A two-week course of antiviral therapy with interferon beta-1b plus lopinavir-ritonavir and ribavirin, started within 7 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, according to the first randomised 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) in the new study suggest that clinical improvement and length of hospital stay may be significantly shorter in people treated with triple combination less than 7 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 hospitalised 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 hypothesised 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 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. 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.
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).
Further secondary analyses also looked at timing of treatment and patient outcomes. They found that the 52 patients who started combination treatment (with interferon beta-1b) less than 7 days after the onset of symptoms had better clinical and virological outcomes than the control group who received their treatment at the same time (24 patients). However, people who were treated 7 days or more after showing symptoms there was no difference in outcomes between the combination treatment and control groups (34 patients in the combination group, who received lopinavir-ritonavir and ribavirin but did not receive interferon beta-1b, and 17 in the control group) [5].
“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. 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.
Reference: World Pharma news and Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial.
The Lancet, 2020. doi: Lancet
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