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#261 Antivirals for COVID-19


CLINICAL QUESTION
QUESTION CLINIQUE
Do treatments such as remdesivir or other anti-virals change patient outcomes in COVID-19 patients?


BOTTOM LINE
RÉSULTAT FINAL
To date, published RCTs have not demonstrated benefit of treating COVID-19 patients with remdesivir, lopinavir-ritonavir or oseltamivir.  There are signals of potential benefits from one interim analysis of remdesivir and non-statistically different results, but more research is needed. Full publication of studies and ongoing trials will help to answer this question.     



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EVIDENCE
DONNÉES PROBANTES
Focusing on randomized, controlled trials (RCTs) as cohort studies of treatments can be misleading.  
  • Currently >300 RCTs evaluating different COVID-19 treatments underway.1 
Remdesivir: 
  • Industry supported, double-blind, placebo-controlled trial of 237 admitted (non-ventilated) patients with confirmed COVID-19, oxygen saturation ≤94% and radiographic pneumonia in Wuhan, China.2  Patients were ~66 years old, and received concomitant antibiotics (~90%), steroids (~70%), or anti-virals (18%). 
    • Outcomes: 
      • 28-day mortality: 14% versus 13% (placebo): no difference. 
      • Duration of mechanical ventilation (days): 7 versus 15.5 (placebo): not statistically different. 
      • Time to clinical improvement: 21 versus 23 days (placebo) not statistically different. 
      • Adverse events leading to medication discontinuation: 12% versus 5% (placebo), number needed to harm=15.  
    • Limitations:  
      • Study ended early (sample size not achieved) due to “outbreak being controlled in Wuhan”. 
      • Baseline imbalances suggest inadequate allocation concealment. 
  • Double-blind, placebo-controlled trial of remdesivir. Information from clinical trial registry3 and interim results available via media release;4 1063 hospitalized patients, oxygen saturation ≤94% and radiographic pneumonia. 
    • Median time to recovery: 11 days versus 15 days (placebo), statistically different. 
    • Mortality (unknown time frame): 8% versus 11.6% (placebo), not statistically different. 
  • Another pharmaceutical company press release reported similar outcomes between 5 and 10 days of remdesivir but did not report whether treatment improved outcomes compared to no remdesivir.5 
  • Other RCTs ongoing.6-8 
Lopinavir-Ritonavir (Kaletra®): 
  • Open-label RCT of 199 admitted COVID-19 positive patients with Sp02 <94% in Wuhan, China.9 Patients randomized to lopinavir-ritonavir for 14 days or usual care. Patients were ~58 years and 60% were men. 
    • Outcomes:  
      • 28-day mortality19% lopinavir-ritonavir, 25% usual care: not statistically different. 
      • Time to clinical improvement: no difference: 15 versus 16 days. 
      • Length of ICU stay shorter: 6 versus 11 days (control), not quite statistically different. 
      • Adverse events leading to medication discontinuation: 14%. 
    • Limitations: enrollment suspended when remdesivir became available for clinical trials. 
Oseltamivir:  
  • No RCTs in COVID-19 or other coronaviral infections.10 
Context: 
  • Remdesivir is currently only available in Canada through clinical trials.11 
  • Guidelines do not recommend any COVID-19 specific antiviral treatments.12,13 


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Author(s)
Auteur(s)
  • Michael R. Kolber MSc MD CCFP
  • Adrienne J Lindblad BSP ACPR PharmD

1. Sanders JM, Monogue ML, Jodlowski TZ et al. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19) A Review. JAMA doi:10.1001/jama.2020.6019

2. Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial. Lancet Published online April 29, 2020 https://doi.org/10.1016/S0140-6736(20)31022-9

3. National Institute of Allergy and Infectious Disease. Adaptive COVID-19 Treatment Trial. NCT#04280705 from clinicaltrials.gov. Accessed May 1, 2020.

4. National Institutes of Health. NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19 [news release]. Available at: https://www.nih.gov/news-events/news-releases/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19 Accessed May 1, 2020.

5. Gilead. Gilead announces results from phase 3 trials of investigational antiviral remdesivir in patients with severe COVID-19 [new release]. Available at: https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19 Accessed Apr 30, 2020.

6. Cao B et al. A Phase 3 Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir in Hospitalized Adult Patients With Mild and Moderate COVID. NCT# 04252664 from Clinicaltrials.gov. Accessed Apr. 22, 2020

7. Kaiser Permanante. Study to Evaluate the Safety and Antiviral Activity of Remdesivir in Participants With Severe Coronavirus Disease (COVID-19). NCT# 04292899 from Clinicaltrials.gov. Accessed Apr. 22, 2020

8. Kaiser Permanante. Study to Evaluate the Safety and Antiviral Activity of Remdesivir in Participants With Moderate Coronavirus Disease (COVID-19). NCT# 04292730 from Clinicaltrials.gov. Accessed Apr. 22, 2020.

9. Cao B, Wang Y, Wen D et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. NEJM DOI: 10.1056/NEJMoa2001282

10. Rios P, Radhakrishan A, Antony J, et al. Effectiveness and safety of antiviral or antibody treatments for coronavirus: a rapid review. Prepared for the Public Health Agency of Canada. Submitted Feb 25, 2020. Available at: https://www.medrxiv.org/content/10.1101/2020.03.19.20039008v2 Accessed Apr 30, 2020.

11. Coronavirus disease (COVID-19): for health professionals. Available at: https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infection/health-professionals.html Accessed May 4, 2020.

12. National Institutes of Health. COVID-19 Treatment guidelines. Available at: https://www.covid19treatmentguidelines.nih.gov/introduction/ Accessed May 4, 2020.

13. Ye Z, Rochwerg B, Wang Y et al. Treatment of patients with nonsevere and severe coronavirus disease 2019: an evidence-based guideline. CMAJ 2020. doi: 10.1503/cmaj.200648; early released April 29, 2020. 

Authors do not have any conflicts of interest to declare.

Les auteurs n’ont aucun conflit d’intérêts à déclarer.