Timing Antiviral Treatment of COVID-19

The randomized, placebo-controlled, clinical trial of remdesivir sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) in 1063 hospitalized patients with advanced COVID-19 and lung involvement began on February 21 and was closed to new enrollments on April 19. The results have not been published to date, but the NIAID reported in a preliminary final analysis that patients who received remdesivir had a 31% faster time to recovery (the primary endpoint); the median time to recovery (no longer needing oxygen or discharged from the hospital) was 15 days with placebo and 11 days with the active drug (p<0.001). The results also suggested a survival benefit; the mortality rate was 11.6% with placebo and 8% with remdesivir (p=0.059). At that point, the sponsors offered remdesivir to the patients who had been randomized to placebo, and on May 1, the FDA authorized emergency use of the drug to treat COVID-19 patients with severe respiratory illness.

The decision to stop the trial when less than half of the patients had recovered and no statistically significant survival benefit had been achieved has been criticized, but there was general agreement that the effectiveness of remdesivir against SARS-CoV-2 had been demonstrated and that continuing to give half of the patients a placebo would have raised ethical questions.

There is another problem with the trial, though: the drug may have been given too late in the course of the disease. Remdesivir is a nucleotide analog that inhibits viral replication by blocking RNA polymerase. When the virus is no longer replicating, the drug stops working. In one study, the median time to the onset of dyspnea in patients with symptomatic COVID-19 was 8 days.1 That is just about the time when infectious virus can no longer be isolated from the respiratory tract.2 The widely used polymerase chain reaction diagnostic tests detect viral RNA, which can still be present when active viral replication has stopped.  According to the CDC, isolation of infectious virus from upper respiratory specimens has not been demonstrated >9 days after the onset of illness.3

Just think of the difference from the way we treat influenza with neuraminidase inhibitors: we start as soon as possible because they are most effective when started in the first 48 hours of illness. Of course, there are 2 problems with treating COVID-19 with remdesivir in the same way: first, it’s given IV, and second, there probably isn’t enough available to treat everyone who develops fever or a cough and tests positive for viral RNA. But there are oral drugs with some promise that inhibit SARS-CoV-2 RNA polymerase.4 Gilead is said to be working on subcutaneously injected and inhaled formulations of remdesivir. And an early IV remdesivir versus standard care study in patients with moderate COVID-19, hospitalized but SpO2 >94% and started on treatment only 4 days or less after a confirmed diagnosis, is underway in California, with results expected in 2-4 weeks.5 More fulfilling trial results and better days for all of us may be coming.

  1. Huang et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497.
  2. N Sethuraman et al. Interpreting diagnostic tests for Sars-CoV-2. JAMA 2020; May 6 (epub).
  3. Symptom-based strategy to discontinue isolation for persons with COVID-19. Available at: www.cdc.gov/coronavirus/2019-ncov/community/strategy-discontinue-isolation.html. Accessed May 15, 2020.
  4. TP Sheahan et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med 2020; April 29 (epub).
  5. Study to evaluate the safety and antiviral activity of remdesivir (GS-5734™) in participants with moderate coronavirus disease (COVID-19) compared to standard of care treatment. Available at: https://clinicaltrials.gov/ct2/show/NCT04292730?term=remdesivir&cond=COVID&draw=2&rank=4. Accessed May 15, 2020.

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