TY - JOUR T1 - What is the place in therapy for nirmatrelvir/ritonavir? JF - BMJ Evidence-Based Medicine JO - BMJ EBM DO - 10.1136/bmjebm-2022-112064 SP - bmjebm-2022-112064 AU - Todd C Lee AU - Jason M Pogue AU - Erin K McCreary AU - Andrew M Morris Y1 - 2022/11/16 UR - http://ebm.bmj.com/content/early/2022/11/15/bmjebm-2022-112064.abstract N2 - 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.1Nirmatrelvir/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.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; … ER -