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Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings
  1. C M Chu2,
  2. V C C Cheng1,
  3. I F N Hung1,
  4. M M L Wong3,
  5. K H Chan1,
  6. K S Chan2,
  7. R Y T Kao1,
  8. L L M Poon1,
  9. C L P Wong1,
  10. Y Guan1,
  11. J S M Peiris1,
  12. K Y Yuen1,
  13. on behalf of the HKU/UCH SARS Study Group*
  1. 1Department of Microbiology and Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong
  2. 2Department of Medicine, United Christian Hospital, Hong Kong
  3. 3Department of Medicine and Geriatrics, Caritas Medical Centre, Hong Kong
  1. Correspondence to:
    Professor K Y Yuen
    Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong Special Administrative Region, China; kyyuenhkucc.hku.hk

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.

  • severe acute respiratory syndrome (SARS)
  • coronavirus
  • lopinavir/ritonavir
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Footnotes

  • * Members of the HKU/UCH SARS Study Group are listed at the end of the paper.

  • Conflict of interest: none declared.

  • Funding: Public Health Research Grant A195357 from the National Institute of Allergy and Infectious Diseases, USA, The Wellcome Trust Grant GR067072/D/02/Z, The University of Hong Kong and the Hospital Authority of Hong Kong, SAR.

  • Other members of the HKU/UCH SARS Study Group: B S F Tang, P C Y Woo, S K P Lau, Department of Microbiology, The University of Hong Kong; K I Law, Y H Hui, W S Leung, V L Chan, J S C Ng, United Christian Hospital; M W Tse, Caritas Medical Center.

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