4 th annual clinical care options for hepatitis symposium: hbv highlights

4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights

clinicaloptions.com/hep


Anna S.F. Lok, MDProfessor of Internal Medicine and Director of Clinical HepatologyUniversity of Michigan, Ann ArborAnn Arbor, Michigan

Hepatitis B Virus Resistance:

An Overview by a Clinician for a Clinical Audience



Why Do Antiviral-Resistant HBV Mutants Arise? High rate of virion production: 1012-13 virions per day

High rate of spontaneous mutations—lack of proofreading capacity of HBV reverse transcriptase: 10-5 substitution/base/cycle

All possible single base changes can be produced each day

Antiviral resistant mutations may be present prior to therapy



What Causes Antiviral-Resistant HBV Mutants to Become Dominant?

Antiviral Therapy

SS

S

SS

S SS

SR

R

R RR R R

Survival of the fittest: selection of virus with survival advantage in the presence of antiviral therapy



Factors Associated With Antiviral Resistance

VIRUSDRUG

HOST

Daily production Replication fidelity Preexistent mutations

Potency Structure Genetic barrier to resistance

Prior therapy Compliance Immune status Pharmacogenetics Body size



Better Viral Suppression Reduces the Risk of Genotypic Resistance

Yuen MF, et al. Hepatology. 2001;34:785-791 Locarnini S, et al. J Hepatol. 2005;42(suppl.2):17.

LAMResistance (median 29 mos)

vs Week 24 HBV DNA

ADVResistance at Week 144

vs Week 48 HBV DNA

% R

esis

tan

ce

8%13%

32%

64%

4%

26%

67%

Week 24 HBV DNA (log10 c/mL)N = 159 HBeAg-positive patients

< ND 3-6 >6< ND > 4< 4< 3

Week 48 HBV DNA (log10 c/mL) N = 114, primarily HBeAg-negative

patients



Genetic Barriers to Antiviral Resistance No. of amino acid changes required to confer resistance

Decrease in susceptibility (increase in IC50) caused by the mutations

Nucleos(t)ide Analogue Mutation Fold Decrease in Susceptibility

LAM M204V/I > 1000

ADV A181V or N236T 3-15

Entecavir 169 or 202 184 or 250

M204V/I + 1 ETV-RM204V/I + 2 ETV-R

~ 1 2-10

10-250 > 500

ETV-R, entecavir resistance mutation.



Nomenclature for Antiviral Resistance

Virological breakthrough—consistent increase in serum HBV DNA by > 1 log above nadir while on treatment, after achieving initial response

Biochemical breakthrough—consistent increase in serum ALT while on treatment, after achieving initial response

Genotypic resistance—detection of HBV polymerase mutation(s) that has been shown to decrease susceptibility to treatment

Phenotypic resistance—in vitro confirmation that the mutation decreases susceptibility to treatment



Manifestations of Antiviral Resistance

HB

V D

NA

(lo

g1

0 IU

/mL

)

AL

T (

U/L

)

BiochemicalbreakthroughULN

Viralbreakthrough

0 1 2 3

Years

Antiviral Treatment

0

2

4

6

8

Hepatitis flare

Viral rebound

Genotypicresistance

-1



Indicators of Antiviral-Resistant HBV

Detection of antiviral resistant mutations

Viral breakthrough—> 1 log increase in serum HBV DNA

Viral rebound—serum HBV DNA exceeds pretreatment value or defined cutoff (eg, > 5 log)

Biochemical breakthrough—abnormal ALT

Hepatitis flares, hepatic decompensation



Consequences of Antiviral-Resistant HBV Loss of initial virologic, biochemical, and histologic

response

Virologic and biochemical breakthrough

Hepatitis flares, hepatic decompensation, and death

Increased risk of HBV recurrence postliver transplant

Limit future treatment options

Transmission to treatment-naive persons → public health problem



Selection of LAM-Resistant Mutations Limits Future Treatment Options

L18

0M

A18

1V/T

T18

4G/S

/A/C

S20

2G

M20

4V/1

N23

6T

M25

0V

LAM

FTC

LdT

ADV

ETV



Multirug-Resistant HBV Responds Poorly to Combination Therapy

Brunelle MN, et al. Hepatology. 2005;41:1391-1398.

HBV LAMFold Δ

ADVFold Δ

LAM + ADVFold Δ

WT 1.0 1.0 1.0

N236T 1.1 3.2 1.6

L180M + M204V > 40.0 1.0 11.0

L180M + M204V + N236T > 40.0 6.3 58.8



5 samples with single drug resistant mutations

11 samples with MDR mutations

Multidrug-Resistant HBV Mutants

15 samples from 6 patients

Direct sequencing

Clonal analysis215 clones

Mutations to > 1 drug on the same

genome in 183 clones

Mutations to only 1 drug in 31 clones

Wild-type HBV DNA in

1 clone

Mutations to > 1 drug on the same

genome in 5 clones

Mutations to only 1 drug in 89 clones

94 clones

Yim HJ, et al. Hepatology. 2006. In press.



Multidrug-Resistant HBV Mutants (cont’d) Mutations to both therapies locate in same HBV genome

in 85% clones analyzed

Progressive evolution from

– All clones with LAM-R mutations →

– Mixtures of clones with multidrug R mutations and clones with LAM-R mutations →

– All clones with multidrug-resistant mutations

Combination therapy directed against mutants to each treatment may not be adequate in suppressing multidrug-resistant HBV



Prevention of Antiviral-Resistant HBV

Judicious use of antiviral treatment—avoid futile/unnecessary treatment

Initiate treatment with combination therapy—what agents to combine?

Use potent agent that has high genetic barrier to resistance

Monitor viral response—switch therapy if response suboptimal

Avoid sequential monotherapy

Avoid cross-resistant drugs



Management of Patients With Antiviral-Resistant HBV Close monitoring for viral rebound, hepatitis flare, and

decompensation

Strategies

– Stop treatment and observe if patient did not warrant treatment initially (immune tolerant patient, inactive carriers)

– Continue current treatment temporarily and observe if HBV DNA level is low, ALT is normal, and no cirrhosis or immune suppression

– Implement rescue therapy immediately if viral rebound or hepatitis flare and in all patients with cirrhosis or immune suppression



Rescue Therapy for Antiviral-Resistant HBV Lamivudine-R

– Add adefovir/tenofovir

– Switch to emtricitabine + tenofovir or switch to entecavir (risk of subsequent entecavir-R)

Adefovir-R*

– Add lamivudine or switch to emtricitabine + tenofovir

– Switch to entecavir (if no prior LAM-R)

Entecavir-R*

– Add or switch to adefovir or tenofovir

Multidrug R → ???*Limited in vivo data



The Changing Face of Antiviral Therapy

Robert P. Perrillo, MDDirector, Academic AffairsSection of Gastroenterology and HepatologyOchsner Clinic FoundationNew Orleans, Louisiana



HBeAg Seroconversion vs Level of HBV DNA Suppression

Lau GK, et al. N Engl J Med. 2005;352:2682-2695.

On treatment Follow-up

Mea

n H

BV

DN

A (

log

10 c

op

ies/

mL

)

2

4

6

8

10

12

0 6 12 18 24 30 36 42 48 54 60 66 72

-4.48

-5.81

-7.18*

PEG-2a + placebo

HBeAg seroconversionEOF = 32%*

HBeAg seroconversionEOF = 27%*

PEG-2a + LAM

LAM

HBeAg seroconversionEOF = 19%

Weeks



On-Treatment ALT Maximums and HBeAg Seroconversion at Week 72

Piratvisuth T, et al. EASL 2005.

Patients With

HBeAg Seroconversion Rates in

PEG/PLC PEG/LAM LAM

ALT > 5 x bALT 6/14 (43%) 6/16/ (38%) 3/12 (25%)

> 10 x ULN 20/48 (42%) 12/35 (34%) 3/31 (10%)

> 5 - < 10 x ULN 28/74 (38%) 27/86 (31%) 16/64 (25%)

≤ 5 x ULN 39/149 (26%) 35/150 (23%) 33/177 (19%)



On-Treatment Flares (3 x BSL) With PEG-IFN α-2b According to Genotype

Flink HJ, et al. Gut. 2005;54:1604-1609.

015304560

75

An = 19

Per

cen

t

33%

74%

43%

Bn = 7

Cn = 11

Dn = 26

P = .046

On-treatment flares

010203040

50

An = 19

18%

47%

28%19%

Bn = 7

C n = 11

D n = 26

P =.05

Treatment response after flare

27%

NB: Only host-induced flare and height of ALT during flare predicted

response

All HBsAg seroconverters had

host-induced flare

Per

cen

t



HBsAg Seroconversion: PEG-IFN in HBeAg(+) Patients According to Genotype

1. Flink HJ, et al. Am J Gastro. 2006;101:297-303. 2. Hadziyannis S, et al. EASL 2005.

PEG-IFN α-2b[1]

0

3

6

9

12

15

A n = 90

3%

9%

2%

Bn = 23

C n = 39

D n = 103

1814%

Pat

ien

ts (

%)

21

24

PEG-IFN α-2a[2]

0

3

6

9

12

15

A n = 23

2%0% 0%

Bn = 76

C n = 162

D n = 9

18

22%

Pat

ien

ts (

%)

21

24



6-Month and 2-Year Posttreatment Responses in HBeAg-Negative CHB

1. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217. 2. Marcellin P, et al. EASL 2006.

6 Months Posttreatment, %

(n = 177)

2 Years Posttreatment, %

(n = 116)

ALT normal 59[1] 66[2]

HBV DNA < 20,000 copies/mL 43[1] 48[2]

HBV DNA < 400 copies 19[1] 23[2]

HBsAg loss 4[1] 9[2]



Tenofovir vs Adefovir in LAM-Resistant CHB

van Bömmel F, et al. Hepatology. 2004;40:1421-1425.

*P < .001 vs ADV

Week 24 Week 36 Week 480

-7Mean change in log10 HBV DNA (PCR)

Tenofovir 300 mg/day for 72-130 weeks (n = 35)

Adefovir 10 mg/day for 60-80 weeks (n = 18)

% HBV DNA < 400 copies/mL at Week 48

100% of tenofovir patients

44% of adefovir group-5.2*

-2.6

-5.4*

-3.0

-5.5*

-2.8



Virologic Response to Entecavir vs LAM: Week 48 vs 96Parameter Entecavir, %

(n = 354) LAM, % (n = 355)

HBV DNA(-) At Week 48* 67 36*

At Week 96 80 39

HBeAg seroconversion At Week 48 21 18

At Week 96 31 25

Chang TT, et al. N Engl J Med. 2006;354:1001-1010.



Entecavir vs Lamivudine in LAM-Refractory, HBeAg+ CHB

Sherman M, et al. Hepatology. 2004;40:1465-1473.

Pat

ien

ts (

%)

HistologicImprovement

100

0Composite Endpoint†

*55

*55

28

4

0

-0.48

-5.14*-6

HBV DNA Mean Change From Baseline

(log10 copies/mL)

Entecavir 1.0 mg QD (n = 141)

LAM 100 mg QD (n = 145)

†ALT < 1.25 x ULN, ALT < 1.25 x ULN, HBV DNA < 0.7 MEq/mLHBV DNA < 0.7 MEq/mL



Combination LAM + ADV: Efficacy Outcomes at Week 104

*Defined as 1 log increase over lowest prior value on 2 or more successive visits (at least one value > 104) and same criteria at last visit †Roche, Cobas, LLOD 200 copies

LAM + PLAC, % (n = 57)

LAM + ADV, %(n = 54)

HBeAg seroconversion 20 13

HBeAg loss 24 19

Sustained virologic breakthrough* 40 17

HBV DNA negative by PCR† 14 26

ALT normalization 41 47



Virologic Response at Week 52 to LdT, LAM, or Combination Therapy

Lai, et al. Gastroenterology. 2005

LdT + LAM LdTLAM

% with HBeAg loss * 28 % 33% 17%

% HBeAg sero 22% 31% 15%

% Patients HBV DNA negative 32% 61%* 49% by PCR

N 18 42 41

*P < .05 compared to LAM



Hepatitis B: Histology and Normal ALTin 452 Chinese Patients

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

Pa

tie

nts

(%

)

100

0

40 42

7580

34

4652

73

Grade 2 or More Stage 2 or More

Normal ALT,HBeAg positive

Normal ALT,HBeAg negative

Normal ALT,HBeAg negative

Normal ALT,HBeAg positive



Risk of Cirrhosis or HCC According to Baseline HBV DNA

1. Evans AA. AASLD 2004. Abstract 1013. 2.Chen G. AASLD 2004. Abstract 996. 3. Chen G. EASL 2005. Abstract 476. 4.Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

Population Outcome Variable HBV DNA Relative Risk

3754 AsianAmericans[1]

HCC < 105

> 105

4.18.5

1520 Chinese[2] Mild/mod CHBCirrhosis/HCC

< 105 vs > 105 1.4, 1.01.9, 2.5

3851 Taiwanese[3] Cirrhosis ≤103 vs 104 vs ≥ 105

E (-) 1.0, 1.9, 4.9E (+) 2.6, 6.2, 8.6

3582 Taiwanese[4] Cirrhosis ≥ 104 to < 105

≥ 105 to < 106

≥ 106

2.55.66.5



New Drugs for the Treatment of Chronic Hepatitis B

Patrick Marcellin, MD, PhDProfessor of MedicineService d’HepatologieINSERM CRB3Hôpital BeaujonUniversity of ParisClichy, France



Emtricitabine Monotherapy in Chronic Hepatitis B Emtricitabine is approved for treatment of HIV

FTCB 301: double-blind, placebo-controlled, phase III trial 248 patients randomized to receive:

– Emtricitabine (200 mg/day) or placebo for 48 wks

Shiffman M, et al. AASLD 2004. Abstract 22.

48-Week Results Emtricitabine, % (n = 167) Placebo, % (n = 81) P Value

Histologic response 62.0 25.0 < .001

Improvement in fibrosis 21.0 7.0 < .009

Normal ALT 65.0 25.0 < .001

Undetectable HBV DNA 56.0 7.0 < .001

HBeAg seroconversion 12.1 12.0 NS

YMDD resistance 12.6 -- --



Emtricitabine Plus Adefovir

Emtricitabine resistance limits its use as monotherapy

– Combination therapy may resolve this issue

FTC-201: double-blind, placebo-controlled, phase II study

– 30 HBeAg-positive nucleoside-naive patients

– Randomized to adefovir + emtricitabine or adefovir alone

Lau G, et al. AASLD 2004. Abstract 245.

Median Change in HBV DNA

Adefovir, log10 copies/mL

(n = 14)

Adefovir + Emtricitabine, log10 copies/mL

(n = 24)P Value

Week 24 -3.19 -5.08 --

Week 48 -3.40 -5.44 .03



GLOBE: Year 1 Results of Telbivudine for Chronic Hepatitis B

Lai C, et al. AASLD 2005. Abstract LB01.

Summary of Year 1 Results With Telbivudine

Outcome HBeAg-Positive Patients, % HBeAg-Negative Patients, %

LdT(n = 458)

LAM(n = 463)

LdT(n = 222)

LAM(n = 224)

Undetectable HBV DNA Week 52 Week 76

75*75* (n = 163)

6758 (n = 165)

88*84* (n = 68)

7167 (n = 67)

Virologic breakthrough by Week 48 3* 10 2* 9

Normalized ALT Week 52 Week 76

7778* (n = 163)

7568 (n = 165)

7476 (n = 68)

7964 (n = 67)

Fibrosis decline by Week 52 68 61 59 46

HBeAg seroconversion by Week 76 41* (n = 100) 26 (n = 93) N/A N/A

*P < .05 vs LAM

GLOBE trial: phase III international study (N = 1367)



GLOBE: Early HBV DNA Levels and Year 1 Outcomes With Telbivudine

Lai C, et al. AASLD 2005. Abstract 92.

Week 24 HBV DNA Levels, copies/mL

Week 52 Outcome Undetectable 300 to < 3 log10 3-4 log10 > 4 log10

HBV DNA negative HBeAg positive HBeAg negative

9194

6967

3040

510

Normal ALT levels HBeAg positive HBeAg negative

8881

8968

7960

5341

Virologic breakthrough HBeAg positive HBeAg negative

10

47

917

1444

HBeAg seroconversion 41 26 13 4

Year 1 outcomes linked to viral load at Weeks 12 and 24– 93% of individuals with HBV DNA > 3 log10 copies/mL at

Week 24 failed to seroconvert by Year 1



HBV DNA Undetectability at 1 Year by Genotype

Thongsawat S, et al. EASL 2006. Abstract 110.

HBeAg Positive

5765

47

9080

94

40 4335

8074

63

0102030405060708090

100

B C Other B C Other

LdTLAM

HB

V D

NA

Un

det

ecta

ble

(%

)

HBeAg Negative



018 Trial: LdT vs ADV in HBeAg+ CHB Patients Results at 24 Weeks

Chan HL, et al. EASL 2006. Abstract 52.

Ser

um

HB

V D

NA

Mea

n L

og

¹º C

han

ge

Fro

m

Bas

elin

e ±

SE

0

-1

-2

-3

-4

-5

-6

-7

Weeks

Adefovir (n = 89)

Telbivudine (n = 44)

PCR Negative at 6 MonthsTelbivudine: 38.6%Adefovir: 12.4%

P < .01

-6.3

-4.97

HBeAg Loss at 6 MonthsTelbivudine: 16%Adefovir: 10%

0 4 8 12 16 20 24



Tenofovir vs Adefovir in LAM-Refractory Patients Retrospective analysis: LAM-refractory patients switched to tenofovir 300 mg/day (n = 38) or adefovir 10 mg/day (n = 68) More tenofovir patients with undetectable HBV DNA at M6

More patients receiving tenofovir exhibited HBeAg and HBsAg loss vs adefovir after up to 2 years

van Bömmel F, et al. AASLD 2005. Abstract 184.

Undetectable HBV DNA Tenofovir 300 mg/day, %(n = 38)

Adefovir 10 mg/day, %(n = 68)

Month 12 94 32

Month 18 100 35

Month 24 100 49

Outcome Tenofovir 300 mg/day, %(n = 38)

Adefovir 10 mg/day, %(n = 68)

HBeAg loss 49 13

HBsAg loss 19 6



Tenofovir Use in Patients With Incomplete Response to Adefovir Retrospective analysis (N = 20) of tenofovir in patients with

chronic hepatitis B who had suboptimal response to adefovir– Lamivudine experienced prior to adefovir treatment– Mean change from baseline in HBV DNA -0.4 log10 copies/mL (range: -4.2

to +3.4) during the adefovir treatment phase

At tenofovir initiation, the mean HBV DNA was 6.6 log10 copies/mL– Mean changes from baseline in HBV DNA

– -3.2 log10 copies/mL (range: -1.4 to -5.7) at 3 months – -3.8 log10 copies/mL (range: -1.4 to -6.7) at 6 months

– 18 of 20 (90%) patients achieved HBV DNA < 400 copies/mL after a mean of 4 months (range: 1-9)

– 3 patients lost HBeAg after 3-5 months

van Bömmel F, et al. AASLD 2005. Abstract 1000.



12-Week Treatment With Clevudine

Marcellin P, et al. AASLD 2004.

-4.5

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Weeks

Ch

ang

e F

rom

Bas

elin

e in

L

og

10 S

eru

m H

BV

DN

A

Treatmentperiod

10 mg

30 mg

50 mg



Clevudine in HBeAg-Positive Patients

Multicenter, randomized, phase III trial– Patients received 24 weeks of clevudine 30 mg/day (n = 243) or placebo

(n = 61)– Follow-up: 24 weeks

Yoo BC, et al. AASLD 2005. Abstract 186.

OutcomeClevudine 30 mg/day

(n = 182)Placebo (n = 61)

Change in HBV DNA, log10 copies/mL End of treatment End of follow-up

-5.10*-2.02*

-0.27-0.68

HBV DNA undetectable at treatment end, % 59 0

Normalized ALT, % End of treatment End of follow-up

68*61*

1828

HBeAg seroconversion at end of follow-up, % 10 12*P < .0001 vs placebo



Clevudine in HBeAg-Negative Patients

Multicenter, randomized, phase III trial– Patients received 24 weeks of clevudine 30 mg/day (n = 63) or placebo

(n = 23)– Follow-up: 24 weeks

Yoo BC, et al. AASLD 2005. Abstract 183.

OutcomeClevudine 30 mg/day

(n = 63)Placebo (n = 23)

P Value

Change in HBV DNA, log10 copies/mL End of treatment End of follow-up

-4.25-3.11

-0.48-0.66

< .0001< .0001

Undetectable HBV DNA, % End of treatment End of follow-up

9216

00 < .0001

Normal ALT, % End of treatment End of follow-up

7571

3329

.006

.007



Pradefovir for Chronic Hepatitis B: Week 48 Analysis Phase II randomized, open-label, multicenter trial of ADV-naive

patients (N = 244)

– Patients received adefovir 10 mg/day or pradefovir 5, 10, 20, or 30 mg/day for 48 weeks

– Genotype C: 67% – Asian: 100% – HBeAg positive: 70%

Lee KS, et al. EASL 2006. Abstract 741.

Week 48 Outcome

Pradefovir

Adefovir (n = 50)

5 mg/day(n = 47)

10 mg/day(n = 49)

20 mg/day(n = 48)

30 mg/day(n = 48)

HBV DNA < 400 copies/mL, % 45 63 56 71 36

ALT normalized HBeAg-positive patients, n HBeAg-negative patients, n

6457

6481

6565

6967

6479

HBeAg seroconversion, % 18 12 10 19 17



Pradefovir for Chronic Hepatitis B: Week 48 Analysis (cont’d)

Lee KS, et al. EASL 2006. Abstract 741

Week

-4.09

-5.54

Pradefovir 5 mg (n = 47)

0 4 12 18 24 36 48

-4.19

-4.89

-4.84

0

-1

-2

-3

-4

-5

-6Mea

n (

SE

) C

han

ge

in H

BV

DN

A

Fro

m B

asel

ine

(lo

g10

co

pie

s/m

L)

Adefovir 10 mg (n = 50)

Pradefovir 10 mg (n = 49)Pradefovir 20 mg (n = 48)

Pradefovir 30 mg (n = 48)



Effect of Valtorcitabine on Serum HBV DNA

Lim SG, et al. EASL 2005.

-4

-3

-2

-1

0

1

0 1 2 3 4 5

Study Week

Placebo600 mg/day900 mg/day1200 mg/day

Ser

um

HB

V D

NA

Mea

nL

og

10 R

edu

ctio

n F

rom

Bas

elin

e



ANA380 (LB80380) in HBeAg-Positive Patients With LAM Resistance Phase II, multicenter, dose-

escalating study (N = 65)

HBeAg-positive Asian patients

5 dose escalation groups

– ANA380 (30, 60, 90, 150, or 240 mg/day) + LAM for 4 weeks followed by 8 weeks ANA380 monotherapy

Lai CL, et al. EASL 2006.

-5

-2.8-3.2

-3.9 -3.9 -4.1-4

-3

-2

-1

0

30(n = 13)

60(n = 14)

90(n = 14)

150(n = 12)

240(n = 12)

Red

uct

ion

in H

BV

DN

A b

y W

eek

12

(lo

g10

co

pie

s/m

L)

ANA380 Dose



Update on the Management of HBV

Marc Ghany, MDInvestigator, Liver Diseases BranchNIDDK, National Institutes of HealthBethesda, Maryland



Goals of the 2006 NIH Workshop on the Management of CHB Update definitions of response and endpoints of therapy

using more sensitive PCR-based assays

Standardize the format in which clinical trials should be presented

Identify areas for future research



Should HBV Genotyping Be Included in Initial Assessment?Yes

HBV genotypes may correlate with Rate of spontaneous HBeAg seroconversion

Severity of liver disease

Development of clinically important mutations

Response to treatment

No Many of the studies were retrospective, small and cross-sectional

Usually compared 2 major genotypes with each other A vs D, B vs C

Referral bias of studies conducted at tertiary care centers

Assays for genotyping not standardized



Who Should Receive Treatment?

HBsAg Positive

HBeAgInactive carrier/mild

chronic hepatitis

Monitor every 3-6 months

Decompensated cirrhosis

Consider antiviral therapy/ refer for

OLT

HBV DNA > 104 IU/mL; elevated ALT

3-6 months

Pos

Consider antiviral therapy

Neg

HBV DNA < 104 IU/mL; ALT normal 3-6 months

Grey zone

Consider Liver biopsy



Should HBeAg(+) Patients With Normal ALT but High HBV DNA Receive Therapy?Yes

Older patient with higher risk for HCC

Patients with strong family history of HCC

Patients requiring cytoreductive chemotherapy

Patients in third trimester of pregnancy with high viral load

No

Poor response to therapy

Risk of developing antiviral resistance



Definitions of Response

Virological

Full: decrease in HBV DNA to levels that are undetectable by sensitive PCR assay, eg, < 60 IU/mL

Partial: decrease in HBV DNA by at least 2 logs and to less than 20,000 IU/mL

Primary nonresponse: decrease in HBV DNA by < 2 logs

Serological

HBeAg seroconversion: loss of HBeAg with gain of anti-HBe

HBsAg seroconversion: loss of HBsAg with gain of anti-HBs



Definitions of Response

Biochemical

Normalization of serum ALT level

Histological

Decrease in hepatic necroinflammatory score by at least 2 points with no worsening in fibrosis score

Complete response

Combined biochemical, virological, serological (loss of HBsAg), and histological



Timing of Response

On-treatment response Initial response: response achieved at any time within the first

12 months of therapy

End-of-treatment response: response at the end of a defined course of therapy

Maintained response: response that persists while on therapy

Breakthrough: response that is lost while on therapy

Off-treatment response Sustained response: response that is maintained for ≥ 6 months

after therapy is stopped

Relapse: response that is lost after therapy is stopped



Interferon Therapy

Pros

– Finite duration of therapy

– Durable response

– No resistance

Cons

– Route of administration—injection

– Frequent side effects

– Cost



Ideal Clinical Situation for IFN Therapy

High ALT (> 5 x ULN) and low HBV DNA level (< 200,000 IU/mL)

Younger patient

Black

Well-compensated cirrhosis

No contraindications to use of interferon

? Genotype A or B



Lamivudine

Pros

– Oral

– Negligible side effects

– Excellent safety profile

– Low cost

Cons

– High rate of resistance and cross-resistance with other nucleoside analogues

– Long/indefinite duration of therapy



Ideal Clinical Situation for Lamivudine Use Short duration of therapy

– Prevention of disease flares/reactivation during chemotherapy

– Protracted or severe acute hepatitis

Safety a concern

– During pregnancy

Cost a concern

– HBeAg-negative CHB in developing countries



Adefovir

Pros

– Route of administration: oral

– Low rate of resistance

– Effective against lamivudine resistant virus

Cons

– Slow response and high rate of primary nonresponse

– ? Renal toxicity with long-term use




Ideal Clinical Situation for Adefovir Use HBeAg-positive and HBeAg-negative chronic hepatitis B

with low HBV DNA

Management of lamivudine-resistant chronic hepatitis B



Entecavir

Pros

– Route of administration: oral

– Potent with low rate of resistance

– Effective against LAM-R

Cons

– Long-term safety unknown




Ideal Clinical Situation for Entecavir Use HBeAg-positive or HBeAg-negative chronic hepatitis B

with high viral load

Management of lamivudine resistance

Management of HIV/HBV coinfection in patients who do not require HAART

4 th annual clinical care options for hepatitis symposium: hbv highlights

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