63rd annual meeting of the american association for the study of the liver disease (63rd aasld)

63rd Annual Meeting of the American Association for the Study

of the Liver Disease (63rd AASLD)

Boston, MassachusettsNovember 9-13, 2012

Epidemiology and Natural History of HBV Infection

Tram Tran, MDCedars Sinai Medical Center

Los Angeles, CA

HBV Discovered in Korean Mummy Dated to the 16th Century

• Laparoscopic liver biopsies performed on mummified Korean child dated to 16 A.D.

• Complete sequence of the oldest HBV isolate and the most ancient full viral genome known so far

• Genome (3,215 base-pairs) analysis of the ancient HBV revealed a unique HBV genotype C2 (HBV/C2) sequence commonly spread in Southeast Asia

• Comparison of the ancient genome with contemporary HBV/C2 DNA sequences from various regions in East Asia showed significant differences

• Sequence likely dates back to 3,000-100,000 years ago

Bar-Gal G, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 927.

HBV DNA level: Most Important Predictor of HBV DNA and HBsAg Seroclearance

• Study to prospectively analyze factors for HBV DNA and HBsAg clearance in HBeAg-negative patients (N=163 pts; 2 year follow-up)

• Cumulative HBsAg clearance 3%

• Multivariate analysis showed HBV DNA level and APRI* score significantly associated (p<0.0001) with HBsAg clearance

• Conclusion: HBV DNA level is the strongest predictor of HBV DNA and HBsAg seroclearance in HBV inactive carriers (untreated HBeAg-negative HBsAg carriers)

Per

cen

t

HBV DNA Undetectable and HBsAg Loss at 1-2 Years by HBV DNA Level

Knop V, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 349.

*APRI = AST-platelet ratio index

Predictors of HBsAg Seroclearance in CHB

• 3, 014 patients in multicenter U.S. cohort retrospectively enrolled from 2001-2011• HBsAg clearance in 26 patients over 11,751 person-years

− 0.22% annual clearance and 0.86% overall rate• Higher annual clearance associated with male gender, HBeAg-negative and HBV DNA ≤ 10,000 IU/mL

• Conclusion: HBsAg seroclearance rates may be lower than previously described, with or without treatment

(n=2579) (n=1162) (n=1417) (n=1480) (n=1099) (n=612) (n=1967) (n=1286) (n=1293)

Gender Age Baseline HBeAg Baseline HBV DNA(IU/mL)

Annual Incidence of HBsAg Seroclearance by Various Patient Characteristics Among Treatment Naïve Patients

p=0.01 p=0.24 p=0.05 p=0.11

Per

cen

t

Nguyen LH, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 328.

Long Term Follow-up of Inactive HBV Carriers and Relation with HBsAg Levels

• HBeAg-negative, untreated, normal ALT level patients deemed “inactive carriers” with HBV DNA <2,000 IU/ml (N=170) followed for mean of 4.3 years• 1 year 13% became active 2 years 25%5 years 37% • Baseline HBV DNA <2000 IU/ml and HBsAg level <100 IU/ml predictive of remaining inactive

• Conclusion: Combination of HBV DNA and HBsAg gave 100% prediction of remaining inactive carrier

HBsAg<1000 IU/ml

HBsAg>1000 IU/ml

P<0.001

HBV DNA < 200 IU/ml

HBV DNA > 200-2000 IU/ml

P<0.001

Hansen BE, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 338.

Lamivudine in pregnancy: Impact on HBV Flares and HBeAg Seroconversion

Post Partum• Antiviral therapy useful in pregnant CHB

patients to prevent flares and prevent mother to child transmission of HBV, but risks of therapy withdrawal unknown

• 64 pregnant CHB patients recruited 2007-2011− LAM offered 32 weeks until 2-4 weeks postpartum − Median age 29 years, f/u 11 months, baseline

viral load >108 logs

• 48 received LAM median treatment and 16 served as control

• First 3 months postpartum 29% LAM vs. 18% control (p=NS) had flare (ALT >2XULN)

• Seroconversion occurred in 5 patients− Postpartum flare not associated with

seroconversion

• Conclusion: Flares not higher after LAM use in pregnancy and are usually mild

Seroconversion by Genotype

Maximum ALT post partum

1000-900-

800- 700-600-500-

(0-3 months post partum)

(3-18 months post partum)

100

200

300

Tan PK, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 335.

Risk of HBV Vertical Transmission after Amniocentesis in Mothers with CHB

• 63 infants born to mothers who had amniocentesis compared to 198 matched controls− All infants had appropriate vaccinations

• Level of maternal viremia predicts risk of transmission with amniocentesis:− No statistical difference in HBV transmission

when maternal viremia <6.99 log copies/ml− Maternal viremia ≥107 log copies/ml: 50% amnio

vs. 4% controls (p=0.006)

• Amniocentesis performed on HBsAg-positive mothers with HBV DNA ≥ 107 log c/mL increased the risk of vertical transmission.

• Conclusion: HBsAg-positive women who plan to have amniocentesis should be evaluated for the risk of vertical transmission and stratified by their HBV DNA levels

Population Characteristics

Mothers

Mean ±SD (range)

Amniocentesis Cases (n =63)

Controls (n=198) PValue

Age (years) 34±5.37 (20~42) 28 ±4.07 (18~41) 0.000

Primigravid 16/63 28 /198 0.052

Husband HBsAg+

3 /63 8/198 0.804

Prior Infant HBsAg+

3 /63 3 /I98 0.155

Log HBV DNA (copies/mL)

3.78 ±1.80 (2.70~8.09)

5.05 ±2.24 (2.70~8.46)

0.000

Cesarean Section

51 /63 129 /198 0.019

Gestation days277.55 ±7.25

(255~292)272.00±9.97 (215~291)

0.000

Infants

Mean ±SD (range)

Amniocentesis (n=63)

Controls (n=198)

P Value

Male 35 /63 103 /198 0.665

Weight (gm)3384.13±505.52

(1200~4600)3406.31±400.95

(2450~4500)0.378

Length (cm)49.86±3.08

(41~55)50.18±0.88

(47~53)0.419

Apgar at one minute

9.95±0.22 (9-10)

9.93±0.30 (8-10)

0.366

Detectable HBV DNA at

birth3 /63 10 /198 1.000

HBsAg+ at birth

10 /63 47 /198 0.222

Breast-fed 24 /63 63 /198 0.443

Pan C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 904.

Hepatocellular carcinoma: Incidence and Risk for CHB patients on Antiviral

therapy

• In a large US observational cohort study, HBV antiviral therapy and HCC relationship was studied using ICD9 codes/tumor registry and chart review (2463 patients, follow-up 5 years)− 779 received antiviral therapy

• 69 pts developed HCC− 27% of these received antiviral therapy

• Factors associated with increased risk of HCC included no antiviral therapy, male gender, age >40 years at time of CHB diagnosis and higher comorbidity index.

• Conclusion: Despite antiviral therapy, HCC can still occur, especially in an older, male CHB population

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. ≤40years 7.54 (2.07-27.7) .002

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

≥60 years vs. ≤40years 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

Cox Multivariable Regression Model for Prediction of Hepatocellular Carcinoma

Gordon SC, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 318.

Hepatocellular Carcinoma: Risk Factors in CHB

• 11-year retrospective analysis of 101 HCC patients and with viral suppression compared to matched cohort− 30% non-cirrhotic− Median follow-up 35 months

• Multivariate analysis: age> 60, male gender, and LAM use associated with increased HCC risk

• Conclusion: Association of lamivudine exposure with HCC raises the possibility of drug-induced mutations increasing HCC risk

Multivariate analysis for HCC development

Odds Ratio 95% Confidence Interval

Age 60+ 1.84 0.79-4.26

Male gender 1.94 0.93-4.06

HBeAg Positive 0.50 0.25-0.96

Lamivudine Exposure 3.1 1.6 – 6.1

Ghaly S, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 332.

Hepatocellular Carcinoma: Incidence and Risk for Patients

with Family History of HCC

• Study in Taiwan of 22,472 individuals with 18 year f/u and linkage to national cancer registry

• 374 cases of HCC identified during 362,000 person/yrs of follow-up

• Family history of HCC and HBsAg-positive had synergistic interaction with the risk of HCC in multivariable-adjusted analysis (age-sex-BMI-alcohol-smoking-ALT-DM) (HR: 32.33, 95% CI [20.8-50.3], p-value <0.01)

• Conclusion: HBV patients with family history of HCC should be considered very high risk for HCC.

Family History of HCC, HBsAg and HBeAg Serostatus, HBV DNA level, and Risk of Incident

HCC

40.0%

19.1%17.6%

10.3%

5.4%

2.5%

0.64%0.62%

Loomba R, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 598.

Progression to Cirrhosis and Mortality with CHB

• Study examining natural history of untreated CHB patients over 25 years of follow-up

• 105 untreated CHB patients enrolled− 76% male− Mean age 30 years− 64% HBeAg-positive− No evidence of cirrhosis

• 43% became inactive carriers− 47% of these cleared HBsAg

• 30% became HBeAg-negative• 30% developed cirrhosis (incidence rate 13/1000

person/years)− Older age, male sex, absence of sustained remission

and sustained HBV replication predicted cirrhosis• Inactive Carriers and patients without cirrhosis had

improved survival probability• Conclusion: In Caucasian patients with CHB

without cirrhosis at presentation, progression to cirrhosis is relatively slow but cirrhosis occurrence strongly predict disease-related mortality

Cumulative survival probability according to HBV replication during follow-up

100%

79%

Cumulative survival probability according to HBV cirrhosis occurrence

99%

79%

Patients at riskInactive Carriers 45 44 42 41 41 39 22HBeAg-/HBV-DNA+ or HBeAg persistence

45 37 35 29 20 11 9

Patients at risk

No Cirrhosis 73 64 61 60 57 51 27

Cirrhosis at follow-up 32 32 31 24 17 12 6

Fattovich G, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 319.

Epidemiology and Factors Related to Chronicity of Acute HBV

• Study of 350 patients with acute HBV− 155 with one year f/u− Male 76%; mean age 38 years; 9 HIV+;

50% sexual risk factor

• Results:− 96.7% resolution vs. 3.3% CHB− Median time from symptoms to clearance:

HBeAg 23 days and HBsAg 111 days

• Development of CHB following acute infection associated with lower ALT and bilirubin during acute HBV and HIV+ status at time of infection

• Conclusion: HIV patients appear to evolve more frequently to CHB and lower values of biochemical markers appear related to the evolution of acute hepatitis B infection to CHB

Comparative clinical and biochemical characteristics of the non-chronic and chronic evolution group

Autolimited HBV (n=150)

Chronic Evolution HBV (n=5)

P Value

Age (years) 36 (±12) 38 (±9) 0.76

Sex (men) 77% (n=115) 60% (n=3) 0.39

ALT (U/L) 2068 (±1309) 789 (±323) 0.01

Bilirubin (Mg/dL)

10.5 (±7.3) 1.6 (±0.7) 0.001

HIV+ 5% (n=7) 40% (n=2) 0.003

Dirchwolf M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 320.

Rheumatoid Factor in CHB Reflects Disease Activity and Stage

• Study evaluating role of Rheumatoid Factor (RF) as marker of disease activity in CHB

• RF available in 378 CHB pts− 53% Caucasian, 71% male, mean age 41 years

• 35% had positive RF and more likely in:− Older (47 vs. 37 yrs)− Female− Lower platelet counts (183 vs. 214)− Higher AST/platelet ratio index− Increased histologic activity on biopsy

• RF titers increased during flares and decreased on antiviral therapy

• In CHB, RF may reflect disease activity and advanced fibrosis, and disappearance of RF correlates with virological response to therapy.

R=0.94

R=0.98

Hernaez R, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 342.

RF

(IU

/mL

)

HB

V D

NA

(Lo

g IU

/mL

)

Performance of Transient Elastography for Staging

Liver Fibrosis in CHB• Meta-analysis to assess

performance of transient elastography for fibrosis in HBV patients

• A total of 18 studies comprising 2,772 patients were analyzed

• AUROC for diagnosis:− Significant fibrosis (F2): 0.859 (95% CI,

0.857–0.860)− Severe fibrosis (F3): 0.887 (95% CI,

0.886–0.887)− Cirrhosis (F4): 0.929 (95% CI, 0.928–

0.929)

• Conclusion: Transient elastography can be performed with good diagnostic accuracy for quantifying liver fibrosis in patients with CHB.

Characteristics of previous reported meta-analyses versus current study

AUROC Cutoff values (kPa)

≥F2 ≥F3 F4 ≥F2 ≥F3 F4

Talwalkar 0.870 N/A 0.957 N/A N/A N/A

Stebbing 0.84 0.89 0.94 7.81 N/A 15.56

Fredrich-rust et al 0.84 0.89 0.94 7.65 N/A 13.01

Tsochatzis et al N/A N/A N/A 7.3 10.2 15.0

Chon et al (this study) 0.859 0.887 0.929 7.9 8.8 11.7

AUROC, area under the receiver operating characteristic curve; kPa, kilopascal.

Meta-analysis results of LSM cutoff values for staging liver fibrosis

Fibrosis Weighted mean LSM value (kPa) Range (kPa) Sensitivity (%) Specialty (%)

F≥2 7.9 6.1-11.8 74.3 78.3

F≥3 8.8 8.1-9.7 74.0 63.8

F=4 11.7 7.3-17.5 84.6 81.5

Kim SU, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 1376.

Staging Fibrosis in CHB Using APRI and FIB-4

• Large observational cohort study (Chronic Hepatitis B and C Cohort Study) of both treated and untreated CHB

• 277 with lab and biopsy data available (1997-2010)− 64% male, 52% Asian

• Median biopsy age 45 years− 25% F0, 25% F1, 21% F2, 15% F3, 14% F4

• AUC 0.84 APRI*, 0.82 FIB-4, 0.63 AST/ALT ratio• Both APRI* and FIB4 are useful markers for distinguishing severe fibrosis (F3-

F4) from absent-to-moderate fibrosis (F0-F2).

APRI* FIB-4 AST/ALT ratio

Liver biopsy fibrosis stage Mean (95% CI) P-value* Mean (95% CI) P-value* Mean (95% CI) P-value*

No fibrosis (F0) 58 0.38 (0.32-0.45) 58 0.97 (0.85-1.10) 78 0.80 (0.73-0.87)

Fibrosis portal expansion (F1) 67 0.42 (0.36-0.50) <0.01 67 0.90 (0.79-1.04) <0.01 88 0.74 (0.68-0.80) <0.01

Few bridges or septa (F2) 56 0.67 (0.55-0.82) <0.01 56 1.48 (1.26-1.73) <0.01 69 0.72 (0.66-0.80) 0.79

Numerous bridges or septa (F3) 34 0.84 (0.67-1.05) 0.15 34 1.65 (1.30-2.08) 0.41 43 0.75 (0.68-0.83) 0.65

Cirrhosis (F4) 43 1.55 (1.17-2.05) <0.01 43 3.55 (2.79-4.51) <0.01 47 0.90 (0.78-1.04) 0.44

Mean (95% CI) APRI, FIB-4, and AST/ALT values by liver biopsy fibrosis stage

Lu M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 346.

*APRI = AST-platelet ratio index

Using Noninvasive Serum Markers to Predict Survival in CHB

• Study of 600 patients who underwent FibroTest, APRI, biopsy, and FIB-4 on same day− Male 64%, age 42 years, 36% inactive carriers

• Overall survival was very high at 5 years and predicted by liver stiffness and FibroTest:− 97.1% with liver stiffness ≤9 kPa vs. 61.5% with liver stiffness >20 kPa (p<0.01)− 96.8% with FibroTest ≤0.73 vs. 49.2% with FibroTest >0.85 (p<0.01)

• Conclusion: Non-invasive diagnosis of liver fibrosis, either by liver stiffness measurement or FibroTest, can predict survival in chronic hepatitis B. ≤20kPa

Liver Stiffness and FibroTest and Survival

>20kPa

P<0.001

≤0.85

>0.85

P<0.001

de Ledinghen V, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 1321.

Cost-Effectiveness of Universal HBV Vaccination in Adults

with Diabetes Mellitus• Data show increased risk of HCC in diabetics and CDC recommends vaccinating adults with DM

for HBV

• Markov model of diabetic adults in US evaluated effect of HBV vaccine on morbidity and mortality

• One-time HBVac program of 50,000 diabetic adults would be expected to prevent 423 cases of CHB and 4.7 cases of HCC death assuming annual progression rate of 0.33% in HBV liver disease to HCC

• Model projected an estimated cost per Quality-adjusted life-year saved of $51,200 for diabetic adults who received HBVac.

• Conclusion: This Markov model suggests that routine HBV vaccination in US adults with DM is cost effective and may be associated with decreased risk of HCC mortality

1 11 21 31 41 51

Mortality by HBV Vaccine Status

Njei B, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 343.

Durability of Antibody Response Following HBV Vaccination in Healthcare Workers (HCW)

• Study assessing durability of HBV vaccine in 159 Health care workers− Assessed 10-14 years (group 1), 15-19 years (group

2), and ≥20 years (group 3) after vaccination− Mean age at vaccination 31-34 years

• Anti-HBs negativity was 16%, 26% and 25% among groups 1, 2 and 3, respectively.

• HCWs without detectable anti-HBs were older (51 vs. 47 years; p=0.04), vaccinated at a later age (35 vs. 32 years; p=0.02) and non-smokers (92% vs. 76%; p=0.04)

• Booster vaccination highly effective (94%) in HCWs with negative anti-HBs titers.

• Conclusion: anti-HBs titers appear to wane over time in HCWs vaccinated as adults. Older age at vaccination was associated with negative anti-HBs titer.

Efficacy of Booster HBV Vaccination

Gara N, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Oral Presentation.

Hepatitis B and C Association with Non-Hodgkin’s Lymphoma (NHL)

• Analysis of risk of NHL with HBV or HCV (2005-2009)

• 1,055,912 patient discharges included:− HCV ICD-9: 45%− HBV ICD-9: 5%− No Hepatitis ICD-9: 50%

• In multivariate analysis, hepatitis status was an independent risk factor for NHL with HBV having the largest effect size (OR=3.32, p<0.001)

• Conclusion: This study confirms previous reports linking HBV and HCV and further elucidation of the mechanisms of the hepatitis and lymphoma relationship is needed

Multivariate analysis results of the relationship between hepatitis status and

NHL

Moehlen M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 907.

Pre-Immunosuppressant HBV Screening Practices

• Survey distributed to 523 specialists (overall response rate was 79%): hematology (131), oncology (125), gastroenterology (102), rheumatology (68), dermatology (63), and other (34).

• Physicians were predominantly women (54%) of average age 41 years, and with 14 years of professional experience.

• 74% stated they were aware of recommendations for management of HBV reactivation risk− Trend stronger in gastroenterology and rheumatology (>80%) and weaker in oncology (56%), p<0.0001.

• 37% never or only sometimes asked about HBV risk factors and 35% never or only sometimes requested HBsAg before starting treatment.

• Conclusion: HBV screening practices vary among the medical specialties and depend on familiarity with the guidelines, particularly in high risk specialties such as oncology

SpecialtyNEVER Investigates

risk factors for HBV infection

NEVER requests HBsAg

NEVER requests anti-HBc

ALL 40 (8%) 22 (4%) 34 (7%)

Hematology 5 (4%) 0 (0%) 0 (0%)

Oncology 28 (22%) 18 (15%) 23 (19%)

Gastroenterology 2 (2%) 0 (0%) 0 (0%)

Rheumatology 4 (6%) 2 (3%) 5 (7%)

Dermatology 1 (2%) 2 (3%) 3 (5%)

Others 0 (0%) 0 (0%) 3 (10%)

García-Bengoechea, M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 915.

Therapeutic Strategies for HBV TreatmentS. Martin Cohen, MD

Case Western Reserve UniversityCleveland, OH

Continuing ETV with Partial Virologic Response is Beneficial

• Naïve HBV patients receiving ETV 0.5 mg daily− Partial Virologic Response (PVR) >1 log IU/ml

decrease in HBV-DNA but still > 20 IU/ml at 48 weeks

− Complete virologic response (CVR) < 20 IU/ml at 48 weeks

• Viral Breakthrough:− Week 96: 1.6% CVR vs. 0% PVR (NS)− Week 144: 1.6% CVR vs. 5.9% PVR (p=0.092)

• Cumulative Resistance:− 0% CVR vs. 5.9% PVR (p=0.067)

• Conclusion: Long-term continuous ETV monotherapy in naïve patients with PVR at 48 weeks can achieve additional virologic response without significantly increasing antiviral resistance

Kim IH, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 376.

Virologic Response for Patients Continued on ETV

P <0.001

P=<0.0001

-2.28

0.0018 0.0272 0.1203

-2.77

-1.78

-2.58

PEG-IFN Lambda for HBV is More Effective than PEG-IFN 2a

• Phase 2B study of PEG-IFN Lambda vs. PEG-IFN alfa-2a n HBeAg-positive CHB patients− Baseline: IFN naïve, HBV-DNA > 105 copies/ml− 75% males, 90% Asians, 5% cirrhotics, 85% genotype B or C

• 24 week interim data of planned 48 week treatment course− HBV-DNA dropped more at 12 and 24 weeks with Lambda− HBsAg dropped more with Lambda− HBeAg loss was equivalent− ALT normalized more with alfa-2a

Chan HLY, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. LB-14.

80 77 78 32 75 74 75=N

83 78 81 35 75 74 72=N

Serum HBV DNA Change From Baseline

PEG-IFN Lambda has Fewer Adverse Events than PEG-IFN 2a

• Adverse events− PEG-IFN alfa had more fever, headache, alopecia, myalgia, dizziness, rash, arthralgia, and

dose-modifications due to hematologic AE’s− Lambda had more ALT flares

• Conclusions:− PEG-Lambda had significantly better decrease in HBV-DNA at week 12, as well as better

decreases in HBsAg levels− HBeAg seroconversion was equivalent between the 2− PEG-alfa had better normalization of ALT at week 24− PEG-Lambda had less flu-like symptoms and required less dose-modifications for hematologic

side effects.

Chan HLY, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. LB-14.

Patients, n (%)Lambda 180 µg

N = 80Alfa 180 µg

N = 83

Any AE 72 (90) 75 (90)

Serious AEs 4 (5) 6 (7)

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

Dose reductions due to AENeutropenia

ThrombocytopeniaALT increase

6 (8)004 (5)

21 (25)12 (15)1 (1)2 (2)

ALT flares>2 x baseline and >10 x ULN>2 x baseline and >5 x ULN

12 (15)27 (34)

6 (7)13 (16)

Tenofovir is Effective Salvage Therapy for NA-resistant HBV

• Single center, retrospective, cohort study of TDF vs. TDF + nucleoside analog in NA-resistant CHB patients (N=148)

• Study population− M204 – 62%− A181T or N236T – 2%− Viral breakthrough – 36%

• 95.5% became HBV-DNA negative (mean 5.8 months)− 58 TDF monotherapy− 90 TDF + nucleoside analogue

Conclusions:− TDF is effective salvage therapy for those who have failed other NA’s− No resistance was seen in this study− No advantage in adding a nucleoside analogue to TDF alone

So J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 364.

Virologic Response

TDF TDF + NA p value

Mean Baseline viral load 4.44 log 4.65 log p=0.53

Mean Duration to HBV DNA<60 IU/mL 5.2 months 6.2 months p=0.34

PEG-IFN is Effective and Safe in Patients with HBV and Advanced Fibrosis/Compensated Cirrhosis

• To evaluate efficacy and safety of PEG-IFN 2a in HBV patients with advanced fibrosis (Ishak 4-6) compared to Ishak 0-3

• PEG-2a X 48 weeks with 24 week follow-up

• 13% of HBeAg+ and 21% of HBeAg- had Ishak 4-6

• For HBeAg+, the presence of advanced fibrosis had significantly better HBeAg seroconversion and DNA < 2,000, sAg loss, and ≥ 1 point decrease in Ishak fibrosis score

• For HBeAg-, Overall response rates were similar

• Safety− Overall no difference in med discontinuation rates− Advanced fibrosis HBeAg+ pts had more hematologic

AE’s requiring dose reductions

• Conclusions:− PEG-2a can be effectively and safely used in patients

with compensated cirrhosis.

Piratvisuth T, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 397.

Efficacy rates 24 weeks post-treatment according to baseline disease status in HbeAg-positive patients

Response variable 24 weeks post-treatment, n(%)

HBeAg-positive

Fibrosis score0-3

N=184

Fibrosis score4-6

N=27p-value

HBeAg seroconversion 63 (34.2) 13 (48.1) 0.1980

HBeAg seroconversion+ HBV DNA <2000 IU/mL

39 (21.2) 11 (40.7) 0.0494

HBeAg loss +HBV DNA <2000 IU/mL

42 (22.8) 11 (40.7) 0.0572

HBV DNA <2000 IU/mL 44 (23.9) 11 (40.7) 0.0975

HBsAg clearance 2 (1.1) 5 (18.5) 0.0004

≥1-point decrease in Ishak score 57 (31.0) 14 (51.9) 0.0484

HBsAg <1000 IU/mL 40 (21.7) 9 (33.3) 0.2214

Efficacy rates 24 weeks post-treatment according to baseline disease status in HBeAg-negative patients

Response variable 24 weeks post-treatment, n(%)

HBeAg-negative

Fibrosis score0-3

N=113

Fibrosis score4-6

N=30p-value

HBV DNA <2000 IU/mL+ ALT normalization

41 (36.3) 9 (30.0) 0.6673

HBV DNA <2000 IU/mL 48 (42.5) 11 (36.7) 0.6778

HBsAg clearance 5 (4.4) 2 (6.7) 0.6373

≥1-point decrease in Ishak score 41 (36.3) 15 (50.0) 0.2081

HBsAg <1000 IU/mL 46 (40.7) 7 (23.3) 0.0920

No Difference in Renal Toxicity with 2 years of Entecavir or Tenofovir

• Single center, retrospective study of patients treated for at least 2 years with TDF, ETV, or nothing

• Conclusions:−There was a slight decrease in GFR on TDF or ETV after 2 yrs

(compared to controls)−There was no difference between ETV and TDF

Le ST, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 443.

Untreated (N=73)

ETV(N=74)

TDF ± LAM (N=50)

p-value

Age 40.8 ± 11.12 46.69 ± 11.2941.75 ± 11.44

0.0043

Sex, male 40 (54.79%) 50 (67.57%) 32 (64%) 0.264

Cirrhosis 0 32 (43.24%) 19 (38%) <0.0001

HCC 0 4 (5.41%) 2 (4%) 0.146

HTN 10 (13.70%) 12 (16.22%) 4 (8%) 0.410

DM 4 (5.48%) 7 (9.46%) 2 (4%) 0.432

eGFR(ml/min) MDRD

100.93 ± 22.45 96.73 ± 28.6498.92 ± 28.85

0.30

Baseline Characteristics Mean eGFR Over 24 Month Period

• Liver stiffness measurements by transient elastography represent a non-invasive measure of liver fibrosis

• 46 patients on ETV had a baseline and annual TE on Rx

Conclusion: Long-term ETV improved liver stiffness beginning in year 1 and continuing through at least year 3

Long-term Entecavir Decreases Liver Stiffness Measurements

Papatheodoridia G, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 384.

(n=46) (n=42) (n=35) (n=28) (n=12)

P=0.037 P=0.002 P=0.007 P=0.461

Tenofovir is Safe and Effective in Real-life Practice

• 400 TDF-naïve patients treated with TDF, 2 year data− 46% were treated with TDF as 1st-line treatment− 54% were switched from another agent

• 70% males, 76% white, 70% eAg-, 37% fibrosis score ≥2

• Naïve patients: 81% of HBeAg+ were HBV DNA negative, 88% for HBeAg-• Experienced: 84% of HBeAg+ were HBV DNA negative, 90% for HBeAg-• HBeAg loss and seroconversion was seen in 23% and 19% of HBeAg+ pts• HBsAg loss occurred in 5.1% of HBeAg+ and 1% of HBeAg-

Petersen J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 413.

HBV-DNA (IU/mL)

Viremia in Treatment Naïve Patients

≥200 Mio

<200 Mio-20 Mio

<20 Mio- 2 Mio

<2 Mio-200,000

<200,000-20,000

<20,000-2000

<2000-200

<200-20

<20

Baseline Month 6 Month 12 Month 18 Month 24

HBV-DNA (IU/mL)

Viremia in Treatment Experienced

≥ 200 Mio

<200 Mio- 20 Mio

<20 Mio- 2 Mio

<2 Mio-200,000

<200,000-20,000

<20,000-2000

<2000-200

<200-20

<20

Baseline Month 6 Month 12 Month 18 Month 24

• No significant issues were seen at 96 weeks regarding phosphorus levels or CrCl

• Conclusions:−TDF suppressed HBV DNA through 2 years in the majority of patients

regardless of pre-treatment status−HBeAg loss/seroconversion was seen in 23%/19% of HBeAg+ patients− 5.1% of HBeAg+ patients lost HBsAg−Safety (including renal) was favorable in this real-life study

Petersen J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 413.

Serum Phosphorus

BL (n=34)

Month 6 (n=63)

Month 12 (n=59)

Month 24 (n=42)

Mean [mmol/L] (SD)

1.11 (0.21)

1.07 (0.23)

1.10 (0.35)

1.07(0.19)

Creatinine Clearance

Estimated CrCl (Cockcroft-Gault)

BL (n=361)

Month 6 (n=299)

Month 12 (n=289)

Month 24 (n=255)

Mean[ml/min] (SD)

106.9 (31.6)

105.9 (33.8)

104.7 (31.7)

102.2 (31.3)

Mean change[ml/min] (SD)

-1.4 (16.1)

-3.2 (16.2)

-3.4 (15.4)

Tenofovir is Safe and Effective in Real-life Practice

HBIG-free Post-liver Transplant Regimen Using Oral Antiviral Therapy Alone Effectively Suppresses HBV-DNA

• Retrospective review of 363 HBV OLT patients in Hong Kong

• Non-randomized study− LAM (176), ETV (142), or LAM + ADV (44)

• Mean follow-up 53 months

Fung J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 12.

Pre-OLT Characteristics

• 98% HBV DNA negative at 8 years• 88% HBsAg negative at 8 years

ParametersLamivudine

(n=176)Entecavir(n=142)

Combination(n=44)

P value

AgeGender, MaleMELD score

51 (24-67)84%

26 (6-40)

52 (23-67)85%

25 (6-40)

55 (30-66)84%

17 (6-36)

0.1410.9720.002

Transplant typeDeceased donorLiving donor

34%66%

44%56%

45%55%

0.117

Pre-transplantAntiviral therapyHBeAg positivityHBV DNA (IU/ml)

30%29%

3.6 (0.9-9.1)

58%25%

2.7 (0.9-8.1)

98%57%

3.0 (0.9-8.0)

<0.001<0.0010.011

Donor anti-HBsPositivity

63% 67% 74% 0.413

Long Term HBsAg Seronegativity & HBV DNA Undetectability

LAM Alone Without HBIG Should Probably be Avoided as Post-OLT HBV Treatment

• Overall 8 year survival was 83%,with no difference between the 3 treatment groups (p=0.98)

Conclusions:− Oral NA’s after OLT are associated with excellent HBV suppression

and long-term survival− Agents with less resistance potential should be used to prevent development

of virological rebound

Virologic rebound was significantly higher in the LAM group (36 total of which 25 had YMDD)

The RR for viral rebound was 15.21 for the LAM group

Fung J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 12.

Lamivudine

Combination

Entecavir

Virological Rebound (≥1 log IU/mL Increase)

42 Patients with VR

P<0.0019%

17%

5%7%

0% 0%

Cu

mu

lati

ve R

ate

of

Vir

olo

gic

al R

ebo

un

d

Adding PEG-IFN Alfa-2a to ETV Increases HBsAg Decline and HBeAg

Clearance• PEG-IFN alfa-2a add-on strategy at weeks 24-48 to ETV in HBeAg+ pts

− 48 weeks ETV (n=83) vs. 24 wks ETV + 24 wks ETV + PEG-IFN (n=77)

• PEG-IFN 2a add-on group had significantly better HBV-DNA, HBeAg, and HBsAg responses

• HBeAg loss at 48 weeks was 18% vs. 8%• 2 PEG add-on patients had grade 4 neutropenia• Conclusions:

− Adding PEG-IFN 2a to ETV improves HBV-DNA, HBeAg, and HBsAg responses− PEG was reasonably well-tolerated− This might allow a more finite course of NA therapy for chronic HBV.

Sonneveld M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 19.

24

HBsAgHBeAgHBV DNA

ETV

ETV+Peg-IFN

P<0.001

ETV

ETV+Peg-IFN

P<0.001

ETV

ETV+Peg-IFN

P<0.001

• HBeAg+ patients (n=146) received PEG-IFN for 48 weeks (conventional arm, n=74) or ETV for 12 weeks with a 48-week course of PEG-IFN starting at week 5 (sequential arm, n=74)

• No differences of HBeAg seroclearance, normalization of aminotransferase, or HBV-DNA levels at EOT (6 month post-treatment data not yet available)

Conclusion: PEG-IFN add-on to ETV therapy did not provide EOT benefit regarding HBV-DNA, eAg, or sAg levels

Sequential Therapy of ETV Followed by PEG-IFN 2a Showed No Difference vs.

ETV Alone

Jun DW, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 377.

P=0.215 P=0.174 P=0.99

Biochemical and Virological Response at 48 Weeks

• 418 consecutive naïve patients treated with ETV 0.5 mg for 52 months• Mean age 58 years; 76% males, 83% HBeAg-negative, HBV DNA 6.0 log

IU/ml, 85% with elevated ALT, 49% cirrhotics

Rate of Viral Suppression through 5 years was 100%in HBeAg-positive and negative

5 Year ETV Effectively Suppresses HBV-DNA in Naïve HBV Patients

Lampertico P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 366.

Virological response by HBeAg Status (Undetectable HBV DNA)

Months

67 66 48 42 32 11 Patients on f-up 338 327 296 265 227 86

Months

33%

HBsAg Loss Occurred in 33% of HBeAg+ Pts Treated With 5 Years of ETV

• HCC developed at an yearly rate of 2.5% despite good viral suppression

Conclusions:• Long-term ETV monotherapy efficiently suppressed HBV replication in

naïve HBV patients• High rates of HBsAg loss can also be seen with this therapy

Lampertico P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 366.

Patients at risk

72 70 65 54 48 41 35 28 19 8 3

HBsAg Loss in HBeAg-positive Patients

• Retrospective study of naïve patients with CHB− HBeAg-positive (N=54), CHB-related cirrhosis (N=67)− 5 year data

• No resistance was seen• No safety issues were reportedConclusion: De novo combination long-term therapy of LAM and ADV has a high virological and

biochemical response rate without drug resistance emergence.

Long-term De Novo LAM and ADV Combination

Long-term Treatment is Effective

Zhu B, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 437.

• The usefulness of quantitative HBsAg (qHBsAg) level as an indicator for cessation of antiviral therapy.

• 97 patients (with qHBsAg levels available) who had stopped HBV therapy − 47 relapsed, 50 non-relapsers

• Only significant variable predicting relapse was qHBsAg levels− qHBsAg < 567 IU/ml at treatment cessation had an 81% sensitivity and 70% specificity of

predicting no relapse

Conclusion: qHBsAg level might be a useful indicator of predicting relapse, and thus could provide a guide to determining if/when HBV therapy can be stopped.

Quantitative HBsAg Levels May be an Effective Indicator for Cessation of HBV

Therapy

Park UG, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 353.

Patients with CHB who have stopped antivirals with measurement of qHBsAg level at the time of cessation from

January 2008 to December 2011 (n = 306)

Analyzed (n = 97)

Non-Relapser (n = 50) Relapser (n = 47)

Exclusion (n = 209)1) F/U loss or F/U < 6month2) Stopped NAs arbitrarily (HBV DNA (+) or abnormal ALT at the time of cessation)3) Acute hepatitis4) Patients with liver cirrhosis5) Patients with other comorbid medical conditionsRelapse:

HBV DNA > 100IU.mL

Viral Resistance IssuesKris Kowdley, MD

Virginia Mason Medical CenterSeattle, WA

TDF/FTC vs. TDF Monotherapy for CHB Patients with LAM-R

• Randomized, double-blind, phase IIIb trial

• Chronic HBV with documented LAM-R (INNO-LiPA HBV)

• N= 280 patients

TDF 300 mg once daily(N=141)

TDF 300 mg + FTC 200 mg once daily(N=139)R

and

om

izat

ion

1:

1

Further anti-HBV therapy at discretion

of investigator – up to 24 weeks follow-up

Dosing x 96 weeks

Baseline Week 96Primary Endpoint

Fung S, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 20.

Baseline Characteristics

TDF (N=141) FTC + TDF (N=139)

Age, mean years (range) 47 (18-73) 46 (18-72)Male, n (%) 104 (74) 107 (77)

Race, n (%)AsianWhite

83 (59)52 (37)

89 (64)42 (30)

HBeAg (+), n (%) 65 (46) 68(49)

HBV DNA, mean log10 IU/mL (SE) 6.4 (1.83) 6.5 (1.97)

Region, n (%)EuropeNorth AmericaAsia

84 (60)50 (35)

7 (5)

85 (6145 (32)

10 (7)

ALT, mean U/L (SE) 71 (91) 87 (147)Normal ALT, n (%) 62 (44) 56 (40)Mean duration of LAM, weeks (range) 210 (34-648) 189 (7-832)

Fung S, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 20

Results at Week 96:Primary Endpoint: HBV DNA <69 IU/mL

TDF (N=141) FTC + TDF (N=139) P-value

HBV DNA <400 cp/mL, n (%) 126 (89) 120 (86) nsNormal ALT, n (%) 99 (70) 97 (07) nsSerology, n (%)HBsAg lossHBeAg lossHBeAg seroconversion

0 (0)10/65 (15)

7/65 (11)

1 (<1)9/68 (13)7/68 (10)

ns

TDF Resistance 0 (0) 0 (0) nsAdverse Events (AE) resulting in study drug discontinuation

1 (0.7) 2 (1.4) ns

Deaths, n (%) 1 (0.7) 2 (1.4) nsSAE, n (%) 0 (0) 1 (0.7) nsSCr ≥ 0.5 mg/dL above baseline 0 0 nsPO4 < 2 mg/dL, n (%) 2 (1.4%) 0 nsCrCL <50 mL/min, n (%) 5 (3.5%) 4 (2.9%) ns


TDF vs. FTC/TDF Conclusions

• Nearly 90% of subjects with documented LAM-R achieved suppression to HBV DNA <400 cp/mL at week 96 with both TDF and FTC/TDF

• No significant differences in efficacy were observed between monotherapy and combination therapy regimens

• No detectable TDF resistance was observed with TDF or FTC/TDF through 96 weeks

• TDF demonstrated favorable safety and tolerability with a low rate of renal events and no evidence of clinically relevant bone loss


TDF vs. FTC/TDF Resistance

• Analysis of amino acid changes within HBV polymerase /reverse transcriptase (pol/RT) after 96 weeks of TDF or FTC/TDF in 280 subjects with LAM-R mutations

• Viremia at Week 96:− TDF arm = 7/133 subjects (5.3%) – 6 without virologic breakthrough

− 2 had reversions toward consensus (rtM180L/M, rtV204M/V, rtI204M) or changes (rtV173L/V) at conserved sites

− 2 had unique polymorphic site changes− 1 had no change− 2 had no genotype

− FTC/TDF = 8/132 subjects (6.1%) – 4 without virologic breakthrough− 1 had unique polymorphic site change− 1 had no change− 1 was unable to genotype

• 12/15 viremic subjects had genotype data at week 96− 10/12 maintained baseline LAM-R mutations

• Conclusions: no virologic resistance to TDF identified through 96 weeks in patients with LAM-R at baseline

Croso AC, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 389

DEFINE Trial: ETV/ADV vs. LAM/ADV vs. ETV for LAM-R HBeAg+ CHB

• Randomized, open-label, comparative phase IIIb trial

• Chronic HBV with documented LAM-R (rtM204V/I/S by INNO-Lipa)

• N= 415 patients

Heo J, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 407.

ETV (1.0 mg) + ADV (10 mg) QD(N=138)

LAM (100 mg) + ADV (10 mg) QD(N=137)

Ran

do

miz

atio

n

1:1:

1

Dosing x 96 weeks

Baseline Week 96Primary Endpoint

ETV (1.0 mg) QD(N=139)


ETV+ADV (N=138)

LAM+ADV (n=137)

ETV (n=140)

Age, mean years (range) 45 (18-69) 44 (16-74) 44 (19-71)Male, n (%) 91 (66) 97 (71) 88 (63)

Race, n (%)AsianWhite

132 (96)6 (4)

126 (92)11 (8)

389 (94)26 (6)

Time on prior LAM, yrs 3.2 3.0 3.5HBV DNA, mean log10 IU/mL (SE)

6.7 (0.08) 7.5 (0.09) 7.4 (0.09)

HB V genotype, n (%)ABCDOther/missing

6 (4)3 (2)

124 (90)3 (2)2 (2)

11 (8)6 (4)

113 (93)5 (4)2 (2)

27 (7)16 (4)

356 (86)11 (3)

5 (1)ALT, mean U/L (range) 71 (10-480) 89 (14-1300) 69 (12-367)BMI, mean (range) 24 (16-36) 24 (18-33) 24 (16-33)


Results at Week 96:Primary Endpoint: HBV DNA <50 IU/mL

ETV/ADV (N=138)

LAM/ADV (N=137) ETV (n=140) P-value

HBV DNA <50 IU/mL at week 48, n (%)

25 20 16 ns

HBV DNA <50 IU/mL at week 96, n (%)

44 29 n/a 0.01

Normal ALT, n (%) 77 80 74 nsSerology, n (%)HBsAg lossHBeAg lossHBeAg seroconversion

0 (0)17/138 (12)

10/138 (7)

0 (0)17/135 (13)

7/135 (5)

0 (0)15/139 (11)

5/139 (4)

ns

Adverse Events (AE) resulting in study drug discontinuation

1 (0.7) 2 (1.5) 3 (2.1) ns

Deaths, n (%) 1 (0.7) 0 (0) 1 (0.7) nsSAE, n (%) 14 (10.1) 13 (9.5) 21 (15.0) nsSCr ≥ 0.5 mg/dL above baseline

1 (0.7) 2 (1.5) 1 (0.7) ns

ETV-R (%) 0.8 1.5 9.8 nsADV-R (%) 0.7 2.2 1.5 ns


DEFINE Trial: Conclusions

• Although the efficacy of ETV+ADV was comparable to that of LAM+ADV and ETV monotherapy at week 48, ETV+ADV was superior to LAM+ADV at week 96

• ALT normalization rates were comparable across all 3 treatment groups

• Serologic responses were low with all 3 treatments, similar to previous reports with LAM+ADV or ETV in LAM-R CHB patients

• Treatment with either ETV+ADV or LAM+ADV was associated with low rates of resistance development

• Overall, ETV+ADV was well-tolerated and more effective than LAM+ADV for the treatment of LAM-R CHB over 96 weeks of treatment


Korean Study: ETV/ADV vs. ETV for ADV-refractory LAM-R CHB

• Retrospective analysis of long-term efficacy of ETV/ADV or ETV at weeks 48 and 96 at one university liver center in Korea

• Chronic HBV with documented LAM-R (rtM204V/I/S by INNO-Lipa)

• N= 91 patients

ETV (1.0 mg) QD(N=46)

ETV (1.0 mg) + ADV (10 mg) QD(N=45)R

etro

spec

tive

O

bse

rvat

ion

al

Dosing x 48-96 weeks

BaselineWeek 96



ETV+ADV (N=45) ETV (n=46) P-value

Age, mean years (range) 46 48 nsMale, n (%) 35 (78) 38 (83) ns

LAM-R MutationsOverallrtM204I/VrtL+rtM204I/V

43 (96)16 (36)25 (56)

44 (96)7 (15)

31 (67)

ns

ADV-R MutationsrtN236TrtA181T/VrtN236T+rtA181T/V

2 (4) 1 (2) ns

HBV DNA, mean log10 IU/mL 5.1 5.7 0.067

HBeAg positive, n (%) 40 (89) 40 (87) ns

ALT, mean U/L 56 82 0.016Duration of ETV, months 33 30 nsCirrhosis, n (%) 14 (31) 14 (30) ns


Results at Weeks 48 and 96:

ETV/ADV (N=45) ETV alone (N=46) P-value

HBV DNA <20 IU/mL, n (%)Week 48Week 96

14 (31)17 (45)

11 (24)10 (35)

nsns

Serum HBV DNA, mean reduction from baseline, log10 IU/mLWeek 48Week 96

-3.03.3

-2.0-3.0

0.022ns

Normal ALT, n (%)Week 48Week 96

27 (60)23 (61)

28 (61)18 (62)

nsns

HBeAg loss/seroconversion,n (%)Week 48Week 96

3/40 (8)5/34 (15)

5/40 (13)5/26 (19)

nsns

Virologic breakthrough, n (%)Week 48Week 96

0/45 (0)1/38 (3)

8/46 (17)13/29 (45)

0.006<0.001


Factors Associated with Virologic Breakthrough (multivariate analysis): only ETV monotherapy vs. ETV+ADV was associated (OR 5.89, p=0.015)

Korean Study: Conclusions

• In a cohort of 91 Korean patients with adefovir-refractory LAM-R CHB, ETV+ADV trended towards stronger efficacy than ETV monotherapy in suppressing HBV DNA to undetectable levels at week 96, but this was not statistically significant

• Only ETV monotherapy was associated with a higher rate of virologic breakthrough in multivariate analysis (OR 5.89, p=0.015)

• Other biochemical and serologic outcomes (normalization of ALT, HBeAg loss/seroconversion) not significantly improved with ETV+ADV than ETV monotherapy

Kim, IH et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 405.

ALTER Study: ADV/LAM Therapy for ETV-R CHB

• Prospective, open-label single arm roll-over study at 9 Korean hospitals with 20 patients with prior LAM-R who were randomized to ETV in one of 2 arms of the ACE Trial (RCT) and developed ETV-R, and then retreated with open-label ADV/LAM for 12 months

• Documented ETV-R by MALDI-TOF

Yim HJ, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 409.

ADV (10 mg)/LAM (100 mg) QD(N=110)

ETV (1.0 mg) QD(N=109)R

and

om

ized

1:

1

ACE TRIAL: 104 weeks

Baseline Week 104

ADV (10 mg)/LAM (100 mg) QD

(N=20)

ETV-RALTER STUDY: 12 mo


ADV/LAM (N=20)

Age, mean years (range) 47 (29-74)Male, n (%) 15 (75)

Baseline LAM-R MutationsM204V + L180MM204V/I + L180MM204I

17 (95)1 (5)

2 (10)

Baseline ETV-R MutationsT184L/I/A/FS202GT184I + S202GT184L + I169TT184L + I169T + M250V

11 (50)5 (25)3 (15)1 (5)1 (5)

HBV DNA, mean log10 IU/mL (range) 5.66 (3.36-7.45)

HBeAg positive, n (%) 17 (85)

ALT, mean U/L 39 (11-185)Duration of ETV, months (range) 31 (12-39)Cirrhosis, n (%) 7 (35)


Results at Months 3, 6, 9, and 12:

ADV/LAM (N=20)HBV DNA <20 IU/mL, n (%)Month 3Month 6Month 9Month 12

4/19 (21)5/19 (26)5/18 (28)4/17 (24)

Serum HBV DNA, mean decrease from baseline, log 10 IU/mLMonth 3Month 6Month 9 Month 12

-2.08-2.24-2.27-2.35

Normal ALT, n (%)Month 3Month 6Month 9Month 12

14/19 (74)16/19 (84)17/18 (94)14/17 (82)

HBeAg loss,n (%)Month 3Month 6Month 9Month 12

4/12 (33)5/16 (32)5/14 (36)3/14 (21)


ALTER Study: Conclusions

• In a cohort of 20 Korean patients with LAM-R treated with ETV who developed ETV-R, ADV/LAM significantly reduced serum HBV DNA levels at 12 months, but only approximately ¼ achieved undetectable HBV DNA at 1 year of salvage therapy

• Of 16 patients with available ETV mutant data at 12 months, 1 (6%) showed disappearance of ETV-R mutants, 9 (56%) had reduction in proportion of ETV-R mutants – 1 patient developed ADV-R without VR

• Further long-term studies evaluating the role of ADV/LAM in ETV-R CHB in a larger cohort are needed to clarify the safety and efficacy of this treatment strategy


GS-102 and GS-103:No Detectable Resistance at 6 Years

Week 72 HBV DNA ≥400 copies/mL: Option to add FTC to TDF in a fixed dose tablet

Week 240Liver Biopsy

Week 48Liver Biopsy

Pre-treatment Liver Biopsy

RA

ND

OM

IZA

TIO

N 2

:1

Tenofovir 300 mg

Adefovir 10 mg

Open-label

8 Years

Double Blind

TDF 300 mg

Week 96 End of Study

5 Years2 Years1 Year

TDF 300 mg

Randomized, Double-Blind, Comparison of TDF vs. ADV for CHB

Marcellin P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 374

GS-102 and GS-103:Resistance Patterns in HBeAg(-) and

HBeAg(+) During Year 6

Conclusion: No resistance to TDF was detected through 6 years

N=4

N=1

N=3

Patients on TDF Who Qualified for Genotypic Analysis (n=8)

Conserved site change

No change

Polymorphic site change

Unable to genotype

• 73% (466/641) of enrolled patients remain on study at Year 6• 80% (466/585) of patients entering the open-label phase remain on study at Year 6• HBV DNA <400 cp/mL on-treatment at Year 6: 99.6% Study 102 and 99.0% Study 103• 1.2 % (8/641) Qualified for Resistance Surveillance During Year 6

Marcellin P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 374.

Predictors of LAM-R in Long-Term LAM Treatment

• Retrospective analysis of 227 German patients treated at 3 German liver centers with LAM 100 mg/day (130 patients) or 150 mg/day (97 patients) for a mean duration of 35 months (6-146 months)

• 77/227 patients (34%) developed LAM-R− 7% (Year 1), 24% (Year 2), 35% (Year 3), 41% (Year 4), 46% (Year 5),

52% (Year 6), 55% (Year 7), only 2 additional cases at months 139 (11 yrs) and 146 (12 yrs)

• LAM-R in HBeAg positive patients was correlated with HBeAg loss:− LAM-R in 7/27 patients with HBeAg loss (26%) versus 18/41 patients

without HBeAg loss (44%), p= 0.01

• Predictors of LAM-R: baseline HBV DNA >105 copies/mL (p=0.03)

• Conclusion: Lamivudine resistance is common with long-term LAM treatment but occurs uncommonly after 6 years of virologic response, and is less frequent in patients with baseline HBV DNA < 105 copies/mL

Brodzinski A, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 418

Frequency of HBV Resistance Mutations in Treatment-Naïve CHB

• Presence of viral variants with drug-resistance mutations in untreated CHB arising from transmission of resistant HBV strains may compromise response to nucleos(t)ide analogues

• Retrospective analysis of 557 treatment-naïve Brazilian CHB patients who underwent population-based sequencing

• Results: 10/557 patients (1.8%) harbored HBV variants with primary resistance mutations, four of which harbored secondary mutations

• An additional 18 patients (3.2%) demonstrated variants with novel amino acid substitutions at positions reported to be associated with adefovir resistance

• Conclusion: The prevalence of clinically significant resistant variants in a population of treatment-naïve Brazilian patients is relatively low, but may explain some early treatment failures.

Gomes-Gouvea MS et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 916

63rd Annual Meeting of the American Association for the Study

of the Liver Disease (63rd AASLD)

Boston, MassachusettsNovember 9-13, 2012

63rd annual meeting of the american association for the study of the liver disease (63rd aasld)

Documents

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