At A Glance
- Most trials have suggested little to no decrease in the length of hospital stay or in mortality for patients treated with hydroxychloroquine.
- Remdesivir is generally well tolerated and continues to be actively evaluated in clinical trials.
- A recent trial showed that treatment with dexamethasone had the greatest benefits in hospitalized patients who required mechanical ventilation or supplemental oxygen without mechanical ventilation.
What a wild ride 2020 has already been! It is likely that none of us ever thought that we would be living square in the middle of a global pandemic. SARS-CoV-2 has challenged people emotionally, spiritually, physically, professionally, and financially.
As medical professionals, we surely understand the gravity of this infection, even if we do not fully understand how to navigate it. As we slowly adapt to our new normal, it is vital that we stay up to date on the therapies that might save lives and shape our futures.
Like our patients, we hear the news reports on COVID-19 treatments. This article provides a brief overview on a few of the latest trends.
After SARS-CoV-2 came to the world’s attention, much of the original therapeutic information on this novel viral pathogen came from the little that we knew about Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS-CoV-1). During the subsequent months, researchers and clinicians sorted through more than two dozen treatments from all over the world, none of which had been evaluated in clinical trials.
Experts with the World Health Organization (WHO), the Infectious Diseases Society of America (IDSA), the Centers for Disease Control and Prevention, the National Institutes of Health (NIH), and dozens of institutes across the globe have contributed their opinions. Scientists and clinicians assessed the diverse pharmacologic choices, the virus itself, clinical trial results, cases, and evolving recommendations.
In May, the WHO recommended “drugs not be administered as treatment or prophylaxis for COVID-19 outside of the context of clinical trials.”1 This statement was an important step forward because it indicated that plans were in place to standardize the evaluation of drugs’ safety and efficacy to prevent or treat COVID-19.
Generally speaking, most data suggest that no drugs currently prevent infection with SARS-CoV-2, but some clinical trials point to several agents that hold promise for treating patients with COVID-19.
If I were hydroxychloroquine (Plaquenil, Sanofi-Synthelabo), I would be having some sort of identity crisis. We have heard both that hydroxychloroquine works to treat SARS-CoV-2 and that it does not. We’ve heard that it works for some people but not others. We’ve heard that, if the drug does work, that is a good thing because it is so well tolerated. We’ve heard that the benefits of the drug may not outweigh the risks because the drug is so toxic. Clear as mud.
Early in the pandemic, news of hydroxychloroquine’s potential benefits for patients with COVID-19 was spread far and wide by the news media. An Emergency Use Authorization (EUA) was implemented by the FDA. Clinical trials were initiated, and case reports began pouring in.2 An initial evaluation indicated that hydroxychloroquine monotherapy might be safe and effective in hospitalized patients with mild COVID-19 symptoms. When hydroxychloroquine was combined with azithromycin, antipsychotics, antifungals, or fluoroquinolones, however, the risk of serious cardiac effects such as ventricular arrhythmias and QT prolongation seemed to outweigh the modest benefits being reported.3-5
In June, the general reception to the data on hydroxychloroquine’s benefits was lukewarm. Most large trials suggested little to no decrease in the length of hospital stay or mortality (when compared with placebo), some important studies evaluating hydroxychloroquine stopped enrolling patients, and the EUA was revoked.6-9
On August 20, the IDSA panel revised its consensus statement regarding hydroxychloroquine to say that the drug should not be used alone or in combination with azithromycin for the treatment of COVID-19 in hospitalized patients.8,10 Although some are quick to assume that politics played a role in the rejection of hydroxychloroquine as a treatment for COVID-19, it seems that more effective options for treatment lie elsewhere.
Remdesivir (Veklury, Gilead Sciences) was the first antiviral to show consistent activity against SARS-CoV-2. This drug was initially evaluated because it is known to have some activity against MERS and SARS.11-13 Early in the pandemic, both the manufacturer and the NIH conducted large-scale, multicenter clinical trials to evaluate the efficacy and toxicity of remdesivir in hospitalized patients with COVID-19.14,15 The results were so promising that the FDA issued an EUA on May 1.16 Additionally, the NIH discontinued the placebo arm of their Adaptive COVID-19 Treatment Trial because investigators believed the trend in mortality benefit for patients treated with remdesivir was too great to continue enrolling patients in the placebo group.14,17
The use of remdesivir continues to be actively evaluated in clinical trials. If the drug’s availability is limited, then the NIH recommends that it be reserved for hospitalized patients with COVID-19 who require supplemental oxygen but do not require high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation, as the best mortality benefit (initially) was shown in this group. If there is ample supply of remdesivir, however, most recent recommendations now suggest that any patient who is hospitalized with COVID-19 should receive remdesivir, regardless of severity.14,18
Remdesivir is generally well tolerated. The most common adverse effect is increased liver transaminases, followed by diarrhea, rash, renal impairment, arrhythmia, and thrombosis in a small number of patients.15
The use of steroids in patients with infections has a long and fickle history. This form of therapy can sometimes worsen an infection by suppressing the immune system and by increasing replication and/or decreasing clearance of certain organisms. Sometimes, however, steroid therapy lowers morbidity and mortality rates.19 At the beginning of the pandemic, treating patients who were infected with SARS-CoV-2 with a corticosteroid initially produced confusing outcomes data, mainly because patients who were taking concomitant treatments were included in the analyses.10
The WHO, NIH, Centers for Disease Control and Prevention, and IDSA have since issued guidelines on the use of corticosteroids in patients infected with SARS-CoV-2. These recommendations are based upon a variety of factors, including the severity of disease and comorbid diseases.1,10,18,20 In noncritical patients infected with SARS-CoV-2, corticosteroids generally are not recommended due to the aforementioned concerns.18,21,22
Promising data from the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial were published in July in The New England Journal of Medicine. This multicenter investigator-initiated, open-label trial randomly assigned more than 6,000 hospitalized patients with COVID-19 to receive either usual care or usual care plus dexamethasone. The greatest benefits (decreased mortality and a shorter duration of hospitalization) were observed in hospitalized patients who required mechanical ventilation or supplemental oxygen but not mechanical ventilation. Little to no benefit was found in patients not receiving respiratory support. The IDSA and NIH have used these findings in their recommendations.22
THE GOOD FROM THE BAD
As this pandemic continues, none of us can know how it will play out. Many of us believe that our greatest chance lies with the development of one or more vaccines. That race is under way, with estimates on widespread US availability ranging from the fall of 2020 to late in 2021. This health crisis has brought forth ingenuity and innovation in medicine that we never thought we would need. That is something to hang our hopes and futures on.
- 1. Clinical management of COVID-19. World Health Organization. May 27, 2020. Accessed August 21, 2020. www.who.int/publications/i/item/clinical-management-of-covid-19.
- 2. Hinton DM. Letter of authorization: Emergency Use Authorization for use of chloroquine phosphate or hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of 2019 Coronavirus disease. US Food & Drug Administration. March 28, 2 2020. Accessed September 17, 2020. www.fda.gov/media/136534/download.
- 3. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271.
- 4. Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020;55(4):105932.
- 5. Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine. Int J Antimicrob Agents. 2020;55(4):105945.
- 6. Hinton DM. Memorandum explaining basis for revocation of emergency use authorization for emergency use of chloroquine phosphate and hudroxychloroquine sulfate. US Food & Drug Administration. June 15, 2020. Accessed September 17, 2020. www.fda.gov/media/138945/download.
- 7. Nuffield Department of Population Health. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. RECOVERY. June 5, 2020. Accessed September 17, 2020. www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19.
- 8. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020;50(4):384.
- 9. National Institutes of Health. NIH halts clinical trial of hydroxychloroquine. US Department of Health & Human Services. June 20, 2020. Accessed September 17, 2020. www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine.
- 10. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Infectious Diseases Society of America. Updated August 20, 2020. Accessed August 24, 2020. www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/.
- 11. Brown AJ, Won JJ, Graham RL, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res. 2019;169:104541.
- 12. Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396):eaal3653.
- 13. Ko WC, Rolain JM, Lee NY, et al. Arguments in favour of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents. 2020;55(4):105933.
- 14. NIH US National Library of Medicine. Adaptive COVID-19 Treatment Trial (ACCT). NCT04280705. Accessed September 17, 2020. clinicaltrials.gov/ct2/show/NCT04280705.
- 15. Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe COVID-19. N Engl J Med. 2020;382(24):2327-2336.
- 16. Hinton DM. Letter of authorization: emergency use authorization for use of remdesivir for the treatment of hospitalized 2019 coronavirus disease (COVID-19) patients. US Food & Drug Administration. August 28, 2020. Accessed September 17, 2020. www.fda.gov/media/137564/download.
- 17. Herper M. Inside the NIH’s controversial decision to stop its big remdesivir study. STAT. May 11, 2020. Accessed September 17, 2020. www.statnews.com/2020/05/11/inside-the-nihs-controversial-decision-to-stop-its-big-remdesivir-study.
- 18. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. www.covid19treatmentguidelines.nih.gov/whats-new/. Updated July 24, 2020. Accessed August 22, 2020.
- 19. Aberdein J, Singer M. Clinical review: a systematic review of corticosteroid use in infections. Crit Care. 2006;10(1):203.
- 20. Clinical Questions about COVID-19: Questions and Answers. Centers for Disease Control and Prevention. Updated August 4, 2020. Accessed September 17, 2020. www.cdc.gov/coronavirus/2019-ncov/hcp/faq.html.
- 21. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473-475.
- 22. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19 - preliminary report [published online ahead of print July 17, 2020]. N Engl J Med. 2020;NEJMoa2021436.