Update on Chronic Hepatitis B Management

John M. Vierling, M.D., F.A.C.P., F.A.A.S.L.D.

Professor of Medicine and Surgery Chief of Hepatology

Director of Advanced Liver Therapies Baylor College of Medicine

Baylor St. Luke’s Medical Center Houston, TX

HBV: A Global Problem • 2 billion people worldwide infected with HBV[1]

• ~ 350 million chronic carriers[2] • Leading cause of cirrhosis and HCC worldwide[2]

• Causes 80% of all HCC in Asian Americans[3]

• In the absence of cirrhosis, 30% to 50% of HCC associated with HBV[4]

• Second only to tobacco as cause of cancer deaths[5]

• HBV 50-100 times more infectious than HIV[1]

1. World Health Organization. HBV fact sheet. 2. Conjeevaram HS, et al. J Hepatology. 2003;38(suppl 1):s90-s103. 3. Stanford Asian Liver Center. For hepatitis B and liver cancer patients. 4. Bosch FX, et al. Clin Liver Dis. 2005;9:191-211. 5. World Health Organization. Global alert and response: hepatitis B-Introduction.

Chronic Hepatitis

Cirrhosis Hepatocellular Carcinoma

Decompensated Cirrhosis

-8% to 17% for HBeAg + -13% to 38% for HBeAg -

-17% in East Asian -10% in Europe and US

-15%

Natural History: 5-Year Rates of Chronic Hepatitis B Progression

Fattovich G, Bortolotti F, Donato F. J Hepatol 2008; 48:335

Inactive Carriers

-1% in East Asian -0.1% in European/US

-3% in East Asian -1% in Europe and US

Liver Related Death

-14% to 15%

70-85%

Natural History of Untreated CHB

8.9% 4.1% 4.8%

1.2%

40%

10-yr Death Rate HBV Related Deaths HBV Related Deaths After Age 40

Men Women Overall Death Rate

Kaiser Permanente Cohort Study from 3/1/96-12/31/05 N = 3,445 Males, 3,244 Females

HCC deaths represented 70% of cancer death in males and 37% in females HBV related deaths were 2X as common from HCC as from decompensated cirrhosis Mortality increased markedly in men >40 and women >50 Lifetime risk of dying from HBV related causes was 42.2%, with 27.6% risk for women and 48.7% risk for men

Szpakowski JL, Tucker LY. Hepatology 2013 July;58(1):21-30

Adju

sted

RR*

0

2.0

4.0

6.0

8.0

10.0

REVEAL: Relationship Between Baseline HBV DNA and Cirrhosis

• Baseline HBV DNA predicted progression to cirrhosis – Relationship independent of HBeAg status

Chen CJ, et al. EASL 2005. Abstract 476.

*With 42,115 patient-yrs of follow-up and adjusted for sex, age, anti-HCV levels, smoking, and alcohol use.

†1 IU/mL equals approximately 5.6 genomes/mL.

P = NS

HBeAg-Negative Patients

< 104

(n = 2132)

HBeAg-Positive Patients

P < .01

P < .001

2.6

6.2

8.6

Cases of Cirrhosis: 104 55 96 2 3 135

≥ 104 to < 105

(n = 631) ≥ 105

(n = 451) < 104

(n = 22) ≥ 105

(n = 520) ≥ 104 to < 105

(n = 18)

BL HBV DNA, c/mL†:

Adju

sted

RR*

P < .001

P < .001

1.0 1.9

4.9

0

2.0

4.0

6.0

8.0

10.0

Cumulative Incidence of HCC by Serum HBV DNA Level at Study Entry

Yr of Follow-up

Cum

ulat

ive

Inci

denc

e of

HCC

(%)

N = 3653 Taiwanese patients

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

0

2

4

6

8

10

12

14

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Baseline HBV DNA Level, copies/mL ≥ 1 million

100,000-999,999

10,000-99,999

300-9999

< 300

13.5%

7.96%

3.15%

0.89% 0.74%

Parameters Used to Determine Candidates for Treatment of HBV

• ALT – “New” normal or “healthy” ALT: < 30 U/L for men and

< 19 U/L for women[1]

– Presence of 1 normal value does not exclude significant disease or subsequent complications

• HBV DNA – Predicts development of cirrhosis and HCC[2,3]

– Interpret in conjunction with ALT and/or histology • Liver biopsy

– Useful in situations where ALT or HBV DNA do not provide clear guidelines for treatment[1]

1. Lok AS et al. Hepatology. 2009;50:661-662. 2. Iloeje UH et al. Gastroenterology. 2006;130:678-686. 3. Chen CJ et al. JAMA. 2006;295:65-73.

Goals of Response to Therapy in Chronic Hepatitis B

• Biochemical Response: Normalization of ALT • Virologic Response: Undetectable HBV DNA and loss

of HB E Ag in HBeAg (+) with sero-conversion to anti HB E Ab

• Histologic Response: Decrease in histology activity index by at least 2 points and no worsening of fibrosis

• Oncologic Response: Prevent HCC • Complete response: BR + VR + (HCC) + HBsAg loss

Emmet B. Keeffe et al. Clinical Gastroenterology and Hepatology 2008;6:1315-1341 Anna S. F. Lok, Brian J. McMahon. AASLD Practice Guidelines. Hepatology. Sept. 2009

Phases of Chronic HBV Infection

0 20 40 60 Years

Immune tolerance

Immune clearance HBeAg-positive chronic

hepatitis

Inactive carrier state

HBV DNA

Reactivation HBeAg-negative chronic hepatitis

ALT

HBeAg Anti-HBe

Yim HJ, et al. Hepatology. 2006;43:S173-S181.

HBV DNA ↑↑↑ ≥ 10⁷ IU/ml Persistently normal ALT

HBV DNA ↑↑ ≥ 20,000 IU/ml Elevated ALT

HBV DNA = low, < 2000 IU/ml Persistently normal ALT

HBV DNA = Fluctuating, > 2000 IU/ml Fluctuating ALT Elevations

Significance of Precore/BCP Mutation

• Most patients with HBeAg (-) chronic hepatitis B harbor precore or basal core promoter (BCP) mutations¹.

• Precore and BCP along with genotype C are associated with risk of HCC².

• BCP mutations are associated with increased risk for disease progression in genotype B and C patients³.

• Precore mutations are associated with ALT elevations, increased HBV DNA levels and persistent necroinflammatory activity in CHB³.

1- Lok As, McMahon BJ. AASLD Practice Guidelines. Hepatology 2009 2-Yang HI et al. J Natl Cancer Inst. 2008;100(16):1134-43 3- Tong MJ et al. Dig Dis Sci. 2011;56:3143-3162.

AASLD Recommendations Treatment Initiation

HBeAg(+)

HBeAg(-)

HBV DNA >20,000 IU/mL ALT <1 x ULN

HBV DNA >20,000 IU/mL ALT 1-2 x ULN

HBV DNA >20,000 IU/mL ALT >2 x ULN

• Q 3-6 mo ALT • Q 6-12 mo HBeAg

• Q 3 mo ALT • Q 6 mo HBeAg • Consider biopsy if persistent

or age >40 • Treat as needed

• Q 1-3 mo ALT, HBeAg • Treat if persistent • Liver biopsy optional

HBV DNA< 2,000 IU/mL ALT <1 x ULN

HBV DNA 2,000-20,000 IU/mL ALT 1-2 x ULN

HBV DNA >20,000 IU/mL ALT >2 x ULN

• Q 3 mo ALT x 3 • Q 6-12 mo if ALT still <1

x ULN

• Q 3 mo ALT & HBV DNA • Consider biopsy if persistent • Treat as needed

• Treat if persistent • Liver biopsy optional

Lok ASF, McMahon BJ. Hepatology. 2009;50:1-36.

Expert Consensus: Asian American Treatment Algorithm Assessing Patients for Monitoring and Treatment

Clinical Stage HBeAg HBV DNA ALT Recommendation

Immune Tolerant

+ >2000 IU/ml ≤ ULN Monitor

Chronic Hepatitis (based on biopsy or ALT)

+ >2000 IU/ml > ULN Treat

Chronic Hepatitis (based on biopsy or ALT)

- >2000 IU/ml > ULN Treat

CHB - >2000 IU/ml ≤ ULN Risk Score Assessment

CHB ± ≤ 2000 IU/ml > ULN Risk Score Assessment

Inactive Carrrier - ≤ 2000 IU/ml ≤ ULN Monitor

Tong MJ, et al. Dig Dis Sci. 2011;56:3143-3162.

Expert Consensus: Asian American Treatment Algorithm Assessing Patients for Monitoring and Treatment

Risk Factors Impact score

Age ≥ 40 1

Male Gender 1

Male ALT>30 U/L Female ALT > 19 U/L

1

Basal Core Promoter Mutation (BCP)

2

HCC in First Degree Relative

3

Albumin≤ 3.5 g/dl or Platelet≤ 130,000 mm³

3

<3

≥3

HBV DNA ≤2000 IU/ml

HBV DNA >2000 IU/ml

Recommend Treatment

Monitor w/o treatment

Total Score

Tong MJ, et al. Dig Dis Sci. 2011;56:3143-3162.

Differentiating HBeAg-Negative CHB From Inactive Carrier State

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341 Brunetto MR, et al. Gastroenterology 2010 Aug;139(2):483-90. Chan HL, et al. J Hepatol 2011 Nov;55(5):1121-31.

Status HBeAg-Negative Disease Inactive Carrier HBsAg positive

Anti-HBe positive

Anti-HBc positive

HBV DNA Moderate, often fluctuating levels; serum HBV DNA

> 2000 IU/mL

Low or undetectable; serum HBV DNA negative or

< 2000 IU/mL

ALT Elevated, often fluctuating levels

Normal

Precore/BCP ? +

HBsAg level in genotype D ?

<1000 IU/ml and HBV DNA < 2000 IU/ml

HBsAg level in genotype B/C ?

<100 IU/ml and HBV DNA < 2000 IU/ml

Liver biopsy Serologic tests Fibroscan

+++

Serial laboratory monitoring is recommended!

Risk Factors for HCC in CHB

Host factors

Male gender

Older age > 40

FH of HCC in first degree relative

Co-infection HDV, HCV

Aflatoxin , ETOH, Tobacco

NAFLD, Hypothyroidism

A-1-AT def, Hemochromatosis, Porphyria (AIP, PCT)

Viral Factors

Genotype C

BCP/Precore mutation

Viral/Host interactions

Cirrhosis

High HBV DNA

High level of HBsAg

Persistently (+) HBs or eAg

Dragani TA. J Hepatol 2010;52:252-257 Guerrieri F et al. Semi Liver Dis 2013;33:147-156 Xu C et al. Cancer Lett (2013) in press: http://dx.doi.org/10.1016

Risk of HCC and HBeAg Positive Patients

1 5.4

15.5 17.7 9.6

60.2

age 30-39 age 40-49 age 50-59 age ≥60 HBS Ag(+) +HB eAg(-)

HBS Ag(+) +HB eAg(+)

Relative Risk for HCC Relative Risk for HCC

Prospective Study: N = 11,893 men in Taiwan Incidence rate for HCC/100,000 person-yr Age = 30-65 HBsAg(-) + HBeAg(-) = 39.1 HCC = 111, follow up = 92,359 person-years HBsAg(+) + HBeAg(-) = 324.3 HBsAg(+) + HBeAg(+) = 1169.4

Yang HI, et al. NEJM 2002;347(3):168-174

Antiviral Therapies in CHB

Agents • IFN-alpha • Lamivudine • Adefovir • Pegylated IFN • Entecavir • Telbivudine • Tenofovir

Preferred First Line Agents Endpoints Therapy • Tenofovir • Entecavir

Finite Injection Therapy • Pegylated IFN • Exceptions: pregnancy,

chemotherapy prophylaxis, decompensated cirrhosis, acute infection

1-Emmet B. Keeffe et al. Clinical Gastroenterology and Hepatology 2008;6:1315-1341 2-Anna S. F. Lok, Brian J. McMahon. AASLD Practice Guidelines. Hepatology. Sept. 2009

Definitions Related to Antiviral Resistance to Nucleos(t)ide Analogues

Term Definition

Virologic breakthrough

↑ HBV DNA by 1 log10 (10-fold) above nadir after achieving virologic response, during continued tx

Viral rebound ↑ HBV DNA to > 20,000 IU/mL or above pre-tx level after achieving virologic response, during continued tx

Biochemical breakthrough

↑ ALT to above ULN after achieving normalization, during continued tx

Genotypic resistance

Detection of mutations shown by in vitro studies to confer resistance to the NA administered

Phenotypic resistance

In vitro confirmation that mutation detected decreases susceptibility (as demonstrated by increase in inhibitory concentrations) to the NA administered

Lok AS, et al. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases. Reproduced with permission of the American Association for the Study of Liver Diseases.

Manifestations of Antiviral Resistance Antiviral Treatment

Virologic rebound

Virologic breakthrough

Genotypic resistance

Hepatitis flare

Biochemical breakthrough ULN

HBV

DNA

(log 1

0 IU/

mL)

AL

T (U

/L)

Yrs

8

6

4

2

0 -1 0 1 2 3

5-Yr Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients

70

29

17

1.2 0 0

20

40

60

80

100

Lamivudine[1] Adefovir[1] Telbivudine*[1] Entecavir[1] Tenofovir[2]

Cum

ulat

ive

Resi

stan

ce R

ate

(%)

1. EASL. J Hepatol. 2009;50:227-242. 2. Marcellin P, et al. AASLD 2011. Abstract 1375. *Telbivudine rate determined at Yr 2.

Response Rate to First Line Therapies HBeAg (+) CHB

Response Parameters

Entecavir Tenofovir PEG IFN

Response at weeks 48-52

Log reduction in HBV DNA, c/ml

6.9 6.2 2-4.5

Undetectable HBV DNA % 67 76 25 ALT normalization % 68 77 34-39

Loss of HBE Ag % 22 21 ~30 HBeAg seroconversion % 21 21 27 Loss of HBS Ag % 2 3 3 Histologic improvement % 72 74 38 Genotypic Resistance % 0 0 0 Responses during extended treatment % (years)

Undetectable HBV DNA % 94 (5) 65 (5) 19 (3.5) HBeAg seroconversion % 41 (5) 40(5) 37 (3.5) Loss of HBS Ag % 5 (5)n 10 (5) 11 (3.5) Genotypic resistance % 1.2 (6) 0 0

Scaglione S, Lok A. Gastroenterology 2012;142:1360-1368; Marcellin, P, et al. AASLD 2011; Poster #1375.

Response Rates to Approved Therapies HBeAg (-) CHB

Response Parameters Entecavir Tenofovir PEG IFN

Responses week 48-52

Histologic improvement %

70 72 48

Undetectable HBV DNA %

90 93 63

HBS Ag loss % <1 0 4 Genotypic resistance 0.2 0 0 Responses: Extended Treatment % (years)

Undetectable HBV DNA %

NA 83 (5) 18 (3)

HBS Ag loss % NA 0.3 (5) 8 (3)

Genotypic resistance % NA 0 0

Scaglione S, Lok A. Gastroenterology 2012;142:1360-1368 Marcellin, P, et al. AASLD 2011; Poster #1375.

Improvement in Necroinflammation Tenofovir Therapy

01020304050607080

baseline Year 1 Year 5

Knodell = 0-3

baselineYear 1Year 5

p < 0.001

Percentage of patient with Knodell = 0-3 increased over time Marcellin P, et al. Lancet 2013 Feb 9;381(9865):468-75

Improvement in Fibrosis Score Tenofovir Therapy

0

10

20

30

40

50

60

70

Baseline Year 1 year 5

No or Mild Fibrosis

Bridging Fibrosis-Cirrhosis (Ishak ≥4)

Marcellin P, et al. Lancet 2013 Feb 9;381(9865):468-75

Incidence of HCC in CHB on Nucleo(t)ide Therapy

05

101520

6.4 2.8

0.5

10.8

0

17.6

2.3 7.5

5.9 8.8

HCC %

Systematic review 21 studies of CHB (RCT or observational cohort), 3881 treated patients, 534 untreated, during 46 (32-108) month period Antiviral therapy = LAM in 14 studies, FTC in one and ADV in one 5 studies with LAM-R treated with ADV or LAM+ADV

Papatheodoridis GV, Lampertico P, Mnolakopoulos S, Lok A . J Hepatol 2010;53:348-356

%

Incidence of HCC in CHB on Nucleo(t)ide Therapy

Rate of HCC was higher in LAM-R than Nuc naïve Even among cirrhotics, HCC rate was higher in LAM-R than Nuc naïve Achievement of virological response did not seem to significantly reduce the risk of HCC in LAM-R

Papatheodoridis GV, Lampertico P, Mnolakopoulos S, Lok A . J Hepatol 2010;53:348-356

ETV-Therapy and HCC Risks in CHB

Comparison of hepatocellular carcinoma cumulative incidence rates between the ETV-treated group and the non-treated control group after propensity score matching Greatest risk reduction is seen in cirrhotic patients

Control (n=316)

ETV (n=316)

Log-rank test: P < 0.001

Treatment duration (yr)

Cum

ulat

ive

deve

lopm

ent r

ates

of H

CC (%

)

0 1 3 5 7

0

10

20

30

40

50

4% 7.2%

10.0%

13.7%

3.7% 2.5% 1.2% 0.7%

316 316 316 277 246 223 200 187 170

2 2 44 101 185 264 316 No at risk

ETV Control

Tetsuya Hosaka et al. Hepatology. Mar 2013 doi:10.1002/hep26180

Retrospective cohort study N = 472 NA-naïve pts treated with ETV 0.5mg from 2004-2010 N = 1143 non NA treated pts from 1973-1999 Primary outcome: HCC diagnosis 1 year after start of observation

When to Consider PegIFN • Favorable predictors of response[1,2]

HBeAg (+) – Low HBV DNA* < 2 x 10⁸ IU/ml⁽⁶⁾ – High ALT* ≥ 2 x ULN ⁽⁶⁾ – Genotype A >B > C or D[3-5]

– No advanced disease HBeAg (-) – No reliable predictor

1.Lok AS, et al. Hepatology. 2009;50:661-662. 2. Lok AS. Hepatology. 2010;52:743-747. 3. Janssen HL, et al,Lancet. 2005;365;123-129. 4. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. 5. Flink HJ, et al. Am J Gastroenterol. 2006;101:297-303. 6. Buster EH, et at. Gastro. 2009 Dec; 137(6):2002-9

Specific patient demographics[1,2]

– Generally young people

– Young women wanting pregnancy in near future

– Absence of comorbidities

Patient preference[1,2]

Concomitant HCV/HDV infection

*Also predictive of response to nucleos(t)ide analogues.

PEG IFN-α2a in HBeAg(-) CHB

PEG IFN n = 116/177 LAM n = 85/181 Patients were treated for 48 wks then follow up 44% of PEG IFN treated group with undetectable HBV DNA cleared HG S Ag

Marcellin P, et al. Gastroenterology 2009;136:2169-79

IFN Therapy in HBeAg (+) Reduces Progression to Cirrhosis and HCC

P = 0.031 P = 0.03 P = 0.041 P = 0.011

N = 233 IFN α VS 233 matched untreated control Significant reduction in HCC was seen in those with preexisting cirrhosis HB E Ag seroconverters in untreated and IFN treated group had lower incidence of cirrhois and HCC Hetergenous IFN regimens for 11-28 weeks Cumulative incidence at 15 years follow up. Median = 6.8 years (1.1-16.5)

Lin SM et al. J Hepatol 2007;46:45-52

Treatment Endpoints in HBeAg(+) Patients for Oral Nucleos(t)ide Agents AASLD Guidelines US Algorithm Recommendations for Asian

American Patients

• Seroconversion from HBeAg(+) to HBeAb(+)

• Duration of therapy: minimum 1 year; continue until at least 6 months after HBeAg seroconversion

• Seroconversion from HBeAg(+) to Anti-HBe(+) – Treat until HBV DNA is

undetectable, then continue treatment for additional 12 months

• Seroconversion from HBeAg(+) to Anti-HBe(+) – If HBV DNA is steady and

detectable, patients should continue treatment for 6 months, redocument seroconversion, and consider stopping treatment in patients without cirrhosis

• Patients who fail to lose HBeAg should be treated long-term

• Seroconversion from HBeAg(+) to HBeAb(+) – Continue treatment

for additional 12-24 months

• After treatment cessation, patients should be monitored closely for relapse

Lok ASF, et al. Hepatology. 2009;50:1-36. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Tong MJ, et al. Dig Dis Sci. Epub ahead of print September 21, 2011.

Treatment Endpoints in HBeAg(-) Patients for Oral Nucleos(t)ide Agents AASLD Guidelines US Algorithm Recommendations for

Asian American Patients

• Undefined endpoint • Duration of therapy:

>1 year • Treatment should

be continued until the patient has achieved HBsAg clearance

• Long-term therapy using entecavir or tenofovir

• Treatment should be considered indefinitely

• If HBsAg is undetectable, treatment may be discontinued

• After treatment discontinuation, close follow-up is mandatory – Retreat patients

promptly if HBV DNA or ALT levels increase

Lok ASF, et al. Hepatology. 2009;50:1-36. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Tong MJ, et al. Dig Dis Sci. Epub ahead of print September 21, 2011.

AASLD Guideline Recommendations for Treatment of Patients With HBV Cirrhosis

HBeAg HBV DNA (PCR), IU/mL

ALT Treatment Strategy

+/- Detectable Cirrhosis Compensated HBV DNA > 2000 IU/mL: treat HBV DNA < 2000 IU/mL: consider

treatment if ALT elevated Decompensated Coordinate treatment with transplant

center; refer for liver transplant +/- Undetectable Cirrhosis Compensated: observe

Decompensated: refer for liver transplant.

Lok AS, et al. Hepatology. 2009;50:661-662.

Management of Patients With Compensated Cirrhosis

Preferred therapies

• ETV or TDF

– NAs should be used; IFN can be associated with hepatitis flare

Treatment duration

• Long-term treatment

– Can discontinue in HBeAg-positive patients with confirmed HBeAg seroconversion and ≥ 6 mos consolidation therapy

– Can discontinue in HBeAg-negative patients with confirmed HBsAg clearance

• Treatment discontinuation requires close monitoring for flare or relapse

Lok AS, et al. Hepatology. 2009;50:661-662.

Management of Patients With Decompensated Cirrhosis

Preferred therapies • TDF or ETV monotherapy • (LAM or LdT) + (ADV or TDF) • Treatment should be coordinated with

transplantation center – IFNs should not be used in decompensated

cirrhosis Treatment duration • Lifelong treatment recommended

Lok AS, et al. Hepatology. 2009;50:661-662.

Summary

• Treatment indicated in patients with evidence of inflammation and fibrosis

• Effective treatments available, safe and well tolerated

• First line agents: TDF, ETV and Peg-IFN • Avoid LAM • Inadequate data supporting treatment of

immune tolerant patients