Kidney Transplant Recipients and Omicron: Outcomes, effect of vaccines and the efficacy and safety of novel treatments
et al., medRxiv, doi:10.1101/2022.05.03.22274524, May 2022
Retrospective 116 kidney transplant recipients diagnosed with COVID-19 in the community during the Omicron era in the UK, showing lower hospitalization with sotrovimab, but no significant difference with molnupiravir. Two molnupiravir-treated patients requiring dialysis had features of thrombotic microangiopathy, raising potential safety concerns.
Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-15. Multiple analyses have identified variants potentially created by molnupiravir16-20.
Standard of Care (SOC) for COVID-19 in the study country,
the United Kingdom, is very poor with very low average efficacy for approved treatments21.
The United Kingdom focused on expensive high-profit treatments, approving only one low-cost early treatment, which required a prescription and had limited adoption. The high-cost prescription treatment strategy reduces the probability of early treatment due to access and cost barriers, and eliminates complementary and synergistic benefits seen with many low-cost treatments.
Study covers molnupiravir and sotrovimab.
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risk of death, 128.6% higher, RR 2.29, p = 0.52, treatment 1 of 21 (4.8%), control 1 of 48 (2.1%), COVID-19.
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risk of death, 14.3% higher, RR 1.14, p = 1.00, treatment 1 of 21 (4.8%), control 2 of 48 (4.2%), all-cause.
|
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risk of ICU admission, 128.6% higher, RR 2.29, p = 0.52, treatment 1 of 21 (4.8%), control 1 of 48 (2.1%).
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risk of hospitalization, 31.4% lower, RR 0.69, p = 0.74, treatment 3 of 21 (14.3%), control 10 of 48 (20.8%), NNT 15.
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| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
1.
Swanstrom et al., Lethal mutagenesis as an antiviral strategy, Science, doi:10.1126/science.abn0048.
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Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.
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Shum, C., An investigational study into the drug-associated mutational signature in SARS-CoV-2 viruses, The University of Hong Kong, PhD Thesis, hub.hku.hk/handle/10722/344396.
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Waters et al., Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471.
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Huntsman, M., An assessment of the reproductive toxicity of the anti-COVID-19 drug molnupiravir using stem cell-based embryo models, Master's Thesis, scholarspace.manoa.hawaii.edu/items/cd11342c-b4dc-44c0-8b44-ce6e3369c40b.
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Huntsman (B) et al., Detection of developmental toxicity of the anti-COVID-19 drug molnupiravir using gastruloid-based in vitro assays, Toxicological Sciences, doi:10.1093/toxsci/kfaf093.
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Zibat et al., N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody, iScience, doi:10.1016/j.isci.2023.107786.
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Shiraki et al., Convenient screening of the reproductive toxicity of favipiravir and antiviral drugs in Caenorhabditis elegans, Heliyon, doi:10.1016/j.heliyon.2024.e35331.
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Gruber et al., Molnupiravir increases SARS‐CoV‐2 genome diversity and complexity: A case‐control cohort study, Journal of Medical Virology, doi:10.1002/jmv.29642.
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Marikawa et al., An active metabolite of the anti-COVID-19 drug molnupiravir impairs mouse preimplantation embryos at clinically relevant concentrations, Reproductive Toxicology, doi:10.1016/j.reprotox.2023.108475.
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Rahman, M., Elucidation of the DNA repair mechanisms involved in the repair of DNA damage caused by the Arabinosides and Anti-COVID-19 drugs, tokyo-metro-u.repo.nii.ac.jp/records/2000972.
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Zhou et al., β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells, The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247.
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Chamod et al., Molnupiravir Metabolite--N4-hydroxycytidine Causes Cytotoxicity and DNA Damage in Mammalian Cells in vitro: N4-hydroxycytidine Induced Cytotoxicity DNA Damage, Asian Medical Journal and Alternative Medicine, 23:3, asianmedjam.com/index.php/amjam/article/view/1448.
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Standing et al., Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients, Nature Communications, doi:10.1038/s41467-024-45641-0.
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Mori et al., Reactive oxygen species-mediated cytotoxic and DNA-damaging mechanism of N4-hydroxycytidine, a metabolite of the COVID-19 therapeutic drug molnupiravir, Free Radical Research, doi:10.1080/10715762.2025.2469738.
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Focosi et al., The fitness of molnupiravir-signed SARS-CoV-2 variants: imputation analysis based on prescription counts and GISAID analyses by country, Intervirology, doi:10.1159/000540282.
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Sanderson et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature, doi:10.1038/s41586-023-06649-6.
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Gleeson et al., 3 May 2022, prospective, United Kingdom, preprint, 14 authors, study period 21 December, 2021 - 10 February, 2022.
Contact: m.willicombe08@imperial.ac.uk.
Kidney Transplant Recipients and Omicron: Outcomes, effect of vaccines and the efficacy and safety of novel treatments
doi:10.1101/2022.05.03.22274524
We aimed to describe the outcomes of Omicron infection in kidney transplant recipients (KTR), compare the efficacy of the community therapeutic interventions and report the safety profile of molnupiravir. From 142 KTRs diagnosed with COVID-19 infection after Omicron had become the dominant variant in the UK, 116 (78.9%) cases were diagnosed in the community; 47 receiving sotrovimab, 21 molnupiravir and 48 no treatment. 10 (20.8%) non-treated patients were hospitalised following infection, which was significantly higher than the sotrovimab group (2.1%), p=0.0048, but not the molnupiravir treated group (14.3%), p=0.47. The only admission following sotrovimab occurred in a patient infected with BA.2. One patient from the molnupiravir and no-treatment groups required ICU support, and both subsequently died, with one other death in the no-treatment group. No patient receiving sotrovimab died. 6/116 (5.2%) patients required dialysis following their diagnosis; 2 (9.5%) patients receiving molnupiravir and 4 (8.3%) no-treatment. This requirement was significantly higher in the molnupiravir group compared with the sotrovimab treated patients, in whom no patient required dialysis, p=0.035. Both molnupiravir treated patients requiring dialysis had features of systemic thrombotic microangiopathy. Post-vaccination serostatus was available in 110 patients. Seropositive patients were less likely to require hospital admission compared with seronegative patients, 6 (7.0%) and 6 (25.0%) respectively, p=0.023. Seropositive patients were also less likely to require dialysis therapy, p=0.016. In conclusion, sotrovimab treatment in the community was associated with superior patient and transplant outcomes; it's clinical efficacy against the BA.2 variant requires a rapid review. The treatment benefit of molnupiravir was not evident, and wider safety reporting in transplant patients is needed.
risk group with poor infection outcomes, immunosuppressed people often with significant comorbidities, have been excluded from policy informing studies from the start of the pandemic. Relying on extrapolating data from these studies to inform management of transplant recipients, may and has led to suboptimal outcomes.
References
Benotmane, Pre-exposure prophylaxis with Evusheld™ elicits limited neutralizing activity against the omicron variant in kidney transplant patients, medRxiv
Bernal, Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients, N Engl J Med
Broecker, Clinical-pathological correlations in post-transplant thrombotic microangiopathy, Histopathology
Callaghan, Real-world Effectiveness of the Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S Vaccines Against SARS-CoV-2 in Solid Organ and Islet Transplant Recipients, Transplantation
Chavarot, Early treatment with sotrovimab monoclonal antibody in kidney transplant recipients with Omicron infection
Extance, Covid-19: What is the evidence for the antiviral molnupiravir?, BMJ
Gupta, Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab, N Engl J Med
Iketani, Antibody evasion properties of SARS-CoV-2 Omicron sublineages, Nature
Kemp, SARS-CoV-2 evolution during treatment of chronic infection, Nature
Prendecki, Immunological responses to SARS-CoV-2 vaccines in kidney transplant recipients, Lancet
Villanego, Trends in COVID-19 Outcomes in Kidney Transplant Recipients During the Period of Omicron Variant Predominance, Transplantation
Willicombe, Scanlon, Miranda, Loud, Lightstone, Should we be clinically assessing antibody responses to covid vaccines in immunocompromised people?, BMJ
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