Transcript AASLD Feedback on HBV

AASLD 2011- Feedback on HBV
Dr Allister J Grant
Consultant Hepatologist
University Hospitals Leicester NHS Trust
62th Annual Meeting
November 4 – 8, 2011
San Francisco, CA
No Resistance to Tenofovir (TDF) Following up to 240 Weeks
of Treatment in HBeAg+ and HBeAg- CHB Infection
Study 102 (HBeAg- Patients) and 103 (HBeAg+ Patients)
Tenofovir DF
300 mg
N=250 & N=176
2:1
RANDOMIZATION
Year 1
Pre-treatment
Liver Biopsy
Year 8
N=235
N=154
Tenofovir DF
300 mg
N=112
N=84
Tenofovir DF
300 mg
Adefovir Dipivoxil
10 mg
N=125 & N=90
Year 1
Liver Biopsy1
Week 72
Year 5/ Week 240
Year 8
Year 3 Liver 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+
Marcellin, P, et al. AASLD 2011; Oral #238
Study 102 (HBeAg-): Proportion of
Patients with HBV DNA <400 copies/mL
Week 240:
TDF-TDF 83%
ADV-TDF 84%
Overall: 83%
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.
The Addition of FTC to TDF Between Weeks 72-240
Did Not Impact Subsequent HBV DNA Decline
57/641 (9%) eligible to add
FTC to TDF at/after Week
72
19/57 (33%) remained on
TDF monotherapy
38/57 (67%) added
FTC to TDF
14/19 (74%)
HBV DNA < 400 copies/mL
At Week 240/ last visit
24/38 (63%)
HBV DNA < 400 copies/mL
At Week 240/ last visit
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)
Marcellin, P, et al. AASLD 2011; Oral #238.
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%)
na
50%
(40%)
HBsAg loss
(seroconversion)
0
9%
(7%)
n=1
11%
(9%)
Marcellin, P, et al. AASLD 2011; Oral #238.
(Week 240)
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,
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
3Auckland
Marcellin, P, et al. AASLD 2011; Poster #1375.
Change in Ishak Fibrosis Scores at Year 5
by Baseline Fibrosis Score
Percentage of Subjects
100
%
90%
n=10
n=126
n=79
n=37
n=19
n=77
Improvement
No Change
Worsening
80%
70%
348 paired biopsies
at Year 5 (71%)
60%
50%
40%
96% (335/348) of patients with
paired biopsies either improved
(≥ 1 unit decrease in fibrosis score)
or did not change at Year 5
30%
20%
10%
0
1
2
3
4
5
6
Baseline Ishak Fibrosis Score
Marcellin, P, et al. AASLD 2011; Oral #238.
Percentage of the population with
cirrhosis (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
100%
Ishak Fibrosis Score
6
5
4
3
2
1
0
Percentage of Patient s
90%
80%
70%
60%
50%
40%
30%
20%
10%
0
Baselin e
•
•
Year 1
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
Marcellin, P, et al. AASLD 2011; Poster #1375.
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
Marcellin, P, et al. AASLD 2011; Poster #1375.
Effects of Tenofovir on Vitamin D Levels
in 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.
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
1 Mueller
NJ et al. AIDS 2010; 24(8):1127-34.
Nguyen, HL, et al. AASLD 2011; Poster #509.
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
Nguyen, HL, et al. AASLD 2011; Poster #509.
Baseline Vitamin D Analysis
Median VD
according to ethnicity
Median VD
according to season
20
20
18
18
16
16.5
14
12
11
8
6
4
2
16.45
14
Vitamin D μg/L
Vitamin D μg/L
15.7
14.3
12
10
16
0
16.9
13.8
10
11.4
11.2
8
6
4
2
0
Winter
Spring
Summer Autumn
Season
p = 0.015, Kruskal-Wallis, n = 272
Ethnic Group
p = 0.005 Kruskal-Wallis, n = 272
• 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%
Nguyen, HL, et al. AASLD 2011; Poster #509.
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
1.05 (0.88-1.86)
1.05 (0.94-2.47)
0.973
29 (12-215)
40 (20-328)
<0.001
INR
AST (IU/L)
ALP = Alkaline phosphatase
• 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
Nguyen, HL, et al. AASLD 2011; Poster #509.
12 Months Interval Data
Antiviral agent
Bone markers
Baseline
12 Months
P-value
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
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
70 (42-229)
68 (36-168)
0.202
VD
TDF (N=142)
ETV (N=77)
ALP
• 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
Nguyen, HL, et al. AASLD 2011; Poster #509.
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
Nguyen, HL, et al. AASLD 2011; Poster #509.
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
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
a. T Score ranges: normal > -1, osteopenia -1 to -2.5, osteoporosis < -2.5; pooled data (N=266 hip; N=276 spine)
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
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
Lok, AS, et al. AASLD 2011; Oral #223.
ETV-110: Study Design
RANDOMIZATION
1:1
Dosing x 100 weeks
ETV 0.5 mg, once daily
(N = 182) *
Further anti-HBV
therapy at
discretion of
investigator – up
to 24 weeks
follow-up
ETV 0.5 mg + TDF 300 mg, once daily
(N = 197) *
Baseline
Week 96
Primary endpoint
• 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
Lok, AS, et al. AASLD 2011; Oral #223.
HBV DNA <50 IU/mL at Weeks 48
and 96: Overall
Difference 6.9%
(95% CI -1.0, 14.9)
HBV DNA <50 IU/mL
(% patients)
Difference 9.9%
(95% CI 1.5, 18.4)
*
Number of
Patients:
Lok, AS, et al. AASLD 2011; Oral #223.
128
182
158
197
139
182
164
197
Non-completer = failure
*Primary endpoint
HBV DNA <50 IU/mL at Weeks 48 and 96:
By Baseline HBeAg Status
HBeAg(+)
Lok, AS, et al. AASLD 2011; Oral #223.
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
Lok, AS, et al. AASLD 2011; Oral #223.
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
1.0
0.8
0.6
0.4
Baseline HBsAg (IU/mL)
≥ 10,000
100-999
1000-9999
< 100
86.0%
42.2%
41.9%
P < .001
0.2
17.4%
0
0
2
4
6
8 10
Yrs
Liu J, et al. AASLD 2011. Abstract 239.
12
14
HBsAg Seropositives (N = 2946)
Cumulative Incidence of
HBsAg Seroclearance
Cumulative Incidence of
HBV DNA Seroclearance
Baseline HBV DNA ≥ 104 copies/mL (N = 1449)
1.0
0.6
Baseline HBsAg (IU/mL)
≥ 10,000
10-99
1000-9999
< 10
100-999
0.4
P < .001
0.8
86.6%
49.1%
45.9%
32.1%
0.2
3.3%
0
0
2
4
6
8
Yrs
10
12
14
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
P = .003
P = .004
40
30.4
24.4
P < .001
20
11.8
0
Han GR, et al. AASLD 2011. Abstract 236.
Infants’ HBsAg status at birth
Infants’ HBsAg status at 28 wks
60
Infants With HBsAg+ in the
Venous Blood (%)
•
14/
119
0
LAM Use
in the 2T
11/
45
0
LAM Use
in the 3T
8.7
28/ 8/
92 92
Untreated
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
100
–
–
–
–
–
–
Patients With
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
22% prophylaxis
vs. 71% Rescue
vs. 72% No Rx
Hwang JP, et al. AASLD 2011. Abstract 172.
60
40
28
20
0
– 26% prophylaxis Rx and 32% rescue Rx
– All cause mortality
•
•
•
80
14
Solid
(9/63)
Hematologic
(23/82)
Cancer Type

Mean age: 47 yrs with reactivation vs
54 yrs for no reactivation
Thank you