Promising results for treatment against coronavirus arrive from the first randomized study that evaluated different combinations of antiviral drugs, associated or not with interferon.
It emerged that a two week period of antiviral therapy with interferon beta-1b plus lopinavir-ritonavir and ribavirin, initiated within 7 days of the onset of COVID-19 symptoms, is safe and more effective in reducing the duration of viral shedding than lopinavir–ritonavir alone in patients with mild to moderate illness.
This research, conducted on 127 adults hospitalized in six public hospitals in Hong Kong and published in The Lancet, did not include serious cases of COVID-19. The authors also stress the need for larger phase 3 studies to examine the efficacy of this triple combination even in critically ill patients.
Shorter hospital stay with the triple combination
Secondary outcome 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 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.
“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. 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.”
Coronavirus: triple combination with lopinavir-ritonavir and ribavirin
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 severe acute respiratory syndrome (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 Middle East respiratory syndrome (MERS) coronavirus infection.
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 (400 mg/100 mg) and ribavirin (400 mg) 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 (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.
Study primary and secondary endpoint
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. All participants had a SARS-CoV-2 positive nasopharyngeal swab at the start of the study.
The endpoint was time to a nasopharyngeal swab negative for SARS-CoV-2. Secondary outcomes included time for symptoms of COVID-19 achieving a National Early Warning Score (NEWS) score of 0 and a Sequential Organ Failure Assessment (SOFA) score of 0. Moreover, they included 30-day mortality and length of hospital stay.
Coronavirus: an effective suppression of the viral load
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 virologic 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 evidenced 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).
Coronavirus: interferon beta 1-b as a key component of treatment
“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 diarrhea, 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 analyzed as part of the combination group.
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