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

Ivan Fan-Ngai Hung, Kwok-Cheung Lung, Eugene Yuk-Keung Tso, Raymond Liu, Tom Wai-Hin Chung, Man-Yee Chu, Yuk-Yung Ng, Jenny Lo, Jacky Chan, Anthony Raymond Tam, Hoi-Ping Shum, Veronica Chan, Alan Ka-Lun Wu, Kit-Man Sin, Wai-Shing Leung, Wai-Lam Law, David Christopher Lung, Simon Sin, Pauline Yeung, Cyril Chik-Yan Yip, Ricky Ruiqi Zhang, Agnes Yim-Fong Fung, Erica Yuen-Wing Yan, Kit-Hang Leung, Jonathan Daniel Ip, Allen Wing-Ho Chu, Wan-Mui Chan, Anthony Chin-Ki Ng, Rodney Lee, Kitty Fung, Alwin Yeung, Tak-Chiu Wu, Johnny Wai-Man Chan, Wing-Wah Yan, Wai-Ming Chan, Jasper Fuk-Woo Chan, Albert Kwok-Wai Lie, Owen Tak-Yin Tsang, Vincent Chi-Chung Cheng, Tak-Lun Que, Chak-Sing Lau, Kwok-Hung Chan, Kelvin Kai-Wang To, Kwok-Yung Yuen, Ivan Fan-Ngai Hung, Kwok-Cheung Lung, Eugene Yuk-Keung Tso, Raymond Liu, Tom Wai-Hin Chung, Man-Yee Chu, Yuk-Yung Ng, Jenny Lo, Jacky Chan, Anthony Raymond Tam, Hoi-Ping Shum, Veronica Chan, Alan Ka-Lun Wu, Kit-Man Sin, Wai-Shing Leung, Wai-Lam Law, David Christopher Lung, Simon Sin, Pauline Yeung, Cyril Chik-Yan Yip, Ricky Ruiqi Zhang, Agnes Yim-Fong Fung, Erica Yuen-Wing Yan, Kit-Hang Leung, Jonathan Daniel Ip, Allen Wing-Ho Chu, Wan-Mui Chan, Anthony Chin-Ki Ng, Rodney Lee, Kitty Fung, Alwin Yeung, Tak-Chiu Wu, Johnny Wai-Man Chan, Wing-Wah Yan, Wai-Ming Chan, Jasper Fuk-Woo Chan, Albert Kwok-Wai Lie, Owen Tak-Yin Tsang, Vincent Chi-Chung Cheng, Tak-Lun Que, Chak-Sing Lau, Kwok-Hung Chan, Kelvin Kai-Wang To, Kwok-Yung Yuen

Abstract

Background: Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir-ritonavir, and ribavirin for treating patients with COVID-19.

Methods: This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688.

Findings: Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3-7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5-11]) than the control group (12 days [8-15]; hazard ratio 4·37 [95% CI 1·86-10·24], p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir-ritonavir because of biochemical hepatitis. No patients died during the study.

Interpretation: Early 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.

Funding: The Shaw-Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile
Figure 2
Figure 2
Outcomes over time (A) National early warning score 2; (B) nasopharyngeal swab viral load; (C) posterior oropharyngeal saliva viral load; (D) throat swab viral load; (E) stool viral load; and (F) serum IL-6 cytokine concentration (first 60 recruited patients). Data points are medians and error bars are IQRs.

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