Paxlovid shows organ-specific and age-specific impacts on risk of developing post-acute sequelae of COVID-19
et al., Communications Medicine, doi:10.1038/s43856-026-01535-4, Mar 2026
Retrospective 19,413 COVID-19 outpatient and hospitalized patients showing no overall reduction in long COVID risk with paxlovid. Stratification by organ system found a 37% reduction in gastrointestinal PASC (OR 0.63, p=0.002) - biologically plausible given oral drug absorption through gut tissue with established viral tropism - and a 97.4% increase in eye/ear PASC (OR 1.97, p=0.035). A sensitivity analysis of non-hospitalized patients aged 60-75 found a modest 16% reduction (OR 0.84, p=0.044), but this required subsetting to reach significance while the authors did not discuss a near-significant harm signal in the 75+ group (OR 1.21, p=0.064) - the primary target population for paxlovid. Disease severity was measured using only three crude categories (outpatient/hospitalized/ICU), with 85-99% of each group classified as outpatient, meaning the severity covariate had no discriminating power for the vast majority of the cohort and cannot address confounding by indication within outpatients. The control group was not restricted to paxlovid-eligible patients, meaning contraindicated (likely sicker) patients contaminate the comparator, expected to overestimate benefit. Paxlovid recipients differ substantially by race, vaccination, and hospitalization (2% vs 9%), suggesting significant healthy-user and access bias that entropy balancing on observed covariates is unlikely to fully resolve. No adjustment for multiple comparisons was performed across dozens of tests - the eye/ear and non-hospitalized 60-75 findings do not survive Bonferroni correction. The abstract contradicts the main text, reporting OR 0.832 for non-hospitalized age range 65-75, while the results report OR 0.837 for a different age range 60-75. The supplementary methodology describes a different matched case-control design spanning 2020-2023 with 2018 pre-pandemic controls and minimum one-year follow-up, contradicting the main text's January-June 2022 cohort design with median 4.5-month follow-up.
The biases in this study all point towards making paxlovid look better than it actually is - confounding by contraindication, healthy-user bias, access bias, crude severity measurement and confounding by indication, and confounding by adjuvant treatment will all overestimate benefit. After correction, the signal for harm in the 75+ group is likely to become significant (currently p=0.06). This is biologically plausible - the 75+ group is where paxlovid's drug interaction profile creates the greatest risk of iatrogenic harm.
Ritonavir is one of the most potent CYP3A4 inhibitors known. It was originally developed as an HIV protease inhibitor but is used in paxlovid purely as a pharmacokinetic booster to block the liver enzyme that would otherwise rapidly metabolize nirmatrelvir. However, CYP3A4 also metabolizes a huge number of other drugs, and blocking it for 5 days dramatically raises blood levels of other CYP3A4-metabolized drugs the patient is taking. Even after the 5-day course ends, the downstream effects of the pharmacokinetic disruption may trigger a cascade of complications. There is also a more direct mechanism - elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require an adjustment in the dose for patients receiving ritonavir. Reduced hepatic and renal clearance means both nirmatrelvir and ritonavir persist at higher concentrations for longer, potentially turning the standard 5-day dose into an overdose in some elderly patients with subclinical organ impairment.
Resistance. Variants may be resistant to paxlovid1-8. Use may promote the emergence of variants that weaken host immunity and potentially contribute to long COVID9. Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of Paxlovid10. 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 paxlovid11. Kidney and liver injury. Studies show significantly increased risk of acute kidney injury12 and liver injury13,14. Viral rebound. Studies show significantly increased risk of replication-competent viral rebound15-17.
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.
|
risk of long COVID, 6.7% higher, HR 1.07, p = 0.29, all patients.
|
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risk of long COVID, 1.3% higher, HR 1.01, p = 0.94, <45.
|
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risk of long COVID, 11.5% higher, HR 1.11, p = 0.36, 45-60.
|
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risk of long COVID, 5.7% lower, HR 0.94, p = 0.55, 60-75.
|
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risk of long COVID, 21.4% higher, HR 1.21, p = 0.06, >75.
|
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risk of long COVID, 1.7% higher, HR 1.02, p = 0.85, all patients.
|
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risk of long COVID, 5.5% higher, HR 1.05, p = 0.73, outpatients, <45.
|
|
risk of long COVID, 8.2% higher, HR 1.08, p = 0.51, outpatients, 45-60.
|
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risk of long COVID, 16.3% lower, HR 0.84, p = 0.04, outpatients, 60-75.
|
|
risk of long COVID, 16.9% higher, HR 1.17, p = 0.13, outpatients, >75.
|
| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
1.
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.
2.
Moghadasi et al., Rapid resistance profiling of SARS-CoV-2 protease inhibitors, npj Antimicrobials and Resistance, doi:10.1038/s44259-023-00009-0.
3.
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.
4.
Lopez et al., SARS-CoV-2 Resistance to Small Molecule Inhibitors, Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6.
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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.
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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.
7.
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.
8.
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.
9.
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.
10.
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.
11.
FDA, Fact sheet for healthcare providers: emergency use authorization for paxlovid, www.fda.gov/media/155050/download.
12.
Kamo et al., Association of Antiviral Drugs for the Treatment of COVID-19 With Acute Renal Failure, In Vivo, doi:10.21873/invivo.13637.
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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.
14.
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.
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Edelstein et al., SARS-CoV-2 virologic rebound with nirmatrelvir-ritonavir therapy, medRxiv, doi:10.1101/2023.06.23.23288598.
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Shah et al., SARS-CoV-2 infectious shedding and rebound among adults with and without oral antiviral use: two case-ascertained prospective household studies, The Lancet Microbe, doi:10.1016/j.lanmic.2025.101227.
Azhir et al., 24 Mar 2026, retrospective, USA, peer-reviewed, 5 authors, study period 1 January, 2022 - 7 June, 2022.
Contact: hestiri@mgh.harvard.edu.
Abstract: ARTICLE IN PRESS
Communications Medicine
https://doi.org/10.1038/s43856-026-01535-4
Article in Press
Paxlovid shows organ-specific and age-specific
impacts on risk of developing post-acute sequelae
of COVID-19
Alaleh Azhir, Jingya Cheng, Jiazi Tian, Shawn N. Murphy & Hossein Estiri
S
Received: 1 May 2025
PR
We are providing an unedited version of this manuscript to give early access to its
findings. Before final publication, the manuscript will undergo further editing. Please
note there may be errors present which affect the content, and all legal disclaimers
apply.
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If this paper is publishing under a Transparent Peer Review model then Peer
Review reports will publish with the final article.
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C
Cite this article as: Azhir, A., Cheng, J.,
Tian, J. et al. Paxlovid shows organspecific and age-specific impacts on
risk of developing post-acute
sequelae of COVID-19. Commun Med
(2026). https://doi.org/10.1038/
s43856-026-01535-4
ES
Accepted: 9 March 2026
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ARTICLE IN PRESS
Paxlovid shows organ-specific and age-specific
impacts on risk of developing post-acute sequelae of
COVID-19
Alaleh Azhir, MD, MSc1,2*; Jingya Cheng, M.B.1*; Jiazi Tian, M.Sc.1; Shawn N. Murphy, MD, PhD3
Hossein Estiri, PhD1†
1 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
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2 Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
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TI
C
LE
IN
PR
ES
3 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
* contributed equally
† Corresponding author: Hossein Estiri
Email: hestiri@mgh.harvard.edu
399 Revolution Drive, Suite 790, Somerville, MA, 02145, USA
ARTICLE IN PRESS
Abstract
Background: The impact of antiviral therapies, including Paxlovid, on post-acute sequelae of
COVID-19 (PASC) remains inconclusive.
S
Methods: We analyzed data from 19,413 patients (age > 18) from a validated PASC research
cohort in New England who experienced at least one COVID-19 infection episode between
January 1, 2022, and June 7, 2022, totaling 22,094 episodes. Multivariable logistic regression
with inverse probability weights was used to infer the causal effects of Paxlovid treatment during
acute infection and the risk of PASC overall (primary outcome), stratified by age group and organ
system.
IN
PR
ES
Results: Across all age groups, Paxlovid shows no statistically significant effect in lowering overall
PASC risk. Stratification by organ system reveals a..
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