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Patients hospitalized with COVID-19 who received a combination therapy with three antivirals -- protease inhibitor lopinavir-ritonavir (Kaletra), nucleoside analogue ribavirin, and injectable interferon beta-1b (Betaseron, Extavia) -- showed significantly shorter median time to a negative SARS-CoV-2 test versus controls, a small phase II trial found.

Median number of days from start of study treatment to a negative test result, the trial's primary endpoint, was 7 days compared with 12 days in a control group that only received lopinavir-ritonavir, reported Kwok-Yung Yuen, MD, of the University of Hong Kong, and colleagues .

Each "modestly active" drug has its own pedigree that makes it a candidate for a combination therapy. The authors noted that lopinavir-ritonavir and ribavirin "reduced the mortality and need for intensive respiratory support" in hospitalized SARS patients, and lopinavir-ritonavir and interferon reduced viral load and improved lung pathology in preclinical models.

The team also highlighted that the viral load of COVID-19 peaks around the time of presentation, similar to influenza.

"Experience from the treatment of patients with influenza who are admitted to hospital suggested that a combination of multiple antiviral drugs is more effective than single drug treatments in this setting of patients with a high viral load at presentation," the authors wrote.

An accompanying editorial by Sarah Shalhoub, MD, of Western University in London, Ontario, said because most studies have been retrospective or observational, "this prospective, [randomized] controlled design adds notable value to the growing evidence on treatments."

"This study presents ," she wrote.

The open-label trial from Yuen and colleagues was comprised of adult patients hospitalized for COVID-19 from six Hong Kong hospitals, and assigned to either the combination therapy (lopinavir 400 mg and ritonavir 100 mg every 12 hours, ribavirin 400 mg every 12 hours, and three doses of 8 million IU of interferon beta-1b on alternate days) or a control group with lopinavir-ritonavir only. Only patients enrolled less than 7 days after symptom onset received interferon beta-1b in the combination group, the authors noted.

Among 127 patients recruited from Feb. 10 to March 20, there were 86 assigned to the combination group (52 receiving interferon beta-1b and 34 who did not) and 41 to the control group. Baseline demographics were similar, median age was 52, and 54% were men. Median time from symptom onset to start of treatment was 5 days, with fever and cough as the most common presenting symptoms, the authors said.

Seventeen patients required oxygen treatment, and six were admitted to the intensive care unit, five of whom received non-invasive ventilator support. A little over half of the patients received concomitant antibiotics, the researchers said.

In an intent-to-treat analysis, the combination group had a significantly shorter median time to negative SARS-CoV-2 test, albeit with a wide confidence interval (HR 4.37, 95% CI 1.86-10.24, P=0.0010).

Clinical improvement and time to complete alleviation of symptoms was also significantly shorter in the combination group versus controls (4 days vs 8 days, respectively), and the combination group had a significantly shorter median hospital stay (9 days vs 14.5 days).

Combination therapy was associated with shorter time to negative viral load in all specimens, including nasopharyngeal swab, oropharyngeal saliva, throat swab, and stool samples, the authors said.

Adverse events occurred in 41 patients in the combination group and 20 in the control group. The most common were diarrhea (41%), nausea (34%), and elevated alanine transaminase (14%). Four patients reported sinus bradycardia. No serious adverse events were reported in the combination group, while one patient in the control group reported impaired hepatic enzymes leading to treatment discontinuation. There were no deaths.

Limitations to the data, Yuen and co-authors said, include that it was an open-label study, with an absence of critically ill patients, and was confounded by a subgroup omitting interferon beta-1b within the combination, due to time of symptom onset.

"A subsequent phase 3 trial with interferon beta-1b as a backbone treatment with a placebo control group should be considered, because subgroup comparison suggested that interferon beta-1b appears to be a key component of our combination treatment," the authors wrote.

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