Treatment of Coronavirus Disease 2019 Patients With Prolonged Postsymptomatic Viral Shedding With Leflunomide: A Single-center Randomized Controlled Clinical Trial

Clin Infect Dis. 2021 Dec 6;73(11):e4012-e4019. doi: 10.1093/cid/ciaa1417.


Background: We aimed to evaluate the efficacy and safety of leflunomide, an approved dihydroorotate dehydrogenase inhibitor, to treat coronavirus disease 2019 (COVID-19) patients with prolonged postsymptomatic viral shedding.

Methods: We conducted a prospective, randomized controlled, open-label trial involving hospitalized adult COVID-19 patients with prolonged polymerase chain reaction (PCR) positivity. Patients were randomly assigned to receive either leflunomide (50 mg every 12 hours, 3 consecutive times, orally; then 20 mg once daily for 8 days), in addition to nebulized interferon alpha 2a (IFN-α-2a, 3 million IU each time, twice daily for 10 days), or nebulized IFN-α-2a alone for 10 days. The primary endpoint was the duration of viral shedding.

Results: A total of 50 COVID-19 patients with prolonged PCR positivity were randomized into 2 groups: 26 were assigned to the leflunomide plus IFN-α-2a group, and 24 were assigned to the interferon-alone group. Treatment with leflunomide was not associated with a difference from the interferon-alone group in the duration of viral shedding (hazard ratio for negative reverse-transcription PCR, 0.70 [95% confidence interval, .391-1.256]; P = .186). In addition, the patients given leflunomide did not have a substantially shorter length of hospital stay than patients treated with interferon alone, with median durations of 29.0 (interquartile range [IQR], 19.3-47.3) days and 33.0 (IQR, 29.3-42.8) days, respectively (P = .170). Two leflunomide recipients were unable to complete the full 10-day course of administration due to adverse events.

Conclusions: In COVID-19 patients with prolonged PCR positivity, no benefit in terms of the duration of viral shedding was observed with the combined treatment of leflunomide and IFN-α-2a beyond IFN-α-2a alone.

Keywords: COVID-19; SARS-CoV-2; interferon alpha 2a; leflunomide; viral shedding.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • COVID-19*
  • Dihydroorotate Dehydrogenase
  • Humans
  • Leflunomide / pharmacology
  • Prospective Studies
  • SARS-CoV-2
  • Treatment Outcome
  • Virus Shedding


  • Antiviral Agents
  • Dihydroorotate Dehydrogenase
  • Leflunomide