Antiviral treatment for COVID-19: ensuring evidence is applicable to current circumstances.

E996 CMAJ | July 25, 2022 | Volume 194 | Issue 28 © 2022 CMA Impact Inc. or its licensors In related research, Pitre and colleagues1 present the findings of a network meta-analysis that sought to establish the relative efficacy of oral antiviral therapies in reducing the risk of hospital admission or death in patients with mild-to-moderate COVID-19. This is an important patient population to enroll in randomized trials, as most patients with COVID-19 have mild disease and are treated as outpatients. The authors conclude that there is compelling evidence supporting the efficacy of nirmatrelvir–ritonavir and molnupiravir in reducing the risk death or hospital admission. The challenge lies in applying the findings to current patients with COVID-19. The largest trial on nirmatrelvir–ritonavir, EPIC-HR, which was included in the network meta-analysis, enrolled unvaccinated participants who were infected with the Delta variant and had no evidence of previous SARS-CoV-2 infection.2 Yet, currently, 83% of eligible people in Canada have received 2 doses of SARS-CoV-2 vaccine, which confers a high degree of protection against the same outcomes as these therapies have been shown to prevent.3–5 Many people who acquire SARS-CoV-2 now have had a previous infection, and most recent cases have been infected with Omicron subvariants, which are less virulent than Delta.6 Nirmatrelvir–ritonavir is likely less effective in the real-world setting than suggested by the findings of the related network metaanalysis. Indeed, the manufacturer of nirmtrelvir–ritonavir recently terminated a trial that included vaccinated patients who were enrolled during the Omicron wave after an interim analysis found no statistically significant reduction in hospital admissions or deaths.7 A recent observational study examining the effectiveness of nirmatrelvir–ritonavir among vaccinated patients infected with Omicron and without evidence of previous infection concluded that it was effective in reducing severe COVID-19; however, estimates of its effectiveness in preventing severe COVID-19 or death was lower than was observed in the EPIC-HR trial.8 Indeed, the study suggested that vaccination alone was as or more effective than nirmatrelvir–ritonavir, and that the effectiveness of nirmatrelvir–ritonavir did not vary by vaccination status.8 Applying available evidence to clinical and policy decisions as the virus and population characteristics evolve is challenging. This is reflected in current Canadian guidelines for the use of novel antiviral drugs, which vary by province in terms of the age groups and comorbidities that define “high risk” to determine eligibility for publicly funded oral antiviral therapy. These therapeutic decisions would benefit from additional evidence from randomized controlled trials (RCTs), but this evidence is unlikely to emerge soon. In a search of clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform and the Cochrane CENTRAL register, we identified only 4 RCTs of monulpiravir or nirmatrelvir–ritonavir with clinical outcomes that were recently completed or actively recruiting, with 1 additional trial in children underway. None of these trials specifically addressed high-risk subgroups (e.g., older adults, immunocompromised people, pregnant patients), which were underrepresented in preapproval trials. The PANORAMIC adaptive platform trial, based in the United Kingdom, is evaluating COVID-19 therapeutics in patients with mild-to-moderate COVID-19 and only recently added nirmatrelvir– ritonavir to its list of study medications.9 Coordinated national and international approaches to rapidly generate the evidence required to guide clinical and policy decisions for COVID-19 therapeutics are sorely needed. National and international adaptive platform trials, which allow researchers to Commentary