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

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 mg/ml and 50 mg/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.

Duration of RT-PCR positivity in severe acute respiratory syndrome

“…Positive urine RT-PCR for SARS-CoV may reflect a higher viral load and/or the susceptibility for dissemination in an individual, with resulting delayed clearance of the virus. Treatment with LPV/r was associated with earlier RT-PCR conversion, and this finding is consistent with the current authors' previous report that LPV/r was associated with lowering of viral load during the course of illness and improved clinical outcomes when compared with historical controls [9].…”

“…All patients were treated with a standard protocol of broadspectrum antibiotics, ribavirin and a tailing regimen of corticosteroid [7,8]. A proportion of patients were treated additionally with an experimental agent, lopinavir/ritonavir (LPV/r) in an open-label clinical trial [9]. The clinical, haematological, biochemical, radiological and virological findings were prospectively entered into a pre-set database, and the findings in the first 75 patients had been reported previously [8].…”

Evaluation of Immunomodulators, Interferons and Known in Vitro SARS-CoV Inhibitors for Inhibition of SARS-Cov Replication in BALB/c Mice

“…) (Keyaerts et al, 2004;Vincent et al, 2005;Biot et al, 2006). None of the other compounds evaluated were inhibitory, including two HIV PIs previously shown to inhibit SARS-CoV replication (Chu et al, 2004;Yamamoto et al, 2004).…”

“…This mechanism may be important in treating SARS-CoV, since the virus induces a severe inflammatory response in the lungs of patients (Yen et al, 2006). Several other FDA-approved drugs, including HIV protease inhibitors (PIs), were found to inhibit SARS-CoV in vitro (Chu et al, 2004;Yamamoto et al, 2004). Nelfinavir, an isoquinoline carboxamide-based HIV PI (Yamamoto et al, 2004) protease, a probable target of inhibition (Liu et al, 2005).…”

“…Nelfinavir, an HIV PI, was evaluated in vivo because of data from other laboratories that demonstrated inhibition of SARS-CoV replication in vitro (Chu et al, 2004;Yamamoto et al, 2004). It has the potential to inhibit the two proteases of SARS-CoV that are responsible for virus maturation (Lindner et al, 2005;Liang, 2006) (Barnard et al, 2006).…”