AASLD 2011- Feedback on HBV

AASLD 2011- Feedback on HBV

Dr Allister J GrantConsultant Hepatologist

University Hospitals Leicester NHS Trust

62th Annual MeetingNovember 4 – 8, 2011

San Francisco, CA

No Resistance to Tenofovir (TDF) Following up to 240 Weeks of Treatment in HBeAg+ and HBeAg- CHB Infection

Marcellin, P, et al. AASLD 2011; Oral #238

Pre-treatment Liver Biopsy

RAN

DO

MIZ

ATIO

N

2:1

Tenofovir DF300 mg N=250 & N=176

Adefovir Dipivoxil 10 mg N=125 & N=90

Year 1Liver Biopsy1

Year 1

Week 72 Year 8

Year 8

Tenofovir DF300 mg

Tenofovir DF300 mg

Year 3

N=235N=154

N=112N=84

Year 5/ Week 240Liver Biopsy

• At Week 72, patients with HBV DNA ≥ 400 copies/mL had the option at the discretion of the investigator to add emtricitabine (FTC)

• Retention rate at Week 240: 81% for HBeAg-, 70% for HBeAg+

Study 102 (HBeAg- Patients) and 103 (HBeAg+ Patients)

Study 102 (HBeAg-): Proportion of Patients with HBV DNA <400 copies/mL

Long-term evaluation [LTE-TDF] (missing/ addition of FTC = failure)

Marcellin, P, et al. 2011 AASLD, Poster #1375. Marcellin, P, et al. AASLD 2011; Oral #238.

Week 240:

TDF-TDF 83% ADV-TDF 84% Overall: 83%

The Addition of FTC to TDF Between Weeks 72-240 Did Not Impact Subsequent HBV DNA Decline

All subjects analyzed with >400 copies/mL had no evidence of TDF resistance

Marcellin, P, et al. AASLD 2011; Oral #238.

Virologic Breakthrough was Infrequent and Associated with Non-adherence

• 4/495 (0.8%) of patients were classified as having virologic breakthrough during Year 5

• 3 patients had documented non-adherence during the time of breakthrough (TFV plasma levels undetectable)

• All 4 patients had HBV DNA return to <400 copies/mL during Year 6

• Phenotypic analysis revealed isolates from all virologic breakthrough patients were sensitive to tenofovir (fold change values <2 compared to baseline)


Efficacy Summary

Year 3 Year 5

102(eAg-)

103(eAg+)

102(eAg-)

103(eAg+)

HBV DNA <400 c/mL 87% 71% 83% 65%

HBV DNA <400 c/mL 99% 93% 99% 97%

ALT normalization 84% 74% 85% 73%

HBeAg loss (seroconversion)

na3 34%(26%)

na50%

(40%)

HBsAg loss(seroconversion)

09%

(7%)n=1

(Week 240)

11%(9%)


Five years of Treatment with Tenofovir DF for Chronic Hepatitis B Infection is Associated with

Sustained Viral Suppression and Significant Regression of Histological Fibrosis and Cirrhosis

P. Marcellin1, M. Buti2, E.J. Gane3, Z. Krastev4, R. Flisiak5, G. Germanidis6, M.K. Washington7, C.N. Barnes8, J.F. Flaherty8, J.D. Bornstein8, J.G. McHutchison8, E.J.

Heathcote9

1Hôpital Beaujon, APHP, Clichy, France, 2Hospital General Universitari Vall d’Hebron and Ciberehd, Barcelona, Spain, 3Auckland City Hospital, Auckland, New Zealand ,4University Hospital “St. Ivan Rilsky”, Sofia, Bulgaria, 5Medical University

ofBialystok, Bialystok, Poland, 6University Hospital of Thessaloniki, Thessaloniki, Greece, 7Vanderbilt University, Nashville, TN, United States, 8Gilead Sciences Inc., Foster City, CA, United States, 9University of Toronto, Toronto, ON, Canada

Marcellin, P, et al. AASLD 2011; Poster #1375.

Change in Ishak Fibrosis Scores at Year 5 by Baseline Fibrosis Score

Baseline Ishak Fibrosis Score

ImprovementNo ChangeWorsening

1 2 3 4 5 60

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Perc

enta

ge o

f Sub

ject

s

n=10 n=126 n=79 n=37 n=19 n=77


348 paired biopsies at Year 5 (71%)

96% (335/348) of patients with paired biopsies either improved (≥ 1 unit decrease in fibrosis score) or did not change at Year 5

Percentage of the population withcirrhosis (Ishak Score ≥5) progressively decreased from 28% at baseline to 8% at Year 5

Distribution of Ishak Fibrosis Scores at Baseline, Year 1, and Year 5

• 344/348 patients had liver biopsy data available at all three time points• Percentage of the population with cirrhosis (Ishak Score ≥5) progressively decreased from 28% at baseline to 8% at Year 5

Baselin e Year 1 Year 5

0

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%P

erce

nta

ge

of

Pat

ien

ts

Ishak Fibrosis Score

6543210


Authors’ Conclusions• Over 5 years, sustained virologic suppression is associated with histologic

improvement and regression of liver fibrosis – Largest prospective dataset of chronic HBV patients with sequential biopsies– 96% of patients with paired biopsies had either improvement or no worsening

of fibrosis– 74% of patients with cirrhosis at baseline were no longer cirrhotic at year 5– 98% of patients on TDF had undetectable HBV DNA levels of < 400 copies/mL

• Virologic and biochemical responses are maintained– Sustained virologic suppression maintained through 5 years– ALT normalization maintained in the majority of patients– 11% of patients had confirmed HBs-Ag loss (8% with seroconversion) with 5

years of TDF– No resistance detected to TDF through 5 years


Effects of Tenofovir on Vitamin D Levelsin Chronic Hepatitis B Mono-infected Patients: A Single Centre “Real Life”

Cohort Experience

Huyen-Ly Nguyen, Mohammad A B Al-Freah, Roy Sherwood, Ivana Carey, Dorothy Joe, Abid Suddle, Phillip M. Harrison, Kosh Agarwal

Institute of Liver Studies, King’s College Hospital, London, UK

Nguyen, HL, et al. AASLD 2011; Poster #509.

1 Mueller NJ et al. AIDS 2010; 24(8):1127-34.

Introduction

• Vitamin D deficiency has been shown to be prevalent in patients with viral diseases such as HIV. Data derived from HIV population demonstrate negative effects of Tenofovir (TDF) on vitamin D levels and bone mineral density1

• To determine the impact of Tenofovir on vitamin D levels as well as metabolic bone parameters in patients mono-infected with HBV


Methods• Retrospective study of all patients treated with TDF or Entecavir (ETV) in our

centre (n=313) from May 2006 to September 2010

• Collected data included demographic, clinical variables, Vitamin D (VD), phosphate, calcium and alkaline phosphatase levels at baseline and at 12 months after initiation of TDF or ETV

• Data collection at baseline (initiation of TDF or ETV) and following 12 months of treatment (+/- 3 months)

• Patients on combination of TDF and ETV (n=22) and those that received VD supplementation within 3 months prior to initiation of antiviral therapy or at any point during the 12 months follow up (n=114) we excluded


Baseline Vitamin D Analysis

• Significant seasonal variability, with higher vitamin D levels detected during the Summer and lowest levels during the Winter

• The prevalence of vitamin D deficiency in this cohort of patients was 71.7%, defined as vitamin D levels < 22 µg/L

• There is a significant variability in vitamin D levels among the different racial groups of patients being treated at our centre in South East London

• Vitamin D deficiency was more prevalent in men than women 85% vs 72%

Median VDaccording to season

p = 0.015, Kruskal-Wallis, n = 272

15.716.5

14.3

11

Vit

am

in D

μg/L

Season

Winter Spring Summer Autumn

20

18

16

14

12

10

8

6

4

0

2

Median VDaccording to ethnicity

p = 0.005 Kruskal-Wallis, n = 272

11.4

16.916.45

13.8

Vit

am

in D

μg/L

Ethnic Group

Afro-

Caribbean

20

18

16

14

12

10

8

6

4

0

2

11.2

SE Asian

EuropeanIndian

Other



Comparison of Baseline Characteristics According to Anti-Viral Therapy (cont.)

Variables Tenofovir (142) Entecavir (77) P-value

VD (µg/L) 16.1 (4-49) 16.1 (6-50) 0.465

VD deficiency (%) 84 (66.3) 41 (73.2) 0.343

Calcium (mmol/L) 2.23 (1.88-3.16) 2.25 (2.08-2.46) 0.147

Phosphate (mmol/L) 0.98 (0.38-1.71) 0.93 (0.58-1.27) 0.04

ALP (IU/L) 73 (37-296) 69 (42-229) 0.177

Hb (g/dL) 14.2 (9.2-17.8) 14.6 (11-17.7) 0.02

PLT x 109/mL3 202 (63-503) 208 (63-418) 0.53

Bilirubin (µg/L) 11 (3-148) 12 (4-37) 0.581

Albumin (g/dL) 44 (24-50) 44 (29-50) 0.687

INR 1.05 (0.88-1.86) 1.05 (0.94-2.47) 0.973

AST (IU/L) 29 (12-215) 40 (20-328) <0.001

• The TDF cohort had a higher baseline phosphate level than those on ETV

• There was no significant difference in the remaining metabolic bone parameters at baseline

ALP = Alkaline phosphatase


12 Months Interval Data

Antiviral agent Bone markers Baseline 12 Months P-value

TDF (N=142)

VD 16.10 (4-49) 14.7 (4.6-60.7) 0.43

Calcium 2.24 (2.01-2.41) 2.23 (2.11-2.35) 0.032

Phosphate 0.99 (0.38-1.71) 1.07 (0.43-1.39) 0.121

ALP 72 (45-215) 79 (42-769) <0.001

ETV (N=77)

VD 16.00 (4-50) 13.65 0.456

Calcium 2.25 (2.08-2.40) 2.23 (2.10-2.37) 0.056

Phosphate 0.91 (0.58-1.27) 0.96 (0.55-1.43) 0.228

ALP 70 (42-229) 68 (36-168) 0.202

• No difference in vitamin D levels at baseline and at 12 months in either of the treatment groups

• The TDF cohort showed a significant rise in alkaline phosphatase and a fall in calcium which may indicate development of metabolic bone disease

Authors’ Conclusions• Vitamin D deficiency is highly prevalent in this cohort of chronic hepatitis B

mono-infected patients

• No significant decrease in vitamin D levels after 12 months of treatment with either TDF or ETV

• Significant rise in ALP and decline in calcium in the TDF cohort and a downward calcium trend in the ETV cohort suggesting adverse effects on bone metabolism

• Further long term follow-up with additional radiological assessment of bone mineral density is warranted to establish if AVT such as TDF and ETV are associated with a negative effect on bone metabolism


Bone Mineral Density Results (Year 4 to Year 5)

• No significant changes were observed in mean (SD) BMD results from year 4 to year 5 for hip and lumbar spine

• No consistent trends were observed in T score (see Table) or Z score (data not shown) category shifts between year 4 and year 5

a. T Score ranges: normal > -1, osteopenia -1 to -2.5, osteoporosis < -2.5; pooled data (N=266 hip; N=276 spine)

Year 4 to 5 shifts in T scoresa Hip Spine

normal → osteopenia 3 patients 7 patients

osteopenia → normal 2 patients 8 patients

osteopenia → osteoporosis 0 patients 1 patient

osteoporosis → osteopenia 0 patients 2 patients

Marcellin, et al. AASLD 2011; Poster #1385.

Entecavir (ETV) Monotherapy for 96 Weeks is Comparable to Combination Therapy with ETV Plus Tenofovir (TDF) in Nucleos(t)ide-naïve Patients with

Chronic Hepatitis B (CHB): The BE-LOW Study

A.S. Lok1, H. Trinh2, G. Carosi3, U. Akarca4, A. Gadano5, F. Habersetzer6, W. Sievert7, D. Wong8, M. Lovegren9, D. Cohen9, C.

Llamoso9

Lok, AS, et al. AASLD 2011; Oral #223.

1. University of Michigan, Ann Arbor, MI, United States. 2. Pacific Health Foundation, San Jose, CA, United States. 3. Institute of Infectious and Tropical Disease, University of Brescia, Brescia, Italy. 4. Department of Gastroenterology, Ege University, Izmir, Turkey. 5. Seccion Hepatologia, Hospital Italiano de Buenos Aires – Argentina, Ciudad de Buenos Aires, Argentina. 6. Service d’Hepato-gastroenterologie, Nouvel Hopital Civil, Strasbourg, France. 7. Department of Medicine, Monash University, Melbourne, VIC, Australia. 8. Toronto Western Hospital, University Health Network, Toronto, ON, Canada. 9. Research and Development, Bristol-Meyers Squibb Company, Wallingford, CT, United States

ETV-110: Study Design

Week 96

Primary endpoint

Baseline

Dosing x 100 weeks

ETV 0.5 mg + TDF 300 mg, once daily(N = 197) *

ETV 0.5 mg, once daily(N = 182) *

Further anti-HBV therapy at discretion of investigator – up to 24 weeks follow-up

• Randomized, open-label, Phase IIIb trial• NA-naïve CHB, HBeAg(-) patients capped at 30%

*Modified intent-to-treat (ITT) population: received at least one dose of study medication


HBV DNA <50 IU/mL at Weeks 48 and 96: Overall

HB

V D

NA

<5

0 IU

/mL

(% p

atie

nts

)

Difference 9.9%(95% CI 1.5, 18.4)

Number of 128 158 139 164

Patients: 182 197 182 197

Non-completer = failure *Primary endpointLok, AS, et al. AASLD 2011; Oral #223.

Difference 6.9%(95% CI -1.0, 14.9)

*

HBV DNA <50 IU/mL at Weeks 48 and 96: By Baseline HBeAg StatusHBeAg(+) HBeAg(-)


Authors’ Conclusions

• At Week 96, both treatment arms (ETV monotherapy and ETV + TDF combination therapy) showed comparable antiviral efficacy in a mixed population (70% HBeAg[+]) of NA-naïve CHB patients

• Both treatments were well tolerated with comparable safety profiles

• Combination of ETV + TDF did not provide an overall benefit compared to ETV monotherapy. However, it may– Provide incremental benefit in HBeAg(+) patients with baseline viral load ≥ 108

IU/mL– Have a role in clinical settings in patients with high viral load where rapid HBV

DNA decline is important


Quantitative HBsAg as Predictor of Outcomes in Chronic Hepatitis B

• Patients with chronic hepatitis B enrolled 1991-1992 (N = 4155) and followed until 2004– Natural history study of previously untreated patients

• In multivariate analysis, baseline HBsAg level independently predicted spontaneous HBV DNA and HBsAg clearance

Liu J, et al. AASLD 2011. Abstract 239.

0Cum

ula

tive

Inc

iden

ce o

f H

BV

DN

A S

eroc

lea

ranc

e

0Yrs

2 4 6 128 10 14

17.4%

41.9%42.2%

86.0%

0.2

0.4

0.6

0.8

1.0

P < .001

Baseline HBV DNA ≥ 104 copies/mL (N = 1449)

Baseline HBsAg (IU/mL)≥ 10,0001000-9999

100-999< 100

0Cum

ula

tive

Inc

iden

ce o

f H

BsA

g S

eroc

lear

ance

0Yrs

2 4 6 128 10 14

32.1%45.9%49.1%

86.6%

0.2

0.4

0.6

0.8

1.0

P < .001

HBsAg Seropositives (N = 2946)

Baseline HBsAg (IU/mL)≥ 10,0001000-9999100-999

10-99< 10

3.3%

Initiation of LAM in 2nd vs 3rd Trimester in Pregnant Women With High HBV Viremia

• Retrospective analysis of lamivudine initiated in 2nd vs 3rd trimester in women with HBV DNA > 6 log10 copies/mL

– All babies received HBIG and appropriate vaccinations

– Vertical transmission determined by HBsAg and HBV DNA status at 7-12 month

• Significant reduction of perinatal transmission with similar efficacy when LAM administered in 2nd or 3rd trimester among highly viremic women

Han GR, et al. AASLD 2011. Abstract 236.

0

Infa

nts

With

HB

sAg+

in t

he

Ven

ous

Blo

od (

%)

LAM Usein the 2T

20

40

60

LAM Usein the 3T

Untreated

Infants’ HBsAg status at birthInfants’ HBsAg status at 28 wks

P = .003

P = .004

P < .001

30.4

24.4

11.8

014/119

11/45

28/92

8/920

8.7

HBV Reactivation Among Patients With Cancer

• Retrospective cohort, chart review of 10,729 patients with solid or hematologic cancers who received initial chemotherapy between 2004-2007

• 17% of patients at risk for HBV reactivation screened– HBsAg: 87– HBsAg and anti-HBc: 1665– Anti-HBc: 35

Hwang JP, et al. AASLD 2011. Abstract 172.

High HBV Reactivation Rate Among Patients With Cancer

• 34 patients experienced HBV reactivation

– HBsAg+: 14/26 (54%)– Anti-HBc+: 20/125 (16%)– Leukemia: 14– Lymphoma: 8– Myeloma: 1– Solid tumors (eg, lung, colon,

HCC): 11– Rituximab treated: 10

– 26% prophylaxis Rx and 32% rescue Rx– All cause mortality

• 22% prophylaxis• vs. 71% Rescue • vs. 72% No Rx

Hwang JP, et al. AASLD 2011. Abstract 172.

Mean age: 47 yrs with reactivation vs 54 yrs for no reactivation

100

80

60

40

20

0

Pat

ient

s W

ith

Rea

ctiv

atio

n (%

)Cancer Type

14

28

Solid(9/63)

Hematologic(23/82)

Thank you

AASLD 2011- Feedback on HBV

Documents

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