In patients who were hospitalized with severe coronavirus disease (COVID-19), treatment with lopinavir-ritonavir did not provide a substantial benefit beyond standard care, according to the results of a Chinese clinical trial published in the New England Journal of Medicine (Chinese Clinical Trial Register number: ChiCTR2000029308).
Researchers randomly assigned 199 patients with laboratory-confirmed severe SARS-CoV-2 infection to receive either lopinavir-ritonavir (n=99) or standard care (n=100). The primary end point was time to clinical improvement, defined as either the time of randomization to a 2-point improvement on a 7-category ordinal scale or period from randomization to live discharge from the hospital, whichever came first.
Ordinal scales have been used as end points in clinical trials for severe influenza and include the following categories: (1) not hospitalized with resumption of normal activities; (2) not hospitalized but unable to resume normal activities; (3) hospitalized but not requiring supplemental oxygen; (4) hospitalized and requiring supplemental oxygen; (5) hospitalized and requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; (6) hospitalized and requiring extracorporeal membrane oxygenation, invasive mechanical ventilation, or both; and (7) death.
The median patient age was 58 years (range, 49-68 years) and the median interval time between symptom onset and randomization was 13 days. In the sample, 60.3% of patients were men. In the intention-to-treat (ITT) population, patients assigned to lopinavir-ritonavir did not experience a time to clinical improvement different from that of patients who received standard care (median, 16 vs 16 days; hazard ratio [HR] for clinical improvement, 1.31; 95% CI, 0.95-1.85; P =.09). In the modified ITT population that excluded 3 early deaths, the median time to clinical improvement was 15 days in the lopinavir-ritonavir group vs 16 days in the standard care group (HR, 1.39; 95% CI, 1.00-1.91).
Patients in the ITT population who received lopinavir-ritonavir treatment within 12 days of symptom onset appeared to experience a shorter time to clinical improvement compared with patients who did not (HR, 1.25; 95% CI, 1.77-2.05 vs HR, 1.30; 95% CI, 0.84-1.99).
Mortality at 28 days was numerically lower in the liponavir-ritonavir group compared with the standard care group in both the ITT and modified ITT populations (19.2% vs 25.0%; -5.8%; 95% CI, -1.73 to 5.7 and 16.7% vs 25.0%; -8.3%; 95% CI, -19.6 to 3.0, respectively). Patients who received lopinavir-ritonavir had shorter stays in the intensive care unit (ICU) vs patients who received standard care (difference, -5 days; 95% CI, -9 to 0 days) and the time from randomization to discharge was numerically shorter (difference, 1 day; 95% CI, 0-3 days). Finally, 45.5% of patients in the lopinavir-ritonavir group had clinical improvements at day 14 compared with 30.0% in the standard care group (difference, 15.5%; 95% CI, 2.2-28.8).
There were no significant differences in other secondary outcomes, including oxygen therapy duration and time from randomization to death. While gastrointestinal adverse events were more common in the lopinavir-ritonavir group, serious adverse events were more common in the standard care group. A total of 13 patients in the lopinavir-ritonavir group stopped treatment early because of adverse events.
Researchers reported several study limitations, including the fact that the trial was not blinded. In addition, patients in the lopinavir-ritonavir group had higher throat viral loads, indicating that those patients may have had more viral replication, and concurrent pharmacologic interventions may have acted as confounders.
“These early data should inform future studies to assess this and other medication in the treatment of infection with SARS-CoV-2,” the researchers wrote. “Whether combining lopinavir-ritonavir with other antiviral agents, as has been done in SARS and is being studied in MERS-COV, might enhance antiviral effects and improve clinical outcomes remains to be determined.”
Cao B, Wang Y, Liu W, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 [published online March 18, 2020]. N Engl J Med. doi:10.1056/NEJMoa2001282