A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19
Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020;382(19):1787‐1799. doi:10.1056/NEJMoa2001282
Review written by:
Lily Xu, edited by Naomi Ali
Green - Published by NEJM, properly controlled, relatively large sample size
There is a pressing need for therapeutic agents for the COVID-19 pandemic while a vaccine is in development. Lopinavir was identified as an effective inhibitor of SARS-CoV, the virus that caused the SARS outbreak in the early 2000s. Ritonavir is a cytochrome P450 inhibitor that is commonly added to Lopinavir to extend the latter’s half-life. The lopinavir-ritonavir treatment for SARS patients led to reduced risk of adverse clinical outcomes. This study examined the efficacy and safety of lopinavir-ritonavir for SARS-CoV-2 infection in 199 adult patients hospitalized at the Jin Yin-Tan Hospital in Wuhan, China.
Eligible participants fulfilled the following requirements: confirmed SARS-CoV-2 presence in the respiratory tract via RT-PCR, confirmed pneumonia by chest imaging, and breathing impairment. A total of 199 participants were enrolled and randomized to control (n=100) and treatment (n=99) arms. The control group received standard supportive care such as oxygen support, antibiotics, vasopressor support, and more. The experimental group received standard care in addition to lopinavir-ritonavir treatment (400/100 mg BID for 14 days). Subjects were followed for 28 days and the end point of the study was defined as either hospital discharge, or an improvement of 2 points on a 7-category ordinal scale ranging from non-hospitalized and returned to normal activity [category 1] to hospitalized on oxygen support [category 4] to death [category 7]. Results were analyzed using intention-to-treat (ITT) cohorts.
Overall, lopinavir-ritonavir therapy was not associated with significant clinical improvement [HR 1.24;95% CI, 0.90-1.72] or change in mortality in seriously ill patients [19.2% in L-R group vs. 25% for standard treatment; 95% CI, -17.3 to 5.7 point difference] compared to those receiving standard care alone. Time to clinical improvement, mortality at 28 days, and the percentages of patients with detectable viral RNA at various time points were all similar between the two groups. Cao et al. also performed a modified ITT analysis; three patients with early death were excluded from the experimental group as they did not receive any doses of lopinavir-ritonavir. In the modified ITT analysis, it was found that the median time to clinical improvement was lower by one day in the experimental group [hazard ratio of 1.39, 95% CIs of 1.00-1.91]. Viral RNA load over time also did not differ between the treatment and control groups.
High dosages or long term treatment of lopinavir-ritonavir caused severe gastrointestinal (GI) side-effects in the experimental group, but the control group experienced more serious adverse events. Nearly 14% of patients in the treatment group were unable to complete the 14-day course, primarily due to GI adverse effects. This research is still in the early stages and future studies should provide more information on the efficacy of lopinavir-ritonavir treatment for SARS-CoV-2.
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Baden LR, Rubin EJ. Covid-19 — The Search for Effective Therapy. N Engl J Med. March 2020. doi:10.1056/NEJMe2005477
The trial was designed to detect an 8 day median time to improvement difference between experimental and control groups, which is quite a lofty goal. For comparison, oseltamivir for influenza has been shown to alleviate symptoms by about 16 hours faster than control (1). The authors mention that at re-assessment, the trial was deemed to be underpowered.
It is debated what the effective concentration (EC) is for inhibition of the virus with lopinavir-ritonavir and thus it is possible dosing in this trial was too low. The subjects in this trial had a mean trough-peak concentration of 5.5 - 9.6 ug/mL. The reported 50% EC is between 4.0 to 10.7 ug/mL, and may be as high as 25 ug/mL. However the side effect profile suggests increasing or prolonging dosage to improve outcomes may not be feasible.
Although no difference in viral load outcomes were found, more frequent samples may have characterized viral load kinetics in more detail, as they only tested on days 1, 5, 10, 14, 21, 28. In addition, the treatment group had slightly higher viral load initially. Note that these viral loads are measures of nucleic acid and not of infectious virus (2).
The study was not open-label and not blinded, and may have influenced clinical decision-making, especially regarding the ordinal scale measurements, which are qualitative in nature.