Robert S. Brown, Jr., MD, MPH Frank Cardile Professor of Medicine Chief, Center for Liver Disease Columbia University College of Physicians & Surgeons

Robert S. Brown, Jr., MD, MPH Frank Cardile Professor of MedicineChief, Center for Liver DiseaseColumbia University College of Physicians & SurgeonsNewYork-Presbyterian HospitalNew York, New York

Treatment Selection for HBV-Infected Patients With Decompensated Cirrhosis

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clinicaloptions.com/hepatitisTreatment Selection for CHB Patients With Decompensated Cirrhosis

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Faculty Disclosures

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


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]

1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. de Jongh FE, et al. Gastroenterol. 1992;103:1630-1635.


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

3. Lok AS, et al. Hepatology. 2009;50:661-662. 4. EASL. J Hepatol. 2012;[Epub ahead of print]. 5. Buster EH, et al. Hepatology. 2007;46:388-394.


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

Tenofovir [package insert]. January 2012.


Study 0108: Safety of TDF vs FTC/TDF vs ETV in CHB Pts With Decomp Cirrhosis

HBV-infected pts with decompensated

liver disease*(N = 112)

TDF 300 mg(n = 45)

ETV 0.5 mg or 1 mg(n = 22)

FTC/TDF 200/300 mg(n = 45)

Liaw YF, et al. Hepatology. 2011;53:62-72.

Wk 48: interim analysis Wk 168

*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.

Randomized, double-blind phase II study


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† 6.7 4.5

Confirmed ≥ 0.5 mg/dL increase in creatinine 8.9† 2.2 4.5

Confirmed phosphorus < 2.0 mg/dL 2.2 4.4 0

Confirmed ≥ 0.5 mg/dL increase in creatinine and confirmed phosphorus < 2.0 mg/dL

2.2 0 0

*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.


Study 0108: Median Serum Creatinine by Study Visit


0.90 TDF0.90 TDF/FTC0.80 ETV

No cases of lactic acidosis reported in any treatment arm

1.0M

edia

n C

reat

inin

e (m

g/d

L)

0

0.90.8

0.70.6

0.5

0.4

0.3

0.2

0.1

04 8 12 16 20 24 28 32 36 40 44 48

Wks on Study

454522

454421

424319

404220

394219

394218

404219

384219

374219

374218

384117

374216

374216

TDFFTC/TDFETV

Pts at Risk, n


Study 0108: Efficacy Results at Wk 48


Efficacy Result 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, % 0 2.6 0

Median change in serum ALT from baseline, U/L -7.0 -16.5 -25.5

HBeAg loss, % 21.4 26.7 0

HBeAg seroconversion, % 21.4 13.3 0


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

Entecavir [package insert]. December 2010.


ETV-048: ETV vs ADV in CHB Patients With Evidence of Hepatic Decompensation Randomized, open-label phase IIIb 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


ETV-048: Mean HBV DNA Change From Baseline Through Wk 48

Difference in HBV DNA responses favoring ETV persisted when analyzed by subgroup (LAMr or HBeAg status), although magnitude of differences varied


Mea

n H

BV

DN

A

(lo

g1

0 c

op

ies/

mL

)

B/L

9

8

7

6

5

4

3

2

1

4 8 12 16 20 24 28 32 36 40 44 48Treatment (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 MeasurementsETVADV

10091

9888

9280

8780

7673

7166

6961


ETV-048: Improvement in MELD/CTP Scores


ParameterWk 24 Wk 48

ETV ADV 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)

*Noncompleter = failure.†CTP class C/B to A only.


ETV-048: Safety of ETV vs ADV in CHB Patients With Decompensated Cirrhosis


Grade 2 lactic acidosis reported in only 1 ETV-treated patient; it resolved on continued ETV and did not require treatment

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) 18 (20)

Liver transplantation 11 (11) 3 (3)


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 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

*P values not significant for any parameter at any time point between compensated and decompensated group.

Shim JH, et al. J Hepatol. 2010;52:176-182.


Improved CTP and MELD Scores in Decomp CHB Patients Treated With ETV

Shim JH, et al. J Hepatol. 2010;52:176-182.

Ch

ang

e i

n C

TP

Sco

re T

hro

ug

h

12 M

os 8

6

4

28.1 ± 1.7

P < .001

10

12

6.6 ± 2.4

At 12 Mos

At Pretreatment

Ch

ang

e i

n M

EL

D S

core

Th

rou

gh

12

Mo

s 16

12

10

211.1 ± 3.8

P < .00118

20

8.8 ± 2.3

At 12 Mos

At Pretreatment

14

8


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 = .002), INR (P = .003), bilirubin (P = .003), and creatinine (P = .008)

Lactic Acidosis During Treatment With ETV

No lactic acidosis (n = 11)

Lactic acidosis(n = 5)

All patients had MELD scores ≥ 22

All patients had MELD scores ≤ 17

Lange CM, et al. Hepatology. 2009;50:2001-2006.


Resolved, OLT, virologic response

Outcome

Death

Resolved,virologic response

Resolved

Resolved, virologic response

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

Lange CM, et al. Hepatology. 2009;50:2001-2006.

Characteristics of Lactic Acidosis in 5 PatientsPatient A

Patient B

Patient C

Patient D

Patient E

pH: 7.1, lactate: 200 mg/dL



pH: 7.4, lactate: 26 mg/dL, BE: -6 mmol/L

pH: 7.4, lactate: 35 mg/dL, BE: -5 mmol/L

Tenofovir

Tenofovir

Lamivudine

0 240Days of ETV Therapy

LA

LA

LA

LA

LA


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]

20. Sherman M, et al. Hepatology. 2008;48:99-108. 21. Lok AS, et al. Hepatology. 2009;50:661-662. 22. EASL. J Hepatol. 2012;[Epub ahead of print]. 23. Amarapurkar D. EASL 2009. Abstract 901.


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


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

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

http://www.clinicaloptions.com/Cirrhosis

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Robert S. Brown, Jr., MD, MPH Frank Cardile Professor of Medicine Chief, Center for Liver Disease Columbia University College of Physicians & Surgeons