Hepatitis for Life

Dr Frank WeilertClinical Director Gastroenterology

Waikato Hospital

Is HBV a problem?Is HBV a problem?

10

1. WHO Fact Sheets, available at www.who.int Accessed September 24 20042. Conjeevaram et al. J Hepatology 2003;38:S90–S1033.Lee. N Engl J Med 1997;337:1733–17454. Lok. N Engl J Med 2002;346:1682–1683

Global impact of hepatitis BGlobal impact of hepatitis B

World population6 billion

2 billion with evidence of HBV infection

350–400 million with chronic hepatitis B (CHB)

25–40% (75–160 million) die of cirrhosis or

liver cancer

annual mortality rate of 1 million

Prevalence of HBV and Incidence of Prevalence of HBV and Incidence of Hepatocellular Carcinoma (HCC)Hepatocellular Carcinoma (HCC)

World prevalence of HBV carriersWorld prevalence of HBV carriers

HBsAg carriers HBsAg carriers –– prevalenceprevalence<2%<2%22––7%7%>8%>8%Poorly documentedPoorly documented

Annual incidence of primary HCCAnnual incidence of primary HCC

Cases/100,000 populationCases/100,000 population11––3333––10101010––150150Poorly documentedPoorly documented

WHO 1999

NZ impact of HBVNZ impact of HBV

Asia-Pacific

Maori, 625000

Pacific295000

Asian, 395,000

European2.7million

1.2millio

n

1.2millio

n

Estimated >100,000 HBsAg+living in New Zealand

http://www.stats.govt.nz/products-and-services/Articles/pop-proj-Jun04.htm

National HBV Screening Programme National HBV Screening Programme

7.7%5.8% 6.2%6.5% 1%

45%

9%

59%59%54%

0%

25%

50%

75%

100%

Overall Maori Pacifican Asian European

HBV

Stat

us

HBsAg(-)/anti-HBs(-)= HBV naïve

anti-HBs(+) = immune to HBV

HBsAg+ = chronic HBV

177,292 Screened 177,292 Screened (July 1999 (July 1999 -- July 2002)July 2002) 11,300 HBsAg+ identified11,300 HBsAg+ identified

5.8%7.4%

9.1%

13.3%

0.6%

9.3% 9.4%

0%

5%

10%

15%

20%Ma

ori

Cook

Is

Niue

an

Tong

an

Indi

an

(50,

000)

SE A

sian

(2

0,00

0)

Chin

ese

(7

2,50

0)

% H

BsA

g+National HBV Screening Programme National HBV Screening Programme Prevalence Rates according to Prevalence Rates according to

EthnicityEthnicity

http://www.stats.govt.nz/products-and-services/Articles/pop-proj-Jun04.htm

(i) Maori(i) Maori (ii) Pacific(ii) Pacific

(iii) Asian(iii) Asian (iv) European(iv) European

Projected Ethnic Populations 2001-’21

They are all healthy carriers!They are all healthy carriers!

His

tolo

gy A

ctiv

ity In

dex

(HAI

)

Baseline HBV DNA Level, (log10 copies/mL)

Correlation between HAI and HBV DNACorrelation between HAI and HBV DNAin untreated patients (r=0.78; P=0.0001)in untreated patients (r=0.78; P=0.0001)

MommejaMommeja--Marin H et al. Hepatology 2003Marin H et al. Hepatology 2003

Review of 26 prospective studies (n=3428)

0

2

4

6

8

10

12

0 2 4 6 8 10 12

Viral Load determines Disease ActivityViral Load determines Disease Activity

7 Taiwanese townships Individuals aged 30–65 years eligible

(n = 89,293)

Baseline HBV DNA(n = 3851)

Baseline HBsAg+(n=9800)

1991-1992: recruitment

June 2004: 43,993 PYs follow-up

Follow-up analysisFor Cirrhosis/HCC

(n = 3774)

Chen CJ ,Chen CJ , JAMA JAMA 20062006

RRisk isk EEvaluation of valuation of VViremia iremia EElevation & levation & AAssociated ssociated LLiver iver DiseaseDisease

prospective, multicenter, observational cohort study prospective, multicenter, observational cohort study (REVEAL)(REVEAL)

Viral Load predicts Disease ProgressionViral Load predicts Disease Progression

Iloeje UH et al. Gastroenterology 2006; 130: 678–86.

Higher viral loads are associated with increased rate of cirrhosis

≥106cpm

Year of follow-up

Cum

ulat

ive

inci

denc

eof

live

r cirr

hosi

s

36.2%36.2%

4.5%4.5%

RR=9.6RR=9.6

0

.01

.02

.04

.03

0 21 3 4 5 6 7 8 9 10 11 12 13

105-106cpm

<300 cpm

104-105cpm300-104cpm

>10>1066cpmcpm

101055--101066cpm cpm

101044--101055cpm cpm 300300--101044cpm cpm < 300cpm < 300cpm

Higher viral loads are associated with Higher viral loads are associated with increased rate of increased rate of HepatomaHepatoma

15%15%

1.3%1.3%

RR=11RR=11

0

2

4

6

8

10

12

14

0 1 2 3 4 5 6 7 8 9 10 11 12 13Year of follow-up

Cum

ulat

ive

inci

denc

e of

HC

C %

Year of follow-up

Yang et al. J Hepatol 2005: 42(suppl 2); 195.

Cum

ulat

ive ra

te o

f live

r fail

ure

≥105 cpm

104-105 cpm<104 cpm

00

21 3 4 5 6 7 8 9 10 11 12

5%

10%

15%

20%

25%

30%

Higher viral loads are associated with increased rate of decompensation

1.00

0.96

0.92

0.88

0.84

0.800 1 2 3 4 5 6 7 8 9 10 11 12

Cum

ulat

iev

Surv

ival

Survival Time (Years)

HBV DNA 3-5 logsRR=1.5 (0.2–11.8)

HBV DNA (-)

HBV DNA >5 logsRR=15.2 (2.1–110)

Higher Viral Loads are associated with Higher Viral Loads are associated with increased Liverincreased Liver--related Mortalityrelated Mortality

Chen G et al., Am J Gastro, 2006

Median log10 HBV DNA Decrease

Medi

an Im

prov

emen

t in

HAI

Correlation between change in HBV DNACorrelation between change in HBV DNAand HAI with treatment (r=0.96; and HAI with treatment (r=0.96; PP<3x10<3x10--66))

Mommeja-Marin H, Hepatology 2003

Review of 26 prospective studies

–5–4-3-2-10

1 2 3 4 5

Viral Suppression reduces Disease Viral Suppression reduces Disease ActivityActivity

Alcohol31%

Other4%

HBV63%

HCV8%

LiverLiver--related Mortalityrelated Mortality19991999

Weir,2002Weir,2002

HCV26%

Alcohol8%

Biliary12%

Acute6%

HBV30%

Liver TransplantLiver Transplant19981998--20062006

(n=290)(n=290)

NZLTU,2006NZLTU,2006

Alcohol7% Other

9%

HBV75%

HCV9%

Hepatoma Clinic Hepatoma Clinic 20002000--20062006

(n=544)(n=544)

Gane,2006Gane,2006

Impact of HBV InfectionImpact of HBV Infection

9090--100 cases 100 cases per annumper annum

15 cases per 15 cases per annumannum

200+ cases 200+ cases per annumper annum

Is HBV serology confusingIs HBV serology confusing

HBV serologyHBV serology

sAgsAg determines carrier statusdetermines carrier statuseAgeAg determines replicationdetermines replication

»» (and infectivity)(and infectivity)

cAbcAb confirms natural infectionconfirms natural infection

HBV DNA measures infectivityHBV DNA measures infectivity

Case studiesCase studies

HBVHBV

34 year old Maori woman34 year old Maori woman»» HBsAgHBsAg pospos»» HBeAgHBeAg negneg»» ALT 150ALT 150»» AFP 13.8AFP 13.8

Spider Spider naevinaeviLiver span normalLiver span normal

HBVHBV

Next best investigationNext best investigation»» 1) Serum alcohol1) Serum alcohol»» 2) Liver biopsy2) Liver biopsy»» 3) HBV DNA3) HBV DNA»» 4) U/S4) U/S»» 5) Triple phase CT scan5) Triple phase CT scan

HBVHBV

Next best investigationNext best investigation»» 1) Serum alcohol1) Serum alcohol»» 2) Liver biopsy2) Liver biopsy»» 3) HBV DNA3) HBV DNA»» 4) U/S4) U/S»» 5) Triple phase CT scan5) Triple phase CT scan

CORE PROMOTERCORE PROMOTERA1762TA1762TG1764AG1764A

STOP-CODON AT CODONSTOP-CODON AT CODON28 OF PRE-CORE REGION28 OF PRE-CORE REGION

eX

S

C

pre-c

P

Selection of mutant HBV

1970–1985 1990s• HIV impact• vaccination• > hygiene

decades decades

HBeAg anti-HBe

Okamoto 1990; Raimondo 1990; Uchida 1994; Lai 1994

Increasing Prevalence of Increasing Prevalence of HBeAgHBeAg--Negative Chronic HBVNegative Chronic HBV

HBsAg-positive Chronic hepatitis in Italy: HBeAg/anti-HBe status

1975 - 1985N = 534 1

41.5%

58.5%

Rizzetto M, XI Triennial International Symposium on Viral Hepatitis and Liver Disease, 2003.1. Giusti G, et al. Ital. J. Gastroenterol., 1991; 23:111-118; 2. Gaeta GB, et al. J. Hepatol., 2003

HBeAg-positive HBeAg-negative

90.5%

9.5%

1992 - 1997N = 841 2

HBeAg+

43%

HBeAg neg

57%

National HBV Screening ProgrammeReferred for Antiviral TherapyReferred for Antiviral Therapy

HBsAg+

ALT

14%14%

Clinical and Virologic Course ofHBeAg-ve Chronic HBV

Bilirubin(mg/100mL) 1.8 1.0 8.6 1.7 45

INR 1.0 1.0 1.5 1.3 3.7

Ascites - - - - +

HBV-DNA ++ - ++ - ++

Anti-HBe + + + + +

years

ALT

Screening for HCCScreening for HCC

6 monthly AFP6 monthly AFP12 monthly U/S12 monthly U/S

Controversial on population basisControversial on population basisAccepted as targeted screeningAccepted as targeted screening

p valuep valueNonNon--ScreenedScreened(n=222)(n=222)

Screen DetectedScreen Detected(n=118)(n=118)

p<0.001p<0.00187%87%1%1%Symptomatic Symptomatic

p<0.001p<0.001675 675 ngng/ml/ml62 62 ngng/ml/mlMedian AFPMedian AFP

NSNS54 yrs54 yrs52 yrs52 yrsAge (median)Age (median)NSNS83%83%82%82%Male Male

NSNS78%78%76%76%CirrhosisCirrhosis

24%24%24%24%AFP Level AFP Level <20<20

NSNS

0102030405060708090

Chemo-emobolisation

Radiofrequencyablation

SurgicalResection

LiverTransplantation

Overall

Screened (n=118)

Non-screened (n=222)

% o

f pat

ient

s tr

eate

d

p=0.001P=0.002

P<0.001P <0.001

P <0.001

81%

10%

31%

1%

35%

6%8%1%

12%3%

Screened vs. NonScreened vs. Non--screenedscreenedTreatment of Treatment of HepatomaHepatomascreening increases

chance of receiving curative therapy

7766554433221100

YearsYears

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.0

Cum

ulat

ive

Sur

viva

lC

umul

ativ

e S

urvi

val

Screened group (n=118)Screened group (n=118)Median survival = 1974 daysMedian survival = 1974 days

(66 months)(66 months)

NonNon--screened group screened group (n=222)(n=222)Median survival = 107 Median survival = 107 days (3 months)days (3 months)

P<0.0001

88

Screened Screened vsvs NonNon--screened screened Survival in Hepatocellular CarcinomaSurvival in Hepatocellular Carcinoma

2%

52%

screening increases survival in HBV-Hepatoma

Treatment options for CHBTreatment options for CHB

eAg(+) CHB

eAg(-) CHB

HBV Cirrhosis

Decompensation

Death

Hepatocellular carcinoma

Treatment options for CHBTreatment options for CHB

eAg(+) CHB

eAg(-) CHB

HBV Cirrhosis

Decompensation

Death

Hepatocellular carcinoma

Treatment options for CHBTreatment options for CHB

IFN/LAM

IFN/LAM IFN/LAM/ADV LAM/ADV

InterferonsInterferons

Nucleoside/Nucleotide AnaloguesNucleoside/Nucleotide Analogues

IFNIFN--2a2a

Time (hours)

IFN- 2a05

1015202530

0 24 48 72 96 120 144 168 192

[IFN

] pla

sma.

(ng/

mL)

Tue Wed Thu Fri Sat SunMon

Pegylated IFN-2a

Pegylated IFN- 2a

N

N

NH2

N

OSHO

Lamivudine

(a) Purine Analogues

(b) Pyrimidine Analogues

Telbivudine

Nucleoside/Nucleotide AnaloguesNucleoside/Nucleotide Analogues

HN

NO

OH

OHO

OCH3 Emtricitabine

N

NO

S

OH

NH2F

O

N

NO OH

NH2CH3

O

OR

Valtorcitabine

Entecavir

N

NO P

OOH

OH

NH2

O

OH

TenofovirN

HO

N

N

N

NH2

HN N

N N

N

O PO

OHOH

NH2

Adefovir

Identified mutations associated with Identified mutations associated with drug resistancedrug resistance

1. Allen et al. Hepatology 1998;27:1670–7; 2. Gish et al. J Hepatol 2005;43:60–6;3. Qi et al. J Hepatol 2004;40(Suppl 1):20–1; 4. Tenney et al. AAC 2004;48:3498–507;

5. Lai et al. Gastroenterology 2005;129:528–36; 6. Sheldon et al. Antivir Ther 2005;10:727–34

RNaseH

845 a.a.

Terminal protein Spacer Pol/RT

A B C ED

1 183 349 692

YMDD

V173LL180M M204I/V

GVGLSPFLLA

I(G) II(F)

(rt1) (rt 344)

LAM1 / FTC2

ETV *4 I169T T184G S202G/I M250VADV 3 A181V N236T

LdT 5 M204I

* All ETV resistance requires background YMDD mutations

TDF6 A194T ?

Incidence of Resistance in Incidence of Resistance in TreatmentTreatment--naïve Patients Over Timenaïve Patients Over Time

0%3%

11%

18%

29%

0% 0%

13%18%

23%

46%

55%

71%65%

4.5%

14%

0%

20%

40%

60%

80%

Year 1 Year 2 Year 3 Year 4 Year 5

% o

f pat

ient

s

Lai et al. Clin Infect Dis. 2003;36:687-96; Lok et al Gastroenterology 2003; 125 : 1714-1722; Zoulim et al J Viral Hepatitis 2006;13:278-288; Hadzyiannis et al NEJM 2005; 352 : 2673-2681; Chang et al. NEJM 2006; 351: 1001-1010; Lai et al NEJM 2006; 354: 1011-1020; Lai et al Abstract # 91, AASLD 2006. Colonno R et al. Abstract #110, AASLD 2006.

ADV ETV FTC LAM TEL

???

2

3

4

5

6

7

8

M0 M3 M6 M9 M12 M15 M18 M21 M24

HBV DNADrug ADrug A

Drug ADrug A++

Drug BDrug B

Seru

m H

BV

DN

A

(Log

10 c

opie

s/m

L)

Month of therapy

VeryVery EarlyEarly AddAdd--on on TherapyTherapy to to KeepKeep Viral Viral LoadLoad as as LowLow as Possibleas Possible

From Zoulim, F. 2006

Drug A: high genetic barrier

Drug B: different cross-resistance profile

Di Bisceglie et al., AASLD 2006

Degree of Early Viral Suppression Predicts HBeAg seroconversion with Telbivudine

46%36%

19%

6%

0%

25%

50%

75%

100%

< QL (N=150)

QL-3 log (N=17)

3 - 4 log (N=15)

> 4 log (N=10)

HBV DNA at Week 24

% S

eroc

onve

rt a

t 2 y

ears

Wk 24 viral load predicts HBeAg conversion at Wk 24 viral load predicts HBeAg conversion at 104 wks104 wks

0%2%

8%

13%

0%

10%

20%

30%

40%

< QL (N=150)

QL-3 log (N=17)

3 - 4 log (N=15)

> 4 log (N=10)

HBV DNA at Week 24

% R

esis

tanc

e

Telbivudine

Degree of Early VDegree of Early Viral Suppression iral Suppression Predicts Predicts VirologicVirologic BreakthroughBreakthrough with with TelbivudineTelbivudine Wk 24 viral load predicts resistance at 52wksWk 24 viral load predicts resistance at 52wks

Wk Wk 4848 viral load predicts resistance at 144 wksviral load predicts resistance at 144 wks

Locarnini J. Hepatology 2005

4%

67%

26%

0

20

40

60

80

100

< 3 log 3 - 6 log > 6 logSerum HBV DNA at Week 48Serum HBV DNA at Week 48

n = 114

% R

esis

tanc

e

Degree of Early VDegree of Early Viral Suppression iral Suppression Predicts Predicts VirologicVirologic BreakthroughBreakthrough with Adefovirwith Adefovir

ConclusionConclusion

HBV is a New Zealand ProblemHBV is a New Zealand Problem»» Identifying all carriersIdentifying all carriers

Refer patients with known HBVRefer patients with known HBV»» Surveillance is necessarySurveillance is necessary

Treatment is availableTreatment is available»» Prevents disease progressionPrevents disease progression