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OVERVIEW
This guidance was developed by a multi-specialty team of Boston Children’s Hospital (BCH) clinicians to assist with evaluating and treating patients
who present to BCH seeking care related to symptoms or complications of coronavirus disease 2019 (COVID-19), including Multisystem
Inflammatory Syndrome in Children (MIS-C). As this guidance was developed for BCH patients, any use of this document by other clinicians or
facilities should be based on the individual clinical circumstances of their own patients and the resources available to the patient’s treating clinicians.
As the evidence base for COVID-19 and MIS-C treatment and care management is evolving rapidly, this guidance will change frequently as
identified by the date stamp on the document.
This guidance outlines the team approach at Boston Children’s related to laboratory evaluation and subspecialty consultation (Section A), antiviral
therapy (Section B), and immunomodulatory therapies (Section C), as well as other agents, including convalescent plasma (Section D), for BCH
patients. The BCH Hematology service has created separate guidance on anti-coagulation in patients with COVID-19.
This treatment guidance was developed based on available in vitro and animal model data, limited clinical evidence issued in public sources, federal
and state treatment guidance as issued to date, and the experiences of our treating clinicians based on our patient population. The therapies
offered for consideration are hypothesized to be effective against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection or its
sequelae, but they have not been proven, and definitive evidence of their benefit has not been published in a peer-reviewed journal. As of the date
of this guidance, they are not FDA-approved for use in COVID-19.
Given the lack of established therapies, possibility of harm, and limited drug supply, BCH does not recommend any treatment outlined in this
document for (1) prevention or post-exposure prophylaxis or (2) non-hospitalized patients with confirmed or suspected COVID-19. Any questions
related to this guidance should be directed to Dr. Mari Nakamura (mari.nakamura@childrens.harvard.edu).
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Boston Children’s Hospital COVID-19 Treatment: Internal Guidance
Disease Respiratory Status Concern for MIS-C Diagnostic Evaluation Subspecialty Consultation
Category (see Section C for definition) (pre-consultation)
Mild No dyspnea • Fever and • SARS-CoV-2 PCR and/or serologies • Consult Rheumatology if
• GI symptoms and • Consider CBC with differential, BUN, concern for MIS-C
• Kawasaki disease features (rash, creatinine, LFTs, ESR, CRP • Supportive care; no antiviral or
conjunctivitis, extremity changes, • Consider chest x-ray immunomodulatory treatment
mucositis, lymphadenopathy) and recommended
• Epidemiologic link to SARS CoV-2
Moderate Dyspnea and/or Same as mild cases plus: • SARS-CoV-2 PCR and/or serologies • Consult Immunology and
chest imaging • Myocardial dysfunction (without • CBC with differential, BUN, Infectious Diseases (ID) for all
consistent with need for vasopressors) creatinine, LFTs, LDH, ESR, CRP, cases
COVID-19, but no • Significant abdominal pain, PT & PTT, D-dimer, procalcitonin, • Consult Rheumatology if
change from pre- vomiting, diarrhea ferritin1 concern for MIS-C or Cytokine
illness baseline • Neurologic features (severe • Troponin and BNP Storm
respiratory support headache, meningismus, focal • If available, cytokine panel1 • Consult Cardiology if concern for
requirement neurologic deficits, mental status • Chest x-ray for respiratory symptoms MIS-C
changes) • EKG
Severe Dyspnea and/or Same as for moderate cases Same as for moderate cases Consult Immunology, ID,
chest imaging Rheumatology, and Cardiology for
consistent with all cases
COVID-19, with new
or increased
supplemental O2
and/or non-invasive
ventilatory support
requirement
Critical Respiratory failure • Myocardial dysfunction and/or low- Same as for moderate cases Same as for severe cases
requiring mechanical output heart failure requiring
ventilation +/- acute vasopressor support or ECMO
respiratory distress • Systemic inflammatory response
syndrome (ARDS) syndrome (SIRS)
• Multi-organ failure
• Encephalopathy
1
At BCH, order these studies using the COVID-19 Immunology Panel Plan [found within the COVID-19 (Novel Coronavirus) Evaluation Plan].
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Boston Children’s Hospital COVID-19 Treatment: Internal Guidance
B. ANTIVIRAL THERAPY
Antiviral treatment decisions should weigh individual risks and benefits for the patient in question, taking into account considerations such as potential risk
factors for disease progression, clinical trajectory, and drug contraindications or interactions. Refer to Table 2 for proposed pediatric risk factors; adult
risk factors for progression to severe disease include age >60 years, immunocompromising conditions, active malignancy, structural lung disease, chronic
kidney disease, hypertension, coronary artery disease, or diabetes in patients requiring admission for treatment of COVID-19 disease (Zhou et al. Lancet
11 Mar 2020).
A decision not to treat with an antiviral would be reasonable in many circumstances. ID consultation is required for all patients for whom COVID-19
treatment is being considered.
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Boston Children’s Hospital COVID-19 Treatment: Internal Guidance
• Coronary heart disease, with or without history of myocardial infarction (e.g., Kawasaki disease, homozygous familial
hyperlipidemia)
• Age >21 years with moderate or severe CHD OR any ACHD patient with physiologic class C or D (see Appendix Tables 1, 2, and
3 for definitions)
• Congenital and/or acquired pediatric heart disease not specified above but judged by the patient’s cardiologist to be in a high-risk
category
Gastroenterology • Immunosuppressed patients: Those on >10 mg prednisone daily, mercaptopurine, methotrexate, or biologics such as infliximab
• Patients with intestinal failure (short bowel syndrome, microvillous inclusion disease) that require parenteral nutrition
• Serious chronic liver disease (e.g., biliary atresia)
• Patients with central lines due to requirement for parenteral nutrition or hydration (e.g., motility disorders such as pseudo-
obstruction)
• Patients with ileostomies who may be prone to dehydration
HSCT • Stem cell transplant patients with active or history of (including pre-transplant) inflammatory lung disease
Immunology • Prior history of infections with opportunistic pathogens or severe infections requiring hospitalization
• Anatomic or functional asplenia or splenic dysfunction
• Documented impairment in T cell-mediated immunity, including: T cell lymphopenia prior to COVID-19, reduced lymphocyte
proliferation to mitogens or antigens, reduced CD8 cytotoxicity
• Documented impairment in B cell-mediated immunity, including reduced levels of IgG, IgA, or IgM, reduced antibody response to
vaccines
• Documented impairment in NK cell-mediated immunity: reduced NK cell number or NK cell cytotoxicity
• Other defects in innate immunity, including abnormal response to Toll-like receptor stimulation
• Documented immune dysregulation syndrome characterized by multiple autoimmune diseases and/or overactive immune
signaling pathways, including patients on immune modulators.
• Patients with allergic or immune-related disease who are on immunomodulatory agents, including high-dose inhaled
corticosteroids, tacrolimus/sirolimus/cyclosporine, and biologic agents
Nephrology • Immunosuppression with cyclophosphamide, calcineurin inhibitor therapy, azathioprine, mycophenolate mofetil, and/or chronic
high dose steroids (>0.5 mg/kg/day or 20 mg/day for >1-2 months)
• Immunomodulatory therapy (such as rituximab) within the last year
• Active nephrotic syndrome with anticipated depressed IgG levels (ongoing losses)
• Chronic kidney disease (eGFR <60 ml/min/1.73 m2)
• End-stage renal disease requiring chronic dialysis
Oncology • Metastatic lung disease
• History of lung irradiation (including irradiation to mediastinum)
• Other underlying cardiopulmonary disease
• Acute leukemia, not in remission (e.g., undergoing induction, reinduction, treatment for refractory disease)
• AML, receiving high-dose chemotherapy cycles for new diagnosis or relapsed disease
• Any patient on active therapy with low ALC (<200)
Pulmonary The following patients are at high risk of mortality based on poor physiologic reserve:
• Patients with a history of one or more episodes of ICU admission for respiratory decompensation, including severe asthma
exacerbation, RSV or other pneumonia, hypercarbic or hypoxemic respiratory failure.
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The following patients have a high risk of severe disease, regardless of current level of disease severity:
• Patients on active immunosuppressive or biologic therapy
• All cystic fibrosis or primary ciliary dyskinesia patients
• All patients with interstitial lung disease
• All patients with bronchopulmonary dysplasia
• All patients with pulmonary hypertension
Rheumatology • Current treatment with cyclophosphamide
• Current treatment with chronic high-dose steroids (>0.5 mg/kg/day or >20 mg/day for >1-2 months)
• Immunomodulatory drugs, including biologics, should not be stopped unless a patient has symptoms of COVID-19 and either has
(1) a positive SARS-CoV-2 PCR or (2) a close contact with confirmed COVID-19.
Solid Organ Heart: All heart transplant recipients
Transplant Kidney: All kidney transplant recipients
Liver/Intestine: All liver and intestine transplant recipients
Lung: All lung transplant recipients
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Note: Convalescent plasma (see Table 5) is another therapeutic option for pediatric patients with critical COVID-19 or adult patients with severe or critical
COVID-19, particularly those not improving with antiviral treatment.
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Boston Children’s Hospital COVID-19 Treatment: Internal Guidance
i
Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours
ii
Including, but not limited to, one or more of the following: an elevated CRP, ESR, fibrinogen, procalcitonin, D-dimer, ferritin, LDH, or IL-6; elevated
neutrophils; reduced lymphocytes; and low albumin
* Some individuals may fulfill full or partial criteria for Kawasaki disease but should be considered to have MIS-C if they meet the case definition for MIS-C.
As patients with MIS-C may have significant cardiac involvement, appropriate labs (BNP and troponin) and imaging (echocardiogram) with Cardiology input
are essential for any child thought to have MIS-C, regardless of the presence or absence of features of Kawasaki disease.
In general, patients with signs of CSS in COVID-19 and the shock presentation of MIS-C are more likely to have severe disease and require ICU-level
care.
PLEASE NOTE: There are no established therapies for COVID-19-associated CSS or MIS-C.
These medications are to be used only with guidance from Rheumatology, Cardiology and Infectious Diseases. Patients who are being evaluated for
immunomodulatory therapy should also be considered for antiviral therapy if they are not already receiving it.
The evidence base for management of MIS-C in COVID-19 is evolving rapidly, and this guidance will change frequently. Please do not print this
document.
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Potential adverse
reactions: anaphylaxis,
infusion reaction,
hemolysis, transaminitis,
aseptic meningitis
Glucocorticoids: NCT04344288 Liquid, 1-2 mg/kg/day divided BID None Monitor blood pressure None
Methylprednisolone, NCT04325061 tablets, (prednisone, prednisolone, daily
prednisone, NCT04244591 IV methylprednisolone)
prednisolone, solution Monitor glucose and
dexamethasone 5 mg/m2 daily electrolytes
(dexamethasone)
MIS-C with features of
shock or coronary artery
dilation/aneurysm
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Boston Children’s Hospital COVID-19 Treatment: Internal Guidance
OR
Severe or critical
COVID-19 with evidence
of CSS
Anakinra NCT04324021 100-mg 2-4 mg/kg/dose (max 100 CrCL<30mL/min, CBC w/diff, BUN, Cr, AST, Live vaccines
NCT04330638 syringe mg) BID (can increase to consider QOD ALT, ferritin, LDH, D-
MIS-C that has failed TID or QID if there is a lack dosing dimer, fibrinogen in 24-48 Simultaneous
other therapies of full response) hours and then at least treatment with
IV/SQ Not dialyzable 2x/weekly more than one
OR biologic
Continue for up to 7 days if Potential adverse medication is not
Severe or critical good response reactions: anaphylaxis, recommended
COVID-19 with evidence neutropenia, eosinophilia,
of CSS Half-life 4-6 hours transaminitis,
immunosuppression
Improvement in fever curve,
CSS labs, clinical status
expected in 1-3 days
Tocilizumab NCT04310228 IV <30 kg:12 mg/kg IV None CBC w/diff, BUN, Cr, AST, Live vaccines
NCT04331795 solution ≥30 kg: 8 mg/kg IV ALT, ferritin, LDH, D-
Severe or critical NCT04320615 Max 800 mg dimer, fibrinogen in 24-48 Simultaneous
COVID-19 with evidence Typically given as single hours and then at least treatment with
of CSS dose 2x/weekly more than one
Elevated CRP and/or IL- biologic
6 May repeat dose in 8 to 12 Potential adverse medication is not
hours if signs/symptoms reactions: anaphylaxis, recommended
worsen or do not improve neutropenia,
thrombocytopenia,
Half-life in children up to 16 transaminitis,
days hyperlipidemia,
immunosuppression, GI
perforation
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Boston Children’s Hospital COVID-19 Treatment: Internal Guidance
Adult patients (≥18 years): Consider for severe or critical COVID-19, particularly if no improvement with antiviral
treatment. Available via enrollment in national Expanded Access Program,4 which will be performed by the ID service.
Requires coordination with Dr. Sloan. May be used concurrently with other COVID-19 therapies, including remdesivir.
Glucocorticoids Do not use routinely for COVID-19 pneumonia except if treating another indication.5 If required, use glucocorticoids at the
lowest dose for the shortest duration. Possible indications include asthma, shock with history of chronic steroid use, or
multi-pressor shock without history of chronic steroid use.
The Society of Critical Care Medicine (SCCM) draft guidelines suggest using systemic corticosteroids for adults with
COVID-19 and ARDS (weak recommendation, low-quality evidence).6
Glucocorticoids are a potential option for treatment of COVID-19-associated cytokine storm syndrome or MIS-C with
features of shock or coronary artery dilation/aneurysm (see Section C).
Hydroxychloroquine We do not recommend use of hydroxychloroquine based on safety concerns due to potential COVID-19 cardiac
involvement in children and adults.
NSAIDS Concern has been raised that NSAIDs may worsen COVID-19 disease. As reflected in an FDA statement,7 there is no
evidence to support this concern.
Patients on remdesivir therapy may not receive concomitant NSAIDS due to risk of nephrotoxicity.
Ribavirin We do not recommend use of ribavirin for COVID-19 due to insufficient evidence of activity against SARS-CoV-2 and
significant toxicity risk.
1
HFSA/ACC/AHA guidance: https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-
antagonists-in-covid-19
2
See, for example: Chorin et al. Nature Med 2020 (https://www.nature.com/articles/s41591-020-0888-2) and Borba et al. medRxiv 2020
(https://www.medrxiv.org/content/10.1101/2020.04.07.20056424v2).
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3
Single Patient eIND for convalescent plasma: https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-
process-cber/recommendations-investigational-covid-19-convalescent-plasma
4
COVID-19 Convalescent Plasma Expanded Access Program: https://www.uscovidplasma.org/
5
WHO interim guidance: https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-
infection-is-suspected
6
Society of Critical Care Medicine draft guidelines: https://link.springer.com/article/10.1007/s00134-020-06022-5
7
FDA statement on use of NSAIDs in COVID-19: https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-patients-use-non-steroidal-anti-
inflammatory-drugs-nsaids-covid-19
12 Version 6/17/20
1
Appendix
2
Table of Contents
WORKGROUPS
CARDIOLOGY
Kevin Friedman
CRITICAL CARE Jane Newburger
Greg Priebe (lead)
Michael Agus INFECTIOUS DISEASES
Adrienne Randolph Bob Husson
Ravi Thiagarajan Mari Nakamura
SUBSPECIALTY ADVISORS ON
POTENTIAL HIGH-RISK GROUPS
Given the uncertain benefit and potential harms of candidate therapies, clinical
judgment is paramount. Treatment decision-making should weigh risks and benefits for
the particular patient, accounting for such factors as illness severity, risk of severe
disease potentially conferred by underlying conditions, clinical trajectory, and drug
contraindications or interactions.
Selection of antivirals
Based on review of the evidence, which is limited and of variable quality but evolving
rapidly, we believe that remdesivir is the antiviral agent that could be considered as part
of COVID-19 management.
Currently, remdesivir is only accessible for pediatric patients (<18 years of age) at BCH
with severe manifestations of COVID-19 via an individual compassionate use request to
the manufacturer, Gilead Sciences. Remdesivir became available for adult patients
(≥18 years of age) at BCH in mid-May 2020, when we received a limited supply under
the FDA’s Emergency Use Authorization.
Data on potential pediatric risk factors for severe or critical COVID-19 are extremely
scarce. The few larger analyses of children and adolescents exclude information on
underlying conditions or have significant missing data. Nevertheless, one could
hypothesize that some pediatric patient populations may be at higher risk of illness
progression, based on experience with other respiratory viruses or extrapolations from
emerging data on adult risk factors. This treatment guidance therefore reflects input
from multiple subspecialties on potential risk factors that raise concern for a worse
disease course and thus might inform consideration of empiric therapy. It also lists
reported risk factors in adults that could be considered in antiviral decision-making.
6
Since the 1960s, an expanding literature has established the in vitro antiviral properties of
chloroquine (CQ) against several RNA viruses, including several coronaviruses
(including SARS-CoV-1 and MERS), as well as influenza, chikungunya, dengue,
enteroviruses, Zika and others (5, 6). The antiviral effects of CQ have been attributed to
interference with terminal glycosylation of cellular receptor angiotensin converting
enzyme 2 (ACE2) (7) and elevation of endosomal pH (5); the immunomodulatory effects
of CQ have also been proposed to mitigate the clinical effects of viral infections (8). Both
CQ and its analog HCQ—designed to have fewer drug-drug interactions and a more
favorable side-effect profile than chloroquine—have been used wide in children to treat
malaria and auto-inflammatory syndromes, establishing their short-term and long-term
safety for pediatric patients (9, 10).
Modeling Data
An in silico structure modeling study noted that human coronaviruses depend upon sialic
acid-containing glycoproteins and gangliosides to attach along the respiratory tract (13).
Using models of the SARS-CoV-2 Spike protein, the authors identified a potential
6
7
ganglioside-binding domain that may enhance viral interaction with the ACE-2 receptor.
This sialic acid-containing ganglioside binding domain is conserved between clinical
isolates of SARS-CoV-2. The authors demonstrate that both CQ and HCQ inhibit Spike
protein-ganglioside binding in silico. HCQ was found to be a particularly potent steric
inhibitor of Spike protein-ganglioside binding. Although an intriguing hypothesized
mechanism of action for CQ and HCQ, the authors do not establish that the potential
ganglioside binding site functions as such in vivo. This proposed mechanism of CQ and
HCQ action will need confirmation with structure imaging studies.
In Vitro Data
SARS-CoV-2
Limited in vitro results suggest antiviral effect of CQ and HCQ at doses achievable in
vivo. Wang et al., demonstrated inhibition of viral replication in Vero E6 cells with an
EC50 of 1.1uM. Effect was noted when CQ was administered before (prophylactically),
after, and throughout viral challenge (8) (Figure 1).
Similarly, Yao et al. demonstrated inhibition of SARS-CoV-2 with both CQ and HCQ
(Figure 2) (14). EC50 of HCQ was lower than CQ at 24 and 48 hours. In simulations of
lung concentrations of CQ and HCQ using five different dosing schemes, the RLTEC (ratio
of drug concentration to EC50) was found to be higher for HCQ than for CQ, suggesting
superiority of HCQ over CQ. A loading dose of HCQ was found to enhance initial RLTEC.
There was no difference between once daily and twice daily maintenance dosing on
RLTEC from days 2-5. Notably, a five-day treatment course was found to produce
concentrations above target concentration (based on “proven” CQ dosing, see below) on
day 10. A key limitation of this study is that it used modeled lung tissue concentrations,
rather than in vivo or autopsy results. Dosing recommendations are therefore largely
speculative.
7
8
Liu et al. (same team as Wang et al., above) similarly found effect of both CQ and HCQ
against SARS-CoV-2 in Vero E6 cells (15). Contrary to Yao et al., they found that EC50
for HCQ was significantly higher than for CQ at MOI of 0.01 and 0.2, and trended
towards higher EC50 for other MOIs (Figure 3). In this paper, they noted higher EC50
for CQ than their team had previously reported.
Other Viruses
In vitro studies have demonstrated antiviral properties of CQ and HCQ against a number
of viruses, including circulating seasonal coronaviruses, SARS-CoV-1 and MERS.
8
9
In vitro studies have also assessed inhibition of MERS in cell culture. These studies
demonstrate EC5 ranging from 3-8.2 (18, 19), which similarly fall within the range
achievable with malaria-dosed CQ. However, one study of infection of human monocyte-
derived macrophages demonstrated no effect (20).
Animal Models
SARS-CoV-2
Mouse Models
Animal studies have reported mixed results for use of CQ against RNA viruses. In a
C57BL/6 mouse model, increasing doses of CQ administered to mouse mothers was
associated with improved survival in suckling mouse pups inoculated with HCoV-OC43
after birth (24). However, CQ administered to BALB/c mice starting 3 hours before
infection with SARS-CoV-1 did not significantly decrease lung viral titers (17).
Additionally, CQ was associated with increased viral replication of Semliki Forest Virus
and Encephalomyocarditis Virus in mice, even in low concentrations of CQ (25).
Non-Human Primates
9
10
SARS-CoV-2
Adult Studies
To date, several heterogeneous clinical trials assessing the efficacy of CQ and HCQ in
adults with COVID-19 have begun. These include at least 23 clinical trials in China (4),
as well as studies in France, Brazil, the US, Spain, Thailand, and a multinational, multi-
arm clinical trial initiated by the World Health Organization. Unpublished, pre-print and
published data to date provide inconclusive evidence for the efficacy of CQ and HCQ
against COVID-19. Studies are summarized below and in Table 1.
• Unpublished data from China purport to demonstrate efficacy and safety of QC
and HCQ in treatment of 100 patients in 10 hospitals in China with SARS-CoV-2-
associated pneumonia, including radiographic improvement, viral clearance and
shortened disease course (1). Data supporting these conclusions have not been
published to date.
• A small (n=42) case-controlled study in which patients were treated with HCQ
(200mg PO TID x10d) or HCQ plus azithromycin reported fewer patients with
persistent PCR positivity from NP specimens in the treatment compared to control
group at 6 days (30% positive versus 87.5% positive) (28). Notably, in 6 patients
who were incidentally treated with azithromycin in addition to HCQ, there was
increased viral clearance. Patients at a single hospital were offered treatment.
Patients at other surrounding hospitals, patients who refused treatment, or patients
who had contraindications to CQ/HCQ served as controls. This study’s results and
applicability to children are highly limited. Of enrolled patients, 6 patients in the
treatment group were lost to follow-up due to early cessation of therapy, including
4 who discontinued due to critical illness, one of whom ultimately died (who
received HCQ); clinical outcomes data on remaining cases and controls are
deferred to a later publication. Furthermore, children were excluded from
treatment (i.e. no patients <18yo received either HCQ or azithromycin); all did
well (4/5 remained asymptomatic). Moreover, a large proportion of patients who
did not receive HCQ did not have daily PCR testing, including on day 6 of
therapy (despite the fact that day-6 negative PCR was the primary outcome).
10
11
11
12
12
13
13
14
To date, data on antiviral treatment of children with COVID are limited to retrospective
case series. No trials of antiviral treatment of pediatric patients have been published. Use
of CQ in children has been reported in one retrospective case series from Iran, in which 9
children were treated with CQ plus oseltamivir, and 2 of these children also received
lopinavir/ritonavir (40). Of these children, 2/9 required CPAP, but none ultimately
required mechanical ventilation; there was no mortality reported.
14
15
HCQ assoc
w decreased
time to Chest CT
HCQ normothermi improvement: Headache
Hospitalized Open-label 200mg PO a and cough HCQ: 25/31 (1)
Chen (32) China , ≥18yo RCT 62 BID x5d recovery Not reported Control: 17/31 Rash (1) Low Yes
HCQ QTc
Hospitalized Prospective 600mg/d 2 transferred Day 5-6 NP prolongatio
Molina (31) France , ≥18yo cohort 11 x10d to ICU PCR Not reported n (1) Very low Undetermined
15
16
Azithromyc clearance
in 500mg 1 death 2/10
day 1,
250mg day
2-5
QTc
HCQ prolongatio
Perinel (41) France ICU, ≥18yo PK study 13 200mg TID Not reported Not reported Not reported n (2) Very low Undetermined
Transferred
to ICU w/in
7 days:
HCQ: 20.5%
Control:
22.1%
(RR 0.61,
95% CI
0.13-2.90)
Emulated trial
using ARDS w/in
retrospective 7 days:
cohorts with HCQ: 27.7% EKG
Hospitalized propensity HCQ Control: changes
Mahevas (33) France , ≥18yo weighting 181 600mg/day 24.1% Not reported Not reported (9.5%) Low No
QTc
prolongatio
High dose: n >500ms
CQ 600mg High dose:
BID x10d 7/28
Low dose: Mortality by Low dose:
CQ 450mg day 28 3/28
BID load; High dose:
Prospective then 450mg 7/40? VTach (2)
Hospitalized double- daily day 1- Low dose: Rhabdomy
Borba (34) Brazil , ≥18yo blinded RCT 81 4 4/41? Not reported Not reported olysis (2) Low Undetermined
QTc
HCQ, dose prolongatio
New not listed n by >40ms
York Azithro, (30%)
City, Hospitalized Retrospective dose not QTc
Chorin (42) USA , ≥18yo cohort 84 listed Not reported Not reported Not reported prolongatio Low Undetermined
16
17
n >500ms
(11%)
Symptom
improvemen
t:
HCQ more
HCQ rapid than Day 28 NP
1200mg standard PCR
daily x3d, care in post- clearance:
then 800mg hoc HCQ: 85.4%
Hospitalized Open-label daily for 2- controlled Control: Blurry
Tang (35) China , ≥18yo RCT 150 3 weeks analysis 81.3% Not reported vision (1) Low Yes
Greater
proportion
Open-label of CQ No No
RCT (note: patients differences in differences
baseline CQ 500mg discharged virologic No differences in toxicity
characteristics BID x10d, by day 14 clearance for in CT resolution of CQ
Hospitalized imbalanced versus compared to CQ versus in CQ versus versus
Huang (36) China , adults favoring CQ) 22 lop/rit x10d lop/rit lop/rit lop/rit lop/rit Low Possible
Increased
mortality in
HCQ (but
not
HCQ+azithr
o) compared
to no HCQ,
although
HCQ pts had
more severe
disease at
baseline
No mortality
HCQ (dose difference in
not patients
specified); requiring
HCQ+ mechanical
Hospitalized Retrospective azithro; no ventilation Not
Magagnoli (37) USA , adults case-control 368 HCQ Not assessed Not assessed assessed Low No
17
18
No
difference in
need for
mechanical
ventilation
Substantial
morbidity
and
mortality,
Hospitalized HCQ (dose but no
, adults with Retrospective not control Not
Mathian France lupus case series 17 specified) group Not assessed Not assessed assessed Low Undetermined
18
19
Other Viruses
CQ and HCQ have been trialed widely against several human viruses, summarized below
(5) (Figure 4), but have not been shown effectiveness in treating human viral infections.
Negative results include a double-blinded, placebo-controlled trial of weekly CQ to
prevent influenza (43); a double-blinded, placebo-controlled trial of 3 days of CQ to treat
Dengue (44); and a double-blinded, placebo-controlled trial of 5 days of CQ to treat acute
chikungunya (45).
Figure 4. Summary of human trials of CQ and HCQ against viral infections (5).
Based on in vitro data and modeling of drug concentrations in human lung tissue, Yao et
al. conclude that the optimal dose of HCQ that balances efficacy and potential side
effects is: a loading dose of HCQ sulfate 400mg PO BID x1 day followed by
maintenance dosing of 200mg PO BID x 4 days (14).
A small PK modeling study from France used HCQ trough levels in critically ill adults to
model PK characteristics, and simulate optimal dosing (41). This study enrolled 13
patients in a French ICU: 12/13 were mechanically ventilated, 1/13 was on ECMO, and
1/13 was receiving renal replacement therapy. All patients received HCQ 200mg TID;
co-administration of azithromycin is not stated. Serial HCQ troughs were drawn during
patients’ ICU stays. The authors postulated that HCQ troughs between 1-2mg/L were in
19
20
the therapeutic range; this assumption was based on prior in vitro data from Yao et al.
(14), studies in lupus, and concern that levels >2mg/L could lead to toxicity. In this
cohort, mean time to reach minimum therapeutic level was 2.7 days. Ultimately 8/13
patients achieved levels >1mg/L, and 2/13 had levels >2mg/L. A total of 4/13 patients
required dose de-escalation to 200mg BID, and HCQ was withdrawn in 2/13 patients due
to QTc prolongation (levels at time of discontinuation were 0.03mg/L and 1.74mg/L).
Using measured PK parameters, the authors modeled optimal dosing, concluding that in
this population, a loading dose of 800mg x1, followed by 200mg TID, would provide
optimal therapeutic levels while minimizing toxic levels. Notably, this study did not
attempt to model lung concentrations of HCQ, and it is not clear that blood HCQ levels
are a meaningful parameter to judge adequate HCQ dosing.
Another dose modeling study has addressed dosing of CQ specifically in children (46).
Using PBPK simulations based on pre-defined North European Caucasian “Sim-
Pediatric” patients, the authors assessed model dosing and subsequent drug
concentrations across pre-defined pediatric age groups. The total pediatric dose was
calculated using the ratio of adult to pediatric AUC, normalized to the total adult dose.
Simulations using a total adult dose of 44mg/kg (determined from prior modeling studies)
yielded age-specific pediatric dosing regimens (see the authors’ Table 1). The authors
note that their models are limited by lack of pediatric pharmacokinetic data, particularly
in children less than 6 months of age. The authors also acknowledge the uncertainty
surrounding the clinical and virologic assumptions underlying CQ dosing for COVID-19
generally.
Prophylaxis
Similarly, enrollment has begun for a blinded RCT of CQ for post-exposure prophylaxis,
sponsored by the University of Minnesota (NCT04308668). This study uses dosing of
800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 6
consecutive days.
Addition of Azithromycin
Azithromycin has been used in COVID-19 for three primary purposes. First, a number of
studies have found evidence of possible concomitant mycoplasma infection in children,
and azithromycin was added for mycoplasma PCR or IgM positive patients. Second,
azithromycin has been used for non-specific community acquired bacterial pneumonia
treatment, primarily in hospitalized adults. Third, one early study showed possible
enhanced SARS-CoV-2 viral clearance in a subgroup of patients who received
azithromycin in addition to HCQ, compared to HCQ alone or no HCQ. Studies on
20
21
One retrospective trial from China found that 4/20 (20%) pediatric patients had
mycoplasma co-infection at time of SARS-CoV-2 detection (47). Method of detection
was not reported, and there was no comment on specific treatment of mycoplasma
pneumonia. An additional retrospective, unpublished study found 1/31 pediatric patients
was mycoplasma IgM-positive; this patient received azithromycin (Chen, under review).
Neither study assessed for effect of mycoplasma or mycoplasma treatment on clinical
outcome.
Gautret noted that patients incidentally treated with azithromycin had faster time to NP
viral clearance (28). Notably, none of the 5 children included in this study received either
HCQ or azithromycin.
CQ and HCQ have been used for years in children for malaria and for rheumatologic
conditions, and they therefore have an extensive safety profile. In general, short courses
of CQ and HCQ in children have been found to be safe, and confer minimal adverse
effects. Studies relating to toxicity in children being treated for COVID-19 are described
below.
Cardiac toxicity
A large, claims-based preprint study of nearly 1 million rheumatoid arthritis patients >18
years old analyzed cardiac symptoms and outcomes in patients receiving HCQ versus
sulfasalazine (a non-cardiotoxic control), plus azithromycin versus amoxicillin (a non-
cardiotoxic control) (48). The authors were able to assess nearly 1 million patients
receiving HCQ, including more than 300,000 who received HCQ plus azithromycin. In
their analysis, HCQ was not found to increase risk of cardiovascular mortality, chest
pain/angina or heart failure, compared to patients receiving sulfasalazine. However, when
azithromycin was added to HCQ, there was significantly increased risk of 30-day
cardiovascular mortality (calibrated HR 2.19 [95%CI 1.22-3.94]), chest pain/angina
(calibrated HR 1.15 [95%CI 1.05-1.26]), and heart failure (calibrated HR 1.22 [95%CI
1.02-1.45]). Notably, this study was unable to assess electrographic changes in patients,
and is subject to the usual limitations of a retrospective claims-based comparison study,
including inability to assess causality.
Prolongation of the QTc interval has been identified in several studies of CQ and HCQ
used to treat COVID-19 in adults. Notably, most of these studies assess
electrocardiographic changes in the setting of co-administration with azithromycin. In
two studies that reported timing of QTc prolongation, maximum QTc occurred 3-4 days
after drug administration.
• A retrospective study of 84 adults hospitalized at NYU who received HCQ (dose
not specified) and azithromycin specifically assessed electrocardiographic
21
22
changes after drug administration (42). Authors found that QTc was prolonged
>40ms in 30% of patients and was prolonged to >500ms in 11% of patients. In
multivariate analysis, increased QTc was associated with AKI; baseline QTc was
not found to be a predictor of subsequent prolongation. QTc was maximally
prolonged 3-4 days after initiation of therapy. No arrhythmias were reported.
Notably, there was no control group, although the temporal association between
electrocardiographic changes and administration of HCQ plus azithromycin
suggests that one or both of these drugs contributed to prolonged QTc.
• A small prospective case series from France found that 1/11 patients receiving
HCQ (600mg/day x10 days) plus azithromycin experienced QTc prolongation
(31).
• A study of HCQ pharmacokinetics in 13 adult patients admitted to a French ICU
incidentally reported QTc prolongation in 2/13 patients (41). Co-administration of
azithromycin was not documented.
• A model-randomized trial of HCQ versus no-HCQ in which 17/84 HCQ patients
also received azithromycin found that 9.5% of patients in HCQ group experienced
EKG changes requiring discontinuation, at median 4 days (33). Of these patients,
7/8 had QTc prolongation >60ms (1 with QTc > 500ms), and 1 patient developed
1st degree AV block after 2 days. The subgroup of patients who received both
azithromycin and HCQ was not analyzed separately.
• A pre-print case series of 98 adults with confirmed COVID-19 or who were PUI
treated at Cedars Sinai Hospital compared QTc prolongation in patients who
received azithromycin, HCQ, or the combination, up to 24 hours after the last
dose of medication was administered (49). The authors noted that there was
substantial heterogeneity in timing and dosing of these medications. Results
showed significant increase in QTc following medication administration
compared to baseline; mean change in QTc was greatest in patients who received
both HCQ and azithromycin. A total of 12% of patients had “critical” QTc
prolongation (defined as QTc ≥500ms when QRs <120ms, QTc ≥550ms when
QRs >120ms, or change in QTc ≥ 60ms). Patients with critical QTc prolongation
had significantly greater use of loop diuretics and were more likely to have had an
acute MI. Notably, baseline QTc was not significantly associated with subsequent
QTc prolongation. There were no episodes of torsades de pointes.
• A study of 117 COVID-19 adult patients treated with HCQ (400mg x1, then
200mg BID x4 days) +/- azithromycin described use of a remote telemetry system
to monitor electrocrdiographic changes (50). The authors found a mean maximum
QTc prolongation of 33.9ms from baseline across the cohort; there was no
difference in change in QTc from baseline in patients receiving HCQ alone versus
HCQ+azithromycin.
Due to increasing evidence of cardiotoxicity when HCQ and azithromycin are combined,
the NIH now recommends against this combination.
22
23
Although caution has been recommended when using HCQ in patients with G6PD
deficiency, recent literature of HCQ dosed to treat rheumatologic conditions has not
found correlation of HCQ use with incidence of hemolytic anemia (51). The CDC does
not recommend assessing G6PD deficiency prior to use of HCQ for acute malaria. To
date, there has been one case report of an adult with G6PD deficiency treated with HCQ
who subsequently developed hemolytic anemia (52). Use of CQ/HCQ has also been
associated with rare reports of cardiomyopathy (53), retinopathy (54), and
neuropsychiatric effects (55). These effects have not been reported in children receiving
short courses of HCQ. The American Academy of ophthalmology does not recommend
baseline ophthalmologic exams in patients starting CQ or HCQ for COVID (56).
Apart from the cardiac effects described above, studies of CQ and HCQ in patients with
COVID-19 have documented rare adverse symptoms possibly attributed to these drugs.
These include nausea (28), headache (32), rash (32), rhabdomyolysis (34), diarrhea (35),
and blurred vision (35).
A number of society and organization guidelines have been issued that address use of CQ
and HCQ.
Early in the pandemic, the CDC listed CQ and HCQ as potential therapies for COVID-
19, and provided potential dosing, although noted that these suggested doses were based
on a paucity of data. In early April, the CDC tempered its language on CQ/HCQ, and
now notes that these drugs are being trialed in COVID-19, but does not provide dosing
ranges. Additional society recommendations are listed in Table 2.
23
24
24
25
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36. Huang M, Tang T, Pang P, et al. Treating COVID-19 with Chloroquine. J Mol Cell Biol.
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41. Perinel S, Launay M, Botelho-Nevers E, et al. Towards Optimization of
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44. Tricou V, Minh NN, Van TP, et al. A randomized controlled trial of chloroquine for the
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45. De Lamballerie X, Boisson V, Reynier JC, et al. On chikungunya acute infection and
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51. Mohammad S, Clowse MEB, Eudy AM, Criscione-Schreiber LG. Examination of
Hydroxychloroquine Use and Hemolytic Anemia in G6PDH-Deficient Patients. Arthritis Care
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52. Beauverd Y, Adam Y, Assouline B, Samii K. COVID-19 infection and treatment with
hydroxychloroquine cause severe haemolysis crisis in a patient with glucose-6-phosphate
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53. Zhao H, Wald J, Palmer M, Han Y. Hydroxychloroquine-induced cardiomyopathy and
heart failure in twins. J Thorac Dis. 2018;10:E70-E73.
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Online: Critical Care Medicine | Society of Critical Care Medicine. 9000;Online First.
29
Efficacy
COVID-19
There is limited experience with convalescent plasma to treat COVID-19, to date only four
published case series, one non-randomized trial, one retrospective cohort study, one case report,
and one preprint case series comprising 37 patients total.5–12
Published in the Journal of Infectious Diseases, Zeng and colleagues conducted a retrospective
cohort study comparing outcomes for adults with critical COVID-19 and respiratory failure
who either did or did not receive convalescent plasma therapy.5 Convalescent plasma was not
randomly distributed; rather, six patients were identified who had received convalescent
plasma while another 15 critically-ill COVID-19 patients at the same hospitals did not have
ABO-matched convalescent plasma available. Five of the six treated patients were
mechanically-ventilated at the time of treatment, with four on ECMO. Within three days of
convalescent plasma treatment, all six treated patients had virologic clearance, while only 26.7%
of the control group cleared SARS-CoV-2. Ultimately, five of the six treated patients (83.3%) and
14 of 15 untreated patients (93.3%) died, with the remaining patients surviving to hospital
discharge. Time to death was longer in treated patients. Since plasma treatment was associated
with viral clearance though without clinical recovery, the authors speculated that earlier
treatment should have been attempted. Most patients in both groups received adjunctive
therapies including unspecified antiviral drugs and glucocorticoids.5
Writing in JAMA, Shen and colleagues describe a series of five adults with confirmed critical
COVID-19 who were treated with convalescent plasma.6 At the time of enrollment, all five were
mechanically ventilated with ARDS and remained positive for SARS-CoV-2 by nasopharyngeal
swab PCR. Following convalescent plasma transfusion, organ dysfunction, hypoxemia, and
inflammation improved, as measured by SOFA score, PaO2/FIO2, and CRP and IL-6 levels,
respectively. Four patients became afebrile, ARDS resolved in four, and three were weaned
from mechanical ventilation within nine days of transfusion. Two patients remained intubated
at the time of publication, however. There was no control group in this small, single-center
study in Shenzen, China, limiting the conclusions that can be drawn. Confounding these results,
all patients were also treated with methylprednisolone and two or more antiviral drugs,
including lopinavir/ritonavir, interferon-alpha, favipiravir, umifenovir and darunavir.6
30
In a non-randomized trial, Duan and colleagues describe 10 adults with confirmed severe
COVID-19 who were treated with convalescent plasma.7 Within three days of transfusion,
clinical symptoms—specifically fever, cough, dyspnea and chest pain—had subjectively
improved. Objectively, oxygen saturation, degree of respiratory support, lymphopenia, CRP
elevation and extent of infiltrates on chest CT also improved. At study enrollment, seven
patients were viremic; when next assessed seven days after plasma transfusion, all were
negative for SARS-CoV-2 by serum PCR. When compared to a 10-patient historical control
cohort, convalescent plasma therapy was associated with improved mortality and time to
discharge. This study from three hospitals in Wuhan, China is limited by a lack of control
group, as well as confounding by the multiple drugs with potential antiviral activity given,
including remdesivir, umifenovir, ribavirin, interferon-alpha, oseltamivir and peramivir. The
clinical response could have been due to adjunctive therapies, such as the methylprednisolone
given to six patients.7
In another case series, Zhang and colleagues describe another heterogenous group of four
adults with severe or critical COVID-19 treated with convalescent plasma in three Chinese
hospitals.8 All four became negative for SARS-CoV-2 by PCR from different respiratory tract
samples, with varied clinical improvement; one of two patients on VV-ECMO was
decannulated and ultimately discharged, with details not clearly specified for the other patient,
one mechanically ventilated patient was extubated and later discharge, and one patient on high-
flow nasal cannula was also discharged. The time to these outcomes varied significantly,
however, up to a month following the first plasma transfusion. Similar to other studies, these
results were confounded by administration of additional medications with potential antiviral
activity, as well as steroids.8 Unlike other studies, patients in this series received one to eight
plasma transfusions, with no attempt to measure the neutralizing antibody titer in the infused
plasma.8
Ahn and colleagues report on two adults with critical COVID-19 treated with convalescent
plasma in a tertiary care hospital in Seoul, South Korea.10 The two, mechanically ventilated with
ARDS despite hydroxychloroquine, were treated with convalescent plasma, with subsequent
improvement in respiratory support, fevers, CRP and IL-6 in the following eight days. Both
cleared SARS-CoV-2 from NP swabs by PCR and were extubated within an additional two
weeks, with no adverse effects noted.10 These results were confounded, however, by recent
initiation of steroids within two days before convalescent plasma transfusion.10
Ye and colleagues describe a highly heterogeneous group of six adults with COVID-19 who
were treated with convalescent plasma.11 These patients were largely in the recovery phase of
COVID-19 infection, though one required oxygen supplementation at the time of plasma
transfusion. Patients received up to three doses of convalescent plasma, all at least a month after
symptom onset, followed by improvements in hypoxia, infiltrates on chest CT and viral load by
NP swab PCR.11
Zhang and colleagues report on a single patient mechanically ventilated for COVID-19 who was
treated with convalescent plasma 20 days after symptom onset.12 She was extubated 11 days
later, though no other testing for improvement in viral load or inflammation was reported.12
A preprint case series not yet peer-reviewed describes three patients treated with convalescent
plasma for COVID-19, with few details about baseline clinical characteristics or follow-up
available, other than that two of the three had conversion to negative SARS-CoV-2 PCR tests
after treatment.9
No studies have evaluated the efficacy of convalescent plasma therapy for COVID-19 in
children or immunocompromised patients.
31
During the 2015 MERS outbreak in South Korea, the three most critically-ill patients at one
center received convalescent plasma. Described in a case series without any control groups, all
three healthy adults recovered.14 CRP and viral loads decreased, though the timing did not
always correlate well with plasma transfusion and recipients inconsistently developed
neutralizing antibody titers.14
With limited availability of convalescent plasma early in the COVID-19 pandemic, early studies
have reasonably used this option as salvage therapy for otherwise-refractory patients, as was
done for SARS and MERS.13,14 Historical experience with monoclonal antibodies, such as those
directed at RSV, suggest that early treatment, when patients are less critically ill, is likely to be
more effective.1–3 In the COVID-19 human studies to date, convalescent plasma was usually
administered two to three weeks after symptom onset, with a mean of 20.8 days,6 15.7 days,7
and 17.0 days8 in several of the larger series. One of two patients in the Ahn et al series was
treated only seven days after symptom onset, though she had been intubated two days earlier.10
The one patient in the Zeng et al cohort who survived after convalescent plasma was,
interestingly, treated only 11 days after first detection of SARS-CoV-2, compared to a median of
21.5 days for the cohort as a whole.5 Earlier treatment, while theoretically advantageous, has not
been studied rigorously.
From experience with other viral infections, convalescent plasma may be even more effective
when used for prophylaxis. In a commentary advocating for considering convalescent plasma
during the COVID-19 pandemic, Casadevall and Pirofski observe that Hepatitis B immune
globulin (HBIG) and human rabies immune globulin (HRIG) are used for postexposure
prophylaxis, with the monoclonal antibody palivizumab used to prevent RSV infection in
vulnerable infants.1 COVID-19 prophylaxis will need to be studied in clinical trials, as it is not
currently an acceptable indication for access via eIND. Clinical trials are being planned to assess
32
convalescent plasma use for postexposure prophylaxis, as well as treatment of outpatient, non-
ICU inpatient, mechanically ventilated and pediatric cases of COVID-19.16
Dose
The dose of convalescent plasma needed to prevent or treat COVID-19 is not clear. FDA
guidance recommends selecting donors with SARS-CoV-2 neutralizing antibody titers >1:320,
but testing is not required for eIND submission.15 All plasma donors in the Shen et al study had
neutralizing antibody titers by end point dilution >1:40, though only one >1:320.6 The Duan et al
study included plasma only from donors with a neutralizing antibody titer by plaque reduction
>1:640.7 It is unclear how important it will be to quantify these titers in potential donors; of the
40 COVID-19 survivors tested in one study, 39 had neutralizing antibody titers >1:160,7 though
the fraction considered positive for neutralizing antibodies depends on the threshold used, as
another study concluded only ~70% of survivors developed neutralizing antibodies.17 By
contrast, during the 2015 MERS outbreak in South Korea, only two of four plasma donors
displayed neutralizing activity against MERS-CoV despite being evaluated within three weeks
of illness.14 The donors had all recovered from mild illness, however, which was associated with
a lower seroconversion rate than those who developed pneumonia, implying that potential
donors should be selected carefully.14 How quickly neutralizing antibody titers may decay in
potential donors is not yet clear, particularly for SARS-CoV-2.1 In the COVID-19 studies
currently available, 15 patients received 200 mL plasma per dose, for one7 or two6 doses, while
in another series, four patients received up to eight doses.8
Safety
COVID-19
In 36 COVID-19 patients with information detailed in published and preprint studies, two
adverse events were noted, a transient facial rash in one patient and anaphylaxis in another,
though that patient survived and was ultimately discharged.6–12 In one study, five of six treated
patients died, but mortality was similar in the control group in this non-randomized study, and
deaths were not temporally associated with convalescent plasma.5 Safety concerns with any
plasma therapy include allergic reactions, transfusion-related acute lung injury and transfusion-
associated circulatory overload,1,3 the latter two of particular importance in patients with
respiratory failure. No episodes of TRALI or TACO have been observed in the small human
studies of plasma therapy for COVID-19 so far. One potential concern specific to convalescent
plasma is antibody-dependent enhancement of infection, but the viral load decreases in the
nasopharynx and serum of treated patients argue against this possibility. Convalescent plasma
could theoretically also enhance inflammation, but CRP and IL-6 decreased in treated
patients.6,7,10
No studies have evaluated the safety of plasma therapy for COVID-19 in children or
immunocompromised patients.
antibodies that correlated with skewed alveolar macrophage responses, a form of antibody-
dependent enhancement of inflammation, while still reducing viral replication.20 In a small case
series, viremia in MERS patients decreased after convalescent plasma transfusion, and all three
treated patients ultimately recovered, further arguing against antibody-dependent
enhancement in humans.14
34
References
1. Casadevall A, Pirofski L-A. The convalescent sera option for containing COVID-19. J
Clin Invest. Published online 2020. doi:10.1172/jci138003
2. Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19.
Lancet Infect Dis. Published online 2020. doi:10.1016/s1473-3099(20)30141-9
3. Roback JD, Guarner J. Convalescent Plasma to Treat COVID-19. JAMA. 2020;323(16).
doi:10.1001/jama.2020.4940
4. Zhang L, Liu Y. Potential Interventions for Novel Coronavirus in China: A Systemic
Review. J Med Virol. 2020;92(5):479–490. doi:10.1002/jmv.25707
5. Zeng Q-L, Yu Z-J, Gou J-J, et al. Effect of Convalescent Plasma Therapy on Viral
Shedding and Survival in Patients With Coronavirus Disease 2019. J Infect Dis. Published online
April 29, 2020:jiaa228. doi:10.1093/infdis/jiaa228
6. Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With
Convalescent Plasma. JAMA. 2020;323(16). doi:10.1001/jama.2020.4783
7. Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe
COVID-19 patients. Proc Natl Acad Sci. Published online April 6, 2020:202004168.
doi:10.1073/pnas.2004168117
8. Zhang B, Liu S, Tan T, et al. Treatment with convalescent plasma for critically ill patients
with SARS-CoV-2 infection. Chest. Published online March 2020:S0012369220305717.
doi:10.1016/j.chest.2020.03.039
9. Pei S, Yuan X, Zhimin Zhang Z, et al. Convalescent Plasma to Treat COVID-19: Chinese
Strategy and Experiences. medRxiv; 2020. doi:10.1101/2020.04.07.20056440
10. Ahn JY, Sohn Y, Lee SH, et al. Use of Convalescent Plasma Therapy in Two COVID-19
Patients with Acute Respiratory Distress Syndrome in Korea. J Korean Med Sci. 2020;35(14):e149.
doi:10.3346/jkms.2020.35.e149
11. Ye M, Fu D, Ren Y, et al. Treatment with convalescent plasma for COVID-19 patients in
Wuhan, China. J Med Virol. Published online April 15, 2020. doi:10.1002/jmv.25882
12. Zhang L, Pang R, Xue X, et al. Anti-SARS-CoV-2 virus antibody levels in convalescent
plasma of six donors who have recovered from COVID-19. Aging. Published online April 22,
2020. doi:10.18632/aging.103102
13. Cheng Y, Wong R, Soo YOY, et al. Use of convalescent plasma therapy in SARS patients
in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44–46. doi:10.1007/s10096-004-1271-9
14. Ko J-H, Seok H, Cho SY, et al. Challenges of convalescent plasma infusion therapy in
Middle East respiratory coronavirus infection: a single centre experience. Antivir Ther.
2018;23(7):617–622. doi:10.3851/imp3243
15. FDA. Investigational COVID-19 Convalescent Plasma - Emergency INDs.
https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-
exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds
16. Bloch EM, Shoham S, Casadevall A, et al. Deployment of convalescent plasma for the
prevention and treatment of COVID-19. J Clin Invest. Published online April 7, 2020.
doi:10.1172/JCI138745
17. Wu F, Wang A, Liu M, et al. Neutralizing Antibody Responses to SARS-CoV-2 in a COVID-
19 Recovered Patient Cohort and Their Implications. medRxiv; 2020.
doi:10.1101/2020.03.30.20047365
18. Wan Y, Shang J, Sun S, et al. Molecular Mechanism for Antibody-Dependent
Enhancement of Coronavirus Entry. J Virol. 2020;94(5). doi:10.1128/jvi.02015-19
19. Kam YW, Kien F, Roberts A, et al. Antibodies against trimeric S glycoprotein protect
hamsters against SARS-CoV challenge despite their capacity to mediate FcγRII-dependent entry
into B cells in vitro. Vaccine. 2007;25(4):729–740. doi:10.1016/j.vaccine.2006.08.011
20. Liu L, Wei Q, Lin Q, et al. Anti-spike IgG causes severe acute lung injury by skewing
macrophage responses during acute SARS-CoV infection. JCI Insight. 2019;4(4):e123158.
doi:10.1172/jci.insight.123158
35
Ibuprofen
The adverse effects of ibuprofen on SARS-CoV-2 are largely theoretical and based on reports of
otherwise healthy individuals with confirmed COVID-19 who took NSAIDs for symptom relief and
developed severe illness, especially pneumonia. For example, a letter published in The Lancet
Respiratory Medicine hypothesized that ibuprofen makes it easier for the SARS-CoV-2 to enter
respiratory cells, and some scientists have hypothesized that non-steroidal anti-inflammatory drugs
(NSAIDs) may dampen the immune system because of their anti-inflammatory properties, therefore
slowing down the recovery process.1,2 Furthermore, some health care providers have provided their own
anecdotal experiences, such as an infectious disease physician in southern France who cited four cases
of young, otherwise healthy patients who developed serious symptoms after using NSAIDs.1 Because of
this speculation, France’s health minister warned against using ibuprofen if individuals have symptoms
of COVID-19 and several other health officials worldwide also raised alarm on NSAIDs.
A systematic review concluded that the existing literature does not provide conclusive evidence for or
against the use of NSAIDs in the management of COVID-19 patients.3 The World Health Organization
currently recommends that patients with COVID-19 can use either acetaminophen or ibuprofen.4
ACE-inhibitors
ACE2 is an enzyme that physiologically counters RAAS activation and is broadly expressed in the heart,
kidney, and lung alveolar epithelial cells. ACE2 functions as the receptor for SARS-CoV-2.5,6 A few studies
have suggested that some ACE inhibitors and angiotensin-receptor blockers may increase ACE2
expression.7,8 Consequently, there is a theoretical risk that with increased ACE2 expression, SARS-CoV-
2 can more easily invade alveolar epithelial cells to cause a more severe coronavirus infection.
A Lancet Respiratory Medicine correspondence letter reviewed three publications from China,
covering almost 1,300 patients gravely-ill with COVID-19.2 The letter’s authors observed that 12-30%
of the patients in those studies had high blood pressure and diabetes, which are often treated with
ACE-inhibitors, and theorized that higher rates of ACE2 expression in these individuals may increase
their risk or severity of coronavirus infection since ACE2 is also thought to facilitate virus attachment
to respiratory cells (Figure 1).
36
Figure 1. Interaction between ACE2 receptors and the RAAS system. ACE inhibitors have been shows to
increase circulating levels of ACE2. Figure from Vaduganathan et al.9
However, researchers in a NEJM article9 pointed out that diabetes and hypertension track closely with
advancing age,10 which seems to be the strongest predictor of COVID-19 related death.11 The
researchers highlight that only 30-40% of patients who have hypertension in China are on
antihypertensive therapy, and only one-third of these patients use ACE-inhibitors. They argue that
data examining specifically the outcomes of patients on ACE-inhibitors and angiotensin-receptor
blockers are needed to make any conclusions about ACE inhibitors. The authors recommended that
“RAAS inhibitors should be continued in patients in otherwise stable condition who are at risk for, are
being evaluated for, or have Covid-19.”9 The authors progress to even hypothesize that ACE inhibitors
may even benefit patients because they prevent the downregulated expression of ACE2, an action
which the SARS-CoV2 virus seems to do and which facilitates lung injury.9
Interestingly, some data on ACE inhibitors has shown that they are associated with reduced
mortality:12,13
• A retrospective, multi-center study of 1128 adult hospitalized patients with hypertension
diagnosed with COVID-19, including 188 taking ACE inhibitors/angiotensin II receptor blockers
(ARB) and 940 without using ACE inhibitors/ARBs, found that adjusted all-cause mortality was
lower in the ACE/ARB group versus the non-ACE/ARB group (adjusted HR, 0.42, 95% CI 0.19-
0.92, P=0.03).12 The authors concluded that it is unlikely that in-hospital use of ACE/ARBs are
associated with an increased mortality risk.
• A retrospective, observational study of 8,910 hospitalized patients with COVID-19 in 11
countries.13 5.8% of this cohort died in the hospital, and after multivariate regression, use of
ACE inhibitors or ARBs at admission was associated with a decreased risk of mortality. Factors
that increased risk of in-hospital mortality were (from highest to lower odds ratio): chronic
37
obstructive pulmonary disease, coronary artery disease, heart failure, current arrhythmia, age
over 65 years old, and current smoking.13
Other data suggest that ACE inhibitors do not affect COVID-19 mortality:14
• A population-based case-control study in Italy using 6272 case patients with COVID-19
matched by age, sex, and residence municipality to 30,759 controls.14 Although use of ACE
inhibitors and ARBs was more common among controls, after adjusting for confounders, use
of ACE inhibitors or ARBs was not associated with COVID-19 infection (adjusted OR 0.95 (95%
CI 0.86-1.05) and not associated with severe or fatal COVID-19 disease course (adjusted OR
0.83 (95% CI 0.63-1.10).
• A study of 12,594 patients tested for COVID-19 in New York City were evaluated, of whom
5894 (46.8%) were positive.15 17.2% (1002/5894( of these patients had severe COVID-19
illness. The authors found no association between ACE inhibitor use or ARB use and increased
likelihood of a positive test.15
In summary, studies suggest that use of ACE inhibitor and ARBs does not increase the risk of, or the
severity of, COVID-19 illness. As ACE inhibitors and ARBs have known benefits for certain individuals
(e.g. individuals with diabetes, hypertension, or acute myocardial infarctions), use of ACE inhibitors
and ARBs should continue.
38
REFERENCES
1. Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and
scientists. BMJ. 2020;368. doi:10.1136/bmj.m1086
2. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at
increased risk for COVID-19 infection? The Lancet Respiratory Medicine. 2020;0(0). doi:10.1016/S2213-
2600(20)30116-8
3. Russell B, Moss C, George G, et al. Associations between immune-suppressive and stimulating
drugs and novel COVID-19—a systematic review of current evidence. doi:10.3332/ecancer.2020.1022
4. Could #ibuprofen worsen disease for people with #COVID19? Twitter. Accessed April 2, 2020.
https://twitter.com/who/status/1240409217997189128/photo/1
5. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by
full-length human ACE2. Science. 2020;367(6485):1444-1448. doi:10.1126/science.abb2762
6. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and
TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. Published online March
2020:S0092867420302294. doi:10.1016/j.cell.2020.02.052
7. Hristova M, Stanilova S, Miteva L. Serum concentration of renin-angiotensin system components
in association with ACE I/D polymorphism among hypertensive subjects in response to ACE inhibitor
therapy. Clin Exp Hypertens. 2019;41(7):662-669. doi:10.1080/10641963.2018.1529782
8. Vuille-dit-Bille RN, Camargo SM, Emmenegger L, et al. Human intestine luminal ACE2 and amino
acid transporter expression increased by ACE-inhibitors. Amino Acids. 2015;47(4):693-705.
doi:10.1007/s00726-014-1889-6
9. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin–
angiotensin–aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020;382(17):1653-
1659. doi:10.1056/NEJMsr2005760
10. Wu JT, Leung K, Bushman M, et al. Estimating clinical severity of COVID-19 from the
transmission dynamics in Wuhan, China. Nature Medicine. Published online March 19, 2020:1-5.
doi:10.1038/s41591-020-0822-7
11. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with
COVID-19 in Wuhan, China: A retrospective cohort study. The Lancet. 2020;0(0). doi:10.1016/S0140-
6736(20)30566-3
12. Zhang Peng, Zhu LiHua, Cai Jingjing, et al. Association of Inpatient Use of Angiotensin Converting
Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With
Hypertension Hospitalized With COVID-19. Circulation Research. 0(0).
doi:10.1161/CIRCRESAHA.120.317134
13. Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Cardiovascular Disease, Drug Therapy, and
Mortality in Covid-19. New England Journal of Medicine. 2020;0(0):null. doi:10.1056/NEJMoa2007621
14. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin–Angiotensin–Aldosterone System
Blockers and the Risk of Covid-19. New England Journal of Medicine. 2020;0(0):null.
doi:10.1056/NEJMoa2006923
15. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin–Angiotensin–Aldosterone System Inhibitors and
Risk of Covid-19. New England Journal of Medicine. 2020;0(0):null. doi:10.1056/NEJMoa2008975
39
Since first emerging in Wuhan, China in December 2019, SARS-CoV-2 has rapidly spread around
the globe. We continue to primarily rely on infection-control measures for prevention and
supportive care for treatment in the absence of therapeutics with proven clinical efficacy. In the
search for possible antiviral options, lopinavir/ritonavir has emerged as an attractive candidate
based on modest in vitro and in vivo activity against other coronaviruses (SARS-CoV-1, MERS-
CoV) as well as its widespread and immediate availability.1
The 3CL protease is highly conserved between SARS-CoV-1 and SARS-CoV-2. However, the
proteases of HIV and coronavirus differ in composition – HIV protease belongs to the aspartic
protease family, whereas coronavirus proteases are from the chymotrypsin-like protease family.
Additionally, HIV protease inhibitors were specifically optimized to fit the C2 symmetry in the
catalytic site of the HIV protease dimer, which is notably absent in coronavirus proteases.5
In vitro data
SARS-CoV-2
Choy and colleagues studied the antiviral effect of lopinavir against SARS-CoV-2 in Vero E6 cells.6
By measuring infectious virus yielded in culture supernatant at 48 hours post-infection, they
determined the EC50 to be 26.6 μM for lopinavir, but no antiviral effect with ritonavir. They note
HIV patients treated with 400 mg/100 mg LPV/r twice daily reach a minimal lopinavir serum
concentration of 9.4 μM (IQR 7.2 to 12.1 μM), which is below the EC50 against SARS-CoV-2 in
vitro.
SARS-CoV-1
Following the emergence of the SARS epidemic in 2003, Chu and colleagues sought to identify an
antiviral agent that could exploit the therapeutic window occurring during the early viral
replication phase.7 They evaluated 13 antivirals for SARS-CoV-1 susceptibility in vitro and found
only lopinavir (EC50 of 4 μg/mL) and ribavirin (EC50 of 50 μg/mL) had inhibitory effect at 48 hours
of incubation, and that this effect was synergistic. Early pharmacokinetic studies of LPV/r
suggest this effective antiviral concentration is achievable both at peak (9.6 μg/mL) and trough
(5.5 μg/mL) serum concentrations.8
Chen and colleagues also investigated in vitro antiviral susceptibility of 10 isolates of SARS-CoV-1
to numerous commercially available antiviral agents and found lopinavir to have activity, with an
40
EC50 ranging from 1-8 μg/mL.3 de Wilde and colleagues similarly found that low micromolar
concentrations of lopinavir inhibited SARS-CoV-1 replication in infected Vero cells (EC50 17 μM).
MERS-CoV
Sheahan and colleagues evaluated the in vitro efficacy of lopinavir and ritonavir against a
recombinant MERS-CoV.4 They found similar efficacy as in SARS-CoV-1, with an EC50 for
lopinavir, ritonavir and LPV/r of 11.6 μg/mL, 24.9 μg/mL, and 8.5 μg/mL, respectively, however
this was far inferior to the antiviral activity of remdesivir and interferon β (INFβ). Additionally,
the addition of LPV/r to INFβ did not significantly enhance antiviral activity of INFβ alone (EC50
160 IU/mL vs 175 IU/mL, respectively).
de Wilde and colleagues found that low micromolar concentrations of lopinavir inhibited MERS-
CoV replication in infected Vero cells (EC50 8 μM).9 This concentration is reportedly within the
range of LPV plasma concentration (8 to 24 μM) typically observed in HIV patients. However,
other in vitro studies have found lopinavir to be inactive against MERS-CoV with a suboptimal
EC50.9,10
Animal Studies
MERS-CoV
In a mice model, Sheahan and colleagues found that when administered prophylactically LPV/r +
INFβ only modestly reduced viral lung titer without impact on other disease parameters, while
therapeutic doses of LPV/r + INFβ improved pulmonary function but did not reduce viral
replication or prevent acute lung injury, in comparison to remdesivir.4 Chan and colleagues
studied the therapeutic efficacy of LPV/r against MERS-CoV in common marmosets and noted
modest improvements in clinical outcome.11
41
In vivo data
SARS-CoV-2
At a single center in Wuhan, China, Cao and colleagues performed an open label randomized
clinical trial to evaluate the efficacy of LPV/r to treat severe COVID-19.12 199 adults hospitalized
with pneumonia, hypoxemia and laboratory confirmed SARS-CoV-2 infection were randomized
to receive LPV/r (400/100mg PO BID) plus standard of care (n= 99) or standard of care alone (n=
100), stratified based on illness severity by ventilatory support. The primary outcome was time
to clinical improvement, defined as time from randomization to either discharge from the
hospital or clinical improvement of two points on a seven-category ordinal scale (ranging from
normal activity to death), whichever came first. In both groups, the median time from symptom
onset to randomization was 13 (IQR 11-16) days. Both groups were heterogenous, receiving
glucocorticoids (34%) and interferon (11%), for example.
There was no difference in time to clinical improvement (median 16 days). The 28-day mortality
was numerically less in the LPV/r group compared to the standard-care group (19.2% vs 25%,
difference -5.8 percentage points [-17.3 to 5.7]) and even more so in a modified intention-to-
treat analysis accounting for 5 patients randomized to
LPV/r but who never received a single dose (3/5 died prior
to dosing) (16.7% vs 25%, difference -8.3 [-19.6 to 3.0]),
but the between group differences were not significant.
There was no significant difference in time from
randomization to discharge, duration of time in the ICU,
duration of mechanical ventilation, duration of viral RNA
detectability, nor the reduction of viral load over illness
course. Incidence of adverse events was similar in each
group (48.4% and 49.5%), although the standard-care
group had more serious adverse events (20 vs 32%).
Notably 14% of patients in the LPV/r group were unable to
complete the full 14-day course secondary to adverse
effects.
In a small, single center, retrospective cohort study, Deng and colleagues attempted to
investigate the use of LPV/r to reduce viral load earlier in the disease course by evaluating adults
hospitalized with mild COVID-19.13 One group received oral arbidol (influenza antiviral not
licensed in the US) and LPV/r (n= 16), the other LPV/r alone (n= 17). The authors suggest a
benefit to combined versus monotherapy for both their primary outcomes – negative conversion
rate via RT-PCR NP specimen (75% vs 35% at 7 days, 94% vs 53% at 14 days) and radiographic
improvement on CT (69% vs 29% at 7 days). Whether these endpoints are significant is
questionable. Notably there was no non-LPV/r control group for comparison, and nearly half of
all patients developed gastrointestinal adverse effects, although none requiring premature
discontinuation.
Schoergenhofer and colleagues measured the LPV/r trough plasma concentrations in eight
COVID-19 patients and found a median of 13.6 μg/mL (range 6.2 to 24.3 μg/mL).14 These non-
42
severely ill patients received the standard dosing (400 mg/100 mg lopinavir/ritonavir twice daily),
and all had favorable outcomes. The authors note despite receiving the same dosing used for
treatment of HIV in adults, the trough levels were nearly twice as high as observed in HIV
patients (13.6 vs 7.1 μg/mL). However, the trough concentrations of lopinavir were still less than
the assumed EC50 of SARS-CoV-2 (16.4 μg/mL) at the current doses.6
SARS-CoV-1
After noting in vitro activity of lopinavir against SARS-CoV-1, Chu and colleagues studied clinical
response to antiviral therapy in an open label study of 152 adult patients with SARS.7 The
treatment group (n= 41) received a combination of ribavirin, corticosteroids and LPV/r (400/100
mg PO BID), and was compared to a historical control (n= 111) which received ribavirin and
corticosteroids only. The primary outcome – a composite adverse outcome of development of
ARDS criteria or death at 21 days – was significantly reduced in the treatment compared to the
control group (2.4% vs 28.8%, effect size 95% CI 16.8 to 36, p<0.001). In a subgroup analysis of
the treatment group, the outcome reduction was only appreciated in patient receiving LPV/r
early (“initial treatment,” median time from symptom onset 3.5 days) as opposed to a “rescue
treatment” (median time from symptom onset 14 days). Additionally, the initial treatment
subgroup required significantly lower cumulative salvage methylprednisolone doses and had
fewer nosocomial infections than both the rescue treatment subgroup and the historical
controls. The treatment group also experienced a significantly more rapid reduction in viral load
in both nasopharynx and stool (2.4% vs 67% positive at day 21) via RT-PCR.
MERS-CoV
A multicenter, placebo-controlled, double-blind, randomized clinical trial is currently under way
in Saudi Arabia to investigate the efficacy of lopinavir/ritonavir combined with interferon β1b in
the treatment of MERS-CoV (Trial Identifier: NCT02845843).15 Nearly 200 patients have been
enrolled at last update, however no results have been posted as of the most recent update of
this document.
Lopinavir/ritonavir + Interferon
In studies of MERS-CoV, the virus appears to attenuate the interferon response of the innate
immune system, thought to impair the antiviral Th1 response. In vitro and animal studies of
interferon have demonstrated inhibition of MERS-CoV.16 The combination of lopinavir/ritonavir
and the immunomodulator interferon β1b is currently being studied for the treatment of MERS-
CoV in a multicenter, placebo-controlled, double-blind, randomized trial in Saudi Arabia (Trial
Identifier: NCT02845843).15 The primary outcome is 90-day mortality, however no results have
been posted as of the most recent update of this document.
Additional studies are investigating whether other interferon and antiviral combinations with
efficacy in treating other viral infections (i.e. HBV, HCV) could be used to stimulate innate
antiviral responses in patients infected with SARS-CoV-2.5 Pegylated interferon ⍺2a and ⍺2b in
combination with ribavirin is being investigated in a clinical trial in China.
Notably, due to ritonavir’s potent inhibition of CYP3A, numerous medications commonly utilized
in the intensive care setting are dependent of CYP3A metabolism and concomitant use is
contraindicated. Examples include fentanyl, midazolam, phenytoin, and amiodarone, among
others.15
Conclusion
While the data from SARS-CoV-1 and MERS-CoV are suggestive there may be a role for LPV/r, in
vitro data and limited clinical data are less encouraging for its use in treating SARS-CoV-2. The
recent randomized controlled trial by Cao and colleagues12 did not demonstrate a significant
benefit of LPV/r over standard-care in terms of clinical improvement or mortality. It is notable
that patients in this trial were severely ill (mortality 25% in the control arm), and the median
time to randomization occurred 13 days after symptom onset. More data in SARS-CoV-2 is
needed to determine whether there might be a benefit if therapy is started earlier, as in the
SARS-CoV-1 experience, as opposed to use as salvage therapy in patients who already have signs
of on-going lung damage. Additionally, further evaluation of concomitant use of LPV/r with
other therapies (i.e. ribavirin, interferon) are needed.
44
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online March 18, 2020. doi:10.1056/NEJMe2005477
2. Lopinavir/ritonavir (Kaletra). North Chic IL AbbVie. Published online 2019:57.
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coronavirus to selected antiviral compounds. J Clin Virol. 2004;31(1):69-75.
doi:10.1016/j.jcv.2004.03.003
4. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and
combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun.
2020;11(1):1-14. doi:10.1038/s41467-019-13940-6
5. Li G, Clercq ED. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev
Drug Discov. 2020;19(3):149-150. doi:10.1038/d41573-020-00016-0
6. Choy K-T, Wong AY-L, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and
homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020;178:104786.
doi:10.1016/j.antiviral.2020.104786
7. Chu CM, Cheng VCC, Hung IFN, et al. Role of lopinavir/ritonavir in the treatment of SARS:
initial virological and clinical findings. Thorax. 2004;59(3):252-256.
doi:10.1136/thorax.2003.012658
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9. de Wilde AH, Jochmans D, Posthuma CC, et al. Screening of an FDA-Approved Compound
Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome
Coronavirus Replication in Cell Culture. Antimicrob Agents Chemother. 2014;58(8):4875-4884.
doi:10.1128/AAC.03011-14
10. Chan JFW, Chan K-H, Kao RYT, et al. Broad-spectrum antivirals for the emerging Middle
East respiratory syndrome coronavirus. J Infect. 2013;67(6):606-616.
doi:10.1016/j.jinf.2013.09.029
11. Chan JF-W, Yao Y, Yeung M-L, et al. Treatment With Lopinavir/Ritonavir or Interferon-β1b
Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common
Marmoset. J Infect Dis. 2015;212(12):1904-1913. doi:10.1093/infdis/jiv392
12. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with
Severe Covid-19. N Engl J Med. Published online March 18, 2020:NEJMoa2001282.
doi:10.1056/NEJMoa2001282
13. Deng L, Li C, Zeng Q, et al. Arbidol combined with LPV/r versus LPV/r alone against
Corona Virus Disease 2019: A retrospective cohort study. J Infect. Published online March
2020:S0163445320301134. doi:10.1016/j.jinf.2020.03.002
14. Schoergenhofer C, Jilma B, Stimpfl T, Karolyi M, Zoufaly A. Pharmacokinetics of Lopinavir
and Ritonavir in Patients Hospitalized With Coronavirus Disease 2019 (COVID-19). Ann Intern
Med. Published online May 12, 2020. doi:10.7326/M20-1550
15. Arabi YM, Alothman A, Balkhy HH, et al. Treatment of Middle East Respiratory Syndrome
with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a
randomized controlled trial. Trials. 2018;19. doi:10.1186/s13063-017-2427-0
47
16. Hart BJ, Dyall J, Postnikova E, et al. Interferon-β and mycophenolic acid are potent
inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol.
2014;95(Pt 3):571-577. doi:10.1099/vir.0.061911-0
17. Hung IF-N, Lung K-C, Tso EY-K, et al. Triple combination of interferon beta-1b, lopinavir–
ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-
label, randomised, phase 2 trial. The Lancet. Published online May 2020:S0140673620310424.
doi:10.1016/S0140-6736(20)31042-4
48
Nitazoxanide, a thiazolide, has been proposed for possible use in the treatment of
COVID-19.1–3 Originally developed and utilized as an antiprotozoal medication, it has
demonstrated potent, broad-spectrum in vitro antiviral activity against a variety of
viruses including: RSV, parainfluenza, rotavirus, norovirus, hepatitis B and C, dengue,
yellow fever, Japanese Encephalitis virus, and human and animal coronaviruses.1–4 The
broad antiviral activity is thought to be secondary to the mechanism of action which is
based on interfering with host responses involved in viral replication.3,4 It specifically has
activity against coronaviruses by inhibiting expression of the coronavirus N protein, and
by suppressing production of cytokines and IL-6.4
Nitazoxanide has been used extensively in clinical trials, is highly orally bioavailable,
and has demonstrated safety based on extensive post-marketing experience in more
than 75 million adults and children.3,4 In a phase 2b/3 study for outpatient management
of influenza, administration of nitazoxanide BID for 5 days was associated with a one-
day improvement in time to resolution of symptoms compared to placebo. This same
study suggested potential benefit for subjects with influenza-like illness who did not
have influenza or other documented respiratory infection.5 There have also been three
RCTs for use of nitazoxanide in uncomplicated influenza, but these results are
unavailable.1 Contrary to the influenza data, a double-blind, placebo-control trial with
260 participants > 1 year-old hospitalized with an influenza-like illness in 6 hospitals in
Mexico, demonstrated no difference in duration of hospitalization or adverse effects in
those who received nitazoxanide vs placebo.6
References
1. McCreary EK, Pogue JM. COVID-19 Treatment: A Review of Early and Emerging Options. Open
Forum Infect Dis. doi:10.1093/ofid/ofaa105
2. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently
emerged novel coronavirus (2019-nCoV) in vitro. Cell Research. 2020;30(3):269-271.
doi:10.1038/s41422-020-0282-0
3. Rossignol J-F. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res.
2014;110:94-103. doi:10.1016/j.antiviral.2014.07.014
4. Rossignol J-F. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory
syndrome coronavirus. J Infect Public Health. 2016;9(3):227-230. doi:10.1016/j.jiph.2016.04.001
5. Haffizulla J, Hartman A, Hoppers M, et al. Effect of nitazoxanide in adults and adolescents with
acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. The
Lancet Infectious Diseases. 2014;14(7):609-618. doi:10.1016/S1473-3099(14)70717-0
6. Gamiño-Arroyo AE, Guerrero ML, McCarthy S, et al. Efficacy and Safety of Nitazoxanide in
Addition to Standard of Care for the Treatment of Severe Acute Respiratory Illness. Clin Infect Dis.
2019;69(11):1903-1911. doi:10.1093/cid/ciz100
50
MERS
Remdesivir has been shown to inhibit MERS-CoV replication in 2B4 cells (human T cell
hybridoma) in vitro with an IC50 of 0.03 uM and minimal toxicity, and to prevent
replication in human airway epithelial cells with an EC50 of of 0.074 ± 0.023 uM 2,3. An
EC50 of 0.09 uM was calculated for MERS-CoV in Calu-3 cells (human lung
adenocarcinoma) 4.
Animal Models
SARS-CoV-2
Non-human primates
In a study performed jointly between NIH and Gilead that was released as a pre-print (not
yet peer reviewed as of April 27, 2020), daily remdesivir begun within 12 hours of SARS-
CoV-2 exposure in rhesus macaques led to less severe clinical, virologic, and
histopathologic outcomes. Twelve rheusus macaque monkeys were infected with SARS-
CoV-2. Twelve hours later, six animals began daily treatment with remdesivir, and six with
vehicle (controls). The animals were assessed daily for 7 days by investigators blinded to
treatment groups. An overall clinical score was better throughout the study for the
remdesivir-treated animals than the controls. All control animals developed tachypnea and
dyspnea, whereas only one remdesivir- treated animal developed dyspnea. Radiographic
evaluation showed less pulmonary infiltration in the treatment group. There was little
difference in viral load in upper respiratory tract secretions, but there was reduced
infectious virus in BAL samples from remdesivir-treated animals at 1 and 3 days post
infection. At 7 days post infection, necropsy lung tissue from remdesivir-treated animals
contained less infectious virus than that from controls. Histology showed significantly less
frequent and less extensive interstitial pneumonia in the treatment group. Sequencing of
viral genomes showed no evidence that remdesivir treatment selected for resistance
mutations during the study. Notably, some of the authors work for Gilead which
manufactures remdesivir – these conflicts of interest are disclosed. Other limitations
include: the study size was small, with a limited follow up period, and some clinical score
data was omitted without explanation in this pre-print. Importantly the short time-frame
between exposure and treatment in this study could not be practically replicated in
humans outside prophylactic strategies5.
Other CoVs
In mouse models of SARS and MERS and in primate models of MERS remdesivir treatment
decreases viral load and disease. Prophylaxis is more effective than therapeutic treatment.
Mouse Models
Sheahan and colleagues compared prophylactic (starting 1 day prior to exposure) and
therapeutic (starting 1 day post infection, dpi) administration of remdesivir in mice
infected with SARS-CoV. Both reduced viral titer in mouse lungs compared to vehicle
control (measured at 2 and 5 dpi for prophylaxis, and at 4 dpi for therapeutic). Weight loss
and airway constriction after SARS-CoV infection were prevented by both prophylactic and
therapeutic administration of remdesivir compared to vehicle control, but these two
markers of clinical disease were more greatly abrogated by prophylactic dosing than
therapeutic dosing of remdesivir2.
MERS, and reduced tissue pathology in lungs of infected mice compared to vehicle-treated
controls 4.
Non-Human Primates
De Wit and colleagues evaluated remdesivir in rhesus macaques infected with MERS-
CoV. There were three groups of 6 animals each. Prophylactic (daily starting 1 day prior to
infection) and therapeutic (daily starting 12 hr post infection) administration of remdesivir
were compared to vehicle control. Viral loads were decreased in both the prophylactic and
therapeutic groups compared to vehicle control in respiratory tissues including lung,
bronchi, trachea, pharynx. Treatment groups also saw decreased disease in overall clinical
findings (using a clinical scoring system), histopathological findings and radiographic
findings. Prophylactic treatment had a greater protective effect than the therapeutic course
for each of the measured outcomes 6.
Human Trials
SARS-CoV-2
Trials underway by Gilead as of April 27, 2020 are listed at the end of this document. Two
trials have been terminated early in China due to low enrollment. To date, only case
reports/series are available.
Adult Studies
Remdesivir was used in the first described US hospitalized COVID-19 patient, presented in
a case report 7. This was an adult male in whom remdesivir was started on day 7 of
hospitalization after two days of acute clinical worsening including the development of an
oxygen requirement. By day 8 of hospitalization (1 day post remdesivir), he was
significantly clinically improved without oxygen requirement.
This report was followed by a case series of 12 US adult patients with COVID-19, 3 of whom
received remdesivir for 4-10 days. All three experienced improved respiratory status.
There was potential temporal correlation with decrease in temperature (in ⅔ patients, 3rd
was afebrile at initiation), and an increase in WBC and platelets (from initial low-normal
value). All developed elevated aminotransferase levels. Mild GI side effects were described:
nausea, loose stools, and abdominal discomfort8.
Gilead (the makers of remdesivir) have published the clinical outcomes of 53 patients with
basely hypoxia treated with remdesivir on a compassionate use protocol. An additional 8
patients received remdesivir, but were excluded from this analysis due to missing data or
dosing error. Patients were hospitalized in Asia, North America, and Europe. Among
included patients, overall mortality was 13%; in subgroup analysis, 18% of patients
initially receiving mechanical ventilation died. At time of analysis (median follow up period
of 18 days), 68% of patients had improved oxygenation, and 47% had been discharged. The
authors note that these mortality and improvement rates compare favorably to prior rates
from China, although they acknowledge that remdesivir effect cannot be inferred without a
control group 9.
53
Other Viruses
A report by Gilead Sciences Inc. delineates the discovery, early in-vitro studies and clinical
studies on remdesivir as an antiviral for ebola. They report that single and multiple dose
phase I clinical trials were conducted without serious adverse events. They further detail
the courses of two patients who received remdesivir under compassionate use request,
both of whom recovered without serious adverse events10.
Prophylaxis
See animal studies of MERS-CoV and SARS-CoV above.
Any dosing for human trial would be dictated by Gilead.
Safety and Drug Monitoring
Monitoring scheme would be dictated by Gilead.
WHO Ebola guidelines12: daily monitoring of LFTs and renal function12.
hr post dosing in this animal model. They estimated the half life of the drug in normal
human broncheolar epithelial cells to be 22 hr in vitro 2.
Finally, in an interview with STAT news on March 13, 2020, a spokesperson from Gilead
reported that in a phase 1 study with >80 healthy humans, there were “predictable dose-
proportional pharmacokinetics with no observed serious adverse effects. Transient low-
grade elevations in liver transaminases were observed…”13.
Age
Title Status Interventions Groups Locations
A Trial of Remdesivir in Adults With
Mild and Moderate COVID-19 Suspended Remdesivir vs placebo Adults China
Study to Evaluate the Safety and
Antiviral Activity of Remdesivir (GS- 12 yr
5734) in Participants With Severe and International,
Coronavirus Disease (COVID-19) Recruiting Remdesivir vs Standard of care older includes US
Study to Evaluate the Safety and
Antiviral Activity of Remdesivir (GS-
5734) in Participants With Moderate
Coronavirus Disease (COVID-19) 12 yr
Compared to Standard of Care and International,
Treatment Recruiting Remdesivir vs Standard of care older includes US
A Trial of Remdesivir in Adults With
Severe COVID-19 Terminated Remdesivir vs placebo Adults China
Expanded Access Treatment Protocol:
Remdesivir (RDV; GS-5734) for the 12 yr
Treatment of SARS-CoV2 (CoV) and International,
Infection (COVID-19) Available Remdesivir older includes US
The Efficacy of Different Anti-viral Hydroxychloroquine, remdesivir, standard
Drugs in COVID 19 Infected Patients Recruiting of acre Adults Norway
Adaptive COVID-19 Treatment Trial International,
(ACTT) Recruiting Remdesivir vs placebo Adults includes US
Expanded Access Remdesivir (RDV; GS-
5734) Available Remdesivir
Drug: Remdesivir| Lopinavir/ritonavir|
Interferon Beta-
Trial of Treatments for COVID-19 in 1A|Hydroxychloroquine|Other: Standard
Hospitalized Adults Recruiting of care Adults France
55
Works cited:
1. Wang, M. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus
(2019-nCoV) in vitro. Cell Res. 30, 269–271 (2020).
2. Sheahan, T. P. et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.
Sci. Transl. Med. 9, (2017).
3. Agostini, M. L. et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the
Viral Polymerase and the Proofreading Exoribonuclease. MBio 9, (2018).
4. Sheahan, T. P. et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir,
and interferon beta against MERS-CoV. Nat. Commun. 11, 222 (2020).
5. Williamson, B. N. et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2.
bioRxiv 2020.04.15.043166 (2020) doi:10.1101/2020.04.15.043166.
6. de Wit, E. et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque
model of MERS-CoV infection. Proc. Natl. Acad. Sci. U. S. A. (2020) doi:10.1073/pnas.1922083117.
7. Holshue, M. L. et al. First Case of 2019 Novel Coronavirus in the United States. N. Engl. J. Med. 382, 929–
936 (2020).
8. Kujawski, S. A. et al. First 12 patients with coronavirus disease 2019 (COVID-19) in the United States.
medRxiv 2020.03.09.20032896 (2020).
9. Grein, J. et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N. Engl. J. Med. (2020)
doi:10.1056/NEJMoa2007016.
10. 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.
60, 1648–1661 (2017).
11. Mulangu, S. et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N. Engl. J. Med. 381,
2293–2303 (2019).
12. Ebola | WHO R&D Blueprint – Ad-hoc Expert Consultation on clinical trials for Ebola Therapeutics.
(2019).
13. Silverman, E. New paper about a Gilead drug to combat coronavirus has analysts skittish. STAT
https://www.statnews.com/pharmalot/2020/03/13/gilead-coronavirus-covid19-clinical-trials/ (2020).