Current Status of HBV and Liver HBV as Indication for Liver ation in U.S. Significant decrease in rate of wait listing for decompensated cirrhosis since 2003 (since s) No change in rate of wait listing for HCC since 2003 US Liver s 1985 2006 Approval LMV ADV Francis Yao, MD Professor of Medicine and Surgery Medical Director, Liver University of California San Francisco Kim WR, Terrault NA Gastroenterology 2009;137:1680 6 HBV as Indication for Liver ation in U.S. Significant decrease in rate of wait listing for decompensated cirrhosis since 2003 (since s) No change in rate of wait listing for HCC since 2003 HBV in the era LT could have been avoided in many cases Failure to recognize and treat HBV stopped by mistake Reactivation of HBV during chemotherapy without preemptive HBV therapy Graft Survival for HBV LT Recipients: Impact of HBIG Post HBIG Pre HBIG ELTR 1988-2010 1
ion and Treatment HBV of Post Listed graft HBIG Plus or Acute Chronic cirrhosis and graft failure Graft loss Algorithm for Management of Patients With Cirrhosis Compensated Any HBV DNA Level Treat Indefinitely Decompensated Any HBV DNA Level Treat Indefinitely Pre Therapy Prophylactic Therapies Lifelong therapy needed therapy for recurrent disease Refer for Liver ation Terrault NA, AASLD HBV Treatment Guidelines 2016 Preferred Treatments for Treatment of HBV in Patients with Cirrhosis Drug Name Potency Side Effects Risk of Resistance (ETV) +++ Lactic acidosis (rare) Very Low* disoproxil fumarate (TDF) Alafenamide (TAF)** +++ +++ Lactic acidosis (rare) Some risk renal and bone toxicity Lactic acidosis (rare) Minimal renal and bone toxicity None None * Rate of resistance higher in patients who have prior lamivudine resistance **TAF has not been studied in patients with decompensated cirrhosis AASLD HBV Treatment Guidelines EASL HBV Treatment Guidelines Alafenamide (TAF) for Chronic HBV Renal Safety Spine and Hip BMD Spine Change in Bone Mineral Density Mean (SD) % Change Mean (SD)% from Change Baseline from Baseline Mean (±SD) change in egfr CG (ml/min) -0.88-2.51 P<0.001-6 24 48 Week 0 Week 0 24 48 Buti EASL 2016, Oral GS06; Chan, EASL 2016, Oral GS12 2 0-2 -4 Hip -0.6-4.7 TAF TDF p <0.001 P<0.001-0.29-2.16 2
s may Reverse Decompensation and Need for LT Compassionate access program for adefovir 1999 2003 43% ed N=100 CPS A=40%, B=40%, C=21% 36% Still Wait Listed 21% Removed from Wait List 86% Improved 14% Not Improved 50% Improved/Stabilized 14% Not Improved 30% Death* * All deaths occurred 2% No F/U within 24 weeks Schiff E et al, Liver, 2007 Maintained Virologic Response (MVR) Influences Free Survival N=295 HBV patients with decompensation initiated on antiviral therapy Median follow up 5.2 yrs; median survival 7.7 yrs Highest mortality in first 6 months: 17.3% vs 25.3% between 6 mos 10 yrs MVR is key to better long term survival (HR 2.30) more likely to achieve MVR than Lamivudine survival difference Jang JW, CGH 2018 60 50 40 30 % 20 10 Severity of Decompensation Strongly Influences Short Term Survival 0 Short Term Mortality 10.3 MELD 20 55.3 MELD 20 Multivariate Analysis of Predictors of Mortality within 6 Months Multiple Complications HR (95%CI) 3.60 (1.71 7.55) MELD>20 8.32 (3.98 17.41) P Value 0.001 <0.001 Pre Management of Patients with HBV All patients with cirrhosis should be maintained on antiviral therapy life long ETV, TDF or TAF are preferred options If decompensated, highest risk of death/need for LT in first 6 months Maintenance of viral suppression important for long term survival with and without LT Monitor HBV DNA every 3 6 months Jang JW, CGH 2018 3
ion and Treatment HBV of Post Listed graft Pre Therapy HBIG Plus or Prophylactic Therapies Acute Lifelong therapy needed Chronic cirrhosis and graft failure therapy for recurrent disease Graft loss HBV Prophylaxis in Liver Recipients HBIG plus is standard of practice in most LT centers Efficacy ~95% with current s + HBIG Target anti HBs titer ~100 U/L Use of s with high genetic barrier to resistance Move towards minimization of HBIG in recent decade Factors Influencing Practice Patterns in HBV Prophylaxis Limitations of HBIG Cost Availability (especially in Asia) Inconvenient parenteral administration Availability of effective antiviral therapy () Many patients have undetectable HBV DNA levels at time of LT Efficacy of Prophylactic Regimens in ing HBV Recurrent Post LT % Recurrence HBsAg positive P<0.001 Systematic review Median follow-up 30 months ETV/TDF 37 months LMV P=0.51 HBIG HBIG + HBIG HBIG +LMV ETV/TDF + ETV +TDF Total N: 1889 309 197 106 Cholongitas E, Am J 2013 4
Prophylaxis for HBV Post : Discontinuation of HBIG Systematic review: Median duration of HBIG before discontinuation= 24 months (range: 11 31) HBsAg % HBIG + ETV HBIG + TDF ETV /TDF with HBIG D/C Stopping HBIG and Continuing Unique Features of Recurrence HBsAg may reappear but HBV DNA remains undetectable (especially if (s) with high genetic barrier to resistance used) HBsAg may subsequently disappear spontaneously or with change in anti viral therapy Lack of adherence frequently cited a cause for recurrence resistance reported primarily in studies with LMV used as maintenance Cholongitas E, Am J 2013 Fox and Terrault, J Hepatol 2012 Cholongitas E, Am J 2013 HBV Prophylaxis Using Short Course Peri operative HBIG Plus Single center study N=46 consecutive patients with HBV DNA <1000 IU/mL at LT (without HIV or HDV) HBIG 5000 IU intraop and daily for 5 days plus life long N=2 patients with recurrence of HBsAg positivity or viremia had HCC diagnosed within a month of detection % 10 8 6 4 2 0 Cumulative Incidence at 3 Years 2.9 3.3 N=1 N=1 Recurrence HBsAg+ HBV DNA+ Radhakrishnan K, ation 2017 HBV Prophylaxis with Alone with high barrier to resistance needed Early experience with LMV revealed high rates of resistance prophylaxis failure Virologic failure in absence of rescue therapy results in rapidly progressive disease and graft loss Adherence to treatment is critical ETV (if no prior LMV), TDF or TAF best options Suppression of HBV DNA to low levels pre LT may improve success of only strategy post LT Perrillo R, Hepatology 2001;33:424-32 Nery J, ation 1998;65:1615-21 Fung J, Gastroenterology 2011;141:1121-9 5
Prophylaxis with Monotherapy Efficacy Measures by Used Individualize Prophylactic Therapy Consider if high or low risk for recurrent HBV used N HBV DNA relapse 3 yrs HBsAg + last f/u Survival* LMV 176 17% 20% 87% ETV 142 0% 17% 92% 44 7% 21% 93% Combo (mostly LMV+ADV) Median * No HBV-related follow-up 4.4 deaths; yrs 1 re-transplant for recurrent cholestatic Fung J, Am J Gastroenterol 2013; 108(6):942-8. High Risk HDV or HIV co HBV DNA 10 4 IU/ml pre LT (unrecognized or acute HBV) Drug resistant HBV Risks for non adherence Combination HBIG and s (possibly long-term) Include combination s with known efficacy against drug-resistant HBV Low Risk HBV DNA undetectable to <100 IU/mL pre LT (on antivirals) Wild type HBV Compliant Short duration HBIG (5 days-4 wks) + ETV or TDF/TAF long-term ETV or TDF/TAF monotherapy Terrault NA et al. AASLD HBV Guidance 2018 ion and Treatment HBV of Post Treatment of HBV Recurrence Post LT Listed graft Pre Therapy HBIG Plus or Prophylactic Therapies Acute Lifelong therapy needed Chronic cirrhosis and graft failure therapy for recurrent disease Graft loss No role of HBIG Preferred antivirals are those with high barrier to resistance: ETV, TDF or TAF No convincing evidence that combination better than monotherapy if preferred drugs used TDF/TAF preferred if prior LMV treatment Life long suppressive therapy needed HCC surveillance for those with advanced fibrosis Terrault NA et al. AASLD HBV Guidance 2018 6
Unique Aspects of HDV Patients Using Livers from Anti HBc+ Donors No effective antivirals for HDV (prior to or post LT) Interferon is only potential therapy but efficacy modest HBV (HBsAg) is necessary for active HDV ion of HBsAg reappearance of paramount importance to HDV patient Several studies report presence of latent HDV in liver in the absence of detectable HDV RNA in serum for prolonged periods (months to years) post LT ETV/TDF /TAF ±HBIG ETV/TDF/TAF Preferred 1 Samuel, D Hepatology 1999;21:333-9. 2 Mederacke I, J Hepatol 2012;56:155-122 Adapted from Cholongitas E, J Hepatol 2010;52:272 279 Terrault NA et al. AASLD HBV Guidance 2018 Summary HBV and Liver Pre: if cirrhosis, should be on antiviral therapy with preferred drug: ETV, TDF, TAF Prophylaxis is highly effective but should be individualized to risk profile Low risk patients: No or short term HBIG + life long HDV need special attention to prevent HBsAg reappearance Post: life long suppression with ETV, TDF or TAF Consider if HCC surveillance warranted Anti HBc positive donor: prophylaxis determined by recipient status 7