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Review 2: "The Safety of Antivirals and Neutralising Monoclonal Antibodies Used in Prehospital Treatment of Covid-19"

Reviewers emphasize addressing potential confounding factors and providing more comprehensive methodological details for stronger conclusions.

Published onJun 13, 2024
Review 2: "The Safety of Antivirals and Neutralising Monoclonal Antibodies Used in Prehospital Treatment of Covid-19"
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key-enterThis Pub is a Review of
The safety of antivirals and neutralising monoclonal antibodies used in prehospital treatment of Covid-19
The safety of antivirals and neutralising monoclonal antibodies used in prehospital treatment of Covid-19

Abstract Objective This proof-of-principle pharmacovigilance study used Electronic Health Record (EHR) data to examine the safety of sotrovimab, paxlovid and molnupiravir in prehospital treatment of Covid-19.Method With NHS England approval, we conducted an observational cohort study using OpenSAFELY-TPP, a secure software-platform which executes analyses across EHRs for 24 million people in England. High-risk individuals with Covid-19 eligible for prehospital treatment were included. Adverse events (AEs) were categorised into events in the drug’s Summary of Product Characteristics (SmPC), drug-reactions and immune-mediated. Cox models compared risk across treatments. A pre-pandemic record analysis was performed for comparative purposes.Results Between 2021-2023, 37,449 patients received sotrovimab, paxlovid or molnupiravir whilst 109,647 patients made up an eligible-but-untreated population. The 29-day rates of AEs were low: SmPC 0.34 per 1000 patient-years (95%CI 0.32-0.36); drug-reactions 0.01(95% CI0.01-0.02) and immune-mediated 0.03(95%CI 0.03-0.04), and similar or lower than the pre-pandemic period. Compared with the eligible but untreated population, sotrovimab and paxlovid associated with a risk of SmPC AE [adjHR 1.36(95%CI 1.15-1.62) and 1.28(95%CI 1.05-1.55), respectively], whilst sotrovimab associated with a risk of drug-reactions [adjHR 2.95(95%CI 1.56-5.55)] and immune-mediated events [adjHR 3.22(95%CI 1.86-5.57)].Conclusion Sotrovimab, paxlovid and molnupiravir demonstrate acceptable safety profiles. Although the risk of AEs was greatest with sotrovimab, event rates were lower than comparative pre-pandemic period.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.


Review: The authors conducted an observational study based on UK OpenSAFELY-TPP recorded patients between 2021-2023, comparing 37,449 sotrovimab, paxlovid or molnupiravir treated patients versus 109,648 eligible-but-untreated patients, to see the adverse events of those COVID-19 treatments at 29-days after the infection.

First, overall good job for generating real-world safety evidence of those COVID-19 treatments in UK. There are several issues needed to be addressed:

  1. The authors claimed trial emulation method. It is informative to explicitly show the hypothetical trial protocols and how to emulate them.

  2. Regarding the COVID-19 identification, did authors consider the 1st documented COVID-19 infection or also considering the reinfection?

  3. There lack balance performance after adjustment.

  4. The biggest potential concern is the competing risk. The acute mortality is the competing risk which precludes the happening of the AEs. Not sure if the cox model considered the competing risks and the cumulative incidence need to be reported. If not, the conclusions might not be valid, because according to both RCTs and RWE, those COVID-19 treatments significantly reduce acute death, and thus in the untreated groups the acute death preclude the AEs's happening and thus the directionality might be reversed.

  5. An sensitivity analyses based on different infection time should be conducted considering different variants-of-concerns and the accessibility of treatments overtime change over time.

  6. Long term AES are also of interests.

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