Early triple antiviral therapy for COVID-19 – Authors' reply

Abstract

We thank Nelson Lee and colleagues for the important questions. We agree that there are limitations to our study,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 (988) Google Scholar including the absence of a placebo and no intervention group, which was mentioned in the discussion section of our Article.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 (988) Google Scholar As explained in the methods section of the Article,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 (988) Google Scholar a placebo group was not accepted in Chinese culture and therefore, we had to use lopinavir–ritonavir as a control. We also agree that the efficacy of lopinavir–ritonavir and ribavirin might be weak.2Yuan S Chan CC Chik KK et al.Broad-spectrum host-based antivirals targeting the interferon and lipogenesis pathways as potential treatment options for the pandemic coronavirus disease 2019 (COVID-19).Viruses. 2020; 12: 628Crossref Scopus (35) Google Scholar Nevertheless, our study was designed in January, 2020, and commenced in early February, 2020, and it was based on results from our previous in-vitro and in-vivo studies,3Chu CM Cheng VC Hung IF et al.Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings.Thorax. 2004; 59: 252-256Crossref PubMed Scopus (1181) Google Scholar, 4Chan JF Yao Y Yeung ML et al.Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset.J Infect Dis. 2015; 212: 1904-1913Crossref PubMed Scopus (497) Google Scholarin which we found that lopinavir–ritonavir and ribavirin are active against severe acute respiratory syndrome and Middle East respiratory syndrome coronavirus (MERS-CoV). This work was done well before the lopinavir–ritonavir trial5Cao 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 (3419) Google Scholar was completed and published online in March, 2020. Additionally, most of the trials listed by Lee and colleagues were non-randomised studies on COVID-19 and MERS-CoV. Although 40% of the combination group was not given interferon beta-1b due to late presentation, both the group and subgroup analyses showed high statistical significance, with clinical (national early warning score 2 and sequential organ failure assessment scores) and virological improvement in the combination group. Despite a mild to moderate illness, all patients were symptomatic, and 96 (76%) of 127 patients had pneumonia at baseline. Most patients were admitted to hospital within the first week of symptom onset, and early antiviral treatment probably prevented a substantial proportion of these patients from further deterioration by rapidly reducing viral load and by cytokine suppression. These patients would otherwise have needed a ventilator and intensive care support. The discharge policy was based on two consecutive negative PCR results at least 24 h apart, and all patients were afebrile for 48 h. The 2-week low-dose ribavirin treatment was safe with negligible side-effects, and none of the patients in our study had any harmful drug effects. Overall, our work showed that early interferon-based combination therapy resulted in both clinical and virological improvement in patients with mild to moderate COVID-19. In the future, larger and high-powered studies on interferon-based combination therapy are needed. We declare no competing interests. Early triple antiviral therapy for COVID-19In the trial led by Ivan Hung and colleagues,1 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. Full-Text PDF 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