Management of Decompensated Chronic Hepatitis B · 2012. 12. 9. · Decompensated HBV Patients 88%...
Transcript of Management of Decompensated Chronic Hepatitis B · 2012. 12. 9. · Decompensated HBV Patients 88%...
Management of Decompensated Chronic
Hepatitis B Dr James YY Fung, FRACP, MD Department of Medicine The University of Hong Kong Liver Transplant Center Queen Mary Hospital State Key Laboratory for Liver Research The University of Hong Kong
International Symposium on Hepatology 2012 25th Annual Scientific Meeting 18th November, 2012, Hong Kong
Natural History of HBV Cirrhosis
Acute flare Of CHB
Long term Benefits in Compensated Cirrhosis treated with Lamivudine
Patie
nts,
%
Placebo (n = 215)
Lamivudine (n = 436)
All P values ≤ .05
18%
9% 7% 8%
3% 4%
0
10
20
30
Overall Disease Progression
CPT Increase
HCC
651 patients – 41 sites (Asia-Pacific) – Randomized 2:1 LAM:Placebo
Liaw YF et al. N Engl J Med 2004;351:1521-31
Beneficial Effects of Antiviral Effects Diminished with Resistance
Wild type (n = 221)
0
5
10
15
20
25
0 6 12 18 24 30 36
Placebo (n = 215)
5%
21% M204I/V mutations (n = 209, 49%)
13%
Time after randomisation (months)
Patie
nts
with
dis
ease
pro
gres
sion
(%)
Liaw YF. Seminars in Liver Disease 2005; 25: 40-47.
Adefovir HBeAg+
Adefovir HBeAg-
Telbivudine HBeAg+
% re
sist
ance
Fung J, et al. J Gastroenterol Hepatol 2008; 23:1182-92
5Lamivudine Entecavir
0
20
40
60
80
1 1 1 1 1 1 2 2 2 2 2 2 3 3 3 3 4 4 5 4 1 2 Tenofovir
6 3
Telbivudine HBeAg-
Antiviral Resistance in Oral Therapies in Chronic Hepatitis B
Cirrhotic patients and patients with decompensated liver disease are unlikely to tolerate further flares if resistance occurs
2005-2008
1998
Virological Response for ETV According to Severity of Liver Disease
Zoutendijk R et al, 2012. Gut; doi:10.1136/gutjnl-2012-302024
Tenofovir vs Placebo in Acute on Chronic Liver Failure from HBV
Garg H et al. Hepatology 2011;53:774-780
Tenofovir (n=14)vs plaecbo (n=13) INR>1.5; bilirubin >85mmol/L, ascites/encephalopathy
Tenofovir vs Placebo in Acute on Chronic Liver Failure from HBV
Garg H et al. Hepatology 2011;53:774-780
TDF vs FTC + TDF vs ETV in HBV Pts With Decompensated Liver Disease
Outcome at 48 weeks TDF (n = 45)
TDF/FTC (n = 45)
ETV (n = 22)
HBV DNA <400 cpm 71% 88% 73%
Median log HBV DNA decline 3.11 3.92 3.40
Child Pugh score ≥2 decrease 26% 48% 42%
Median MELD score change -2 -2 -2
Pts with chronic hepatitis B and decompensated liver
disease (N = 112)
Tenofovir DF (n = 45)
Emtricitabine + Tenofovir DF (n = 45)
Entecavir (n = 22)
Wk 168 Randomized 2:2:1 Interim analysis at
Wk 48
Liaw YF et al. Hepatology 2011;53:62-72
Viral suppression and Mortality in Decompensated Cirrhosis treated with ETV
Shim JH et al. J Hepatol 2010;52:176-182
92.3%
6.9%
17%
70 patients with HBV decompensated cirrhosis treated with ETV 0.5mg
Changes in CTP and MELD Score at 12 Months with ETV
Cha
nge
in C
TP S
core
Thr
ough
12
Mos
8
6
4
2 8.1 ± 1.7
P < .001
10
12
6.6 ± 2.4 At 12
Months At
Pretreatment
Cha
nge
in M
ELD
Sco
re
Thro
ugh
12 M
os 16
12
10
2 11.1 ± 3.8
P < .001 18
20
8.8 ± 2.3 At 12
Months At
Pretreatment
14
8
Shim JH et al. J Hepatol 2010;52:176-182
ETV vs ADV in CHB Decompensation – Randomized Open Label Study
HBV-infected patients with
decompensated liver disease*
(N = 191)
ETV 1.0 mg (n = 100)
ADV 10 mg (n = 91)
Wk 24 Yr 5
§ Primary efficacy endpoint: mean reduction in serum HBV DNA at Wk 24
Wk 48 Wk 96
Follow-up
Liaw YF et al. Hepatology 2011;54:91-100
ETV vs ADV in CHB Decompensation – Randomized Open Label Study
Liaw YF et al. Hepatology 2011;54:91-100
Mea
n H
BV
DN
A
(log 1
0 cop
ies/
mL)
B/L
9 8
7 6
5 4 3 2
1 4 8 12 16 20 24 28 32 36 40 44 48
Treatment (Wks)
Limit of detection 300 copies/mL
P < .0001
-3.40
-4.48
ETV 1.0 mg (n = 100)
ADV 10 mg (n = 91)
Patients With Measurements ETV ADV
100 91
98 88
92 80
87 80
76 73
71 66
69 61
ETV vs ADV in CHB Decompensation – Randomized Open Label Study
Liaw YF et al. Hepatology 2011;54:91-100
ADV (N=91) ETV (N=100)
Δ MELD score (median) -1.7 -2.6 ¤CPT score ≥2 pts 27% 35%
1 ETV patient had lactic acidosis
ETV vs LAM in Decompensated CHB ALT normalization & HBV DNA suppression
Hsu YC et al, 2012. Antiviral Ther; doi:10.3851/IMP2027
LAM LAM ETV ETV
Retrospective study on Decompensated HBV Hyperbilirubinemia >2x ULN
Coagulopathy (Prolonged >3 secs) Antiviral therapy with LAM/ETV >1 week
ETV vs LAM in Decompensated CHB Overall Survival & Liver-Related Mortality
Hsu YC et al, 2012. Antiviral Ther; doi:10.3851/IMP2027
ETV & LAM in Severe Acute Flares of CHB
Wong VWS et al. J Hepatol 2011(54):236-242
ALT >10x ULN, Br >3x ULN ETV (n=36)
LAM (n=117)
ETV & LAM in Severe Acute Flares of CHB Outcomes
Wong VWS et al. J Hepatol 2011(54):236-242
Overall Survival Liver-related Mortality
ETV & LAM in Severe Acute Flares of CHB Deaths Within 48 Weeks
Wong VWS et al. J Hepatol 2011(54):236-242
ETV & LAM in Severe Acute Flares of CHB Factors Associated with Deaths Within 48 Weeks
Wong VWS et al. J Hepatol 2011(54):236-242
Univariate Multivariate Hazard ratio 95% CI P-value Hazard ratio 95% CI P-value
Could there be a possible cause for mortality associated with ETV use?
• 16 patients with HBV cirrhosis treated with ETV – 5 developed lactic acidosis
• The MELD score (and not CPS) correlated with development of lactic acidosis – All had MELD >18 – All had impaired CrCl
• Important to dose-adjust for renal impairment
Lange CM et al. Hepatology 2009;50:2001-2006
0.90 TDF 0.90 TDF/FTC 0.80 ETV
• No cases of lactic acidosis reported in any treatment arm
1.0 M
edia
n C
reat
inin
e (m
g/dL
)
0
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
0 4 8 12 16 20 24 28 32 36 40 44 48
Wks on Study
45 45 22
45 44 21
42 43 19
40 42 20
39 42 19
39 42 18
40 42 19
38 42 19
37 42 19
37 42 18
38 41 17
37 42 16
37 42 16
TDF FTC/TDF ETV
Pts at Risk, n
TDF vs FTC + TDF vs ETV in HBV Pts With Decompensated Liver Disease
Liaw YF et al. Hepatology 2011;53:62-72
LDT & LAM in Decompensated CHB Clinical Response
Chan HLY et al , 2012. J Viral Hep; doi:10.1111/j.1365-2893.2012.01600.x
Multicenter Phase III Randomized Double Blind Trial Cirrhotics with CTP score ≥7, HBV DNA ≥5 log cpm
N=114 N=114
LDT & LAM in Decompensated CHB Overall Survival
Chan HLY et al , 2012. J Viral Hep; doi:10.1111/j.1365-2893.2012.01600.x
LDT & LAM in Decompensated CHB Renal Function
Chan HLY et al , 2012. J Viral Hep; doi:10.1111/j.1365-2893.2012.01600.x
Biphasic Pattern of Survival in Decompensated HBV Patients
88%
Fontana RJ et al. Gastroenterology 2002;123:719-727
Overall Survival
154 HBV decompensated patients treated with LAM 6-month survival independent of early treatment efficacy
>6 months Survivors
<6 months Survivors
Poor Survival éBr éCr
éHBV DNA
Oral Therapy in Decompensated HBV Cirrhosis 1 year survival
70
75
80
85
90
95
100
LAM ADV TNV TVD ETV
% 1
yea
r sur
viva
l
84%
Fontana RJ et al. Gastroenterology 2002;123:719-727 Schiff ER et al. Liver Transplant 2007;13:349-360 Schiff ER et al. Hepatology 2009;50:222 (Abstract) Shim et al. J Hepatol 2010;52:176-182
86% 86%
93%
87%
*Non-head to head comparisons
LAM and ETV in Decompensated Cirrhosis
Und
etec
tabl
e H
BV
DN
A (%
)
Months Months
Viro
logi
cal b
reak
thro
ugh
(%)
Hyun JJ et al, 2012. Liver Int;32(4):656-64
86 HBV decompensated patients (CTP ≥7) Treated with either LAM or ETV
No difference in early mortality rates
Clinical Events for those with Cirrhosis and Without Virological Response
Zoutendijk R et al, 2012. Gut; doi:10.1136/gutjnl-2012-302024
N=372 ETV treated patients Clinical events = HCC, decompensation, death
Cirrhotic patients
(<80 IU/mL)
HBV DNA threshold of 2000 IU/mL was not associated with lower disease Progression in cirrhotic patients
HBV Cirrhosis Who Do We Treat?
Asia Pacific Consensus on Chronic Hepatitis B 2012
Treatment of Decompensated CHB Summary I
• The short term outcome is not likely to be altered by antiviral therapy – Determined by underlying liver reserve
• IFN-based therapy are contraindicated
• Oral NAs are comparable in – Reducing viral load – Improving MELD score and CTP score – Short term survival
Treatment of Decompensated CHB Summary II
• All cirrhotics who are HBsAg+ should be considered for treatment
• Treatment should be lifelong
• Treat with a highly potent antiviral agent with high genetic barrier to resistance – Patients unlikely to tolerate any further breakthrough
flares – Selection of mutant strains likely to limit choice of
further treatment
Treatment of Decompensated CHB Summary III
• Early referral to a transplant unit is recommended for those with evidence of decompensation – ↑Br, ↑Cr, ↑INR, ↑HBV DNA – Hepatic encephalopathy
Thank You