Lopinavir-Ritonavir in treatment of COVID-19: A dynamic systematic benefit-risk assessment

Background: COVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required due to the urgent unmet public need. Importantly it allows additional data to be incorporated as it becomes available, and re-evaluation of the benefit-risk profile. Methods: A systematic benefit-risk assessment was conducted using the Benefit-Risk Action team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and EmBase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance. Results: In comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (HR=1.31, 95% CI:0.95, 1.80). There appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). In particular, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared to standard of care (13% vs 27%). Limited data were available for comparison of lopinavir-ritonavir to other treatments. Conclusions: Based on currently available data, there was no clear benefit for use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events, including acute respiratory distress syndrome. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.