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

Hung. The Lancet 2020; in press. doi: 10.1016/S0140-6736(20)31042-4

Clinical Question

• In adult patients with COVID-19, does combined interferon beta-1b, lopinavir–ritonavir, and ribavirin, compared with lopinavir-ritonavir alone, reduce the time to a negative swab result?

Background

• A prior case series by Young et al showed variable results in patients treated with lopinavir-ritonavir
• A recently published clinical trial with lopinavir-ritonavir did not demonstrate efficacy in reducing mortality and did not reduce viral loads or duration of viral detectability
• Prior data with lopinavir-ritonavir/ribavirin in combination was shown to be beneficial in patients with SARS, and interferon beta-1b may decrease viral load
• The authors state that this is the first RCT on the triple combination of interferon β-1b, lopinavir–ritonavir, and ribavirin, compared with single-drug lopinavir–ritonavir in the treatment of patients admitted to hospital with COVID-19

Design

• Phase 2, multicentre, open-label, randomised trial
• Patients were randomly assigned (2:1) to either treatment group or control
  • Simple randomization with no stratification
  • Open label randomization
  • Computer generated randomization
• Primary efficacy analysis was on an intention-to-treat basis
• The necessary sample size had been calculated to be 30 patients per group to detect such a difference at a two-sided α level of 0.05, with 80% power
  • The protocol proposed recruiting at least 35 patients per group to
    allow for a 17% dropout rate
  • These numbers were based on the authors’ prior study with the 2003 SARS-CoV virus, as there were insufficient mortality data on SARS-CoV-2, with estimated reduction of 26.4% in the 21 day mortality or ARDS rate from a baseline of 28.8%
• No placebo group
  • Authors stated that placebos are generally not accepted in Chinese culture
  • The authors’ previous study showed that interferon β-1b and lopinavir–ritonavir are active against SARS-CoV and MERS-CoV

Setting

• Six major public hospitals in Hong Kong, serving 75% of the population of 7.5 million
• All patients with SARS-CoV-2 infection were routinely admitted to hospital
• Study conducted from February 10 to March 20, 2020

Population

• Inclusion:
  • Age at least 18 hospitalized for virologically confirmed SARS-CoV-2 infection
  • National early warning score 2 (NEWS2) of at least 1
  • Symptom duration of 10 days or less upon recruitment (changed to 14 days after study commencement)
  • Auditory temperature ≥38°C or other symptoms including cough, sputum production, sore-throat, nasal discharge, myalgia, headache, fatigue or diarrhea upon admission
  • Within 48 hours of hospital admission
• Exclusion:
  • Allergy or severe reactions to the study drugs
  • Known prolonged QTc syndrome, ventricular cardiac arrhythmias,
    including torsade de pointes, second or third degree heart block, QTc interval ≥480ms
  • Taking medication with potential interactions with study drugs
  • Known history of severe depression
  • Pregnant or lactating women
  • Received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month prior to recruitment in this study or expected to receive an experimental agent during the study
  • History of alcohol or drug abuse in the last 5 years
• 144 patients screened, 127 patients recruited
  • 86 patients randomly assigned to the combination group
  • 41 patients assigned to the control group
    • One patient discontinued treatment on day 7 due to adverse event
• Comparing baseline characteristics of treatment vs control group
  • Age: median 51 vs 52 years old
  • Men: 52% vs 56%
  • Time from symptoms onset to start of treatment: median 5 days vs 4 days
  • Co-morbidities
    • Diabetes: 13% vs 15%
    • Hypertension: 27% vs 32%
    • Coronary artery disease: 6% vs 12%
  • Signs and symptoms
    • Fever 81% vs 78%
    • Chills 15% vs 15%
    • Cough 52% vs 56%
    • Sputum 34% vs 32%
    • Shortness of breath 8% vs 17%
    • Sore throat 19% vs 24%
    • Myalgia 12% vs 20%
    • Malaise 22% vs 12%
    • Diarrhea 20% vs 17%
    • Anosmia 5% vs 2%
  • Baseline laboratory findings (median)
    • White cell count: 4.9 vs 5.4
    • Neutrophils: 3.4 vs 3.5
    • Lymphocytes: 1 vs 1.3
    • Platelets: 195 vs 192
    • C-reactive protein: 3 vs 3
  • Baseline radiological findings (%)
    • Abnormal chest x-ray:74% vs 78%

Intervention

• If presented <7 days from symptoms onset (n=52):
  • Lopinavir-ritonavir 400-100 mg twice daily for 14 days
  • Ribavirin 400 mg twice daily for 14 days
  • Interferon β-1b 8 million IU alternate day until day 6 post symptom onset (median of two doses administered, range 1-3 doses)
•  If presented between 7 and 14 days from symptoms onset (n=34)
  • Combination lopinavir-ritonavir 400-100 mg and ribavirin 400 mg twice daily without interferon β-1b

Control

• Combination of 14-day course of oral lopinavir-ritonavir 400-100 mg capsule twice daily (n=40)

Management common to both groups

• Standard of care
  • Oxygen
  • Dialysis
  • Non-invasive and invasive ventilatory support
  • Extracorporeal membrane oxygenation support
  • Antimicrobial treatment for secondary bacterial infection as indicated clinically
  • Stress doses of corticosteroid (50 mg hydrocortisone every 8 h intravenously, tapering over 7 days) were given to patients who developed oxygen desaturation and required oxygen support
  • Daily nasopharyngeal swab (RT-PCR) were taken until hospital discharge
• Criteria for lopinavir-ritonavir reduction to once-daily administration
  • Prolonged QTc less than 480 ms
  • First-degree heart block or bundle branch block
  • Bradycardia upon ECG examination
  • Increased alanine transaminase of three times the upper limit of normal (ULN)
• Criterion for lopinavir-ritonavir cessation
  • Alanine transaminase levels exceeded six times the ULN

Outcome

• Primary outcome comparing treatment group to control group:
  • Time to negative nasopharyngeal swab (NPS) SARS-CoV-2 viral RT-PCR – significantly reduced in intervention group
    • Median 7 days vs 12 days; HR 4.37 (1.86–10.24), p=0.0010
• Secondary outcomes, 
  • Significantly reduced in intervention group:
    • Time to resolution of symptoms as defined by NEWS2 of 0  maintained for 24 hours
      • Median 4 days vs 8 days; HR 3.92 (1.66–9.23), p<0.0001
    • Time to resolution of symptoms as defined by SOFA of 0  maintained for 24 hours
      • Median 3 days vs 8 days; HR 1.89 (1.03–3.49), p=0.041
    • Length of hospitalization
      • Median 9 days vs 14.5 days; HR 2.72 (1.2–6.13), p=0.016
    • Time of negative SARS-CoV-2 RT-PCR for all samples
      • Median 8 vs. 13 days, p=0.001
    • Daily viral load from from 1-7 (measured on nasopharyngeal, oropharyngeal, and throat swab, and stool viral load)
      • Statistically significant reduction on most days
  • No significant difference between intervention vs. control group:
    • Need for Ventilator support
      • 0% vs. 2%, p=0.15
    • 30-day mortality
      • 0 vs 0, p=1
    • Adverse events during treatment
      • All adverse events: 48% vs. 49%
      • Diarrhoea: 40% vs. 44%
      • Increased alanine transaminase: 13% vs. 17%
        • The authors reported only 1 treatment discontinuation (in the control group) due to an elevated ALT. In comparison, LOTUS China reported nearly 14% of their lopinavir-ritonavir group did not complete treatment due to side effects
  • Cytokine/chemokine changes (analyzed in the first 84 recruited patients)
    • The IL-6 concentration in the combination group (64 patients) was significantly lower than in the control group (24 patients) on days 2 (p=0.0060), 6 (p=0.0040), and 8 (p=0.0020)
    • TNFα concentrations and IL-10 concentrations: no significant differences
  • Emergence of amino acid mutations in the nsp5 gene encoding a 3C-like protease
    • No significant mutations detected
• Post-hoc analyses
  • Statistically significant clinical and virological differences were seen between the treatment (n=52) and control group (n=24) for patients who started treatment <7 days after symptom onset, across all measured
    variables except stool samples
  • No significant differences seen between the treatment (n=34) and control group (n=17) for patients who started treatment 7 or more days after symptom onset

Authors’ Conclusions

• “Triple antiviral therapy with interferon β-1b, lopinavir–ritonavir, and ribavirin were safe and superior to lopinavir–ritonavir alone in shortening virus shedding, alleviating symptoms, and facilitating discharge of patients with mild to moderate COVID-19”

Strengths

• Median time from symptom onset to start of treatment was 5 days (4–7) for the combination group and 4 days (3–8) for the control group
  • This may have captured the patients within a more optimal window of opportunity for treatment
  • In comparison, the LOTUS CHINA study showing negative results with lopinavir-ritonavir had a median time to treatment of 13 days which may have been too late in the disease course
• The number of patients screened accounted for 80% of the confirmed COVID-19 cases in Hong Kong during this period
  • Increases external validity by using a sample that likely is a good representation of the general population of interest
• The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report
• Primary efficacy analysis was on an intention-to-treat basis

Weaknesses

• No placebo group, trial used an active control
  • Authors attribute this in part to Chinese culture
• Open-label nature of the trial meant a lack of blinding
  • Introduces bias to the study
• Some patients in the treatment group did not receive interferon β-1b, depending on when they presented
  • Difficult to tease out the role of interferon β-1b
• Absence of critically ill patients did not allow the generalization of our findings to severe cases
  • Only one patient in the study (control group) was placed on ventilator support
• Authors note that “Under the Hong Kong Special Administrative Region
  public health ordinance, all patients with COVID-19 must stay in hospital until nasopharyngeal swab viral loads are negative on 2 consecutive days”
  • Unclear if these patients would have been hospitalized in the United States or other health care systems
• Power and sample size calculations were based on SARS-CoV-1 due to a lack of clinical information on SARS-CoV-2
  • Assumes that the viruses are similar in their virulence, if incorrect then the study design is impacted
• Primary outcome was not patient centred

The Bottom Line

• A small RCT demonstrated that aggressive triple therapy combination treatment with lopinavir-ritonavir, ribavirin, and interferon β-1b was superior to lopinavir-ritonavir alone in reducing the time to a negative swab result
• In a population with a low severity of illness they reported secondary outcomes that demonstrated a shorter time to clinical improvement and a reduced duration of hospital stay with the combination therapy. Post-hoc analysis reported that the benefits were limited to when the treatment was started within 7 days of symptom onset and included interferon
• Larger RCTs will be required to clarify the therapeutic potential/role of each individual agent and determine their applicability to patients who present later in the disease progression and who have more severe symptoms. These studies should utilise a patient centred primary outcome
• This is a unique study that adds to the literature and should serve as a springboard for other, larger studies

External Links

• Hung I et al. Triple Combination of Interferon Beta-1b, Lopinavir-Ritonavir, and Ribavarin in the Treatment of Patients Admitted to Hospital with COVID-19: An Open-Label, Randomised, Phase 2 Trial. Lancet 2020. [Epub Ahead of Print]
• PulmCrit: Virus Wars: Return of Lopinavir/Ritonavir (along with ribavirin and interferon)
• The Bottom Line Summary: LOTUS CHINA
• The Bottom Line Summary: Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial
• REBEL EM: COVID-19: Triple Antiviral Therapy & IL-1 Inhibition

Metadata

Summary author: Daniel Hu, PharmD, BCCCP
Summary date: 14th May 2020
Peer-review editor: David Slessor