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

  • Lancet. 2020 May 30;395(10238):1695-1704. doi: 10.1016/S0140-6736(20)31042-4.
Ivan Fan-Ngai Hung  1 ,  Kwok-Cheung Lung  2 ,  Eugene Yuk-Keung Tso  3 ,  Raymond Liu  4 ,  Tom Wai-Hin Chung  5 ,  Man-Yee Chu  6 ,  Yuk-Yung Ng  7 ,  Jenny Lo  4 ,  Jacky Chan  8 ,  Anthony Raymond Tam  9 ,  Hoi-Ping Shum  10 ,  Veronica Chan  3 ,  Alan Ka-Lun Wu  11 ,  Kit-Man Sin  7 ,  Wai-Shing Leung  8 ,  Wai-Lam Law  6 ,  David Christopher Lung  12 ,  Simon Sin  13 ,  Pauline Yeung  13 ,  Cyril Chik-Yan Yip  5 ,  Ricky Ruiqi Zhang  1 ,  Agnes Yim-Fong Fung  14 ,  Erica Yuen-Wing Yan  14 ,  Kit-Hang Leung  14 ,  Jonathan Daniel Ip  14 ,  Allen Wing-Ho Chu  14 ,  Wan-Mui Chan  14 ,  Anthony Chin-Ki Ng  14 ,  Rodney Lee  11 ,  Kitty Fung  15 ,  Alwin Yeung  4 ,  Tak-Chiu Wu  6 ,  Johnny Wai-Man Chan  6 ,  Wing-Wah Yan  10 ,  Wai-Ming Chan  13 ,  Jasper Fuk-Woo Chan  14 ,  Albert Kwok-Wai Lie  9 ,  Owen Tak-Yin Tsang  8 ,  Vincent Chi-Chung Cheng  5 ,  Tak-Lun Que  16 ,  Chak-Sing Lau  9 ,  Kwok-Hung Chan  14 ,  Kelvin Kai-Wang To  14 ,  Kwok-Yung Yuen  17
Affiliations
  • 1. Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region (SAR), China; State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region (SAR), China.
  • 2. Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China.
  • 3. Department of Medicine, United Christian Hospital, Hong Kong SAR, China.
  • 4. Department of Medicine and Geriatrics, Ruttonjee Hospital, Hong Kong SAR, China.
  • 5. Department of Microbiology, The University of Hong Kong, Hong Kong Special Administrative Region (SAR), China.
  • 6. Department of Medicine, Queen Elizabeth Hospital, Hong Kong SAR, China.
  • 7. Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China.
  • 8. Department of Medicine, Princess Margaret Hospital, Hong Kong SAR, China.
  • 9. Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region (SAR), China.
  • 10. Department of Intensive Care, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China.
  • 11. Department of Microbiology, Pamela Youde Nethersole Eastern Hospital, Hong Kong SAR, China.
  • 12. Department of Microbiology, Queen Elizabeth Hospital, Hong Kong SAR, China.
  • 13. Department of Intensive Care, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region (SAR), China.
  • 14. State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region (SAR), China.
  • 15. Department of Microbiology, United Christian Hospital, Hong Kong SAR, China.
  • 16. Department of Microbiology, Tuen Mun Hospital, Hong Kong SAR, China.
  • 17. State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong Special Administrative Region (SAR), China. Electronic address: [email protected].
PMID: 32401715 DOI: 10.1016/S0140-6736(20)31042-4
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.

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