Hung

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

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

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

Metadata

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

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