Effectiveness of oral antivirals in reducing adverse outcomes in asthmatic patients with non-severe COVID-19: A multi-institutional retrospective cohort study
et al., Medicine, doi:10.1097/md.0000000000048378, Apr 2026
TriNetX retrospective 29,143 matched pairs of asthmatic non-hospitalized adults with COVID-19 showing lower mortality, hospitalization, and mechanical ventilation with oral antiviral treatment (nirmatrelvir/ritonavir or molnupiravir).
This study has multiple major issues:
Immortal time bias in index date definition: the index date was defined as the date of antiviral prescription for the study group, but the date of COVID-19 diagnosis for the control group. This guarantees that patients in the treatment group survived long enough to receive their medication, artificially inflating their apparent survival and freedom from hospitalization compared to the control group.
Confounding by contraindication in the control group: the study's exclusion criteria failed to remove patients with contraindications for nirmatrelvir/ritonavir (such as severe chronic kidney disease or complex interacting medication regimens) from the control pool. Consequently, the control group will disproportionately contain higher-risk patients who were ineligible for the drug. The limited matching performed can only partially correct for this bias.
Mathematical impossibilities in propensity score matching: the post-matching baseline characteristics reported in Table 1 contain fundamental calculation errors. For example, the absolute count for diabetes in the post-match study group is reported as 2402 out of an n of 29,143. Mathematically, this is 8.24%, yet the table incorrectly reports it as 16.8%, casting doubt on the integrity of the data balancing process.
Unmeasured healthy-user bias and differential access: the analysis relies solely on electronic medical records, explicitly lacking data on health literacy, detailed socioeconomic status, and the use of other non-prescription treatments. By also excluding rapid progressors who required hospitalization within 5 days of diagnosis, the study artificially selects for a "healthier" outpatient cohort that possessed the resources and stability to successfully acquire antiviral prescriptions.
The abstract claims "After matching, each group comprised 19,235 patients", contradicting the results showing 29,143 matched pairs.
Overall, the combination of severe methodological flaws - immortal time bias, confounding by contraindication, and unmeasured healthy-user bias - potentially accounts for the entire observed treatment effect, with the greater observed effect for paxlovid consistent with the additional confounding by contraindication.
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. Studies show significantly increased risk of acute kidney injury21, cardiovascular toxocity22, and neurological symptoms21. Treatment may increase viral rebound23,24.
1.
Swanstrom et al., Lethal mutagenesis as an antiviral strategy, Science, doi:10.1126/science.abn0048.
2.
Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.
3.
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.
4.
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.
5.
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.
6.
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.
7.
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.
8.
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.
9.
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.
10.
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.
11.
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.
12.
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.
13.
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.
14.
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.
15.
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.
16.
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.
17.
Sanderson et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature, doi:10.1038/s41586-023-06649-6.
18.
Fountain-Jones et al., Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study, The Lancet Microbe, doi:10.1016/S2666-5247(23)00393-2.
19.
Kosakovsky Pond et al., Anti-COVID drug accelerates viral evolution, Nature, doi:10.1038/d41586-023-03248-3.
21.
Siby et al., Temporal Trends in Serious Adverse Events Associated with Oral Antivirals During the COVID-19 Pandemic: Insights from the FAERS Database (2020–2023), Open Forum Infectious Diseases, doi:10.1093/ofid/ofaf695.1825.
22.
Ozhan et al., Evaluation of the cardiopulmonary effects of repurposed COVID-19 therapeutics in healthy rats, Scientific Reports, doi:10.1038/s41598-025-31048-4.
Fang et al., 17 Apr 2026, retrospective, Taiwan, peer-reviewed, 4 authors, study period 1 January, 2022 - 16 March, 2024.
Contact: ccm870958@yahoo.com.tw.
Abstract: ®
Effectiveness of oral antivirals in reducing adverse outcomes in asthmatic patients with nonsevere COVID-19
A multi-institutional retrospective cohort study
Shao-Chi Fang, MD a , Ya-Wen Tsai, PhD b , Chien-Ming Chao, MD c,d, *, Chih-Cheng Lai, MD e
Abstract
Preventing the progression of coronavirus disease 2019 (COVID-19) is a critical issue, particularly in patients with comorbidities such as asthma. However, real-world data on the effectiveness of oral antivirals in patients with asthma and non-severe COVID19 are limited. This study was conducted to evaluate the effectiveness of 2 oral antivirals, nirmatrelvir/ritonavir (NMV-r) and molnupiravir, in reducing adverse outcomes in asthmatic patients with non-severe COVID-19. This retrospective cohort study included non-hospitalized adults with asthma who were diagnosed with COVID-19 between January 1, 2022, and March 16, 2024, using data from the TriNetX Research Network. The study group received NMV-r or molnupiravir; the control group received no antivirals. Covariates were balanced between the groups using propensity score matching. The primary outcome was the composite incidence of all-cause mortality, all-cause hospitalization, and mechanical ventilation use within 30 days. After matching, each group comprised 19,235 patients. The study group showed significantly lower composite primary outcome (hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.49-0.66). Specifically, the study group was associated with significantly lower risk of all-cause hospitalization (HR: 0.59; 95% CI: 0.50-0.69) and all-cause mortality (HR: 0.34; 95% CI: 0.16-0.73) and mechanical ventilation requirements (HR: 0.08; 95% CI: 0.01-0.58). Significantly risk reduction was also observed in subgroups including both sexes, different ages, those with hypertension, dyslipidemia, diabetes mellitus, those receiving NMV-r, and those who had received less than 1 dose and more than 3 doses of vaccine. Our findings suggest oral antivirals, particularly NMV-r, reduce adverse outcomes in asthmatic patients with non-severe COVID-19.
Abbreviations: ATC = anatomical therapeutic chemical, CI = confidence interval, COVID-19 = coronavirus disease 2019, HCOs = healthcare organizations, HR = hazard ratio, ICD-10-CM = International Classification of Diseases, Tenth Revision, Clinical Modification, ICS = inhaled corticosteroid, LABA = long-acting beta-2 agonist, LAMA = long-acting muscarinic antagonist, MOV = molnupiravir, MV = mechanical ventilation, NMV-r = nirmatrelvir/ritonavir, PSM = propensity score matching, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
Keywords: asthma, COVID-19, molnupiravir, nirmatrelvir/ritonavir, SARS-CoV-2
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"abstract": "<jats:sec>\n <jats:title/>\n <jats:p>Preventing the progression of coronavirus disease 2019 (COVID-19) is a critical issue, particularly in patients with comorbidities such as asthma. However, real-world data on the effectiveness of oral antivirals in patients with asthma and non-severe COVID-19 are limited. This study was conducted to evaluate the effectiveness of 2 oral antivirals, nirmatrelvir/ritonavir (NMV-r) and molnupiravir, in reducing adverse outcomes in asthmatic patients with non-severe COVID-19. This retrospective cohort study included non-hospitalized adults with asthma who were diagnosed with COVID-19 between January 1, 2022, and March 16, 2024, using data from the TriNetX Research Network. The study group received NMV-r or molnupiravir; the control group received no antivirals. Covariates were balanced between the groups using propensity score matching. The primary outcome was the composite incidence of all-cause mortality, all-cause hospitalization, and mechanical ventilation use within 30 days. After matching, each group comprised 19,235 patients. The study group showed significantly lower composite primary outcome (hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.49–0.66). Specifically, the study group was associated with significantly lower risk of all-cause hospitalization (HR: 0.59; 95% CI: 0.50–0.69) and all-cause mortality (HR: 0.34; 95% CI: 0.16–0.73) and mechanical ventilation requirements (HR: 0.08; 95% CI: 0.01–0.58). Significantly risk reduction was also observed in subgroups including both sexes, different ages, those with hypertension, dyslipidemia, diabetes mellitus, those receiving NMV-r, and those who had received less than 1 dose and more than 3 doses of vaccine. Our findings suggest oral antivirals, particularly NMV-r, reduce adverse outcomes in asthmatic patients with non-severe COVID-19.</jats:p>\n </jats:sec>",
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