New triple antiviral drug combination shows early promise for treating COVID-19 in phase 2 randomized trial

A two-week course of antiviral therapy with interferon beta-1b, plus lopinavir-ritonavir and ribavirin, started within seven days of showing COVID-19 symptoms, is safe and more effective at reducing the duration of viral shedding than lopinavir-ritonavir alone in patients with mild to moderate illness.

That's according to the first randomized trial of this triple combination therapy involving 127 adults, aged 18 and older, from six public hospitals in Hong Kong.

These early but important findings, published in The Lancet, do not include severe cases of COVID-19, and the authors stress the need for larger phase 3 trials to examine the effectiveness of this triple combination in critically ill patients.

Secondary outcomes – planned outcome measures that are not as important as the primary outcome measure, but are still of interest in evaluating the effect of an intervention – suggest that clinical improvement and length of stay may be significantly shorter in people treated with the triple combination fewer than seven days after showing symptoms, compared to lopinavir-ritonavir alone.

Experience with influenza, which has a high viral load (how much virus is present in an infected person's body) around the time symptoms appear, suggests that treating hospitalized patients with a combination of multiple antiviral drugs may be more effective than single-drug treatments and minimize the risk of antiviral resistance. The authors hypothesized that this could be a possible therapeutic approach for COVID-19, in which the viral load also peaks around the time of symptom onset.

The trial also suggests this treatment reduces the risk to healthcare workers, because it reduces the duration and quantity of "viral shedding," which is when the virus is detectable and potentially transmissible.

WHAT'S THE IMPACT?

Previous research found that a combination of oral lopinavir-ritonavir (normally used to treat HIV) and ribavirin (an oral hepatitis C virus drug) significantly reduced respiratory failure and death in patients hospitalized with SARS during the 2003 outbreak. Interferon beta-1b, which was developed to treat multiple sclerosis, has been shown to reduce viral load and improve lung problems in animal studies of the MERS coronavirus infection.

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

Participants were randomly assigned to 14 days of either the triple combination of oral lopinavir-ritonavir and ribavirin every 12 hours, plus up to three doses of injectable interferon beta-1b on alternate days for patients admitted to hospital less than seven days from symptom onset – or lopinavir-ritonavir alone every 12 hours.

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 five days.

During the course of the trial, the researchers looked at the clinical course of symptoms, changes in laboratory findings such as blood examinations and chest x-rays, and viral shedding with regular molecular testing for viral load in a nasopharyngeal swab. All participants had a SARS-CoV-2 positive nasopharyngeal swab at the start of the study.

Treatment with the triple drug combination effectively suppressed viral load, with no detectable virus, in the nasopharyngeal swab within an average of seven days of starting treatment, which was significantly shorter than the average of 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, with and average of four days versus eight days. This resulted in a much shorter hospital stay.

Further analyses also looked at the timing of treatment and patient outcomes. They found that the 52 patients who started combination treatment less than seven days after the onset of symptoms had better clinical and virological outcomes than the control group who received their treatment at the same time. But in people who were treated seven days or more after showing symptoms there was no difference in outcomes between the combination treatment and control groups.

There was no difference in adverse events between the treatment groups, 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 there was discontinuation of treatment. The most common adverse events were diarrhoea, fever, and nausea. No patients died.

The authors highlight several limitations, 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 seven days or more after symptom onset, and were not offered interferon beta-1b, but were analysed as part of the combination group.

THE LARGER TREND

The rapidly escalating demand for medications due to COVID-19 is placing increased pressure on hospitals and health systems to appropriately manage drug inventory to support patient care. Essential medications used to alleviate breathing difficulties, relieve pain and sedate coronavirus patients are in short supply.

Meanwhile, Vizient found in late March that there has been a 6,842% increase in chloroquine tablets ordered, with fill rates dropping to as low as 1.4%, and a 2,196% increase in hydroxychloroquine tablets ordered, with fill rates dropping to as low as 12.1%, since March 16, when the World Health Organization declared COVID-19 to be a pandemic.

Twitter: @JELagasse

Email the writer: jeff.lagasse@himssmedia.com