HBV Therapy in Special Populations: Liver Cirrhosis Universitätsklinikum Leipzig Thomas Berg Sektion Hepatologie Klinik und Poliklinik für Gastroenterologie und Rheumatologie Leber- und Studienzentrum am Checkpoint, Berlin
Therapy of HBV cirrhosis compensated and decompensated disease 1. Who should be treated? 2. How treatment regimen? 3. Efficacy effect on long-term prognosis - Prevention of decompensation/ liver transplantation? - Regression of cirrhosis? 4. Predictors of response? 5. Safety
Actuarial Survival in HBV End Stage Liver Disease 100 Historical Comparisons 80 Patients surviving (%) 60 Cirrhosis 2 55% 40 20 Decompensated cirrhosis 3 14% 0 1 2 3 4 5 Years Perrillo et al., 2001 1, Weissberg et al., 1984 2, and De Jongh et al., 1992 3
Patients With End Stage Chronic Hepatitis B Treated with Lamivudine Median 4 2 Median Albumin (g/dl) 3.5 Bilirubin (mg/dl) 3 1.5 2.5 2 1 Baseline 52 104 n= 27 n=22 n=17 Weeks of Therapy Perrillo et al. Hepatology 2001
Actuarial Survival in HBV End Stage Liver Disease Historical Comparisons 100 Lamivudine in decompensated CHB 1 80 70% Patients surviving (%) 60 Cirrhosis 2 55% 40 20 Decompensated cirrhosis 3 14% 0 1 2 3 4 5 Years Perrillo et al., 2001 1, Weissberg et al., 1984 2, and De Jongh et al., 1992 3
NUCs - Lamivudine (LMV) and Entecavir (ETV) in decompensated HBV cirrhosis: predictors of survival 51 Hyun JJ et al. Liver Int 2012; 32: 656
NUCs - Lamivudine (LMV) and Entecavir (ETV) in decompensated HBV cirrhosis: predictors of survival Predictor 6 months mortality Sensitivity Specificity Child Pugh Score at Baseline 11 100% 75.6% MELD Score at months 3 17.5 100% 91% 51 Hyun JJ et al. Liver Int 2012; 32: 656
Patients on Waitlist, n Decline in the number of patients placed on the liver transplantation waiting list for hepatitis B-related indications in the US Kim WR. Hepatology 2009;49:S28-S34 500 450 400 350 300 250 Patients on the liver transplantation list due to: End-stage Cirrhosis HCC Acute Liver Failure HBV end-stage cirrhosis 200 150 100 HCC 50 0 1985 1990 1995 2000 2005 Year
EASL Clinical Practice Guideline Recommendations Patients with compensated cirrhosis and detectable HBV DNA must be considered for treatment even if ALT levels are normal (B1). Patients with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NUCs. Significant clinical improvement can be associated with control of viral replication. However, antiviral therapy may not be sufficient to rescue some patients with very advanced liver disease who should be considered for liver transplantation at the same time (A1). J Hepatol 2012; 57: 167
How to treat?
Antiviral potency Charakteristics of different HBV nucleos(t)id analogues Nucleosid analogue Nucleotid analogue LdT (Sebivo ) Lam (Zeffix ) ADV TDF ETV (Viread *) (Baraclude ) (Hepsera ) Genetic barrier
Lamivudine (LMV) vs. Entecavir (ETV) in decompensated HBV cirrhosis: Survival 51 Hyun JJ et al. Liver Int 2012; 32: 656
Lamivudine (LMV) vs. Entecavir (ETV) in decompensated HBV cirrhosis Undetectable HBV DNA Viral breakthrough 51 Hyun JJ et al. Liver Int 2012; 32: 656
Efficacy of different nucleos(t)ide analogs in patients with decompensated HBV liver cirrhosis HBV DNA < 400 cop/ml 51 Liaw Y-F et al. Hepatology 2011; 53:62
Safety?
Renal safety of different nucleos(t)ide analog regimens in patients with decompensated liver cirrhosis 51 Liaw Y-F et al. Hepatology 2011; 53:62
Lactate (mg/dl) / Creatinine-Clearance Lactic acidosis during entecavir treatment in patients with decompensated cirrhosis ph Lange C et al. Hepatology 2009; 50: 2001 80 60 40 20 0 ETV TDF 28 31 34 37 40 43 46 49 52 55 58 Day of ETV treatment 7,45 7,40 7,35 7,30 7,25 7,20 7,15 Lactate Clearance ph Creatinine-Clearance Patient D ETV, entecavir TDF, tenofovir disoproxil fumarate
Lactic acidosis during entecavir treatment in patients with decompensated cirrhosis Lange C et al. Hepatology 2009; 50: 2001 MELD score 22 (22, 25, 28, 29, 38) No lactic acidosis n=11 lactic acidosis n=5 Lactic acidosis reversible after entecavir discontinuation: n=4 Lethal outcome: n=1 (fulminant liver failure is a differential diagnosis) MELD score < 22 (6-17) Development of lactic acidosis correlated with the MELD score and its single parameters INR, bilirubin, creatinine (p<0.005 each)
Long-term efficacy?
Improvement in histologic activity (Median Histoloical Activitity Index) Correlation between HBV DNA Response during antiviral therapy and histologic response 5 N=3,428 4 3 2 1 0-1 -2 1 2 3 4 5 log 10 decline in HBV DNA during treatment Mommeja-Marin H et al. Hepatology 2003; 37: 1309
Percentage of subjects Impact of Tenofovir DF Treatment on Fibrosis Response at Year 5 100% 90% 80% 70% n=10 n=126 n=79 n=37 n=19 n=77 Year 5 Response (348 paired biopsies) Improvement No Change Worsening 60% 50% 40% 30% 71/96 (74%) of cirrhotic patients had cirrhosis reversed (Ishak fibrosis score 4) at year 5 20% 10% 0 1 2 3 4 5 6 Baseline Ishak fibrosis score Marcellin, P, et al. AASLD 2011; Poster #1375.
Change from Baseline in Fibrosis Score Change in Ishak Fibrosis Scores at Year 5 for Patients with Cirrhosis at Baseline -5-4 -3-2 -1 0 +1 +2 +3 +4 +5 Change from Baseline in Fibrosis Score n = 1 n = 14 n = 41 n = 15 n = 24 n = 1 96 patients with cirrhosis (Ishak fibrosis score 5) had paired BL and Year 5 biopsies 74% (n=71) of patients had cirrhosis reversed (Ishak fibrosis score <5) at Year 5 73% (n= 70) had decreases of 2 points at Year 5 25% (n=24) did not change Of 94 patients who did not add FTC, 73% had cirrhosis reversed; 26% showed no change Marcellin, P, et al. AASLD 2011; Poster #1375.
Studies 102/103 Comparative improvements in Ishak fibrosis scores for patients with normal vs abnormal ALT at Year 5 Both groups showed significant improvements in Ishak scores at Year 5 A significantly lower percentage of patients in the normal ALT group vs the ALT > ULN group had cirrhosis (Ishak 5) at Year 5 (5% vs 19%) Jacobson I, et al. AASLD 2012; Boston. #411.
Long-term ADV+LAM therapy in patients with cirrhosis and lamivudine resistance Lampertico P et al. Gastroenterology 2007; 133: 1445 100 80 60 40 HCC Decompensation 20 0 0 6 12 18 24 30 36 42 48 Months 15% 0% Patients at risk 94 92 89 86 68 53 46 94 94 93 89 71 58 51 27 30 10 10
% Patients with HCC HCC risk during long-term NUC treatment? Papatheodoridis G et al. Gut 2011; 60: 1109 25 20 Greece HEPNET Greece cohort study; N=818 Chronic Hepatitis B, no cirrhosis compensated Cirrhose (n=160) Decompensated Cirrhose (n=56) (n=517) 19,3 15 13,9 10 5 0 0,2 0,6 5,9 1 2,7 10,6 1 2 3 5 Years on treatment (HBeAg negativ > 12 months on treatment starting with lamivudine) 1,7 6,8 3,2 9,2
Summary of studies evaluating the HCC risk in NUC naive cirrhotic patients under long-term therapy Aghemo A et al. J Hepatol 2012; 57: 1326 Author (year) HCC/Year % Liaw et al. (2004) LAM 1.5% Papatheodoridis et al. (2010) LAM 2.4% Papatheodoridis et al. (2011) LAM 2.5% Kurokawa et al. (2012) LAM 2.8% Lampertico et al. (2011) ETV 2.5%
Cumulative Development Rates of HCC (%) HCC Incidence in Patients Treated with Long Term ETV Cumulative Development Rates of HCC (%) Retrospective cohort study in 472 NA naïve patients who received ETV (2004-2010) vs historical control group of 1143 non-na-treated HBV patients (1973-1999). Primary outcome: confirmed HCC diagnosis >1 year after start of therapy 50 40 Log-rank test: P < 0.001 Cirrhosis 38.9% Control 50 40 Log-rank test: P = 0.440 No Cirrhosis 30 28.5% 30 20 11.4% 20.9% 20 10 0 2.6% 4.3% 7.0% 7.0% ETV 10 0 0% 1.0% 0% 1.6% 2.2% 0.8% 3.6% 2.5% Control # at Risk ETV Control 0 1 3 5 Treatment Duration (Years) 79 85 79 85 72 76 53 65 35 54 17 47 # at Risk ETV Control 0 1 3 5 Treatment Duration (Years) 237 231 237 231 192 201 132 181 66 169 27 143 Hosaka T, et al. AASLD 2012; Boston. #357.
Factors associated with HCC Risk in CHB Patients Achieving Viral Suppression with Anti-Virals Multi-center, retrospective analysis of HCC development in 101 patients who achieved viral suppression on anti-viral therapy compared to 99 matched controls with viral suppression but without HCC development Mean duration of therapy (months) 42.25 ± 30.7 in HCC group 44.00 ± 33.14 in control group LAM exposure: 79% in HCC group 56% in control group Predictors of HCC development Multivariate analysis Lamivudine Exposure HBeAg negative Favors lack of HCC development LAM exposure HBeAg-positive Male gender Age 60+ 0,5 Favors HCC development 1,94 1,84 3,1 0 1 2 3 4 5 6 7 Odds Ratio for HCC Development In this group, despite achieving viral suppression with antiviral therapy, there was still an increased risk of the HCC primarily related to HBeAg negative disease and LAM exposure. Ghaly S, et al. AASLD 2012; Boston. #332.
EASL Clinical Practice Guideline Treatment of HBV Cirrhosis J Hepatol 2012; 57: 167 Among NUCs, monotherapies with tenofovir or entecavir are preferred. Lamivudine should not be used in such patients. NUC therapy should usually be continued indefinitely in cirrhotic patients. Treatment might be stopped after confirmed anti-hbe seroconversion (in HBeAg-positive patients) or ideally HBsAg loss and anti-hbs seroconversion. PEG-IFN may increase the risk of bacteraemic infection and hepatic decompensation in patients with advanced cirrhosis However, PEG-IFN in regimens similar to those used in CHB can be used for the treatment of well compensated cirrhosis Regression of fibrosis and even reversal of cirrhosis have been reported in patients with prolonged suppression of viral replication. Nonetheless, long-term monitoring for HCC is mandatory despite virological remission under NUCs, since there is still a risk of developing HCC