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The choice of viral load endpoint in early phase trials of COVID-19 treatments aiming to reduce 28-day hospitalization and/or death

Mateja et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiaf282, Jun 2025
https://c19early.org/mateja.html
Meta-analysis of individual participant data from 23 COVID-19 studies confirming early viral load changes as surrogate endpoints for 28-day hospitalization or death, with the change in log10(viral load) from baseline to day 3 showing the strongest correlation. Day 5 changes also showed moderate correlation, day 7 changes were weaker, and more complex viral load calculations like slope or area under the curve minus baseline offered no advantage.
Mateja et al., 3 Jun 2025, peer-reviewed, 22 authors.
DOI record: { "DOI": "10.1093/infdis/jiaf282", "ISSN": [ "0022-1899", "1537-6613" ], "URL": "http://dx.doi.org/10.1093/infdis/jiaf282", "abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>Virologic endpoints are used in Phase 2 trials for COVID-19 therapeutics, but they have not been established as surrogates for clinical endpoints. No meta-analysis using individual participant data (IPD) has been undertaken to identify viral load outcomes for which treatment effects are best associated with effects on hospitalization/death.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>This meta-analysis combined IPD from 23 COVID-19 treatment vs. control comparisons to calculate R2, a surrogacy measure quantifying the relationship between the treatment effect on 28-day hospitalization/death and the treatment effect on the surrogate. R2 ranges from 0-1, with a strong relationship ≥0.72, moderate 0.49&amp;lt;R2&amp;lt;0.72, and weak ≤0.49. We estimated R2 for various viral load outcomes at Days 3, 5, and 7, including change-from-baseline, slope, average area under the curve minus baseline (AAUCMB), and a change of at least 0.5 log10 copies/mL from baseline to Day 3.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>R2 was numerically highest for the change-from-baseline to Day 3 (0.53 [0.26, 0.79]), slightly lower for change-from-baseline to Day 5 (0.49 [0.24, 0.75]) and numerically lower for change-from-baseline to Day 7 (0.40 [0.15, 0.65]). All were statistically significant.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Discussion</jats:title>\n <jats:p>Our study is the first to use IPD, allowing us to evaluate viral load collected on various study days as a surrogate to clinical outcomes. Change in log10(viral load) from baseline to Day 3 or Day 5 are moderate surrogates for 28-day hospitalization/death and suitable primary endpoints in Phase 2 clinical trials and are preferred over change-from-baseline to Day 7. Slope and AAUCMB require more calculation but didn’t improve prediction so aren’t recommended.</jats:p>\n </jats:sec>", "author": [ { "ORCID": "https://orcid.org/0000-0002-2810-478X", "affiliation": [ { "name": "Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research , Frederick, MD ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Mateja", "given": "Allyson", "sequence": "first" }, { "affiliation": [ { "name": "Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research , Frederick, MD ,", "place": [ "USA" ] } ], "family": "Chu", "given": "Eric", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-2769-4957", "affiliation": [ { "name": "Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota , Minneapolis, MN ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Murray", "given": "Thomas A", "sequence": "additional" }, { "affiliation": [ { "name": "General Internal Medicine, Department of Medicine, University of Minnesota Medical School , Minneapolis, MD ,", "place": [ "USA" ] } ], "family": "Bramante", "given": "Carolyn T", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-5601-9112", "affiliation": [ { "name": "Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health , Boston, MA ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Moser", "given": "Carlee", "sequence": "additional" }, { "affiliation": [ { "name": "GlaxoSmithKline , Stevenage ,", "place": [ "United Kingdom" ] } ], "family": "Givens", "given": "Naomi", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-5192-8659", "affiliation": [ { "name": "Gilead Sciences, Inc. , Foster City, CA ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Abdelghany", "given": "Mazin", "sequence": "additional" }, { "affiliation": [ { "name": "Gilead Sciences, Inc. , Foster City, CA ,", "place": [ "USA" ] } ], "family": "Blair", "given": "Chris", "sequence": "additional" }, { "affiliation": [ { "name": "Gilead Sciences, Inc. , Foster City, CA ,", "place": [ "USA" ] } ], "family": "Chen", "given": "Shuguang", "sequence": "additional" }, { "affiliation": [ { "name": "Redwood AI , Vancouver, BC ,", "place": [ "Canada" ] } ], "family": "Lat", "given": "Prince Kumar", "sequence": "additional" }, { "affiliation": [ { "name": "Redwood AI , Vancouver, BC ,", "place": [ "Canada" ] } ], "family": "Harari", "given": "Ofir", "sequence": "additional" }, { "affiliation": [ { "name": "Eli Lilly and Co , Indianapolis, IN ,", "place": [ "USA" ] } ], "family": "Kallewaard", "given": "Nicole L", "sequence": "additional" }, { "affiliation": [ { "name": "Eli Lilly and Co , Indianapolis, IN ,", "place": [ "USA" ] } ], "family": "Macpherson", "given": "Lisa Farmer", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-4715-0060", "affiliation": [ { "name": "Department of Medicine, University of Minnesota Medical School , Minneapolis, MD ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Boulware", "given": "David R", "sequence": "additional" }, { "affiliation": [ { "name": "Skin Neglected Tropical Diseases and Sexually Transmitted Infection section, Fight Infectious Diseases Foundation, University Hospital Germans Trias i Pujol , Badalona ,", "place": [ "Spain" ] }, { "name": "ISGlobal, Hospital Clínic - Universitat de Barcelona , Barcelona ,", "place": [ "Spain" ] } ], "family": "Suñer", "given": "Clara", "sequence": "additional" }, { "affiliation": [ { "name": "Skin Neglected Tropical Diseases and Sexually Transmitted Infection section, Fight Infectious Diseases Foundation, University Hospital Germans Trias i Pujol , Badalona ,", "place": [ "Spain" ] }, { "name": "Infectious Diseases Department, Universitat de Vic-Universitat Central de Catalunya , Vic ,", "place": [ "Spain" ] } ], "family": "Mitjà", "given": "Oriol", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-4590-5175", "affiliation": [ { "name": "The Foundation for the National Institutes of Health , North Bethesda, MD ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Adam", "given": "Stacey J", "sequence": "additional" }, { "affiliation": [ { "name": "Herbert Wertheim School of Public Health and Human Longevity Science, University of California , San Diego, La Jolla, CA ,", "place": [ "USA" ] } ], "family": "De Gruttola", "given": "Victor", "sequence": "additional" }, { "affiliation": [ { "name": "Harvard TH Chan School of Public Health , Boston, MA ,", "place": [ "USA" ] } ], "family": "Hughes", "given": "Michael D", "sequence": "additional" }, { "affiliation": [ { "name": "Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring , MD ,", "place": [ "USA" ] } ], "family": "Rubin", "given": "Daniel", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-3603-1733", "affiliation": [ { "name": "Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California , San Diego, La Jolla, CA ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Smith", "given": "Davey M", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-6667-6992", "affiliation": [ { "name": "Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Potter", "given": "Gail E", "sequence": "additional" } ], "container-title": "The Journal of Infectious Diseases", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2025, 6, 4 ] ], "date-time": "2025-06-04T03:19:26Z", "timestamp": 1749007166000 }, "deposited": { "date-parts": [ [ 2025, 6, 4 ] ], "date-time": "2025-06-04T03:19:26Z", "timestamp": 1749007166000 }, "indexed": { "date-parts": [ [ 2025, 6, 4 ] ], "date-time": "2025-06-04T03:40:09Z", "timestamp": 1749008409257, "version": "3.41.0" }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2025, 6, 3 ] ] }, "language": "en", "link": [ { "URL": "https://academic.oup.com/jid/advance-article-pdf/doi/10.1093/infdis/jiaf282/63430824/jiaf282.pdf", "content-type": "application/pdf", "content-version": "am", "intended-application": "syndication" }, { "URL": "https://academic.oup.com/jid/advance-article-pdf/doi/10.1093/infdis/jiaf282/63430824/jiaf282.pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "286", "original-title": [], "prefix": "10.1093", "published": { "date-parts": [ [ 2025, 6, 3 ] ] }, "published-online": { "date-parts": [ [ 2025, 6, 3 ] ] }, "publisher": "Oxford University Press (OUP)", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaf282/8156441" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "The choice of viral load endpoint in early phase trials of COVID-19 treatments aiming to reduce 28-day hospitalization and/or death", "type": "journal-article" }
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