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. 2004 Mar;59(3):252–256. doi: 10.1136/thorax.2003.012658

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings

C Chu 1, V Cheng 1, I Hung 1, M Wong 1, K Chan 1, K Chan 1, R Kao 1, L Poon 1, C Wong 1, Y Guan 1, J Peiris 1, K Yuen 1
PMCID: PMC1746980  PMID: 14985565

Abstract

Background: The clinical response of patients with severe acute respiratory syndrome (SARS) to a combination of lopinavir/ritonavir and ribavirin was examined after establishing the in vitro antiviral susceptibility of the SARS associated coronavirus to a panel of antiviral agents.

Methods: The in vitro susceptibility of the prototype of SARS associated coronavirus to a panel of nucleoside analogues and protease inhibitors currently licensed for clinical use was studied. Forty one patients with SARS followed for 3 weeks were treated with a combination of lopinavir/ritonavir and ribavirin. The clinical progress and virological outcomes were monitored and compared with 111 patients treated with ribavirin only who served as historical controls.

Results: In vitro antiviral activity against SARS associated coronavirus was demonstrated for lopinavir and ribavirin at concentrations of 4 µg/ml and 50 µg/ml, respectively, only at 48 hours. The adverse clinical outcome (ARDS or death) was significantly lower in the treatment group than in the historical controls (2.4% v 28.8%, p<0.001) at day 21 after the onset of symptoms. The adverse outcome remained significantly lower in the treatment group than in the controls—both those diagnosed early (p<0.001) and those diagnosed later in the course of the epidemic (p = 0.002)—but there was no significant difference in adverse outcome rates between the two time periods (p = 0.548). No time related difference in outcome was observed in the control groups. A reduction in steroid usage and nosocomial infections was seen in patients initially treated with lopinavir/ritonavir, and these patients had a decreasing viral load and rising peripheral lymphocyte count. Multivariate analysis showed that age, hepatitis B carrier status, and lack of treatment with this antiviral combination were independent predictors of an adverse outcome. Lopinavir/ritonavir treatment was associated with a better outcome even when adjusted for baseline lactate dehydrogenase level.

Conclusions: The apparent favourable clinical response with lopinavir/ritonavir and ribavirin supports further randomised placebo controlled trials in patients with SARS.

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Selected References

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  1. Bernard G. R., Artigas A., Brigham K. L., Carlet J., Falke K., Hudson L., Lamy M., Legall J. R., Morris A., Spragg R. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994 Mar;149(3 Pt 1):818–824. doi: 10.1164/ajrccm.149.3.7509706. [DOI] [PubMed] [Google Scholar]
  2. Booth Christopher M., Matukas Larissa M., Tomlinson George A., Rachlis Anita R., Rose David B., Dwosh Hy A., Walmsley Sharon L., Mazzulli Tony, Avendano Monica, Derkach Peter. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003 May 6;289(21):2801–2809. doi: 10.1001/jama.289.21.JOC30885. [DOI] [PubMed] [Google Scholar]
  3. Chan J. W. M., Ng C. K., Chan Y. H., Mok T. Y. W., Lee S., Chu S. Y. Y., Law W. L., Lee M. P., Li P. C. K. Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS). Thorax. 2003 Aug;58(8):686–689. doi: 10.1136/thorax.58.8.686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cvetkovic Risto S., Goa Karen L. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs. 2003;63(8):769–802. doi: 10.2165/00003495-200363080-00004. [DOI] [PubMed] [Google Scholar]
  5. Donnelly Christl A., Ghani Azra C., Leung Gabriel M., Hedley Anthony J., Fraser Christophe, Riley Steven, Abu-Raddad Laith J., Ho Lai-Ming, Thach Thuan-Quoc, Chau Patsy. Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong. Lancet. 2003 May 24;361(9371):1761–1766. doi: 10.1016/S0140-6736(03)13410-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Drosten Christian, Günther Stephan, Preiser Wolfgang, van der Werf Sylvie, Brodt Hans-Reinhard, Becker Stephan, Rabenau Holger, Panning Marcus, Kolesnikova Larissa, Fouchier Ron A. M. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med. 2003 Apr 10;348(20):1967–1976. doi: 10.1056/NEJMoa030747. [DOI] [PubMed] [Google Scholar]
  7. Falsey Ann R., Walsh Edward E. Novel coronavirus and severe acute respiratory syndrome. Lancet. 2003 Apr 19;361(9366):1312–1313. doi: 10.1016/S0140-6736(03)13084-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fouchier Ron A. M., Kuiken Thijs, Schutten Martin, van Amerongen Geert, van Doornum Gerard J. J., van den Hoogen Bernadette G., Peiris Malik, Lim Wilina, Stöhr Klaus, Osterhaus Albert D. M. E. Aetiology: Koch's postulates fulfilled for SARS virus. Nature. 2003 May 15;423(6937):240–240. doi: 10.1038/423240a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ho James C., Ooi Gaik C., Mok Thomas Y., Chan Johnny W., Hung Ivan, Lam Bing, Wong Poon C., Li Patrick C., Ho Pak L., Lam Wah K. High-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome. Am J Respir Crit Care Med. 2003 Aug 28;168(12):1449–1456. doi: 10.1164/rccm.200306-766OC. [DOI] [PubMed] [Google Scholar]
  10. Hurst M., Faulds D. Lopinavir. Drugs. 2000 Dec;60(6):1371–1381. doi: 10.2165/00003495-200060060-00009. [DOI] [PubMed] [Google Scholar]
  11. Ksiazek Thomas G., Erdman Dean, Goldsmith Cynthia S., Zaki Sherif R., Peret Teresa, Emery Shannon, Tong Suxiang, Urbani Carlo, Comer James A., Lim Wilina. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med. 2003 Apr 10;348(20):1953–1966. doi: 10.1056/NEJMoa030781. [DOI] [PubMed] [Google Scholar]
  12. Lee Nelson, Hui David, Wu Alan, Chan Paul, Cameron Peter, Joynt Gavin M., Ahuja Anil, Yung Man Yee, Leung C. B., To K. F. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003 Apr 7;348(20):1986–1994. doi: 10.1056/NEJMoa030685. [DOI] [PubMed] [Google Scholar]
  13. Nicholls John M., Poon Leo L. M., Lee Kam C., Ng Wai F., Lai Sik T., Leung Chung Y., Chu Chung M., Hui Pak K., Mak Kong L., Lim Wilina. Lung pathology of fatal severe acute respiratory syndrome. Lancet. 2003 May 24;361(9371):1773–1778. doi: 10.1016/S0140-6736(03)13413-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Peiris J. S. M., Chu C. M., Cheng V. C. C., Chan K. S., Hung I. F. N., Poon L. L. M., Law K. I., Tang B. S. F., Hon T. Y. W., Chan C. S. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003 May 24;361(9371):1767–1772. doi: 10.1016/S0140-6736(03)13412-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Peiris J. S. M., Lai S. T., Poon L. L. M., Guan Y., Yam L. Y. C., Lim W., Nicholls J., Yee W. K. S., Yan W. W., Cheung M. T. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet. 2003 Apr 19;361(9366):1319–1325. doi: 10.1016/S0140-6736(03)13077-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. So Loletta K-Y, Lau Arthur C. W., Yam Loretta Y. C., Cheung Thomas M. T., Poon Edwin, Yung Raymond W. H., Yuen K. Y. Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet. 2003 May 10;361(9369):1615–1617. doi: 10.1016/S0140-6736(03)13265-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Tsang Kenneth W., Lam Wah K. Management of severe acute respiratory syndrome: the Hong Kong University experience. Am J Respir Crit Care Med. 2003 Aug 15;168(4):417–424. doi: 10.1164/rccm.2305012. [DOI] [PubMed] [Google Scholar]
  18. Wong Raymond S. M., Wu Alan, To K. F., Lee Nelson, Lam Christopher W. K., Wong C. K., Chan Paul K. S., Ng Margaret H. L., Yu L. M., Hui David S. Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis. BMJ. 2003 Jun 21;326(7403):1358–1362. doi: 10.1136/bmj.326.7403.1358. [DOI] [PMC free article] [PubMed] [Google Scholar]

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