hepatitis b update - chronic liver disease foundation

Hepatitis B Update Highlights from AASLD 2012

Efficacy and Safety of Tenofovir DF (TDF) in

Chronic Hepatitis B Virus Infected Patients with

Documented Lamivudine Resistance (LAM-R)

Scott Fung, Peter Kwan, Milotka J. Fabri, Andrzej Horban, Mijomir

Pelemis, Petr Husa, Hie-Won Hann, John F. Flaherty, Benedetta Massetto,

Phillip Dinh, Amoreena C. Corsa, Kathryn M. Kitrinos, John G.

McHutchison, Edward J. Gane

Highlights of AASLD 2012

Hepatitis B

Study ID #20, AASLD 2012

BACKGROUND • Treatment of chronic hepatitis B (HBV) with lamivudine (LAM)

leads to resistance development (LAM-R) in up to 70% of

patients

• Tenofovir DF (TDF) has demonstrated favorable HBV DNA

suppression, safety and tolerability, and no resistance

development through 5 years in treatment-naïve patients.

OBJECTIVE • To evaluate the efficacy and safety of TDF in LAM-R patients in a

in a prospective, randomized trial.

Highlights from AASLD 2012

Efficacy and Safety of Tenofovir DF (TDF) in HBV Infected Patients with

Documented Lamivudine Resistance

Fung, S., et al. ID #20; AASLD 2012


TDF (N=141) FTC/TDF (N=139) P value

HBV DNA (<400 cp/ml) n (%) 126 (89) 120 (86) 0.43

Normal ALT n (%) 99 (70) 97 (70) 0.94

Normalized ALT a n (%) 49/79 (62) 52/83 (63) 0.93

HBsAg loss b 0 1 (<1)c 0.31

HBeAg loss b 10/65 (15) 9/68 (13) 0.72

HBeAg seroconversion 7/65 (11) 7/68 (10) 0.93




RESULTS

a Includes only patients with ALT>ULN at baseline. b HBeAg-positive patients only. c No anti-HBs observed.

Efficacy at Week 96

RESULTS

• Both treatments were well tolerated with 1% (3/280)

discontinuing for an AE (1-TDF, 2-FTC/TDF).

• No patients had a confirmed increase in serum creatinine of

≥ 0.5 mg/dL from BL, 1% (2-TDF) had serum phosphorus

<2 mg/dL, and 3% (5-TDF, 4-FTC/TDF) had CrCL <50 mL/min

(pre-treatment CrCL range for these 9 patients: 49-61 mL/min).

• No clinically relevant bone loss was observed by assessment of

spine and hip bone mineral density monitoring by DEXA and Z

scores; all fractures were trauma-related (5 patients: 3 receiving

TDF, 2 receiving FTC/TDF ).

• No resistance to TDF was detected through 96 weeks.





CONCLUSIONS

• A high rate of HBV DNA suppression with no detectable TDF

resistance was achieved with TDF in patients with documented

LAM-R through 96 weeks.

• Similar efficacy between the mono- and combination therapy

arms supports the use of TDF monotherapy in this population.

• TDF was safe and well tolerated, with a low rate of renal events

and no evidence of clinically relevant bone loss.





Is HBsAg Seroclearance Following

Nucleoside Analogue Therapy Durable in

Patients with Chronic Hepatitis B?

Gi Ae Kim, Young-Suk Lim, Jihyun An, Danbi Lee, Ju Hyun Shim, Kang

Mo Kim, Han Chu Lee, Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh


Hepatitis B


OBJECTIVE

• To evaluate the long term serological and virological

durability of NUC-induced HBsAg seroclearance in

patients with chronic hepatitis B.

METHODS • Retrospective cohort study

• 4578 CHB patients treated with LAM or entecavir; 121 achieved

HBsAg seroclearance; 54 recruited for analysis (LAM, 53;

entecavir, 1).

• Evaluate serological and virological reversion


Is HBsAg Seroclearance Durable in HBV Patients Following

Nucleoside Analogue Therapy

Kim, G., et al. ID #313





Clinical Outcomes after Seroconversion

RESULTS

Characteristic At HBsAg seroclearance

N=54 End of Follow up

N=54 P value

Anti-HBs positive, n (5) 7 (13) 28 (52) <0.001

HBeAg-positive, n (5) 0 0 -

Anti-HBe positive, n (5) 38 (70) 42 (78) 0.289

HBV DNA-positive, n(%) 5 (9) 1 (2) 0.219

ALTa IU/L 16 (12-30) 20 (13-25) 0.564

Cirrhosis, n(%) 14 (26) 12 (22) 0.500

Follow up period, months - 26 (14-43) - a Median (interquartile range).





Characteristics OR 95% CI P value

Age 1.008 0.953-1.066 0.777

Gender (Male) 1.345 0.312-5.798 0.691

HBeAg positivity 2.275 0.616-8.396 0.217

Anti-HBe positivity 0.308 0.080-1.189 0.088

HBV DNA level (log10 IU/mL) 1.086 0.859-1.372 0.492

Development of drug-resistant HBV mutations 0.500 0.095-2.628 0.413

Duration of treatment (months) 0.969 0.940-0.999 0.044

Anti-HBsAg seroconversion during follow up after HBsAg seroclearance

0.051 0.006-0.043 0.006

Predictive factors for serological and/or virological conversion

RESULTS

N=54, event (serological and/or virological reversion) number =12.

CONCLUSIONS

• HBsAg seroclearance in CHB patients was durable after

discontinuation of nucleoside analog therapy and was

associated with favorable clinical outcomes.

• Even in patients with lamivudine-resistance HBV

mutations, HBsAg seroclearance in CHB patients was

durable control of HBV infection.





Hepatitis B therapy and incidence of

hepatocellular carcinoma in a U.S.

population

Stuart C. Gordon, Lois Lamerato, Loralee B. Rupp, Scott D. Holmberg,

Anne C. Moorman, Philip R. Spradling, Eyasu H. Teshale, Cynthia

Nakasato, Joseph A. Boscarino, Emily Henkle, David R. Nerenz, Nancy

Oja-Tebbe, Mei Lu


Hepatitis B


PURPOSE • To determine the incidence of hepatocellular carcinoma (HCC)

among treated and untreated chronic hepatitis B (CHB) patients

in four large US health care systems enrolled in the Chronic

Hepatitis Cohort Study (CHeCS).

METHODS • Administrative health care data, supplemented with medical

chart abstraction, were used to identify the time of CHB

diagnosis, start time of antiviral treatment, and time of HCC

diagnosis.

• HCC diagnoses were initially identified via the presence of

ICD9 codes 155.x in administrative data, then confirmed via

chart review and/or tumor registry report.


Hepatitis B therapy and incidence of hepatocellular carcinoma in a

U.S. population

Gordon, S., et al. ID #318



U.S. population


• 2547 patients in the study population

• 748 of the 2547 received CHB antiviral therapy

• Follow up time after CHB diagnosis was 5 yrs overall

(interquartile range, 3-9 yrs); 6.8 yrs among those receiving

antiviral therapy; 4.9 yrs among those that did not receive

therapy

• During follow up: 71 patients (2.8%) received a diagnosis of

HCC; 19 of 71 (25.4%) received antiviral therapy

• Crude HCC incidence rates: 4.5 cases per 1000 person-yrs

overall; 3.5 cases per 1000 person-yrs for those receiving

antiviral therapy; 5.1 cases per 1000 person-yrs for those not

receiving antiviral therapy

RESULTS

Hepatitis B therapy and incidence of heaptocellular

carcinoma in a U.S. population Gordon, S. et al ID #318

Variable Hazard Ratio (95% CI) P

Antiviral HBV therapy (received vs not received)

0.50 (0.36-0.71)

<.001

Age <.001

40-<50 years vs. 40 years 7.54 (2.07-27.7) .002

50-<60 years vs. 40 years 9.69 (2.73-33.76) <.001

60 years vs. 40 years 23.3 (6.59-81.7) <.001

Charlson/Deyo comorbidity index <.001

Score of 1 vs. 0 1.38 (0.87-2.19) .174

Score 2 or 3 vs. 0 2.15 (1.46-3.16) <.001

Male vs. female 1.94 (1.30-2.87) .001

Final Cox Multivariable Regression Model for Prediction of Hepatocellular Carcinoma

CONCLUSIONS • HBV antiviral therapy was associated with a 50% decrease in

risk of developing HCC in patients with CHB infection

• Other factors associated with increased risk of HCC included

male gender and increasing age>40 at time of CHB diagnosis



U.S. population


Durability after discontinuation of

nucleos(t)ide therapy in hepatitis e antigen

negative chronic hepatitis B patients

Sung Won Cho, Soon Sun Kim, Dami Lee, Jin Hee Cho, Kee Bum Kim, Jae Youn Cheong, Sung won Cho


Hepatitis B


BACKGROUND • The ideal treatment duration of HBeAg negative hepatitis

patients is not well known. APASL guidelines suggest that if

undetectable HBV-DNA has been documented on three

occasions 6 months apart, discontinuation of treatment can be

considered.

OBJECTIVE • To investigate the frequency of lapse after discontinuation of

nucleos(t)ide (NUC) treatment

• To study factors associated with one year sustained virological

response in chronic HBeAg(-) hepatitis patients


Durability after discontinuation of nucleos(t)ide therapy in

hepatitis e antigen negative chronic hepatitis B patients

Cho, S.W., et al. ID #336




Virological Relapse Clinical Relapse

6 months after stopping NUC treatment 22 (48.9%) 16 (35.6%)

12 months after stopping NUC treatment 33 (73.3%) 24 (53.3%)

ETV 18/25 (72%) -

LAM 9/14 (64.3%) -

ADV 6/6 (100%) -

Virological and Clinical Relapse Rate After Discontinuation of

NUC Treatment

RESULTS

ETV, entecavir; LAM, lamivudine; ADV, adefovir




Relapse (+) n=33

Relapse (-) n=12

P value

Male, n(%) 23 (69.7) 10 (83.3) 0.466

Mean Age, years (SD) 44.4 (±7.16) 45.4 (±8.12) 0.685

Mean baseline AST, IU/L (SD) 156.45 (±104.9) 159.2 (±85.4) 0.937

Mean baseline ALT, IU/L (SD) 240.3 (±215.7) 235.9 (±124.3) 0.948

Mean HBV DNA, log10 copies/mL (SD) 7.14 (±0.95) 6.9 (±0.74) 0.436

HBV DNA, >108 copies/mL (%) 12 (38.7%) 1 (8.3%) 0.070

Mean duration of treatment, months 36.0 (±6.74) 45.0 (±15.6) 0.077

Liver cirrhosis, n (%) 2 (6.1%) 7 (58.3%) 0.000

Factors Associated with Sustained Virological Response 12 months

After Stopping NUC Treatment

RESULTS

SD, standard deviation; AST, aspartate aminotransferase; ALT, alanine aminotransferase

CONCLUSIONS

• Virological relapse developed in the majority (73.3%) of patients

and clinical relapse developed in approximately half (53.3%) by

12 months after discontinuation of therapy.

• Low baseline HBV DNA levels (<108 copies/ml) and presence

of liver cirrhosis were found to be associated with a low rate of

virological relapse.




Tenofovir monotherapy is effective salvage

therapy of nucleoside-resistant hepatitis B

Jeffrey So, Lay Lay Win, Nitin Sarin, Colina Yim, Hemant Shah,

Jordan J.Feld , E. Jenny Heathcote, David K. Wong


Hepatitis B



Tenofovir monotherapy is effective salvage therapy of

nucleoside-resistant hepatitis B

So, J., et al. ID #364

AIM • To assess the effectiveness of tenofovir (TDF) monotherapy in those

with chronic hepatitis B (HBV) infection who have failed treatment with

at least one other nucleos(t)ide reverse transcriptase polymerase

inhibitor (NRTI)

METHODS • Single center, retrospective cohort study

• Identified HBV(+) patients from Nov 1, 2006 to March 31, 2012;

included patients >18 yrs of age with resistance to an NRTI

• Evaluated demographic information, adherence, rate of complete viral

suppression (defined as HBV DNA <60 IU/mL), and viral kinetics and

adverse events of TDF therapy





HBV DNA <60 IU/mL on TDF N=148 (95.5%)

HBV DNA >60 IU/mL at time of initiating TDF (n=155)

HBV DNA still positive on TDF N=7 (4.5%)

Treated with TDF monotherapy (Group 1)

N=58

Treated with TDF and other NRTI (Group 2)

N=90

Switched to TDF monotherapy later

N=58

Still on TDF and other NRTI

N=32

HBV DNA > 60 IU/mL at Time of Initiating Tenofovir (n=155)

Mean HBV DNA at time of initiating TDF, log IU/mL 4.5 (1.8-9.6)

Number achieving HBV DNA <60 IU/mL on TDF 148/155 (95.5%)

Mean time to HBV DNA <60 IU/mL on TDF (months) 5.8 (0.4-39.4)

Number achieving HBV DNA <60 IU/mL within 12 months of starting TDF

134/155 (86.5%)

RESULTS




Virologic Response in Group 1 vs. Group 2

Group 1 Group 2 P value

Mean baseline viral load, log IU/mL 4.44 4.65 0.53

Mean duration to HBV DNA <60 IU/mL, months 5.2 6.2 0.34





CONCLUSIONS

• Tenofovir (TDF) is a very effective salvage therapy for those

who fail treatment with other NRTI’s

• Despite concerns raised in the mid-2000’s, TDF treatment

failure due to multidrug resistant HBV strains has not been

observed

• There is no obvious/large advantage for combination therapy

vs. TDF monotherapy

Six Years of Treatment with Tenofovir DF for

Chronic Hepatitis B Virus Infection is Safe and

Well Tolerated and Associated with Sustained

Virological, Biochemical and Serological

Responses with no Detectable Resistance

Patrick Marcellin, Maria Buti, Edward J. Gane, Naoky Tsai, William Sievert,

Ira M. Jacobson, George Germanidis, John F. Flaherty, Phillip Dinh, Kathryn M. Kitrinos, John G. McHutchison, Nezam Afdhal


Hepatitis B



Evaluation of 6 Years of Treatment with Tenofovir DF for

Chronic Hepatitis B Infection

Marcellin, P., et al. ID #374

Chronic HBV Patients (HBeAg-

and HBeAg+

TDF 300 mg N=250, 176

Open Label TDF 300 mg QD

ADV 10 mg N=125, 90

Design of Studies 102 (HBeAg-) and 103 (HBeAg+)

Study Year 0 2 1 8 3 4 6 5

Note: Emtricitabine (FTC) could be added for confirmed viremia on/after week 72





Response HBeAg- Patients

(study 102) HBeAg+ Patients

(study 103)

Year 5 Year 6 Year 5 Year 6

HBV DNA <400 copies/mL intent-to-treatA

83% 291/350

81% 281/345

65% 160/248

62% 157/251

HBV DNA <400 copies/mL on-treatmentB

99% 292/295

99.6% 283/284

97% 170/175

99% 167/169

Virologic Suppression at Year 6

RESULTS

A LTE-TDF (missing = failure; addition of FTC = failure) B Observed (missing = excluded; addition of FTC = included)





TDF-TDF ADF-TDF Total

Adverse events leading to drug discontinuation 9 (2.3%) 2 (1.0%) 11 (1.9%)

Deaths 6 (1.5%) 3 (1.5%) 9 (1.5%)

Serious adverse events 5 (1.3%) 2 (1.0%) 7 (1.2%)

Grade 3 or 4 adverse events 3 (0.8%) 3 (1.5%) 6 (1.0%)

Serum creatinine ≥ 0.5 mg/dL above baseline 5 (1.3%) 4 (2.0%) 9 (1.5%)

Creatinine clearance <50 mL/min 3 (0.8%) 3 (1.5%) 6 (1.0%)

PO4 <2 mg/dL 5 (1.3%) 3 (1.5%) 8 (1.4%)

Summary of Safety During Open-Label Period by Prior

Treatment Assignment

RESULTS

Reasons for discontinuation - Study 102: septic shock (n=1), abdominal pain (n=1), HCC (n=3), dizziness/ fatigue/ attention disturbance (n=1), endometrial cancer (n=1); Study 103: osteoporosis (n=1), blood creatinine increase (n=1), breast cancer (n=1), drug dependence (n=1).





CONCLUSIONS

• Virological, biochemical and serological responses were

maintained through 6 years

• HBeAg loss/seroconversion rates of 50% and 37% through 6 yrs

• 11% of patients had confirmed HBsAg loss (8% with seroconversion)

• No resistance to TDF was detected through 6 yrs

• Treatment with TDF was well tolerated

• 80% of 585 patients remained on study at year 6

• <2% of patients discontinued TDF for an adverse event

• Renal events were uncommon (<1.5%) and manageable

• No evidence of bone loss after 2 years of follow up

Incidence and Risk Factors in the

Development of Hepatocellular Carcinoma

(HCC) in Non-Cirrhotic and Cirrhotic Patients

with Chronic Hepatitis B (CHB): Results of a

Multicenter U.S. Cohort Study

Irene S. Sonu, Long H. Nguyen, Christy Chen, Kevin C. Kin, Nghiem B. Ha, Huy

N. Trinh, Aijaz Ahmed, Jiayi Li, Jian Q. Zhang, Mindie H. Nguyen


Hepatitis B



Incidence and Risk Factors in the Development of HCC in Non-

Cirrhotic and Cirrhotic Patients with Chronic Hepatitis B (CHB)

Sonu, I. S., et al. ID #593

OBJECTIVE • To determine the incidence of HCC in non-cirrhotic and cirrhotic

patients with chronic hepatitis B and investigate factors related

to higher HCC incidence.

METHODS • Retrospective cohort study involving 3,108 patients with CHB,

including 253 with cirrhosis, seen between 2001 to 2010 at a university

medical center, a community multispecialty medical center, 2

community primary care clinics, and 2 GI clinics in California.

• Patients who had undergone HCC surveillance with imaging studies

and alpha-fetoprotein for at least 12 months were included.

• Patients diagnosed with HCC during the first 6 months of follow up or

co-infected with hepatitis C virus of HIV were excluded.





Overall (n=63) No Cirrhosis (n=25)

Cirrhosis (n=38)

P value

Annual incidence 0.48% (0.38-0.62%) 0.21% (0.14-0.31%) 3.2% (2.4-4.5%) <0.0001

Annual incidence in:

Male (n=1306, 1242, 64)

0.6% (0.5-0.9%)

0.32% (0.2-0.5%)

3.1% (2.2-4.5%)

<0.0001

Female (n=1802, 1613, 189)

0.24% (0.1-0.4%)

0.06% (0.02-0.2%)

3.6% (2.0-6.8%)

Annual HCC Incidence in CHB Patients With and Without Cirrhosis

RESULTS





Adjusted Hazard Ratio P value

Age 1.05 (1.03-1.08) <0.0001

Sex Female (reference)

Male

2.55 (1.31-4.97)

0.006

Chronic hepatitis B Without Cirrhosis (reference)

With Cirrhosis

3.10 (2.36-4.07)

<0.001

Ethnicity Non-Asian (reference)

Asian

2.39 (0.58-9.87)

0.23

Predictors for HCC Using a Cox Proportional Hazards Model





CONCLUSIONS

• Across all patients with CHB recruited from both community and

academic centers, HCC incidence is higher in males and

increases with increasing age.

• In patients without cirrhosis, annual HCC incidence ranged from

0.8% in young males to close to 1.0% in males older than 50,

while it remained near 0.1% in females older than 50.

• Among those with cirrhosis, annual incidence of HCC is similarly

high in males and females and

Peginterferon Lambda, a New Potential

Therapeutic Option for the Treatment of Chronic

Hepatitis B: A Phase 2B Comparison with

Peginterferon Alfa in Patients with

HBeAg-Positive Disease

Henry Lik-Yuen Chan, Sang Hoon Ahn, Ting-Tsung Chang, Cheng-Yuan Peng, David

K. Wong, Carla S. Coffin, Seng Gee Lim, Pei-Jer Chen, Harry L. Janssen, Patrick

Marcellin, Lawrence Serfaty, Stefan Zeuzem, Wenhua Hu, Linda Critelli, Juan Carlos

Lopez-Talavera, Elizabeth L. Cooney


Hepatitis B

Study ID #LB-14, AASLD 2012


Peginterferon Lambda, a New Potential Therapeutic Option for

the Treatment of Chronic Hepatitis B: A Phase 2B Comparison

Chan, H. L., et al. ID #LB-14

BACKGROUND

• Peginterferon lambda-1a (Lambda) is the pegylated form of interferon

lambda-1a, a type 3 interferon with demonstrated activity against the

hepatitis B virus (HBV) in vitro and in transgenic mice

• Lambda is currently in phase III development for chronic hepatitis C

virus (HCV), where Lambda has shown greater early virologic effect

and improved tolerability compared to alpha-interferon

• A phase 2b study of Lambda vs. pegylated interferon alpha-2a for

chronic hepatitis B (CHB) has been initiated (LIRA-B study); this

reports the week 24 interim results





Mean value for HBV DNA at baseline: 7.8 log10 IU/mL

Serum HBV DNA Change From Baseline

Lambda Alfa

0.0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

-4.00 4 8 12 16 20 24

HB

V D

NA

me

an lo

g10

ch

an

ge

fro

m b

ase

line

± S

E (

IU/m

L)

Weeks

80

83

77

78

78

81

32

35

75

75

74

74

75 = N

72 = N

P= <0.0001 0.0018 0.0272 0.1203

-1.78

-2.58

-2.28

-2.77





Mean value for qHBsAg at baseline: 4.0 log10 IU/mL

Serum qHBsAg Change From Baseline

Lambda Alfa

0.0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

-0.7

-0.8

-0.9

-1.00 4 8 12 16 20 24

qH

Bs

Ag

a

mea

n log

10

ch

an

ge

fro

m b

ase

line

± S

E

Weeks

77

83

75

76

75 = N

73= N

P= <0.0002 0.0075

-0.27

-0.67

-0.39

-0.65





Patients, n (%) Lambda (180 µg)

N=80 Alpha (80 µg)

N=83

Any AE 72 (90) 75 (90)

Serious AE 4 (5) 6 (7)

Aes leading to discontinuation of therapy 4 (5) 7 (8)

Dose Reductions due to AEc Neutropenia Thrombocytopenia ALT increase

6 (8) 0 0

4 (5)

21 (25) 12 (15)

1 (1) 2 (2)

ALT Flares >2xbaseline and >10x ULNb >2xbaseline and >5xULNc

12 (15) 27 (34)

6 (7)

13 (16)

A Selected events of interest shown. B NIH adopted criteria for ALT flare. C Minimum-accepted criteria for ALT flare per literature.

Safety and Adverse Events





CONCLUSIONS

• Lambda demonstrated greater early efficacy than alfa, as

defined by HBV DNA and qHBsAg change from baseline at

weeks 12 and 24; HBeAg responses were comparable through

week 24.

• There were fewer hematologic abnormalities and flu-like or

musculoskeletal symptoms with Lambda vs alfa.

• These interim study results are consistent with findings from

Lambda studies in HCV and support ongoing study of Lambda

in CHB.

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