Arevir meeting 2017 Reconstructing the HCV migration history to - - PowerPoint PPT Presentation

Reconstructing the HCV migration history to support public health efforts

Lize Cuypers

KU Leuven – University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology

Friday 5th May 2017

Arevir meeting 2017

Hepatitis C: the silent killer

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• Globally 80 million people currently infected
• Majority develops chronic infection: risk for liver-

associated diseases

• High genetic diversity: 7 genotypes, >50 subtypes

=> HCV1a, 1b and 3a most prevalent

Normal Liver Chronic Hepatitis Cirrhosis HCC

Adapted from Hepatitis C online

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From Cuypers L, et al. Rev Med Virol. 2016

Antiviral treatment: DAAs

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• Major evolution in the HCV antiviral treatment field
• Variants naturally produced or emerging under

therapy: resistance-associated substitutions (RASs)

2011 2013 2014 2015

2001

Telaprevir HCV GT1 Boceprevir S imeprevir S

• fosbuvir

Peg-IFNα + ribavirin Daclatasvir Ledipasvir Grazoprevir Elbasvir

S VR (% )

100 80 60 40 20

50-60 70-80 <30

IFN (+RBV)

83-96 89-100 Paritaprevir Dasabuvir Ombitasvir

IFN

DAA + IFN

2016

Velpatasvir 90-95 >95

DAAs

2017

ABT-493 + ABT-530 >95

NS3/4A protease inhibitors NS5A inhibitors NS5B polymerase inhibitors

In-depth phylogeography

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• Interpretation of impact RAS on DAA treatment

=> expanding sequencing efforts

• Temporal and geographical dimensions of

sequences to reconstruct the virus migration history => public health policy

• Bayesian phylogenetic inference:
• Ancestral reconstruction in time and its relation

with amino acid usage patterns

• Inferring patterns of spatial spread:

migration rates between locations

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Mapping the importance of NS3 variant Q80K in the current Italian HCV1a epidemic

NS3 RAS Q80K

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• High natural prevalence in HCV1a

(Cuypers et al. Viruses 2015 – Cuypers et al. Virus Evolution 2016)

• Interference with action of NS3/4A

protease inhibitor simeprevir

• High HCV burden in Italy
• Dataset: new Italian

sequences supplemented with data from Genbank

Adapted from European centre for disease control and prevention - From Cuypers L, et al. Rev Med Virol. 2016

Timing and origin Q80K

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• HCV1a variability: two clades - Q80K in clade I
• Single origin in US
• Introduction Q80K

in Italy: 1961.5

(95% HPD: 1957.6-1965.7)

• Similar migration

patterns in different clades

NS3 80

From Cuypers et al. BMC Evol Biol 2017

Clade I Q80K Clade II

Migration patterns

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• Seeding role of US to Italy and Europe
• Continental HCV1a circulation gained importance
• Italy exports to
• ther European

countries

• Within-Italy: no local sub epidemics for North,

Central and South Italy

From Cuypers et al. BMC Evol Biol 2017

Genotyping strategy Q80K in Italy

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• Both immigration and national circulation of NS3

variant Q80K fuel the Italian HCV1a epidemic

• Public health strategy: test all HCV1a infected

patients eligible for simeprevir based therapy for the absence of variant Q80K

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Frequent de novo introduction of HCV3a NS5A variant Y93H in Spain

Vrancken et al. Manuscript in preparation Vrancken, Cuypers, Pérez, et al. Frequent de novo generation of HCV3a resistance-associated subsitutions in Spain. 15th European Meeting on HIV & Hepatitis, Rome, Italy, June 2017. Poster #79

NS5A variant Y93H

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• HCV3a: difficult-to-treat and highly prevalent
• Therapy: NS5A + NS5B inhibitors => RAS
• NS5A and NS5B sequences: Spain + Genbank
• NS5A RAS Y93H
• verrepresented

in Spanish strains

• De novo generation on

external branches => Spain: ‘host-spot’ region of Y93H

Indian subcontinent as HCV3a origin

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• Earliest strains sampled in Pakistan, India and the

UK: around 1934 (95% HPD: 1909.3 - 1950.9)

• NS5A RAS A30L

dominant role in Pakistanian strains

• Other NS5A and NS5B

RASs no clear pattern

What not went in - cannot come out

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• Strengths and intensities of migration links between

locations (both countries and regions) vary between NS5A and NS5B data

European backbone Anglosphere backbone

Combined phylogeography

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• Spain acts as a sink for HCV3a: import from

Germany (NS5A) <-> UK (NS5B)

• Export from Spain towards Europe and Anglosphere
• NS5A – NS5B: different sample from the epidemic

<-> combined: complementary picture of migration

• Use data from multiple genomic regions (longer

fragments!) – need for broader sampling strategies

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Migration patterns of NS3 and NS5A RAVs in the European HCV1a epidemic

HCV1a European migration

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• Q80K study in Italy:
• sample size: number of taxa per country - number
• f European countries
• NS3: one fragment - poor phylogenetic signal
• HCV3a study in Spain:
• NS5A and NS5B: complementary picture
• what not went in, cannot come out: small sample

=> large European HCV1a study: taxa – countries => multiple regions: NS3 and NS5A

HCV1a European study NS3 – NS5A

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• Dataset compilation and QC: NS3 = 2514 taxa -

NS5A = 1957 sequences (with location and date)

• Prior estimation
• f the

evolutionary rate using full- genome strains

• Analyses ongoing

for NS3 and NS5A

Acknowledgments

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• Clinical and Evolutionary Virology – KU Leuven, Belgium

Anne-Mieke Vandamme Kristel Van Laethem Bram Vrancken

• Hepatology department UZ Leuven, Belgium

Frederik Nevens

• University Tor Vergata, Rome, Italy

Francesca Ceccherini-Silberstein - Lavinia Fabeni – Valeria Cento – Velia Chiara Di Maio

• San Cecilio University Hospital, Granada, Spain

Féderico Garcia – Ana Belen Perez

• Institute for Virology, University Cologne, Germany

Rolf Kaiser – Saleta Sierra-Aragon

• J.W. Goethe University Hospital, Frankfurt, Germany

Christoph Sarrazin

• Institute of Infection and Global Health, University of Liverpool, UK

Anna Maria Geretti, Apostolos Beloukas

• University College Dublin, Ireland

Martha Neary

• Pomeranian Medical University, Szczecin, Poland

Milosz Parczewski

• Clinical Microbiology, Egas Moniz Hospital, Lisbon, Portugal

Perpétua Gomes

• Central Research Institute of Epidemiology, Moscow, Russia

Vladimir Chulanov