COVID-19 GRAND ROUNDS April 14, 2020 Michael Melia, MD Natasha - - PowerPoint PPT Presentation

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

COVID-19 GRAND ROUNDS

April 14, 2020 Michael Melia, MD Natasha Chida, MD, MSPH Annie Antar, MD, PhD

With NATASHA CHIDA, MD, MSPH MICHAEL MELIA, MD

ABOUT COVID-19 GRAND ROUNDS

Hosted by Drs. Michael Melia and Natasha Chida, COVID-19 Grand Rounds utilizes clinical cases, in-depth literature reviews, and clinical expertise within the Johns Hopkins School of Medicine to provide clinicians with relevant and timely information about the care of patients with COVID-19. All case presentations in this program have been standardized and quality assured in selection, presentation and discussion. Our goal is to publish and build a library of cases that will aid providers treating patients with COVID-19 in a rapidly changing landscape. COVID-19 Grand Rounds is intended solely as an educational resource specifically for healthcare providers, and is not be construed as medical guidance for patients on disease prevention, diagnosis, or

• treatment. Patients should consult their healthcare providers for clinical guidance related to their care.

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

OBJECTIVES

• 1. Describe in vitro data of Remdesivir as a SARS-CoV-2 therapeutic agent
• 2. State current clinical trials of Remdesivir
• 3. Describe in vitro data of Lopinavir/ritonavir as a SARS-CoV-2 therapeutic

agent

• 4. Discuss clinical trial data of Lopinavir/ritonavir as a SARS-CoV-2 therapeutic

agent

• 5. State the biologic plausibility for Chloroquine/Hydroxychloroquine as SARS-

CoV-2 therapeutic agents

• 6. Describe in vitro data of Chloroquine/Hydroxychloroquine as a SARS-CoV-2

therapeutic agent

• 7. Discuss clinical trial data of Chloroquine/Hydroxychloroquine as a SARS-CoV-

2 therapeutic agent

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CASE PRESENTATION

• 52 year old man with worsening dyspnea.
• HPI:
• D1 – symptoms begin – slight cough
• D2 – fevers, chills, myalgias
• D6 – symptoms peaked so presented to urgent care. Tested for COVID-19.
• D7 – symptoms improving, but appetite is gone. Lost all sense of smell/taste.
• D10 – test resulted – COVID-19 positive
• D11 – awoke with severe SOB and chest tightness. Couldn’t lay flat. JHH ED.
• PMH/PSH: HTN on losartan 25mg, HLD on rosuvastatin 5mg, OSA on CPAP.
• Social History: Never tobacco/drugs/alcohol. Married. Works in law enforcement. No

recent travel

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

PRESENTATION TO JHH

• Vitals: T

emp 39.4oC, BP 148/63, HR 106, O2 sat 91% on room air

• Exam: BMI 30.6. Mild

respiratory distress. No rhinitis. Tachycardic, Coughing. Crackles and rhonchi in posterior lungs

• Lab work: UA 1+ protein, urine

legionella & strep pneumo Ags negative, D-dimer 1.02, PT normal, CRP 13.3, CK 625, LDH 384, ferritin 917

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

AP CXR

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CLINICAL COURSE

• D11 – Given CTX/azithro and admitted. 2L O2.
• D12 – Requiring 3-4L O2. 1x fever. Tachycardic and tachypneic. Started on
• hydroxychloroquine. Satting 93% on 4L by end of day, proning helps.

Consulted MICU. Recommended continued proning

• D13 – Requiring 2-2.5L O2. Afebrile. Normal heart rate. RR 18-25. Abs

lymph 1K. Ferritin peak at 1296. AST/ALT peak at 80/39. CRP peak at 18.7.

• D14 –In AM satting 90% on 6L – re-consulted MICU. Proning helps.

Continuous pulse ox, proned, weaned down to 4L by end of day.

• D15 – Requiring 3L O2. ESR 23. LDH declined to 344. CRP decline to 5.1.
• D18 – Requiring 0-1L. Discharged.
• D20 – Follow-up phone call – feeling good except occasional dry cough.

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CLINICAL PEARS FROM THE FLOOR

• 1. HCQ has an antipyretic effect
• 2. People seem to desaturate with walking more than you

might expect

• 3. Many patients didn’t bring a cell phone charger and cannot

contact family (don’t have numbers memorized; phone dies) nor can family bring charger to them. This is a real hardship for patients who are already afraid and isolated during severe disease.

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CLINICAL QUESTIONS FROM THIS CASE

• HCQ started on Day 12
• Improved 6 days later
• Did HCQ facilitate clinical improvement?
• What is the evidence in support other antiviral therapeutic agents

that have been used/studied in COVID-19?

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

ANTIVIRAL AGENTS FOR COVID-19

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

SAMPLE OF COVID-19 THERAPEUTIC LANDSCAPE

Antivirals Immune Modulators Other Baloxavir Anakinra ACEI/ARB Chloroquine/Hydroxychloroquine Convalescent Plasma Ascorbic Acid DAS-181 Corticosteroids Azithromycin Favipiravir IVIG Epoprostenol Interferon Lenzilumab Indomethacin Lopinavir/Ritonavir Ruxolitinib Ivermectin Neuraminidase inhibitors Sarilumab Niclosamide Remdesivir Sirolimus Nitazoxanide Ribavarin Tocilizumab Statins Umifenovir

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

SARS-CoV-2

Liu C, et al. ACS Cent Sci. doi: 10.1021/acscentsci.0c00272 (2020). Jiang S, Hillyer C, Du L. Trends Immunol doi: 10.1016/j.it.2020.03.007 (2020). Remdesivir Lopinavir/ritonavir DAS181 HCQ/CQ HCQ/CQ

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

REMDESIVIR

• 2013 Ebola outbreak
• CDC/USAMRIDD/Gilead Sciences

identified nucleoside lead à prodrug, RDV

• Metabolized to active form, adenosine

nucleoside analog

• Interferes with RNA polymerase
• Evades viral exoribonuclease

proofreading

• Decrease in RNA production
• In cell/animal models efficacious in MERS-CoV,

SARS-CoV, Marburg, Nipah, more

• IV formulation

Remdesivir Warren TK, et al. Nature. 2016;531(7594):381-5. Sheahan TP , et al. Sci Transl Med. 2017;9(396).

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

REMDESIVIR ACCESS

• Clinical trials
• Compassionate use: pregnant women/children
• Expanded access protocol

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CLINICAL TRIALS

Name /Sponsor Pertinent Characteristics Estimated Completion China-Japan Friendship Hospital/Capital medical University

• 1. Hospitalized, severe

April 2020

• 2. Hospitalized, mild-moderate

April 2020 Gilead Sciences

• 3. Hospitalized, severe

May 2020

• 4. Hospitalized, mild-moderate

May 2020

• 5. Expanded access protocol, ventilated

N/A NIAID

• 6. Adaptive, hospitalized

April 2023 U.S. Army Medical Research and Development Command

• 7. Expanded access, DOD personnel, mod-

severe N/A SOLIDARITY/WHO

• 8. Hospitalized

March 2020-2022 DISCOVERY/INSERM

• 9. Hospitalized

March 2020-2023

No civilian studies in non-hospitalized

JHU

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CLINICAL DATA

• Report of patients Jan-March-61

patients à 53

• 40 (75%) received the full 10-

day course of Remdesivir

• 34 (64%) ventilated at baseline
• Median duration of

ventilation prior to Remdesivir 2 days [IQR 1-8]

Grein J, et al. N Engl J Med. doi: 10.1056/NEJMoa2007016 (2020).

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

• 18 days
• 36 (68%) showed improvement in oxygen support
• 57% ventilated patients extubated
• Most recent follow up
• 25 (47%) discharged
• 7 (13%) died
• 6 (18%) of those ventilated, 1(5%) not ventilated

Grein J, et al. N Engl J Med. doi: 10.1056/NEJMoa2007016 (2020).

CLINICAL DATA

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

• 23% serious adverse events
• Summary:
• Essentially a case series
• Open label
• No comparator
• Mortality is a range
• Can’t draw conclusions

Grein J, et al. N Engl J Med. doi: 10.1056/NEJMoa2007016 (2020).

CLINICAL DATA

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

LOPINAVIR/RITONAVIR

• In-vitro activity against SARs-CoV, MERS-CoV
• Hypothesis: inhibition of SARs/MERS protease
• Benefit in retrospective studies in SARs-CoV
• Some in vitro data SARS-CoV-2, but EC50 much

higher than levels reached in HIV dosing

• HIV protease different protease family
• Optimized to fit in a specific part of the catalytic site
• f HIV protease, absent in coronaviruses
• Some benefit in animal studies MERS-CoV
• Widely used in China
• Numerous retrospective studies

Li G, De Clercq E. Nat Rev Drug Discov. 2020;19(3):149- 150., Yao TT, et al. J Med

• Virol. doi: 10.1002/jmv.2572

(2020)., Jiang S, Hillyer C, Du L. Trends Immunol doi: 10.1016/j.it.2020.03.007 (2020)., Choy KT et al. Antiviral

• Res. doi: 10.1016/j.antiviral.2020.104786 (2020).

Lopinavir/ritonavir

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

LOPINAVIR/RITONAVIR DATA

Trial Pertinent Characteristics Results

A Trial of Lopinavir-Ritonavir in Adults)

• Sao2 of ≤ 94% on ambient air or

Pao2/Fio2 ‹ 300 mmHg

• 199 patients
• 99 randomized to LPV/r
• No difference in time to clinical

improvement (HR 1.24; 95% confidence interval [CI], 0.90 to 1.72)

• Mortality at 28 days similar (19.2% vs.

25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7).

• Detectable viral RNA similar.
• LPV/r stopped early in 13.8%, adverse

events. Clinical efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease 2019 (Eur Rev Med Pharmacol Sci)

• 47 patients
• “According to whether they had been

treated with LPV/r or not during hospitalization, patients were classified into the test group (n=42) and control group (n=5)”

• Outcomes: Resolution of fever, virus

clearance, labs

• Resolution of fever: test group: 4.8±1.94

days vs. control group: 7.3±1.53 days, p=0.0364.

• Time to negative PCR: test group:

7.8±3.09 days vs. control group: 12.0±0.82 days, p=0.021 Cao B, et al. N Engl J Med. doi: 10.1056/NEJMoa2001282 (2020). , Ye XT, et al. Eur Rev Med Pharmacol Sci. 2020;24(6):3390-339

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

LOPINAVIR/RITONAVIR CLINICAL TRIALS

Name/Sponsor Pertinent Characteristics Estimated completion COVID MED (single center, NY) Adaptive, LPV/r, HCQ, Losartan Hospitalized April 2021 ELACOI LPV/r + arbidiol July 2020 Lopinavir/ Ritonavir, Ribavirin and IFN-beta Combination for nCoV Treatment (HK) hospitalized July 2022 THDMS-COVID-19 (India) Multiple drugs Nov 2020 SOLIDARITY/WHO

• 8. Hospitalized

March 2020-2022 DISCOVERY/INSERM

• 9. Hospitalized

March 2020-2023

Clinicaltrials.gov

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

DAS181

• Inhaled recombinant sialidase fusion protein
• Respiratory viruses use cell surface sialic acids as host receptors
• Cleaves/removes sialic receptors from airway epithelium à virus

cannot enter cells

• In vitro activity against parainfluenza, influenza, more
• Phase II trials parainfluenza, influenza
• Trial at JHH

Qing E, et al. mBio. doi: 10.1128/mBio.02764-19 (2020)., Jiang S, Hillyer C, Du L. Trends Immunol doi: 10.1016/j.it.2020.03.007 (2020). DAS181

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

REMDESIVIR, LOPINAVIR/RITONAVIR, DAS181 KEY POINTS

• Remdesivir has biological plausibility and in vitro data to support its

candidacy as a SARS-CoV-2 therapeutic agent

• Most promising antiviral agent
• Clinical trial data forthcoming
• Lopinavir/ritonavir some in vitro data in SARS-CoV-2; may be

efficacious in SARS-CoV, MERS-CoV

• Current clinical data does not support its candidacy as a SARS-

CoV-2 therapeutic agent

• Clinical trial data forthcoming
• DAS181 has biological plausibility as a SARS-CoV-2 therapeutic agent
• Clinical trial data forthcoming

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CHLOROQUINE & HYDROXYCHLOROQUINE

• Introduction and history
• In vitro data
• Clinical trials and case series
• Dosing considerations
• Ongoing clinical trials

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CHLOROQUINE & HYDROXYCHLOROQUINE

• Disease-modifying anti-rheumatic drugs
• Immunomodulatory activity & pleiotropic benefits
• Wide tissue distribution, large volume of distribution, long half-life

Schrezenmeier E and Doerner T. Nat Rev Rheumatol. 2020 Mar;16(3):155-166. Wang M et al. Cell Research (2020) 30:269–271; https://doi.org/10.1038/s41422-020-0282-0. Perinel S et al. Clin Infect Dis. 2020 Apr 7. pii: ciaa394. doi: 10.1093/cid/ciaa394. [Epub ahead of print]. Carmichael SJ, Charles B, Tett SE. Ther Drug Monit. 2003;25(6):671–681.

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES Schrezenmeier E and Doerner T. Nat Rev Rheumatol. 2020 Mar;16(3):155-166.

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CHLOROQUINE MECHANISMS AGAINST SARS-CoV-2

• Blocks viral infection by

increasing endosomal pH required for virus-cell fusion

• Interferes with glycosylation of

SARS-CoV cellular receptors

• Chloroquine interferes with

entry and post-entry stages of SARS-CoV-2 infection in Vero E6 cells

Wang M et al. Cell Research (2020) 30:269–271; https://doi.org/10.1038/s41422-020-0282-0. Vincent MJ et al. Virol J. 2005 Aug 22;2:69.

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CHLOROQUINE ACTIVITY AGAINST SARS-CoV-2

• Vero E6 cells infected with SARS-

CoV-2 at MOI 0.05

• Efficacy evaluated by quantification of

viral copy numbers in cell supernatant by RT

• PCR, confirmed

with visualization of virus nucleoprotein expression through immunofluorescence microscopy at 48h post-infection

• EC90 = 6.90 μM (clinically

achievable)

Wang M et al. Cell Research (2020) 30:269–271; https://doi.org/10.1038/s41422-020-0282-0.

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CQ VERSUS HCQ IN VITRO

• Cytotoxicity in

VeroE6 cells measured

• HCQ less potent than CQ at

some MOI

Liu J et al. Cell Discovery ( 2020) 6:16. https://doi.org/10.1038/s41421-020-0156-0

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CHLOROQUINE & HYDROXYCHLOROQUINE

• Prior demonstrations of CQ in vitro anti-viral activity
• SARS-CoV, influenza, Zika, HIV
• Has not been effective clinically
• CQ failed for influenza prevention
• CQ no meaningful impact on immune activation among PLWH on

ART

• HCQ → greater decline in CD4 count and increased HIV

replication among patients not on ART

Keyaerts E et al. Biochem Biophys Res Commun. 2004 Oct 8;323(1):264-8. Zhang S et al. Antiviral Res. 2019 Sep;169:104547. Romanelli F, Smith KM, Hoven AD. Curr Pharm Des. 2004;10(21):2643-8. Paton NI et al. Lancet Infect Dis. 2011;11(9):677-83. Jacobson JM et al. AIDS Res Hum Retroviruses. 2016;32(7):636-47. Paton NI et al. JAMA 2012;308(4): 353-61. Savarino A. Lancet Infect Dis. 2011;11(9):653-4.

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CHLOROQUINE/HYDROXYCHLOROQUINE CLINICAL DATA

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE RCT I

• Randomized, parallel-group trial
• Inclusion criteria:
• Age ≥18y
• SARS-CoV-2 RT
• PCR positive
• Chest CT with pneumonia
• SaO2:SpO2 >93% or

PaO2:FiO2 >300 mm Hg

• Exclusion criteria:
• Severe, critical illness
• Retinal disease
• Heart block
• Severe liver disease, including

AST >2x ULN

• Pregnant or breastfeeding
• eGFR ≤30 or RRT

Chen Z. medRxiv preprint doi: https://doi.org/10.1101/2020.03.22.20040758

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE RCT I

• 62 patients
• 47% men
• Mean age 44.7y ±15.3
• All received standard therapy
• Oxygen
• Antiviral and antibacterial agents
• Immunoglobulin ± corticosteroids
• Randomization to HCQ 200 mg BID

x5d vs standard treatment

• Outcomes
• Time to clinical recovery =

afebrile and cough relief ≥72h

• Chest CT d0 vs d6
• Initially planned PCR and T
• cell

recovery data not reported

• HCQ: 9 no fever, 9 no cough
• Control: 14 no fever, 16 no cough

Chen Z. medRxiv preprint doi: https://doi.org/10.1101/2020.03.22.20040758. https://www.ashp.org/-/media/assets/pharmacy-practice/resource- centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx. Accessed 13 April 2020.

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE RCT I

• Fever duration shorter with HCQ (2.2 ± 0.4d vs 3.2 ± 1.3d)
• Cough duration shorter with HCQ (2.0 ± 0.2d vs 3.1 ± 1.5d)
• More patients had radiographic improvement with HCQ [25/31 (81%)

vs 17/31 (55%), p=0.05]

• All 4 patients who progressed to severe illness were in control group
• 2 patients with mild adverse reactions in HCQ group (rash, HA)

Chen Z. medRxiv preprint doi: https://doi.org/10.1101/2020.03.22.20040758

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE RCT II

• 30 patients at a single center in China
• Randomized to HCQ 400 mg daily x5d + conventional treatment or

conventional treatment only

• Both groups received interferon
• Most received umifenovir or lopinavir/ritonavir
• Primary endpoint: negative NP swab 7d after randomization
• No difference in primary endpoint between groups
• 13/15 (87%) cases negative in HCQ group, 14/15 (93%) in control group
• No difference in time from hospitalization to negative NP swab, fever

resolution, radiographic findings, diarrhea or abnormal liver enzymes

Chen J. J Zhejiang University. 2020:[Epub ahead of print]. https://doi.org/10.3785/j.issn.1008-9292.2020.03.03. https://www.ashp.org/-/media/assets/pharmacy- practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx. Accessed 13 April 2020.

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE ± AZITHROMYCIN I

• Open-label, non-randomized trial in France
• Patients aged ≥12y with NP SARS-CoV-2 carriage on admission
• Excluded: retinopathy, G6PD deficiency, QT interval prolonged, pregnancy
• HCQ 200 mg TID x10d ± azithromycin 500 mg x1 then 250 mg QD

x4d

• Controls: untreated patients from another center, patients refused protocol
• NP swab

VL measured daily

• End point: presence of virus at day 6 post-inclusion

Gautret P and Lagier JC et al. Int J Antimicrob Agents (2020), doi: https://doi.org/10.1016/j.ijantimicag.2020.105949

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE ± AZITHROMYCIN I

• 36* patients
• Mean age 45.1 ± 22y
• 42% (15/36) men
• 4.0 ± 2.6d between symptom onset & inclusion
• Clinical characteristics
• 8 patients with LRTI symptoms (all had evidence of pneumonia by

CT scan)

• 22 patients with URTI symptoms (rhinitis, pharyngitis, fever,

myalgia)

• 6 asymptomatic patients

Gautret P and Lagier JC et al. Int J Antimicrob Agents (2020), doi: https://doi.org/10.1016/j.ijantimicag.2020.105949

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE ± AZITHROMYCIN I

• At day 6 post-inclusion:
• 70% HCQ-treated patients (vs

12.5% controls) tested NP RT

• PCR negative
• 100% HCQ + azithromycin-

treated patients (vs 57% patients treated with HCQ monotherapy) tested NP RT

• PCR negative

Gautret P and Lagier JC et al. Int J Antimicrob Agents (2020), doi: https://doi.org/10.1016/j.ijantimicag.2020.105949

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE ± AZITHROMYCIN I

• One patient treated with HCQ + azithromycin tested RT
• PCR

negative at day 6 and then positive at day 8

• Patients treated with HCQ + azithromycin had lower viral RNA loads

at treatment initiation than HCQ and control groups

• Sites other than the primary site did not perform daily PCR testing
• 38% of data for control group imputed (vs 5% for treatment group)
• 6 treated patients omitted from analysis owing to ICU transfer (3),

death (1), hospital discharge (1), nausea (1)

Gautret P and Lagier JC et al. Int J Antimicrob Agents (2020), doi: https://doi.org/10.1016/j.ijantimicag.2020.105949. Kim AHJ, Sparks JA et al. Ann Intern Med. Doi:10.7326/M20-1223

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE + AZITHROMYCIN II

• 11 consecutive patients
• 7 men, 4 women
• Mean age 59y (range 20-77)
• 8 with significant comorbidities
• HCQ 600 mg daily x10d + azithro 500 mg x1 then 250 mg QD x4d
• At treatment initiation, 10/11 had fever and were receiving oxygen

Molina JM et al. Medecine et Maladies Infectieuses (2020), doi: https://doi.org/10.1016/j.medmal.2020.03.006

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE + AZITHROMYCIN II

• Within 5d, one patient died, two transferred to ICU
• One course discontinued after 4d (QT 405 → 460-470)
• NP RT
• PCR positive in 8/10 patients at 5-6d after treatment initiation

Molina JM et al. Medecine et Maladies Infectieuses (2020), doi: https://doi.org/10.1016/j.medmal.2020.03.006

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE + AZITHROMYCIN III

• Case series of 80 patients at one institution
• All patients treated with HCQ 200 mg TID + azithromycin 500 mg

x1 then 250 mg QD for ≥3d & followed for ≥6d included

• Excluded: QTc >500 ms, ECG suggesting channelopathy
• HCQ 200 mg TID x10d ± azithromycin 500 mg x1 then 250 mg QD

x4d

• Ceftriaxone added for pneumonia and NEWS score ≥5

Gautret P and Lagier JC et al. https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE + AZITHROMYCIN III

• NP swab

VL measured ~daily by RT

• PCR
• Primary end points:
• Clinical outcome, including O2 therapy or ICU transfer after ≥3d

treatment

• Contagiousness as assessed by PCR and culture
• Length of inpatient stay

Gautret P and Lagier JC et al. https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE + AZITHROMYCIN III

• 80 patients
• Median age 52.5y (IQR 42-

62)

• 52.5% (42/80) men
• 57.5% at least one chronic

condition

• 4.9 ± 3.6d between symptom
• nset & treatment initiation
• Clinical characteristics
• 54% LRTI symptoms
• 41% URTI symptoms
• 5% asymptomatic
• 15% had fever
• 92% low NEWS score (0-4)

Gautret P and Lagier JC et al. https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE + AZITHROMYCIN III

• 15% (12/80) received O2
• 81% (65/80) discharged
• 17% (14/80) still hospitalized
• 4% (3/80) transferred to ICU
• 1% (1/80) died
• Mean time from initiation to

hospital discharge 4.1d

• Mean LOS 4.6d

Gautret P and Lagier JC et al. https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

SUMMARY COMMENTS

• In patients with non-severe

disease, and as part of multi- component therapy, HCQ may:

• Be associated with shorter

durations of fever and cough

• Be associated with

radiographic improvement

• Inadequate data to comment on

impact of HCQ on viral RNA shedding

Gautret P and Lagier JC et al. https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CARDIAC TOXICITY NOTES

• Most cardiac toxicity occurs with high cumulative dose (>100 grams)
• For inpatients, ACC advises (partial list):
• If QTc increases by >60 msec or absolute QTc >500 msec (or >530 in

patients with QRS >120 msec), consider stopping HCQ

• Relative contraindications
• History of long QT syndrome
• Baseline QTc >500 msec (or >530 in patients with QRS >120 msec)
• High-dose CQ (600 mg BID x10d) arm of Brazil study stopped owing to

25% (7/28) patients developing QTc >500 ms

• Also received azithromycin + ceftriaxone; 90% received oseltamivir

Chatre C et al. Drug Saf. 2018;41(10):919-931. https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment- for-covid-19. Accessed 13 April 2020. Borba M et al. https://www.medrxiv.org/content/10.1101/2020.04.07.20056424v1 Accessed 13 April 2020.

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CLINICAL TRIALS

• Use of HCQ for inpatients:
• AIDS Clinical Trial Group (ACTG) 5396
• Overall study PI and JHH PI: Dick Chaisson, MD
• JHH co-PI: David Sullivan, MD
• Use of HCQ for outpatients:
• AIDS Clinical Trial Group (ACTG) 5395
• JHH PI: Kelly Dooley, MD, MPH, PhD
• In lieu of a clinical trial, see the JHMI Clinical Guidance for Available

Pharmacologic Therapies for COVID-19

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

HYDROXYCHLOROQUINE/CHLOROQUINE KEY POINTS

• Several examples of discordant in vitro and in vivo data for chloroquine
• r hydroxychloroquine and viruses
• In patients with non-severe disease, and as part of multi-component

therapy, HCQ may:

• Be associated with shorter durations of fever and cough
• Be associated with radiographic improvement
• Inadequate data to comment on impact of HCQ on viral RNA shedding
• Immunomodulatory benefits vis-à-vis SARS-CoV-2 unknown
• If any benefit, starting early likely important

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

REMDESIVIR, LOPINAVIR/RITONAVIR, DAS181 KEY POINTS

• Remdesivir has biological plausibility and in vitro data to support its

candidacy as a SARS-CoV-2 therapeutic agent

• Most promising antiviral agent
• Clinical trial data forthcoming
• Lopinavir/ritonavir has minimal supportive in vitro data in SARS-CoV-2;

may be efficacious in SARS-CoV, MERS-CoV

• Current clinical data does not support its candidacy as a SARS-CoV-2

therapeutic agent

• Clinical trial data forthcoming
• DAS181 has biological plausibility as a SARS-CoV-2 therapeutic agent
• Clinical trial data forthcoming

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

CLINICAL QUESTIONS FROM THIS CASE

• HCQ started on Day 12
• Improved 6 days later
• Did HCQ facilitate clinical improvement?
• Unknown
• What is the evidence in support other antiviral therapeutic agents that

have been used/studied in COVID-19?

• Remdesivir has promise but clinical data needed
• Lopinavir/ritonavir less promising
• Chloroquine/hydroxychloroquine possible but current data not

sufficient

COVID-19 GRAND ROUNDS

JOHNS HOPKINS DIVISION OF INFECTIOUS DISEASES

• 1. Describe in vitro data of Remdesivir as a SARS-CoV-2 therapeutic agent
• 2. State current clinical trials of Remdesivir
• 3. Describe in vitro data of Lopinavir/ritonavir as a SARS-CoV-2 therapeutic

agent

• 4. Discuss clinical trial data of Lopinavir/ritonavir as a SARS-CoV-2 therapeutic

agent

• 5. State the biologic plausibility for Chloroquine/Hydroxychloroquine as SARS-

CoV-2 therapeutic agents

• 6. Describe in vitro data of Chloroquine/Hydroxychloroquine as a SARS-CoV-2

therapeutic agent

• 7. Discuss clinical trial data of Chloroquine/Hydroxychloroquine as a SARS-CoV-

2 therapeutic agent

OBJECTIVES