1 Fad Connecta HBV therapy in naive pts Lampertico revised...

Efficacia terapeuticaAntiviral treatment of chronic Hepatitis BPietro LamperticoU.O. Gastroenterologia IFondazione IRCCS Cà Granda - Ospedale Maggiore PoliclinicoUniversità di Milano

Compensated CirrhosisVito Di MarcoGastroenterologia & EpatologiaDi.Bi.M.I.S.Università di Palermo

Antiviral treatment of chronic Hepatitis BPietro LamperticoU.O. Gastroenterologia IFondazione IRCCS Cà Granda - Ospedale Maggiore PoliclinicoUniversità di Milano

Goals and Endpoints of Therapy

To improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, HCC, and death

Therapy must reduce HBV DNA level to as low as possible, ideally below the lower limit of detection of real-time PCR assays (10-15 IU/mL)

Adapted from EASL Clinical Practice Guidelines. J Hepatol 2009;50:227-242.

Anti-HBV Active Compounds

Classes Drug type ApprovedAnalogues • Nucleoside • Lamivudine

• Entecavir

• Telbivudine

• Clevudine (Korea)

• Nucleotide • Adefovir dipivoxil

• Tenofovir DF

Cytokines • Interferon alfa

• Peg-IFN alfa-2a

Undetectable HBV DNA in HBeAg Positive and HBeAg Negative Patients at 1 Year

HBeAg Positive HBeAg Negative


These trials used different HBV DNA assays and they were not head-to-head comparisons for all the drugs.

100

80

60

40

20

0

ADV Peg-IFN

alfa

LAM LDT ETV TDF

21 24

39

6067

74

100

80

60

40

20

0

ADV LAM LDT ETV TDF

51

6372

88 90 91

Peg-IFN

alfa

Incidence of Resistance in NUC-Naïve Patients


*Collation of currently available data – not from head-to-head studies

29

70

18

67

0

11

49

0.5

38

0.20

24

0

20

40

60

80

LAM ADV LDT ETV TDF

Patie

nts

(%)

17

3 1.2?4?1.2

1.20

1st generation

2nd generation

3rd generation

0

Anti-HBV Therapy: How to Start

*TDF not available.

CHB treatment guidelines

ANZ CHB guidelines(Oct 2008)

EASL(Apr 2009)

AASLD(Nov 2009)

Keeffe et al algorhythm (Aug 2008)

APASL*(Sep 2008)

Preferredfirst line

treatments

TDFETV

Peg-IFN

Peg-IFNETVTDF

TDFETV

Peg-IFN

Peg-IFNETVTDF

IFN/Peg-IFNADVETV

LDT, LAM

Therapeutic Strategies for CHB

SHORT-TERM “CURATIVE” TREATMENT

HBV DNA <2000 IU/mLALT < UNL

On treatment response

HBsAgloss

Follow-up (mo/yrs)IFN

LONG-TERM "SUPPRESSIVE" TREATMENT

HBV-DNA undetectable by PCR (<10-15 IU)

NUC

HBsAgseroconv.

YEARS

HBeAg Positive

Modulo 1

48-Week Therapy in NUC-Naïve HBeAg Positive CHB: Virological and Serological Response


*Collation of currently available data – not from head-to-head studies (LLQ of HBV DNA assays: 300-400 copies/mL)

0%

20%

40%

60%

80%

100%

Peg-IFN LAM ADV TDF

Undetectable HBV-DNA

25%

39%

21%

ETV

67%

LdT

60%

74%

Peg-IFN LAM ADV TDF

HBeAg seroconversion

22%

12%

ETV

22%

LdT

26%30%

21%

0%

20%

40%

60%

80%

100%

3-Year Follow-Up Peg-IFN alfa-2b in HBeAg(+) CHB

Buster EH, et al. Gastroenterology 2008;135:459-467.

Outcome at 3 years of follow-up in 64 patients with HBeAg loss at 6 months post-treatment

HBeAgnegative

ALTnormal

HBV-DNA<10,000

copies/mL

HBsAgnegative

0

10

20

30

40

50

60

70

80

90

100In

itial

resp

onde

rs (%

)

81%78%

58%

30%

Kaplan-Meier: 69% 78% 52% 29%

52 492937

45%

HBV-DNA<400

copies/mL

19

85%

3-Year Follow-Up of Peg-IFN HBeAg Responders: Outcome by HBV Genotype

Buster EH, et al. Gastroenterology 2008;135:459-467; Flink HJ, et al. Am J Gastroenterol 2006;101:297-303.

0

20

40

60

80

100

B C D

9686

6777

A

HB

eAg

nega

tive

(%)

0

20

40

60

80

100

B C D

96

71

89

47

A

HBV genotype

Nor

mal

ALT

(%)

C6

0

20

40

60

80

100

B D

58

14 0AHBV genotype

HB

sAg

nega

tive

(%)

n=64

0

20

40

60

80

100

B C D

81

29

4435

AHB

V-D

NA

<10,

000

c/m

L(%

)

HBeAg neg activedisease

Peg-IFN HBV in HBeAg Positive CHB: Baseline Predictors

Buster EH, et al. Gastroenterology 2008;135:459-467.

C D

HBV genotype

HBV genotype

Average chance of SVR

HBV-DNA (copies/mL)

ALT

HBV-DNA (copies/mL)

ALT

Average chance of SVR

BA

<9 log ≥9 log ≥9 log

≥2 x ULN <2 x ULN

28%31%54%

<2 x ULN

and andor


≥2 x ULN <2 x ULN

21%28%30%

<2 x ULN

and andor


≥2 x ULN <2 x ULN

16%22%36%

<2 x ULN

and andor


≥2 x ULN <2 x ULN

6%9%17%

<2 x ULN

and andor

>30% sustained viral response

Peg-IFN alfa-2a in HBeAg Positive. On-Treatment Predictor: HBV-DNA at Week 12

Lau GK, et al. AASLD 2008, P919 DISCLOSURE INFORMATION.

CR = HBeAg seroconversion + HBV DNA ≤10,000 copies/mL

32.123.6 21.0

14.4

3.30.0

10.0

20.0

30.0

40.0

50.0

60.0

HBeAgseroconv

HBV-DNA≤10,000

HBV-DNA≤400

HBsAgloss

CR

ALL PATIENTS

HBV-DNA at WEEK 12 (Peg-IFN)

29%

47%

24% ≤5 log10

5.01-9 log10

>9 log10

HBV-DNA <5 log10copies/mL (n=78)

28.2

18.5 16.17.3

3.20.0

10.0

20.0

30.0

40.0

50.0

60.0

HBeAgseroconv

HBV-DNA≤10,000

HBV-DNA≤400

HBsAgloss

CR

14.37.9 6.3 7.9

1.60.0

10.0

20.0

30.0

40.0

50.0

60.0

HBeAgseroconv

HBV-DNA≤10,000

HBV-DNA≤400

HBsAgloss

CR

53.8

43.6 41.0

29.5

5.1

0.0

10.0

20.0

30.0

40.0

50.0

60.0

HBeAgseroconv

HBV-DNA≤10,000

HBV-DNA≤400

HBsAgloss

CR

HBV-DNA 5-9 log10copies/mL (n=124)

HBV-DNA >9 log10copies/mL (n=63)

24% ≤1500

1501–20,000

21%

55% >20,000

Peg-IFN alfa-2a in HBeAg-Positive. On-Treatment Predictor: HBsAg at Week 12

Lau GK, et al. AASLD 2008, P919 DISCLOSURE INFORMATION.

CR = HBeAg seroconversion + HBV-DNA ≤10,000 copies/mL

27.924.0 19.9

14.0

3.70.0

10.0

20.0

30.0

40.0

50.0

60.0

HBeAgseroconv

HBV-DNA≤10,000

HBV-DNA≤400

HBsAgloss

CR

ALL PATIENTS; PEGASYS ± LAM

HBsAg LEVELS AT WEEK 12

HBsAg ≤1500 IU/mL; PEGASYS ± LAM (n=109)

29.4

22.6 19.411.1

1.80.0

10.0

20.0

30.0

40.0

50.0

60.0

HBeAgseroconv

HBV-DNA≤10,000

HBV-DNA≤400

HBsAgloss

CR

15.68.2 4.9 4.1 3.3

0.0

10.0

20.0

30.0

40.0

50.0

60.0

HBeAgseroconv

HBV-DNA≤10,000

HBV-DNA≤400

HBsAgloss

CR

53.846.8

41.331.2

10.1

0.0

10.0

20.0

30.0

40.0

50.0

60.0

HBeAgseroconv

HBV-DNA≤10,000

HBV-DNA≤400

HBsAgloss

CR

HBsAg 1501-20,000 IU/mL;

PEGASYS ± LAM (n=279)

HBsAg >20,000 IU/mL;PEGASYS ± LAM (n=122)

5-Year ETV for HBeAg Positive CHB: Virological Response

Han S, et al. 59th AASLD, October 31-November 4 ,2008. San Francisco, USA. Poster 893.

*Different dosing regimen for naïve patients in the 901 study.†Five patients who remained on treatment at year-5 visit had missing PCR values (NC=M).

Prop

ortio

n of

pat

ient

s (%

)H

BV-

DN

A <

300

copi

es/m

L

n =

ETV-022

55%

Year 1

83%

Year 2

89%

Year 3

67%

236/354

Year 4

91%

80/146 116/140 116/131 98/108

Year 5

88/94†

94%Year 1

0

20

40

60

80

100

HBeAg(+) Baraclude long-term cohort (ETV-022 → ETV-901)

Long-Term ETV Treatment in NUC-Naïve Patients: Histological Improvement

Adapted from Liaw Y-F, et al. AASLD, October 3–November 4, 2008. San Francisco, USA. Poster 894. Hepatology 2008;48:706A.

Histological improvement*

* ≥2-point decrease in Knodell necroinflammatory score and no worsening of Knodell fibrosis score compared to baseline.

‡ Median time of long-term biopsy: 280 weeks (range 144–316 weeks).

73%

96%

Prop

ortio

n of

pat

ients

(%)

0

20

40

60

80

100

Week 48 Long-term‡

41/56† 55/57

Improvement in Ishak fibrosis score(≥1-point decrease)

32%

88%

0

20

40

60

80

100

Week 48 Long-term‡

18/56† 50/57

Prop

ortio

n of

pat

ients

(%)

† One patient had an inadequate week 48-biopsy.

ETV in NUC-Naïve Patients with CHB. Six-Year Histological Data: Staging

Adapted from Liaw Y-F, et al. AASLD, October 3–November 4, 2008. San Francisco, USA. Poster 894. Hepatology 2008;48:706A.

Ishakfibrosis score

123456

Missing0

n=570

10

20

30

40

50

60

Baseline Week 48 Long-term

Patie

nts (

n)

*Median time of long-term biopsy: 6 years (range 3-7 years).

3-Year TDF for HBeAg Positive CHB: Virological Response

Heathcote J-E, et al. AASLD 2009; Poster #483.

*Includes 17 patients who had HBV-DNA <400 copies/mL at week 144 on FTC + TDF

Open-label TDF

Patie

nts

with

HB

V-D

NA

<400

cop

ies/

mL

(%)

Randomized double-blind

95% TDF-TDF91% ADV-TDF

On treatment observed*

0

10

20

30

40

50

60

70

80

90

100

W eeks on s tudy0 24 48 72 96 1 20 1 4 4


LTE-TDF analysis

3-Year TDF for HBeAg Positive CHB. Serological Response: HBeAg


0

5

10

15

20

25

30

35

On treatment

% P

atie

nts

0

5

10

15

20

25

30

35

On treatment

% P

atie

nts

23%

30%34%

22%

26% 26%

HBeAg loss HBeAg seroconversion

Year 1 2 3

3-Year TDF for HBeAg Positive CHB. Serological Response: HBsAg


• 14/20 patients with HBsAg loss discontinued treatment and entered treatment-free follow-up, (mean 171 days off treatment)

• 2/20 patients who seroconvertedto anti-HBs have discontinued from the study

8% , 8% HBeAg+ patients

At week 48 all patients started open-label TDF

HBeAg Negative

Modulo 1

48-Week Therapy in NUC-Naïve HBeAg Negative CHB. Virological Response


0%

20%

40%

60%

80%

100%

Peg-IFN LAM ADV ETVLDT TDF

63%72%

51%

90%88% 91%

*Collation of currently available data – not from head-to-head studies (LLQ of HBV-DNA assays: 300-400 copies/mL)%

Pat

ient

s w

ith H

BV-

DN

A <

LOQ

Peg-IFN alpha-2a in HBeAg Negative CHB. Sustained Response (5-yr)

Marcellin P, et al. APASL 2009; Abstract PE086.

0

10

20

30

40

50

17

HBV-DNA <400 copies/mL

21

HBV-DNA<10,000 copies/mL

22

ALTnormalization

Patie

nts

(%)

PEGASYS ±lamivudine (n=230)

HBsAgclearance

12

Virological Response Rates During Post-Treatment Follow-Up (ITT Analysis)

0

10

20

30

40

50

60

70

80

P=0.03

11/51 15/52 6/51 15/52

6 months post-treatment 12 months post-treatment

Patie

nts

with

HB

V-D

NA

<2

000

IU/m

L(%

)

22

29

12

29

48 weeks (Arm A)

96 weeks (Arm B)

P=NS

HBsAg Response at EOT and During Post-Treatment Follow-Up (ITT Analysis)

0

10

20

30

Patie

nts

with

resp

onse

(%)

HBsAg ≤10 IU/mLHBsAg clearance

End of treatment

12 monthspost-treatment

1/52 3/520/510

0/510 2

6

5/520/51

10

02/51 4/52

4

8

P=0.06

End of treatment

12 monthspost-treatment

48 weeks (Arm A)

96 weeks (Arm B)

Peg-IFN in HBeAg(–) Disease. Stopping Rule at Week 12

Any HBsAg decline

HBV-DNA decline(copies/mL)

102*patients

NON=54

YESN=48

<2 logN=20

≥2 logN=34

<2 logN=20

≥2 logN=28

*Serum at week 12 was not available in 5/107 patients

Chance of SR 0% 24% 25% 39%

Rijckborst V, et al. Hepatology 2010; in press.

HBsAg Decline from BL Is Significantly Associated with Sustained Immune Control

Marcellin et al. submitted

47 P=0.0005 P=0.0078

HBsAg decline from BL to week 12≥10%

<10%44% of patients56% of patients

WEEK 12 WEEK 24

HBsAg decline from BL to week 24≥10%

<10%56% of patients44% of patients

43

1613

0

10

20

30

40

50

60

N=25 N=11 N=29 N=53

HB

V-D

NA

≤10

,000

cop

ies/

mL

1-ye

ar p

ost-t

reat

men

t (%

)

ETV in HBeAg(–) Retreatment Cohort. Virological Response through 3 Years*

Adapted from Shouval D, et al. 59th AASLD Meeting, October 31–November 4, 2008, San Francisco, USA. Poster 927.

*<300 copies/mL = 57 IU/mL†Different dosing regimen for naïve patients in the 901 study.‡10 patients who remained on treatment at week 144 of ETV-901 visit had missing PCR samples.

ETV-901†

Off treatm

ent >60 days

4%

59%

83%93% 94% 91% 95%94%

Prop

ortio

n of

pat

ient

s (%

)

0

20

40

60

80

100

n 93/99 4/99 56/95 79/95 84/90 72/77 67/74 54/57‡

EOD Baseline Wk 12 Wk 24 Wk 48 Wk 72 Wk 96 Wk 144

ETV-027

3-Year TDF for HBeAg Negative CHB. Virological Response

Marcellin P, et al. AASLD 2009; Poster 481.


*Includes 3 patients who had HBV-DNA <400 copies/mL at week 144 on FTC + TDFPa

tient

s with

HBV

-DNA

<400

copi

es/m

L(%

)

0 24 48 72 96 120 144

Weeks on study

Randomized double-blind Open-label TDF


LTE-TDF analysis

On treatment observed*

0

10

20

30

40

50

60

70

80

90

100

Safety NUC

Modulo 1

ETV in Patients with Chronic Hepatitis B. Safety through 5 Years†

ETVN=354

LAMN=355

On-treatment AEs, % 87 84

Serious AEs, % 8 8

On-treatment AEs attributed to study therapy (≥5%)Fatigue, %Increased ALT, %Headache, %

64

10

578

Discontinuation due to AEs, n (%) 1 (<1) 9 (3)

On-treatment ALT flares, n (%)‡ 12 (3) 23 (7)

*ETV = Mean duration: 80.8 weeks (range 0.1-134.4); LVD = Mean duration: 67.7 weeks (range 0.1-104.6).†ETV monotherapy received for mean 193 weeks (median 196 weeks); 132 patients with ETV + LVD for mean 26 weeks (median 24 weeks) followed by ETV monotherapy for mean 194 weeks (median 221 weeks). ‡ ETV group: 11/12 ALT flares associated with at least a 2-log10 HBV-DNA reduction. 11/12 ALT flares resolved within 1-7 weeks.LVD group: 11/23 on-treatment ALT flares associated with increasing HBV-DNA levels that preceded or coincided with the flare. 8/11 of these flares persisted up to treatment discontinuation (treatment failure).

The 5-year safety profile for ETV in NA-naïve HBeAg(+) patients (n=146) was consistent with previously reported experience

Gish RG, et al. Gastroenterol 2007;133:1437-1444.Han S, et al. 59th AASLD, October 31-November 4, 2008, San Francisco, USA. Poster 893. Hepatology 2008;48(suppl):705A.

TDF in Patients with Chronic Hepatits B. Summary of Safety through 3 YearsHBeAg negative

(Study 102)HBeAg positive

(Study 103)

TDF-TDF(N=235)

ADV-TDF(N=112)

TDF-TDF(N=154)

ADV-TDF(N=84)

Study drug-related SAE 1 (<1%) 0 2 (1.3%) 2 (2.4%)

DeathsCholangiocellular carcinomaCervical cancer metastasesNasopharyngeal carcinoma

2 (<1%)101

1 (<1%)010

0000

0000

G3 or G4 laboratory 32 (14%) 17 (15%) 19 (12.3%) 13 (15.5%)

Discontinue due to an AEHCCDizziness, fatigue, lack of concentrationCreatinine Septic shock

3 (1.3%)1101

00000

1 (<1%)0010

00000

Confirmed ↓ phosphorus <2 mg/dL 2 (<1%) 1 (<1%) 0 1 (1%)

Confirmed 0.5 mg/dL in creatinine 0 0 0 2 (2%)

Confirmed creatinine clearance <50 mL/min 0 0 0 0

NUC in Clinical Practice

Modulo 1

Real-World Studies Can Add Valuable Additional Insights to RCT Data

RCTs systematically exclude special populations –patients with concurrent diseases, concurrent drug use, at age extremes, or at risk of non-compliance

Studying real-world populations gives valuable additional insights in heterogeneous populations

http://www.fda.gov/Safety/SafetyofSpecificProducts/ucm180547.htm. (Accessed April 2010).

VIRGIL Network: ETV in Real Life Patients with CHB. Virological Response through 12 Months

Adapted from Reijnders JG, et al. 44th EASL, 22-26 April 2009; Copenhagen.

*HBV-DNA <80 IU/mL0 2 4 6 8 10 12

0

20

40

60

80

100 104 NUC-naïve patients

Treatment (months)

Cum

ulat

ive

prob

abili

ty o

f res

pons

e (%

)

79%

VIRGIL Network: ETV in Patients with CHB. Secondary Outcomes through 12 Months

Reijnders JG, et al. Oral presentation. 19th APASL, 13-16 February, 2009. Hong Kong, China. Published by Reijnders JG, et al. J Hepatol 2010;52:493-500.

19%

70%

0%2%

Prop

ortio

n of

pat

ient

s (%

)

NUC-naïve patients (N=104)

0

20

40

60

80

100

HBeAg loss

0%

HBsAg loss ALTnormalization

Virologicbreakthrough

Genotypic ETVresistance

Italian Network: ETV in Real Life Patients with CHB Virological Response through Week 96

Lampertico P, et al. 60th AASLD October 30-November 3, 2009. Boston, MA, USA.

0

20

40

60

80

100

0%

24

73%

% P

atie

nts

with

und

etec

tabl

eH

BV-

DN

A

87%

7248

94%

Baseline

359376 335 246Patients on follow-up

96%

120

Weeks96

Italian Network: ETV in Real Life Patients with CHB HBeAg Seroconversion through Month 24

Lampertico P, et al. 60th AASLD October 30-November 3, 2009. Boston, MA, USA.

38%

0

20

40

60

80

100

20%Patie

nts

with

HB

eAg

sero

conv

ersi

on

65Patients:

At riskOn follow-up

Months6

596065

124453

182338

6

24

18

0

Asian Study: ETV in NUC-Naïve Patients with CHB. HBV-DNA Undetectability through Year 3

Adapted from Seto WK, et al. 20th APASL, 25-28 March, 2010. Beijing, China. FP95. Hepatol Int 2010;4;58.

Lower limit of quantification: 60 copies/mL

Year 1 Year 2 Year 3

0

20

40

60

80

100

Cum

ulat

ive

prop

ortio

n w

ith

unde

tect

able

HB

V-D

NA

(%)

71

8882

95

80

98

HBeAg(+)

HBeAg(–)

No. of patients 76 4190 132 112 60

Asian Study. ETV in NUC-Naïve Patients with CHB. HBeAg Seroconversion through Year 3

Seto WK, et al. 20th APASL, 25-28 March, 2010. Beijing, China. FP95.

No. of patients 90 76 39

Year 1 Year 2 Year 30

20

40

60

80

100

Cum

ulat

ive

prop

ortio

n w

ithH

BeA

gse

roco

nver

sion

(%)

22

41 44

Challenges to NUC Therapy

When to start antiviral therapy?

When to stop antiviral therapy?

Anti-HBV Therapy: When to Start



EASL(Apr 2009)

AASLD(Nov 2009)


APASL*(Sep 2008)

HBeAg positiveHBV-DNA

>20,000 IU/mL+ ALT >2 x ULNBx prior to Rx

HBV-DNA>2,000 IU/mL

and/orALT ≥ ULN

+ Bx

HBV-DNA>20,000 IU/mL

+ ALT ≥2 x ULNor

Moderate/severe hepatitis on Bx

HBV-DNA>20,000 IU/mL+ elevated ALT


+ ALT >2 x ULNor


HBeAg negative

HBV-DNA>2,000 IU/mL

+ ALT >2 x ULNor



+ ALT ≥2 x ULN

HBV-DNA>2,000 IU/mL

+ elevated ALT

HBV-DNA>2,000 IU/mL

+ ALT >2 x ULNor


*TDF not available.

Anti-HBV Therapy: Endpoints/Stopping Rules



EASL(Apr 2009)

AASLD(Nov 2009)


APASL(Sep 2008)

HBeAg positive on NA

HBeAgseroconversionfollowed by 6-12 months treatment

HBeAgseroconversion + undetectable DNAfor 6-12 months

HBeAgseroconversion +

undetectable HBV-DNA for 6 months

HBeAgseroconversion + undetectable DNA

Continue for 12 months

HBeAgseroconversion + undetectable DNA

for 6 months

HBeAg negativeon NA

Continue untilHBsAg clearance

HBsAgseroconversion

Continue untilHBsAg clearance

HBsAgseroconversion

Consider if DNA undetectable 3 times 6 months

apart

Compensated CirrhosisVito Di MarcoGastroenterologia & EpatologiaDi.Bi.M.I.S.Università di Palermo

Management of HBV Compensated Cirrhosis: Key Points

1. To evaluate the stage of cirrhosis

2. To identify factors associated with increased risk of HCC and decompensation

3. To identify patients requiring treatment

4. To choice antiviral drugs

5. To evaluate surrogate markers of efficacy of antiviral therapy

6. To manage adverse events of antiviral drugs

7. To assess the effectiveness of antiviral therapy

Characteristics of Patients with HBV Compensated Cirrhosis in ItalyCharacteristics Fattovich (1) Benvegnù (2) Di Marco (3) Lampertico (4)

Number of patients 161 43 198 94

Age (years, mean) 48 52 53 56

Gender (% males) 89 88 87 84

HBeAg positive (%) 36 ND 0 14

HBeAg negative (%) 64 ND 100 86

Esophageal varices (%) 38 ND ND ND

ALT >2 ULN (%) 55 ND 60.5 ND

(1) Fattovich G, et al. Am J Gastroenterol 2002;97:2886 -2895. (2) Benvegnù L, et al. Gut 2004;53:744-749.

ND: not done; ULN: Upper Limit of Normal.

(3) Di Marco V, et al. Hepatology 2004;40:883-891.(4) Lampertico P, et al. Gastroenterology 2007;133:1445-1451.

Natural Course of HBV Compensated Cirrhosis

Cumulative incidence of HCC and decompensation in 161 untreated Italian patients with compensated HBV cirrhosis

Fattovich G. Am J Gastroenterol 2002;97:2886-2895.

Hepatocellular Carcinoma (HCC)

Incidence per 100 person/year: 2.25-year cumulative incidence: 9% • HBeAg negative/HBV-DNA negative: 8%• HBeAg negative/HBV-DNA positive: 14%• HBeAg positive: 9%

Liver decompensation

Incidence per 100 person-year: 3.3 5-year cumulative incidence: 16% • HBeAg negative/HBV-DNA negative: 4%• HBeAg negative/HBV-DNA positive: 14% • HBeAg positive: 16%

0 1 2 3 4 5 6 7 8 9 100

20

40

60

80

100%

HCC

decompensation

No. at Risk

Relationship Between Serum HBV-DNA and HCC IncidenceC

umul

ativ

e in

cide

nce

of H

CC

in 3

,653

obs

erve

d pa

tient

s (%

)

Baseline HBV-DNA (copies/mL)1 Million

100,000-999,999

10,000-99,999

300-9,999

<300

627 621 611 604 593 582 571 561 550 541 528 513 499 414

349 346 342 338 333 327 321 317 310 304 302 294 288 228

643 637 633 633 627 625 622 615 609 606 597 588 586 490

1161 1155 1146 1139 1137 1131 1129 1123 1119 1113 1102 1091 1082 879

873 865 862 854 850 845 836 826 823 819 814 807 802 720

Chen CJ, et al. JAMA 2006;295:65-73.

14

12

10

8

6

4

2

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13Year of Follow-up

Baseline HBV-DNA level (copies/mL)1 million100,000-999,99910,000-99,999300-9,999<300

Risk factors at study entry Risk factors at study entry

Risk Factors for HCC in Patients with Chronic HBV Infection

Chen CJ, et al. JAMA 2006;295:65-73.

HBsAg Clearance and Survival in Patients with Compensated Cirrhosis

Probability of survival in patients with and without HBsAg seroconversion

Fattovich G, et al. Am J Gastroenterol 1998;93:896-900.

0 24 48 72 96 120 144 168Months

No HBsAgclearance

20

40

60

80

100

Surv

ival

%

With HBsAgclearance

P<0.001

Retrospective study of 309 patients: 196 untreated and 82 treated with IFN.Mean follow-up: 5.7 years

End-Points of Antiviral Therapy in HBV Compensated Cirrhosis

Clinical end-points

• Reversal of cirrhosis

• Reduce rates of decompensation

• Reduce rates of HCC

• Prevent need for liver transplantation

• Reduce liver-related mortality

Virological end-points

• Sustained HBsAg loss, with seroconversion to anti-HBs(ideal end-point)

• Durable HBe seroconversion(satisfactory end-point)

• Maintained undetectable HBV-DNA level (desirable end-point)

NIH Consensus Development Conference Statement, Ann Intern Med 2009;150:104-110. EASL, Guidelines, 2009

Criteria for the Treatment of HBV Compensated Cirrhosis

Treatment of chronic hepatitis B: recommendations from an Italian workshop (1)

Treatment is mandatory in patients with compensated cirrhosis and detectable HBV-DNA, independently of ALT levels.

EASL Clinical Practice Guidelines: Management of chronic hepatitis B (2)

Treatment of patients with cirrhosis should not be based on ALT levels, as these may be normal in advanced disease.

AASLD Practice Guidelines. Chronic Hepatitis B: Update 2009 (3)

Treatment should be considered for patients with ALT >2 times normal, and for patients with normal or minimally elevated ALT if serum HBV-DNA levels are high (>2,000 IU/mL).

(1) Infection 2010 (in press); (2) J Hepatol 2009;50(2):227-242; (3) Hepatology 2009;50(3):661-662.

First Line Strategy: Interferon Therapy


Pegylated or standard interferon should only be considered in patients without a history of decompensation or without an imminent risk of decompensation and without features of portal hypertension (oesophagogastric varices), particularly if they are young, HBeAg positive and have predictors of favourable response (HBV-DNA <2,000,000 IU/mL, elevated ALT, non-D HBV genotype). As in the HBeAg positive setting interferon may induce hepatic flares, this treatment should be used with caution and in centres with experience in treating hepatitis B.


Interferon alpha increases the risk of sepsis and decompensation in patients with advanced cirrhosis. However, interferon can be used for the treatment of well compensated cirrhosis.


Patients with compensated cirrhosis are best treated with NAs because of the risk of hepatic decompensation associated with interferon-related flares of hepatitis.



Nucleoside-nucleotide analogues (NUCs) can be considered in all patients. First line option is the monotherapy with Entecavir or Tenofovir. Monotherapy with Telbivudine could be considered in patients with HBV-DNA <2,000,000 IU/mL. Lamivudine monotherapy is not indicated for the consistent risk of raising resistance.


The use of potent NUCs with very low risk of resistance, i.e. Tenofovir or Entecavir, is particularly relevant in this group of patients. Close monitoring of HBV-DNA levels is important and resistance must be prevented by adding a second drug without cross-resistance if HBV-DNA is not undetectable at week 48 of therapy. If Lamivudine has to be prescribed (because of localpolicy), it should be used in combination with Adefovir or preferably Tenofovir.


Patients with compensated cirrhosis are best treated with NAs because of the risk of hepatic decompensation associated with interferon-related flares of hepatitis. In view of the need for long-term therapy, Tenofovir or Entecavir is preferred.

First Line Strategy: Nucleosi(ti)de Analogues Treatment


Response to IFN in Patients with and without Cirrhosis

Niederau + 63% 47% nsLau D + 59% 24% 0.01van Zonneveld + 50% 29% 0.034Lin + 39% 35% nsBuster Peg-IFN2b + 33% 14% 0.02Papatheodoridis - 28% 27% nsBrunetto - 26% 18% nsCooksley Peg-IFN2a - 40% 45% ns

Cirrhosis Non-cirrhosisHBeAg P value

Response rates

Chu CM and Liaw YF. Semin Liver Dis 2006;26:142-152.

Safety of PEG-IFN-2b ± Lamivudine in Patients with Advanced Fibrosis

Advacend fibrosis:Ishak fibrosis score 4-6

No advanced fibrosis:Ishak fibrosis score 1-3

Buster EH, et al. Hepatology 2007;46:388-394.

Prop

ortio

nof

pat

ient

sw

ithou

tHC

C

Years0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0 Responder, no cirrhosis

Non responder, no cirrhosis

Responder, cirrhosis

Non responder, cirrhosis

Independent predictors of HCC

Age RR 1.07, p=.032Albumin RR 0.79, p=.003Cirrhosis RR 9.62, p=.009IFN response RR 0.08, p=.027

HCC Incidence in HBeAg Positive Patients Treated with Interferon

Patients included in the study:165

Patients with cirrhosis: 60 (36.3%)

Response to treatment:HBeAg loss within 12 months after the end of IFN therapy.

Patients with virological response: 54 (33%)

Median follow-up: 8.8 years

Van Zonneveld M, et al. Hepatology 2004;39:804-810.

Clinical Events in HBeAg Negative Cirrhosis Treated with Interferon

Patients withcirrhosis

Patients with virologicalresponse

Follow-up(years, median)

Clinical events during the follow-up

HCC Decompensation

Papatheodoridis(2001)

125 16 (12.8%)

6 27(21.6%)

41 (32.8%)

Brunetto(2002)

62 8 (12.9%)

6 6(9.7%)

8 (12.9%)

Lampertico(2003)

35 12 (34.2%)

4.5 5 (14.2%)

7 (20.1%)

Papatheodoridis GV. J Hepatol 2001;34:306-313.Brunetto M. J Hepatol 2002;36:263-270.Lampertico P. Hepatology 2003;37:756-763.

Improvement of Liver Fibrosis in Patients Treated with Entecavir

BaselineIshak fibrosis=6

Week 48 Ishak fibrosis=6

Week 268 Ishak fibrosis=2

Chang TT, et al. 19th APASL meeting, February 13-16, 2009, Hong Kong, China.

Regression of Fibrosis in Patients on Treatment with Entecavir

Knodell fibrosis score

n=19 with evaluable biopsies at baseline,year 1 and year 3

1=portal

3=bridging

4=cirrhosis

0=none

Adapted from Takehara T, et al. 18th APASL meeting, March 23-26, 2008, Seoul, Korea. Poster PP007.

Num

ber o

f pat

ient

s

0

3

6

9

12

15

18

Baseline Year 1 Year 3

Reversal of Cirrhosis

Adefovir

7/12 (58%) patients with bridging fibrosis or pretreatment cirrhosis improved in their Ishak fibrosis scores by at least 2 points with up to 5-year treatment

3/4 patients with cirrhosis improved by 4 points

Hadziyannis S. Gastroenterology 2006;131:1743-1751

Effects of Lamivudine on Disease Progression and HCC

Cas

es w

ith d

isea

se

prog

ress

ion

(%)

Time to disease progression (months))

PLB (n=215) ITT populationLAM (n=436) P=0.001

Placebo

Lamivudine

36302416126

0

5

10

15

20

25

n=122

n=43

n=173

n=385

n=417

n=198

Liaw YF, et al. N Engl J Med 2004;351:1521-1531.

Incidence of HCC in Advanced CHB Treated with Lamivudine

0

5

10

15

0 6 12 18 24 36 48 Months

Dia

gnos

is o

f HC

C(%

of p

atie

nts)

Placebo

Lamivudine

No. at riskPlaceboLamivudine

215 198 184 173 153 43209

436 417 400 385 347 122429

P=0.047


Disease Progression in Patients Treated with Lamivudine

LAM 100 mg Placebo Hazard ratio P

(n=436) (n=215) (95% CI)

Overall disease progression 34 (7.8%) 38 (18%) 0.45 (0.28-0.73) 0.001

Increase in C-P score 15 (3.4%) 19 (8.8%) 0.45 (0.22-0.90) 0.023

Hepatocellular carcinoma 17 (3.9%) 16 (7.4%) 0.49 (0.25-0.99) 0.047*

Renal insufficiency 2 (0.5%) 0 -- -- --

Bleeding varices 2 (0.5%) 3 (1.4%) -- -- --

*If 5 HCC cases in yr 1 excluded, HR=0.47; P=0.052


Lamivudine for Chronic Hepatitis B and Advanced Liver Disease

Variable in model Comparison Hazard ratio (95% CI) P

Treatment group LAM vs PLB 0.42 (0.26, 0.68) <0.001

Sex Female vs Male 0.71 (0.35, 1.43) 0.34

Fibrosis staging score 5 vs 4 1.60 (0.83, 3.09) 0.16

6 vs 4 1.90 (1.04, 3.47) 0.036

Child-Pugh score 6 vs 5 2.85 (1.62, 5.04) <0.001

(7, 8, 9) vs 5 6.24 (3.36, 11.58) <0.001

Baseline ALT (/ULN) Per unit increase 0.91 (0.76, 1.08) 0.29

Age Per 10-year increase 1.41 (1.12, 1.77) 0.003

Baseline HBV-DNA (log10) Per 10-fold increase 0.93 (0.75, 1.15) 0.50

Covariate modelling of time to disease progression using Cox’s proportional hazards model


Wild-Type (n=221)YMDDm (n=209) (49%)Placebo (n=215)

Time after randomization (months)

0

5

10

15

20

25

0 6 12 18 24 30 36

% w

ith d

isea

se p

rogr

essi

on

5%

13%

21%


Correlation Between Viral Mutations and Liver-Related Complications

Prognosis According to HBV-DNA Level on Treatment with Lamivudine

Di Marco V, et al. Hepatology 2004;40:883-889.

HBV-DNA >105 copies/mLHBV-DNA <105 copies/mL

Survival

n=116

n=69

P=0.027

HCC

P<0.001 n=87

n=192

Four-year cumulative rates of clinical decompensation and HCC

in 94 cirrhotic patients without HCC at baseline treated with ADV+LAM

Months

HCCDecompensation

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48

Patie

nts

with

com

plic

atio

ns (%

)

15%

0%

Patientsstill at risk

94 92 89 86 68 53 4694 94 93 89 71 58 51 30

1010

27

Incidence of Clinical Events in Cirrhosis Treated with LAM+ADV

Lampertico P, et al. Gastroenterology 2007;133:1445-1451.

Development of HCC in LAM-Resistant Patients Treated with Adefovir

Hosaka T, et al. Hepatol Res 2010;40:145-152.

*p= 0.002 *p= 0.001

Factors independently associated with the development of hepatocellular carcinoma: AST >70 IU/L, YIDD mutants, age >50 years, and cirrhosis at the baseline.

247 patients with LAM resistance treated with ADV: 186 with chronic hepatitis and 61 cirrhosis

Conclusion (1)

In Italy, patients with compensated HBV cirrhosis are prevalently males, older than 50 years, and HBeAg negative.

In untreated patients with compensated cirrhosis, the 5-year cumulative incidence of HCC and liver decompensation is higher than 15%.

All patients with compensated cirrhosis and detectable HBV-DNA should be evaluated for antiviral therapy (EASL, AASLD, and Italian Guidelines).

The treatment is aimed at suppressing viral replication to the lowest possible level.

The loss of HBsAg is the best surrogate because it decreases the risk of liver decompensation and HCC.

Undetectable HBV-DNA by real-time PCR assay (<10-15 IU/mL) within 48 weeks of therapy is the desirable virological end-point.

Conclusion (2)

Pegylated interferon can be considered in patients without history of decompensation, specially if they are young, HBeAg positive, and have favourable predictors of response (high ALT values, low serum HBV-DNA, no D genotype).

Nucleoside and nucleotide analogues (NUCs) can be considered in all patients. First line option is the monotherapy with Entecavir or Tenofovir.

Early cirrhosis can be reversed with long-term suppression of HBV.

Cirrhotic patients with profound virological suppression do not develop clinical decompensation, butthe emergence of drug resistance leads to loss of benefits.

In patients with compensated cirrhosis the risk of HCC is maintained despite long-term suppressive therapy.

All cirrhotics who receive long-term NUCs treatment need to be screened for HCC on a regular basis, regardless the response to therapy.

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