the incidence of hospitalizations/ED visits between sotrovimab and remdesivir.\n \n \n Conclusions\n Our highest-risk outpatients with Omicron-related COVID-19 who received early sotrovimab or remdesivir had significantly lower likelihoods of a hospitalization and/or ED visit.\n ", "author": [ { "ORCID": "http://orcid.org/0000-0002-6246-7533", "affiliation": [ { "name": "Department of Pharmacy, Tampa General Hospital , Tampa, FL , USA" } ], "authenticated-orcid": false, "family": "Piccicacco", "given": "Nicholas", "sequence": "first" }, { "affiliation": [ { "name": "Department of Pharmacy, Tampa General Hospital , Tampa, FL , USA" } ], "family": "Zeitler", "given": "Kristen", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Pharmacy, Vanderbilt University Medical Center , Nashville, TN , USA" } ], "family": "Ing", "given": "Austin", "sequence": "additional" }, { "affiliation": [ { "name": "Division of Infectious Diseases, Department of Internal Medicine, University of South Florida Morsani College of Medicine , Tampa, FL , USA" } ], "family": "Montero", "given": "Jose", "sequence": "additional" }, { "affiliation": [ { "name": "Esoteric Testing/R&D and Microbiology Laboratories, Tampa General Hospital , Tampa, FL , USA" } ], "family": "Faughn", "given": "Jonathan", "sequence": "additional" }, { "affiliation": [ { "name": "Esoteric Testing/R&D and Microbiology Laboratories, Tampa General Hospital , Tampa, FL , USA" } ], "family": "Silbert", "given": "Suzane", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-3384-152X", "affiliation": [ { "name": "Division of Infectious Diseases, Department of Internal Medicine, University of South Florida Morsani College of Medicine , Tampa, FL , USA" }, { "name": "Global Emerging Diseases Institute, Tampa General Hospital , Tampa, FL , USA" } ], "authenticated-orcid": false, "family": "Kim", "given": "Kami", "sequence": "additional" } ], "container-title": "Journal of Antimicrobial Chemotherapy", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2022, 8, 1 ] ], "date-time": "2022-08-01T16:50:21Z", "timestamp": 1659372621000 }, "deposited": { "date-parts": [ [ 2022, 8, 1 ] ], "date-time": "2022-08-01T16:50:37Z", "timestamp": 1659372637000 }, "indexed": { "date-parts": [ [ 2022, 8, 2 ] ], "date-time": "2022-08-02T04:28:47Z", "timestamp": 1659414527716 }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2022, 8, 1 ] ] }, "language": "en", "license": [ { "URL": "https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2022, 8, 1 ] ], "date-time": "2022-08-01T00:00:00Z", "timestamp": 1659312000000 } } ], "link": [ { "URL": "https://academic.oup.com/jac/advance-article-pdf/doi/10.1093/jac/dkac256/45210080/dkac256.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "syndication" }, { "URL": "https://academic.oup.com/jac/advance-article-pdf/doi/10.1093/jac/dkac256/45210080/dkac256.pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "286", "original-title": [], "prefix": "10.1093", "published": { "date-parts": [ [ 2022, 8, 1 ] ] }, "published-online": { "date-parts": [ [ 2022, 8, 1 ] ] }, "publisher": "Oxford University Press (OUP)", "reference": [ { "author": "Johns Hopkins University", "key": "2022080116401611900_dkac256-B1" }, { "DOI": "10.1056/NEJMoa2001017", "article-title": "A novel coronavirus from patients with pneumonia in China, 2019", "author": "Zhu", "doi-asserted-by": "crossref", "first-page": "727", "journal-title": "N Engl J Med", "key": "2022080116401611900_dkac256-B2", "volume": "382", "year": "2020" }, { "author": "CDC", "key": "2022080116401611900_dkac256-B3" }, { "DOI": "10.15585/mmwr.mm7101a4", "article-title": "Risk factors for severe COVID-19 outcomes among persons aged ≥18 years who completed a primary COVID-19 vaccination series - 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