Nirmatrelvir and Molnupiravir and Post–COVID-19 Condition in Older Patients

Kin Wah Fung; Fitsum Baye; Seo H. Baik; Clement J. McDonald

Nirmatrelvir and Molnupiravir and Post–COVID-19 Condition in Older Patients

Fung et al., JAMA Internal Medicine, doi:10.1001/jamainternmed.2023.5099, Oct 2023

Retrospective 51,658 paxlovid 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 paxlovid also recommended them, or because the patient seeking out paxlovid is more likely to be familiar with the efficacy of additional treatments and more likely to take the time to use them. Malden et al. confirm significant bias in the use of paxlovid, showing that treated patients are more likely to be from affluent neighborhoods, be more health-conscious, and have better access to care. Therefore, these kind of studies may overestimate the efficacy of treatments.

Resistance. Variants may be resistant to paxlovid5-12. Use may promote the emergence of variants that weaken host immunity and potentially contribute to long COVID13.

Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid14. Retrospective studies that do not exclude contraindicated patients may significantly overestimate efficacy.

Black box warning. The FDA notes that severe, life-threatening, and/or fatal adverse reactions due to drug interactions have been reported in patients treated with paxlovid15.

Kidney and liver injury. Studies show significantly increased risk of acute kidney injury16 and liver injury17.

Standard of Care (SOC) for COVID-19 in the study country, the USA, is very poor with very low average efficacy for approved treatments18. 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.

Important missing comments or errors? Let us know.

Study covers paxlovid and molnupiravir.

risk of long COVID, 7.0% lower, HR 0.93, p < 0.001, COVID-19 only, Cox proportional hazards.

risk of long COVID, 13.0% lower, HR 0.87, p < 0.001, including patients without COVID-19 code, Cox proportional hazards.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. c19early.org, c19early.org/p.

2. c19early.org (B), c19early.org/ph.

3. c19early.org (C), c19early.org/d.

4. Malden et al., Predictors of nirmatrelvir–ritonavir receipt among COVID-19 patients in a large US health system, Scientific Reports, doi:10.1038/s41598-024-57633-7.nature.com, doi.org.

5. Zhou et al., Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system, Science Advances, doi:10.1126/sciadv.add7197.science.org, doi.org.

6. Moghadasi et al., Rapid resistance profiling of SARS-CoV-2 protease inhibitors, npj Antimicrobials and Resistance, doi:10.1038/s44259-023-00009-0.nature.com, doi.org.

7. Jochmans et al., The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir, mBio, doi:10.1128/mbio.02815-22.asm.org, doi.org.

8. Lopez et al., SARS-CoV-2 Resistance to Small Molecule Inhibitors, Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6.springer.com, doi.org.

9. Zvornicanin et al., Molecular Mechanisms of Drug Resistance and Compensation in SARS-CoV-2 Main Protease: The Interplay Between E166 and L50, bioRxiv, doi:10.1101/2025.01.24.634813.biorxiv.org, doi.org.

10. Vukovikj et al., Impact of SARS-CoV-2 variant mutations on susceptibility to monoclonal antibodies and antiviral drugs: a non-systematic review, April 2022 to October 2024, Eurosurveillance, doi:10.2807/1560-7917.ES.2025.30.10.2400252.eurosurveillance.org, doi.org.

11. Deschenes et al., Functional and structural characterization of treatment-emergent nirmatrelvir resistance mutations at low frequencies in the main protease (Mpro) reveals a unique evolutionary route for SARS-CoV-2 to gain resistance, The Journal of Infectious Diseases, doi:10.1093/infdis/jiaf294.oup.com, doi.org.

12. Zhou (B) et al., SARS-CoV-2 Mpro inhibitor ensitrelvir: asymmetrical cross-resistance with nirmatrelvir and emerging resistance hotspots, Emerging Microbes & Infections, doi:10.1080/22221751.2025.2552716.tandfonline.com, doi.org.

13. Thomas et al., Nirmatrelvir-Resistant Mutations in SARS-CoV-2 Mpro Enhance Host Immune Evasion via Cleavage of NF-κB Essential Modulator, bioRxiv, doi:10.1101/2024.10.18.619137.biorxiv.org, doi.org.

14. Hoertel et al., Prevalence of Contraindications to Nirmatrelvir-Ritonavir Among Hospitalized Patients With COVID-19 at Risk for Progression to Severe Disease, JAMA Network Open, doi:10.1001/jamanetworkopen.2022.42140.jamanetwork.com, doi.org.

15. FDA, Fact sheet for healthcare providers: emergency use authorization for paxlovid, www.fda.gov/media/155050/downloadfda.gov.

16. Kamo et al., Association of Antiviral Drugs for the Treatment of COVID-19 With Acute Renal Failure, In Vivo, doi:10.21873/invivo.13637.iiarjournals.org, doi.org.

17. Wang et al., Development and validation of a nomogram to assess the occurrence of liver dysfunction in patients with COVID-19 pneumonia in the ICU, BMC Infectious Diseases, doi:10.1186/s12879-025-10684-1.biomedcentral.com, doi.org.

18. c19early.org (D), c19early.org/soc/usa.html.

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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