key: cord-0915086-84bqpnmk
authors: Gaibani, Paolo; Tonetti, Tommaso; Bartoletti, Michele; Re, Maria Carla; Viale, PierLuigi; Ranieri, V. Marco
title: Antiviral activity of interferon-based combination therapy in critically ill patients with COVID-19: Preliminary observations
date: 2020-12-29
journal: J Glob Antimicrob Resist
DOI: 10.1016/j.jgar.2020.12.011
sha: e12b1b9e3c77039e7e426fa9c6814d6b208a472d
doc_id: 915086
cord_uid: 84bqpnmk

nan

Letter to the Editor Antiviral activity of interferon-based combination therapy in critically ill patients with COVID-19: Preliminary observations Keywords: COVID-19 Lopinavir/ritonavir Hydroxychloroquine Interferon β-1a

Sir,

In early 2020, COVID-19 (coronavirus disease 2019), caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), spread worldwide causing more than 4,500,000 cases and 300,000 deaths as of May 2020. Several molecules have shown promising antiviral activity against SARS-CoV-2, but no specific therapy has proven effective for COVID-19 [1] . Therapy with β-interferons has shown in vitro activity against SARS-CoV-2 [2] . At the same time, triple antiviral therapy with interferon β-1b (IFN-β1b), lopinavir/ritonavir (LPV/r) and ribavirin proved superior to LPV/r alone for the treatment of mild-tomoderate COVID-19 [3] . Recently, Hong et al. showed that with triple combination therapy with LPV/r, hydroxychloroquine (HCQ) and IFN-β1b demonstrated improvement of severe pneumonia in five patients with COVID-19 pneumonia [4] .

Here we evaluated the effect of an interferon-based combination therapy in critically ill patients with COVID-19.

Eight patients admitted to the intensive care unit (ICU) of Sant'Orsola University Hospital (Bologna, Italy) for COVID-19related severe acute respiratory distress syndrome between 10 March 2020 and 10 April 2020 were included in this study. Diagnosis of SARS-CoV-2 infection was confirmed by RT-PCR on nasopharyngeal swabs. All patients were intubated within 12 h from ICU admission. All patients in the interferon group (n = 5) were treated according to local clinical protocols with interferon β-1a (IFN-β1a; Rebif 1 ) in combination with HCQ (Plaquenil 1 ) and LPV/r (Kaletra 1 ). Patients in the control group did not received antivirals or immunomodulators, whereas two patients received HCQ (Plaquenil 1 ) prior to hospitalisation. Baseline demographic and clinical characteristics of the patients are given in Supplementary Table S1 . Bronchoalveolar lavage samples were collected by bronchoscopy at intubation and 7 days thereafter. Viral load was assessed in triplicate by the DCt method (Ct gene -Ct housekeeping ). The effect on viral load was assessed with 95% confidence interval (CI) of the mean of the differences in DCt between Day 0 and Day 7 (DDCt).

Compared with the control group, the interferon group showed no significant DCt reduction from Day 0 through Day 7 in the lower respiratory tract of critically ill patients (Fig. 1A) . Compared with baseline, the mean viral load reduction after 7 days of intubation in patients treated with interferon was 4.7 DCt (95% CI À0.09 to 10.33), whereas the viral load reduction in patients in the control group was 11.54 DCt (95% CI 6.05-17.01) (Fig. 1B) .

Clinical variables were not significantly different between the groups. Two of five patients in the interferon group and two of three patients in the control group died within 28 days after ICU admission; time to ICU discharge in surviving patients was 12 AE 2 days and 15 AE 2 days in the interferon and control groups, respectively. Clearance of viral RNA of SARS-CoV-2 in nasopharyngeal swabs was not significantly different between the groups and occurred in 13 AE 3.9 days and 11 AE 3.9 days in the interferon and control groups, respectively.

Overall, our findings show only a slight reduction in SARS-CoV-2 viral load in lower respiratory specimens of critically ill patients with COVID-19 treated with IFN-β1a in combination with HCQ and LPV/r. These findings are in accordance with a previous study showing that treatment with interferon plus ribavirin was not associated with a significant reduction in 90-day mortality or faster RNA clearance in critically ill patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection [5] . Moreover, we started IFN-β1a therapy at ICU admission, on average 7 days after symptom onset, so the long interval between infection and IFN administration may also have played a role in reducing antiviral efficacy.

We believe that our preliminary results-although limited to viral load clearance-may be helpful in better characterising treatment options for critically ill COVID-19 patients. These two authors contributed equally and should be both considered joint first authors.

Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review

Antiviral activities of type I interferons to SARS-CoV-2 infection

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

Five severe COVID-19 pneumonia patients treated with triple combination therapy with lopinavir/ ritonavir, hydroxychloroquine, and interferon β-1b

Ribavirin and interferon therapy for critically ill patients with Middle East respiratory syndrome: a multicenter observational study