Nirmatrelvir and Molnupiravir and Post–COVID-19 Condition in Older Patients
et al., JAMA Internal Medicine, doi:10.1001/jamainternmed.2023.5099, Oct 2023
Retrospective 8,089 molnupiravir patients in the USA showing a small reduction in long COVID with treatment.
Confounding is likely significant as below, and may eliminate the benefit. Results specific to the COVID-19 code should be closer to the actual efficacy due to likely lower average severity of the additional treatment patients included based on home tests.
Confounding by treatment propensity. This study analyzes a population
where only a fraction of eligible patients received the treatment. Patients
receiving treatment may be more likely to follow other recommendations, more
likely to receive additional care, and more likely to use additional
treatments that are not tracked in the data (e.g., nasal/oral hygiene1,2, vitamin D3, etc.) — either because the physician
recommending molnupiravir also recommended them, or
because the patient seeking out molnupiravir is more
likely to be familiar with the efficacy of additional treatments and more
likely to take the time to use them.
Therefore, these kind of studies may
overestimate the efficacy of treatments.
Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity4-18. Multiple analyses have identified variants potentially created by molnupiravir19-23.
Standard of Care (SOC) for COVID-19 in the study country,
the USA, is very poor with very low average efficacy for approved treatments24.
Only expensive, high-profit treatments were approved for early treatment. Low-cost treatments were excluded, reducing the probability of early treatment due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.
Study covers paxlovid and molnupiravir.
|
risk of long COVID, 4.0% lower, HR 0.96, p = 0.001, COVID-19 only, Cox proportional hazards.
|
|
risk of long COVID, 8.0% lower, HR 0.92, p < 0.001, including patients without COVID-19 code, Cox proportional hazards.
|
| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
4.
Swanstrom et al., Lethal mutagenesis as an antiviral strategy, Science, doi:10.1126/science.abn0048.
5.
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.
13.
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.
14.
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.
15.
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.
16.
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.
17.
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.
18.
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.
19.
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.
20.
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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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.
Fung et al., 23 Oct 2023, retrospective, USA, peer-reviewed, 4 authors, study period January 2022 - September 2022.
Contact: kfung@mail.nih.gov.
Abstract: Letters
RESEARCH LETTER
Nirmatrelvir and Molnupiravir and Post–COVID-19
Condition in Older Patients
While the COVID-19 pandemic appears to be winding down, its
effects are still felt by the millions of people worldwide experiencing post–COVID-19 condition (PCC, or long COVID).1 The
antiviral drug nirmatrelvir (marketed as Paxlovid [Pfizer], in
combination with ritonavir)
and molnupiravir (Lagevrio
Supplemental content
[Merch]) are recommended as
first- and second-line treatments for acute illness in patients with
specific risk factors (eg, diabetes).2 However, there are still no
US Food and Drug Administration–approved drugs for the treatment or prevention of PCC. Recent studies among US veterans
(mostly male) suggest that nirmatrelvir and molnupiravir reduce the risk of some sequelae of COVID-19.3,4 We performed a
cohort study of the 2 drugs in PCC in older patients who were
Medicare enrollees.
Methods | The cohort came from Medicare enrollees aged 65
years or older diagnosed with COVID-19 between January
and September 2022. COVID-19 was identified with an
outpatient International Statistical Classif ication of
Diseases, Tenth Revision, Clinical Modification code of
U07.1. In January 2022, free home COVID-19 tests became
available and not all positive self-tests were captured in
Medicare data. Therefore, we also considered the prescription of nirmatrelvir or molnupiravir to be indicative of
COVID-19 because no other indications existed. Following
previous work, 5 we identified PCC based on the World
Health Organization (WHO) consensus clinical definition.6
Any new occurrence (not present prior to COVID-19 diagnosis) of the 11 symptoms between 4 to 12 weeks after infection was considered as PCC. We used an extended Cox
regression with propensity score adjustment to examine the
2 drugs and the incidence of PCC. We included age, sex,
race, geographic region, dual eligibility, low-income subsidy, and 51 chronic comorbidities as covariates as included
Table 1. Hazard Ratio Based on Cox Regression Modela
Event rate, % (95% CI)
Index variable
Reference
No. (%)
Hazard ratio (95% CI)
Index group
Reference group
Absolute risk
reductionb
Nirmatrelvir
None
439 134 (19.5)
0.87 (0.86 to 0.88)
11.8 (11.7 to 11.9)
14.5 (14.4 to 14.6)
2.7
Molnupiravir
None
58 914 (2.6)
0.92 (0.90 to 0.94)
13.7 (13.5 to 14.0)
14.5 (14.4 to 14.6)
0.8
Female
Male
1 313 415 (58.5)
1.17 (1.16 to 1.18)
14.5 (14.4 to 14.6)
13.2 (13.1 to 13.2)
−1.3
70-74
65-69
656 324 (29.2)
0.78 (0.77 to 0.79)
12.7 (12.7 to 12.8)
12.0 (11.9 to 12.1)
−0.7
75-79
65-69
509 291 (22.7)
0.70 (0.69 to 0.71)
14.2 (14.1 to 14.3)
12.0 (11.9 to 12.1)
−2.2
80-84
65-69
324 008 (14.4)
0.64 (0.63 to 0.66)
15.8 (15.7 to 16.0)
12.0 (11.9 to 12.1)
−3.8
≥85
65-69
313 754 (14.0)
0.61 (0.60 to 0.63)
16.9 (16.7 to 17.0)
12.0 (11.9 to 12.1)
−4.9
Asian
White
81 073 (3.6)
1.10 (1.07 to 1.12)
13.3 (13.0 to 13.5)
13.9 (13.9 to 14.0)
0.6
Black
White
82 249 (3.7)
1.24 (1.22 to 1.27)
15.3 (15.0 to 15.5)
13.9 (13.9 to 14.0)
−1.4
Hispanic
White
93 325 (4.2)
1.02 (1.00 to 1.04)
15.4 (15.1 to 15.6)
13.9 (13.9 to 14.0)
−1.5
Otherd
White
93 011 (4.1)
1.04 (1.02 to 1.06)
12.4 (12.1 to 12.6)
13.9 (13.9 to 14.0)
1.5
Dual eligibility
Nondual
244 874 (10.9)
1.06 (1.05 to 1.08)
16.6 (16.5 to 16.8)
13.6 (13.5 to 13.6)
−3.0
Low-income subsidy
Nondual
21 049 (0.9)
1.07 (1.03 to 1.10)
16.4 (15.9 to 16.9)
13.6 (13.5 to..
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