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Introduction and Program Overview. Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF Program Chair Leonard Miller Professor of Medicine University of Miami School of Medicine Miami, Florida. Program Overview.

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Presentation Transcript
slide2

Introduction and Program Overview

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

Program Chair

Leonard Miller Professor of Medicine

University of Miami School of Medicine

Miami, Florida

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 objectives
Educational Objectives

Upon 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
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 faculty
Program Faculty

Program Chair

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

Leonard Miller Professor of Medicine

Director, Schiff Liver Institute

Director, Center for Liver Diseases

Division of Hepatology

University of Miami School of Medicine

Miami, FL

Marion Peters, MD, FRACP

Professor of Medicine

Chief of Hepatology Research

University of California, San Francisco

San Francisco, CA

Mark Sulkowski, MD

Associate Professor of Medicine

Medical Director, Viral Hepatitis Center

Johns Hopkins University School of Medicine

Baltimore, MD

Norah A. Terrault, MD

Associate Professor of Medicine

Director, Viral Hepatitis Research in Liver Transplantation

Dept of Medicine, Division of Gastroenterology

University of California, San Francisco

San Francisco, CA

Tram T. Tran, MD

Assistant Professor of Medicine

Geffen UCLA School of Medicine

Division of Gastroenterology

Medical Director of Liver Transplant

Comprehensive Transplant Center

Cedars Sinai Medical Center

Los Angeles, CA

audience participation
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
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
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
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.

slide12

Tram T. Tran, MD

Assistant Professor of Medicine

Geffen School of Medicine at UCLA Medical Director of Liver Transplant

Comprehensive Transplant Center

Cedars-Sinai Medical Center

Los Angeles, California

The Hepatitis B Virus:A Silent Killer

case presentation
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

audience response question
Audience Response Question

0

New CDC 2008 Guidelines recommend HBV screening in immigrants from endemic areas with hepatitis B prevalence of:
  • > 25%
  • >10%
  • >8%
  • >2%
incidence of acute hepatitis b by age group sex and year united states 1990 2002
Incidence* of Acute Hepatitis B, by Age Group, Sex, and Year – United States, 1990-2002

20

Males aged 0-19 yr

Males aged 20-39 yr

Males aged ≥40 yr

Females aged 0-19 yr

Females aged 20-39 yr

Females aged ≥40 yr

Total

16

12

Incidence

8

4

0

1990

1992

1994

1996

1998

2000

2002

Year

*Per 100,000 population.

hepatitis b disease progression
Hepatitis B: Disease Progression

Liver Cancer (HCC)

5%-10%

2%-6%

Death

Liver Transplantation

Acute Infection

Cirrhosis

Chronic Infection

10%-30%

90% in perinatal

30%-90% in children <5 years old

5% in healthy adults

Higher in HIV, immunosuppressed

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

Liver Failure

(Decompensation)

23% within 5 years

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.

asian american age adjusted liver cancer rates california 2000 2002
Asian-American Age-Adjusted Liver Cancer Rates (California, 2000-2002)

Incidence

Mortality

Male

Female

Male

Female

54.3

35.5

33.7

Rate (per 100,000)

Rate (per 100,000)

26.6

23.3

19.9

16.8

15.8

15.9

11.5

12.0

10.4

9.3

8.1

8.3

7.6

7.8

7.8

6.8

6.0

5.4

4.2

2.5

2.7

Chinese

Filipino

Viet-

namese

Korean

Japanese

White

Chinese

Filipino

Viet-

namese

Korean

Japanese

White

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

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

case presentation laboratory findings
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

audience response question22
Audience Response Question

0

This patient is most likely in which stage of CHB infection?
  • Immune tolerant
  • Immunoactive/immune clearance
  • Inactive carrier
  • HBeAg CHB
  • Can’t tell
phases of hbv infection
Phases of HBV Infection

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

case presentation cont d
Case Presentation (cont’d)

Serial follow-up of his liver tests reveals

- ALT fluctuation 30105

- HBV DNA 1800 IU/mL 7600 IU/mL

alt and histology
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.

grade of inflammation by alt group
Grade of Inflammation by ALT Group

78%

54%

34%

PNALT, persistently normal ALT.

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

case presentation cont d28
Case Presentation (cont’d)

Liver biopsy is performed:

- Grade 2-3 inflammation

- Stage 2 fibrosis

hbeag seroconversion
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.

hbeag seroconversion to anti hbe
HBeAg Seroconversion to Anti-HBe

Development of cirrhosis complications and HCC

- 3233 Chinese patients

- Mean follow-up 46.9 months

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

incidence of cirrhosis hbeag status
Incidence of Cirrhosis: HBeAg Status

Taiwan and Korea

Europe

50

50

HBeAg negative

HBeAg positive

HBeAg negative

HBeAg positive

40

40

30

30

20

20

Percent

Percent

10

10

0

0

0

1

2

3

4

5

0

1

2

3

4

5

Years

Years

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

cumulative incidence of hepatocellular carcinoma hcc
Cumulative Incidence of Hepatocellular Carcinoma (HCC)

Taiwan, China, Singapore, Koreaand Japan

Europe and USA

20

20

Cirrhosis

Chronic hepatitis

Inactive carrier

Cirrhosis

Chronic hepatitis

Inactive carrier

15

15

10

10

5

5

Percent

Percent

1

1

0

0

0

1

2

3

4

5

0

1

2

3

4

5

Years

Years

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

aasld guidelines periodic screening for hcc
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.

case presentation cont d34
Case Presentation (cont’d)

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

audience response question36
Audience Response Question

0

Is it necessary to screen patients for HBV before anti-TNF therapy?
  • Yes, screen all patients
  • Yes, but only those with risk factors for HBV
  • No, just monitor
  • No, never
screening new cdc guidelines
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

case presentation cont d38
Case Presentation (cont’d)

Patient started on antiviral therapy prior to anti-TNF treatment

HBV DNA becomes undetectable

ALT remains persistently normal

summary
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

slide41

Norah Terrault, MD, MPH

Associate Professor of MedicineDirector of Viral Hepatitis Research in Liver TransplantationUniversity of California, San FranciscoSan Francisco, California

Whom to TreatWhen to Treat

goals of treatment
Goals of Treatment

Improvedsurvival

Improvedhistology

Anti-HBs+

Loss of

HBsAg

Anti-HBe+

Loss of

HBeAg

Loss of

HBV DNA

HBV is controlled not eradicated

TIME

decision to treat balancing benefits and risks
Decision to Treat: Balancing Benefits and Risks

Costs

Side EffectsDrug Resistance

Risk of Liver

Complications

factors associated with disease progression in patients with chb
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

Environmental Factors

  • Concurrent infection (HCV, HDV, HIV)
  • Alcohol consumption
  • Diabetes mellitus
  • Obesity

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

persistent elevated hbv dna and cumulative incidence of hcc
Persistent Elevated HBV DNA and Cumulative Incidence of HCC

P<.001

12

67% ≥40 yrs and 62% male

10.1

(6.3-16.2)

P<.001

10

7.3

8

(3.5-15.3)

Adjusted HR for HCC

(95% CI)

P<.001

6

3.8

(1.7-8.4)

4

P= NS

2

1

10/120

55/537

26/2034

8/146

0

≥105 →

104 -<105

≥105

<104

≥105

≥105

<104

Not Tested

HBV DNA : Baseline

Follow-up (copies/mL)

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

case presentation46
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

case presentation cont d47
Case Presentation (cont’d)

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

audience response question49
Audience Response Question

0

What do you recommend at this point?
  • Continue monitoring ALT every 3-6 months and treat if ALT increases to ≥2 X ULN
  • Obtain HBV genotype and treat if genotype A
  • Start treatment, regardless of HBV genotype
  • Obtain liver biopsy and treat if significant inflammation or fibrosis
recommendations whom to treat
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
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 treat54
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 10 5 copies ml
Patients With CHB With Significant Liver Disease (ALT<2 ULN and HBV DNA >105 copies/mL)

* <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
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]

audience response question58
Audience Response Question

0

Based upon the AASLD Guidelines, which of the following HBeAg-positive profiles warrants treatment?
  • ALT 45, HBV DNA 50,000 IU/mL, no biopsy available
  • ALT 45, HBV DNA 500 million IU/mL, biopsy shows F0, G1-2 disease
  • ALT 18, HBV DNA 22 million IU/mL, no biopsy
  • ALT 45, HBV DNA 57,000 IU/mL, biopsy shows F2, G2-3 disease
fluctuating course of hbeag negative chronic hepatitis b
Fluctuating Course of HBeAg-negative Chronic Hepatitis B

73 pts

(44.5%)

With flares and normalization

Asymptomatic

flare-up:

90% of cases

A

L

T

Without flares

59 pts

(36.0%)

Flare-up yearly

frequency:

once 57.1%

twice 20%

< once 22.8%

With flares and without normalization

32 pts

(19.5%)

0 12 24

months

Brunetto MR et al, J Hepatol 2002

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

audience response question62
Audience Response Question

0

Based upon the AASLD Guidelines, which of the following HBeAg-negative profiles warrants treatment now?
  • ALT 60, HBV DNA 500 IU/mL, no biopsy available
  • ALT 40, HBV DNA 8000 IU/mL, biopsy shows G2, F2, no steatosis
  • ALT 40, HBV DNA 200,000 IU/mL, biopsy shows G0-1, F0-1 fibrosis, G2 steatosis
  • ALT 20, HBV DNA 100 IU/ml, biopsy shows F4 (cirrhosis)
chb treatment algorithm for cirrhotic patients
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.

considerations in applying treatment guidelines
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

case presentation cont d65
Case Presentation (cont’d)

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

audience response question67
Audience Response Question

0

What do you recommend?
  • Defer treatment until after delivery of infant
  • Deferral of pregnancy to undergo treatment with peg-IFN for 24 weeks
  • Proceed with pregnancy but add lamivudine in last trimester for prevention of perinatal transmission
  • Start treatment now with tenofovir
hbv treatment and pregnancy
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. JViral Hepat. 2003(4);10:294-297.

hepatitis b treatment summary
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

slide71

Mark Sulkowski, MD

Associate Professor of Medicine

Divisions of Infectious Diseases and Gastroenterology/Hepatology

Johns Hopkins University

Baltimore, Maryland

Treatment Options for Chronic Hepatitis B Infection

case presentation72
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”

audience response question74
Audience Response Question

0

Which of the following evaluations may be helpful for guiding HBV treatment decisions?
  • HBV genotype
  • Resistance testing
  • Liver biopsy
  • ALT level
  • All of the above
case presentation cont d75
Case Presentation (cont’d)

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

*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.

audience response question79
Audience Response Question

0

A 55-year-old man- Genotype C- HBV DNA = 28.8 million IU/mL- ALT = 54 - Histologic evidence of cirrhosisWhich of the following characteristics is/are associated with a favorable response to interferon?

  • Male sex
  • Genotype C
  • Elevated ALT
  • High HBV DNA level
  • Cirrhosis
peg ifn for chronic hepatitis b
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

Peg-IFN

  • Finite duration
  • No resistance
  • Higher rates of seroconversion
  • Poor tolerance
  • SQ injection

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

audience response question82
Audience Response Question

0

Which of the following factors may influence the selection of nucleos(t)ide analogue therapy:
  • Cost
  • Genetic barrier to resistance
  • Safety
  • Potency
  • All of the above
antiviral agents safety tolerability cost and risk benefit
Antiviral Agents: Safety, Tolerability, Cost, and Risk:Benefit

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

hbeag postive chronic hbv hbv dna suppression and hbe seroconversion at 1 year
HBeAg-Postive Chronic HBV: HBV DNA Suppression and HBeSeroconversion 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
Higher Rates of Seroconversion With Longer Viral Suppression

30

27

26

22

21

20

%

10

5

3

2

1

0

48 weeks

64 weeks

HBeAg loss

HBeAb

HBsAg loss

HBsAb

Heathcote J. EASL 2008. Abstract #1593

slide86

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 with long-term HBV DNA suppression with ETV

Improvement in Ishak fibrosis score†

Histologic Improvement*

96%

100

100

88%

73%

80

80

60

60

Proportion of patients (%)

Proportion of patients (%)

40

40

32%

20

20

41/56‡

55/57

18/56‡

50/57

0

0

48 Weeks

Long-term§

48 Weeks

Long-term§

*≥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 weeks

inadequate Week 48 biopsy; § Median time of long-term biopsy: 280 weeks

Liaw Y-F et al. AASLD 2008; Poster #894

clinical outcomes by treatment and resistance status
Clinical Outcomes by Treatment and Resistance Status

25

Placebo (n=215)

YMDDm (n=209) (49%)

Placebo

21%

20

Wild Type (n=221)

15

YMDDm

% With Disease Progression

13%

10

WT

5%

5

0

0

6

12

18

24

30

36

Time After Randomization (Months)

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

incomplete suppression of virus replication leads to resistance
Incomplete Suppression of Virus Replication Leads to Resistance

Dominant Strain

Treatment

Initiated

Naturally Occurring Variants

Drug Resistant Variant

  • Incomplete Suppression

- Inadequate Potency/Drug Levels

- Inadequate Adherence

- Pre-Existing Resistance Variants

HBV Replication

Detection

Level

Time

Fung SK & Lok ASF. Antivir Ther 2004; 9:1013–1026

Locarnini S, et al. Antivir Ther 2004; 9:679–693

viral suppression reduces the incidence of resistance
Viral Suppression Reduces the Incidence of Resistance

ADV

in HBeAg-Negative Patients

(Follow-up 144 weeks, n=114)

LAM

in HBeAg-Positive Patients

(Follow-up 29 months, n=159)

P < .001 between groups

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

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

monitoring for treatment failure with nucleos t ide analogue therapy
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
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 therapy cross resistance i n v i tro
HBV Antiviral TherapyCross-Resistance in Vitro

N236T

L180M

A184G

M204V

M250V

A181V/T

V173L

M204I

S202I

LAM

ETV

LdT

FTC

ADV

TDF

?

?

hbv resistance to entecavir affected by previous resistance to lamivudine
HBV Resistance to Entecavir Affected by Previous Resistance to Lamivudine

100

Entecavir (naive): genotypic resistance

Entecavir (lamivudine resistant): genotypic resistance

80

60

51

Cumulative Incidence (%)

46

40

36

15

20

6

1.2

1.2

1.2

0.5

0.2

0

1

2

3

4

5

Year

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.

tdf in nucleos t ide experienced patients undetectable hbv dna at month 12
TDF in Nucleos(t)ide-Experienced Patients: Undetectable* HBV DNA at Month 12

P = NS

P = NS

P =.001

100

100

92

92

90

85

90

73

80

70

60

Undetectable* HBV DNA

at Month 12 (%)

50

40

30

30

20

10

0

All Patients

HBeAgPositive

HBeAgNegative

Wild-Type HBV

YMDDMutations

ADV-R

No ADV-R

n = 101 85 26 42 36 20 81

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

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

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

case presentation cont d96
Case Presentation (cont’d)

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 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?

slide99

Combination Therapy for Treatment of Chronic HBV Infection

Marion Peters, MD

Professor of Medicine

Chief of Hepatology Research

University of California, San Francisco

San Francisco, California

case presentation100
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
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

audience response question103
Audience Response Question

0

How would you treat his HBV?
  • Pegylated interferon (Peg-IFN) for 48 weeks
  • Lamivudine (LAM) 100 mg per day
  • Adefovir (ADV) 10 mg per day
  • Entecavir (ETV) 0.5 mg per day
  • Telbivudine (LdT) 600 mg
  • Tenofovir (TDF) 300 mg per day
  • Combination LAM + TDF
case presentation treatment
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

audience response question108
Audience Response Question

0

What has occurred?
  • LAM nonresponse
  • LAM resistance
  • Noncompliance
hbv dna at month 6 of lam predicts later risk of resistance
HBV DNA at Month 6 of LAM Predicts Later Risk of Resistance

HBeAg-Positive Patients (N = 159)

Median Follow-up: 29.6 Months

100

80

64

60

Patients With YMDD Variants (%)

Patients With Resistance (%)

40

32

20

13

8

12

23

41

118

n =

0

≤ 2

≤ 3

≤ 4

> 4

HBV DNA at 6 Months (log10 copies/mL)

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

slide110
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

audience response question112
Audience Response Question

0

How would you treat his HBV?
  • Switch to ADV 10 mg per day
  • Switch to ETV 0.5 mg per day
  • Switch to TDF 300 mg per day
  • Add ADV 10 mg per day
  • Add ETV 0.5 mg per day
  • Add TDF 300 mg per day
audience response question116
Audience Response Question

0

What has occurred?
  • ADV resistance
  • ADV primary nonresponse
  • ADV suboptimal response
  • Worsening liver failure
  • Noncompliance
nonresponse suboptimal response and virologic breakthrough
Nonresponse, Suboptimal Response, and Virologic Breakthrough

1.0

Antiviral Drug

0

Primary nonresponse

Virologic breakthrough

-1.0

Change in HBV DNA

(log10 IU/mL)

Suboptimal response

-2.0

-3.0

1 log

Nadir

-4.0

0

6

12

18

Months

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

hbv dna at week 48 of adv predicts risk of resistance at week 144
HBV DNA at Week 48 of ADV Predicts Risk of Resistance at Week 144

N = 114 Patients,

Primarily HBeAg Negative1

N = 124 Patients, HBeAg Negative2

100

100

80

80

67

60

60

49

Resistance (%)

40

40

26

20

20

6

4

0

0

< 3

3-6

> 6

< 3

> 3

HBV DNA at Week 48 (log10copies/mL)

1. Locarnini S et al. 40th EASL; 2005; Paris. Abstract 36.

2. Hadziyannis SJ et al. Gastroenterology. 2006;131:1743-1751.

audience response question120
Audience Response Question

0

What would you do?
  • Continue ADV
  • Add TDF 300 mg
  • Change to TDF and ADV
  • Change to TDF and LAM or emtricitabine (FTC)
  • Change to TDF and ETV
case presentation laboratory findings cont d121
Case Presentation: Laboratory Findings (cont’d)

LAM

AddADV

Switch  to TDF + LAM

why consider combination therapy
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 failureincreases 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
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
PEG-IFN alfa-2a +/- LAM for HBeAg+ CHB

0

Patients (%)

Patients (%)

Week 48 (End of therapy)

Week 72 (24 weeks off-therapy)

*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.

adv vs adv lam for hbeag lam resistant patients
ADV vs ADV + LAM for HBeAg-LAM-Resistant Patients

Multicenter cohort study; retrospective/prospective

Mean follow-up: 33 months

Undetectable HBV DNA* (%)

Year 3 Cumulative ADV Resistance

ADV + LAM (n = 285)

100

100

ADV (n = 303)

80

80

60

60

P = NS

Patients (%)

40

40

P < .001

20

20

16

0

0

0

0

6

12

18

24

30

36

ADV

(n = 303)

ADV + LAM

(n = 285)

Month

*< 1000 copies/mL.

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

adv resistance not observed with lam combination therapy
ADV Resistance Not Observed With LAM Combination Therapy

ADV monotherapy (Study 438: naive patients)

60

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

40

Incidence of Resistance (%)

30

20

19

11

3

0

0

0

0

0

0

Year 1

Year 2

Year 3

Year 4

Year 5

*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.

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
Managing Responses in the Treatment of CHB

Week 12

Assess for primary nonresponse

Week 24

Assess early predictors of efficacy

Partial response

HBV DNA

60 to < 2000 IU/mL

Complete response

HBV DNA negative by PCR

Inadequate response

HBV DNA ≥ 2000 IU/mL

Add another drug without cross-resistance or continue

Monitor every 3 months

Add/switch to more potent drug

Monitor every 3 months

Continue

Monitor every 6 months

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

combination therapy128
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.