With many countries now ending their quarantines and the coronavirus far from being defeated, studies are still continuing worldwide to find an effective treatment for SARS-CoV-2. On Friday 8 May, researchers announced promising results from a two-week triple antiviral therapy (interferon beta-1b, lopinavir, ritonavir and ribavirin) in combination with standard treatment in a study published in The Lancet. However, these results do not include the severe cases of Covid-19, and larger Phase 3 trials are still required to ensure the efficacy of this triple combination in critically ill patients.
In 2003, during the SARS epidemic, previous research had already shown that a combination of oral lopinavir-ritonavir (originally used to treat HIV) and ribavirin (an oral drug for hepatitis C) was effective in reducing respiratory failure and patient mortality. Beta-1b interferon, which was developed for the treatment of multiple sclerosis (MS), has subsequently been shown to be useful in reducing the viral load and improving lung problems in animal studies of MERS (Middle East Respiratory Syndrome) coronavirus infection in 2012.
The current study was conducted in Hong Kong, where anyone who tests positive for Covid-19 is hospitalized. The researchers tracked 127 patients with a mean age of 52 years with mild to moderate symptoms of Covid-19 in six public hospitals. They began treatment on average five days after the onset of clinical symptoms. The participants were randomly assigned to a triple combination of lopinavir, ritonavir, and ribavirin every 12 hours for 14 days. They also received up to three doses of interferon injection beta-1b on alternate days. The control group received lopinavir, ritonavir every 12 hours.
A combination that appears to be “safe and well-tolerated by the patients”.
In parallel, both patient groups received respiratory support, dialysis, antibiotics, and corticosteroids in addition to the standard treatment. In the course of the study, the researchers followed the evolution of the disease, changes in laboratory results, as well as the viral loads of the patients through regular testing.
They found that the viral load of patients treated with the triple therapy went down faster than in the control group, which was treated with lopinavir-ritonavir alone. In addition, 52 volunteers who received combination therapy with interferon beta-1b within seven days of the onset of the first symptoms showed better clinical and virological results than the control group treated over the same period. In contrast, the researchers found no difference between the results of the combined treatment and those of the control groups for those who were treated seven days or more after the onset of symptoms. Finally, no differences in adverse effects were observed between the treatment groups.
“Our study shows that early treatment of Covid-19 with light to moderate symptoms with a triple combination of antiviral drugs can rapidly reduce the viral load in a patient’s body, alleviate symptoms and reduce the risk to caregivers by reducing the duration and viral load. In addition, the combination of treatments appeared to be safe and well-tolerated by patients,” commented Professor Kwok-Yung Yuen of Hong Kong University.
“We will need to confirm the results in a more comprehensive Phase 3 trials” he added.
This could be explained by the fact that, as in influenza, the viral load of Covid-19 reaches its peak at the onset of symptoms. In addition, a combination of antivirals could minimize the risk of drug resistance.
However, the researchers recognize some limitations in their work. This is an open trial where scientists and patients know what treatment they are getting. In addition, there was no placebo group and no critical patients were included in the trial. So the work is far from complete.
“Despite these encouraging results, we need to confirm in larger Phase 3 trials that interferon beta-1b, alone or in combination with other drugs, is effective in patients with more severe diseases (where the virus has had a long time to replicate),” concludes Kwok-Yung Yuen, whose work had already shown that SARS-CoV-2 can replicate up to 100 times in 48 hours in some cases, compared to 10 to 20 times for SARS-CoV in 2003.
Although the Hong Kong researchers are the first to use ribavirin for SARS-CoV-2, they are not the only ones interested in lopinavir/ritonavir and interferon-beta. This treatment is being studied as part of the European Trial Discovery which is being conducted on thousands of patients in about ten European countries. In the European trial in addition to the group receiving the combination of lopinavir/ritonavir and interferon beta, another group is receiving only lopinavir/ritonavir, while other subjects are testing chloroquine and remdesivir.
Remdesivir is an experimental antiviral drug originally developed by Gilead against Ebola, which has just been approved by the FDA. Unfortunately, it is not yet known when the results of the trial will be announced, as the trial has been extremely delayed.