Transcript Infezione cronica da HBV

Infezione cronica da virus B
Trattamento antivirale e controllo della malattia:
benefici a lungo termine
Nuovi target di terapia antivirale:
la lunga strada verso la cura
Pietro Andreone
Dipartimento di Scienze Mediche e Chirurgiche
Università di Bologna
Ospedaletto di Pescantina, 25 Giugno 2014
Outline
− Long term benefit
− News from EASL
− The long way to cure
Long-term benefits
• Clinical
– Control of symptoms
• Biochemical
– AST/ALT normalization
• Serological
– HBeAg loss
– HBsAg loss
• Virological
– HBV-DNA suppression
• Histological
– Inflammation/Fibrosis reduction
• Portal pressure measurement
– HVPG decrease
• Liver Function
– CTP/MELD scores
Long-term benefits
Clinical: control of symptoms
• Advantages
– Relevant to patients
• Disadvantages
– Often asymptomatic even with advanced disease
– Non specific
Long-term benefits
Biochemical: normalization of AST/ALT
• Advantages
– Inexpensive
– Correlation with disease activity
• Disadvantages
– Significant fluctuation
– Not specific to HBV
– Imprecise correlation with histology
Long-term benefits
Serological: HBeAg loss ± HBeAb development
• Advantages
– Predicts favorable outcome if maintained off therapy
• Disadvantages
– Durability limited when treatment-induced
– HBeAg-negative disease may develop
Long-term benefits
Serological: HBsAg loss ± HBsAb development
• Advantages
– Associated with excellent prognosis (particularly if before 50 yrs)
• Disadvantages
– Rare event with current therapy
– Difficult to predict (?)
Surrogate Endpoints in CHB
Virological: HBV-DNA suppression
• Advantages
– On-treatment suppression associated with favorable short to mediumterm outcome
– Useful to identify viral resistance
• Disadvantages
– Poor durability off treatment (especially in HBeAg-negative)
Long term benefits
Serological: HBsAg loss ± HBsAb development
Virological and serological responses after 12 mo
(Peg-IFN after 6 mo of FU)
Aghemo A et al, J Hepatol 2012
Long-term benefits
Histological: inflammation/fibrosis improvement
• Advantages
– Accurate assessment of liver injury
– Clinically relevant
• Disadvantages
– Invasive
– Costly
– Subject to sampling error
– Slow to change (especially fibrosis)
Long-term benefits
Histological: inflammation/fibrosis improvement
Fibrosis regression during long-term ETV treatment in 57 pts (10 with ≥F5)
HBeAg+ and HBeAb+
Chang TT et al, Hepatology 2010
Long-term benefits
Histological: inflammation/fibrosis improvement
Fibrosis regression during long-term TDF treatment in 396 pts (96 with ≥F5)
HBeAg+ and HBeAb+
Marcellin P et al, Lancet 2013
Long-term benefits
Fibrosis serum markers/Fibroscan improvement
• Advantages
– Non invasive
– Relatively good correlation with histology
• Disadvantages
– Limited validation in HBV
– Longitudinal data lacking
Long-term benefits
Portal pressure reduction
• Advantages
– Accurate assessment of portal hypertension
– Clinically relevant
• Disadvantages
– Invasive
– Costly
– Subject to sampling error
– Slow to change (linked to fibrosis regression)
Long-term benefits
Portal pressure reduction
HVPG decrease in cirrhotic patients with significant (>10 mm Hg)
portal hypertension treated with LMV
Manolakopoulos S et al, J Hepatol 2009
Outline
− Long term benefit
− News from EASL
− The long way to cure
News from EASL 2014
Combined Impact of Baseline Steatosis and
HBeAg Status on pALT after 5 yrs of TDF
*Fisher exact test
Coexisting steatosis and HBeAg+ status were independent predictors of pALT in HBV patients
receiving long-term TDF treatment
Jacobson I, EASL, 2014, Poster #1084
News from EASL 2014
Prediction of Liver Cirrhosis Regression
in TDF-treated CHB Patients with Hepatic Steatosis
Regression of Cirrhosis in Obese and Non-Obese Patients With and Without Steatosis
P=0.05
Presence of steatosis was associated with a lower likelihood of regression of cirrhosis
Buti MM, EASL, 2014, Poster #677
News from EASL 2014
TDF in Treatment-Naïve or –Experienced CHB Patients (n=440)
in a 3 yrs Real Life Practice
Patients with HBV-DNA
<69IU/mL (%)
Virologic Response Rates
97%
94%
n=119
n=110
n=101
n=189
n=171
n=158
Overall Population (N=440)
eGFR ≥ 60 and < 90 (n=98)
eGFR ≥ 90 (n=238)
eGFR ≥ 30 and < 60 (n=24)
 94–97% HBV DNA undetectable, with no difference between TN and TE
 Overall HBsAg-loss: 12 (2.7%)
 3 cases of HCC reported over 3 years
Pageaux G-P, EASL, 2014, Poster #1061
News from EASL 2014
TDF in CHB Patients with Older Age and Comorbidities
100%
Patients with HBV-DNA
<69IU/mL (%)
95%
n=268 n=252 n=233
n=40
n=29
n=26
 Incidence of comorbidities in elderly patients: 35% HTN, 17% diabetes
 58% were F3-F4 (METAVIR) at baseline
Causse X, EASL, 2014, Poster #1062
News from EASL 2014
TDF Monotherapy vs. TDF+ETV in ADV*-Resistant HBV
Proportion of Patients with Virologic Response
n=50
n=52
Mean Change in Serum Creatinine
n=50
n=52
Intention-to-treat analysis
* 30/102 had rtA181T/V and rtN236T mutations
Lim Y-S, EASL, 2014, Poster #1064
News from EASL 2014
Risk of Hepatitis B-Related HCC with Antiviral Therapy
External validation of three HCC risk models (NGM1-HCC, CU-HCC, REACH-B)
in a North American mixed genotype population (n=2,105)
REACH-B Full Patient Cohort
0.5
patients developed HCC
(median f/u of 47 months)
 Cumulative incidence of HCC
– 5-year, 2.53%
– 10-year, 3.32%
Observed HCC Risk
 778 patients treated; 70
0.4
0.3
0.2
0.1
HR
MR
MR
0 LR
0.0
HR
0.1
3 Years
HR
0.2
0.3
Predicted HCC Risk
5 Years
0.4
0.5
High Risk
Treatment modified the predicted risk of HCC, with lower than predicted incidence
observed to a greater extent in high risk groups
Abu-Amara M, EASL, 2014, Poster #194
News from EASL 2014
Efficacy of ETV in Naïve and LAM-Experienced CHB Patients
Retrospective analysis of 342 consecutive NUC-naïve and LAM-experienced
patients without LAM resistance treated with ETV for ≥ 30 months from
2006–2012
 Independent predictive
NA-Naïve
n=270
LAMExperience
d
n=72
Pvalue
44.1 (10.0)
44.8 (9.9)
0.584
Virologic response, %
97
94.4
0.295
Virologic breakthrough*,
%
3.5
17
0.000
ETV resistance*, %
2.6
12.2
0.013
factors for developing ETV
resistance:
– Lack of virologic response at
Month 12, HR 20.71,
P=0.005
– LAM exposure, HR 5.01,
Median duration of ETV,
months (SD)
P=0.035
*At Month 60
Ahn SJ, EASL, 2014, Poster #1069
News from EASL 2014
Virologic Relapse Rate After NUC Discontinuation in CHB
International study investigating off-treatment response after NUC therapy
discontinuation in 94 CHB patients
Cumulative Rate of Virologic Relapse in Patients
With and Without Cirrhosis
 Mean f/u: 19.4 months
100
 Cirrhosis: 27 (28.7%)
years
 Patients with cirrhosis had
lower risk of relapse (HR:
0.39; 95% CI 0.21-0.74)
80
Cumulative Rate, %
 Median therapy duration: 4.1
82.9%
70.1%
No Cirrhosis
Cirrhosis
66.2%
60
40
44.7%
20
P=0.037
0
0
Number at Risk
No Cirrhosis
Cirrhosis
67
27
12
24
36
Months After Discontinuation
17
12
10
4
5
2
48
4
1
Chi H, EASL, 2014, Poster #1077
News from EASL 2014
Treatment Cessation After Prolonged Suppression with NUCs in
HBeAg-Negative Non-Cirrhotic Patients
Single-center, retrospective chart review of HBeAg-negative patients on treatment
with suppression for 4–5 years who stopped treatment
 Median f/u: 3 years
 33 patients met eligibility criteria (LAM,
3; ADV, 14; ETV, 4; TDF, 12)
Cumulative Proportional
Rate of Relapse
100
80
60
63%
40
20
0
0
10
20
30
40
50
Duration of Follow Up (Months)
60
37% of patients stayed off treatment safely and without viral relapse
after 5 years on suppressive NUC therapy
Patwardhan V, EASL, 2014, Poster #1080
Outline
− Long term benefit
− News from EASL
− The long way to cure
The long way to cure HBV
Next-Generation Delivery System of Tenofovir
N
N
HO
N
N
O
O
OH
O
P
O
O
O O
O
N
N
N
N
O
O
P
NH2
NH2
NH2
N
O
O
O
O
P
N
H O
N
O
TDF
TAF
Tenofovir
Tenofovir
Disoproxil Fumarate
Tenofovir
Alafenamide
LYMPHOID CELLS/
HEPATOCYTES
PLASMA
TFV
TDF
TDF/TFV
TAF
TAF
TAF
TFV
Cathepsin A
CES1
TFV-MP
TFV-DP
CES1 = carboxylesterase 1; DP= di-phosphate; MP= mono-phosphate.
N
O
TFV
GUT
N
♦
Improved stability in plasma:
– Enhanced delivery of
active form (TFV-DP) to
hepatocytes
– Lower doses are used;
systemic exposures of TFV
reduced
The long way to cure HBV
TAF Phase 3 Program
TAF 25 mg
Study 1
HBeAg+
N=864
Study 2
HBeAgN=390
Week 96
2:1 randomization
Open-label
TAF
Week 144
(Year 3)
TDF 300 mg
• 2 phase 3, randomized, double-blind studies
• Primary endpoint (non inferiority margin of 10%)
–
HBV DNA <29 IU/mL at Week 48
• Secondary endpoints
–
–
Bone mineral density
Renal parameters
GS-US-320-0108 – Clinicaltrials.gov NCT01940341
GS-US-320-0110– Clinical trials.gov NCT01940471
The long way to cure HBV
Combination therapy of TDF and PEG-IFN on HBsAg loss in
noncirrhotic HBeAg(+) and HBeAg(-) CHB
Primary endpoint: loss of HBsAg at Week 72
Weeks
Arm A
N=186
48
72
120
PEG
TDF
16 wks
N=184
PEG
TDF
Arm C
TDF
Arm B
N=185
Arm D
PEG
N=185
GS-US-174-0149 - Clinicaltrials.gov NCT01940341
The long way to cure HBV
Combination therapy of ETV and PEG-IFN on HBsAg and HBeAg
loss in CHB
HBsAg loss 8.5%
HBsAb seroconversion 4.3%
HBsAg loss 0%
HBsAb seroconversion 0%
Ning Q et al, J Hepatol 2014 in press
The long way to cure HBV
Oral Toll-Like Receptor 7 (TLR7) Agonist
TLR7
TLR7: part of the innate immune system
• Expressed in pDCs and B cells
• Activated by ssRNA or small molecules
MyD88
IRF7
NF-B
GS-9620
IFN-α and
other IFNs
Pro-inflammatory
cytokines
Roethle et al. J Med Chem 2013
The long way to cure HBV
HBV-Specific Therapeutic Vaccine
•
•
Recombinant yeast is efficiently taken up by professional antigen-presenting cells
(APCs)
Processed viral antigens are then presented to T cells via MHC I and II.
Haller AA, et al. Vaccine 2007;25:1452-63;
Lu Y, et al. Cancer Res 2004;64:5084-8;
Franzusoff A, et al. Expert Opin Biol Ther 2005;5:565-75
The long way to cure HBV
Tarmogen Phase 2 in Chronic Hepatitis B
• On treatment with nucleos(t)ide polymerase inhibitor (HBV
DNA undetectable), excludes cirrhotics
• Endpoints
–
–
–
Wk
HBsAg decline at Week 24 (primary)
HBsAg loss/seroconversion (secondary)
Immunology evaluation*
0
24
48
n=25
Antiviral
Antiviral
n=50
Antiviral + 2 YU GS-4774 (q4wk)
Antiviral
n=50
Antiviral + 10 YU GS-4774 (q4wk)
Antiviral
n=50
Antiviral + 40 YU GS-4774 (q4wk)
Antiviral
* Flow cytometry, ELISpot response to HBV antigens, pentamer evaluation for HBV-specific T-cells (number and phenotype), serum cytokine profile, PBMC mRNA expression changes, HLA typing.
GS-US-330-0101 - Clinicaltrials.gov NCT01943799
The long way to cure HBV
NUC
Agent to prevent viral spread,
cccDNA re-amplification
+
Immune
activator
Agents to activate antiviral immunity or
relieve repression of the system
+
cccDNA
inhibitor
Selective agent to deplete or
perturb cccDNA
+
HBV antigen
inhibition
Agents to inhibit other components in the
HBV life cycle [entry or cell-spread, capsid,
HBX, HBsAg]