Clinical and molecular landscape of prolonged SARS-CoV-2 infection with resistance to remdesivir in immunocompromised patients
et al., PNAS Nexus, doi:10.1093/pnasnexus/pgaf085, Mar 2025
Clinical and virological study of 3 immunocompromised B-cell lymphoma patients with prolonged SARS-CoV-2 infection showing development of remdesivir and sotrovimab resistance. Through serial viral genome sequencing, authors identified NSP12 mutations that conferred 2.4-4.8-fold reduced susceptibility to remdesivir. Using recombinant viruses, they demonstrated that these mutations conveyed remdesivir resistance while attenuating viral pathogenicity in hamsters. The study also found resistance to sotrovimab in one patient through spike protein mutations (E340A, E340D, F342INS).
Gérard, Zhou, Wu, Kamo, Choi, Kim show increased risk of acute kidney injury, Leo, Briciu, Muntean, Petrov show increased risk of liver injury, and Negru, Cheng, Mohammed show increased risk of cardiac disorders with remdesivir.
Study covers remdesivir and sotrovimab.
1.
Gérard et al., Remdesivir and Acute Renal Failure: A Potential Safety Signal From Disproportionality Analysis of the WHO Safety Database, Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.2145.
2.
Zhou et al., Acute Kidney Injury and Drugs Prescribed for COVID-19 in Diabetes Patients: A Real-World Disproportionality Analysis, Frontiers in Pharmacology, doi:10.3389/fphar.2022.833679.
3.
Wu et al., Acute Kidney Injury Associated With Remdesivir: A Comprehensive Pharmacovigilance Analysis of COVID-19 Reports in FAERS, Frontiers in Pharmacology, doi:10.3389/fphar.2022.692828.
4.
Kamo et al., Association of Antiviral Drugs for the Treatment of COVID-19 With Acute Renal Failure, In Vivo, doi:10.21873/invivo.13637.
5.
Choi et al., Comparative effectiveness of combination therapy with nirmatrelvir–ritonavir and remdesivir versus monotherapy with remdesivir or nirmatrelvir–ritonavir in patients hospitalised with COVID-19: a target trial emulation study, The Lancet Infectious Diseases, doi:10.1016/S1473-3099(24)00353-0.
6.
Kim et al., Investigating the Safety Profile of Fast‐Track COVID‐19 Drugs Using the FDA Adverse Event Reporting System Database: A Comparative Observational Study, Pharmacoepidemiology and Drug Safety, doi:10.1002/pds.70043.
7.
Leo et al., Hepatocellular liver injury in hospitalized patients affected by COVID-19: Presence of different risk factors at different time points, Digestive and Liver Disease, doi:10.1016/j.dld.2021.12.014.
8.
Briciu et al., Evolving Clinical Manifestations and Outcomes in COVID-19 Patients: A Comparative Analysis of SARS-CoV-2 Variant Waves in a Romanian Hospital Setting, Pathogens, doi:10.3390/pathogens12121453.
9.
Muntean et al., Effects of COVID-19 on the Liver and Mortality in Patients with SARS-CoV-2 Pneumonia Caused by Delta and Non-Delta Variants: An Analysis in a Single Centre, Pharmaceuticals, doi:10.3390/ph17010003.
10.
Petrov et al., The Effect of Potentially Hepatotoxic Medicinal Products on Alanine Transaminase Levels in COVID-19 Patients: A Case–Control Study, Safety and Risk of Pharmacotherapy, doi:10.30895/2312-7821-2025-458.
11.
Negru et al., Comparative Pharmacovigilance Analysis of Approved and Repurposed Antivirals for COVID-19: Insights from EudraVigilance Data, Biomedicines, doi:10.3390/biomedicines13061387.
Iriyama et al., 18 Mar 2025, Japan, peer-reviewed, 30 authors.
Contact: atomita@fujita-hu.ac.jp, fukut@pop.med.hokudai.ac.jp.
Clinical and molecular landscape of prolonged SARS-CoV-2 infection with resistance to remdesivir in immunocompromised patients
doi:10.1093/pnasnexus/pgaf085/8083008
Patients with hematologic diseases have experienced COVID-19 with prolonged, progressive course. Here we present clinical, pathological, and virological analyses of three cases of prolonged COVID-19 among patients undergoing treatment for B-cell lymphoma. These patients had all been treated with anti-CD20 antibody and bendamustine. Despite various antiviral treatments, high SARS-CoV-2 levels persisted for more than 4 weeks, and two of them succumbed to COVID-19. Autopsy showed bronchopneumonia, interstitial pneumonia, alveolar hemorrhage, and fibrosis. Overlapping CMV, fungal and/or bacterial infections were also confirmed. Sequencing of SARS-CoV-2 showed accumulation of mutations and changes in
Significance statement In immunocompromised patients with hematological malignancies, prolonged/progressive course of COVID-19 is still a critical problem, even in an era when vaccines and several antiviral therapeutics have been developed. Here we analyzed serial viral specimens of three B-cell lymphoma patients undergoing immuno-chemotherapies who experienced prolonged/progressive course of COVID-19 and demonstrated that diverse genetic mutations on SARS-CoV-2 accumulated on therapy within each individual. In vitro drug susceptibility assay revealed that specific genetic alterations on NSP12 (V792I and M794I) were responsible for acquisition of remdesivir resistance. These findings indicate that mutations related to drug resistance accumulate in SARS-CoV-2 in immunocompromised patients, suggesting the importance of treatment strategies that can eradicate the virus at an early stage of COVID-19 onset. (116 words)
Authorship contribution
Sequence data availability The RNAseq data of case #1 specimens 1 to 12 in Figure 1A will be available from NCBI SRA (PRJNA1049969). The data of case #1 specimen 13 in Figure 1A and Supplementary Figure S2 (at autopsy) will be available from DDBJ DRA (DRA017735). The sequence data of case #2 and 3 are available from DDBJ (accession numbers: case #2. LC798944, LC753061, LC753062; case #3. LC798945, LC798946, LC798947).
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DOI record:
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:p>Patients with hematologic diseases have experienced COVID-19 with prolonged, progressive course. Here we present clinical, pathological, and virological analyses of three cases of prolonged COVID-19 among patients undergoing treatment for B-cell lymphoma. These patients had all been treated with anti-CD20 antibody and bendamustine. Despite various antiviral treatments, high SARS-CoV-2 levels persisted for more than 4 weeks, and two of them succumbed to COVID-19. Autopsy showed bronchopneumonia, interstitial pneumonia, alveolar hemorrhage, and fibrosis. Overlapping CMV, fungal and/or bacterial infections were also confirmed. Sequencing of SARS-CoV-2 showed accumulation of mutations and changes in variant allele frequencies over time. NSP12 mutations V792I and M794I appeared independently in two cases as COVID-19 progressed. In vitro drug susceptibility analysis and animal experiment using recombinant SARS-CoV-2 demonstrated that each mutation, V792 and M794I, was independently responsible for remdesivir resistance and attenuated pathogenicity. E340A, E340D and F342INS mutations in the spike protein were found in one case, which may account for the sotrovimab resistance. Analysis of autopsy specimens indicated heterogeneous distribution of these mutations. In summary, we demonstrated temporal and spatial diversity in SARS-CoV-2 that evolved resistance to various antiviral agents in malignant lymphoma patients under immunodeficient conditions caused by certain types of immunochemotherapies. Strategies may be necessary to prevent acquisition of drug resistance and improve outcome, such as selection of appropriate treatment strategies for lymphoma considering patients’ immune status and institution of early intensive antiviral therapy.</jats:p>",
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