A Retrospective Observational Study on COVID-19 Patients Receiving Treatment with Nirmatrelvir/Ritonavir (PAXLOVID)

Murad et al., Pulmonary Therapy, doi:10.1007/s41030-025-00316-z, Oct 2025
Retrospective 3,011 outpatients in Bahrain showing lower hospitalization with paxlovid treatment. However, the study has significant methodological limitations that likely substantially overestimate paxlovid's benefit:
Contraindicated/sicker patients likely contaminate the control group: authors do not appear to have excluded all contraindicated patients in the control group (and likely do not have the data to do so), therefore patients with severe liver disease, severe CKD, or major drug interactions may have been placed in the "declined" group rather than excluded, systematically loading the control arm with higher-risk patients.
Severe confounding by indication inadequately adjusted: the untreated group had far more cardiopulmonary disease (50% vs 31%), more patients aged ≥75 (20% vs 7%), and more high-risk WHO classification (10% vs 5%), yet the primary analysis adjusted only for a crude 3-level WHO risk variable. The propensity score sensitivity analysis attenuated several findings to non-significance, confirming confounding explains a substantial portion of the effect.
The abstract claims no difference in age, vaccination, or viral load between groups, but Tables 1–2 show highly significant differences (age p<0.001; vaccination p<0.001), and viral load data doesn't appear anywhere in the paper.
Seelction bias: treated patients were younger and more vaccinated. The primary models adjusted only for coarse WHO risk categories, not for age or vaccination.
Undisclosed conflicts of interest: seven of fourteen authors are Pfizer employees, Pfizer funded the study and contributed to design, interpretation, writing, and submission - yet all authors declare "nothing to disclose."
Asymmetric follow-up methods: treated patients received structured day-5 telephone follow-up; untreated patients had only passive EMR review, creating differential outcome ascertainment.
Retrospective registration and long publication delay: the study was registered approximately 2 years after data collection, with a 3-year gap to submission, removing safeguards against outcome switching and raising selective reporting concerns.
Table 2 arithmetic error: the low-risk category total is reported as 327 but the treated + untreated columns sum to only 177, a discrepancy of 150 patients.
Adverse event reporting gaps: adverse events were collected for only 1,427 of 2,005 treated patients (71%) with no explanation, and the 85% dysgeusia rate is an order of magnitude higher than clinical trial literature.
Reasons for non-compliance (n=160+125+117=402) exceed the number of non-compliant patients (n=277) without explanation.
Overall, the confounding issues could plausibly account for the entire observed treatment effect.
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.
Murad et al., 6 Oct 2025, retrospective, Bahrain, peer-reviewed, 14 authors, study period February 2020 - September 2021. Contact: mmurad@rcsi.com, satkin@rcsi-mub.com, psulaiman@rcsi-mub.com, dr.abehzad@gmail.com, dr.aamalmohamed@gmail.com, florencelefebvredhellencourt@gmail.com, lu.wang4@pfizer.com, moe.kyaw@pfizer.com, jean.joury@pfizer.com, mohamed.abdelaziz@pfizer.com, hammam.haridy@pfizer.com, julia.spinardi@pfizer.com, fionaboland@rcsi.ie, manaf.alqahtani@rms.bh.
A Retrospective Observational Study on COVID-19 Patients Receiving Treatment with Nirmatrelvir/Ritonavir (PAXLOVID)
Mariam M Murad, Stephen L Atkin, Pearl W Wasif, Alwaleed Abdulaziz Behzad, Aamal M J Abdulla Husain, Florence Lefebvre D’hellencourt, Jean Joury, Mohamed Abdel Aziz, Hammam Haridy, Julia Spinardi, Lu Wang, Fiona Boland, Moe H Kyaw, Manaf Al-Qahtani
Pulmonary Therapy, doi:10.1007/s41030-025-00316-z
Introduction: This study was undertaken in COVID-19 patients treated with and without Paxlovid™ (Paxlovid) in an outpatient setting to determine hospitalization from the community. Methods: This retrospective secondary data observational cohort study was conducted between February and November 2022. All patients diagnosed by polymerase chain reaction for COVID-19 and at risk of COVID-19 disease progression were offered Paxlovid in the outpatient setting. Potential associations between Paxlovid use and likelihood of hospitalization, antibiotic use, and other clinical outcomes were explored using regression models as appropriate
Funding. This study was conducted as a collaboration between RCSI Medical University of Bahrain and Pfizer. The study was funded by Pfizer grant number 76181715. The funder contributed to the study design, to the interpretation of the data, to the writing of the manuscript, and to the decision to submit the manuscript for publication and payment of rapid service fees. Representatives of Pfizer were not involved in the collection, management, and analysis of data. Data Availability. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Upon request, and subject to review, the study sponsor, RCSI Medical University of Bahrain, will provide data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, RCSI Medical University of Bahrain may also provide access to the related individual de-identified participant data. Contact RCSI Medical University of Bahrain for more information. Declarations Ethics approval. The study was conducted according to the guidelines and approved by the National COVID-19 Taskforce ethical Pulm Ther approval, obtained in June 2023 for this retrospective study (CRT-COVID2022-160). A waiver which aligns with FDA guidelines that permits us to use the participants' information for this study, including for publication purposes, was obtained from the National COVID-19 Taskforce ethics committee, allowing us to proceed without..
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Please send us corrections, updates, or comments. c19early involves the extraction of 200,000+ 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. IMA and WCH provide treatment protocols.
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