[PDF] - Current Status of HBV decompensated cirrhosis since 2003 (since PDF Document

SLIDE 1

9/26/2018 1

Francis Yao, MD Professor of Medicine and Surgery Medical Director, Liver Transplant University of California San Francisco

Current Status of HBV and Liver Transplant

HBV as Indication for Liver Transplantation in U.S.

Significant decrease in rate of wait‐listing for

decompensated cirrhosis since 2003 (since NUCs)

No change in rate of wait‐listing for HCC since 2003

Approval LMV ADV

US Liver Transplants 1985‐2006

Kim WR, Terrault NA Gastroenterology 2009;137:1680‐6

HBV as Indication for Liver Transplantation in U.S.

Significant decrease in rate of wait‐listing for

decompensated cirrhosis since 2003 (since NUCs)

No change in rate of wait‐listing for HCC since 2003

HBV in the NUC era

LT could have been avoided in many cases ‐ Failure to recognize and treat HBV ‐ NUC stopped by mistake ‐ Reactivation of HBV during chemotherapy without preemptive HBV therapy

Graft Survival for HBV LT Recipients: Impact of HBIG

ELTR 1988-2010

Post‐HBIG Pre‐HBIG

SLIDE 2

9/26/2018 2

Transplant

Prevention and Treatment HBV of Post‐ Transplant

Prevent graft infection Pre‐Transplant Antiviral Therapy Prevent infection

r

hepatitis Prophylactic Therapies Prevent cirrhosis and graft failure Antiviral therapy for recurrent disease

Listed Chronic hepatitis Graft loss Acute hepatitis

Entecavir Tenofovir HBIG Plus NUC Entecavir Tenofovir

Lifelong therapy needed

Algorithm for Management of Patients With Cirrhosis

Compensated Decompensated

Any HBV DNA Level

Refer for Liver Transplantation

Terrault NA, AASLD HBV Treatment Guidelines 2016

Treat Indefinitely

Any HBV DNA Level

Treat Indefinitely

Preferred Treatments for Treatment of HBV in Patients with Cirrhosis

Drug Name Antiviral Potency Side Effects Risk of Resistance

Entecavir (ETV) +++ Lactic acidosis (rare) Very Low* Tenofovir disoproxil fumarate (TDF) +++ Lactic acidosis (rare) Some risk renal and bone toxicity None Tenofovir Alafenamide (TAF)** +++ Lactic acidosis (rare) Minimal renal and bone toxicity None

* Rate of resistance higher in patients who have prior lamivudine resistance

AASLD HBV Treatment Guidelines EASL HBV Treatment Guidelines

**TAF has not been studied in patients with decompensated cirrhosis

Tenofovir Alafenamide (TAF) for Chronic HBV

Mean (SD) % Change from Baseline

2

6
4
2

P<0.001

0.88
2.51

P<0.001

0.29
2.16

24 48 Week 24 48 Week

Spine and Hip BMD

Mean (SD)% Change from Baseline

Spine Hip

0.6
4.7

p <0.001 Mean (±SD) change in eGFRCG (mL/min)

Renal Safety

Change in Bone Mineral Density TAF TDF

Buti EASL 2016, Oral GS06; Chan, EASL 2016, Oral GS12

SLIDE 3

9/26/2018 3 Antivirals may Reverse Decompensation and Prevent Need for LT

N=100

CPS A=40%, B=40%, C=21%

43% Transplanted

86% Improved 14% Not Improved

21% Removed from Wait List 36% Still Wait Listed

50% Improved/Stabilized 14% Not Improved 30% Death* 2% No F/U * All deaths occurred within 24 weeks

Schiff E et al, Liver Transplant, 2007

Compassionate access program for adefovir 1999‐2003

Maintained Virologic Response (MVR) Influences Transplant‐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)
Entecavir more likely to achieve MVR than Lamivudine  survival difference

Jang JW, CGH 2018

Severity of Decompensation Strongly Influences Short‐Term Survival

10.3 55.3

10 20 30 40 50 60

Short‐Term Mortality

MELD≤20 MELD≥20

HR (95%CI) P Value Multiple Complications 3.60 (1.71‐7.55) 0.001 MELD>20 8.32 (3.98‐17.41) <0.001

Multivariate Analysis of Predictors

f Mortality within 6 Months

%

Jang JW, CGH 2018

Pre‐Transplant 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

SLIDE 4

9/26/2018 4

Transplant

Prevention and Treatment HBV of Post‐ Transplant

Prevent graft infection Pre‐Transplant Antiviral Therapy Prevent infection

r

hepatitis Prophylactic Therapies Prevent cirrhosis and graft failure Antiviral therapy for recurrent disease

Listed Chronic hepatitis Graft loss Acute hepatitis

Entecavir Tenofovir HBIG Plus NUC Entecavir Tenofovir

Lifelong therapy needed

HBV Prophylaxis in Liver Transplant Recipients

HBIG plus NUC is “standard of practice” in most LT

centers

Efficacy ~95% with current NUCs + HBIG
Target anti‐HBs titer ~100 U/L
Use of NUCs 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

(NUC)

Many patients have undetectable HBV DNA

levels at time of LT

Efficacy of Prophylactic Regimens in Preventing HBV Recurrent Post‐LT

HBIG +LMV HBIG + ETV/TDF HBIG + ETV HBIG +TDF

Total N: 1889 309 197 106

P<0.001 P=0.51

Systematic review

Cholongitas E, Am J Transplant 2013

% Recurrence HBsAg positive

Median follow-up 30 months ETV/TDF 37 months LMV

SLIDE 5

9/26/2018 5

HBsAg %

Prophylaxis for HBV Post‐Transplant: Discontinuation of HBIG

Systematic review:

Cholongitas E, Am J Transplant 2013

HBIG + ETV ETV /TDF with HBIG D/C HBIG + TDF

Median duration of HBIG before discontinuation= 24 months (range: 11–31)

Stopping HBIG and Continuing NUC Unique Features of Recurrence

HBsAg may reappear but HBV DNA remains

undetectable (especially if NUC(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

NUC resistance reported primarily in studies with LMV

used as maintenance NUC

Fox and Terrault, J Hepatol 2012 Cholongitas E, Am J Transplant 2013

HBV Prophylaxis Using Short‐Course Peri‐operative HBIG Plus NUC

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 NUC

N=2 patients with

recurrence of HBsAg positivity or viremia had HCC diagnosed within a month of detection

2.9 3.3

2 4 6 8 10

Recurrence

Cumulative Incidence at 3 Years

HBsAg+ HBV DNA+ N=1 N=1

%

Radhakrishnan K, Transplantation 2017

HBV Prophylaxis with NUC Alone

NUC 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 NUC only strategy post‐LT

Perrillo R, Hepatology 2001;33:424-32 Nery J, Transplantation 1998;65:1615-21 Fung J, Gastroenterology 2011;141:1121-9

SLIDE 6

9/26/2018 6 Prophylaxis with NUC Monotherapy Efficacy Measures by NUC Used

NUC used N HBV DNA relapse 3 yrs HBsAg + last f/u Survival* LMV 176 17% 20% 87% ETV 142 0% 17% 92% Combo

(mostly LMV+ADV)

44 7% 21% 93%

Median follow-up 4.4 yrs

Fung J, Am J Gastroenterol 2013; 108(6):942-8.

* No HBV-related deaths; 1 re-transplant for recurrent cholestatic hepatitis

Individualize Prophylactic Therapy

High Risk

HDV or HIV coinfection
HBV DNA ≥104 IU/ml pre‐LT

(unrecognized or acute HBV)

Drug‐resistant HBV
Risks for non‐adherence

Low Risk

HBV DNA undetectable to <100

IU/mL pre‐LT (on antivirals)

Wild‐type HBV
Compliant
Combination HBIG and

NUCs (possibly long-term)

Include combination NUCs

with known efficacy against drug-resistant HBV

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

Consider if high or low risk for recurrent HBV

Transplant

Prevention and Treatment HBV of Post‐ Transplant

Prevent graft infection Pre‐Transplant Antiviral Therapy Prevent infection

r

hepatitis Prophylactic Therapies Prevent cirrhosis and graft failure Antiviral therapy for recurrent disease

Listed Chronic hepatitis Graft loss Acute hepatitis

Entecavir Tenofovir HBIG Plus NUC Entecavir Tenofovir

Lifelong therapy needed

Treatment of HBV Recurrence Post‐LT

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

SLIDE 7

9/26/2018 7 Unique Aspects of HDV Patients

No effective antivirals for HDV (prior to or post‐LT)
Interferon is only potential therapy but efficacy modest
HBV infection (HBsAg) is necessary for active HDV

infection

Prevention of HBsAg reappearance of paramount

importance to HDV patient

Several studies report presence of latent HDV infection in

liver in the absence of detectable HDV RNA in serum for prolonged periods (months to years) post‐LT

1Samuel, D Hepatology 1999;21:333-9. 2Mederacke I, J Hepatol 2012;56:155-122

Using Livers from Anti‐HBc+ Donors

ETV/TDF /TAF ±HBIG

ETV/TDF/TAF Preferred

Adapted from Cholongitas E, J Hepatol 2010;52:272–279 Terrault NA et al. AASLD HBV Guidance 2018