Can One Pill A Day Keep Hepatitis B Away?

Scott K. Fung, MD, FRCPCToronto General Hospital

University of Toronto

November 30, 2009 TGH

Learning Objectives

• To discuss new ‘normal’ values for ALT and define significant HBV DNA levels

• To briefly review antiviral treatment options for chronic HBV infection in 2009

• To illustrate indications for treatment of chronic hepatitis B and monitoring strategies using case studies

Quiz

1 2 3 4

A. Wilson diseaseB. Hereditary hemochromatosisC. Chronic hepatitis B and HCCD. Fatty liver

Liver Disease in Canada

HBV

HCVNAFLD

Alcohol

Others

Age-Standardized MortalityCause of Death 2001* 2003* 2005*

Chronic liver disease/ cirrhosis 6.5 6.4 6.1

Renal failure 8.3 8.5 8.3

Diabetes mellitus 19.3 20.5 19.1

Heart disease 143.1 133.3 121.5

Malignant neoplasm 178.7 175.6 170.3

*Rate per 100,000 population, both sexes

Hepatitis B and HCC in Canada• Rate of HCC is rising in Canada and

most Western countries• Related to immigration from HBV

endemic parts of the world• No accurate data on overall prevalence

of HBV and HCC in Canada• Estimated 1981-2005 using 2006

National census

Hepatitis B and HCC in Canada• Between 1981-2005, Canada accepted • 4 million new immigrants• 90% from HBV endemic areas (>3-7%)• HBsAg+ immigrants = 209,401 individuals• HBsAg+ nonimmigrants = 182,000 indiv.• Overall prevalance in Canadian pop =1.3 %• Limited impact of HBV vaccine • ~500 immigrants will develop HCC per yr (0.22/100,000/yr)

Leber et al, Can J Gastro 2009

All HBV Carriers are Potential Treatment Candidates

Slow down

Observe closely

May need Rx later

Stop

Rx not indicated

Go ahead with Rx

Stages of Chronic Hepatitis B Infection

Lok, Gastroenterology 2007

HBeAg-negative CHB

• Viral Load >3–4 log IU/mL

• HBeAg-negative– pre-core / core promoter

mutant

• ALT intermittently abnormal

• Biopsy– inflammation intermittent– fibrosis progression

• Risk of complications (cirrhosis/ HCC) higher

Adapted from Yim & Lok, Hepatology 2006; 43: S173

Disease Progression

Chronic hepatitis

Cirrhosis

Liver Failure

Death or OLTx20%

15-40%

HCC

10-20%

EASL Consensus Guidelines. J Hepatol 2003 Lok et al, Hepatology 2004

Age 40 50 60 Years

12

Complications of HBV

Ascites

Varices

HCC

Danger Signs: Time To Worry

CirrhosisINR

Bilirubin

Albumin

Platelets

Confusion

Jaundice

GI bleeding

Ascites

HBV DNA

New unit of measurement for HBV DNA = logs IU/ml

HBV Viral load in Log Scale

• Log scales simplify large numeric differences in HBV DNA values

• Error of the test = 0.5 log IU • Tripling of viral load = within the error of

the test• Following trends in HBV DNA important• If in doubt, repeat testing to confirm

How High Can You Go?

1 = 100 = 1E0

10 = 101 = 1E1

100 = 102 = 1E2

1,000 = 103 = 1E3

10,000 = 104 = 1E4

100,000 = 105 = 1E5

1,000,000 = 106 = 1E6

10,000,000 = 107 = 1E7

100,000,000 = 108 = 1E8

1,000,000,000 = 109 = 1E9

10,000,000,000 = 1010=1E10

Low

Medium

High

HB

eAg

-neg

HB

eAg

-po

s

REVEAL HBV

Iloeje et al, JAMA 2006 Chen et al, Gastroenterology 2006

Cirrhosis

HCC

HCC in HBeAg-negative patients with normal ALT

HBV DNA

HBV DNA Report

4.3 E+7

43,000,000

7.4 log

20

“Normal” ALT Levels

Yuen et al, Gut 2005

Upper Limit of Normal

Male 53 U/L

Female 31 U/L

ALT and Liver Mortality

Tai et al, Hepatology 2009

ALT Normal Values

• Current upper limit of normal too high

• New standard for ALT

– Male <30 U/L

– Female <19 U/L

• Normal ALT does not exclude significant liver disease

• Patients should not be denied antiviral treatment based on normal ALTSherman et al, Can J Gastro 2007

Histology in HBeAg-positive CHB

Yang et al, Chinese J Dig Dis 2002; 3: 150

Note: This study population consisted of males over the age of 30

Beware ‘Normal’ ALT

Nguyen et al, Am J Gastro 2009

Predictors of Sig. Fibrosis:

Older Age

Fluct. ALT

HBeAg-positive Patients

Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C

HBeAg-positive

No treatment. Monitor every

3 months with ALT and

HBV DNA

Rule out other causes of liver

disease

Monitor ALT every 3 months. Consider biopsy

if age >35–40 years, and treat

if significant disease

Treat

ALT normalALT normalALT elevated

for 3–6 monthsALT elevated

for 3–6 months

HBV DNA >20,000 IU/mL(>105,200 copies/mL)

HBV DNA <20,000 IU/mL(<105,200 copies/mL)

Based on a conversion factor of 1 IU/mL = 5.26 copies/mL

Selection of Specific Agents for HBeAg-positive CHB

Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C

Standard interferon

Pegylated interferon

Adefovir

Entecavir*

Tenofovir*†

Entecavir*

Tenofovir*†

HBV DNA <20 million IU/mL(<105.2 million copies/mL)

HBV DNA >20 million IU/mL(>105.2 million copies/mL)

HBeAg-positive

*If Entecavir or Tenofovir not available, use Telbivudine or Lamivudine†Approved since publication of the guidelines

Based on a conversion factor of 1 IU/mL = 5.26 copies/mL

HBeAg-negative Patients

Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C

Based on a conversion factor of 1 IU/mL = 5.26 copies/mL

HBeAg-negative

No treatment. Monitor every 3 months for 1–2 years with ALT and HBV DNA

Rule out other causes of liver

disease

Monitor ALT every 3 months, or consider

biopsy, since ALT often fluctuates. Treat if

significant disease. Long-term treatment required (oral agents)

Treat. Long-term treatment required

(oral agents)

ALT normalALT normal ALT elevated ALT elevated

HBV DNA >2,000 IU/mL(>10,520 copies/mL)

HBV DNA <2,000 IU/mL(<10,520 copies/mL)

Selection of Specific Agents for HBeAg-negative CHB

Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C

Pegylated interferon

Adefovir

Entecavir*

Tenofovir*†

Entecavir*

Tenofovir*†

HBV DNA <20 million IU/mL(<105.2 million copies/mL)

HBV DNA >20 million IU/mL(>105.2 million copies/mL)

HBeAg-negative

*If Entecavir or Tenofovir not available, use Telbivudine or Lamivudine†Approved since publication of the guidelines

Based on a conversion factor of 1 IU/mL = 5.26 copies/mL

Comparison of Oral Therapy for Chronic Hepatitis B

Lamivudine Adefovir Entecavir* Telbivudine Tenofovir*

RelativeAntiviralPotency

++ ++ ++++ +++ ++++

Resistance High Low Very low Intermediate Very low

* Recommended as first-line therapy for HBV

HBV Treatment in Ontario in 2009Public Formulary Private Formulary

Treatment-Naive(1st Line)

Tenofovir*Entecavir*LamivudineStandard IFN-α

AdefovirTenofovirTenofovir + FTCTelbivudinePEG-IFNStandard IFNLamivudine

Treatment-Experienced(2nd Line)

Adefovir**Tenofovir**├

EntecavirTenofovirTenofovir + FTCTelbivudinePEG-IFNStandard IFNLamivudine

* Cirrhosis with DNA > 6 log IU/ml** LAM virologic breakthrough and F3/F4 fibrosis or LAM-resistant HBV├ Suboptimal response to LAM after 6 months

On Treatment Monitoring*

•Frequency can be decreased once stable on treatment (HBV DNA undetectable)

Patterns of Response

Lok 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

Mos

60 12 18

Primary nonresponse

Suboptimal response

HBV Resistance Pathways

R

LAM-R

180/204 Pathway

S

LdT-R

236 Pathway

ADV-R

R

ETV-R

Pre-existing

resistant mutants

LAM ADV

184/202/250 Pathway

181 Pathway

Endpoints of Therapy

HBsAgClearance

HBV DNASuppression

HBeAgLoss

Regression of Fibrosis

Pre-Tx

Post-Tx

Adefovir

Antiviral Therapy for Advanced Liver Disease

Liaw et al, NEJM 2004

True Goals of Therapy

Lower Mortality

PreventHCC and Cirrhosis Decrease

Liver Transplant

New Kid on the Block:

Tenofovir

RA

ND

OM

IZA

TIO

N 2

:1 Tenofovir 300 mg

Adefovir 10 mg

Open-label8 Years

Week 240Liver Biopsy

Week 48

Liver BiopsyPre-treatment Liver Biopsy

Double Blind

Week 72

Tenofovir 300 mg

Tenofovir 300 mg

Marcellin P et al., NEJM 2008

Study 102 N=250Study 103 N=176

Study 102 N=125Study 103 N=90

Tenofovir for Chronic Hepatitis B

Per

cent

age

(%)

0

10

20

30

40

50

60

70

80

90

100

Weeks on Study

0 8 16 24 32 40 48 56 64 72 80 88 96

250TDF-TDF N= 250250 245245245 243243243 248248248 247247247 242242242 243243243 234234234125ADV-TDF N= 125125 125125125 124124124 120120120 123123123 123123123 122122122 122122122

% Patients with HBV DNA <400 c/mL

89%

91%[P=0.672]

One patient was <400 copies/mL on FTC + TDF at Week 96.Long Term Evaluation ITT Analysis: Patients who discontinued for administrative reasons with HBV DNA <400 copies/mL excluded (N= 7)

Randomized Double Blind Open Label

Marcellin P, et al., AASLD 2009; Oral # 146.

HBeAg (-) Study 102

99%100%

[P=0.166]

On-Treatment Analysis

~ 89%Patient Retention

Per

cen

tage

(%)

0

10

20

30

40

50

60

70

80

90

100

Weeks on Study

0 8 16 24 32 40 48 56 64 72 80 88 96

176TDF-TDF N= 176176 174174174 170170170 172172172 171171171 168168168 164164164 16616616690ADV-TDF N= 9090 898989 888888 888888 909090 898989 878787 868686

78%78%

[P=0.801]

Five patients were <400 copies/mL at Week 96 on FTC + TDF.Long Term Evaluation: Patients who discontinued for administrative reasons with HBV DNA <400 copies/mL had their data excluded for visits after discontinuation (N = 8.)

% Patients with HBV DNA <400 c/mL

Randomized Double Blind Open Label

HBeAg (+) Study 103

Heathcote J, et al., AASLD 2009; Oral # 153.

89%85%

[P=0.374]

On-Treatment Analysis

~ 86%Patient Retention

77%

61%

P= 0.014

Per

cent

age

(%)

0

10

20

30

40

50

60

70

80

90

100

Weeks on Study

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

176TDF N= 176176 165165165 160160160 146146146 90ADV N= 90 90 85 85 85 84 84 84 82 82 82

Randomized Double Blind Open Label TDF

ALT Normalization

HBeAg Loss & Seroconversion

HBeAg Loss HBeAg Seroconversion

TDF (Wk 48); TDF-TDF (Wk 64)

ADV (Wk 48); ADV-TDF (Wk 64)

0

5

10

5

20

25

30

22%

18%

P=NS

27%

21%

P=NS

Week 48 Week 64

% P

atie

nts

0

5

10

15

20

25

30

26%

21%

P=NS

21%

18%

P=NS

Week 48 Week 64

% P

atie

nts

Cumulative Probability* of HBsAg Loss in HBeAg (+) Patients

Cum

ula

tive

Pro

babi

lity

Fun

ctio

n E

stim

ate

0.00

0.05

0.10

Weeks on Study

0 12 24 36 48 64 80 96

*Kaplan-Meier

6% TDF-TDF6% ADV-TDF

Switch to Open label TDF

Heathcote, et al., EASL 2009; Poster #909.

Resistance Surveillance

• Loss of viral response in 2 patients between Weeks 48 and 72 related to non-adherence documented in both patients

• Viremic patients received combo TDF + FTC

• Neither patient developed genotypic changes associated with AVR

• No genotypic changes associated with AVR were detected up to 72 weeks

Case 1: To Be or Not To Be

Mr. W.

• 48 year old Chinese male patient

• Known to be HBV ‘carrier’

• Otherwise healthy

• History of liver CA in older brother

• On no prescription medications or herbals

• Routine diagnosis of HBV in China

• No previous ‘Western’ medication for HBV

Labs

ALT

Total bilirubin

AST

INR

Albumin

ALPHb

WBC Platelets

Baseline Bloodwork

35

12

40

0.89

42

97148

9.7 138

HBV Testing

3 Months Later

75

11

55

1.07

35

99133

4.0 132

Assessment of Fibrosis

Liver Biopsy:

A1F4

Abdominal U/S:

Coarse liver

Spleen sl. enlarged

FibroScan:

16 kPa

Clinical Course on TDF Month ALT AST ALP Total BR Albumin INR

0 75 55 99 11 35 1.07

3 103 86 90 15 38 1.06

6 68 43 95 10 40 0.96

9 45 31 87 11 39 0.9

12 19 21 85 12 43 0.9

Clinical Course

0

1

2

3

4

5

6

7

0 3 6

HBV

DN

A l

og I

U/m

l

HBV DNA

HBsAg+ HBsAg+

HBeAg- HBeAg-

Tenofovir 300 mg po od

Months on treatment

Case 2:To Treat Now or Later?

Miss L.

• 27 year old teacher born in Canada

• Family history of HBV (mother)

• Healthy, seasonal allergies

• Meds: Claritin tabs occasionally

• Married but no children

• Contemplating pregnancy in 1-2 years

Baseline Bloodwork

25

5

20

0.91

40

68122

8.7 267

HBV TestingHBsAg +

HBeAg +

Anti-HBe -

HBV DNA 3.5 E+9 IU/ml

3,500,000,000 IU/ml

3 Months Later

20

7

18

0.89

39

68119

7.6 253

Assessment of Fibrosis

Liver Biopsy:

A1F0

Abdominal U/S:

Hemangioma segment 6

FibroTest:

0.35

6 Months Later

78

7

16

0.91

40

65126

6.5 237

Question

She is wondering about treatment prior to

starting a family. What would you suggest?

1. Standard IFN-alpha x 20 weeks

2. Long-term lamivudine monotherapy

3. Entecavir x 1 year

4. Pegylated IFN-alpha x 6-12 months

5. Adefovir 10 mg po od

Course on PEG-IFN

PEG-IFN

0

1

2

3

4

5

6

7

8

9

10

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

Time (months)

HB

VD

NA

(lo

g c

/ml)

0

10

20

30

40

50

60

70

80

90

100

AL

T (

IU/L

)

HBVDNA

ALT

HBeAg + +

Anti-HBe - -

Question

HBeAg seroconversion was not achieved.

What would you suggest now?1. Observe off therapy for the next 6 months

2. Start oral antiviral therapy before pregnancy

3. Repeat a liver biopsy to assess response

4. Retreat with a different PEG-IFN

5. Start combination oral agents

10 Months Post PEG

22

9

16

0.91

35

100120

6.5 226

Miss L is pregnant, 12 weeks GA

HBeAg + HBV DNA 8.6 E+8 IU/ml

Question

How can you manage HBV infection

during pregnancy?1. Consult high-risk obstetrician

2. Start entecavir in 1st trimester

3. Start adefovir in 2nd trimester

4. Treat if HBV DNA > 7 logs in 3rd trimester

5. Check HBV DNA only post-partum

Question

Which of the agents can be considered

for use during pregnancy?1. Entecavir

2. Tenofovir

3. Clevudine

4. Telbivudine

5. Lamivudine

Summary

• HBV DNA quantitation is the new standard of care for chronic hepatitis B• Disease progression

• Risk of cirrhosis and HCC

• Beware ‘normal’ ALT • Does not exclude progressive liver damage• Low platelet count is a clue

• Antiviral treatment reduces complications– Use potent agents with low rates of resistance

– Long term therapy is required

Questions?

Can One Pill A Day Keep Hepatitis B Away?

Scott K. Fung, MD, FRCPCToronto General Hospital

University of Toronto

November 30, 2009 TGH