Arevir meeting Lize Cuypers

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1 Arevir meeting 2017 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 5 th May 2017

2 Hepatitis C: the silent killer Globally 80 million people currently infected Majority develops chronic infection: risk for liverassociated 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 2 From Cuypers L, et al. Rev Med Virol

3 Antiviral treatment: DAAs Major evolution in the HCV antiviral treatment field Variants naturally produced or emerging under therapy: resistance-associated substitutions (RASs) SVR (%) IFN DAA + IFN DAAs >95 > < IFN (+RBV) 2001 Peg-IFNα + ribavirin Telaprevir Boceprevir NS3/4A protease inhibitors HCV GT1 Simeprevir Sofosbuvir 3 Daclatasvir Ledipasvir Paritaprevir Dasabuvir Ombitasvir Grazoprevir Elbasvir NS5B polymerase inhibitors Velpatasvir ABT ABT-530 NS5A inhibitors

4 In-depth phylogeography 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 4 4

5 Mapping the importance of NS3 variant Q80K in the current Italian HCV1a epidemic 5

6 NS3 RAS Q80K 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

7 Timing and origin Q80K HCV1a variability: two clades - Q80K in clade I Q80K NS3 80 Single origin in US Introduction Q80K in Italy: (95% HPD: ) Clade I Similar migration patterns in different clades Clade II 7 From Cuypers et al. BMC Evol Biol 2017

8 Migration patterns Seeding role of US to Italy and Europe Continental HCV1a circulation gained importance Italy exports to other European countries Within-Italy: no local sub epidemics for North, Central and South Italy 8 From Cuypers et al. BMC Evol Biol 2017

9 Genotyping strategy Q80K in Italy 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 9

10 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 Poster #79 Frequent de novo introduction of HCV3a NS5A variant Y93H in Spain Vrancken et al. Manuscript in preparation 10

11 NS5A variant Y93H HCV3a: difficult-to-treat and highly prevalent Therapy: NS5A + NS5B inhibitors => RAS NS5A and NS5B sequences: Spain + Genbank NS5A RAS Y93H overrepresented in Spanish strains De novo generation on external branches => Spain: host-spot region of Y93H 11

12 Indian subcontinent as HCV3a origin Earliest strains sampled in Pakistan, India and the UK: around 1934 (95% HPD: ) NS5A RAS A30L dominant role in Pakistanian strains Other NS5A and NS5B RASs no clear pattern 12

13 What not went in - cannot come out Strengths and intensities of migration links between locations (both countries and regions) vary between NS5A and NS5B data European backbone 13 Anglosphere backbone

14 Combined phylogeography 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 14

15 Migration patterns of NS3 and NS5A RAVs in the European HCV1a epidemic 15

16 HCV1a European migration Q80K study in Italy: - sample size: number of taxa per country - number of 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 16

17 HCV1a European study NS3 NS5A Dataset compilation and QC: NS3 = 2514 taxa - NS5A = 1957 sequences (with location and date) Prior estimation of the evolutionary rate using fullgenome strains Analyses ongoing for NS3 and NS5A 17

18 Acknowledgments 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 18