Beyond Injecting Drug Use: HCV Transmission among Men who have Sex with Men

Transcription

1 Beyond Injecting Drug Use: HCV Transmission among Men who have Sex with Men HIV Congress 2014 Mumbai Associate Professor Joe Sasadeusz Royal Melbourne and Alfred Hospitals

2

3 Issues Epidemiology Clinical presentation Natural history Therapy Reinfection

4 Background HCV is traditionally regarded as parenterally transmitted and not thought of as being efficiently sexually transmitted According to prospective cohort studies, sexual transmission in monogamous heterosexual relationships varies between 0-0.6%/year 1,2,3,4,5 No recommendation for safe sex practices 1.Tahan Am J Gastro 2005, 2. Chayama Vandelli Am J Gastro 2004, 3. Piazza Arch Intern Med 1997, 4. Boonyard J Gastroenterol Marincovich. Sex Transm Infect. 2003

5 Epidemiology Outbreaks of acute HCV in HIV+ MSM who deny IDU reported since 2000 in Europe, USA, Canada and Australia Majority related to per mucosal transmission rather than parenteral risks Molecular clock phylogentic analysis suggests emergence of MSM-specific strains after 1996 Van der Laar et.al. AIDS. 2010; 24: , Danta et.al. AIDS 2007; 21:983-91, van der Laar.et.al. Gastroenterology. 2009; 136:

6 HCV Incidence from 12 HIV cohorts in CASCADE collaboration /1000py /1000py /1000 py /1000 py Van der Helm JJ. et.al. AIDS 2011;25:

7 Epidemiology Increase in HCV coincident with Introduction of cart Rise in sexual risk behaviour and STIs Probably related to: Increased longevity of HIV-infected individuals Larger population at risk Increased sexual behaviour Serosorting Stolte et.al. AIDS 2004; 18: Van der Laar et.al. AIDS. 2010; 24: , Danta et.al. AIDS 2007; 21:983-91, van der Laar.et.al. Gastroenterology. 2009; 136:

8 No increase in HIV negative MSM Retrospective review of MSM attending STI clinic in Amsterdam 1 HIV +: X10 fold increase : 0.08/100 py : 0.87 HIV neg: no cases in 7807 person years HCV prevalence in Sydney MSM % in HIV neg, same as background population X 10 lower than HIV+ MSM (9.39%) 1. Van der Laar TJ et.al. JID. 2007; 196: 230-8, 2. Jin F et.al. Sex Transm Infect. 2009; 86: 25-28

9 Transmission Risk Factors Serosorting Behaviour HIV Traumatic practices: UAI Fisting, Toys Group sex Disrupted barrier + HCV exposure = HCV transmission Biological susceptibility Non IDU Drug use STIs esp. Ulcerative Adapted from Danta and Rodger Curr Opin HIV AIDS. 2011; 6 : 451-8

10 HIV Biological Factors and Transmission Increased infectivity HCV viral loads ~ 1 log 10 higher 1 HCV in semen Can be detected in 38% HCV + individuals 2 One study suggests more common in HIV+ 3 Another study failed to detect HCV RNA in semen of most HIV+ men, even in acute infection (11% acute Vs 20% chronic) but no comparison to HIV neg 4 1. Sherman KE et.al. Gastroenterology. 2005; 128: Briat AIDS 2005, 4. Turner. 2nd BHIVA/BASHH Conf Abstract O5.

11 HIV Biological Factors and Transmission Immunological susceptility Humoral responses to HCV delayed in acute infection 1 Delayed seroconversion HIV results in impaired HCV specific CMI responses, even at CD4 >500 cells/ul 2 Higher rate of persistent viraemia? Role of loss of GALT 1. Thomson AIDS. 2009; 23: Danta J Infect Dis :

12 Immune Responses to Acute Infection Danta J Infect Dis :

13 RAMPT-C Study Overwhelmingly, men were quite unaware of the possibility of sexual transmission Garrett Prestage. Kirby Institute. Personal Communication

14 Melbourne Cohort: Clinical Presentation Indications for HCV testing (n=31) Abnormal liver function tests 28 Symptoms/signs hepatitis (e.g. jaundice) 3 Drug and alcohol screen 1 STI screen 3 Annual screen as per HIV guidelines 3 Multiple indications 7 Mahoney et.al. Med J Aust 2013; 198 (4):

15 Characteristics of newly acquired HCV-HIV coinfection cases in Victoria, April 2010 June 2011 Characteristics (n=31) Age at HCV diagnosis, median (range) 42 years (26-57 years) Metropolitan versus rural residence (%) 27 (87%) v 4 (13%) Australian versus overseas birthplace (%) 27 (87%) v 4 (13%) Time from HIV to HCV diagnoses, median (range) 22 months (2 months 17 years)* Median CD4+ lymphocyte cell count at Dx 535 cells/μl (25%) Median HIV viral load at Dx Number of cases reporting IDU ever (%) 12 (39%) Number of cases reporting sexual contact with a known HCV-positive partner (%) Mahoney et.al. Med J Aust 2013; 198 (4): <50 copies/ml Range (<50 - >100,000 copies/ml) 10 (32%)

16 Management

17 Acute HCV in HIV - Predicting Clearance n = 92 Clearance Chronic HCV Predictive value prvc 22 3 PPV 88% No prvc 4 23 NPV 85% cevc 32 4 PPV 89% No EVC 2 23 NPV 92% Vogel Abstract # 640, 17th CROI, 2010 prvc =>2log 10 drop after 4 weeks cevr = <600 IU after 12 weeks

18 Sustained Virologic Response in Chronic HCV Suppl Table 1 Naggie and Sulkowski M, Gastroenterology 2012; 142:

19 Treatment Outcomes of Acute HCV in HIV-infected persons Rockstroh, J. AIDS 2011; 25 (4):

20 When do you Lose the benefit of Acute Treatment?

21 When do you Lose the benefit of ATAHC Study HIV coinfection subset of 27/103 patients, 22 treated Advised to wait at least 12 weeks post Dx Median estimated duration of HCV infection of 30 weeks Overall 80 % SVR Acute Treatment? 77% <24 weeks (acute) 86% > 24 weeks (early chronic) One study in HCV monoinfection suggested 100% SVR if Rx started at 8w Vs 53% >1 yr post diagnosis (p = 0.006) 2 1. Matthews. Clin Infect Dis. 2009; 48: Nomura Hepatology. 2004; 39:

22 Reinfection

23 Reinfection 56 HIV+ MSM acutely infected with HCV in Amsterdam Treated with Peg/RBV 24 weeks HCV PCR negative at end of treatment Definition of reinfection: subsequent HCV PCR positive with: Different genotype Same genotype but different clade on phyolgenetic sequencing Median follow up 1.3 years (IQR ) 21 evaluated by behavioural data Lambers. AIDS (15) : F21-7

24 Reinfection 5 relapsed 11 reinfections Incidence 15.2/100-person years (95% CI ) Median time to reinfection 8.4 m (IQR ) Reinfections (n=7) more likely to engage in non IDU recreational drug use than non reinfections (n=14) but no difference in sexual behaviour Lambers. AIDS (15) : F21-7

25 Lambers. AIDS (15): F21-7 Reinfection

26 Cumulative HCV reinfection Reinfection - Royal Free Cohort Follow up period (years) Sasadeusz. et.al J Hepatol Suppl.1 P s466 Abstract # 1179

27 Conclusions 1 Significant change in epidemiology of HCV, now an STI with permucosal transmission Most cases involve combinations of traumatic sex, ulcerative STIs and non IDU recreational drugs Limited to HIV+ MSM, HIV probably plays an important role Most cases subclinical, need to annually screen atrisk patients

28 Conclusions 2 Treatment is highly effective, window of opportunity Education of HIV-infected patients and their practitioners There is a high reinfection rate with poor immunity conferred by prior infection Need to modify high-risk sexual and recreational drug behaviour? Is this an issue in Indian HIV patients

29 Thank You

30 Molecular Epidemiology Phylogenetic analysis showed monophyletic clusters of HCV within MSM in major cities in England, France, Netherlands and Germany 1, 2, 3 International collaborative study confirmed presence of one large European-wide MSM-specific transmission network linking previously documented outbreaks in London, Paris, Amsterdam and Berlin 3 Risk factors suggest a sexual network, distinct strains from IDU Australian outbreak very limited overlap with overseas outbreaks 1. Danta M et.al. AIDS 2007; 21: Serpaggi J et.al. AIDS. 2006; 20: van de Laar. et.al. Gastroenterology ; 136:

31 IDU is still the Predominant Driver of HCV in HIV Individuals EuroSIDA Cohort Overall 33% HIV infected individuals are anti HCV positive Mode od HIV acquisition in anti HCV+: 6.6% MSM 77.5% IDU Consistent with other studies Rockstroh JK et.al. JID.2005; 192:

32 Natural History of Infection Thomson et.al. Gut. 2011; 60:

33 Natural History of Acute HCV Infection - T Cell Responses Thomson et.al. Gut. 2011; 60:

34 Acute Hepatitis C - Clinical Aspects Definition: arbitrarily first 6 months post exposure Lack of evidence when it becomes chronic Difficult to determine precise timing of infection Majority asymptomatic Clinical Dx has low sensitivity Occasional jaundice 1/3 to 1/2 have symptoms but usually non specific Often picked up due to regular LFTs on ART HCV PCR positive as early 1 week while anti-hcv+ is often delayed

35 Time to Seroconversion Median CD4 570 /ul No correlation with seroconversion 75% neg at 1 st detectable PCR 37% neg at 3 months 10% neg at 9 months 5 % neg at 12 months Thomson AIDS. 2009; 23:89-93 * Spontaneous clearance

36 Natural History of Acute Infection 112 patients with HIV and acute HCV at St Mary s, London 102 chronic HIV /acute HCV 10 acute HIV / acute HCV Prospectively followed monthly for 3 months then 3 monthly for median 45 months (IQR 29-69) Viral load T cell responses Phylogenetic analysis Offered Peg/RBV at 12 weeks 26 untreated Thomson et.al. Gut. 2011; 60:

37 Natural History of Acute Infection N=17 N=53 N=42 Thomson et.al. Gut. 2011; 60:

38 Natural History of Infection Thomson et.al. Gut. 2011; 60:

39 Natural History of Acute HCV Infection 13/42 FV patients became transiently HCV PCR negative (LLOD 12 IU/ml) HCV specific T cell responses at baseline were significantly higher in SC compared to: PV (415 Vs 115 SFU, p=0.005) FV (415 Vs 59 SFU, p=0.04) Patients with FV more likely to have superinfecting strains Vs PV (63 Vs 29%, p=0.04) Thomson et.al. Gut. 2011; 60:

40 Acute HCV -Predicting Clearance 54 patients with AHC diagnosed clinically HCV monoinfection Spontaneous clearance 2/24 (8%) if HCV RNA >600 IU/ml at 12 weeks 0/16 if HCV RNA >600 IU/ml at 16 weeks Chronic infection 3/17 (18%) if HCV RNA <600 IU/ml at 12 weeks Gerlach. Gastroenterology. 2003; 125: 80-88

41 ATAHC study HIV coinfection subset of 27/103 patients, 22 treated Advised to wait at least 12 weeks post Dx Estimated duration of HCV: 6 weeks before onset symptoms or peak ALT (>400 U/ml) OR mid point between last negative and first positive anti-hcv Median estimated duration of HCV infection of 30 weeks Overall 80 % SVR 77% <24 weeks (acute) 86% > 24 weeks (early chronic) One study in HCV monoinfection suggested 100% SVR if Rx started at 8w Vs 53% >1 yr post diagnosis (p = 0.006) 2 1. Matthews. Clin Infect Dis. 2009; 48: Nomura Hepatology. 2004; 39:

42 Demographics MSM aged in 30s and 40s From large urban centres in Europe, Australia and USA Usually well controlled HIV Usually not IDUs Table 1 from below Matthews GV et.al.. CID. 2011; 52:803-11

43 Demographics Matthews GV et.al.. CID. 2011; 52:803-11

44 Demographics Matthews GV et.al.. CID. 2011; 52:803-11

45 Transmission Risk Factors Swiss cohort 1 Unsafe sex and syphilis serology associated with HCV acquisition Limited data on specific sexual behaviours Cross sectional study in a London HIV clinic, only fisting remained associated by MVA 2 Cross sectional study in Amsterdam STI clinic 3 HIV infection, IDU, fisting and non IDU drug use (esp. GHB) independently associated with infection 1.Rauch Clin Infect Dis 2005, 2. Turner Sex Transm Dis 2006, 3. Urbanus AIDS 2009,

46 Risk Factors - Case Control Studies Prospective case control study in England of 60 cases and 130 controls investigated sexual risk factors and drug use in acute HCV 1 Univariate analysis associated with HCV transmission: UAI, fisting, rimming, sadomasochistic practices, sex toys and group sex Multivariate analysis associated with HCV transmission: Only group sex with receptive/insertive UPAI and/or receptive/insertive fisting only variable independently associated OR 9.2 if 2 practices OR 23.5 if at least 3 practices 1. Danta AIDS Lifeetime 2007 STIs

47 Risk Factors - Case Control Studies Case control study in Germany involving 34 cases and 67 controls1. Rectal trauma with bleeding, frequent receptive fisting without gloves (or gloves shared), intranasal drugs significant by MVA Hx STI preceding 12m 56% cases vs 31% controls Most cases report combinations of risk factors, highly correlated Can also be seen if only UPAI 2,3 1. Schmidt et.al. PLOS one. 2011; 6 (3): Danta AIDS Rockstroh AIDS 2011; 25: ,

48 Preferred Definitions of Acute HCV HCV Ab seroconversion within last 12 months Detectable HCV PCR with neg anti-hcv and negative HCV PCR in prior 12 months Alternative Detectable HCV PCR and ALT > X10 ULN or >X5 ULN with documented NALT within 12 months No alternative cause of acute hepatitis Rockstroh. NEAT Consensus Conference, AIDS :

49 Therapy

50 Sustained Virologic Response in Coinfection Suppl Table 1 Naggie and Sulkowski M, Gastroenterology 2012; 142:

51 When do you Lose the benefit of Acute Treatment?

52 Reinfection - Royal Free Cohort 61 patients with acute HCV March 2003-December 2007 Reinfection: defined as detectable HCV RNA following SVR or spontaneous clearance 41 patients achieved either 16 (39%) reinfected Median 46 months post initial infection (range months) Reinfection rate of 9.4 (95% CI: 4.8, 14.0)/100 person-years. One patient had 2 reinfections Sasadeusz. J Hepatol Suppl.1 P s466 Abstract # 1179

53 Coinfection: HIV and viral hepatitis Prevalence of HIV/HBV and HIV/HCV coinfection in AHOD Exposure category HIV/HBV (%) HIV/HCV (%) MSM (n=1159, 1236) MSM + IDU (n=92, 102) IDU (n=33, 36) Heterosexual (n=136, 142) Other/Unknown (n=171, 174) Total (n=1605, 1704) Lincoln et al HIV Med 2003

54 Spontaneous Clearance Prospective cohort study of 919 individuals followed for spontaneous clearance (SC) 90 individuals with SC compared with 722 with persistent infection Multiple logistic regression model more frequent SC in: Non blacks (Adj OR 5.15 ; 95% CI ) HIV uninfected (Adj OR 2.19 ; 95% CI ) 14% Vs 7% Thomas. JAMA.2000; 284: 450-6

55 IL28B SNPS are the only common variants associated w spontaneous clearance : Swiss / German collaborative cohort 1362 individuals, 448 were co-infected with HIV N = 347 spontaneous clearance N = 1015 persistent infection IL28B was the only gene region identified to be associated with spontaneous clearance using a genome wide approach Rauch, Kutalik,et al. Gastro, (4):

56 IL28B and Spontaneous Clearance : Rauch, et al. Gastro, (4):

57 van der Laar. AIDS 2010; 24: Acute HCV - Therapy

58 Monotherapy Vs Combo? Cumulative experience 1 SVR in 12/25 mono Vs 96/159 combo (p>0.05) Serpaggi study 2 : 10 treated 7 IFN, 2 IFN +RBV, 1 PEG 0/10 SVR One study of 12 patients with Gt 1/4 treated with PEG mono reported 50% didn t achieve EVR 3 ATAHC showed improved HCV RNA kinetics in HIV+ patients given RBV Vs HIV- given PEG mono 4 1. Rockstroh. AIDS.2011; 25: Serpaggi AIDS. 2006;20: Arends. ICAAC Abstract H-22, 4. Matthews EASL Abstract # O 60.

59 Cumulative Incidence of Reinfection 33% after 2 years (95% CI 16-50) Lambers. AIDS (15) ahead of print

60 Screening recommendations All HIV+ MSM with STI should be screened for HCV with repeat screening at 3 months All HIV individuals with active IDU to be screened every 3 months NEAT consensus conference. AIDS 2010; 25:

61 Modelling of cost-effectiveness

62 RAMPT-C Study Overwhelmingly, men were quite unaware of the possibility of sexual transmission Garrett Prestage. Personal Communication

63 Background 1 HCV is traditionally regarded as parenterally transmitted and not thought of as being efficiently sexually transmitted According to prospective cohort studies, sexual transmission in monogamous heterosexual relationships varies between 0-0.6%/year 1,2,3,4,5 No recommendation for safe sex practices 1.Tahan Am J Gastro 2005, 2. Chayama Vandelli Am J Gastro 2004, 3. Piazza Arch Intern Med 1997, 4. Boonyard J Gastroenterol Marincovich. Sex Transm Infect. 2003

64 Background 2 Outbreaks of acute HCV in HIV+ MSM who deny IDU reported since 2000 Europe, USA, Canada and Australia Majority related to mucosal rather than parenteral risks Several studies show that after introduction of cart in 1996, HCV incidence increased from 1-3 to >10 /1000 person years Molecular clock analysis suggests emergence of MSMspecific strains after 1996 Van der Laar et.al. AIDS. 2010; 24: , Danta et.al. AIDS 2007; 21:983-91, van der Laar.et.al. Gastroenterology. 2009; 136:

65 Molecular Epidemiology Phylogenetic analysis showed monophyletic clusters of HCV within MSM in major cities in England, France, Netherlands and Germany International collaborative study confirmed presence of one large European MSM-specific transmission network linking outbreaks in London, Paris, Amsterdam and Berlin Australian outbreak very limited overlap with overseas outbreaks van de Laar. et.al. Gastroenterology ; 136:

66 Risk Factors Swiss cohort 1 Unsafe sex and positive syphilis serology associated with HCV acquisition Limited data on specific sexual behaviours Cross sectional study in a London HIV clinic, only fisting remained associated by MVA 2 Cross sectional study in Amsterdam STI clinic 3 HIV infection, IDU, fisting and non IDU drug use (esp. GHB) independently associated with infection 1.Rauch Clin Infect Dis 2005, 2. Turner Sex Transm Dis 2006, 3. Urbanus AIDS 2009,

67 Risk Factors - Case Control Studies Case control study in England investigated sexual risk factors and drug use in acute HCV 1 Associated by MVA with mucosal traumatic sexual techniques, esp. in group sex and/or non IDU drug use Case control study in Germany 1. Rectal trauma with bleeding, frequent receptive fisting without gloves (or gloves shared), intranasal drugs significant by MVA Most cases report combinations of risk factors, highly correlated Can also be seen if only UPAI 1,3 1. Danta AIDS Rockstroh AIDS 2011; 25: , 2. Schmidt et.al. PLOS one. 2011; 6 (3): 1-9

68 Biological Factors and Transmission Increased infectivity HCV viral loads higher 1 HCV in semen Can be detected in HCV + individuals 2 One study suggests more common in HIV+ 3 Another study failed to detect HCV RNA in semen of most HIV+ men, even in acute infection 4 Increased susceptibility Humoral responses to HCV delayed in acute infection 5 HIV results in impaired HCV specific CMI responses, even at CD4 >500 cells/ul 6 May also be related to decreased GIT mucosal immunity 7 1. Cribier AIDS 1995; 9 ( ). 2001; 8: Briat AIDS 2005, 4. Turner. 2nd BHIVA/BASHH Conf Abstract O5. 5. Thomson AIDS. 2009; 23: Danta J Infect Dis :

69 Natural History

70 Spontaneous Clearance Prospective cohort study of 919 individuals followed for spontaneous clearance (SC) 90 individuals with SC compared with 722 with persistent infection Multiple logistic regression model more frequent SC in: Non blacks (Adj OR 5.15 ; 95% CI ) HIV uninfected (Adj OR 2.19 ; 95% CI ) Thomas. JAMA.2000; 284: 450-6

71 Immune Responses to Acute Infection Danta J Infect Dis :

72 Acute Hepatitis C - Clinical Aspects Definition: arbitrarily first 6 months post exposure Lack of evidence when it becomes chronic Difficult to determine precise timing of infection Majority asymptomatic Clinical Dx has low sensitivity Occasional jaundice 1/3 to 1/2 have symptoms but usually non specific Often picked up due to regular LFTs on ART HCV PCR positive as early 1 week while anti-hcv+ is often delayed

73 Melbourne Cohort: Presentation Indications for HCV testing (n=30): abnormal liver function tests (LFT) 28 symptoms/signs of hepatitis (eg. jaundice) 3 drug & alcohol screen 1 STI screen 3 annual screen as per HIV guidelines 2 (multiple indications for 7 cases) A. Mahoney. ASHM 2011.

74 Time to Seroconversion Median CD4 570 /u No correlation with seroconversion 75% neg at 1 st detectable PCR 37% neg at 3 months 10% neg at 9 months 5 % neg at 12 months Thomson AIDS. 2009; 23:89-93 * Spontaneous clearance

75 Preferred Definitions of Acute HCV HCV Ab seroconversion within last 12 months Detectable HCV PCR with neg anti-hcv and negative HCV PCR in prior 12 months Alternative Detectable HCV PCR and ALT > X10 ULN or >X5 ULN with documented NALT within 12 months No alternative cause of acute hepatitis Rockstroh. NEAT Consensus Conference, AIDS :

76 Natural History of Acute Infection 112 patients with HIV and acute HCV at St Mary s, London 102 chronic HIV /acute HCV 10 acute HIV / acute HCV Prospectively followed monthly for 3 months then 3 monthly for median 45 months (IQR 29-69) Viral load T cell responses Phylogenetic analysis Offered Peg/RBV at 12 weeks 26 untreated Thomson et.al. Gut. 2011; 60:

77 Natural History of Acute Infection N=17 N=53 N=42 Thomson et.al. Gut. 2011; 60:

78 Natural History of Infection Thomson et.al. Gut. 2011; 60:

79 Natural History of Acute HCV Infection 13/42 FV patients became transiently HCV PCR negative (LLOD 12 IU/ml) HCV specific T cell responses at baseline were significantly higher in SC compared to: PV (415 Vs 115 SFU, p=0.005) FV (415 Vs 59 SFU, p=0.04) Patients with FV more likely to have superinfecting strains Vs PV (63 Vs 29%, p=0.04) Thomson et.al. Gut. 2011; 60:

80 IL28B SNPS are the only common variants associated w spontaneous clearance : Swiss / German collaborative cohort 1362 individuals, 448 were co-infected with HIV N = 347 spontaneous clearance N = 1015 persistent infection IL28B was the only gene region identified to be associated with spontaneous clearance using a genome wide approach Rauch, Kutalik,et al. Gastro, (4):

81 IL28B and Spontaneous Clearance : Rauch, et al. Gastro, (4):

82 When do we Know that a Patient is Unlikely to Clear?

83 Acute HCV - Predicting Clearance Clearance Chronic HCV Predictive value prvc 22 3 PPV 88% No prvc 4 23 NPV 85% cevc 32 4 PPV 89% No EVC 2 23 NPV 92% Vogel Abstract # 640, 17th CROI, 2010 prvc =>2log 10 drop after 4 weeks cevr = <600 IU after 12 weeks

84 Therapy

85 Therapy in Chronic HIV-HCV Coinfection Study n Regimen SVR (%) ACTG Peg 2a 180 vs IFN 2a 6/3 + RBV W 27 Vs 12 RIBAVIC 412 Peg 2b 1.5 Vs IFN 2b 3 + RBV W APRICOT 868 Peg 2a 180 Vs IFN 2a 3 +/- RBV W 26 Vs Vs 20 vs 12

86 van der Laar. AIDS 2010; 24: Acute HCV - Therapy

87 Monotherapy Vs Combo? Cumulative experience 1 SVR in 12/25 mono Vs 96/159 combo (p>0.05) Serpaggi study 2 : 10 treated 7 IFN, 2 IFN +RBV, 1 PEG 0/10 SVR One study of 12 patients with Gt 1/4 treated with PEG mono reported 50% didn t achieve EVR 3 ATAHC showed improved HCV RNA kinetics in HIV+ patients given RBV Vs HIV- given PEG mono 4 1. Rockstroh. AIDS.2011; 25: Serpaggi AIDS. 2006;20: Arends. ICAAC Abstract H-22, 4. Matthews EASL Abstract # O 60.

88 When do you Lose the benefit of Acute Treatment?

89 ATAHC study HIV coinfection subset of 27/103 patients, 22 treated Advised to wait at least 12 weeks post Dx Estimated duration of HCV: 6 weeks before onset symptoms or peak ALT (>400 U/ml) OR mid point between last negative and first positive anti-hcv Median estimated duration of HCV infection of 30 weeks Overall 80 % SVR 77% <24 weeks (acute) 86% > 24 weeks (early chronic) One study in HCV monoinfection suggested 100% SVR if Rx started at 8w Vs 53% >1 yr post diagnosis (p = 0.006) 2 1. Matthews. Clin Infect Dis. 2009; 48: Nomura Hepatology. 2004; 39:

90 Reinfection

91 Reinfection 56 HIV+ MSM acutely infected with HCV in Amsterdam Treated with Peg/RBV 24 weeks HCV PCR negative at end of treatment Definition of reinfection: subsequent HCV PCR positive with: Different genotype Same genotype but different clade on phyolgenetic sequencing Median follow up 1.3 years (IQR ) 21 evaluated by behavioural data Lambers. AIDS (15) ahead of print

92 Reinfection 5 relapsed 11 reinfections Incidence 15.2/100-person years (95% CI ) Median time to reinfection 8.4 m (IQR ) Reinfections (n=7) more likely to engage in non IDU recreational drug use than non reinfections (n=14) but no difference in sexual behaviour Lambers. AIDS (15) ahead of print

93 Reinfection Lambers. AIDS (15) ahead of print

94 Cumulative Incidence of Reinfection 33% after 2 years (95% CI 16-50) Lambers. AIDS (15) ahead of print

95 Reinfection - Royal Free Cohort 61 patients with acute HCV March 2003-December 2007 Reinfection: defined as detectable HCV RNA following SVR or spontaneous clearance 41 patients achieved either 16 (39%) reinfected Median 46 months post initial infection (range months) Reinfection rate of 9.4 (95% CI: 4.8, 14.0)/100 person-years. One patient had 2 reinfections Sasadeusz. J Hepatol Suppl.1 P s466 Abstract # 1179

96 Cumulative HCV reinfection Reinfection - Royal Free Cohort Follow up period (years) Sasadeusz. J Hepatol Suppl.1 P s466 Abstract # 1179

97 RAMPT-C Study Overwhelmingly, men were quite unaware of the possibility of sexual transmission Garrett Prestage. Personal Communication

98 Conclusions 1 Significant change in epidemiology of HCV, now an STI with permucosal transmission Most cases involve combinations of traumatic sex, ulcerative STIs and non IDU recreational drugs Limited to HIV+ MSM, HIV probably plays a critical role Treatment is highly effective, window of opportunity

99 Conclusions 2 Most cases subclinical, need to annually screen at-risk patients with anti HCV There is a high reinfection rate with poor immunity conferred by prior infection Need to follow up with regular PCR post eradication Education of HIV-infected patients and their practitioners Need to modify high-risk sexual and recreational drug behaviour? Issue of repeated therapy

100 Thank You

101 Natural History of Infection Thomson et.al. Gut. 2011; 60:

102 Natural History of Acute HCV Infection - T Cell Responses Thomson et.al. Gut. 2011; 60:

103 Background 3 Coincident with rise in sexual risk behaviour and STIs? Related to perceived decreased threat of HIV/AIDS in cart era Role of sero-sorting HCV prevalence in HIV-neg MSM who deny IDU is comparable to general population Van der Laar et.al. AIDS. 2010; 24: , Danta et.al. AIDS 2007; 21:983-91, van der Laar.et.al. Gastroenterology. 2009; 136:

104 Treatment outcomes of acute HCV in HIV-infected persons Boesecke et.al. Current Opinion in HIV & AIDS. 2011; 6(6):

105 Acute HCV -Predicting Clearance 54 patients with AHC diagnosed clinically HCV monoinfection Spontaneous clearance 2/24 (8%) if HCV RNA >600 IU/ml at 12 weeks 0/16 if HCV RNA >600 IU/ml at 16 weeks Chronic infection 3/17 (18%) if HCV RNA <600 IU/ml at 12 weeks Gerlach. Gastroenterology. 2003; 125: 80-88