Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized, single-blind, placebo-controlled trial (NCT04331899) in 120 outpatients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) within 72 hours of diagnosis could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint). In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively, and symptom duration did not differ significantly between groups (HR 0.94; 95% CI 0.64 to 1.39). Both Lambda and placebo were well-tolerated, though liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.
Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has led to more than 2 million deaths worldwide as of March 20211. Although most infected patients display mild symptoms, even uncomplicated infections can contribute to transmission to those with co-morbid conditions and other high risk groups, increasing overall mortality2. With the unprecedented health and economic threats imposed by COVID-19, therapeutics are urgently needed to shorten the duration of viral shedding, relieve symptoms, and prevent hospitalizations.
Interferons (IFNs) are promising anti-SARS-CoV-2 therapeutics, given their importance in the early response to viral infections3. Innate immune sensing of viral nucleic acids leads to production of type I (IFN-α, IFN-β) and type III (IFN-λ) IFNs that, after binding to their cognate receptors, activate genes critical for host protection4,5,6. SARS-CoV-2 encodes proteins that suppress production of endogenous IFN7, and infection has been associated with markedly reduced type I and type III IFN signaling8, particularly in patients with severe manifestations of disease9,10. Both type I and type III IFNs inhibit SARS-CoV-2 in vitro11,12, suggesting potential utility of exogenous IFN administration to aid in viral control and prevent disease progression. In support of this hypothesis, recent trials in hospitalized COVID-19 patients have reported that both subcutaneous and inhaled type I IFN administration may reduce the duration of viral shedding and symptoms13,14,15,16,17.
Whereas cognate receptors to type I IFNs are expressed ubiquitously, the receptor complex (IL28R) for IFN-λ is expressed on only a few cell types, including epithelial cells in the gastrointestinal and respiratory tracts4,18,19. These cellular affinities have led investigators to use this agent to target viral hepatitides20,21 and respiratory viral infections18. In a murine model of influenza infection, IFN-λ treatment post-infection was associated with significantly lower mortality compared to mice treated with IFN-α, and this was associated with lower influenza viral loads22. A pegylated form of recombinant IFN-λ, Peginterferon Lambda-1a (Lambda) has been developed for the treatment of chronic viral hepatitis. Lambda, given weekly as 180 mcg subcutaneous injections, has comparable antiviral efficacy and an improved tolerability profile compared with type I IFN for the treatment of hepatitis23, likely due to its relatively limited receptor distribution. In a murine model of SARS-CoV-2 infection, subcutaneous administration of Lambda prophylactically or early after infection diminished SARS-CoV-2 replication in the lower respiratory tracts of mice in vivo11.
Lambda has thus emerged as a promising treatment candidate for SARS-CoV-224,25 given a plausible mechanism of action, the suppression of IFN activity by SARS-CoV-2, and in vitro and in vivo studies showing that IFN-λ administration can inhibit SARS-CoV-2 replication. To date, no therapies have been approved for outpatients with mild to moderate COVID-19 disease. We therefore conducted a randomized, placebo-controlled trial of Lambda for outpatients with uncomplicated SARS-CoV-2 infection. We tested the hypothesis that a single, 180 mcg subcutaneous injection of Lambda would be associated with a shorter duration of viral shedding in comparison to a normal saline placebo injection.
In this work, we show that a single subcutaneous injection of Lambda in outpatients with uncomplicated SARS-CoV-2 infection did not significantly reduce time to viral clearance or resolution of symptoms compared with placebo. Lambda was well-tolerated, with few adverse effects, though asymptomatic liver transaminase elevations occurred more frequently in participants randomized to Lambda compared with placebo.
We enrolled 120 participants between April 25 and July 17, 2020, of whom 110 (91.7%) completed 28 days of follow-up (Fig. 1a). The median age was 36 years (range 18–71), 50 participants (41.7%) were female, and 75 (62.5%) were Latinx ethnicity (Table 1). Eight (6.7%) participants were asymptomatic at baseline. Of those with symptoms, the median duration of symptoms prior to randomization was 5 days. The most common symptoms were fatigue, cough, headache, and myalgias (Table 1, Supplementary Fig. 1). Only 13 (10.8%) participants had an elevated temperature (>99.5°F) at baseline; the median oxygen saturation was 98%. The proportion of missing follow-up visits was 44/960 (4.6%). Only 16/960 visits were missed among patients not hospitalized or prematurely withdrawn.
The presence of SARS-CoV-2 RNA was assessed at baseline and at 8 follow-up visits using oropharyngeal swabs, a Centers for Disease Control approved method for SARS-CoV-2 detection26. This method was selected given the frequency of repeated assessments and improved tolerability for participants compared with nasopharyngeal swabs. The median SARS-CoV-2 oropharyngeal viral PCR cycle threshold at enrollment was 30.3 (corresponding to a median viral load of 4.4 Log10 copies/ml), and was comparable between groups (Table 1). Patients were randomized within a median of 2 days (range 0–3 days) following diagnosis. The median time from onset of symptoms before diagnosis was 5 days (IQR 3–6).
IgG antibody titers against the SARS-CoV-2 spike receptor-binding domain (RBD) were assessed at enrollment by enzyme-linked immunosorbent assay27. At enrollment, 49 (40.8%) participants were SARS-CoV-2 IgG seropositive. Baseline SARS-CoV-2 serostatus did not significantly differ between groups (Table 1). The median duration of symptoms prior to enrollment was shorter in SARS-CoV-2 IgG seronegative vs. seropositive participants (median [interquartile range [IQR]]: 3.5 [2.5–5] days vs. 5 [4–7] days, P = 0.0051). Seronegative participants also had significantly higher oropharyngeal viral RNA levels at enrollment compared with seropositive participants (median [IQR] log10 viral load 4.4 [2.5] vs. 2.0 [2.4]).
Of 120 enrolled participants, 60 were randomized to receive Lambda and 60 randomized to receive placebo and included in the analysis. The median time to cessation of oropharyngeal viral shedding was 7 days in both arms. There was no significant difference in the adjusted hazard ratio (aHR) for shedding cessation between Lambda and placebo; participants in the Lambda arm were 19% less likely to cease shedding at any point during the study period compared to participants in the placebo arm (aHR 0.81, 95% confidence interval [CI] 0.56– 1.19; p = 0.29, Fig. 2a). Overall, 108 participants met the primary endpoint and were not censored. Because two participants, after randomization, inadvertently were injected with the incorrect syringe, we also conducted an as-treated analysis according to treatment actually received. Findings from an as-treated analysis (aHR 0.83, 95% CI 0.56–1.21; p = 0.33) and an analysis performed in symptomatic patients only (aHR 0.77, 95% CI 0.52–1.15, p = 0.21) were similar. Full Article