Progression of the disease. Heiner Wedemeyer

Transcription

1 Progression of the disease Heiner Wedemeyer

2 Disclosures Honoraria for consulting or speaking (last 5 years): Abbott, Abvie, Biolex, BMS, Boehringer Ingelheim, Eiger, Gilead, ITS, JJ/Janssen-Cilag, Medgenics, Merck/Schering- Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV Research grants: Abbott, Abbvie, BMS, Gilead, Merck, Novartis, Roche, Roche Diagnostics, Siemens

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4 The hepatitis B-associated disease burden is increasing! Mortality due to HBV 2013 ~ HBV-Cirrhosis Mortality Increase 36% GBD-Study: Lancet Jan 2015 HBV-HCC Mortality Increase 51% Cowie et al.: EASL 2015

5 The hepatitis C-associated disease burden is increasing! GBD-Study: Lancet Jan 2015 HCV-Cirrhosis Mortality Increase 68% Cowie et al.: EASL 2015 Mortality due to HCV 2013 ~ HCV-HCC Mortality Increase 292%

6 Cumulative mortality (%) Cumulative mortality (%) HCV-Infection is associated with an increased mortility from extrahepatic diseases! The REVEAL HCV Cohort Study adults, Taiwan 1095 anti-hcv positive; 69.4% with detectable HCV RNA HCV seropositive, HCV RNA detectable HCV seropositive, HCV RNA undetectable HCV seronegative Hepatic diseases p<0.001 for comparison among three groups p<0.001 for HCV RNA detectable vs undetectable 12.8% 1.6% 2 0.7% Extrahepatic diseases p<0.001 for comparison among three groups p=0.002 for HCV RNA detectable vs undetectable 19.8% 12.2% 11.0% Follow-up (years) Follow-up (years) Lee M-H et al. J Infect Dis 2012;206:

7 Modeling Acute Hepatitis Spontaneously Cured Chronic Hepatitis F0 Chronic Hepatitis F1 Chronic Hepatitis F2 Chronic Hepatitis F3 Compensated Cirrhosis Hepatocellular Carcinoma Decompensated Cirrhosis Liver Related Death Liver Transplantation Razavi H, Waked I, Sarrazin C, et al. J Viral Hepat 2014; 21 Suppl 1:

8 HCC, decompensated cirrhosis and transplant Germany, England, France and Spain Razavi et al., J of Viral Hepatitis 2014

9 Which factors determine disease progression in viral hepatitis? Does disease progression differ between countries? What determines disease progression after viral control / viral cure?

10 Deaths attributable to chronic liver disease by underlying cause as a proportions of all-case mortality in 2013 Cowie et al., EASL 2015

11 HCV Prevalence and Genotype Distribution Europe Ireland United Kingdom Norway Denmark Sweden Finland Hungary Czech Republic Slovakia Poland Lithuania Latvia France Switzerland Germany Austria Netherland s Belarus Russia Serbia Romania Belgium Luxembourg Georgia Estonia Prevalence (Viremic) 0.0%-0.6% 0.6%-0.8% 0.8%-1.3% Total Infected (Viremic) 0-200K 200K-650K 650K-1.9M Turkey Armenia 1.3%-2.9% 2.9%-7.8% 1.9M-3.5M Portugal Spain Italy Greece Slovenia Croatia Bosnia & Herzegovina Montenegro Albania Macedonia Gower, E., Estes C., Hindman, S., Razavi-Shearer, K., Razavi, H., Journal of Hepatology (2014) 11

12 HBV Genotypes in Central and Eastern Europe Deterding et al., J Med Virol 2008

13 Migration and viral hepatitis courtesy of Dr Carballo

14 High HBV prevalence in immigrant populations in Germany Screening of 1313 patients in a private GP practice Anti-HCV prevalence: 1.9% Heidrich et al., EJGH 2014

15 Which factors determine disease progression in viral hepatitis? Does disease progression differ between countries? What determines disease progression after viral control / viral cure?

16 Interindividual Variability in acute hepatitis C 50-80% 20-50% 80-90% asymtomatic chronic hepatitis C symptomatic clearance 20-50% % 1-7%/year liver cirrhosis hepatocellular carcinoma

17 Phases of HBV Infection Immune Tolerant Immune Activation Immune Control Immune Escape HBeAg+ HBeAg HBV-DNA cp/ml cp/ml ALT treatment? Treatment No treatment Treatment HBeAg + chronic Hepatitis B Inactive-Carrier Status HBeAg chronic HBV

18 Which patients are at risk to develop clinical complications?

19 Risk for (Cirrhosis, HCC) Which patients are at risk to develop clinical complications?

20 Risk for (Cirrhosis, HCC) Which patients are at risk to develop clinical complications? Virus HBeAg HBV-DNA qhbsag Genotype Pre-C/BCP Mutations HCV genotype Distinct mutations?

21 Cumulative Mortality HCV genotype 3 infections are associated with highest mortality rates GT3 no SVR GT2 no SVR GT1 no SVR GT1, 2 & 3 SVR Backus et al., Clin Gastroenterol Hepatol 2011

22 Markers to differentiate phases of HBV infection HBV core-related antigen levels as a new tool? Higher Risk for reactivation? Maasoumy, Cornberg et al., CMI 2015

23 Risk for (Cirrhosis, HCC) Which patients are at risk to develop clinical complications? Virus Host HLA-Types KIR IL28B PNLPA3 Age Gender Obesity

24 A risk score based on 7 genetic variants to predict fibrosis progression in hepatitis C Trepo et al., J Hepatol 2011

25 Development of Endpoints: Age matters! HCC 2 years after HBsg loss Jaroszewicz, Cornberg et al., AVT 2011 HBsAg loss after 12 years of therapy

26 Early loss of HBsAg is very important (before the age of 50?) Risk of HCC After HBsAg Loss Follow-up (month) Yuen Disease et Progression al., Gastroenterology 2008

27 Risk for (Cirrhosis, HCC) Which patients are at risk to develop clinical complications? Virus Environmental Factors Host

28 Coffee consumtion reduces the risk to develop HCC in heptitis B virus infection Jang et al., Liver Internationl 2013; 38

29 One of the most challenging problems viral hepatitis: Hepatitis Delta! Calle-Serrano et al., Sem Liver Disease 2013

30 Hepatitis delta takes a more severe long-term course than HBV mono-infection HDV/HBV HBV Manesis et al., J Hepatol 2013

31 BEA-Score to determine the risk for disease progression in hepatitis delta Barcelona: n=77 Düsseldorf: n=58 M. Homs, M. Buti et al. Calle Serrano et al. J Viral Hepatitis 2014 A. Erhardt et al.

32 Which factors determine disease progression in viral hepatitis? Does disease progression differ between countries? What determines disease progression after viral control / viral cure?

33 HBV

34 Improvement of liver fibrosis during long-term anitiviral treatment (here: Entecavir) Stage 6 Stage 6 Stage 2 Baseline Week 48 Week 268 Chang TT, et al. Hepatology 2010

35 Reversion of hepatitis B cirrhosis in 74% of patients on TDF N=96 patients with cirrhosis and paired biopsies Treatment 5 Years with Tenofovir Higher BMI Marcellin et al., Lancet Feb 9;381(9865):

36 Improved survival in patients responding to therapy after an episode of hepatic decompensation Jang et al., Hepatology 2015 epub

37 Probability of event % Virological response is associated with a lower probability of disease progression Hazard Rate: 0.29, 95% CI No virological response Virological response (<80 IU/mL) 10 p = Time at risk (weeks) Zoutendijk et al. Gut 2013

38 Cumulative Development Rates of HCC (%) Virological response is associated with a reduced risk to develop HCC Cumulative Development Rates of HCC (%) Log-rank test: P < Cirrhosis 38.9% Control Log-rank test: P = No Cirrhosis # at Risk ETV Control Treatment Duration (Years) % 2.6% % 4.3% % 7.0% % ETV # at Risk ETV Control Treatment Duration (Years) % 1.0% % 1.6% % 0.8% % 2.5% Control Hosaka et al. Hepatology 2013

39 Greatest benefit of therapy in younger patients (including patients without cirrhosis!) Wu et al. Gastroenterology 2014

40 Risk for HCCs is reduced in successfully treated patients - But HCCs may still develop! age gender platelets cirrhosis Papatheodoridis et al. J Hepatol 2015

41 HCV

42 Patients (%) Reversal of liver cirrhosis in patients successfully treated for hepatitis C A F4 F3 F2 F Before Therapy Post Therapy Ambrosio et al., HEPATOLOGY, Vol. 56, No. 2, 2012

43 SVR is associated with reduced liver-related and all cause mortality! ALL CAUSE MORTALITY LIVER RELATED MORTALITY Van der Meer AJ, et al. JAMA 2012

44 Patients with advanced fibrosis who clear HCV infection have a survival similar to the general population! Recoverd patients Non-SVR Patients Van der Meer et al., JAMA 2014

45 Survival of patients not treated with an IFNa-based regimen?

46 The German LOTOS-Study SVR Patients after IFNa Non-SVR to IFNa treatment Untreated (No IFNa) Clinical effect of IFN-free therapies??

47 HCV Effects of IFN-free therapies

48 Improvement of liver function parameters after IFN-free cure of HCV infection - Analysis of the TURQUOISE-II trial data up to 48 wks after SVR12 Improvement of liver function Improvement of non-invasive fibrosis markers Wedemeyer et al., EASL 2015, P0808

49 Change in MELD Score SOLAR-2: MELD Score Change From Baseline to Follow-up Week 4 Pre/Post-Transplant (CPT B and C, n=136*) (8) n=18 (-17) (-11) *Missing FU-4: n=24. Manns et al, G02, EASL

50 Improvement of liver function parameters in advanced cirrhosis: The Hannover Cohort Albumin Prothrombin time Deterding et al., AP&T 2015

51 Improvement of liver function parameters in advanced cirrhosis: The Hannover Cohort Bilirubin Cholinesterase Deterding et al., AP&T 2015

52 Improvement of liver function parameters in advanced cirrhosis: The Hannover Cohort Changes in MELD Scores baseline-fu-week 12 Deterding et al., AP&T 2015

53 in Viral Hepatitis Summary Heterogeneity of disease progression in different countries and settings should be considered for action plans Successful antiviral therapy reduces liverspecific and overall morbidity and mortality Long-term effects of antiviral therapies need to be investigated in more detail (adaptation of models required?)