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Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial
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Feb 5 2021 Lancet Respiratory Medicine - Jordan J Feld*, Christopher Kandel*, Mia J Biondi*, Robert A Kozak, Muhammad Atif Zahoor, Camille Lemieux, Sergio M Borgia, Andrea K Boggild, Jeff Powis, Janine McCready, Darrell H S Tan, Tiffany Chan, Bryan Coburn, Deepali Kumar, Atul Humar, Adrienne Chan, Braden O’Neil, Seham Noureldin, Joshua Booth, Rachel Hong, David Smookler, Wesam Aleyadeh, Anjali Patel, Bethany Barber, Julia Casey, Ryan Hiebert, Henna Mistry, Ingrid Choong, Colin Hislop, Deanna M Santer, D Lorne Tyrrell, Jeffrey S Glenn, Adam J Gehring, Harry L A Janssen, Bettina E Hansen
The in-vitro and in-vivo efficacy of interferon lambda against SARS-CoV-2 provided strong rationale for investigation in humans. As such, we aimed to investigate the efficacy of a single 180 μg subcutaneous injection of peginterferon lambda or placebo in outpatients with COVID-19.
Summary
Background
To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19.
Methods
In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic.Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ2 test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259.
Findings
Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15–16·73; p=0·029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49–31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported.
Interpretation
Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding.
Funding
The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.
Interferons are produced as part of the innate immune response to viral infections, driving induction of genes with antiviral, antiproliferative, and immunoregulatory properties. 6 The broad array of genes induced by interferons limits the risk of antiviral resistance and makes interferons optimal agents for novel viral pathogens.7 Interferon lambdas, known as type III interferons, promote a similar antiviral state to that of interferon alfa or beta, but use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, resulting in fewer systemic side-effects.7 Interferon lambda-1 controls respiratory viral infections without the risk of promoting cytokine storm syndrome, as has been seen in mice with type I interferon treatment.8 Additionally, interferon lambda inhibits SARS-CoV-2 replication in cell culture and mouse models.9, 10 Peginterferon lambda, a long-acting form of interferon lambda-1, has been assessed in over 3000 patients with viral hepatitis infections, showing similar antiviral efficacy to that of interferon alfa, but with an improved side-effect profile.11, 12
We found a clear antiviral effect of peginterferon lambda. Type III interferons lead to a slower but more sustained induction of interferon-stimulated genes, with peak responses seen after approximately 72 h, aligning with the onset of the antiviral response.22 Studies of monoclonal antibodies for outpatients with COVID-19 have also shown antiviral effects. In the early reports of the Regeneron monoclonal antibody cocktail, the difference in the decline in viral load with treatment compared with placebo by day 7 was 0·51 log copies per mL for the high dose and 0·23 log for the low dose group.23 The differences were greater in those who were seronegative for SARS-CoV-2 antibodies at baseline, with a difference of 0·60 log copies per mL with the high dose and 0·51 log copies per mL with the low dose, compared with the placebo group at day 7.23 Similar to our findings, greater antiviral effects were seen in those with high baseline viral load. Chen and colleagues reported that an intravenous infusion of neutralising antibody LY-CoV555 led to a reduction in viral load that was 0·53 log copies per mL greater with treatment than with placebo at day 11.3 Notably, in both of these studies, clinical benefits were seen with treatment in terms of reduced medical visits or hospitalisation,3, 23 highlighting the importance of even modest acceleration in viral load decline.
Despite the clear antiviral effect of peginterferon lambda, we did not see a marked difference in clinical outcomes. To translate acceleration of viral clearance to clear clinical benefit, the study would likely need to be enriched for those at higher risk of severe disease, such as individuals older than 65 years and those with comorbidities.34 Notably, the antiviral effect of peginterferon lambda compared with that of placebo was similar in those with comorbidities and the entire study population. Interestingly, among those still RNA positive at day 7, the viral concentrations were lower in the peginterferon lambda group than in the placebo group, which might have clinical relevance given the finding in the monoclonal antibody outpatient trial that patients with a higher viral load at day 7 were more likely to require hospitalisation.3 In addition to the risk of disease progression, lowering viral loads might reduce the risk of transmission. In those with high baseline viral load, most participants treated with placebo had detectable virus at day 7, with most of these continuing to exceed 105 copies per mL, raising concern of persistent shedding of competent virus. By contrast, few participants who received peginterferon lambda had detectable virus at day 7, all with viral loads below 106 copies per mL. To identify those most likely to benefit from this therapy, either quantitative testing could be introduced or a qualitative assay, ideally a point-of-care test, could be titrated to achieve an analytical sensitivity of approximately 105–106 copies per mL, allowing for immediate risk stratification and identification of the need for treatment. Indeed, this quantitative detection of SARS-CoV-2 could probably already be achieved using available rapid antigen tests, with detection sensitivities in the range of 10–50 000 copies per mL, safely below the infectious threshold but avoiding those with very low viral loads who are unlikely to require any intervention.35 More Black participants were in the placebo group than in the treatment group, a population typically shown to have reduced responsiveness to type I interferon for treatment of viral hepatitis.36, 37 However, similar proportions of patients in each group had the treatment-responsive interferon lambda genotype (TT), which is strongly associated with response to interferon alfa for hepatitis C infection and thought to explain most of the differential response to interferon by race.14 No effect of the interferon lambda genotype was observed on baseline viral load or response to treatment in the interferon lambda group. A high proportion of eligible individuals declined to participate in the study, probably because of the listed adverse event profile, which reflected weekly injections for a year of treatment for hepatitis B and C infections.11, 12
Peginterferon lambda was well tolerated with no identified safety concerns. Side-effects of peginterferon lambda overlap with COVID-19 symptoms, making distinguishing whether adverse events were related to treatment or the infection difficult. As has been reported previously,3 symptoms were more prominent in those with higher viral loads. With detailed serial symptom assessment, we found that symptoms improved in both groups over time. Notably, among those who were asymptomatic at baseline, we found no difference in the number of adverse events between the treatment and placebo groups. Mild and transient aminotransferase increases were seen more frequently in the peginterferon lambda group than in the placebo group, which has been reported previously.11
D-dimer concentrations reduced with peginterferon lambda treatment, which might be relevant given the association of high concentrations with more severe disease and increased all-cause mortality.34, 38, 39 The side-effect profile and absence of haematological toxicity is consistent with the improved tolerability of type III interferons compared with that of type I interferons. 11
Study limitations include the small sample size, although clearance rates in those with high viral loads were consistent with the power calculations. Based on viral load and antibody data at the baseline visit, several participants were probably clearing the infection, an observation reported in other studies of outpatients with COVID-19. 3, 23 Ideally with the introduction of point-of-care testing, treatment could be initiated promptly at the time of diagnosis, which was not possible in this study because of delays in reporting times of positive results and required time for recruitment and consent. The benefit of treatment was more pronounced in the group with high baseline viral load than in those with low baseline viral load. Quantitative assays or calibrated qualitative tests for COVID-19 could identify those most likely to benefit from therapy. As a phase 2 trial, the study was not powered to show differences in transmission, which are hard to document, or hospitalisation and mortality, which would require a larger study enriched for those at high risk of complications. However, as a first step to confirm efficacy, viral clearance is a key relevant endpoint. Having shown safety and efficacy in an ambulatory cohort, we and others are now investigating the clinical benefit of peginterferon lambda in patients admitted to hospital with COVID-19.
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