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
Open accessAbstract
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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- Authors
- Hung, I. F.-N., Lung, K.-C., Tso, E. Y.-K., Liu, R., Chung, T. W.-H., Chu, M.-Y., Ng, Y.-Y., Lo, J., Chan, J., Tam, A. R., Shum, H.-P., Chan, V., Wu, A. K.-L., Sin, K.-M., Leung, W.-S., Law, W.-L., Lung, D. C., Sin, S., Yeung, P., Yip, C. C.-Y., Zhang, R. R., Fung, A. Y.-F., Yan, E. Y.-W., Leung, K.-H., Ip, J. D., Chu, A. W.-H., Chan, W.-M., Ng, A. C.-K., Lee, R., Fung, K., Yeung, A., Wu, T.-C., Chan, J. W.-M., Yan, W.-W., Chan, W.-M., Chan, J. F.-W., Lie, A. K.-W., Tsang, O. T.-Y., Cheng, V. C.-C., Que, T.-L., Lau, C.-S., Chan, K.-H., To, K. K.-W., & Yuen, K.-Y.
- Affiliations
- Queen Mary Hospital (CN)
- Pamela Youde Nethersole Eastern Hospital (CN)
- United Christian Hospital (CN)
- Ruttonjee Hospital (CN)
- University of Hong Kong (HK)
- Queen Elizabeth Hospital (CN)
- Tuen Mun Hospital (CN)
- Princess Margaret Hospital (HK)
- Corresponding author
- Yuen, Kwok-Yung
- ORCID
- Hung, Ivan Fan-Ngai
- Lung, Kwok-Cheung
- Liu, Raymond
- Chung, Tom Wai-Hin
- Chu, Man-Yee
- Tam, Anthony Raymond
- Shum, Hoi-Ping
- Wu, Alan Ka-Lun
- Leung, Wai-Shing
- Lung, David Christopher
- Yip, Cyril Chik-Yan
- Ip, Jonathan Daniel
- Chu, Allen Wing-Ho
- Chan, Wan-Mui
- Chan, Jasper Fuk-Woo
- Tsang, Owen Tak-Yin
- Cheng, Vincent Chi-Chung
- Que, Tak-Lun
- Chan, Kwok-Hung
- To, Kelvin Kai-Wang
- Yuen, Kwok-Yung
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 395
- Issue
- 10238
- Pages
- 1695-1704
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC7211500
- OpenAlex
- W3023606094
- Cited by
- 1,455
- References
- 35
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 52 · 2023: 86 · 2022: 202 · 2021: 522 · 2020: 541 · 2019: 2 · 2013: 2
- FWCI
- 44.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Lancet (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- reponame:Expeditio Repositorio Institucional UJTL
- Funders
- Health and Medical Research Fund
- Sanming Project of Medicine in Shenzhen (SZSM201911014)
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Keywords
- SARS-CoV-2, interferon beta-1b, lopinavir/ritonavir, ribavirin, antiviral efficacy, viral clearance, hospitalized patients, adverse events, Hong Kong, early treatment initiation, safety and tolerability, treatment discontinuation
- MeSH terms
- Interferon beta-1b, Betacoronavirus, COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Adult, Drug Combinations, Drug Therapy, Combination, Female, Hong Kong, Hospitalization, Humans, Male, Middle Aged, Pneumonia, Viral, Ribavirin, Coronavirus Infections, Ritonavir, Pandemics, Lopinavir
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