Early triple antiviral therapy for COVID-19
Authors: Nelson Lee, Michael Ison, Jake Dunning
Journal: The Lancet (2020)

In the trial led by Ivan Hung and colleagues,1Hung IF Lung KC Tso EY et al.Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial.Lancet. 2020; 395: 1695-1704Summary Full Text Full Text PDF PubMed Scopus (1130) Google Scholar adults admitted to hospital with COVID-19 received two antiviral treatment combinations. In the combination group, 52 (60%) of 86 patients received interferon beta-1b (most patients received one to two doses), lopinavir–ritonavir, and ribavirin, based on the time elapsed from symptom onset to the start of study treatment (median 5 days [IQR 4–7]). However, 34 (40%) patients had interferon beta-1b omitted due to concerns of proinflammatory side-effects in patients who started treatment 7 days or more after symptom onset. In the lopinavir–ritonavir control group, 24 (59%) of 41 patients started treatment less than 7 days from symptom onset, and 17 (41%) started 7 days or more after symptom onset. Although the results suggest accelerated viral clearance with interferon beta-1b, the clinical efficacy of the triple combination is difficult to assess for several reasons. We are concerned with the absence of a more appropriate control group (either a placebo or no intervention group) and the doubtful efficacy of lopinavir–ritonavir and ribavirin (concerns are summarised in the appendix),2Kain T Lindsay PJ Adhikari NKJ Arabi YM Van Kerkhove MD Fowler RA Pharmacologic treatments and supportive care for Middle East respiratory syndrome.Emerg Infect Dis. 2020; 26: 1102-1112Crossref PubMed Google Scholar, 3Arabi YM Shalhoub S Mandourah Y et al.Ribavirin and interferon therapy for critically ill patients with Middle East respiratory syndrome: a multicenter observational study.Clin Infect Dis. 2020; 70: 1837-1844Crossref PubMed Scopus (185) Google Scholar, 4Cao B Wang Y Wen D et al.A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19.N Engl J Med. 2020; 382: 1787-1799Crossref PubMed Scopus (3846) Google Scholar shown by the non-significant results from the subgroup analysis in the combination group without interferon. Further reasons for concern are the omission of interferon beta-1b in 40% of the intended population, and the clinical efficacy might also be difficult to assess in most patients with mild to moderate COVID-19 symptoms who exhibit quick spontaneous viral clearance and clinical resolution (low baseline national early warning score 2 score of 2 [IQR 1–2], day 1 score of 1 [1–2], and baseline sequential organ failure assessment score of 0 [0–1] in the combination group).5Wölfel R Corman VM Guggemos W et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581: 465-469Crossref PubMed Scopus (4681) Google Scholar, 6Zhou F Yu T Du R et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Summary Full Text Full Text PDF PubMed Scopus (18730) Google Scholar Additionally, 17 (13%) of 127 patients required supplemental oxygen, six (5%) were admitted to the intensive care unit, 31 (24%) had a normal chest x-ray, and all patients with COVID-19 were admitted to hospital for isolation purposes (according to public health ordinance in Hong Kong). The discharge policy was also linked to providing an RNA negative sample, and finally, the study had insufficient power to detect clinical outcome differences, despite the original intent. Since a modest decrease in RNA might not translate into clinical signif­icance, and data on the infectious virus were unavailable, future controlled studies should focus on confirming the efficacy of interferon-based therapies. Exclusion of ribavirin should be considered because of its potentially harmful side-effects (appendix). Better defined trial criteria to include patients with more severe manifestations are needed, even though studies of severe acute respiratory syndrome and Middle East respiratory syndrome coronavirus had not shown substantial safety concerns in later-stage disease.2Kain T Lindsay PJ Adhikari NKJ Arabi YM Van Kerkhove MD Fowler RA Pharmacologic treatments and supportive care for Middle East respiratory syndrome.Emerg Infect Dis. 2020; 26: 1102-1112Crossref PubMed Google Scholar, 3Arabi YM Shalhoub S Mandourah Y et al.Ribavirin and interferon therapy for critically ill patients with Middle East respiratory syndrome: a multicenter observational study.Clin Infect Dis. 2020; 70: 1837-1844Crossref PubMed Scopus (185) Google Scholar Host inflammatory responses are probably important in later-stage COVID-19, thus confounding the assessment of antiviral efficacy in clinical trials. Nonetheless, early intervention trials are important to provide information on the course of mild to moderate COVID-19 and, possibly, to assess anti­viral efficacy overall.3Arabi YM Shalhoub S Mandourah Y et al.Ribavirin and interferon therapy for critically ill patients with Middle East respiratory syndrome: a multicenter observational study.Clin Infect Dis. 2020; 70: 1837-1844Crossref PubMed Scopus (185) Google Scholar, 4Cao B Wang Y Wen D et al.A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19.N Engl J Med. 2020; 382: 1787-1799Crossref PubMed Scopus (3846) Google Scholar, 6Zhou F Yu T Du R et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Summary Full Text Full Text PDF PubMed Scopus (18730) Google Scholar NL reports non-financial support from Shionogi; personal fees and non-financial support from Janssen Pharmaceuticals, Roche, and Sanofi Pasteur; personal fees and other support from Gilead Sciences and Genetech; and personal fees from Cidara Therapeutics, outside the submitted work. MI reports grants from AiCuris and Shire; grants, personal fees, and other support from Janssen; personal fees and other support from Allovir; personal fees from Celltrion, Roche, Shionogi, Viracor Eurofins; and other support from Merck, Sequiris, Takeda, Vitaeris, SAB Biotherapeutics, outside the submitted work. JD declares no competing interests. Download .pdf (.08 MB) Help with pdf files Supplementary appendix Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trialEarly triple antiviral therapy was safe and superior to lopinavir–ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted. Full-Text PDF Early triple antiviral therapy for COVID-19 – Authors' replyWe thank Nelson Lee and colleagues for the important questions. We agree that there are limitations to our study,1 including the absence of a placebo and no intervention group, which was mentioned in the discussion section of our Article.1 Full-Text PDF