key: cord-0708478-aye448iq
authors: Hung, Ivan Fan-Ngai; Yuen, Kwok-Yung
title: Early triple antiviral therapy for COVID-19 – Authors' reply
date: 2020-11-05
journal: Lancet
DOI: 10.1016/s0140-6736(20)32268-6
sha: 3458d5afcd432073edc595589377497f8b52285a
doc_id: 708478
cord_uid: aye448iq

nan

www.thelancet.com Vol 396 November 7, 2020

Nicholas DeVito and colleagues 1 reported the low compliance with reporting requirements from the Food and Drug Administration Amend ments Act of 2007 for results of clinical trials registered on ClinicalTrials.gov, which weakens scientific evidence, violates ethical obligations, and pos sibly leads to selective publishing. Since March, 2016, the Chinese Clinical Trial Registry has mandated registrants to report the calculated results for their trials, allowing online public access within 12 months of completion. 2 To illustrate the com pliance of result reporting on this registry, we identified all trials regarding bone fracture 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. 2 Nevertheless, our study was designed in January, 2020, and commenced in early February, 2020, and it was based on results from our previous invitro and invivo studies, 3, 4 in which we found that lopinavir-ritonavir and ribavirin are active against severe acute respiratory syndrome and Middle East respiratory syndrome coronavirus (MERSCoV). This work was done well before the lopinavir-ritonavir trial 5 was completed and published online in March, 2020. Additionally, most of the trials listed by Lee and colleagues were nonrandomised studies on COVID19 and MERSCoV. Although 40% of the combination group was not given interferon beta1b 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 2week lowdose ribavirin treatment was safe with negligible sideeffects, and none of the patients in our study had any harmful drug effects. Overall, our work showed that early interferonbased combination therapy resulted in both clinical and virological improvement on the course of mild to moderate COVID19 and, possibly, to assess anti viral efficacy overall. 3, 4, 6 NL reports nonfinancial support from Shionogi; personal fees and nonfinancial 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. 

We 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 As explained in the methods section of the Article, 1 a placebo group was not accepted in Chinese For more on the Chinese Clinical Trial Registry see http://www. chictr.org in patients with mild to moderate COVID19. In the future, larger and highpowered studies on interferon based combination therapy are needed.

Triple combination of interferon beta1b, lopinavir ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID19: an openlabel, randomised, phase 2 trial

Broad spectrum hostbased antivirals targeting the interferon and lipogenesis pathways as potential treatment options for the pandemic coronavirus disease 2019 (COVID19)

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings

Treatment with lopinavir/ritonavir or interferonβ1b improves outcome of MERSCoV infection in a nonhuman primate model of common marmoset

A trial of lopinavirritonavir in adults hospitalized with severe covid19