Molecular Epidemiology of HCV infections in the Netherlands. Thijs van de Laar GGD Amsterdam

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1 Molecular Epidemiology of HCV infections in the Netherlands. Thijs van de Laar GGD Amsterdam 13 november 2008

2 13 november 2008 Molecular epidemiology of HCV 2 Molecular Epidemiology of HCV HCV - genetic varaibility: 7 genotypes 30-35% BRANCH LENGTH 89 subtypes 15-30% DISTANCE SCALE HCV 1c HCV 1a HCV 1a HCV 1b HCV genotype 1 Genetic diversity: Geographic origin Mode of transmission Timescale of spread BRANCH HCV 1b HCV 1b CC NODE HCV 4a BB HCV 4a AA HCV 4d 100 HCV 3a HCV 3a HCV 3a HCV 3b HCV genotype 4 HCV genotype 3 GBV-C To compare we need: BRANCH 100 GBV-C GBV-C GBV-C Flavivirus GBV-C Consensus region (NS5B) ROOT: non-flavivirus Unified classification system Simmonds et al. (2005) Hepatology; Salemi et al. (2002) J Mol Evol

3 13 november 2008 Molecular epidemiology of HCV 3 Molecular Epidemiology General population Injecting drug users (IDU) Men who have sex with men (MSM)

4 13 november 2008 Molecular epidemiology of HCV 4 General population HCV prevalence Estimated HCV prevalence ( %) Population Year Nr screened Prevalence Author Dutch population % Veldhuijzen A dam pregnant* % Urbanus A dam population % Baaten Arhem/Nijmegen % Slavenburg * Testing still ongoing

5 13 november 2008 Molecular epidemiology of HCV 5 HCV genotype distribution the Netherlands: Treatment (SVR) GT 1a/b : 50% difficult (50%) GT 2a/b : 10% good (90%) GT 3a/b : 30% good (90%) GT 4a/d : 10% intermediate (60%) Prevalent HCV infections BUT genotype distribution is dynamic 1a 1b 2a/b 3a 4a 4d N=179 Lanl N=81 Blood bank Van de Laar et al, 2005 N=351 Hospital De Vries et al., 2006

6 13 november 2008 Molecular epidemiology of HCV 6 Prevalent HCV infection general population Epidemiological profiles of HCV prevalent candidate donors Transmission route % Genotype* Blood products before % 1b + 2a/b + (1a)* IDU-related 21% 3a + 1a + 4d Endemic countries 12% 4a + Other Other parenteral 19% mix No risk 18% 1b + 2a/b *Incidental spillover from high risk groups to he general population Van de Laar et al. (2006) Transfusion

7 13 november 2008 Molecular epidemiology of HCV 7 Incident HCV infection general population Transmission route Patient Genotype* Occupational/Health care F, 35 yrs 1b Nosocomial/Hospitalisation (B) M, 55 yrs Untyped Sexual/household F, 42 yrs 3a (partner ex-idu) Sexual/household F, 56 yrs 3a (partner ex-idu) Sexual/household F, 40 yrs RNA-negative * Incidental spillover (from high risk groups) to he general population through mostly non-parenteral modes of transmission Van de Laar et al. (2006) Transfusion

8 13 november 2008 Molecular epidemiology of HCV 8 Spread general population Screening of donorblood (1992): - Donor selection - HCV serology and HCV-RNA Estimated residual risk in NL ( ): - 1: donations (negligle) Incidental spillover high-risk populations Ongoing spread in dialysis centres ( ) Consequence: Genotype shift towards less HCV GT 1b and 2a/b Schneeberger (2000) JID, Pybus et al (2001) Science, Tanaka et al (2002) PNAS, Van de Laar et al (2006) Transfusion

9 13 november 2008 Molecular epidemiology of HCV 9 Injecting drug users (IDU) HCV prevalence (50-80%) GT-1a GT-3a IDU genotypes: 1a and 3a 1a: 3 separate introductions 3a: 1 single introduction Kok (2007) NTVG, Pybus et al (2005) IGE, Morice (2006) JMV

10 13 november 2008 Molecular epidemiology of HCV 10 Timescale - spread of HCV in Europe Two-phase epidemic: Steady state: west African origin Exponential growth: 1940 IDU Pybus et al (2002) Science; Pybus et al. (2005) Inf. Gen. & Evol.

11 13 november 2008 Molecular epidemiology of HCV 11 Injecting drug users ( ) Less injection drug use: impopularity Van den Berg et al (2007) J Eur Epidemiol : 90% DU < 30 yrs ever injected : 31% DU < 30 yrs ever injected HCV prevalence young DU: 83% 14% Safer injection: Harm reduction NEP combined with methadone treatment Larger window of intervention HCV prevalence young IDU: 91% 44% (30%) Van de Laar et al (2005) JMV; Van den berg et al. (2007) Addiction

12 B B november 2008 Molecular epidemiology of HCV 12 HCV strains young IDU Amsterdam B B AJ ref_1b A A ii A i A B a 1b INTRODUCTION 4d C03-DRU5 Y11604 ref_4a D86538 ref_4d 4 Genotype 1a(II) B C A D00825 ref_1a A A B A A A A i A C03-DRU8 A ii A D14308 ref_3a B B A AY ref_1a A A a 2 3a A A A AF ref_3a B A A A C01-DRU1 C A A C02-DRU10 A Genotype 3a A B B B A AF ref_1a A A A C00-DRU11 C01-DRU4 B D00944 ref_2a Subclade 1a(I) 0.1 B AB30907 ref_2b

13 13 november 2008 Molecular epidemiology of HCV 13 Injecting drug users (IDU) Diversification of HCV genotype 1a and 3a Introduction and spread of HCV genotype 4d Genotypic shift towards difficult-to treat genotypes (1 and 4) HCV incidence is low TREATMENT to decrease HCV reservoir further

14 13 november 2008 Molecular epidemiology of HCV 14 HCV treatment of IDU Cost-effective? What about HCV reinfection and superinfection?

15 13 november 2008 Molecular epidemiology of HCV 15 HCV reinfection and superinfection Reinfection protective immunity YES: Incidence of HCV reinfection < Incidence initial infection NO: Incidence HCV reinfection = incidence initial infection Amsterdam HCV seroconverter (SC) study 59 HCV seroconverters ( ) 5 time points per SC (RNA + viral typing) Frequency HCV reinfection and superinfection Mehta et al (2002) Lancet, Grebely et al. (2006) Hepatology, Micallef et al. (2007) J Vir Hepat, van de Laar (2008) unpublished

16 13 november 2008 Molecular epidemiology of HCV 16 Results: SC without viral clearance

17 18898 Jun90 Reinfection / Superinfection Figure 2 MULTIPLE HCV infections (41%) 1-4 HCV strains per IDU Reinfection with same HCV subtype Lack of immunological protection IDU 13925: 1a 4d 2b 4d IDU 18917: 1a 1a* 3a 1a* IDU 18934: 4a 1a 3a 1a* IDU 12962: 1b/4d 4d 1a IDU 14956: 1a 1a* 1b IDU 18787: 3a 1a 3a* IDU 18898: 1b 4d 1a IDU 12905: 1a 3a IDU 12959: 3a 1a IDU 12970: 3a 1a IDU 16786: 1a 3a IDU 16938: 3a 4d IDU 16941: 3a 3a* IDU 17889: 1a 3a IDU 18781: 4d 2a IDU 18796: 1a 3a IDU 18805: 1a 4d IDU 18822: 4d 1a Genotype 1a Jun Aug Oct Aug Feb May Oct Oct Jun94 * Oct Jan Jan May Mar Aug Feb Sep Sep Nov Jun Jun Mar Oct Sep Apr Aug Jun Sep May Oct Mar Oct Sep Oct Sep Aug Jan Oct Feb Jun Jun Jun Mar87 M a Mar Aug Oct Dec Nov Mar Jul Dec Oct Feb Oct Jun Oct Jun90 II I II Feb Mar Sep Jun Feb Oct Sep Jun Jan Jul Jan Mar Jul Nov Oct Jan Oct Oct May Sep Mar Jul Oct May Sep Jan Jan Aug Oct Aug04 III I III Genotype Genotype Genotype Apr Sep Aug Dec Oct95 D a D b Aug Feb Nov Mar Aug Jan May Sep Jul Aug Sep Apr90 D a Jan Oct Nov May May Feb Sep Jun Oct Jun Jan Feb Sep Jul Aug Mar Jan Jul Dec Jun Oct Jun Jul Feb Oct Oct91 * Jan Mar Nov Nov Aug Apr Jan Aug Dec Mar Aug Feb Jan Jul Aug Aug Feb Jul Feb Aug Oct Jul Apr Dec Jun Oct Feb Jun Mar Mar Sep Jan Feb Nov Jun Jul Apr Apr Apr Oct87A Jan88 IV IV Genotype 1b Nov Dec Nov Sep Oct87B Mar Jun05 D b Jun Nov Feb Jan Nov May Nov97 D d Y a Jul

18 13 november 2008 Molecular epidemiology of HCV 18 New risk groups: MSM Since 2000: Increased HCV-incidence among MSM in the UK. More case reports: The Netherlands (Ruijs 2004; Agtmael 2004; Götz 2005) France (Ghosn 2004; Gambotti 2005) Switserland (Rauch 2005) Germany (Vogel 2005) England (Gilleece 2005) Australia (Matthews, 2006) Figuur uit: Browne et al (2004) STI United States (Bateman, 2006)

19 13 november 2008 Molecular epidemiology of HCV 19 HCV incidentie MSM in NL Screening Amsterdam Cohort Studies : 0.8/1000 PY : 8.7/1000 PY Hospital notifications: (n=34) High risk sexual behavior HIV-positive (97%) Genotypes 1 en 4 (92%) Outbreak: MSM-specific HCV strains 10x S49-HospD-2006 S50-HospD-2006 S12-HospB-2004 S29-HospC-2005 S25-HospA-2004 S20-HospE-2004 S23-HospA S27-HospA-2003 S48-HospC-2006 S26-HospC-2004 M a P21-ACS S30-HospC-2005 S41-HospB-2005 P28-ACS-1988 S45-HospB-2003 H51-HospC-2006 S13-HospB-2005 S15-HospB-2005 S43-HospD-2005 S3-ACS-1996 S22-HospA S44-HospB S6-ACS-2001 S10-HospD-2004 D b 87 P11-ACS-1985 S11-HospD-2004 P18-ACS-1985 P27-ACS-1988 P9-ACS-1985 P10-ACS-1985 S1-ACS-1998 P22-ACS-1988 S39-HospB-2005 D a P16-ACS-1985 S16-HospB P26-ACS-1989 P29-ACS-1988 S7-ACS-2002 D d P2-ACS-1997 P7-ACS S4-ACS-2002 S32-HospA-2002 S33-HospA-2001 S5-ACS-2002 S8-ACS-2001 S31-HospA-2003 S40-HospD-2004 S19-HospD-2004 S17-HospC-2004 S18-HospC-2003 S37-HospB-2005 S14-HospB-2004 S21-HospE-2004 S28-HospC-2005 Cluster I, 1a } paar : genotype 1a Cluster II, 1a } paar : genotype 1a } paar: genotype 1b Cluster III, 4d van de Laar et al (2007) JID

20 13 november 2008 Molecular epidemiology of HCV 20 England: genotype 1a France: genotype 4d Danta et al (2001) AIDS Serpaggi et al (2006) AIDS,

21 13 november 2008 Molecular epidemiology of HCV 21 Sexual HCV transmission Incidental national outbreaks or large international transmission network?

22 13 november 2008 Molecular epidemiology of HCV 22 Clustering (85% of MSM) Clusters en Paren Genotype Country mixing Countries Cluster 1 n = 37 1a Cluster 2 n = 34 4d Cluster 3 n = 19 1a Cluster 4 n = 17 1a Cluster 5 n = 12 1a Cluster 6 n = 12 1a Cluster 7 n = 6 1a Cluster 8 n = 6 1a Cluster 9 n = 6 3a yes yes yes yes yes no yes no yes UK, NL UK, NL, D, F UK, NL, D UK, D UK, NL, D, AUS UK NL, D AUS UK, F Cluster 10 n = 4 1a no AUS Cluster 11 n = 4 1b no UK Paar A,B,C n = 6 1a no Paar D,E n = 4 Paar F n = 2 1b 3a no no

23 13 november 2008 Molecular epidemiology of HCV 23 Engeland Nederland Duitsland Frankrijk Australië

24 13 november 2008 Molecular epidemiology of HCV 24 Introduction and spread of HCV Cluster Genotype Nr. of sequences Year of origin (CI) Number (%) of divergence events since a ( ) 31(86) 29(81) 20(56) 2 4d ( ) 28(85) 26(78) 21(64) 3 1a ( ) 17(94) 16(89) 13(72) 4 1a ( ) 15(94) 14(88) 11(69) 5 1a ( ) 11(100) 10(91) 9(82) 6 4d ( ) 10(91) 8(73) 7(64) 7 1a ( ) 5(100) 5(100) 4(80) 8 1a ( ) 1(20) 1(20) 1(20) 9 3a ( ) 0(0) 0(0) 0(0) 10 1a ( ) 3(100) 3(100) 3(100)

25 13 november 2008 Molecular epidemiology of HCV 25 What causes this unexpected and rapid spread of HCV among HIV+ MSM? Virus versus behaviour

26 13 november 2008 Molecular epidemiology of HCV 26 HCV geïnfecteerde MSM Age CD4-count HAART IDU UK (n=107) % 17% NL (n=58) % D (n=24) % 4% F (n=12) % 0% AUS (n=24) % 50% Total % 14%

27 november 2008 Molecular epidemiology of HCV 27 Transmission Genotype 4 = MSM (SC after 2000) = MSM (SC before 2000) = Injecting drug users (IDU) = Immigrants UNique MSM-specific HCV strain of HCV genotype 4 distinct from the strain circulating among IDU S19-HospD-2004 S31-HospA-2003 S17-HospC-2004 S40-HospD-2004 S18-HospC-2003 S21-HospE-2004 S28-HospC-2005 S33-HospA-2001 S8-ACS-2001 S32-HospA-2002 S5-ACS-2002 S14-HospB S37-HospB-2005 S4-ACS-2002 Ams889-IDU-2005 Ams13-IDU-2001 P2-ACS-1997 Ams5-IDU-2003 Ams335-IDU-2000 Ams860-IDU-2005 Inn41-IDU-1991 Ams201-IDU-1992 Ams226-IDU-2004 Ams203-IDU-1990 Cas91-IDU-1997 Cas89-IDU-1998 Ali69-IDU-1997 Cas62-IDU-1998 Ali76-IDU-1997 Cas63-IDU-1998 Mar108-IDU-1990 Mar109-IDU-1990 Ams866-IDU-2005 Ams48-DON-1997 Ams60-DON-1999 Tur154-IDU-1993 P7-ACS-1985 Ams6-IDU-1989 Ams55-DON-1997 Ams91-DON-2002 Ams140-DU Ams51-DON Ams58-DON-1997 Ams37-IDU-2001 Ams65-DON-2000 Y11604 ref 4a D86537 ref 4d M62331 ref 1a Amsterdam Amsterdam Southern-Europe Amsterdam Rwanda Surinam Egypt MSM IDU Immigrant

28 13 november 2008 Molecular epidemiology of HCV 28 Case control studie: UK (Danta et al, AIDS 2007) control case P-waarde UAI (- ejaculation) 50% (p) 90% (p) % (a) 83% (a) UAI (+ejaculation) 35% (p) 83% (p) % (a) 58% (a) Rimming 77% (p) 98% (p) % (a) 92% (a) 0.03 Fisting 26% (p) 75% (p) % (a) 58% (a) Toys 43% 78% Group sex (>2pers) 53% 88% Partydrugs 71% 97%

29 13 november 2008 Molecular epidemiology of HCV 29 Rough sexual techniques Mucosal damage Shared use HAARToptimism SEX DRUG USE HIV? Groepseks Serosorting Internet STI Lower inhibitions Danta et al (2001) AIDS

30 13 november 2008 Molecular epidemiology of HCV 30 The role of HIV? Spread: 1) Increased susceptibility 2) Increased infectivity 3) HIV sersorting 4) Infectivity and background levels HIV vs HCV Clinical progression: 1) Higher rate of chronicity (> 90%) 3) Faster progression to liver disease 4) Lees favourable treatment outcome 5) Hepatotoxicity caused by HAART

31 13 november 2008 Molecular epidemiology of HCV 31 Update spread HCV among HIV+ MSM UK: HCV incidence among HIV+ increases 20% each year. 20 HCV incidence: HIV+ MSM GUM clinic Brighton HCV rare among HIV- MSM 15 HIV-/unk HIV+ Increase HCV incidence NOT caused 10 by intensified HCV screening 5 HCV prevalence STI-clinic A dam May 2007: 15% Nov 2007: 18% April 2008: 21% jaar Richardson et al (2008) JID, Giraudin et al (2008) STI

32 13 november 2008 Molecular epidemiology of HCV 32 HCV among HIV+ MSM current focus! Implement routine HCV screening in HIV positive MSM Early diagnostics: Early treatment and prevention of new cases Targeted education and prevention strategies to raise awareness of risks HCV among HIV+ MSM Monitor HIV-negative MSM! Are they at risk?

33 13 november 2008 Molecular epidemiology of HCV 33 Thanks Colleagues of Cluster Inefctious Diseases GGD Amsterdam Colleagues of Medical Micriobiology AMC Amsterdam HIV departments: OLVG, AMC, Slotervaart Hosp, VUMC International Collaboration on acute HCV in HIV+ MSM Erasmus MC and GGD Rotterdam Roel Coutinho RIVM Oliver Pybus University of Oxford VHPB Organising comittee