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An open-label trial found no benefit for lopinavir-ritonavir (Kaletra), a protease inhibitor used primarily in HIV treatment, in treating hospitalized patients with COVID-19 coronavirus infection, researchers found.

There was no difference in time to clinical improvement among hospitalized patients with COVID-19 treated with lopinavir-ritonavir along with standard care compared to patients receiving only standard care (HR for clinical improvement 1.24, 95% CI 0.90-1.72), reported Bin Cao, MD, of the National Clinical Research Center for Respiratory Diseases in Beijing, and colleagues.

Both mortality rates at 28 days and the percentages of patients with detectable viral RNA were also similar in both groups, the authors wrote in the .

Some centers and even national guidelines, such as those in Italy, have for patients with COVID-19 infection. Indeed, early reports from doctors in Thailand reported who were treated with a regimen including the drug, which led to anecdotal reports from China about HIV patients not being able to access the medication due to its demand for treating COVID-19.

Cao and colleagues also pointed to an open-label study from 2004 where adding lopinavir-ritonavir to ribavirin reduced risk of adverse clinical outcomes, such as acute respiratory distress syndrome or death, and viral load among patients with SARS.

"It's easy to understand that these patients need antivirals, but unfortunately so far there is no solid evidence-based medicine data to show a specific antiviral therapy" works, said Cao, in a joint China Cardiovascular Association-American College of Cardiology (ACC) webinar. Cao is also leading the CAP China remdesivir 1 trial in mild-to-moderate pneumonia and CAP China remdesivir 2 trial for severe-to-critical pneumonia.

In the current study, researchers examined data from hospitalized adult patients with confirmed COVID-19 infection and an oxygen saturation of 94% or less. Patients were randomized to receive either lopinavir-ritonavir twice a day for 14 days in addition to standard care or standard care (defined as supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, and extracorporeal membrane oxygenation, as needed).

Clinical improvement was defined as time from randomization to an improvement of two points on an ordinal scale or discharge from the hospital. The authors noted this endpoint had previously been used in clinical trials of patients hospitalized with severe influenza.

Overall, 199 patients were randomized -- 99 to the lopinavir-ritonavir group, and 100 to standard of care. Median age was 58, and about 60% were men. Median interval time between symptom onset and randomization was 13 days. Systemic glucocorticoids were administered to 33% of patients in the intervention group and 35.7% of patients in the control group.

A modified intention-to-treat analysis found lopinavir-ritonavir associated with a median time of clinical improvement shorter by 1 day (HR 1.39, 95% CI 1.00-1.91). Interestingly, the intervention group also had a shorter stay in the intensive care unit versus standard care (median 6 vs 11 days, respectively), and duration from randomization to hospital discharge was also shorter.

"What makes lopinavir-ritonavir particularly attractive is that it is widely available and manufacturable to scale and that it could be prescribed immediately," noted Lindsey Baden, MD, of Brigham and Women's Hospital in Boston, and Eric Rubin, MD, PhD, of Harvard Chan School of Public Health, . While they called the trial a "heroic effort," it was ultimately "disappointing."

Secondary endpoints "provide both reason for hope and reason for discouragement," they added, pointing to the somewhat lower number of deaths with lopinavir-ritonavir but no discernible effect on viral shedding. "Since the drug is supposed to act as a direct inhibitor of viral replication, the inability to suppress the viral load and the persistent detection of viral nucleic acid strongly suggest that it did not have the activity desired," they wrote.

The negative results might have been due to selection of a "particularly challenging" population late in the course of infection with already considerable tissue damage. "Even highly active antibacterial agents have limited efficacy in advanced bacterial pneumonia," Baden and Rubin pointed out.

Also, a number of patients were enrolled before testing for the virus was fully defined.

Nevertheless, the trial does have an important lesson, they wrote: "[I't is clear that rapidly initiated, high-quality randomized clinical trials are possible in epidemic conditions, even in the trying circumstances that prevailed in Wuhan."

Cao and colleagues found about half of patients in both groups reported adverse events (AEs). While gastrointestinal AEs, such as nausea, vomiting, and diarrhea were more common in the intervention group, there were more serious AEs recorded in the standard care group (19 vs 32, respectively). In the standard care group, respiratory failure, acute kidney injury, and secondary infection were more common. The four serious gastrointestinal AEs in the lopinavir-ritonavir group were judged to be related to the study medication, the authors said.

Aside from the open-label design, other limitations included that the intervention group had somewhat higher throat viral loads, which raises "the possibility that this group had more viral replication," the authors said. Use of glucocorticoids may have been another confounder, they added.

They concluded that while they found no benefit to lopinavir-ritonavir to treat COVID-19 infection, the effect of combining the drug with other antiviral agents, similar to what was done in SARS and MERS, "remains to be determined."

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