Early triple antiviral therapy for COVID-19

In 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. 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),2, 3, 4 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).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 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.2, 3 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.3, 4, 6

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