Auditori Josep Carreras

Hospital Germans Trias i Pujol

Virtual CROI 2020 Badalona, 17 de Març de 2020

Novedades en el CROI 2020 sobre el SARS-

CoV-2 (COVID19), una pandemia
Dr. José Mª Miró
Infectious Diseases Service
Hospital Clinic - IDIBAPS
University of Barcelona
Barcelona (Spain)
E-mail address: jmmiro@ub.edu
 Abstracts at CROI 2020
 Accepted, 1081 (53%) – Europe 23%
- Oral, 102 (9%)
SARS-CoV-2
- Poster, 979 (91%)
 Hepatitis, 33 (3%)
(COVID19)
 Tuberculosis, 13 (1%)
 Cryptococcal meningitis 5 (<1%)
 CMV, other OIs and IRIS, 16 (1.5%)
 STI, 55 (5%)
COVID19 (SARS-CoV-2) at CROI 2020
 Coronavirus History
 Current Epidemiology
 The Virus & Pathogenesis
 Clinical Manifestations & Diagnosis
 Prognosis
 Treatment & Prevention
 Take-home messages
Human Coronaviruses (HCoVs)
▪ Common HCoVs (lower pathogenicity):
– HCoV-229E (alpha)
– HCoV-NL63 (alpha) Mild Respiratory
– HCoV-OC43 (beta) Infections
– HCoV-HKU1 (beta)

▪ XXI Century HCoVs (higher pathogenicity):

– SARS-CoV (beta)
– MERS-CoV (beta)

Lai & Holmes, Fundamental Virology, 4th Edition 2001.

https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it
SARS-CoV & MERS-CoV Emergence in XXI Century

China
R0 ≈ 1.8-2.5

Middle
East
R0 ≈ 0.3-1.3

www.who.int access on 2020 Jan 21st

Coronavirus are found in Bats all over the world

Anthony et. al. A strategy to estimate unknown viral diversity in mammals. 2013 mBio. Photo: EcoHealth Alliance
Seven Human Coronaviruses (HCoVs)
▪ Common HCoVs (lower pathogenicity):
– HCoV-229E (alpha)
– HCoV-NL63 (alpha)
– HCoV-OC43 (beta)
– HCoV-HKU1 (beta)

▪ XXI Century HCoVs (higher pathogenicity):

– SARS-CoV (beta)
– MERS-CoV (beta)
– SARS-CoV-2* (beta) The illness COVID-19 is caused by SARS-CoV-2,
which is more like SARS-CoV than MERS-CoV
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it
A seafood market in Wuhan, China the probably source
of an outbreak of a novel Coronavirus (COVID19)

Normile D. Science. Jan. 3, 2020 , 10:35 AM

Geo-temporal Spread of COVID-19 in China
(Retrospectively)
By symptom onset date and reporting
January 10, province
A December 31, 2019
14 counties in 1 province
2020
C January 20, 2020
B 113 counties in 20 provinces D January 31, 2020
627 counties in 30 provinces 1,310 counties in 31 provinces E February 12, 2020
1,605 counties in 31 provinces

No. of confirmed cases

China CDC Weekly 2020; 2:113-122

Widespread rapid dissemination in our hyper-connected
world creates real-time challenges to prediction analyses
COVID19 (SARS-CoV-2) at CROI 2020
 Coronavirus History
 Current Epidemiology
 The Virus & Pathogenesis
 Clinical Manifestations & Diagnosis
 Prognosis
 Treatment & Prevention
 Take-home messages
 SARS-CoV-2 Global Cases (CSSE, JHU)

Overall mortality 4%
- Italy 8%
- Spain 3.5%
- Catalonia 1.3%

https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6; accessed on March 17th 2020 at 09:30 h

SARS-CoV-2 Transmission – R0 ≈ 3 (2.4-3.8)
▪ Respiratory secretions – Main mode of transmisión (person to person spread)
– Infection is spread through respiratory droplets in the air (2 m.) and that land on surfaces
– Transmission from persons who are pre-symptomatic is possible. Recent studies suggested
than the rate is around 50% of cases
– Transmission after curation is also possible. WHO recommends isolation measures at least
two additional weeks

▪ Stool – oral-fecal transmission seems unlikely

– Readily detectable by RT-PCR but only one report of replication-competent virus cultured

▪ Perinatal – no transmission yet observed

– Not detected by RT-PCR in amniotic fluid, cord blood, neonatal throat swab, breast milk
Zou 2020, N Engl J Med; DOI: 10.1056/NEJMc2001737. Pan 2020 , Lancet Infect Dis; https://doi.org/10.1016/S1473-3099(20)30113-4.
Zhang 2020; China CDC Weekly: http://weekly.chinacdc.cn/en/article/id/ffa97a96-db2a-4715-9dfb-ef662660e89d. Chen 2020; Lancet: https://doi.org/10.1016/
S0140-6736(20)30360-3 Zhu 2020l Transl Pedtr: http://dx.doi.org/10.21037/tp.2020.02.06; Bai et al JAMA, 2020, Feb 21; Tapiwa 2020, medRxiv
https://doi.org/10.1101/2020.03.05.20031815 WHO March 16th 2020
COVID19 (SARS-CoV-2) at CROI 2020
 Coronavirus History
 Current Epidemiology
 The Virus & Pathogenesis
 Clinical Manifestations & Diagnosis
 Prognosis
 Antiviral Treatment & Prevention
 Take-home messages
Drivers of Coronavirus (CoV) Evolution

Baric RS, CROI, Boston, MA 2020

 Phylogenetic Analysis of SARS-CoV-2 among Betacoronavirus

2019-nCoV=2019 novel coronavirus. MERS-CoV=Middle East respiratory syndrome coronavirus.

SARS-CoV=severe acute respiratory syndrome coronavirus. Lu R et al, Lancet 2020; 395: 565–74
SARS-CoV-2 (COVID19) Genome
Enveloped RNA virus with a genome size of 32 Kb

Spike (S) in
the prefusion
conformation

SARS-CoV-2

De Wit Nature Rev Microbiol, 2016; Zhou P et al, Nature, 2020; Wrapp D et al, Science. 2020
 SARS-CoV-2 (COVID19) Life Cycle
It uses ACE2 for viral entry
(angiotensin-converting enzyme 2)

ACE2

Viral particles in the ultrathin sections were

imaged using electron microscopy at 200
kV. The sample was from virus-infected
Vero E6 cells. The inset shows the viral
particles in an intra-cytosolic vacuole

De Wit Nature Rev Microbiol, 2016; Zhou P et al, Nature, 2020 and bioRxiv, 2020.01.22.914952; Yan R et al. Science. 2020.
SARS-CoV-2 (COVID19) Pathogenesis: ARDS

ACE2

Acute Respiratory Distress Sydrome (ARDS) pathology

Acute diffuse alveolar damage, with pulmonary edema and
formation of a hyaline membrane in a SARS-CoV patient
The airspaces are indicated by asterisks and some of the hyaline membranes lining the alveolar
spaces are highlighted by arrows (hematoxylin and eosin stain; original magnification,x100).

Tse GMK et al. J Clin Pathol 2004;57:260–265

 Schematic representation of SARS CoV infection mediating acute lung injury
through angiotensin-converting enzyme (ACE) and ACE2 signaling pathways.

1) SARS CoV binds to ACE2 causing

downregulation of ACE2 through
internalization of this membrane-
bound protein and leading to viral
replication in the cytoplasm.
2) ACE2 inactivates AT II. AT II binds
the angiotensin II receptor 1a
(AT1aR), leading to tissue damage
and lung edema, or it binds the
angiotensin II receptor 2 (AT2R)
reducing tissue damage.

Hendrickson CM et al. Semin Respir Crit Care Med 2013;34:475–486.

COVID19 (SARS-CoV-2) at CROI 2020
 Coronavirus History
 Current Epidemiology
 The Virus & Pathogenesis
 Clinical Manifestations & Diagnosis
 Prognosis
 Treatment & Prevention
 Take-home messages
Incubation period 5 days (range 2-14 days).

We estimated that fewer than 2.5% of infected persons will

display symptoms within 2.2 days (CI, 1.8 to 2.9 days) o
exposure, whereas symptom onset will occur within 11.5
days (CI, 8.2 to 15.6 days) for 97.5% of infected persons

Lauer SA et al. Ann Intern Med. 2020. doi:10.7326/M20-0504.

Signs/Symptoms of COVID-19 in China
▪ No particular set of signs or symptoms can reliably discriminate SARS-CoV-2 from
other respiratory viral illnesses such as influenza
– Subacute to acute onset
– Non-productive cough
– Fever or “feverish” (often low-grade or not initially measurable)
– Some reports of isolated diarrhea alone preceding cough and fever
▪ Most people will recover spontaneously with supportive care
▪ Complications include pneumonia, respiratory failure, multiorgan system failure
▪ Children tend to have milder disease than adults.

Liu 2020, Chinese Med J; DOI: 10.1097/CM9.0000000000000744. Wang 2020, JAMA; doi:10.1001/jama.2020.1585.
Guan 2020, N Engl J Med; DOI: 10.1056/NEJMoa2002032. Chen 2020, Lancet; https://doi.org/10.1016/S0140-6736(20)30211-7
COVID-19 cases by Sex and Age in China
F M
Median age 47 yr.
20-79 yr., 94%
Females 42%

China CDC/NHC 2020

Common Symptoms of COVID-19 in China

19230 Confirmed cases with detailed epidemiological investigation information

China CDC/NHC 2020

Underlying Medical Conditions of COVID-19 in China

No changes antihypertensive drugs

Hypertension Diabetes Cardiovascular Lung Disease

disease

19230 Confirmed cases with detailed epidemiological investigation information

China CDC/NHC 2020

Chest X-ray and CT findings in SARS-CoV-2

Guang W et al. NEJM 2020; DOI: 10.1056/NEJMoa2002032

Complications of COVID-19 in China

Guang W et al. NEJM 2020; DOI: 10.1056/NEJMoa2002032

Illness Severity COVID-19 in China

Mild Severe
81% 14%
44,672
Critical
patients
5%

Mortality 2.5%
adapted from Zhang China CDC Weekly Report; 2020, 2(8):113-122.
Virology of SARS-CoV-2
• Virus shedding is highest early in the course of disease
(vs. SARS shedding, which peaks at least 5 days after onset)
• Virus shedding can occur in the 24-48 hours prior to symptom
onset
• Virus can be isolated from stool but there is no epidemiologic
evidence of fecal-oral transmission
• Virus shedding usually continues for 7-12 days in mild/moderate
cases, and for more than 2 weeks in severe cases
• Patients who recover can be PCR positive after symptoms resolve
Aylward B et al, WHO-China Mission, 2020
Viral Shedding Greatest At Time Symptoms Start
▪ SARS-CoV-2 viral loads in 17 symptomatic patients
▪ No data regarding duration of replication-competent virus shedding (e.g., culture)

Zou et al., N Engl J Med, 2020; DOI: 0.1056/NEJMc2001737

SARS-CoV-2 Distribution and Shedding Patterns Among
20 Hospitalized Patients

The specimen with a cycle threshold value

above the dashed line is interpreted as positive
fo SARS-CoV-2 RNA; those under, negative.

Wang W et al. JAMA 2020 on line.

COVID19 (SARS-CoV-2) at CROI 2020
 Coronavirus History
 Current Epidemiology
 The Virus & Pathogenesis
 Clinical Manifestations & Diagnosis
 Prognosis
 Treatment & Prevention
 Take-home messages
 Clinical Prognosis and Recovery in China

96%
81%
10-15% Moderate

15-20%
14%
5%
4%*

* ≈50% of deaths (1023/2087) among critically ill patients Huang C et al. Lancet. January 24, 2020 https://doi.org/10.1016/
Aylward B et al, WHO-China Mission, 2020
Age Distribution and Case Fatality Rate COVID-19
China through 11-Feb-2020 (N = 44,672 confirmed cases)
30.0% 20.0%
Fraction of total cases Case fatality rate
25.0% 16% 16.0%
Percent of total cases

Case fatality rate

20.0%
12.0%
15.0% 8%
8.0%
10.0%
4%
5.0% 2% 4.0%

0.0% 0.0%
0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 ≥ 80
Age, years
adapted from Zhang 2020, China CDC Weekly Rep; 2(8):113-122.
 In-hospital Mortality Prognostic factors
Temporal changes in laboratory markers from
illness onset in hospitalized patients
D-dimer Lymphocyte

IL-6 Ferritin

 Age (per yr.): 1.10 (1.03-1.17)

hsTroponin LDH

 SOFA score: 5.65 (2,61-12,23)

 D-dimer >1 µg/mL: 18.42 (2.64-128)
Zhou F et al. Lancet, March 9, 2020 https://doi.org/10.1016/
COVID19 (SARS-CoV-2) at CROI 2020
 Coronavirus History
 Current Epidemiology
 The Virus & Pathogenesis
 Clinical Manifestations & Diagnosis
 Prognosis
 Treatment & Prevention
 Take-home messages
 SARS-CoV-2 life cycle: Potential targets for antivirals
Neutralizing Antibodies?

ACE2 inhibitors?
ACE2
Ribavirin
Chloroquine
Interferon-beta*

Lopinavir/rtv Potential for

combining several
antiviral drugs
Remdesivir

* Interferon induces hundreds of genes which can act on various parts of the lifecycle
from potentially degrading viral RNA (OAS, RNASL) to inhibiting virus egress (BST-2) De Wit Nature Rev Microbiol, 2016; Sheahan TP, personal communication.
 Hydroxychloroquine
 Endosome-mediated viral entry and replication of enveloped viruses interactions
 Two potential beneficial mechanisms
- In vitro: Hydroxychloroquine (HCQ) is more active than chloroquine (CQ)
- Anti-inflammatory properties, stopping production IFN, TNF, IL6, IL1 (ARDS)
 Dosage: 400 mg/12 h first day, then 200 mg/12 h 14 days oral route.
SARS-CoV-2

Savarino A et al. Lancet Infect Dis 2003; 3: 722–27; Yao X et al.Clin Infect Dis; 2020, on line.
The in vitro activity of chloroquine against SARS-CoV-2

Wang M et al. Cell Research; 2020. 30:269–271.

 Lopinavir/ritonavir (Kaletra®)
 Protease inhibitor. Coronavirus encodes two cysteine proteases
 Effective in vitro and in animal models against SARS-CoV and MERS-CoV.
 Synergy with interferon-β1b (MIRACLE trial)
 Limited clinical experience. Used as PEP (post-exposure prophylaxis).
 Important drug-drug interactions (DDI).
 Dosage: 400/100 mg 12 h during 14 days by oral route.

LPV/rtv 400/100 mg
Cmax 157 µM/L

De Wilde AH et al. AAC; 2014; Chan JFW et al. JID 2015; Arabi YM et al. Trials, 2018; Park SY et al. JHI, 2019;
 Lopinavir/ritonavir (Kaletra®)
Change in SARS- Treated group (N=6)
CoV viral load in Do all HIV-1 protease inhibitors
nasopharyngeal have cross-activity against
swabs
SARS-CoV-2?

Historical control group (N=12)
Darunavir/cobicistat*
- In vitro SARS-CoV-2 inhibition at 300 µM
- 800/150 Median Cmin 3.4 µM
→ Different viral proteases: SARS-CoV-2
has a cysteine protease and HIV-1 a dimeric
aspartate protease. Darunavir has low
affinity with the catalytic center of the SARS-
CoV-2 protease active site.

Chu CM et al. Thorax 2004;59:252–256; *Janssen Newsletter, March 16th 2020.

 Remdesevir (GS-5734)
 RNA-dependent RNA polymerase inhibitor.
 Effective in vitro and in animal models against zoonotic and epidemic
SARS-CoV and MERS-CoV as both prophylactic and therapeutic agent.
 Limited clinical experience. Several RCT are underway
 No drug-drug interactions (DDI).
 Dosage: 200 mg IV, then 100 mg/24 h during 5-10 days.

Sheahan TP et al. Sci Transl Med, 2017; De Wit ET al. Proc Natl Acad Sci U S A, 2020; Sheahan TP et al. Nat Commun; 2020.
Remdesivir (RDV) is superior to Lopinavir/ritonavir (LPV/RTV)
Therapeutic RDV but not LPV/RTV-IFNb diminishes signs of Acute Lung Injury

Sheahan TP et al. Nat Commun; 2020.

Remdesevir: RCT in Hospitalized Patients

*Stratified by disease severity at enrollment. Baric RS. CROI 2020 Boston, MA.
 Interferons
 Effective in vitro and in vivo against SARS-CoV and MERS-CoV.
 Synergy with ribavirin and lopinavir/ritonavir
 Some clinical experience mainly in MERS-CoV.
 Dosage: Interferon-β1b 250 mcg/48 h SC during 14 days
Interferon-α2b 100,000-400,000 UI/kg nebulized BID during 5-7 days

Sheahan TP et al. Nat Commun; 2020.

 Corticosteroids
 Effective for treating ARDS (Meta-Analysis and RCT)
 Increased mortality in influenza-related pneumonia and ARDS.
 Pulse-therapy may be beneficial in SARS-CoV and MERS-CoV but no RCT.
 Increased plasma viremia and delayed clearance in a RCT.
Early corticosteroids
Early corticosteroids

Placebo
Placebo

 Preliminary good results with IL-6 antagonists (Tocilizumab). RCTs are underway.
Ho JC, AJRCCM, 2003; Sung JJY, Thorax, 2004; Lau ACW, Respirology, 2004; Lee N, JCV, 2004; Rabaan AA, JMM, 2017; Arabi YM,
AJRCCM, 2018, Sun S, ETM 2019; Zhou Y, Sci Rep, 2020; Villar J, Lancet RM, 2020; Xu X, 2020.
Personal Treatment Regimen in Moderate-Severe
SARS-CoV-2 Pneumonia
 Consider in all patients above 50 years
 Treat early (initial peak viremia) and hard (combination therapy ≠targets).
Remdesevir ARDS
+
Hydroxychloroquine Early pulse
+ corticosteroids
Lopinavir/ritonavir or
+/- Tocilizumab
Interferon
Miro JM, 2020.
 Prevention
 At personal level
- Avoid close contact sick people
- Wash hands with soap & water

→ Antivirals for prevention in close contacts www.cdc.gov/handwashing

- RCTs with hydroxychloroquine ± lopinavir/ritonavir

 At population level
- Aggressive approach to delay transmission
- Implementation of public health measures

 Coronavirus Vaccines Community mitigation measures

CDC & ECDC; 2020.
China is using fundamental public health measures…

• Universal population measures zero cases

• Case isolation & management

Sporadic
cases
• Close contact quarantine
Clusters
of cases
• Suspension of public gatherings
Community
• Movement restrictions transmission

Aylward B et al, WHO-China Mission, 2020

Recommendations for People with HIV
▪ Ensure ample medication supply
– 90-days supply at all times
▪ Keep vaccinations up to date
– Influenza, pneumococcal
▪ Establish plan for clinical care if isolated/quarantined
– Telemedicine options
– Physician on-line portals
▪ Maintain a social network but remotely
– Social contact helps us stay mentally
healthy and fights boredom
 March 16th, 2020

→ Multiple SARS-CoV-2 vaccine candidates being pursued

by >30 organizations globally
COVID19 (SARS-CoV-2) at CROI 2020
 Coronavirus History
 Current Epidemiology
 The Virus & Pathogenesis
 Clinical Manifestations & Diagnosis
 Prognosis
 Treatment & Prevention
 Take-home messages
 Take-home Messages
 We are facing a pandemic of colossal challenges
 SARS-CoV-2 is a new coronavirus with high infectivity (R0=3). Cause mild or
moderate respiratory infection in 80% of cases. Up to 20% of patients will develop
a serious infection that can require ICU admission. Mortality in ICU patients is
50%. Older age is the most important prognostic factor.
 Treat early and hard. Remdesivir is the most powerful antiviral agent. Clinical
trials that are being carried out will determine which is the best antiviral regimen.
 Case isolation, contact tracing and personal and population prevention
measures should contain the epidemic.
 SARS-CoV-2 vaccine studies are already started. An effective vaccine will be
key to controlling the infection in the future.
 Acknowledgements
R.S. Baric
F. Garcia
G. Mora
A. Moreno
C. Sierra
M. Tuset
Z. Wu
J.T. Brooks A.S. Fauci T.P. Sheahan To my colleagues
CDC, Atlanta NIH, Bethesda UNC, Chapel Hill To our patients

http://www.croiconference.org