CMV viral load kinetics as surrogate endpoints after allogeneic transplantation.

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  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
    • Publication Information:
      Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
      Original Publication: New Haven [etc.] American Society for Clinical Investigation.
    • Subject Terms:
    • Abstract:
      BACKGROUNDViral load (VL) surrogate endpoints transformed development of HIV and hepatitis C therapeutics. Surrogate endpoints for CMV-related morbidity and mortality could advance development of antiviral treatments. Although observational data support using CMV VL as a trial endpoint, randomized controlled trials (RCTs) demonstrating direct associations between virological markers and clinical endpoints are lacking.METHODSWe performed CMV DNA PCR on frozen serum samples from the only placebo-controlled RCT of ganciclovir for early treatment of CMV after hematopoietic cell transplantation (HCT). We used established criteria to assess VL kinetics as surrogates for CMV disease or death by weeks 8, 24, and 48 after randomization and quantified antiviral effects captured by each marker. We used ensemble-based machine learning to assess the predictive ability of VL kinetics and performed this analysis on a ganciclovir prophylaxis RCT for validation.RESULTSVL suppression with ganciclovir reduced cumulative incidence of CMV disease and death for 20 years after HCT. Mean VL, peak VL, and change in VL during the first 5 weeks of treatment fulfilled the Prentice definition for surrogacy, capturing more than 95% of ganciclovir's effect, and yielded highly sensitive and specific predictions by week 48. In the prophylaxis trial, the viral shedding rate satisfied the Prentice definition for CMV disease by week 24.CONCLUSIONSOur results support using CMV VL kinetics as surrogates for CMV disease, provide a framework for developing CMV preventative and therapeutic agents, and support reductions in VL as the mechanism through which antivirals reduce CMV disease.FUNDINGMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
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    • Grant Information:
      R01 AI134878 United States AI NIAID NIH HHS; T32 AI007044 United States AI NIAID NIH HHS; KL2 TR002317 United States TR NCATS NIH HHS; K24 HL093294 United States HL NHLBI NIH HHS; P01 CA018029 United States CA NCI NIH HHS; P30 CA015704 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: Clinical Trials; Drug therapy; Infectious disease; Stem cell transplantation
    • Accession Number:
      P9G3CKZ4P5 (Ganciclovir)
    • Publication Date:
      Date Created: 20200924 Date Completed: 20210908 Latest Revision: 20210908
    • Publication Date:
      20240628
    • Accession Number:
      PMC7773411
    • Accession Number:
      10.1172/JCI133960
    • Accession Number:
      32970635