Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. Veterans: target trial emulation studies with one-month and six-month outcomes

Bajema et al., medRxiv, doi:10.1101/2022.12.05.22283134

Dec 2022

Source PDF All Studies Meta AnalysisMeta

Retrospective 112,380 high-risk patients in the USA, showing significantly higher acute or long-term care admission at 180 days with molnupiravir treatment, and no significant difference for other outcomes. The title and headers of Table S14 are conflicting but the data appears to match be title.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-10. Multiple analyses have identified variants potentially created by molnupiravir11-15.

Important missing comments or errors? Let us know.

Study covers paxlovid and molnupiravir.

risk of death, 18.0% lower, HR 0.82, p = 0.40, treatment 24 of 897 (2.7%), control 29.0 of 897 (3.2%), NNT 179, cumulative 0-180 days, propensity score matching, day 180, Table S14.

risk of death, 49.3% lower, RR 0.51, p = 0.19, treatment 7 of 897 (0.8%), control 13.8 of 897 (1.5%), NNT 132, propensity score matching, day 30.

risk of mechanical ventilation, 16.7% lower, RR 0.83, p = 1.00, treatment 3 of 897 (0.3%), control 3.6 of 897 (0.4%), NNT 1495, propensity score matching, day 30.

risk of ICU admission, 1.0% lower, RR 0.99, p = 1.00, treatment 10 of 897 (1.1%), control 10.1 of 897 (1.1%), NNT 8970, propensity score matching, day 30.

risk of hospitalization, 30.0% higher, HR 1.30, p = 0.04, treatment 162 of 897 (18.1%), control 124.3 of 897 (13.9%), cumulative 0-180 days, propensity score matching, day 180, Table S14.

risk of hospitalization, 8.6% lower, RR 0.91, p = 0.73, treatment 37 of 897 (4.1%), control 40.5 of 897 (4.5%), NNT 256, propensity score matching, day 30.

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.science.org, doi.org.

2. Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.mdpi.com, doi.org.

3. 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.wiley.com, doi.org.

4. 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.hawaii.edu.

5. 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.sciencedirect.com, doi.org.

6. 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.sciencedirect.com, doi.org.

7. 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.wiley.com, doi.org.

8. 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.sciencedirect.com, doi.org.

9. 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.oup.com, doi.org.

10. 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.asianmedjam.com.

11. 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.karger.com, doi.org.

12. Sanderson et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature, doi:10.1038/s41586-023-06649-6.nature.com, doi.org.

13. 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.sciencedirect.com, doi.org.

14. Kosakovsky Pond et al., Anti-COVID drug accelerates viral evolution, Nature, doi:10.1038/d41586-023-03248-3.nature.com, doi.org.

15. twitter.com, twitter.com/LongDesertTrain/status/1597353291868155906.twitter.com/LongDesertTrain/status/1597353291868155906.

Bajema et al., 6 Dec 2022, retrospective, USA, preprint, median age 67.0, 18 authors, study period 1 January, 2022 - 28 February, 2022.

This Paper Molnupiravir All

Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. Veterans: target trial emulation studies with one-month and six-month outcomes

MD, MSc Kristina L Bajema, PhD Kristin Berry, PhD Elani Streja, PhD Nallakkandi Rajeevan, MS Yuli Li, PhD Lei Yan, PharmD Francesca Cunningham, MPH Denise M Hynes, MPH Mazhgan Rowneki, PhD, MHS Amy Bohnert, Edward J Boyko, MD, PhD Theodore J Iwashyna, PhD Matthew L Maciejewski, Thomas F Osborne, MD, MPH, MSc Elizabeth M Viglianti, PhD Mihaela Aslan, MPH, PhD Grant D Huang, BMBCh George N Ioannou

doi:10.1101/2022.12.05.22283134

Background: Information about the effectiveness of oral antivirals in preventing short-and longterm COVID-19-related outcomes during the Omicron surge is limited. We sought to determine the effectiveness of nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of COVID-19. Methods: We conducted three retrospective target trial emulation studies comparing matched patient cohorts who received nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir in the Veterans Health Administration (VHA). Participants were Veterans in VHA care at risk for severe COVID-19 who tested positive for SARS-CoV-2 in the outpatient setting during January and February 2022. Primary outcomes included all-cause 30-day hospitalization or death and 31-180-day incidence of acute or longterm care admission, death, or post-COVID-19 conditions. For 30-day outcomes, we calculated unadjusted risk rates, risk differences, and risk ratios. For 31-180-day outcomes, we used unadjusted time-to-event analyses. Results: Participants were 90% male with median age 67 years and 26% unvaccinated. Compared to matched untreated controls, nirmatrelvir-ritonavir-treated participants (N=1,587) had a lower 30-day risk of hospitalization (27.10/1000 versus 41.06/1000, risk difference [RD] -13.97, 95% CI -23.85 to -4.09) and death (3.15/1000 versus 14.86/1000, ). Among persons who were alive at day 31, further significant reductions in 31-180-day incidence of hospitalization (sub-hazard ratio 1.07, 95% CI 0.83 to 1.37) or death (hazard ratio 0.61, 95% CI 0.35 to 1.08) were not observed. Molnupiravir-treated participants aged ≥65 years (n=543) had a lower combined 30-day risk of hospitalization or death (55.25/1000 versus 82.35/1000, . A statistically significant difference in 30-day or 31-180-day risk of hospitalization or death was not observed between matched nirmatrelvir-or molnupiravir-treated participants. Incidence of most post-COVID conditions was similar across comparison groups. Conclusions: Nirmatrelvir-ritonavir was highly effective in preventing 30-day hospitalization and death. Short-term benefit from molnupiravir was observed in older groups. Significant reductions in adverse outcomes from 31-180 days were not observed with either antiviral. for use under a CC0 license.

References

Adjei, Hong, Molinari, Bull-Otterson, Ajani et al., Mortality Risk Among Patients Hospitalized Primarily for COVID-19 During the Omicron and Delta Variant Pandemic Periods -United States, April 2020, MMWR Morb Mortal Wkly Rep

Aggarwal, Molina, Beaty, Bennett, Carlson et al., Real-world Use of Nirmatrelvir-Ritonavir in COVID-19 Outpatients During the Emergence of Omicron Variants BA, BA2

Al-Aly, Xie, Bowe, High-dimensional characterization of post-acute sequelae of COVID-19, Nature

Arbel, Sagy, Hoshen, Battat, Lavie et al., Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge, N Engl J Med

Austin, Cafri, Variance estimation when using propensity-score matching with replacement with survival or time-to-event outcomes, Stat Med

Bajema, Wang, Hynes, Rowneki, Hickok et al., Early Adoption of Anti-SARS-CoV-2 Pharmacotherapies Among US Veterans With Mild to Moderate COVID-19, January and February, JAMA Network Open

Bernal, Da Silva, Musungaie, Kovalchuk, Gonzalez et al., Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients, N Engl J Med

Butler, None

Dickerman, Gerlovin, Madenci, Kurgansky, Ferolito et al., Comparative Effectiveness of BNT162b2 and mRNA-1273 Vaccines in U.S. Veterans, N Engl J Med

Dryden-Peterson, Kim, Kim, Caniglia, Lennes et al., Nirmatrelvir plus ritonavir for early COVID-19 and hospitalization in a large US health system

Hammond, Leister-Tebbe, Gardner, Abreu, Wisemandle, Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19, N Engl J Med

Hernán, Robins, Using Big Data to Emulate a Target Trial When a Randomized Trial Is Not Available, Am J Epidemiol

Ioannou, Locke, Green, Berry, Comparison of Moderna versus Pfizer-BioNTech COVID-19 vaccine outcomes: A target trial emulation study in the U.S. Veterans Affairs healthcare system, EClinicalMedicine

Ioannou, Locke, Green, Berry, Hare et al., Risk Factors for Hospitalization, Mechanical Ventilation, or Death Among 10 131 US Veterans With SARS-CoV-2 Infection, JAMA Netw Open

Ioannou, Locke, Hare, Bohnert, Boyko et al., COVID-19 Vaccination Effectiveness Against Infection or Death in a National U.S. Health Care System : A Target Trial Emulation Study, Ann Intern Med

Labrecque, Swanson, Target trial emulation: teaching epidemiology and beyond, Eur J Epidemiol

Lance, Csp-Cerc, VA Connecticut Healthcare System

Lewnard, Malden, Hong, Puzniak, Kim et al., Effectiveness of nirmatrelvir-ritonavir against hospital admission: a matched cohort study in a large US healthcare system

Maffucci, Va, Nicholas, Smith, Mph, VA Connecticut Healthcare System

Najjar-Debbiny, Gronich, Weber, Khoury, Amar et al., Effectiveness of Paxlovid in Reducing Severe COVID-19 and Mortality in High Risk Patients, Clin Infect Dis

Osborne, Veigulis, Arreola, Röösli, Curtin, Automated EHR score to predict COVID-19 outcomes at US Department of Veterans Affairs, PLoS One

Randall, Stern, Su, Pageshttps

Wong, Au, Lau, Lau, Cowling et al., Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the omicron wave in Hong Kong: an observational study, Lancet

Xie, Bowe, Al-Aly, Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status, Nat Commun

Xie, Choi, Al-Aly, Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19, medRxiv

Xie, Xu, Al-Aly, Risks of mental health outcomes in people with covid-19: cohort study, BMJ

Xie, Xu, Bowe, Al-Aly, Long-term cardiovascular outcomes of COVID-19, Nat Med

Yip, Lui, Lai, Wong, Tse et al., Impact of the use of oral antiviral agents on the risk of hospitalization in community COVID-19 patients, Clin Infect Dis

{ 'institution': [{'name': 'medRxiv'}], 'indexed': {'date-parts': [[2022, 12, 7]], 'date-time': '2022-12-07T06:15:11Z', 'timestamp': 1670393711776}, 'posted': {'date-parts': [[2022, 12, 6]]}, 'group-title': 'Infectious Diseases (except HIV/AIDS)', 'reference-count': 0, 'publisher': 'Cold Spring Harbor Laboratory', 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'accepted': {'date-parts': [[2022, 12, 6]]}, 'abstract': 'Background: Information about the effectiveness of oral antivirals in preventing ' 'short- and long-term COVID-19-related outcomes during the Omicron surge is limited. We sought ' 'to determine the effectiveness of nirmatrelvir-ritonavir and molnupiravir for the outpatient ' 'treatment of COVID-19. Methods: We conducted three retrospective target trial emulation ' 'studies comparing matched patient cohorts who received nirmatrelvir-ritonavir versus no ' 'treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir ' 'in the Veterans Health Administration (VHA). Participants were Veterans in VHA care at risk ' 'for severe COVID-19 who tested positive for SARS-CoV-2 in the outpatient setting during ' 'January and February 2022. Primary outcomes included all-cause 30-day hospitalization or ' 'death and 31-180-day incidence of acute or long-term care admission, death, or post-COVID-19 ' 'conditions. For 30-day outcomes, we calculated unadjusted risk rates, risk differences, and ' 'risk ratios. For 31-180-day outcomes, we used unadjusted time-to-event analyses. Results: ' 'Participants were 90% male with median age 67 years and 26% unvaccinated. Compared to matched ' 'untreated controls, nirmatrelvir-ritonavir-treated participants (N=1,587) had a lower 30-day ' 'risk of hospitalization (27.10/1000 versus 41.06/1000, risk difference [RD] -13.97, 95% CI ' '-23.85 to -4.09) and death (3.15/1000 versus 14.86/1000, RD -11.71, 95% CI -16.07 to -7.35). ' 'Among persons who were alive at day 31, further significant reductions in 31-180-day ' 'incidence of hospitalization (sub-hazard ratio 1.07, 95% CI 0.83 to 1.37) or death (hazard ' 'ratio 0.61, 95% CI 0.35 to 1.08) were not observed. Molnupiravir-treated participants aged ' '≥65 years (n=543) had a lower combined 30-day risk of hospitalization or death (55.25/1000 ' 'versus 82.35/1000, RD -27.10, 95% CI -50.63 to -3.58). A statistically significant difference ' 'in 30-day or 31-180-day risk of hospitalization or death was not observed between matched ' 'nirmatrelvir- or molnupiravir-treated participants. Incidence of most post-COVID conditions ' 'was similar across comparison groups. Conclusions: Nirmatrelvir-ritonavir was highly ' 'effective in preventing 30-day hospitalization and death. Short-term benefit from ' 'molnupiravir was observed in older groups. Significant reductions in adverse outcomes from ' '31-180 days were not observed with either antiviral.', 'DOI': '10.1101/2022.12.05.22283134', 'type': 'posted-content', 'created': {'date-parts': [[2022, 12, 7]], 'date-time': '2022-12-07T05:15:22Z', 'timestamp': 1670390122000}, 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. ' 'Veterans: target trial emulation studies with one-month and six-month outcomes', 'prefix': '10.1101', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-3229-5590', 'authenticated-orcid': False, 'given': 'Kristina L.', 'family': 'Bajema', 'sequence': 'first', 'affiliation': []}, {'given': 'Kristin', 'family': 'Berry', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-1261-0098', 'authenticated-orcid': False, 'given': 'Elani', 'family': 'Streja', 'sequence': 'additional', 'affiliation': []}, {'given': 'Nallakkandi', 'family': 'Rajeevan', 'sequence': 'additional', 'affiliation': []}, {'given': 'Yuli', 'family': 'Li', 'sequence': 'additional', 'affiliation': []}, {'given': 'Lei', 'family': 'Yan', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-7924-8372', 'authenticated-orcid': False, 'given': 'Francesca', 'family': 'Cunningham', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-6436-7157', 'authenticated-orcid': False, 'given': 'Denise M.', 'family': 'Hynes', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-9213-5134', 'authenticated-orcid': False, 'given': 'Mazhgan', 'family': 'Rowneki', 'sequence': 'additional', 'affiliation': []}, {'given': 'Amy', 'family': 'Bohnert', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-3695-192X', 'authenticated-orcid': False, 'given': 'Edward J.', 'family': 'Boyko', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-4226-9310', 'authenticated-orcid': False, 'given': 'Theodore J.', 'family': 'Iwashyna', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0003-1765-5938', 'authenticated-orcid': False, 'given': 'Matthew L.', 'family': 'Maciejewski', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-8896-2487', 'authenticated-orcid': False, 'given': 'Thomas F.', 'family': 'Osborne', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-7439-6322', 'authenticated-orcid': False, 'given': 'Elizabeth M.', 'family': 'Viglianti', 'sequence': 'additional', 'affiliation': []}, {'given': 'Mihaela', 'family': 'Aslan', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-1217-0002', 'authenticated-orcid': False, 'given': 'Grant D.', 'family': 'Huang', 'sequence': 'additional', 'affiliation': []}, {'given': 'George N.', 'family': 'Ioannou', 'sequence': 'additional', 'affiliation': []}], 'member': '246', 'container-title': [], 'original-title': [], 'link': [ { 'URL': 'https://syndication.highwire.org/content/doi/10.1101/2022.12.05.22283134', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 12, 7]], 'date-time': '2022-12-07T05:15:22Z', 'timestamp': 1670390122000}, 'score': 1, 'resource': {'primary': {'URL': 'http://medrxiv.org/lookup/doi/10.1101/2022.12.05.22283134'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 12, 6]]}, 'references-count': 0, 'URL': 'http://dx.doi.org/10.1101/2022.12.05.22283134', 'relation': {}, 'published': {'date-parts': [[2022, 12, 6]]}, 'subtype': 'preprint'}

Download Image

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0