Stephanos HADZIYANNISStephanos HADZIYANNIS

• Following HBeAg seroconversion a proportion of patients retains or redevelops significant HBV replication associated with persistent or intermittent elevations in ALT activity and histological liver changes of chronic hepatitis referred as:

• HBeAg-negative/anti-HBe-positive/precore mutant chronic hepatitis B (CHB).

Why Do I Treat my Patients with Why Do I Treat my Patients with Nucleos(t)ide AnaloguesNucleos(t)ide Analogues

Stephanos J. HadziyannisStephanos J. HadziyannisDepartment of Medicine and Department of Medicine and

Hepatology, Henry Dunant Hospital Hepatology, Henry Dunant Hospital and Hepatitis Research Laboratory and Hepatitis Research Laboratory

of Athens University of Athens University

Flares without normalization

Without flares

Flares with normalization

ALT DNA

% patients

44 %

20 %

36 %

Brunetto, J Hepatol 2002; 36: 263-70

● Asymptomatic hepatitis

flares: 90% of patients

Biochemical and virological patterns in HBeAg - CHBBiochemical and virological patterns in HBeAg - CHB

164 untreated pts monitored monthly for a median of 21 months (12-36)164 untreated pts monitored monthly for a median of 21 months (12-36)

● Annual frequency of flares:

- < Once 23%

- Once 57%

- Twice 20%

AL

T (

U/L

)

HB

V D

NA

(p

g/m

L)ALT

HBV DNA

TIME (days)

In HBeAg-negative chronic HBV infectionHBV replication precedes and induces ALT

increases and liver necroinflammation

Goals and Aims of Therapy in Goals and Aims of Therapy in HBeAg-Negative CHBHBeAg-Negative CHB

• The most ambitious (and closest to “cure”) goal is HBsAg seroconversion but unfortunately this can actually be achieved only in a minority of patients

• Efficient, long term suppression of HBV replication currently remains the most realistic goal.

• It results in return of ALT to normal, reduction of liver necroinflammation and improvement of hepatic fibrosis but its impact on prevention of HCC remains uncertain.

• Problems of cost, toxicity, long term safety and of HBV

resistance still remain unsolved.

Two Treatment Strategies in HBeAg-Two Treatment Strategies in HBeAg-Negative Chronic Hepatitis BNegative Chronic Hepatitis B

A. Virologic/Biochemical Remission Sustained after stopping a finite course of treatment.

B. Virologic/Biochemical Remission Maintained under long term/indefinite

treatment.

A ReminderA Reminder

• A. Treatment courses of finite (1-2 yrs) duration: Can be applied with all approved drugs but sustained responses are practically limited to interferon-alfa.

• B. Long-term / indefinite antiviral treatment: Is currently applicable only with nucleos(t)ide analogues in mono- and combination therapies

Finite treatment courses of 48w duration with Finite treatment courses of 48w duration with pegylated interferonpegylated interferon alfa monotherapy in HBeAg(-) CHB alfa monotherapy in HBeAg(-) CHB have better chances for have better chances for sustainedsustained response than nucl. response than nucl. analogues courses of the same duration and in some analogues courses of the same duration and in some patients achieve the important goal of HBsAg patients achieve the important goal of HBsAg seroconversionseroconversion ((Marcellin et al NEJM 2004, Marcellin et al EASl 2005 and Marcellin et al NEJM 2004, Marcellin et al EASl 2005 and

2006, Hadziyannis et al EASL 2005 2006, Hadziyannis et al EASL 2005 ))

HoweverHowever, , eeven with the best results, the majority of ven with the best results, the majority of treated HBeAg-negative patients are not expected to treated HBeAg-negative patients are not expected to achieve a sustained virologic and biochemical response.achieve a sustained virologic and biochemical response.

Why and When to Treat HBeAg-Negative Why and When to Treat HBeAg-Negative CHB with Nucleos(t)ide AnaloquesCHB with Nucleos(t)ide Analoques

Currently Approved Currently Approved Nucleos(t)ide Analogues for Nucleos(t)ide Analogues for

Chronic Hepatitis BChronic Hepatitis B

DRUGSDRUGS

Lamivudine Adefovir Entecavir Telbivudine

Nucleoside Analogues in HBeAg-Nucleoside Analogues in HBeAg-Negative Chronic Hepatitis BNegative Chronic Hepatitis B

• Sufficient Worldwide 2-Year Data Both on Efficacy and Resistance With all 4 Approved Nucleos(t)ide Analogues.

• Long Term Prospective Data (5yrs) on Efficacy and Resistance Limited to Lamivudine (LAM) and Adefovir Dipivoxil (ADV).

Hadziyannis SJ et al. Hepatology 2000;32:847-51.

Long-term LAM therapy in HBeAg(-) CHB: ALT and HBV DNA responses over time with

development of LAM-R

Lamivudine treatment duration (months)

Nor

mal

ALT

U

ndet

ecta

ble

HB

V D

NA

(%

)

ALT HBV DNA YMDD

0%

20%

40%

60%

80%

100%

6 12 18 24 >= 30

0%

10%

20%

30%

40%

50%

60%

Pat

ien

ts Y

MD

D +

(%

)

Risk for HBV Resistance to LAM Increases With Level of HBV DNA at Week 24

Yuen MF, et al. Hepatology. 2001;34:785-791.

Lam

ivu

din

e R

esis

tan

ce a

t F

oll

ow

-up

* (%

)

Serum HBV DNA Level at 6 Months (copies/mL)

0

20

40

60

80

100

8%13%

32%

64%

< 200(n = 12)

< 3 log10

(n = 23)

< 4 log10

(n = 41)

> 4 log10

(n = 118)

*Median follow-up: 29.6 months.

Prediction of loss of the response under LAM therapy and early diagnosis of HBV

resistance in HBeAg(-) CHB

• Monitoring of HBV DNA levels by sensitive PCR techniques, preferably by the real time TaqMan PCR assay

• Continuation of LAM treatment in those achieving non-detectability of HBV by month 6 and adapting frequency of subsequent HBV DNA monitoring according to disease severity.

• Add Adefovir on Lamivudine in those not achieving the above end point whether with or without selected LAM-resistant HBV mutants.

Long-term Entecavir in HBeAg(-) CHB

Entecavir Lamivudine

P < .0001

Pat

ien

ts (

%)

94

77

0

20

40

60

80

100

HBV DNA< 300 copies/mL Through Week 96*

(n = 325) (n = 313)

7061

P = .01

(n = 296) (n = 287)

Histologic Improvement Through Week 48

0

20

40

60

80

100

Shouval D, et al. EASL 2006. Abstract 45. Lai C, et al. N Engl J Med. 2006;354:1011-1020.

*Cumulative confirmed data: 2 data points or last observation on therapy.

*P ≤ .05 vs lamivudine.

Clinical Efficacy 2-Year Results:Telbivudine vs Lamivudine

HBeAg(+) HBeAg(-)

ResponseLdT

(n = 458)LAM

(n = 463)LdT

(n = 222)LAM

(n = 224)

Mean HBV DNA reduction, log10 copies/mL -5.7* -4.4 -5.0* -4.2

HBV DNA undetectable, % 56* 39 82* 57

ALT normalization, % 70* 62 78 70

Therapeutic response, % 64* 48 78* 66

HBeAg loss, % 35 29 - -

HBeAg seroconversion, % 30 25 - -

Primary treatment failure, % 4.0* 12.3 0* 2.7

Lai C, et al. AASLD 2006. Abstract 91.

Kaplan-Meier survival estimates, by dna056

analysis time0 10 20 30

0.00

0.25

0.50

0.75

1.00

dna056 0

dna056 1

dna056 2

p<0.0001

>6 log

Detectable HBV-DNA*(all patients)

Detectable HBV-DNA*(by baseline levels)

Kaplan-Meier survival estimate

analysis time0 10 20 30

0.00

0.25

0.50

0.75

1.00

5-6 log<5 log

*LLQ of HBV-DNA assay: 2-3 log10 copies/mL

Undetectable HBV-DNA

Virologic Response to ADV in LAM-R Patients Virologic Response to ADV in LAM-R Patients

Lampertico P, et al. 56th Annual AASLD, San Francisco, CA, 2005, Poster #983.

Adefovir Resistance in Patients Adefovir Resistance in Patients Receiving ADV + LAM*Receiving ADV + LAM*

Hadziyannis S, et al. Hepatology. 2005;42(suppl 1):754A.Lampertico P. EASL 2006. Abstract 499.

Inci

den

ce o

f R

esis

tan

ce

*Based on experience in controlled clinical trials.†2 patients enrolled in Study 435, initially on combination therapy with ADV + LAM, and subsequently selected ADV resistant mutation N236T. However, they were on ADV monotherapy when ADV resistance mutation was detected.

0% 0%3%

0%

11%

0%

18%

0

20

40

60

Year 1 Year 2 Year 3 Year 4

0% 0% 0% 0%N/A

Year 5

29%

N/AN/A

ADV monotherapy (Study 438)

ADV + LAM Study 435 - pre and post OLT (LAM-r)

ADV + LAM Study 460i - HIV/HBV (LAM-r)

Probability of Probability of DDeveloping eveloping RResistance to ADVesistance to ADV in LAM Resistant in LAM Resistant Patients with Compensated HBeA-negative CHB Patients with Compensated HBeA-negative CHB (Rapti et al (Rapti et al

Hepatoloy Febr . 2007)Hepatoloy Febr . 2007)

Duration of ADV treatment in Months

6050403020100

1,1

1,0

,9

,8

,7

no

ADV+LAM

ADV only

Patients at Risk

n=32

n=14

Liver Biopsy (Y4 cohort

ADV Baseline)

Liver Biopsy Liver Biopsy†

(Y4 cohort 1st yr ADV)

Liver Biopsy†

* Patients in ADV 10mg group re-randomized in a 2:1 fashion at week 48.** Patients transferred to a general open-label study.† Optional liver biopsy

0 Week 48 Week 96 Week 144

ADV ADV (n=55)(n=55)

ADV ADV (n=70)(n=70)

ADVADV

(n=60)(n=60)

ADVADV(n=80)(n=80)

PLB PLB (n=62)(n=62)

ADV ADV **

(n=123)(n=123)

PLB** (n=40)PLB** (n=40)

Liver Biopsy†

Week 240

ADV for 5 years ADV for 5 years (Y5 cohort)(Y5 cohort)

ADV for 4 years ADV for 4 years (Y4 cohort)(Y4 cohort)

Y5cohort

Y4cohort

ADV for HBeAg- CHB (0-240 weeks) ADV for HBeAg- CHB (0-240 weeks) GS 438 Study DesignGS 438 Study Design

Hadziyannis S, et al. 56th AASLD, San Francisco,.2005

3

4

5

6

7

8

0 12 36 48 60 72 84 96

Weeks

Log 1

0 co

pies

/mL

LLQ*

*Lower limits of quantification (LLQ)=1000 copies/mL.Roche Amplicor PCR Assay.

24

Relapse after stop of 1y treatment with nucl. Relapse after stop of 1y treatment with nucl. analogues (ADV) in HBeAg-negative CHBanalogues (ADV) in HBeAg-negative CHB

2

ADV for 96 weeks

ADV for 48 weeks + placebo for 48

weeks

Hadziyannis et al. N Engl J Med 2005

Serum HBV DNA, ALT, and Serologic Responses Serum HBV DNA, ALT, and Serologic Responses at End of the Study in the 4- and 5-Year at End of the Study in the 4- and 5-Year

CohortsCohorts

Six patients (5%) had HBsAg loss, 5 with anti-HBs at the last available time point. Six patients (5%) had HBsAg loss, 5 with anti-HBs at the last available time point. Four lost HBsAg after > 3.5 years of ADV and 2 after 141 and 419 days of treatment.Four lost HBsAg after > 3.5 years of ADV and 2 after 141 and 419 days of treatment.

†*

* Missing=failure for resistance or hepatocellular carcinoma.

38/5521/30 26/40 37/55

10

70% 65%69% 67%

0

10

20

30

40

50

60

70

80

90

100

ALT normalization* HBV DNA < 3 log copies/mL*

Pa

tie

nts

(%

)

Year 4 Year 5

A Note on the Potency and Timing of A Note on the Potency and Timing of Optimal Virologic Response to ADVOptimal Virologic Response to ADV

• Slow, rather weak maximal suppression of HBV replication linked with the low anti-HBV potency of the approved “safe” 10mg daily dose of the dug

• Maximal initial HBV DNA suppression is achieved at month 12 not as with LAM, ENT and TEL at month 6

• HBV DNA levels remaining detectable at month 12 are predictors of subsequent genotypic ADV resistance

Higher HBV DNA at Year 1 Predictive of Year 3 Higher HBV DNA at Year 1 Predictive of Year 3 Genotypic ADV ResistanceGenotypic ADV Resistance

Locarnini S, et al. EASL 2005.

HBV DNA at Year 1 (log10 copies/mL)

Gen

oty

pic

Res

ista

nce

at

Yea

r 3

(%)

4%

67%

26%

0

20

40

60

80

100

(n = 80)< 3

(n = 31)3-6

(n = 3)> 6

3

Cumulative Probabilities* of Virologic Outcomes With Adefovir Monotherapy

Borroto-Esoda K. EASL 2006. Abstract 483.

0 311

18

29

08

13 16

0 2 6 10 11

0

20

40

60

80

100

Year 1 Year 2 Year 3 Year 4 Year 5

Pat

ien

ts (

%)

Genotypic resistance Virologic rebound† Clinical breakthrough

*Cumulative probabilities calculated by life-table analysis.†Presence of genotypic resistance plus HBV DNA rebound; confirmed ≥ 1 log10 copies/mL increase in HBV DNA from nadir and/or having never achieved HBV DNA suppression ≤ 4 log10 copies/mL.

HBeAg(-) patients from our center achieving HBeAg(-) patients from our center achieving undetectable HBV DNA on ADV monotherapy, undetectable HBV DNA on ADV monotherapy,

maintained for 4-5 years under treatmentmaintained for 4-5 years under treatment

Months

1E8

1E7

1E6

1E5

1E4

1E3

1E2

logs H

BV-D

NA

(cp/m

l)M

edia

n lo

g¹º

HB

V-D

NA

(c/

mL

)

Histological Observations at the Histological Observations at the End of Year 5 of the ADV Study.End of Year 5 of the ADV Study.

• Improvement in necroinflammation by ranked assessment in 80%

• Proportion of patients with improvement in fibrosis (71%)

• Seven of 12 patients (58%) with bridging fibrosis or cirrhosis at baseline, improved by ≥2 points in Ishak Fibrosis Score, including 3 of 4 with cirrhosis at baseline.

Hadziyannis et al Gastronterology Dec. 2006

SUSTAINED BIOCHEMICAL AND VIROLOGICAL SUSTAINED BIOCHEMICAL AND VIROLOGICAL REMISSION AFTER DISCONTIMUATION OF 4 TO 5 REMISSION AFTER DISCONTIMUATION OF 4 TO 5

YEARS OF ADEFOVIR DIPIVOXIL (ADV) TREATMENT YEARS OF ADEFOVIR DIPIVOXIL (ADV) TREATMENT IN HBeAg-NEGATIVE CHRONIC HEPATITIS BIN HBeAg-NEGATIVE CHRONIC HEPATITIS B

S.J.Hadziyannis, V. Sevastianos, I. Rapti and N.Tassopoulos

Department of Medicine and Hepatology, Henry Dunant Hospital and Hepatitis Research Laboratory of Athens University at Evgenidion Hospital, Athens, Greece.

HBV-DNA levels during follow-up in sustained HBV-DNA levels during follow-up in sustained biochemical responders after stopping ADV treatmentbiochemical responders after stopping ADV treatment

0%

21%

79%

33%

17%

50%

43%

14%

43%

44%

31%

25%

33%

33%

34%

30%

40%

30%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 2 6 12 18 22

FOLLOW-UP MONTH

>10,000 copies/mL

Detectable <10,000 copies/mL

HBV-DNA not detectable

100%

0

70% 70% of of

patientspatients<10,000<10,000c/mL c/mL

Median ALT levels (IU/L) during 22 months of follow-Median ALT levels (IU/L) during 22 months of follow-up after stopping 4 or 5 yrs of ADV therapy. Results up after stopping 4 or 5 yrs of ADV therapy. Results among patients in sustained biochemical remissionamong patients in sustained biochemical remission

Months Follow-up

Med

ian

AL

T

0

20

40

60

80

100

2 4 6 12 18 22

ULN

But what to do with the 1/3 of patients not But what to do with the 1/3 of patients not achieving on ADV ‘early’ non-detectability achieving on ADV ‘early’ non-detectability

of HBV DNA?of HBV DNA?

• Switch to a more potent compound with the same or similar resistance profile?

• Increase the dose of Adefovir?

• Switch to Entecavir or Lamivudine?

• Continue Adefovir adding Lamivudine or Entecavir ?

Concluding Comments on Concluding Comments on AdefovirAdefovir

• Maintenance by ADV monotherapy of HBV suppression to serum HBV DNA levels non-detectable by the Taqman Real Time PCR assay for a 5-year period is possible in about 2/3 of HBeAg-negative patients; with a good percentage of them keeping in remission 18 months after stop of this long-term Rx (Hadziyannis et al 2006 Gastroenterology)

• In HBeAg-negative patients with lamivudine resistant HBV adding ADV is clearly superior and preferable than switching to ADV and the same approach is reasonable with addition of LAM or ETV in those with detectable HBV DNA at month 12 on ADV monotherapy.

Final conclusion and answer to the Final conclusion and answer to the question of why to treat HBeAg-negative question of why to treat HBeAg-negative

CHB with nucleos(t)ide analaguesCHB with nucleos(t)ide analagues

• Because in patients non-responding or non-eligible to IFN-α therapy, proper drug selection from the available nucleos(t)ide analogue Armamentarium with careful monitoring of the response to therapy, can achieve very long maintenance of the virologic and biochemical response and

• A number of such patients may also achieve the goal of sustained response and even of HBsAg clearance and seroconversion to anti-HBe.

BACK UP SLIDESBACK UP SLIDES

Why Do I Treat my Patients with Nucleos(t)ide Analogues

Stephanos J. HadziyannisDepartment of Medicine and Hepatology,

Henry Dunant Hospital and Hepatitis Research Laboratory of Athens University

Patients’ CharacteristicsPatients’ CharacteristicsTotal n (%) 33 (100%)

Males n (%) 27 (82%)

Females n (%) 6 (18%)

Mean Age yrs (range) 50 (29-69)

5 Year Cohort 22 (67%)

4 Year Cohort 11 (33%)

Normal ALT 33 (100%)

HBV DNA <1,000c/ml 33 (100%)

HBV DNA TaqMan (-)* 28 (85%)*22/27M, 6/6F

PatientsPatients

• 37 HBeAg(-) patients from our center achieved undetectable HBV DNA on Adefovir therapy, maintained for 4-5 years under treatment

• 33 of them gave informed consent to be included in this post-treatment long-term follow-up study

5956535047444138343128252219161310741

Months

1E8

1E7

1E6

1E5

1E4

1E3

1E2

logs

HB

V-D

NA

(cp

/ml)

Med

ian

log

¹º H

BV

-DN

A (

c/m

L)

0

40

80

120

160

200

SCR 3 6 9 12 OL2 OL5 OL8OL1

1OL1

4OL1

7OL2

0OL2

3OL2

6OL2

9OL3

2OL3

5Fup

2Fup

5Fup

8

Fup11

Fup14

Fup17

Fup20

Fup23

Months

AL

T/A

ST

(IU

/L)

1,E+01

1,E+02

1,E+03

1,E+04

1,E+05

1,E+06

1,E+07

1,E+08

Lo

gs

HB

V-D

NA

ALT HBV DNA

ADV 10mg/day

Transient rise in HBV DNA during the first 2 months after Transient rise in HBV DNA during the first 2 months after stopping ADV therapy in patient keeping in sustained stopping ADV therapy in patient keeping in sustained biochemical and virologic remission to follow-up month 23biochemical and virologic remission to follow-up month 23

HBV DNA and ALT during and after stopping long-term HBV DNA and ALT during and after stopping long-term ADV therapy in an HBeAg-negative patient with ADV therapy in an HBeAg-negative patient with

HBsAg seroconversion under therapyHBsAg seroconversion under therapy

0

20

40

60

80

100

120

140

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 36 42 48 55 61

FUP Mo1

FUP Mo3

FUP Mo5

FUP Mo1

0

FUP Mo1

6

FUP Mo2

2

1

10

100

1000

10000

100000

1000000

ALTHBV-DNA

AL

T (

IU/L

)

Lo

g H

BV

-DN

A

ADV 10mg/day

SummarySummary

• After stopping adefovir dipivoxil treatment of 4 or 5 years duration in HBeAg-negative chronic hepatitis B patients, who have remained persistently HBV DNA negative by PCR under Rx, approximately 2/3 of them may keep in sustained biochemical remission for a hitherto period of 19-24 months.

• Serum HBV DNA levels rise transiently during the first few months of follow-up in all instances but in sustained biochemical responders they progressively decline over time and may even become undetectable in >30% of them

Higher HBV DNA at Year 1 Is Predictive of Higher HBV DNA at Year 1 Is Predictive of ADV-R Development by Year 3ADV-R Development by Year 3

27% (n=31)3-6 log10

70% (n=80)<3 log10

3% (n=3)3% (n=3) >6 log>6 log1010

Serum HBV DNA at year 1 (n=114)

8/31 (26%)

8/31 (26%) ADV-R by yr 3

ADV-R by yr 3

2/3 (67%)

2/3 (67%)

ADV-R by yr 3

ADV-R by yr 3

3/80 (4%)

3/80 (4%)

AD

V-R by yr 3

AD

V-R by yr 3

Histologic Ranked Assessment in 4- and 5-Histologic Ranked Assessment in 4- and 5-Year Cohorts Compared to ADV BaselineYear Cohorts Compared to ADV Baseline

Median change from ADV Baseline in Knodell necroinflammatory score -4.5 and -5.0 at 4 and 5 yrs; Median change from ADV Baseline in Knodell necroinflammatory score -4.5 and -5.0 at 4 and 5 yrs; median change in Ishak fibrosis score was -1.0 in both cohorts.median change in Ishak fibrosis score was -1.0 in both cohorts.

Necroinflam.Y4 Necroinflam.Y5 Fibrosis Y5Fibrosis Y40%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Improved Same Worse