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What is the place in therapy for nirmatrelvir/ritonavir?
  1. Todd C Lee1,
  2. Jason M Pogue2,
  3. Erin K McCreary3,
  4. Andrew M Morris4
  1. 1 Clinical Practice Assessment Unit, Department of Medicine, McGill University Faculty of Medicine, Montreal, Québec, Canada
  2. 2 Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA
  3. 3 Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  4. 4 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Todd C Lee, Clinical Practice Assessment Unit, Department of Medicine, McGill University Faculty of Medicine, Montreal, Canada; todd.lee{at}

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The COVID-19 pandemic presents substantial challenges for governments and providers keen to provide effective treatments. The tensions between supply, uncertainty of which patient populations optimally benefit, time-limited effectiveness (due to need for rapid initiation of treatment on an individual level, and viral evolution and potential development of resistance on a population level), and action bias (ie, most providers to want to ‘do something’ for an ailing patient) have incentivised rapid authorisation of therapeutic agents with relatively broad use criteria.1

Nirmatrelvir/ritonavir (Paxlovid, Pfizer) is a combination protease inhibitor that prevents viral replication of SARS-CoV-2 and was authorised for emergency use in December 2021 for patients age ≥12 and weight ≥40 kg who have proven mild to moderate COVID-19 and who are considered at high risk for progression to severe disease.2 This analysis summarises what is currently known about nirmatrelvir/ritonavir and the discord between clinical trial evidence and real-world usage. We will highlight that the evidence on which the drug was granted emergency approval (high-risk unvaccinated patients during the delta wave) and the patients who are being predominantly treated (including vaccinated patients infected with omicron and its sublineages) differ in expected benefit and that large-scale government purchasing and promotion has been based on the former. Indeed, the influence of vaccine-derived and infection-derived immunity on treatment effect remains largely unknown and non-evidence-based use continues to occur widely.

Efficacy demonstrated in Evaluation of protease inhibition for COVID-19 in high risk

The first available data for nirmatrelvir/ritonavir came from the EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) trial.3 This was a randomised clinical trial in symptomatic, unvaccinated individuals at high-risk for complications of SARS-CoV-2 infection who were treated with either nirmatrelvir/ritonavir or placebo within 5 days of onset of symptoms. ‘High risk’ referred to those having at least one of the following medical conditions: ≥60 years of age; body mass index >25 kg/m2; …

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  • Twitter @DrToddLee, @jpogue1, @ErinMcCreary, @ASPphysician

  • Contributors All authors participated in the conceptualisation, drafting and revisions of the manuscript and have given permission to submit for publication. TCL, as corresponding author, is responsible for the overall content as guarantor.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests TCL reports receiving research salary support from Fonds de Recherche du Québec–Santé and peer-reviewed operating grants for COVID-19-related research from the Canadian Institutes of Health Research and being an investigator for several investigator-initiated trials involving outpatients with Covid-19. JMP discloses serving as a consultant to Merck, Shionogi and Roche. EKM discloses serving as a consultant to Shionogi and is the Director of infectious diseases improvement and clinical research innovation at UPMC. In this role, EKM oversaw clinical trials involving use of sotrovimab (donated by GSK) and evaluation of tixagevimab–cilgavimab in outpatients (funded by AstraZeneca). She does not receive salary support or funding for her involvement in these trials. AMM has no competing interest to declare.

  • Provenance and peer review Not commissioned; externally peer reviewed.