Clinical Case ScenarioClinical Case Scenario:Chronic Hepatitis B

HBeAg Negative

Dr Yeong Yeh LeeMD, MRCP (UK), MMed

May 2007May 2007

Case StudyCase Study• 45 years old gentleman; married; army officer • HBsAg positive > 6/12 in Jan 2003• Promiscuity, father died of jaundice ?cause• HBeAg negative; Anti-HBe positive• ALT 65 mmol/l; repeat 3/12 ALT 70 mmol/l• Ultrasound normal liver echotexture• Alpha-fetoprotein (AFP) normal• Anti-HCV –ve; EIA HIV –ve;

Q : What is the significance of HBeAg -ve Q : What is the significance of HBeAg -ve CHB?CHB?

• clinically silent for years

• Severe necroinflammation in >50%, cirrhosis in 25-40%

• Rare spontaneous sustained remission

• Fluctuations in viraemia and ALT

• HBV DNA may be persistently <105 copies/mL but yet has significant liver disease

• Q1 : Would you order a viral load test?Q1 : Would you order a viral load test?

• Q2 : What level of HBV DNA would you Q2 : What level of HBV DNA would you start treatment?start treatment?

a. HBV DNA a. HBV DNA ≥ log 10≥ log 1044

b. HBV DNA ≥ log 10b. HBV DNA ≥ log 1055

c. Any level of HBV DNA c. Any level of HBV DNA

Chen CJ, et al. JAMA 2006; 295:65–73

HBeAg negative, normal ALT, no liver cirrhosis at entry (n=2,925)

.14

.12

.1

.08

.06

.04

.02

0

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

Cu

mu

lati

ve i

nci

den

ce o

f H

CC

Year of follow-up

Baseline HBV DNA Level

REVEAL: High HBV Viral Load isassociated with increased incidence of HCC

≥106

105–<106

104–<105

300–104

<300

Haimen City Cohort: HBV Viral Load at Baseline is Associated with HCC Mortality

1.00

0.96

0.92

0.88

0.84

0.80

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

Su

rviv

al d

istr

ibu

tio

n f

un

ctio

n

Survival time (Years)

HBV DNA >105

RR=9.9 (3.2–31.0)

HBV DNA >103 – <105

RR=1.8 (0.5–5.8)

HBV DNA <103

Chen et al. Am J Gastroenterol 2006; 101:1797-1803Chen et al. Am J Gastroenterol 2006; 101:1797-1803

• HBV Quantitative 55,000 copies/ml

(or 11,000 iu/ml @ 1 iu/ml=5.6 copies/ml)

• Q3 : Would you suggest for liver biopsy?Q3 : Would you suggest for liver biopsy?

• No treatment• Monitor every 6–12

months

• Monitor ALT, or• Consider biopsy,

since ALT often fluctuates, and treat if significant disease

• Long-term treatment required

• Treat• Long-term

treatment required (oral agents)

HBeAg Negative

ALT Elevated

ALT Normal

HBV DNA≥104 c/mL

HBV DNA<104 c/mL

Updated US Treatment AlgorithmPatients with Compensated Disease

Keeffe EB, et al. Clin Gastroenterol Hepatol 2006; 4:936-962

Liver biopsy : bridging necrosis and fibrosis

Ishak Staging for fibrosis Score 3

Case StudyCase Study

• He was started on lamivudine 100mg OD

• After 1 year of treatment, HBV DNA 500 copies/ml

• ALT 25 mmol/l

• Q4 : Should we continue or stop the Q4 : Should we continue or stop the lamivudine? If continue for how long?lamivudine? If continue for how long?

• Q5 : Besides lamivudine, are there any Q5 : Besides lamivudine, are there any other options?other options?

Lai CL, et al. Hepatology 2005; 42(Suppl 1):748A (abstract LB01); Lau G, et al. NEJM 2005; 352:2882–2695; Chang T-T, et al. NEJM 2006; 354:1000–1010; Lai CL, et al. NEJM 2006; 354:1011–1020; Marcellin P, et al. NEJM 2003;348:808–816; Marcellin P, et al. NEJM 2004;348:1206–1217; Hadziyannis SJ, et al. NEJM 2003;348:800–807

HBV DNA suppression: Comparison of HBV DNA suppression: Comparison of treatments at 1 year in naïve patients*treatments at 1 year in naïve patients*

*Collation of currently available data – not from head-to-head studies

Peg IFN#

Lamivudine*

Adefovir#

Telbivudine*

HB

V D

NA

un

det

ecta

ble

(%

pat

ien

ts)

21

36

25

6760

0

20

40

60

80HBeAg(+) HBeAg(-)

0

20

40

60

80

100

6372

51

90 88

*Undetectable <300 copies/mL#Undetectable <400 copies/mL

Entecavir*

Case StudyCase Study

• He was continued on lamivudine. After 24 months HBV DNA below detectable levels. ALT 20 mmol/l

• Lamivudine was then stopped • Well until 6/12 later (Jun 2005) his ALT

90mmol/l• Repeat HBV DNA 6,000 copies/ml• HBeAg -ve

• Q6 : What is the cause for his virologic Q6 : What is the cause for his virologic and biochemical breakthrough?and biochemical breakthrough?

Case StudyCase Study

• He was restarted with lamivudine 100mg OD

• 6/12 later HBV DNA 18,000 copies/ml

• YMDD mutation found

• Lamivudine was stopped

• Q7 : What treatment options for Q7 : What treatment options for lamivudine resistant YMDD mutation?lamivudine resistant YMDD mutation?

a. switch to adefovira. switch to adefovir

b. lamivudine combines with adefovirb. lamivudine combines with adefovir

c. switch to entecavirc. switch to entecavir

d. switch to interferond. switch to interferon

Lamivudine-resistant mutations result in reduced Lamivudine-resistant mutations result in reduced treatment efficacy and poorer patient outcomestreatment efficacy and poorer patient outcomes

Adapted from Liaw. Semin Liver Dis 2005; 25:40–47; Liaw et al. N Eng J Med 2004; 351:1521–1531

Wild-type (n = 221)

Time after randomisation (months)

0

5

10

15

20

25

0 6 12 18 24 30 36

Per

cen

tag

e o

f p

atie

nts

wit

h

dis

ease

pro

gre

ssio

n

Placebo (n = 215)

5%

21%M204I/V mutations (n = 209, 49%)

13%

12

Cumulative incidence of resistance with LAM or Cumulative incidence of resistance with LAM or ADV ADV monotherapymonotherapy

ADV (N236T/A181V) in study 438a LAM (M204V/I)b

0%

10%

20%

30%

40%

50%

60%

70%

80%

year 1 year 2 year 3 year 4

0%

24%

3%

42%

11%

53%

70%

Incidence of Resistance

18%

aHadzyannis SJ et al J Hepatol (abst) 2005bLai CL et al Clin Infect Dis 2003

13

Entecavir (genotypic resistance in HBeAg[+]/[-] nucleos(t)ide-naive patients)Entecavir (genotypic resistance in LAM-R patients)Entecavir (genotypic resistance plus viral rebound in LAM-R patients)

)

Cu

mu

lati

ve I

nc

ide

nc

e o

f O

utc

om

e (

%)

Colonno R, et al. AASLD 2006. Abstract 110.

Incidence of HBV Resistance Incidence of HBV Resistance

0.1 0.4 1.16

14

32

110

25

0

80

40

60

20

100

Year

1 2 3 4 5

31

Preventing Lamivudine ResistancePreventing Lamivudine ResistanceWith de Novo Combination TherapyWith de Novo Combination Therapy

1. Sung J, et al. J Hepatol. 2003;38(suppl 2):25-26. 2. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217. 3. Lau GK, et al. N Engl J Med. 2005;352:2682-2695.

20% 18%27%

2% 1%9%

0

20

40

60

80

100

Sung[1] Marcellin[2] Lau[3]

LAM LAM LAMLAM +ADV

LAM + PegIFN

LAM + PegIFN

Inc

iden

ce

of

Re

sis

tan

ce*

(%) Incidence of Resistance After 1 Year

P < .003 P < .001

P < .001