3rd Paris Hepatitis Conference: Morning Session on HBeAg-Neg CHB

WHY DO I TREAT MY PATIENTS WITH WHY DO I TREAT MY PATIENTS WITH PEGYLATED INTERFERON?PEGYLATED INTERFERON?

Problems Confronting Clinician with HBeAg Negative Hepatitis B

• High rate of relapse to conventional strategies

• Diagnosis can be a bit challenging

• Patients tend to be older group than HBeAg (+) with more severe disease

• Not much known about predictors of sustained virologic response to IFN

Recent PEG IFN Developments that Impact on Care of Patients with HBeAg (-) CHB

Long-term follow up

• Durability

• HBsAg clearance

On treatment prediction of SVR

• HBV DNA response

• HBsAg response

Clarification of importance of genotype

Better understanding of tolerability

Antiviral Therapy: A Matter of ChoiceAntiviral Therapy: A Matter of ChoiceCase Features Should Determine ApproachCase Features Should Determine Approach

Antiviral Therapy: A Matter of ChoiceAntiviral Therapy: A Matter of ChoiceCase Features Should Determine ApproachCase Features Should Determine Approach

Poor tolerability in elderly and those with comorbid illness

Any age, minimal adverse events

Less effective for high level viremia

Baseline viremia generally not an issue

Chance for SVR determined by baseline ALT

ALT elevation not required for viral suppression

Response genotype dependent Viral suppression independent of genotype

Contraindicated with decompensated disease

Can be used safely in decom- pensated disease

Limited usefulness in special populations

Appropriate in certain settings

Peginterferon Nucleoside Analog

Finite treatment * Diminished infectivity Potential for long term benefit (HBsAg loss)* Durability off treatment

Drug cost /cost of care Indirect costs * Tolerability * Convenience * Need for monitoring *

Many Other Factors Go Into a Treatment Decision

Modified from Perrillo, Hepatology, 2006

Initial and Long Term Follow Up from PEG IFN alfa-2a Study in HBeAg-Neg CHB

0

10

20

30

40

50

60

70

60%

19%

27%

17%

ALT HBV DNA ALT HBV DNA normal <20,000 < 400 normal < 20,000 < 400

Initial study Follow-up study 6 mos after EOT 4years after EOT

n= 356* n = 230*

* w/wo LAM

Marcellin, EASL, 2008Marcellin, NEJM 2005

43%

24%

Follow up Data in PEG IFN-Treated HBeAg-Neg CHB

ALTnormal

ALTnormal

HBV DNA< 400 copies

HBV DNA < 400 copies

HBsAgclearance

HBsAgclearance

Initial study6 months after EOT

n =356

Follow-up study4 years after EOT

n = 230

0

10

20

30

40

50

60

70

3%

11%

~ 3%~ 3%increaseincreaseannually inannually inrespondersresponders

Marcellin, 2005, 2008

2% withlamivudine

0- 2 4 6 8 10 12 14 16 18

Virologic relapse

0.2

0.4

0.6

0.8

Fung, 2004

Months to Relapse

• 50 Chinese patients treated with LAM

• 37 treated for 2 yrs

• 27 neg. by PCR for ≥ 9 mos meet

criteria for treatment withdrawal

Prolonged PCR Negativity Does not Allay Concerns About Relapse

Clinical relapse

Long Term Response in Adefovir-Treated Cohort Negative for HBV DNA x 4-5 Years

• 33 patients neg for HBV DNA x 4-5 yrs on adefovir33 patients neg for HBV DNA x 4-5 yrs on adefovir

• Followed for median duration 18 mos off treatmentFollowed for median duration 18 mos off treatment

• 67% continue with ALT NL67% continue with ALT NL

• HBV DNA becomes detectable in all (“low,” varying from BDL to 5 HBV DNA becomes detectable in all (“low,” varying from BDL to 5 x 10x 1044 copies) copies)

• HBV DNA declines with further ollow upHBV DNA declines with further ollow up

Hadziyannis et al, AASLD, 2006Hadziyannis et al, AASLD, 2006

Worldwide Distribution of HBV GenotypesWorldwide Distribution of HBV Genotypes

Genotype A

Genotype B

Genotype C

Genotype D

Genotype E

Genotype F

Genotype G

1 Westland, Gastroenterology 2003; 2 Chu, Gastroenterology 2003

Asia 1

Europe 1

USA 2Mediterranean 1

42%

46%

9%83%

14%

35%40%

15% 22%

35%

31%

10%

Genotype A

n=174

Genotype B

n=245

Genotype C

n=464

Genotype D

n=346

HBeAg (+)

n=703

36.3% 21.1% 18.5% 14.6%

HBeAg

(-)n=526

34.0% 32% 50.4% 21.4%

Genotype and Virologic Response to IFNAccording to HBeAg Status in 1229 Patients

Erhardt , AASLD 2008, Absract 883Standard =298l PEG = 491; with LAM 440

0

5

10

15

20

25

ALL PATIENTS ASIANS CAUCASIANS

Chronic hep B studies

Chronic hep C studies

Eve

nts

(%

)Frequency of Depression-Related Events During Treatment with PEG IFN alfa-2a

Marcellin et al, Liver International, 2007

4%

22%

2%

9% 10%

23%

P < 0.001 P = 0.003 P = 0.027

Depression events 4% (B) vs 22% (C)

Side Effects: HBeAg (-) CHB (n = 177) vs CHC (n = 791)

Drug Discon-

tinuations

B , C %

Discontinua-

tion for Safety,

B, C %

1 or More

Serious

Adverse

Events

B, C%

Most Common

Serious Event

B, C%

8, 17-33 7, 7-22 5 (n =9),

7-16

Infection (6),

psychiatric

Patients with Cirrhosis Respond Just as Well to IFN As Those Without

modified after Chu and Liaw Sem Liver Dis 2006

Niederau + 63% 47% ns

D Lau + 59% 24% 0.01

van Zonneveld + 50% 29% 0.034

Lin + 39% 35% ns

Cooksley Peg IFN2a + 48% 35% ns

Buster Peg IFN2b + 33% 14% 0.02*

Papatheodoridis - 28% 27% ns

Brunetto - 26% 18% ns

Cooksley Peg IFN2a - 40% 45% ns

Cirrhosis Non-CirrhosisHBeAg P ValueResponse rates

* Dose reduction, early discontinuation, and SAEs comparable for both groups (33% vs 34%, 11% vs 8%, 4% vs 5%)

Peginterferon for Delta Hepatitis

• Patients often HBeAg-negative

• Interferon only effective treatment

• Treatment required long-term

– Where possible, continue until loss of HBsAg

(Farci, J Viral Hep 2007; 14:S58-63)

3rd Paris Hepatitis Conference: Session on HBeAg-Neg CHB

HBsAg Loss, HBsAg Monitoring,

and Relationship of Treatment-

Induced Changes in HBsAg

Concentration to Virologic Response

Why Is HBsAg Clearance So Important?

Qualitative Differences Between HBsAg and Prolonged Viral Suppression

• Durability of virologic response

• Significantly lower levels of intracellular genomic

template (cccDNA)

• Better long-term prognosis

– Lower rate of HCC

– Lower rate of progression to cirrhosis

• Less chance of viral reactivation

– Spontaneous

– Immune suppression

HBsAg Levels with Peg IFN Alfa -2a and Lamivudine in HBeAg (-) CHB

• 63 patients (42 IFN, 21 LAM) analyzed for HBsAg by ADVIA

Centaur [Bayer]; (92% geno D)

• Low BSL HBsAg level predictive of HBsAg clearance

• HBsAg decreased in both treatment groups

- Sharp drop in most IFN treated patients; sustained in VR

- More gradual slope for LAM: ETU of HBsAg is median of 10.6 yrs of treatment vs 5.4 yrs with IFN

Manensis et al, Anitiviral Ther, 2007

HBsAg HBsAg ng/mLng/mL

BaselineBaseline TreatmentTreatment

Week 12Week 12

TreatmentTreatment

Week 60Week 60

Follow upFollow up

Week 12Week 12

Follow up Follow up

Week 24Week 24

Resp 1* 6,515 6,515 7,257 19 77 0

Resp 2 >7692>7692 >7692 273 446 205

Resp 3 1,6191,619 566 9 20 61

Resp 4 >7,692>7,692 196 38 27 19

NR 1NR 1 1,212 1,056 NA 1,910 1,473

NR 2 6,881 >7,692 6,088 6,823 5,219

NR 3 368 392 304 NA 189

NR 4 5,019 6,030 7,584 6,161 7,715

Measuring HBsAg in HBeAg (-) CHB: with 60 Week Extended Course of Peg IFN Alfa -2a

Gish, Lau, Schmid, Perrillo Am J Gastro 2007* Response = PCR negative at FU week 24

HBV DNA SVRs vs Non-responders

0

1

2

3

4

5

6

7

8

BL W12 W24 W48 W72 W96

Lo

g c

op

ies/

mL

Treatment FUP

SVRs (n=12)

NRs (n=18)

Moucari et al, Hepatology, in press

HBsAg LevelSVRs vs Non-Responders

0

0.5

1

1.5

2

2.5

3

3.5

4

BL W12 W24 W48 W72 W96

Lo

g I

U/m

L

FUPTreatment

SVRs (n=12)

NRs (n=18)

Moucari et al, Hepatology, in press

HBsAg: Predictive Value for SVR by Wk 24 Decline (1 Log IU/mL)

48 Patients

n = 12

n = 36

n = 1

n = 35

n = 1

n = 11 PPV = 92 %

NPV = 97 %

Week 24 ↓ HBsAg ≥ 1 Log IU/mL

Week 24 ↓ HBsAg < 1 Log IU/mL

SVR (+)

SVR (-)

SVR (+)

SVR (-)

Predictive Value of qHBsAgPredictive Value of qHBsAg at Wk 48 for Outcome:at Wk 48 for Outcome:

NPVNPV PPVPPV SpecSpec SensSens

Sustained HBsAg Clearance at Yr 3

HBsAg < 380 IU/mL at wk 48 100 25 100

74

HBsAg reduction > 1.9 log10 at wk 48 98 44 92 75

HBV DNA ≤ 400 copies at 3 Yrs

HBsAg < 19 IU/mL at wk 48 98 44 75 92

HBsAg reduction > 0.46 log10 IU/mL at wk 48

95 30 66 81

HBsAg Decline at Wk 48 PredictsOutcomes at Year 3 After End of Rx*

Brunettto et al, Hepatology, in press* Based on subset of 198 patientsIn initial treatment cohort; HBsAg (-) in 16 (8%)

SUMMARY WhyWhy PEG IFN First for HBeAg-Negative CHB?PEG IFN First for HBeAg-Negative CHB?

• Useful as first line therapy in selected patients:

• Age, comorbid illnesses, compensated liver disease

Test for genotype (non geno D)

• Better tolerated than in hepatitis C

• Patients with stable cirrhosis can be treated safely

• Specific advantages:– Discrete interval of treatment– Responses can be durable– HBsAg loss– Possibility of response directed therapy

Summary:

Why PEG IFN FIrst? (2)

• Responses can be durable

• If treatment fails, no impact on success with NA or requirement for more complex therapy

Managing Patients with Limited Access to Care

Identify those chronically infected Government or privately sponsored screening programs

Determine ease of, and need for treatment

Liver biopsy may be optional:•High likelihood of response•Obvious features of cirrhosis•Treatment to prevent HCC?****

Investigate treatment possibilities Government health care programs

Pharmaceutical free/discounted drug

Only monitor what and when it is necessary

•More dependence on ALT•Minimize HBV DNA testing intervals•Monitor compliance•Annual HBeAg assessment

Manage patient education Native language; encourage family participation; reasonable insight

Survey for confounding factors Social circumstances, HIV/HCV/delta,Compliance history

Potential Problem Addressment