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Triple antiviral therapy regimen for interferon beta 1 Lopinavir / ritonavir,and Ribavirin A small study in Hong Kong reduced the median time to negative COVID-19 virus by 5 days.
In an open-label, randomized, phase 2 study in patients with mild or moderate COVID-19 infection, median time to negative virus with nasopharyngeal swabs was 14 days of lopinavir 400 mg It was 7 days with 86 patients assigned. Ritonavir Compared to 100 mg every 12 hours, 400 mg ribavirin every 12 hours, 3 doses every other day of 8 million international units of interferon beta 1b.P = .0010), wrote Ivan Fan-Ngai Hung, MD, Gleaneagles Hospital, Hong Kong, and colleagues.
“ Triple antiviral therapy with interferon beta 1b, lopinavir / ritonavir, and ribavirin has been shown to shorten viral release, alleviate symptoms, and facilitate discharge of patients with mild to moderate COVID-19. , Safer and better than lopinavir / ritonavir alone “in a study published online Lancet..
Patients receiving the combination therapy had symptomatic relief as assessed by a National Early Warning Score 2 (NEWS2, a system for detecting clinical deterioration in patients with acute illness) score 0 (4 and 8 days, respectively). The time to complete was significantly reduced; hazard ratio 3.92, P <.0001), and a Sequential Organ Failure Assessment (SOFA) score of 0 (3 vs. 8 days, HR 1.89, P = .041).
Median hospital stay for patients receiving combination therapy was 9 days compared to 14.5 days for the control group (HR 2.72, P = .016).
In most patients treated with this combination, SARS-CoV-2 viral load was effectively suppressed in all clinical specimens, including nasopharyngeal swabs, throat and posterior oropharyngeal saliva, and stool.
Furthermore, serum levels of interleukin-6 (IL-6), an inflammatory cytokine associated with the cytokine storm frequently found in patients with severe COVID-19 infection, are significantly reduced on days 2, 6, and 8 of treatment. Did. Combination compared to lopinavir / ritonavir treated alone.
“ Our trial shows that early treatment of mild to moderate COVID-19 with three combinations of antiviral drugs can rapidly reduce viral load in patients, alleviate symptoms, reduce duration and dose. It has been shown that reducing can reduce the risk to health care workers (if the virus is detectable and potentially infectious) the potential for viral shedding, and the combination of treatments is safe and well tolerated by the patient. It looked like it was, “said the principal investigator. Professor Kuk Yun Yuen From the University of Hong Kong in a statement.
“ Despite these promising discoveries, we found that in a larger Phase 3 trial, interferon beta 1b alone or in combination with other drugs was more severe in patients (more time allowed for the virus to replicate). Must be confirmed to be effective)))
Plausible basis
Benjamin Medoff, MarylandIn an interview with the pulmonary and critical care department head of the Massachusetts General Hospital in Boston, where he was not involved in the study, the biological basis for the combination was plausible.
“I think this is a promising study. A regimen of interferon beta 1b, lopinavir / ritonavir, ribavirin shortens the duration of infection and improves symptoms in patients with COVID-19.”
“ As the authors point out, it is important to emphasize that the nature of open labels and small studies limit the widespread use of regimens and enrolled subjects were not a very serious disease. (Not in the ICU.) However, research suggests that larger, truly randomized studies are justified. ”
Diverted AIDS drug
Lopinavir / ritonavir is commonly used for treatment HIVAround the world / AIDS, and researchers have shown that antiviral agents combined with ribavirin reduce death and the need for intensive ventilatory support in patients with SARS-CoV, the causative beta coronavirus. Had previously reported Severe acute respiratory syndrome (SARS), and antiviral agents, show in vitro activity against both SARS-CoV and MERS-CoV, a closely related pathogen that causes the Middle East respiratory syndrome.
“But the SARS and MERS viral load peaks about 7-10 days after the onset of symptoms, whereas the COVID-19 viral load peaks at the onset of symptoms. influenza.. The experience of treating influenza patients admitted to the hospital suggested that the combination of multiple antiviral drugs is more effective than monotherapy in this situation in patients with high viral load at the time of examination, “the researchers say. Said the others.
To test this, we enrolled adult patients admitted to one of six Hong Kong hospitals for a virologically confirmed COVID-19 infection from February 10, 2020 to March 20, 2020.
A total of 86 patients were randomly assigned to the combination and 41 were assigned to lopinavir / ritonavir alone as a control at the above doses.
Patients who entered the study within 7 days of the onset of symptoms received three combinations of interferon doses adjusted according to the day treatment started. Patients recruited 1 or 2 days after onset of symptoms received 3 doses of interferon, patients started on day 3 or 4 received 2 doses, started on day 5 or 6. The patients who were given received a single dose of interferon. Patients recruited 7 days or more after the onset of symptoms did not receive interferon beta-1b due to its proinflammatory effects.
A post hoc analysis by treatment start date showed that 52 patients receiving at least one dose of interferon plus lopinavir / ritonavir and ribavirin were hospitalized less than 7 days after onset of clinical and virological outcomes ( (Excluding stool samples) was excellent. We compared 24 patients randomized to the control group (lopinavir / ritonavir only).
In contrast, there was no difference between patients receiving lopinavir / ritonavir alone and receiving ribavirin in combination in patients who were hospitalized and started on day 7 or later. ..
Adverse events were reported in 41 of 86 patients in the combination arm and 20 of 41 patients in the control arm. The most common adverse event is diarrheaOf 127 cases, 52 cases, 48 cases had fever, 43 cases had nausea, and 18 cases had elevated alanine transaminase level. Side effects generally resolved within 3 days of starting treatment.
No serious adverse events were reported in the combination group. One patient in the control group had a liver enzyme disorder that required discontinuation of treatment. No patient died during the study.
The study was funded by the Shaw Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and the Sanming Project of Medicine. The author and Dr. Medoff did not declare competing interests.
Source: Hung IFN et al. Lancet. May 8, 2020. Doi: 10.1016 / S0140-6736 (20) 31101-6..
This article was first published MDedge.com.
