key: cord-0931781-kwi8nre2
authors: Lee, Nelson; Ison, Michael; Dunning, Jake
title: Early triple antiviral therapy for COVID-19
date: 2020-11-05
journal: Lancet
DOI: 10.1016/s0140-6736(20)32274-1
sha: dd5a9e5cfca3ad1db8bc8a726d97369b6c17c200
doc_id: 931781
cord_uid: kwi8nre2

nan

placebo or no intervention group) and the doubtful efficacy of lopinavirritonavir and ribavirin (concerns are summarised in the appendix), [2] [3] [4] shown by the nonsignificant results from the subgroup analysis in the combination group without interferon. Further reasons for concern are the omission of interferon beta1b in 40% of the intended population, and the clinical efficacy might also be difficult to assess in most patients with mild to moderate COVID19 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). 5, 6 Additionally, 17 (13%) of 127 patients required supplemental oxygen, six (5%) were admitted to the intensive care unit, 31 (24%) had a normal chest xray, and all patients with COVID19 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 signif icance, and data on the infectious virus were unavailable, future controlled studies should focus on confirming the efficacy of interferonbased therapies. Exclusion of ribavirin should be considered because of its potentially harmful sideeffects (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 laterstage disease. 2 itching than for participants who did not receive paracetamol with this vaccine, as can be seen in the analysis in figure S2 in the appendix, 1 in which the p value for comparison of itching in partici pants who received paracetamol and participants who did not was p=0·85.

Chauhan and colleagues are correct that an assessment of vaccine efficacy is not usually a part of a phase 2 trial. The large size of the trial and the inclusion of efficacy as an endpoint emphasise the unusual circumstances in which research into COVID19 vaccines is being done. These are unprecedented times in vaccine research.

We are pleased to read the Correspondence from Archie Lodge, a participant in the trial, and thank him for his time and commitment to participating in this important research. As Lodge rightly points out, maintaining participant masking in any trial is of great importance, as a participant with knowledge of which vaccine they received might alter their behaviour, such as physical distancing measures, potentially introducing bias into study findings. For this reason, we selected a control vaccine (MenACWY) that also elicited local and systemic reactions in some participants, although reaction rates were lower than for the ChAdOx1 nCoV19 vaccine. For any individual, it is difficult for them to know whether the reactions that they had were related to the investigational vaccine or the control vaccine. Although some participants might draw conclusions about the vaccine that they received on the basis of figure 1 of our Article, 1 it is important, and standard practice, that safety data are presented openly in this way. We strongly recommend that all trial volunteers continue to protect themselves and their contacts from the pandemic virus by following public health guidance, as participants cannot identify which trial arm they were assigned to until formal unmasking occurs at the end of the trial.

In the trial led by Ivan Hung and colleagues, 1 adults admitted to hospital with COVID19 received two antiviral treatment combinations. In the combination group, 52 (60%) of 86 patients received interferon beta1b (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 beta1b omitted due to concerns of proinflammatory sideeffects 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 beta1b, 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 See Online for appendix Thomas Lohnes/Getty Images 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.

Department of Medicine (MI) and Comprehensive Transplant Center (MI)

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

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A trial of lopinavir ritonavir in adults hospitalized with severe COVID19

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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