1. Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC
Treatment Selection for HBV-Infected Patients With Decompensated Cirrhosis
Robert S. Brown, Jr., MD, MPH Frank Cardile Professor of Medicine
Chief, Center for Liver Disease
Columbia University College of Physicians & Surgeons
NewYork-Presbyterian Hospital
New York, New York
HBV, hepatitis B virus.
This program is supported by an educational grant from

2. Faculty Disclosures
Robert S. Brown, Jr., MD, MPH, has disclosed that he has received fees for non-CME services from Genentech and Gilead Sciences.

3. Rationale for Treating Patients With Advanced Liver Disease
Poor prognosis for HBV-infected patients with decompensated cirrhosis without treatment
Increased risk of hepatocellular carcinoma and death[1]
Estimated 5-yr survival rate: 14%[2]
Liver transplant is effective treatment, but ongoing shortage of donor organs and many patients on waitlists
Antiviral agents able to effectively and safely suppress HBV replication in this population, leading to improvement or stabilization of liver function[1]
HBV, hepatitis B virus.
1. Lok AS, et al. Hepatology. 2009;50: de Jongh FE, et al. Gastroenterol. 1992;103:

4. Approved Agents for the Treatment of Chronic HBV Infection
7 agents approved for first-line treatment of chronic HBV infection
Adefovir, entecavir, interferon alfa-2b, lamivudine, peginterferon alfa-2a, telbivudine, and tenofovir
3 agents recommended as first-line therapy according to major liver disease organizations because of their rapid onset of action, low rate of drug resistance with prolonged use, and generally favorable safety profiles[3,4]
Entecavir, peginterferon alfa-2a, and tenofovir
Peginterferon contraindicated in patients with decompensated liver disease because of risk of worsening liver disease and infectious complications[3-5]
Therefore, HBV clinicians must chose between entecavir and tenofovir for treatment of decompensated cirrhosis
HBV, hepatitis B virus.
3. Lok AS, et al. Hepatology. 2009;50: EASL. J Hepatol. 2012;[Epub ahead of print]. 5. Buster EH, et al. Hepatology. 2007;46:

5. Tenofovir for Treatment of CHB Patients With Decompensated Cirrhosis
Tenofovir studied in a limited number of subjects with CHB-associated decompensated cirrhosis
Currently no formal indication for the use of tenofovir in patients with decompensated liver disease
Both tenofovir and decompensated liver disease may affect renal function
Therefore, the contribution of tenofovir to renal impairment in this population is difficult to ascertain
Risk of lactic acidosis noted in package insert from experience with HIV but no data on lactic acidosis with tenofovir for HBV
CHB, chronic hepatitis B; HBV, hepatitis B virus.
Tenofovir [package insert]. January 2012.

6. HBV-infected pts with decompensated liver disease*
Study 0108: Safety of TDF vs FTC/TDF vs ETV in CHB Pts With Decomp Cirrhosis
Randomized, double-blind phase II study
Wk 48: interim analysis
Wk 168
TDF 300 mg
(n = 45)
HBV-infected pts with decompensated liver disease*
(N = 112)
FTC/TDF 200/300 mg
(n = 45)
CHB, chronic hepatitis B; Decomp, decompensated; ETV, entecavir; FTC, emtricitabine; HBV, hepatitis B virus; TDF, tenofovir.
ETV 0.5 mg or 1 mg
(n = 22)
*Patients with < 2 log10 copies/mL decrease in HBV DNA at Wk 8, with virologic breakthrough (≥ 1 log10 copies/mL increase from nadir on 2 consecutive determinations or consecutive HBV DNA ≥ 400 copies/mL after being < 400 copies/mL), or with HBV DNA levels > 400 copies/mL at or after 24 wks of treatment could begin open-label FTC/TDF; these patients considered failures in efficacy analysis.
Liaw YF, et al. Hepatology. 2011;53:62-72.

7. Study 0108: Summary of Coprimary Safety Endpoints Through Wk 48
Patients, %
TDF (n = 45)
FTC/TDF (n = 45)
ETV (n = 22)
Tolerability failures*
6.7
4.4
9.1
Confirmed ≥ 0.5 mg/dL increase in creatinine or confirmed phosphorus < 2.0 mg/dL
8.9†
4.5
Confirmed ≥ 0.5 mg/dL increase in creatinine
2.2
Confirmed phosphorus < 2.0 mg/dL
Confirmed ≥ 0.5 mg/dL increase in creatinine and confirmed phosphorus < 2.0 mg/dL
AE, adverse event; ETV, entecavir; FTC, emtricitabine; TDF, tenofovir.
*Defined as permanent discontinuation of study drug due to treatment-emergent AE; 6 pts discontinued due to AE (only 1 due to study drug) and 1 pt temporarily discontinued and did not restart.
†Includes the only pt reaching a coprimary endpoint after FTC/TDF switch.
Liaw YF, et al. Hepatology. 2011;53:62-72.

8. Study 0108: Median Serum Creatinine by Study Visit
1.0
0.9
0.8
0.7
0.6
Median Creatinine (mg/dL)
0.5
0.4
0.3
0.90 TDF
0.2
0.90 TDF/FTC
0.1
0.80 ETV
ETV, entecavir; FTC, emtricitabine; TDF, tenofovir. 4 8 12 16 20 24 28 32 36 40 44 48
Wks on Study
Pts at Risk, n
TDF FTC/TDF ETV
No cases of lactic acidosis reported in any treatment arm
Liaw YF, et al. Hepatology. 2011;53:62-72.

9. Study 0108: Efficacy Results at Wk 48
TDF (n = 45)
FTC/TDF (n = 45)
ETV (n = 22)
HBV DNA < 400 copies/mL, %
70.5
87.8
72.7
Median change in MELD score from baseline (IQR)
-2.0 (-12 to 3)
-2.0 (-18 to 4)
-2.0 (-10 to 1)
CTP score ≥ 2 point decrease, %
25.9
48.0
41.7
CTP score ≥ 2 point increase, %
2.6
Median change in serum ALT from baseline, U/L
-7.0
-16.5
-25.5
HBeAg loss, %
21.4
26.7
HBeAg seroconversion, %
13.3
ALT, alanine aminotransferase; CTP, Child-Turcotte-Pugh; ETV, entecavir; HBeAg, hepatitis B e antigen; IQR, interquartile range; FTC, emtricitabine; HBV, hepatitis B virus; MELD, Model for End-Stage Liver Disease; TDF, tenofovir.
Liaw YF, et al. Hepatology. 2011;53:62-72.

10. Entecavir for Treatment of CHB Patients With Decompensated Cirrhosis
Virologic, biochemical, serologic, and safety data available from adult subjects with chronic HBV infection and decompensated liver disease
These data led to an indication for use of entecavir in adult patients with decompensated liver disease
Dose should be increased to 1.0 mg/day in patients with CrCl ≥ 50 mL/min
Appropriate dose adjustments recommended if CrCl < 50 mL/min
Patients with decompensated liver disease treated with entecavir may be at higher risk for lactic acidosis
CHB, chronic hepatitis B; CrCl, creatinine clearance; HBV, hepatitis B virus.
Entecavir [package insert]. December 2010.

11. HBV-infected patients with decompensated liver disease*
ETV-048: ETV vs ADV in CHB Patients With Evidence of Hepatic Decompensation
Randomized, open-label phase IIIb study
Wk 24
Wk 48
Wk 96
Yr 5
ETV 1.0 mg
(n = 100)
HBV-infected patients with decompensated liver disease*
(N = 191)
Follow-up
ADV 10 mg
(n = 91)
ADV, adefovir; CHB, chronic hepatitis B; ETV, entecavir; HBV, hepatitis B virus.
Primary efficacy endpoint: mean reduction in serum HBV DNA at Wk 24
Liaw YF, et al. Hepatology. 2011;54:

12. ETV-048: Mean HBV DNA Change From Baseline Through Wk 48
ETV 1.0 mg (n = 100)
ADV 10 mg (n = 91) 9 8 7 6
P < .0001
Mean HBV DNA (log10 copies/mL) 5
-3.40 4
-4.48 3 2
Limit of detection 300 copies/mL
ADV, adefovir; ETV, entecavir; HBeAg, hepatitis B e antigen; LAMr, lamivudine resistance. 1
B/L 4 8 12 16 20 24 28 32 36 40 44 48
Treatment (Wks)
Patients With Measurements ETV ADV
100 91
98 88
92 80
87 80
76 73
71 66
69 61
Difference in HBV DNA responses favoring ETV persisted when analyzed by subgroup (LAMr or HBeAg status), although magnitude of differences varied
Liaw YF, et al. Hepatology. 2011;54:

13. ETV-048: Improvement in MELD/CTP Scores
Parameter
Wk 24
Wk 48
ETV
ADV
Mean MELD score change from BL (SE)
-2.0 (0.45)
-0.9 (0.46)
-2.6 (0.62)
-1.7 (0.50)
CTP score improvement or no worsening,* n/N (%)
66/100 (66)
65/91 (71)
61/100 (61)
61/91 (67)
CTP score ≥ 2 point reduction,* n/N (%)
32/100 (32)
22/91 (24)
35/100 (35)
25/91 (27)
CTP class improvement,† n/N (%)
25/93 (27)
22/81 (27)
35/93 (38)
29/81 (36)
ADV, adefovir; BL, baseline; CTP, Child-Turcotte-Pugh; ETV, entecavir; MELD, Model for End-Stage Liver Disease; SE, standard error.
*Noncompleter = failure.
†CTP class C/B to A only.
Liaw YF, et al. Hepatology. 2011;54:

14. ETV-048: Safety of ETV vs ADV in CHB Patients With Decompensated Cirrhosis
Safety Parameter, n (%)
ETV (n = 102)
ADV (n = 89)
Any AE
91 (89)
86 (97)
Grade 3-4 AEs
55 (54)
42 (47)
Serious AEs
70 (69)
59 (66)
Discontinuation due to AEs
7 (7)
5 (6)
Death
23 (23)
29 (33)
Serum creatinine ≥ 0.5 mg/dL increase from baseline
17 (17)
21 (24)
ALT flare
2 (2)
18 (20)
HCC
12 (12)
Liver transplantation
11 (11)
3 (3)
ADV, adefovir; AE, adverse event; ALT, alanine aminotransferase; CHB, chronic hepatitis B; ETV, entecavir; HCC, hepatocellular carcinoma.
Grade 2 lactic acidosis reported in only 1 ETV-treated patient; it resolved on continued ETV and did not require treatment
Liaw YF, et al. Hepatology. 2011;54:

15. Compensated Group (n = 144) Decompensated Group* (n = 55)
Efficacy of ETV in Treatment-Naive CHB Patients With Decompensated Cirrhosis
Prospective, nonrandomized study: 70 patients with HBV-related decompensated cirrhosis treated with ETV 0.5 mg/day
Virologic responses compared in 55 patients treated for ≥ 12 mos in decompensated group vs 144 patients with compensated cirrhosis treated with ETV 0.5 mg/day
Characteristics, %
Compensated Group (n = 144)
Decompensated Group* (n = 55)
Mo 6
Mo 12
Serum HBV DNA undetectable
44.4
78.5
58.2
89.1
HBeAg seroconversion
17.8
24.4
18.5
22.2
HBeAg loss
25.6
41.1
33.3
48.1
ALT normalization
75.7
75.0
78.2
76.4
ALT, alanine aminotransferase; CHB, chronic hepatitis B; ETV, entecavir; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.
*P values not significant for any parameter at any time point between compensated and decompensated group.
Shim JH, et al. J Hepatol. 2010;52:

16. Improved CTP and MELD Scores in Decomp CHB Patients Treated With ETV12 20
P < .001
P < .001 18 10 16 8 14
Change in CTP Score Through 12 Mos
Change in MELD Score Through 12 Mos 12 6 10
CHB, chronic hepatitis B; CTP, Child-Turcotte-Pugh; Decomp, decompensated; ETV, entecavir; MELD, Model for End-Stage Liver Disease. 4 8 2 2
8.1 ± 1.7
6.6 ± 2.4
11.1 ± 3.8
8.8 ± 2.3
At Pretreatment
At 12 Mos
At Pretreatment
At 12 Mos
Shim JH, et al. J Hepatol. 2010;52:

17. Lactic Acidosis in Decompensated CHB Patients Treated With ETV
Evaluation of 16 patients with decompensated liver cirrhosis treated with ETV
5 developed lactic acidosis between 4 and 240 days after starting ETV
Lactic acidosis correlated with MELD score (P = ), INR (P = .003), bilirubin (P = .003), and creatinine (P = .008)
Lactic Acidosis During Treatment With ETV
All patients had MELD scores ≥ 22
Lactic acidosis
(n = 5)
No lactic acidosis
(n = 11)
CHB, chronic hepatitis B; ETV, entecavir; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease.
All patients had MELD scores ≤ 17
Lange CM, et al. Hepatology. 2009;50:

18. Severity/Outcomes of Lactic Acidosis in Decomp CHB Patients Treated With ETV
Lactic acidosis reversible after ETV D/C (n = 4)
1 death due to lactic acidosis
Conclusion: ETV should be used cautiously in CHB pts with high MELD score
Characteristics of Lactic Acidosis in 5 Patients
Outcome
Patient A
Resolved, OLT, virologic response
pH: 7.2, lactate: 50 mg/dL LA
Patient B
BE, base excess; CHB, chronic hepatitis B; D/C, discontinued; ETV, entecavir; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation.
pH: 7.1, lactate: 200 mg/dL
Death LA
Resolved, virologic response
Patient C LA
pH: 7.4, lactate: 35 mg/dL, BE: -5 mmol/L
Lamivudine
Patient D LA
pH: 7.3, lactate: 65 mg/dL
Tenofovir
Resolved
Patient E
Resolved, virologic response LA
pH: 7.4, lactate: 26 mg/dL, BE: -6 mmol/L
Tenofovir
Days of ETV Therapy
240
Lange CM, et al. Hepatology. 2009;50:

19. Choice of Agent in Decompensated Cirrhotics With LAM Resistance
ETV monotherapy not a recommended strategy for patients with LAM resistance due to increased risk of ETV resistance over time in this population[20]
Guidelines recommend adding or switching to TDF[21,22]
Therefore, TDF may be preferred in decompensated cirrhotic patients with LAM-resistant HBV infection
Small pilot study showed combination therapy with ETV plus TDF effective and well tolerated in CHB patients with decompensated cirrhosis[23]
CHB, chronic hepatitis B; ETV, entecavir; LAM, lamivudine; TDF, tenofovir.
20. Sherman M, et al. Hepatology. 2008;48: Lok AS, et al. Hepatology. 2009;50: EASL. J Hepatol. 2012;[Epub ahead of print]. 23. Amarapurkar D. EASL Abstract 901.

20. Summary: Choice of Agent for CHB Patients With Decompensated Cirrhosis
Tenofovir
Entecavir
Limited data supporting efficacy and safety
No specific indication in this population
May be preferred in patients with lamivudine resistance
Concerns regarding nephrotoxicity
Risk of lactic acidosis, as with all nucleoside analogues
More extensive data supporting efficacy and safety
Specific indication in this population at 1.0 mg/day
Risk of lactic acidosis specifically studied and reported in this population
CHB, chronic hepatitis B.

21. Special Considerations When Managing HBV Tx in Decompensated Cirrhotics
Higher rate of serious hepatic adverse events observed in this population, particularly in those with CTP class C disease, compared with rates in patients with compensated liver function
Therefore, clinical and laboratory parameters should be closely monitored in this patient population
On-treatment monitoring every 3 mos
Monitor renal function before and during therapy
Adjust dosing frequency of entecavir and tenofovir per manufacturer’s recommendations as needed
Therapy for patients with cirrhosis should be long term
Decompensated patients who undergo HBeAg seroconversion still might develop HCC or have progression of liver disease
Continue therapy until HBV DNA undetectable and patient has lost HBsAg
CTP, Child-Turcotte-Pugh; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; Tx, treatment.

22. Go Online for More Information on Treatment Selection for CHB Patients With Decompensated Cirrhosis!
Clinical Focus Concise online CME-certified module resembling PowerPoint “handout” format, with large slide thumbnails paired with supporting text discussion that includes interactive polling questions
clinicaloptions.com/Cirrhosis