Background
Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir–ritonavir, and ribavirin for treating patients with COVID-19.
Methods
This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population.
Findings
Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3–7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5–11]) than the control group (12 days [8–15]; hazard ratio 4·37 [95% CI 1·86–10·24], p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir–ritonavir because of biochemical hepatitis. No patients died during the study.
Interpretation
Early triple antiviral therapy was safe and superior to lopinavir–ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted
In this multicentre randomised open-label phase 2 trial in patients with COVID-19, we showed that a triple combination of an injectable interferon (interferon beta-1b), oral protease inhibitor (lopinavir–ritonavir), and an oral nucleoside analogue (ribavirin), when given within 7 days of symptom onset, is effective in suppressing the shedding of SARS-CoV-2, not just in a nasopharyngeal swab, but in all clinical specimens, compared with lopinavir–ritonavir alone. Furthermore, the significant reductions in duration of RT-PCR positivity and viral load were associated with clinical improvement as shown by the significant reduction in NEWS2 and duration of hospital stay. Most patients treated with the triple combination were RT-PCR negative in all specimens by day 8. The side-effects were generally mild and self-limiting.
Specific highly active antiviral drugs are always needed for any novel emerging infectious disease because the development of a new antiviral takes years before its approval for clinical use. Therefore, drug repurposing by testing existing broad-spectrum antiviral drugs that have been used to treat other viral infections is the most feasible approach in a pandemic. Many drugs have been shown to have some in-vitro activity against betacoronaviruses, including remdesivir, favipiravir, nitazoxanide, camostat mesilate, interferons, lopinavir–ritonavir, ribavirin, chloroquine, hydroxychloroquine, and convalescent plasma containing neutralising antibodies. These drugs have known pharmacokinetic and pharmacodynamic properties, side-effects, and dosing regimens. As expected, lopinavir–ritonavir alone was shown to have similar effects to placebo on reducing viral load when treatment was initiated at a median of 13 days after symptom onset, despite some improvement in symptoms.Up to now, only two open-label non-randomised trials have been reported. One trial used a combination of oral hydroxychloroquine and azithromycin in 20 patients with COVID-19 showing that this combination might reduce viral load significantly by day 6 after treatment, compared with 16 controls from another hospital, which could be due to chance because this combination was not planned a priori and the addition of azithromycin was at the physician's discretion.
A small retrospective analysis showed that viral load was negative at day 7 post-treatment in 75% of patients with COVID-19 treated with arbidol and lopinavir–ritonavir (16 patients) versus 35% of patients treated with lopinavir–ritonavir alone (17 patients).
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. Thus, most patients were admitted to hospital within 7 days of symptom onset, allowing recruitment into the clinical trial during the early course of COVID-19. With the memory of the 2003 SARS pandemic, most patients with COVID-19 in Hong Kong accepted antiviral treatment, which explained our high recruitment rate. Despite being an open-label study, all patients were enrolled consecutively without bias. Our case demographics and proportion of patients with underlying diseases were similar to other reported cohorts in China. The low crude mortality rate in Hong Kong (four [0·4%] of 1041 cases) could be explained by the highly vigilant infection control measures, efficient contact tracing, and early hospital admission and treatment.
Early treatment with a triple combination of modestly active antivirals is appropriate for the treatment of COVID-19 because the viral load of SARS-CoV-2 peaks at around the time of symptom onset. This is unlike the situation of SARS and MERS when the antiviral treatment has time to suppress the viral load before it peaks at around days 7–10 after symptom onset. The viral load profile of COVID-19 is similar to that of influenza, which has a high viral load at the time of initiation of anti-influenza treatment. The emergence of resistant influenza virus quasispecies during treatment has been well reported with single-drug treatment by amantadine, baloxavir marboxil, and oseltamivir in the setting of severe influenza or diseases caused by H5N1, H7N9, or in immunosuppressed hosts.Thus, the antiviral combination was considered a reasonable option to improve the outcome of severe influenza. Indeed, we have previously shown that a combination of naproxen and clarithromycin, with weak anti-influenza virus activity in vitro individually, when combined with oseltamivir can improve the morbidity and mortality and shorten the duration of hospital stay in patients with influenza A/H3N2 pneumonia. Furthermore, we have previously shown that a combination of lopinavir–ritonavir and ribavirin significantly reduced mortality and respiratory failure in patients during the 2003 SARS outbreak.Thus, we hypothesised that a triple combination of modest antiviral drugs might rapidly suppress the high initial viral load, improve the clinical parameters, and reduce risk of health-care workers by reducing the duration and quantity of virus shedding from these treated patients.
An in-vitro study in cell culture-based assays showed that the 50% effective concentration (EC50) of lopinavir against SARS-CoV is about 17 μM and against MERS-CoV it is about 8 μM, whereas the peak serum lopinavir concentration is about 15 μM with a half-life of 7·4–10·8 h after an oral dose of 400 mg lopinavir and 100 mg ritonavir.The EC50 of interferon beta-1b is 0·12 IU/mL against SARS-CoV and 17·6 IU/mL against MERS-CoV whereas its peak serum level is about 20 IU/mL with a half-life of 2–5 h after a single subcutaneous dose of 8 million IU. Notably, the maintenance of high serum interferon beta-1b level is not essential once the antiviral status of exposed cells is induced. The EC50 of ribavirin against SARS-CoV-2 was 109 μM, which greatly exceeds the drug's serum concentration with the usual oral dosing. Nevertheless, synergistic activity between interferons and a lower dose of ribavirin have been shown in checkerboard assays. However, combining ribavirin with interferons (alfa-2a, alfa-2b, and beta-1a) did not improve outcomes in critically ill patients with MERS.
Thus, the repurposing of this triple combination of modestly active lopinavir–ritonavir, interferon beta-1b, and ribavirin for the treatment of this novel pandemic virus should be a reasonable therapeutic approach.
Furthermore, SARS-CoV-2 did not significantly induce types I, II, or III interferons in ex-vivo infected human lung tissues compared with 2003 SARS-CoV.Thus, the use of interferon beta-1b treatment to jump-start or improve the antiviral response of patients would be a logical approach. Additionally, interferon beta-1b was shown to decrease virus-induced lung fibrosis in a mouse model, which might improve outcomes of patients with COVID-19 complicated by acute respiratory distress syndrome.
Despite the concern of major side-effects arising from a combination of three drugs, no significant differences in incidence of adverse events between treatment groups were reported in our cohort of 127 patients. No haemolysis occurred from the short duration of low dose ribavirin. We did not use triple combination for patients who started treatment 7 days or more after symptom onset because of the concerns about the proinflammatory side-effects of interferon beta-1b, despite that at most three doses were used for each patient. Liver dysfunction was observed in about 14% of these patients and it was mild and self-limiting, except in one patient in the control group, in whom the biochemical hepatitis warranted the discontinuation of lopinavir–ritonavir treatment.
Our study had several limitations. This trial was open label, without a placebo group, and confounded by a subgroup omitting interferon beta-1b within the combination group, depending on time from symptom onset. A subsequent phase 3 trial with interferon beta-1b as a backbone treatment with a placebo control group should be considered, because subgroup comparison suggested that interferon beta-1b appears to be a key component of our combination treatment. Our absence of critically ill patients did not allow the generalisation of our findings to severe cases.
Triple antiviral therapy with interferon beta-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.
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