Triple antiviral drug combo shows promise in COVID-19 treatment: Lancet

Researchers had first evidence from randomised trial conducted in six public hospitals in Hong Kong regarding new tripleantiviral drug combination for treating COVID-19.They have found that early treatment with triple antiviral therapy of interferon beta-1b, lopinavir-ritonavir, and ribavirin – alongside standard care – is safe and shortens duration of viral shedding compared to lopinavir-ritonavir alone (average 7 days vs 12 days), in patients with mild to moderate COVID-19.

The authors stress the need for larger phase 3 studies in critically ill patients to confirm whether this triple regimen can provide clinically meaningful benefit.

These early but important findings have been published in The Lancet.

The open label study enrolled 127 adults (average age 52 years) admitted to one of six public hospitals with laboratory-confirmed SARS-CoV-2 infection between February 10 and March 20, 2020 [4]. In Hong Kong, everyone who tests positive for COVID-19 is admitted to hospital.

Participants were randomly assigned to 14 days of either the triple combination of oral lopinavir-ritonavir (400mg/100mg) and ribavirin (400mg) every 12 hours, plus up to three doses of injectable interferon beta-1b (8 million international units) on alternate days for patients admitted to hospital less than 7 days from symptom onset [5] (86 patients; combination group); or lopinavir-ritonavir alone every 12 hours (41 patients; control group).

In the trial, all patients received standard care including ventilation support, dialysis support, antibiotics, and corticosteroids. The average number of days from symptom onset to start of study treatment was 5 days.

During the study, the researchers looked at the clinical course of symptoms, and changes in laboratory findings (eg, blood examinations, chest x-rays) and viral shedding with regular molecular testing for viral load in nasopharyngeal swab, posterior oropharyngeal saliva, throat swab, stool, and urine (see table 2 for full list). All participants had a SARS-CoV-2 positive nasopharyngeal swab at the start of the study.

The primary endpoint was time to a nasopharyngeal swab negative for SARS-CoV-2. Secondary outcomes included time for symptoms of COVID-19 to go defined as achieving a National Early Warning Score (NEWS) score of 0; a Sequential Organ Failure Assessment (SOFA) score of 0, indicating normal function; 30-day mortality; and length of hospital stay.

Treatment with the triple drug combination effectively suppressed viral load (with no detectable virus) in the nasopharyngeal swab within an average 7 days of starting treatment, which was significantly shorter than the average 12 days in the control group, treated with lopinavir–ritonavir alone .

Secondary outcomes supported the findings, indicating that clinical improvement was significantly better in the triple combination group—with the triple therapy halving the time to complete alleviation of symptoms (average 4 days vs 8 days) and a SOFA score of 0 (average 3 days vs 8 days), and resulting in significantly shorter average hospital stay (9 days vs 14.5 days).

"Our trial demonstrates that early treatment of mild to moderate COVID-19 with a triple combination of antiviral drugs may rapidly suppress the amount of virus in a patient's body, relieve symptoms, and reduce the risk to health-care workers by reducing the duration and quantity of viral shedding (when the virus is detectable and potentially transmissible). Furthermore, the treatment combination appeared safe and well tolerated by patients", says Professor Kwok-Yung Yuen from the University of Hong Kong who led the research.

He continues, "Despite these encouraging findings, we must confirm in larger phase 3 trials that interferon beta-1b alone or in combination with other drugs is effective in patients with more severe illness (in whom the virus has had more time to replicate)."

"These findings suggest that interferon beta 1-b may be a key component of the combination treatment and is worth further investigation for the treatment of COVID-19", says co-author Dr Jenny Lo from Ruttonjee Hospital in Hong Kong. "Interferons are naturally occurring proteins, produced in response to viral infection, and the hope is that interferon beta-1b will boost the body's ability to fight SARS-CoV-2. Future phase 3 trials will soon confirm or refute the usefulness of this candidate drug as a backbone treatment for COVID-19."

There was no difference in adverse events between the treatment groups (48%; 41/86 patient combination group vs 49%; 20/41 controls), and none of the side effects in the combination group were severe. One patient in the control group had a serious adverse event of liver dysfunction, and discontinuation treatment. The most common adverse events were diarrhoea, fever, and nausea (table 4). No patients died during the study.

The authors highlight several limitations of the study, including that it was an open label study in which both the researchers and the patients knew the treatment the participants were receiving, and did not have a placebo group. They also note that the findings may be confounded by the subgroup of 34 patients within the combination group who were admitted 7 days or more after symptom onset, and were not offered interferon beta-1b, but were analysed as part of the combination group.

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