Lopinavir-ritonavir worked against SARS, but it had little effect against coronavirus compared to standard care.
After a randomized, controlled, open-label trial, it seems that lopinavir-ritonavir treatment had no benefit for adult patients hospitalized with severe novel coronavirus infection, according to a paper published in The New England Journal of Medicine.
Investigators from China, the United Kingdom and the United States conducted a trial involving 199 adult patients with laboratory-confirmed SARS-CoV-2 infections. The patients also had an oxygen saturation of 94% or less while breathing ambient air, the study authors reported. The patients were randomly assigned to receive oral lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days in addition to standard care, or standard care alone. The investigators were trying to determine if lopinavir-ritonavir had an advantage over standard care alone in time to clinical improvement.
There are no specific therapeutic agents for coronavirus infections. However, lopinavir has been proven to have an inhibitory effect against severe acute respiratory syndrome (SARS) while ritonavir can also aid lopinavir in treatments.
This combination of lopinavir-ritonavir was shown in a 2004 study to reduce the adverse clinical outcomes (ARDS or death) and viral load for patients with SARS when used with ribavirin.
The median age of the patients was 58 years and 60% of the patients were men, the study authors wrote. They said there were no important differences among the randomized groups in terms of demographics, baseline lab results, or other characteristics. The median time from symptom onset and randomization was 13 days.
There were 99 coronavirus patients assigned to receive lopinavir-ritonavir plus standard care, though ultimately 94 received it. This was due to 3 early deaths within 24 hours after randomization and 2 others because “the attending physician refused to prescribe lopinavir-ritonavir after randomization,” the study authors wrote.
A third (33%) of the lopinavir-ritonavir patients received glucocorticoids during the trial compared to 35.7% of the standard care group cohort, the study authors added.
Both groups demonstrated a time to clinical improvement of 16 days, the investigators found. However, when patients received lopinavir-ritonavir within 12 days from symptom onset, there seemed to be a shorter time to clinical improvement. Later lopinavir-ritonavir treatment was not associated with shorter time to clinical improvement, the investigators said.
The study authors found that there was also no difference in time to clinical deterioration between the standard and treatment cohorts.
The lopinavir-ritonavir treatment group saw lower 28-day mortality compared to the standard care group, the study authors found. The treatment group also had a shorter stay in the intensive care unit compared to the standard group (6 vs 11 days, respectively). The duration from randomization to hospital discharge was also shorter among the treatment group (12 vs 14 days, respectively), the study authors said. There were no notable differences between the groups for secondary outcomes such as duration of oxygen therapy, duration of hospitalization, and time from randomization to death.
About half of the patients in each cohort reported adverse events between randomization and day 28. Lopinavir-ritonavir-treated patients reported more gastrointestinal adverse events compared to the standard care group, such as nausea, vomiting, and diarrhea. There were 4 serious gastrointestinal adverse events in the lopinavir-ritonavir group but none in the standard care group, the study authors added. The standard care group reported more adverse events such as respiratory failure, acute kidney injury, and secondary infection.
“This randomized trial found that lopinavir-ritonavir treatment added to standard supportive care was not associated with clinical improvement or mortality in seriously ill patients with COVID-19 different from that associated with standard care alone,” the study authors concluded. “Of note, the overall mortality in this trial (22.1%) was substantially higher than the 11% to 14.5% mortality reported in initial descriptive studies of hospitalized patients with COVID-19, which indicates that we enrolled a severely ill population.”
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