By David R. Ha, PharmD, BCIDP, and William Alegria, PharmD, BCIDP
Infectious Diseases and Antimicrobial Stewardship Pharmacists, Stanford Antimicrobial Safety and Sustainability Program, Stanford Healthcare, Palo Alto, CA
Drs. Ha and Alegria report no financial relationships relevant to this field of study.
The 2019 novel coronavirus (SARS-CoV-2) is the causative pathogen of 2019 coronavirus disease (COVID-19), an acute respiratory illness, which can range from asymptomatic carriage to life-threatening, severe disease.1 At the time of this writing, there have been hundreds of thousands of reported cases in the United States.2 The global outbreak of SARS-CoV-2 has spawned interest in potential treatment options, particularly for those with more severe illness. This article provides a summary of selected pharmacotherapy options proposed for COVID-19.
Remdesivir is a prodrug of an adenosine nucleoside, which inhibits viral RNA-dependent RNA polymerase.3,4 At the time of this writing, remdesivir is not approved by the Food and Drug Administration (FDA) and is available only as an investigational drug through Gilead Sciences.5 It was studied originally for Ebola virus disease and found to produce no benefit vs. comparators. Despite this, remdesivir has demonstrated a broad spectrum of activity against various coronaviruses, including SARS-CoV, MERS-CoV, and SARS-CoV-2 in preclinical studies.6,7 Although reports on clinical outcomes of remdesivir therapy are limited, it was used in the first confirmed case of COVID-19 in the United States. The patient presented with mild symptoms. However, after the first week of largely supportive care, the patient progressed to pneumonia requiring supplemental oxygenation, which prompted the initiation of remdesivir through compassionate use. The patient’s clinical condition subsequently improved.8 At the time of writing, multiple randomized clinical trials of remdesivir (NCT04252664, NCT04257656, and NCT04280705) are in progress to determine its efficacy against COVID-19 in the United States. In these trials, remdesivir is given as either a five-day or 10-day course, dosed at 200 mg intravenously on day 1, and 100 mg intravenously daily thereafter. Exclusions vary between trials, but, notably, they generally exclude patients 17 years of age or younger, those with severe hepatic or renal impairment, and pregnant or breastfeeding women.9-11
Chloroquine or Hydroxychloroquine
Chloroquine has been proposed as another treatment for COVID-19 and has exhibited in vitro activity against SARS-CoV-2.7 Its antiviral activity may be afforded by an increase in endosomal pH and interference with glycosylation of cellular receptors of SARS-CoV.12 Initial reports from more than 100 patients asserted that there was superiority of chloroquine to control treatment in inhibiting exacerbation of pneumonia, promoting negative conversion, and shortening the disease. However, this information is per a news briefing in China and, at the time of this writing, no patient data has been released yet.12 The purported treatment dosage of chloroquine is 500 mg orally twice daily for 10 days.13 There is an ongoing Phase III, placebo-controlled clinical trial (NCT04261517) of hydroxychloroquine for pneumonia caused by 2019-nCoV. In this trial, the treatment regimen is hydroxychloroquine 400 mg orally daily for five days.14
Lopinavir is an HIV protease inhibitor that has exhibited activity against SARS-CoV-2. It is unclear whether inhibitors of HIV protease (in the aspartic protease family) can effectively inhibit that of SARS-CoV-2 (in the cysteine protease family).15 Use for COVID-19 is based largely on trials in severe acute respiratory syndrome (SARS), suggesting lopinavir was associated with improved clinical outcomes and mortality.16,17 However, as opposed to remdesivir and chloroquine, several detailed reports on clinical experience with lopinavir have been published. That said, the data are not encouraging. In a study of five patients with COVID-19 in Singapore who received lopinavir/ritonavir, the clinical benefit was equivocal, and progressive disease occurred in two patients. Of note, this study used a lower dose (200/100 mg orally twice daily) of lopinavir/ritonavir.18 In a study, four patients in Shanghai with COVID-19, two with mild disease and two with severe disease, received lopinavir/ritonavir (400/100 mg orally twice daily for six to 15 days), along with other treatments including Arbidol and traditional Chinese medicine. Three patients improved, two of whom produced negative viral tests at the end of data collection. The fourth patient, with severe COVID-19, showed signs of improvement at the end of data collection.19 Guidelines for 2019-nCoV pneumonia from the Zhongnan Hospital of Wuhan University Novel Coronavirus Management and Research Team provided a weak recommendation for the use of lopinavir/ritonavir based on benefits found in patients with SARS or Middle East respiratory syndrome (MERS), especially with earlier administration.20
Adjunctive corticosteroids have not shown clinical benefit, have delayed viral RNA clearance in other coronavirus disease (SARS and MERS), and may increase the risk of side effects (e.g., psychosis, diabetes, and avascular necrosis) and increased mortality in influenza.21 Chinese guidance has suggested the use of tocilizumab for cytokine storm in patients with severe disease (e.g., acute respiratory distress syndrome) and elevated interleukin-6 levels.22
- Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19) Situation Summary.
- Coronavirus COVID-19 (2019-nCoV) Global Cases by Johns Hopkins CSSE.
- Siegel D, et al. Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses. J Med Chem 2017;60:1648-1661.
- Ko WC, et al. Arguments in favor of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents 2020:105933. doi:10.1016/j.ijantimicag.2020.105933. [In press].
- Gilead Sciences. COVID-19: Gilead Sciences update on the company’s ongoing response to COVID-19. Updated April 4, 2020.
- Mulangu S, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med 2019;381:2293-2303.
- Wang M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-271.
- Holshue ML, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020;382:929-936.
- ClinicalTrials.gov. Mild/Moderate 2019-nCoV Remdesivir RCT. Updated Feb. 24, 2020.
- ClinicalTrials.gov. Severe 2019-nCoV Remdesivir RCT. Updated Feb. 24, 2020.
- ClinicalTrials.gov. Adaptive COVID-19 Treatment Trial. Updated April 6, 2020.
- Gao J, et al. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020; doi:10.5582/bst.2020.01047. [Epub ahead of print].
- Multicenter Collaboration Group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. [Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi 2020;43:E019.
- ClinicalTrials.gov. Efficacy and Safety of Hydroxychloroquine for Treatment of Pneumonia Caused by 2019-nCoV (HC-nCoV ). Updated March 24, 2020.
- Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov 2020;19:149-150.
- Chan KS, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: A multicentre retrospective matched cohort study. Hong Kong Med J 2003;9:399-406.
- Chu CM, et al. Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings. Thorax 2004;59:252-256.
- Young BE, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 2020; March 3. doi:10.1001/jama.2020.3204. [Epub ahead of print].
- Wang Z, et al. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci Trends 2020. doi:10.5582/bst.2020.01030. [Epub ahead of print].
- Jin YH, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res 2020;7:4.
- Russell CD, et al Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020;395:473-475.
- Interpretation of new coronavirus pneumonia diagnosis and treatment scheme (trial version 7).