eugene r. schiff, md, macp, frcp, macg, agaf program chair leonard miller professor of medicine...

Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF

Program ChairLeonard Miller Professor of MedicineUniversity of Miami School of Medicine

Miami, Florida

Introduction and Program Overview

Program Overview• Chronic hepatitis B (HBV) infection is significantly under-

diagnosed and under-treated in the US

• Much new data has emerged, increasing our knowledge of the natural history of this disease and its treatment

• Effective new anti-HBV agents and novel treatment approaches for long-term management are now in use

• Interactive case presentations will help us review the latest developments in the understanding and treatment of the disease

Educational ObjectivesUpon completion of this activity, participants should be able to:

• DESCRIBE the epidemiology and natural history of hepatitis B virus (HBV) infection

• IMPLEMENT an activity of screening, vaccination, and diagnosis of HBV within their clinical practices

• EVALUATE the risks and benefits of available agents for treating chronic HBV infection

• EVALUATE current data on the potential use of combination therapy for patients with chronic HBV infection

Agenda

• The Hepatitis B Virus: A Silent Killer

• Whom to Treat/When to Treat

• Treatment Options for Chronic HBV Infection

• Combination Therapy: Controversies and Uncertainties

Program FacultyProgram Chair

Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAFLeonard Miller Professor of MedicineDirector, Schiff Liver InstituteDirector, Center for Liver DiseasesDivision of HepatologyUniversity of Miami School of MedicineMiami, FL

Marion Peters, MD, FRACPProfessor of MedicineChief of Hepatology ResearchUniversity of California, San FranciscoSan Francisco, CA

Mark Sulkowski, MDAssociate Professor of MedicineMedical Director, Viral Hepatitis CenterJohns Hopkins University School of MedicineBaltimore, MD

Norah A. Terrault, MDAssociate Professor of MedicineDirector, Viral Hepatitis Research in Liver TransplantationDept of Medicine, Division of GastroenterologyUniversity of California, San FranciscoSan Francisco, CA

Tram T. Tran, MDAssistant Professor of MedicineGeffen UCLA School of MedicineDivision of GastroenterologyMedical Director of Liver TransplantComprehensive Transplant CenterCedars Sinai Medical CenterLos Angeles, CA

Audience Participation

• Audience Response System Used to pose a series of questions during the meeting At slide prompts, key in your answers on the keypads Please return your keypad at the end of the program

• Questions? Question cards

• Please jot down your questions, and staff will pick them up during the course of the meeting

Microphones

Accreditation Statement

• This activity has been planned and implemented through the joint sponsorship of the University of Kentucky College of Medicine and HealthmattersCME

• The University of Kentucky College of Medicine designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credits™

How to Obtain CME Credit

• Complete this activity in its entirety

• After the activity, go to www.cecentral.com/getcredit

• Enter activity code MLN09103• Log in or register for a free account

• Complete activity evaluation and get credit

• A printable certificate will be issued

Disclosure Statements

Program faculty have disclosed their relevant financial relationships with commercial interests that produce health care goods and/or services consumed by, or used on patients.

Written disclosures can be found within your folder.

The Hepatitis B Virus:A Silent Killer

Tram T. Tran, MDAssistant Professor of Medicine

Geffen School of Medicine at UCLA Medical Director of Liver TransplantComprehensive Transplant Center

Cedars-Sinai Medical CenterLos Angeles, California

Case Presentation

• A 44-year-old Russian man who immigrated to the United States in 1989 is seeing you for abnormal transaminase levels. - ROS: occasional flares of diarrhea and

abdominal pain, currently asymptomatic- PMH: Crohn’s disease; previously vaccinated for

hepatitis B virus- Social: 1-2 drinks per week, works construction- Family Hx: Mother d. cirrhosis; was “drinker”- Meds: 5-aminosalicylic acid (5-ASA)- PE: normal

Let’s Vote!

New CDC 2008 Guidelines recommend HBV screening in immigrants from endemic areas with hepatitis B prevalence of:

36%

24%

26%

14%

Audience Response Question

A. > 25%

B. >10%

C. >8%

D. >2%

Hepatitis B: Region/CountryRegion Countries

Africa All countries

Asia All countries

Australia & South Pacific All countries except Australia and New Zealand

Middle East All countries except Cyprus and Israel

Eastern Europe All countries except Hungary

Western Europe Malta, Spain, and indigenous populations of Greenland

North America Alaska and indigenous populations of northern Canada

Mexico and Central America

Guatemala and Honduras

South America Ecuador, Guyana, Suriname, Venezuela, Amazonian areas

Caribbean Antigua, Dominica, Granada, Haiti, Jamaica, St Kitts and Nevis, St Lucia, Turks and Caicos

CDC.MMWR 2008

Incidence* of Acute Hepatitis B, by Age Group, Sex, and Year – United States, 1990-2002

*Per 100,000 population.

Males aged 0-19 yrMales aged 20-39 yrMales aged ≥40 yrFemales aged 0-19 yrFemales aged 20-39 yrFemales aged ≥40 yrTotal

Year

1996 1998 2000 20021994199219900

4

8

12

16

20

Inci

den

ce

Hepatitis B: Disease Progression

Acute Infection

Chronic Infection

Cirrhosis Death

Torresi J et al. Gastroenterology. 2000;118(2 Suppl 1):S83-S103. Fattovich G et al. Hepatology. 1995;21(1):77-82. Moyer LA et al. Am J Prev Med. 1994;10(Suppl):45-55. Perrillo RP et al. Hepatology. 2001;32(2):424-432.

5%-10%

10%-30%

23% within 5 years

Liver Cancer (HCC)

Chronic HBV is the 6th leading cause of liver transplantation in the US

Liver Transplantation

Liver Failure (Decompensation)

2%-6%2%-6%

90% in perinatal30%-90% in children <5 years old5% in healthy adultsHigher in HIV, immunosuppressed

Asian-American Age-Adjusted Liver Cancer Rates (California, 2000-2002)

Incidence

Rat

e (p

er 1

00,0

00)

MaleFemale

23.3

7.6

54.3

15.8

33.7

8.1

McCracken M et al. CA Cancer J Clin. 2007;57:190-205.

Filipino Viet-namese

Korean Japanese WhiteChinese

16.8

5.4

15.9

9.36.8

2.5

Mortality

Rat

e (p

er 1

00,0

00)

MaleFemale

19.9

7.8

35.5

10.4

26.6

7.8

Filipino Viet-namese

Korean Japanese WhiteChinese

12.0

4.2

11.5

8.36.0

2.7

Approximately 3.7 million Asians in California. Cancer data from California Cancer Registry.

Case Presentation: Laboratory Findings

• CBC: WBC 5.5, Hgb 12.5, Plt 288• AST 39 IU/L, ALT 35 IU/L• Bilirubin 1.0 mg/dL, INR 1.1, albumin 3.7 g/dL• HBsAg: positive• HBeAg: negative• Anti-HBe: positive• HBV DNA 1800 IU/mL• HCV, HIV, HDV negative

Let’s Vote!

This patient is most likely in which stage of CHB infection?

15%

21%

38%

8%

18%


A. Immune tolerant

B. Immunoactive/immune clearance

C. Inactive carrier

D. HBeAg CHB

E. Can’t tell

Phases of HBV Infection

Yim JY, Lok AS-F. Hepatology. 2006;43:S173-S181.

Case Presentation (cont’d)

• Serial follow-up of his liver tests reveals- ALT fluctuation 30105- HBV DNA 1800 IU/mL 7600 IU/mL

ALT and Histology

• 192 patients (Boston)

• HBV DNA > 10,000 copies/mL

• Liver biopsy data

• Stratified by ALT- Persistently normal (< 40 IU/L), n=59- 1-1.5 x ULN, n=26- >1.5 x ULN, n=107

Lai M et al. J Hepatol. 2007;47(6):760-767.

0%

10%

20%

30%

40%

50%

60%

70%

PNALT ALT 1-1.5 ULN ALT >1.5 ULN

Per

cen

tag

e

Grade 0

Grade 1

Grade 2

Grade 3

34%

54%

78%

Lai M et al. J Hepatol. 2007;47(6):760-767.

Grade of Inflammation by ALT Group

PNALT, persistently normal ALT.

Stage of Fibrosis by ALT Group

18% 34%

62%


• Liver biopsy is performed:- Grade 2-3 inflammation- Stage 2 fibrosis

HBeAg Seroconversion• 298 patients with documented HBeAg seroconversion

- 116 treatment induced, 182 spontaneous

• Reactivation in 71 patients (39%)- Older age, male gender, and higher ALT at seroconversion

were risks for reactivation (all P <.006)- No difference between interferon, adefovir, lamivudine

treatment

• Treatment-induced seroconversion less durable than spontaneous- Remission of ALT shorter (14 vs 22 months, P=.037)- More likely to have HBeAg reactivation at 48 months

(38% vs 25%, P=.048)

Lim G et al. 58th AASLD; 2007; Boston. Poster 937.

Yuen MF et al. Gut 2005;54(11):1610-1614.

HBeAg Seroconversion to Anti-HBe

Median age (yr)

Percentage

anti-HBe

HBeAg seroconversion 35 -

All complications 57.2 73.5

Ascites 57.7 68.8

Spontaneous bacterial peritonitis 60.0 76.7

Varices 54.3 76.3

Encephalopathy 58.5 65.0

Hepatocellular carcinoma 59.0 81.1

• Development of cirrhosis complications and HCC

- 3233 Chinese patients

- Mean follow-up 46.9 months

50

40

30

20

10

0

HBeAg negativeHBeAg positive

Years

Per

cen

t

0 1 2 3 4 5

Incidence of Cirrhosis: HBeAg Status

Fattovich G et al. J Hepatol. 2008;48(2):335-352.

Taiwan and Korea Europe

50

40

30

20

10

0

HBeAg negativeHBeAg positive

Years

Per

cen

t

0 1 2 3 4 5

Cumulative Incidence of Hepatocellular Carcinoma (HCC)

Fattovich G et al. J Hepatol. 2008;48(2):335-352.

Taiwan, China, Singapore, Koreaand Japan Europe and USA

20

15

10

5

1

0

CirrhosisChronic hepatitisInactive carrier

Years

Per

cen

t

0 1 2 3 4 5

20

15

10

5

1

0

CirrhosisChronic hepatitisInactive carrier

Years

Per

cen

t

0 1 2 3 4 5

AASLD Guidelines: Periodic Screening for HCC

• At-risk hepatitis B carriers- Asian males >40 years of age- Asian females >50 years of age- All cirrhotic hepatitis B carriers- Family history of hepatocellular carcinoma- Africans >20 years of age- Those with high HBV DNA levels and those with

ongoing hepatic inflammatory activity remain at risk for hepatocellular carcinoma

• Liver ultrasound every 6 to 12 months

Bruix J et al. Hepatology. 2007;42:1208-1236.


• Patient’s Crohn’s disease flares; consideration is made for steroids and possibly anti-tumor necrosis factor (TNF) therapy

Let’s Vote!

Is it necessary to screen patients for HBV before anti-TNF therapy?

2%

3%

28%

68%


A. Yes, screen all patients

B. Yes, but only those with risk factors for HBV

C. No, just monitor

D. No, never

Screening: New CDC Guidelines• CDC Guidelines 2006

- Persons born endemic areas >8% prevalence

- Pregnant women, infants- Sexual, household

contacts of HBV+- HIV- Needlestick/assault- Hemodialysis patients- Blood donors

• CDC Guidelines 2008- Persons born endemic

areas >2% prevalence

- US-born children of immigrants from high- risk areas

- Injection drug users

- MSM

- Immunosuppressive Rx• GI, rheumatologic,

oncologic, tx

- ALT/AST elevation

Centers for Disease Control; MMWR Sept 19 2008


• Patient started on antiviral therapy prior to anti-TNF treatment

• HBV DNA becomes undetectable

• ALT remains persistently normal

Summary

• HBV burden is significant, some groups disproportionately affected

• New CDC guidelines have broadened screening recommendations

• Disease progression may be independent of biochemical and serological markers

Whom to TreatWhen to Treat

Norah Terrault, MD, MPH

Associate Professor of MedicineDirector of Viral Hepatitis Research in

Liver TransplantationUniversity of California, San Francisco

San Francisco, California

Goals of Treatment

TIME

Loss of HBeAg

Loss of HBV DNA

Anti-HBe+ Loss ofHBsAg

Anti-HBs+Improvedsurvival

Improvedhistology

HBV is controlled not

eradicated

Decision to Treat: Balancing Benefits and Risks

Risk of Liver Complications

CostsSide Effects

Drug Resistance

Factors Associated With Disease Progression in Patients With CHB

Host Factors• >40 years of age

• Male

• Immune status

Virus Factors

• High serum HBV DNA concentrations

• Prolonged time to HBeAg seroconversion

• Development of HBeAg(-) chronic hepatitis

• Core promoter HBV variant

• Genotype C

Yim HJ, Lok ASF. Hepatology. 2006;43:S173-S181.

Environmental Factors

• Concurrent infection (HCV, HDV, HIV)

• Alcohol consumption

• Diabetes mellitus• Obesity

26/2034

Persistent Elevated HBV DNA and Cumulative Incidence of HCC

10.1

7.3

3.8

1

0

2

4

6

8

10

12

Chen CJ et al. JAMA. 2006;295(1):65-73.

< 104

Not Tested≥105

< 104 ≥105

≥105

≥105 → 104 - < 105

(1.7-8.4)

(3.5-15.3)

(6.3-16.2)

HBV DNA : Baseline Follow-up (copies/mL)

Ad

just

ed H

R f

or

HC

C

(95%

CI)

8/146 10/120 55/537

P = NS

P < .001

P < .001

P < .001

67% ≥40 yrs and 62% male

Case Presentation• A 37-year-old Asian woman is referred for HBsAg-

positive status. Discovered when mother was diagnosed with HCC at age 65

• Asymptomatic, recently married, husband vaccinated, no children

• No medications other than oral contraceptives

• Initial lab results:- HBeAg+, HBV DNA 2.5 million IU/mL- ALT 30 IU/L, AST 27 IU/L, total bilirubin 0.6 mg/dL,

albumin 4.0, g/dL, INR 1.0, platelets 300K


• Ultrasound findings:- Normal-appearing liver with normal echotexture,

no splenomegaly or collaterals

• Repeat labs:- 3 months: ALT 35 IU/L- 6 months: ALT 31 IU/L, HBV DNA 1.3 million

IU/mL

Let’s Vote!

What do you recommend at this point?

45%

25%

4%

25%


A. Continue monitoring ALT every 3-6 months and treat if ALT increases to ≥2 X ULN

B. Obtain HBV genotype and treat if genotype A

C. Start treatment, regardless of HBV genotypeD. Obtain liver biopsy and treat if significant

inflammation or fibrosis

Recommendations: Whom to Treat

AASLD Guidelines 2007

• Treatment indicated for ‘active’ disease:- ALT ≥2 ULN- HBV DNA ≥20,000 IU/mL

Or if- ALT 1-2 ULN and ≥age 40, consider biopsy and

treat if significant fibrosis or necroinflammation is present

Recommendations: Whom to Treat: NIH 2008 HBV Consensus Statement

Treatment Indicated

• Fulminant and decompensated disease

• Cirrhosis with elevated HBV DNA

• Chemotherapy or other IMS therapy

• (Liver transplantation)

Treatment May be Indicated

• Immune active phase

• Reactivation phase

Treatment Not Indicated

• Immune tolerant

• Immune inactive

• Latent HBV

NIH Consensus Development Conference: Management of Hepatitis B. Draft Statement. October 22, 2008 5:50 PM; http://consensus.nih.gov/2008/hepB

Recommendations: Whom to Treat

AASLD Guidelines 2007• HBV DNA ≥20,000 IU/mL

• ALT ≥2 ULN

• If ALT 1-2 ULN and ≥age 40, consider biopsy and treat if significant fibrosis or necroinflammation

EASL Guidelines 2009

• HBV DNA ≥ 2,000 IU/mL

• ALT ≥ ULN

“Gray Areas”• ALT cutoff

- New “normal” ULN for ALT- Is ≥2 ULN appropriate?

• Biopsy criteria- Significant? ≥G2 or G3,

≥F2?

• HBV viral load- Differs for HBeAg negative vs positive CHB?

Patients With CHB With Significant Liver Disease (ALT<2 ULN and HBV DNA >105 copies/mL)

ALT<2 ULN With Laboratory Cutoff

n=451

ALT<2 ULN With Revised ALT ULNs*

n=141

HBeAg(+) CHB

Necroinflammation ≥7

Fibrosis ≥465%

13%

68%

11%

HBeAg(-) CHB

Necroinflammation ≥7

Fibrosis ≥471%

8%

75%

17%

* <30 IU/L males, <19 IU/L females

Terrault NA et al. Digestive Disease Week; 2007; Washington, DC.

Chronic HBV Infection and Normal ALT: Summary of Recent Literature

If focus on fibrosis:• Range 8% to 47% of patients have stage 2

fibrosis or greater• Normal ALT levels often on follow-up• Factors associated with higher fibrosis

- Age >35 yr- Male gender- Level of ALT

Yang LM et al. Chinese J Dig Dis. 2002;3:150-153.Tsang PSY et al. Clin Gastroenterol Hepatol. 2008;6:569-574.Kumar J et al. Gastroenterology. 2008;134:1376-1384.Wang C et al. Hepatology. 2005;42:573A.Lai M et al. Hepatology. 2005;42:720A.Terrault NA et al. Gastroenterology. 2007;132:A72. [#94]

Let’s Vote!

Based upon the AASLD Guidelines, which of the following HBeAg-positive profiles warrants treatment?

71%

3%

14%

12%


A. ALT 45, HBV DNA 50,000 IU/mL, no biopsy available

B. ALT 45, HBV DNA 500 million IU/mL, biopsy shows F0, G1-2 disease

C. ALT 18, HBV DNA 22 million IU/mL, no biopsy

D. ALT 45, HBV DNA 57,000 IU/mL, biopsy shows F2, G2-3 disease

HBeAg-Negative HBV Disease: Diagnostic Dilemmas

Active HBeAg-Negative Disease

Inactive Chronic HBV

Anti-HBe positive

HBV DNA >20,000 IU/mLHBV DNA <2000

IU or negative

ALT Elevated Normal

HistologySignificant

inflammation and fibrosis

Inactive hepatitis with variable

fibrosis

0

100

200

300

400

0

100

200

300

400

0

100

200

300

400

Biochemical patterns in 164 untreated patients after 23 months (range 12-36) monthly monitoring

00 1212 2424monthsmonths

With flares and normalizationWith flares and normalization

Without flaresWithout flares

With flares and without normalizationWith flares and without normalization

73 pts 73 pts (44.5%)(44.5%)

59 pts 59 pts (36.0%)(36.0%)

32 pts 32 pts (19.5%)(19.5%)

Asymptomatic flare-up:

90% of casesAALLTT

Flare-up yearlyfrequency:

once 57.1%twice 20%

< once 22.8%

Brunetto MR et al, J Hepatol 2002

Fluctuating Course of HBeAg-negative Chronic Hepatitis B

Let’s Vote!

Based upon the AASLD Guidelines, which of the following HBeAg-negative profiles warrants treatment now?

35%

21%

41%

3%


A. ALT 60, HBV DNA 500 IU/mL, no biopsy available

B. ALT 40, HBV DNA 8000 IU/mL, biopsy shows G2, F2, no steatosis

C. ALT 40, HBV DNA 200,000 IU/mL, biopsy shows G0-1, F0-1 fibrosis, G2 steatosis

D. ALT 20, HBV DNA 100 IU/ml, biopsy shows F4 (cirrhosis)

CHB Treatment Algorithm for Cirrhotic Patients

Keeffe EB et al. Clin Gastroenterol Hepatol. 2006;4(8):936-962.Lok AS, McMahon BJ. Hepatology. 2007;45(2):507-539.

Treatment Criteria Recommended Action

If HBV DNA ≥2000 IU/mL, any ALTOR

If HBV DNA <2000 IU/mL, elevated ALT Treat

If HBV DNA<2000 IU/mL and normal ALT Observe

Considerations in Applying Treatment Guidelines

• HBV viral load- HBeAg-negative: if 2000-20,000 IU/mL, may

benefit from additional testing to determine disease severity

• ALT cutoff- Use “normal” ULN for ALT- Lack of ALT elevation does not exclude significant

disease, though advance fibrosis infrequent

• Cirrhosis- Levels of HBV DNA differ, any ALT


• You perform a liver biopsy, which shows grade 2 necroinflammation and stage 2 fibrosis

• Additional laboratory testing:- HBV genotype B

• Patient informs you that she and her husband would like to start a family within the year

Let’s Vote!

What do you recommend?

37%

28%

20%

16%


A. Defer treatment until after delivery of infant

B. Deferral of pregnancy to undergo treatment with peg-IFN for 24 weeks

C. Proceed with pregnancy but add lamivudine in last trimester for prevention of perinatal transmission

D. Start treatment now with tenofovir

HBV Treatment and Pregnancy• If can defer, this is often best strategy• If treating in pregnancy:

- Lamivudine is treatment of choice, if limited duration Pregnancy category C drug with long safety record in

HIV+ women

- Tenofovir and telbivudine Pregnancy category B drugs Tenofovir has accumulating safety record in HIV+ women

- Risk-benefit needs to be individualized- Antiviral therapy in last trimester may reduce perinatal

transmission if mother has high HBV DNA (>107-8 IU/mL)

van Zonneveld et al. J Viral Hepat. 2003(4);10:294-297.

Hepatitis B Treatment: Summary• Chronic HBV is dynamic disease

- Regular monitoring needed to determine timing of treatment and other interventions

• Primary determinants of treatment initiation are - HBV DNA level ≥20,000 IU/mL - ALT level ≥2 ULN- ± Histological severity of disease

• Assessment of histology most helpful in borderline ALT and HBV DNA cases

• Cirrhotics: lower thresholds to treat

Treatment Options for Chronic Hepatitis B

Infection

Mark Sulkowski, MDAssociate Professor of Medicine

Divisions of Infectious Diseases and Gastroenterology/Hepatology

Johns Hopkins UniversityBaltimore, Maryland

Case Presentation• A 58-year-old man from Malaysia is referred

for evaluation– No comorbid conditions– He reports that his mother died of liver cancer – He was initially diagnosed ~ 1999 and treated for about

3 months with “a pill”

• Evaluation– AFP = 9 ng/mL– HBeAg +– ALT = 64 (< 40 U/L)– HBV DNA = 28.8 million IU/mL– Liver CT scan = “normal”

Let’s Vote!

Which of the following evaluations may be helpful for guiding HBV treatment decisions?

57%

6%

24%

7%

6%


A. HBV genotype

B. Resistance testing

C. Liver biopsy

D. ALT level

E. All of the above


• Liver biopsy was performed– Chronic portal inflammation with mild focal

lobular hepatitis– Portal and septate fibrosis with ill-defined focal

parenchymal nodularity

• HBV genotype C

• PCR amplification and DNA sequencing reveal polymorphism at position 204 (M → V)

Goal of Anti-HBV Therapy

• Improve QOL and survival by preventing progression to cirrhosis, end-stage liver disease, hepatocellular carcinoma and death

• Mechanisms to achieve this goal– Immune control of HBV replication:

seroconversion – Antiviral control of HBV replication: long term

suppression

• Eradication is not possible, due to cccDNA

EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001.

Recommended First-Line HBV Treatment: Peg-IFN, ETV, TDF

Approved for HBV Unlabeled

• Interferon alfa- Interferon alfa-2b- Peginterferon alfa-2a

• Nucleoside analogues- Lamivudine*- Telbivudine- Entecavir

• Nucleotide analogues- Adefovir- Tenofovir DF*

• Emtricitabine*• Combination therapy

- PegIFN + nucleos(t)ide analogue

- Nucleoside + nucleotide analogue*

*Approved by the FDA for treatment of HIV infection

First-line agents in guidelines: Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008 Aug 23. [Epub ahead of print]; EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001.

Let’s Vote!

A 55-year-old man- Genotype C- HBV DNA = 28.8 million IU/mL- ALT = 54 - Histologic evidence of cirrhosis

Which of the following characteristics is/are associated with a favorable response to interferon?

6%

15%

53%

23%

3%


A. Male sexB. Genotype CC. Elevated ALTD. High HBV DNA levelE. Cirrhosis

Peg-IFN for Chronic Hepatitis B• High ALT activity1,2,3

• Low baseline serum HBV DNA concentration4

• Genotype A or B5,6

• Absence of comorbidities

• No cirrhosis

• No decompensated liver disease

1. Piratvisuth T, et al. Hepatology. 2004;40:656A. Abstract 1137. 2. Flink HJ, et al. Gut. 2005;54(11):1604-1609.3. LauGKK et al. 56th AASLD;2005; San Francisco. Abstract 66086.

4. Fried MW, et al. Hepatology. 2005;42:268A. Abstract 182.5. FlinkHJ, et al. Am J Gastroenterol. 2006;101(2):297-303. 6. Hadziyannis SJ, et al. J Hepatol. 2005;42(suppl 2):178. Abstract 49

Peg-IFN

• Finite duration

• No resistance

• Higher rates of seroconversion

• Poor tolerance

• SQ injection

Let’s Vote!

Which of the following factors may influence the selection of nucleos(t)ide analogue therapy:

78%

7%

2%

12%

2%


A. Cost

B. Genetic barrier to resistance

C. Safety

D. Potency

E. All of the above

Antiviral Agents: Safety, Tolerability, Cost, and Risk:Benefit

LAM ADV Entecavir Telbivudine Tenofovir

Dosing QD QD QD QD QD

Tolerability Well tolerated

Well tolerated; Watch serum Cr

Well tolerated

Well tolerated; Watch CPK

Well tolerated; Watch serum Cr

Pregnancy C C C B B

Approximate cost for 1 year

2500 6500 8700 6000 6000

Potency Moderate Modest High High High

Resistance High Moderate Low High Low

Dienstag JL. N Engl J Med. 2008;35(14):1486-500.

HBeAg-Postive Chronic HBV: HBV DNA Suppression and HBe Seroconversion at 1 Year

EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001; Dienstag JL. N Engl J Med. 2008;359(14):1486-1500.

Higher Rates of Seroconversion With Longer Viral Suppression

Heathcote J. EASL 2008. Abstract #1593

%

22

27

21

26

35

1 2

0

10

20

30

48 weeks 64 weeks

HBeAg loss HBeAbHBsAg loss HBsAb

HBeAg-Negative Chronic HBV: HBV DNA Suppression and ALT Normalization at 1 Year

EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001; Dienstag JL.. N Engl J Med. 2008;35(14):1486-1500.

Histologic improvement with long-term HBV DNA suppression with ETV

Histologic Improvement*

73%

96%

Pro

po

rtio

n o

f p

atie

nts

(%

)

0

20

40

60

80

100

48 Weeks Long-term§

41/56‡ 55/57

Improvement in Ishak fibrosis score†

32%

88%

0

20

40

60

80

100

48 Weeks Long-term§

18/56‡ 50/57P

rop

ort

ion

of

pat

ien

ts (

%)

*≥2-point decrease in Knodell necroinflammatory score and no worsening of Knodell fibrosis score compared with baseline † ≥1-point decreasepatient had an inadequate Week 48 biopsy; ‡One § Median time of long-term biopsy: 280 weeksinadequate Week 48 biopsy; § Median time of long-term biopsy: 280 weeksLiaw Y-F et al. AASLD 2008; Poster #894

Clinical Outcomes by Treatment and Resistance Status

Wild Type (n=221)YMDDm (n=209) (49%)

Time After Randomization (Months)

0

5

10

15

20

25

0 6 12 18 24 30 36

% W

ith

Dis

ease

Pro

gre

ssio

n Placebo (n=215)

YMDDm

Placebo

5%

13%

21%

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

WT

Incomplete Suppression of Virus Replication Leads to Resistance

Fung SK & Lok ASF. Antivir Ther 2004; 9:1013–1026Locarnini S, et al. Antivir Ther 2004; 9:679–693

Drug Resistant Variant

• Incomplete Suppression- Inadequate Potency/Drug Levels- Inadequate Adherence- Pre-Existing Resistance Variants

Time

HB

V R

epli

cati

on

Treatment Initiated

DetectionLevel

Dominant Strain

Naturally Occurring Variants

Viral Suppression Reduces the Incidence of Resistance

Yuen M et al. Hepatology. 2001; 34(4):785-791.

P < .001 between groups

LAM in HBeAg-Positive Patients (Follow-up 29 months, n=159)

ADVin HBeAg-Negative Patients

(Follow-up 144 weeks, n=114)

Locarnini S et al. J. Hepatology . 2005;42(Suppl 2):17.

Monitoring for Treatment Failure With Nucleos(t)ide Analogue Therapy

• Primary nonresponse – Less than 1-log10 drop at week 12

• Partial virological response (detectable)– Week 24: LAM, LdT, ADV – Week 48: TDF, ETV

• Virological breakthrough – Rise in serum HBV DNA (≥ 1.0 log10 IU/mL) above nadir

–

Cumulative Incidence of HBV Resistance

EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001; Dienstag JL. N Engl J Med. 2008;35(14):1486-1500

HBV Antiviral TherapyCross-Resistance in Vitro

M204V

V173L

A181V/T

M250V

L180M

A184GS202I

N236T

M204I

LAMLAM

ADVADV

ETVETV

LdTLdT

FTCFTC

TDFTDF ? ?

HBV Resistance to Entecavir Affected by Previous Resistance to Lamivudine

Colonno RJ, et al. 42nd EASL;2007;Barcelona. Abstract 781; Lai CL, et al. Clin Infect Dis. 2003;36:687-696; Lok AS, et al. Gastroenterology. 2003;125:1714-1722; Tenney DJ, et al. 18th APASL; 2008:Seoul.. Abstract PL02.

Year

Cu

mu

lati

ve In

cid

ence

(%

)

0

20

40

60

80

100

1 2 3 4 5

Entecavir (naive): genotypic resistance

Entecavir (lamivudine resistant): genotypic resistance

1.2

51

1.2

46

36

1.2

15

0.50.26

van Bömmel F, et al. 43rd EASL; 2008; Milan. Abstract 73.

TDF in Nucleos(t)ide-Experienced Patients: Undetectable* HBV DNA at Month 12

Virologic breakthrough not observed during follow-up period, independent of presence of ADV resistance at start of TDF

Un

det

ecta

ble

* H

BV

DN

A a

t M

on

th 1

2 (%

)

P =.001

P = NS P = NS

01020304050607080

10090

All Patients

HBeAgPositive

HBeAgNegative

Wild-Type HBV

YMDDMutations

ADV-R No ADV-R

8573

92100

92

30

90

n = 101 85 26 42 36 20 81

*HBV DNA < 400 copies/mL (< 69 IU/mL)


• Patient initiates treatment with TDF 300 mg/day– HBV DNA

• 3 months: 120,000 IU/mL• 6 months: 785 IU/mL• 12 months: < 22 IU/mL

• Serum Cr stable

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.

HBV Therapy • HBV replication is closely linked to the lifetime risk

of disease outcomes (HCC, ESLD)• New treatment paradigm = long-term control of HBV

replication:– ↓ hepatic inflammation and fibrosis – ↓ risk of hepatic decompensation and/or HCC

• First-line therapy – high potency/low resistance– Peg-IFN – Tenofovir– Entecavir – Combination antiviral therapy?

Combination Therapy for Treatment of

Chronic HBV Infection

Marion Peters, MDProfessor of Medicine

Chief of Hepatology ResearchUniversity of California, San Francisco

San Francisco, California

Case Presentation

• A 45-year-old man was admitted with fatigue, malaise, and abdominal swelling in June 2003

• He was born in Greece, came to United States at age 14

• His brother had a liver transplant for HBV in 1998

• Examination reveals jaundice, ascites, no muscle wasting, spider nevi

Case Presentation: HBV Laboratory

• Bilirubin 3.7, AST 129, ALT 106, albumin 2.4, PT 1.7, ammonia 51, creatinine 0.9

• MELD (model for end-stage liver disease) score, 19

• HBsAg and HBeAg positive

• HBV DNA 1.7 billion copies per mL

• AFP 741 µg/L

• Paracentesis WCC 183, albumin <1

Let’s Vote!

How would you treat his HBV?

37%

22%

3%

23%

1%

5%

10%


A. Pegylated interferon (Peg-IFN) for 48 weeks

B. Lamivudine (LAM) 100 mg per day

C. Adefovir (ADV) 10 mg per day

D. Entecavir (ETV) 0.5 mg per day

E. Telbivudine (LdT) 600 mg

F. Tenofovir (TDF) 300 mg per day

G. Combination LAM + TDF

Case Presentation: Treatment

• June 2003 started LAM 100 mg daily- Well tolerated- Patient has improvement in well-being

• Listed for liver transplantation

• Ultrasound: cirrhotic liver, no masses

• CT, quadruple phase: no masses

Date AST Bili Albumin AFP HBV DNA

6-03 160 3.7 2.5 741 1,700,000,000

11- 03 59 0.9 3.1 14 2,000,000

copies/mL

LAM

Case Presentation: Laboratory Findings


6-03 160 3.7 2.5 741 1,700,000,000

11- 03 59 0.9 3.1 14 2,000,000

2-04 74 1.3 2.9 193 2,500,000,000

copies/mL

LAM

Case Presentation: Laboratory Findings (cont’d)

Let’s Vote!

What has occurred?

8%

87%

5%


A. LAM nonresponse

B. LAM resistance

C. Noncompliance

12 n =

HBV DNA at Month 6 of LAM Predicts Later Risk of Resistance

HBeAg-Positive Patients (N = 159) Median Follow-up: 29.6 Months

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

Pat

ien

ts W

ith

Res

ista

nce

(%

)

813

32

64

0

20

40

60

80

100

≤ 2 ≤ 3 ≤ 4 > 4

Pat

ien

ts W

ith

Y

MD

D V

aria

nts

(%

)

HBV DNA at 6 Months (log10 copies/mL)

23 41 118

CaseCase Presentation: HBV Status

• HBV genotype A, HBeAg positive

• Polymerase mutations- L180M, +M204V- No precore mutations detected- No ADV mutations detected

• HIV negative

• Hepatitis D virus negative

Let’s Vote!

How would you treat his HBV?

47%

8%

19%

15%

7%

3%


A. Switch to ADV 10 mg per day

B. Switch to ETV 0.5 mg per day

C. Switch to TDF 300 mg per day

D. Add ADV 10 mg per day

E. Add ETV 0.5 mg per day

F. Add TDF 300 mg per day

AddADV


6-03 160 3.7 2.5 741 1,700,000,000

11- 03 59 0.9 3.1 14 2,000,000

2-04 74 1.3 2.9 193 2,500,000,000

copies/mL

LAM


AddADV


6-03 160 3.7 2.5 741 1,700,000,000

11- 03 59 0.9 3.1 14 2,000,000

2-04 74 1.3 2.9 193 2,500,000,000

5-04 69 1.5 3.0 169 1,600,000,000

copies/mL

LAM


Let’s Vote!

What has occurred?

4%

4%

54%

28%

10%


A. ADV resistance

B. ADV primary nonresponse

C. ADV suboptimal response

D. Worsening liver failure

E. Noncompliance

Nonresponse, Suboptimal Response, and Virologic Breakthrough

Lok AS et al. Hepatology. 2007;45:507-539.

1 log

Ch

ang

e in

HB

V D

NA

(lo

g10

IU

/mL

)

0

-1.0

-2.0

-3.0

-4.0

1.0

Nadir

Virologic breakthrough

Antiviral Drug

Months

60 12 18

Primary nonresponse

Suboptimal response

HBV DNA at Week 48 of ADV Predicts Risk of Resistance at Week 144

Res

ista

nce

(%

)

1. Locarnini S et al. 40th EASL; 2005; Paris. Abstract 36.2. Hadziyannis SJ et al. Gastroenterology. 2006;131:1743-1751.

HBV DNA at Week 48 (log10copies/mL)

6

49

0

20

40

60

80

100

< 3 > 3

4

67

26

0

20

40

60

80

100

< 3 3-6 > 6

N = 114 Patients, Primarily HBeAg Negative1

N = 124 Patients, HBeAg

Negative2

Let’s Vote!

What would you do?

39%

34%

9%

17%

2%


A. Continue ADV

B. Add TDF 300 mg

C. Change to TDF and ADV

D. Change to TDF and LAM or emtricitabine (FTC)

E. Change to TDF and ETV


6-03 160 3.7 2.5 741 1,700,000,000

11- 03 59 0.9 3.1 14 2,000,000

2-04 74 1.3 2.9 193 2,500,000,000

5-04 69 1.5 3.0 169 1,600,000,000

8-04 68 1.8 3.4 42 78,000,000

11-04 67 1.0 3.7 16.2 97,000

5-06 52 1.1 4.0 8 2,590

5-07 28 1.0 4.4 2.9 undetectable

<5 copies/mL

AddADV

LAM

Switch to TDF + LAM


Why Consider Combination Therapy?• Sequential monotherapy with nucleos(t)ide analogs has

led to HBV resistance • There may be special populations in whom combination

is recommended:- Cirrhotics in whom development of resistance may have

irreversible severe consequences - HIV/HBV coinfected

• Changing to another nucloes(t)ide after failure increases chance of poor or nonresponse and of resistance to next drug, eg, ETV

• Multidrug-resistant mutants described after sequential monotherapy1,2

• Resistance has been low with combination therapy

1. Yim HJ et al. Hepatology. 2006:43:S173-181. 2. Shaw T et al. 58th AASLD; 2007; Boston. Abstract 986.

Combination Therapy

• Peg-IFN and LAM showed more HBV DNA suppression while patients on therapy but suppression lost after end of therapy; no increased HBeAg seroconversion

• ADV and LAM/FTC: less resistance but no increase in efficacy

Lampertico P et al. Gastroenterology. 2007;133(5):1445-1451.

PEG-IFN alfa-2a +/- LAM for HBeAg+ CHB

*P<.05 vs lamivudine **P<.01 vs lamivudine***P<.001 vs lamivudine Lau GK et al. N Engl J Med 2005; 352(26):2682-2695.

Pat

ien

ts (

%)

Pat

ien

ts (

%)

Week 48 (End of therapy) Week 72 (24 weeks off-therapy)

ADV vs ADV + LAM for HBeAg-LAM-Resistant Patients• Multicenter cohort study; retrospective/prospective

‒ Mean follow-up: 33 months

Lampertico P et al. Gastroenterology. 2007;133(5):1445-1451. Lampertico P et al. 57th AASLD; 2006; Boston. Abstract LB5. CCO

P < .001

Undetectable HBV DNA* (%)

0 6 12 18 3630240

20

40

60

80

100

P = NS

ADV (n = 303)ADV + LAM (n = 285)

0

20

40

60

80

100

160

Year 3 Cumulative ADV Resistance

ADV(n = 303)

ADV + LAM(n = 285)Month

Pat

ien

ts (

%)

*< 1000 copies/mL.

ADV monotherapy (Study 438: naive patients)

ADV+ LAM (Studies 435 and 460i: LAM resistance*; Study 435: pre- and post-OLT; Study 460i: HIV/HBV)

ADV Resistance Not Observed With LAM Combination Therapy

*Two patients enrolled in Study 435 initially received combination therapy with adefovir + lamivudine and subsequently selected adefovir resistance mutation N236T. However, they had switched to adefovir monotherapy at a time when adefovir resistance mutation was detected.

Inci

den

ce o

f R

esis

tan

ce (

%)

0 0 3 0

11

0

19

30

0

20

40

60

Year 1 Year 2 Year 3 Year 4 Year 5

0

Lee YS,et al. Hepatology. 2006;43:1385-1391. Lampertico P et al. 57th AASLD; 2006; Boston. Abstract LB5. Schiff E et al. Liver Transpl. 2007;13:349-360. Hepsera [package insert].

Managing Responses in the Treatment of CHB

Adapted from Keeffe E et al. Clin Gastroenterol Hepatol. 2007;5:890-897.

Week 12 Assess for primary nonresponse

Week 24 Assess early predictors of efficacy

Complete responseHBV DNA negative by PCR

Partial responseHBV DNA

60 to < 2000 IU/mL

Inadequate responseHBV DNA ≥ 2000 IU/mL

ContinueMonitor every 6 months

Add another drug without cross-resistance or continue

Monitor every 3 months

Add/switch to more potent drug

Monitor every 3 months

Combination Therapy

• Combination therapy has reduced the emergence of resistance

• This may lead to better long-term outcomes

• At present no FDA-approved indication for use of combination therapy in patients with chronic HBV infection and no synergy in HBV DNA decline noted

• Use in cirrhotic patients especially those with preexisting YMDD mutations and in HIV HBV patients appears warranted

Jacobson IM. J Hepatol. 2008;48:687-691; CDC Guidelines for HIV patients. 2008.

eugene r. schiff, md, macp, frcp, macg, agaf program chair leonard miller professor of medicine...

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