Treatment of COVID-19: A Brief Overview
Emily S. Spivak, MD, MHS
Associate Professor of Medicine
University of Utah School of Medicine
Investigational Agents
• Lopinavir/ritonavir
• Chloroquine
• Hydroxychloroquine
• Remdesivir
• Immunomodulatory agents
No controlled data supporting the use of any of these agents
Efficacy for COVID-19 is unknown
Coronavirus Treatment
• Cell culture screen of 350 FDA-approved drugs
• Four compounds inhibit viral replication in low micro-molar range
• Hits = chloroquine, chlorpromazine, loperamide, lopinavir
AAC 2014
SARS-CoV-2 Treatment
• No known therapies exist for COVID-19
bioRxiv 2020
bioRxiv 2020
Cell Research 2020
Cell 2020
SARS-CoV-2 Treatment
• RCT (n=199)
• LPVr po BID x 14 days vs standard of care
• No difference in time to clinical improvement
• No mortality difference at 28 days (19.2% vs 25%)
NEJM 2020
Chloroquine / HydroxychloroquineChloroquine
• Anti-malarial and immunomodulator
• Increases endosomal pH blocking viral entry
• Interferes with glycosylation of cellular receptors of SARS-CoV-2
• In vitro activity against SARS-CoV-2
• Included in China’s National SARS-CoV-2 treatment guidelines, and reported efficacy but no published primary data
• Chloroquine has shown in vitro activity against other viruses with f/u clinical studies showing no benefit or harm
Hydroxychloroquine (HCQ)
• Same mechanism of action
• In vitro activity against SARS-CoV-2
• More tolerable safety profile
• Based on physiologically-based pharmacokinetic models (PBPK), HCQ found to be more potent
• EC50=0.72μM vs. EC50=5.47μM
Cortegiani A, et al.J Crit Care. 2020; PMID 32171130
Yao, X, et al. Clin Infect Dis. 2020; PMID 32150618
Gautret et al. (2020) International Journal of Antimicrobial Agents – In Press 17 March 2020 DOI:10.1016/j.ijantimicag.2020.105949
HCQ in vivo evidence: March 18• Aimed to enroll hospitalized patients
(age >12) to evaluate efficacy of HCQ
• Administered 200mg HCQ po TID x 10 days
• Patients who refused intervention were followed as controls
• Outcome measure = nasopharyngeal clearance of SARS-CoV-2 by PCR
• HCQ n=26, control n=16
• 6 HCQ participants lost to follow up and not included in analysis
• 6 HCQ participants also received azithromycin
• No clinical outcomes are reported
International Journal of Antimicrobial Agents 2020
GroupSARS-CoV-2 PCR negative
at Day 6 (%)
HCQ + Azithro (n=6) 100.0
HCQ alone (n=14) 57.1
Control (n=16) 12.5
HCQ in vivo evidence: March 28• Aimed to reproduce results of HCQ /
azithro in hospitalized patients
• Enrolled 11 participants
• One died, two transferred to ICU during study period
• At day six, 8 / 10 participants had + PCR for SARS-CoV-2 Medecine et Maladies Infectieuses 2020
Latest on HCQ
MedRxiv 2020
• Retrospective analysis of all confirmed SARS CoV-2 infection admitted VA until April 11, 2020
• 368 patients
• HCQ = 97, HCQ + AZ = 113, No HCQ = 158
• No difference in need for ventilation
• Higher all-cause mortality in HCQ group
• Adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03
https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or
Remdesivir
• Nucleotide prodrug that is metabolized into an analog of adenosine triphosphate to inhibit viral RNA polymerases• Broad spectrum activity against number of viruses (e.g. Ebola, Marburg, SARS-
CoV, MERS-CoV, RSV, Nipah virus, Hendra virus)
• In vitro activity and therapeutic benefit in a mouse model
• Reported clinical benefit in China and Washington
Remdesivir
Grein J, et al. N Engl J Med. 2020 Apr 10. doi: 10.1056/NEJMoa2007016. [Epub ahead of print]
• Inpatients with severe SARS CoV-2 infection
• January 25, 2020, through March 7, 2020
• 61 patients (8 could not be analyzed)
• At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) on ECMO
• 36 patients (68%) had an improvement in oxygen status
• 25 patients (47%) were discharged, and 7 patients (13%) died
Other Investigational Agents• Tocilizumab –
• Recombinant humanized monoclonal antibody against IL-6
• Uncontrolled study of 21 patients in China with severe COVID-19 respiratory disease, reduced oxygen requirement, normalized the CRP, and increased the lymphocyte count, 19/21 discharged
• Steroids• Conflicting data
• WHO and CDC recommend against given evidence of harm and delayed viral clearance for other respiratory viruses
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
In sum
• We have several therapeutic candidates to treat COVID-19
• We desperately need RCT evidence for safety and efficacy
• LPVr is probably ineffective
• HCQ and remdesivir are being actively studied…
• Suspect HCQ is ineffective and potentially toxic…
JAMA 2020
University of Utah Approach
• Preference for all patients to enroll in clinical trials
• Inpatient use of investigational agents for COVID-19 restricted to Antimicrobial Stewardship approval
• Recommend on a case by case basis for inpatients with severe COVID-19 disease• Less as literature has evolved
University of Utah Clinical Trials
Outpatient• Hydroxychloroquine for Outpatients with
Confirmed COVID-19 (HCQ Trial)
• Phase 2, prospective, open-label, parallel group, randomized controlled
• Hydroxychloroquine versus Placebo
• Patient age > 44 years, competent to provide consent
• Within 48 hours of positive test for COVID-19
• Primary outcome:
• Change in viral shedding, measured on days 1 - 14 and 28
• Secondary outcomes:
• Duration of COVID-19-attributable symptoms
• Hospitalization within 14 days of enrollment
• Adult household contact viral acquisition
Inpatient• Two randomized, open-label Remdesivir trials:
• Moderate disease (NCT04292730): 5 days RDV vs 10 days RDV vs standard of care
• Severe disease (NCT04292899): 5 days RDV vs 10 days RDV
• Hydroxychloroquine vs. Azithromycin for Hospitalized Patients With Suspected or Confirmed COVID-19
• 5 days of Hydroxychloroquine vs. 5 days of Azithromycin
• COVID Ordinal Outcomes Scale at 14 days
Convalescent Plasma
CCP Clinical Studies
1. Expanded Access Program authorized by the FDA• Mayo-led case-control study (COVID-19 inpatients treated with CCP vs. untreated)
2. CCP to Stem Coronavirus: A Randomized Controlled Double-Blinded Phase 2 Study Comparing the Efficacy and Safety of CCP vs. Control non-immune plasma among Adults Exposed to COVID-19
3. CCP to Limit Coronavirus Associated Complications: Randomized, Double-Blind, Controlled, Phase 2 Study Comparing the Efficacy and Safety of CCP vs. Control Plasma among Outpatients with COVID-19
4. CCP to Treat Coronavirus - Associated Severe Pulmonary Complications: A Feasibility (Phase 1) Study Assessing the Safety of Multiple Doses of Anti-SARS-CoV-2 Plasma in Mechanically Ventilated Intubated Patients with Respiratory Failure due to COVID-19
CCP Clinical Studies
1. Expanded Access Program authorized by the FDA• Mayo-led case-control study (COVID-19 inpatients treated with CCP vs. untreated)
2. CCP to Stem Coronavirus: A Randomized Controlled Double-Blinded Phase 2 Study Comparing the Efficacy and Safety of CCP vs. Control non-immune plasma among Adults Exposed to COVID-19
3. CCP to Limit Coronavirus Associated Complications: Randomized, Double-Blind, Controlled, Phase 2 Study Comparing the Efficacy and Safety of CCP vs. Control Plasma among Outpatients with COVID-19
4. CCP to Treat Coronavirus - Associated Severe Pulmonary Complications: A Feasibility (Phase 1) Study Assessing the Safety of Multiple Doses of Anti-SARS-CoV-2 Plasma in Mechanically Ventilated Intubated Patients with Respiratory Failure due to COVID-19
Other CCP Trials
https://ccpp19.org/healthcare_providers/component_3/index.html