1. Stato dell’arte nella terapia di HBV
Giovanni B. Gaeta
Cattedra di Malattie Infettive
UOC Malattie Infettive ed Epatiti Virali
Seconda Università di Napoli

2. Pre-therapy work-up in patients with CHB
Personal: Age
Gender
Family history
Provenience
Occupation
Comorbidities
Family planning
HBV genotype and
quantitative HBsAg
are crucial in case of
Peg-IFN treatment
LAB: HBeAg/anti-HBe
HBV DNA level
ALT level
HBV Genotype
qHBsAg
Disease stage/grade
25-27% of patients
with CHB are not
Italian natives1
1. MASTER-B Cohort, AISF, Brancaccio et al, 2014; SIMIT cohort, Fasano et al Infection 2013

3. Whom to treat Clear cut Y N Grey zone ALT≥ 2 x
HBV DNA > 2000 for HBeAg neg
(IU/mL) > for HBeAg pos
Liver disease Y N
True inactive
Grey zone
Immunotolerant
Age > 40; ALT “high normal”
HBV DNA >2000 <20000 IU/mL

4. Optimization of therapy, HBe-pos Optimization of therapy, HBe-neg:
Peg-IFN: still a place
Optimization of therapy, HBe-pos
24 wk stopping rule: HBsAg > IU/ml (99 % NPV for HBeAg loss with HBV-DNA < 2000 IU/ml and 100% NPV for HBsAg loss irrespective of HBV genotype ) 1
Favorable predictors of response
Lower HBV-DNA (< 2 x IU/ml)
High ALT (≥ 2 < 5 x ULN)
HBV Genotype A > B/C > D
Optimization of therapy, HBe-neg:
12 wk stopping rule: < 2 log10 HBV-DNA decline and no HBsAg decline (95-100% NPV, genotype A-D)
HBV-DNA < 2000 IU/ml + normal ALT EOT %
5 y. Post-Treat %
HBeAg negative CHB
HBsAg loss EOT %
5 y. Post-Treat %
HBeAg/anti-HBe seroconversion EOT %
1 y. Post-Treat %
HBeAg positive CHB
1. Sonneveld MJ, Hepatology 2013; 2. Rijckborst V, J Hepatol 2012

5. ETV or TDF therapy for CHB Data from 5-8 year follow-up
Viral suppression in >95% of patients
HBeAg seroconversion in 40-50%
HBsAg clearance in 1% (20% in selected groups)
ALT normal in ~85%
No major safety issues
Regression of fibrosis/cirrhosis in 75-80%
Reduced decompensation rate and improved survival

6. Key points of the presentation
Limited stopping rules with NA
HCC risk
Can we combine NA and Peg-IFN ?
New therapies

7. Stopping rules for NUCs in HBeAg + CHB
CHB treatment guidelines
EASL
(2012)
AISF
(2011)
AASLD
(2009)
APASL
HBeAg +
HBeAg seroconversion + undetectable DNA for 12 months
HBeAg seroconversion + undetectable DNA for 6 months
Author
race
n.pts
Mean age (yr)
NUC
Mean Tx
Duration
(mo)
Mean post Tx FU (mo)
Relapse § %
% Relapse within mo
Yeh 2009
asian 71 41
LAM 17
(7-44) 15 27 NA
Lee 2010
178 39 26
(12-77) 22 82
Wang 2010
125 29 24
(12-89) 30 90
Tseng 2012
148 35
LAM (92%)
ADF (6%) 20
(7-80) 37 52
Reijnders 2010
Caucasian
(55%) 9
16-45
LAM (66%)
ADF/ETV/TDF (33%)
19-72 13 77
100

8. Virological outcome after stopping adefovir treatment
in anti-HBe positive patients
HBV DNA neg 11 10 9 8
HBsAg loss 6 3 3
Hadziyannis S. et al, Gastroenterology 2012

9. HBsAg levels at EOT in relapsers, patients with SR without HBsAg loss,
patients with SR and HBsAg loss
P=0.002
P=0.07
Hadziyannis S. et al, Gastroenterology 2012

10. NA treatment can be stopped safely only after HBsAg loss
HBV-DNA, ALT and HBsAg profiles after TDF discontinuation
42 HBeAg neg pts on TDF from ≥ 4 years were randomized to stop or stay on treatment: the primary endpoint was HBsAg loss by Week 144
HBV DNA became detectable in 21/21 (100%) of TDF-Stop subjects
HBV DNA up to W48:
Median: 5.32 log10 IU/mL (range: )
At W 48
89% (16/18) HBV DNA < IU/mL
78% (14/18) HBV DNA < IU/mL
HBV DNA (log10 IU/mL)
Patients requiring TDF re-initiation (n=3)
Time TDF was restarted
NA treatment can be stopped safely only after HBsAg loss
and anti-HBs seroconversion
★ ALT peaked at >2xULN in 12/21 TDF-Stop
subjects (57%) ★ At W 48: 100% (18/18) ALT < 2xULN;
Stopping TDF was associated with a more profound decline in HBsAg levels compared with continuous TDF (median 0.28 vs log10 reduction, respectively), 1.40 median log10 decline in TDF-Stop subjects with HBsAg <25,000 IU/mL at BL
HBsAg loss was observed in two subjects (9.5%) 48 weeks after TDF discontinuation
T Berg et al., O0119 EASL 2015

11. Key points of the presentation
Limited stopping rules with NA
HCC risk
Can we combine NA and Peg-IFN ?
New therapies

12. Risk factors of HBV-related HCC
Host-related risk factors
Age >40 years
Asian ethnicity
Male gender
Family history of HCC
Chronic aflatoxin exposure
High alcohol consumption
Viral risk factors
HBV genotype C
HCV or HDV infection
PC/BCP HBV variants
Risk factors related to
host–virus interaction
Cirrhosis
High HBV-DNA level
Prolonged HBeAg positivity
Prolonged HBsAg positivity
High HBsAg level
PC=precore; BCP=basal core promoter.
Created from 1. Fattovich G, et al. Gastroenterol. 2004;127:S35–S50; 2. Hosaka T, et al. Hepatology 2012 Dec 5. [Epub ahead of print] doi: /hep

13. ETV for NUC-naïve chronic hepatitis B patients
HCC rates per year – A review
Duration of ETV therapy: 4-6 years 4 3
HCC per year (%) 2
1.4%
1.4%
0.8% 1
0.7%
0.6%
0.5%
18/813
2/237
n=754
n=878
6/209
9/428
Wong
Hong Kong
(Gastro. 2013)
Hosaka
Japan
(Hepato. 2013)
Cho
Korea
(Gut 2014)
Lim
Korea
(Gastro. 2014)
Lampertico
Italy
(EASL 2013)
Papatheodoridis
Europe
(EASL 2014)
HCC/yr in untreated CHB patients: 0.6% (Asia) and 0.3% (Europe)
(Fattovich G et al, J Hepatol 2008)
Papatheodoridis et al. J Hepatol 2015

14. ETV for NUC-naïve compensated cirrhotics HCC rates per year – A review
Duration of ETV therapy: 4-6 years
4.1% 4
3.5% 3
2.7%
2.7%
2.6%
2.0%
HCC per year (%) 2 1
21/247
n=100
n=378
n=860
18/155
8/111
Wong
Hong Kong
(Gastro. 2013)
Chen
Taiwan
(EASL 2013)
Cho
Korea
(Gut 2014)
Lim
Korea
(Gastro. 2014)
Lampertico
Italy
(EASL 2013)
Papatheodoridis
Europe
(EASL 2014)
HCC/yr in untreated cirrhotics: 3.7% (Asia) and 2.2% (Europe)
(Fattovich G et al, J Hepatol 2008)
Papatheodoridis P, Lampertico P et al. J Hepatol 2015

15. HCC risk in ETV treated vs untreated CHB
Propensity score matched study – Japan
Propensity score (PS) matched ETV vs untreated patients
No cirrhosis
Cirrhosis
p<0.001*
p=0.019**
P=ns
*ETV vs untreated
**LAM vs untreated
Hosaka et al, Hepatology 2013

16. Is the risk of HCC declining over time ?

17. Regression of fibrosis after 5 and 10 years of virological suppression
Baseline
5 years
10 years
Viral Hepatitis Unit, Naples

18. HCC incidence in ETV/TDF treated pts beyond yr 5
All patients
Patients with CIR vs CH
CIR
1.07%
HCC
(%)
p=0.046
p=0.086
3.27%
0.63%
1.22% CH
0.45%
0.51%
Pts at risk
CHB
CIR
HCC beyond yr-5 associated only with older age (P=0.062) or age ≥55 at ETV/TDF onset (P=0.02)
Papatheodoridis G, et al. AASLD 2015

19. HBeAg+ and HBeAg- patients treated with TDF for up to 8 years
Predicted HCC Incidence using Risk Scores vs. Actual cases in TDF treated patients
HBeAg+ and HBeAg- patients treated with TDF for up to 8 years
Cumulative No. HCC Cases 1 2 3 4 5 6 7 8 10 15 20 25 30 35
Observed
REACH-B
CU-HCC
GAG-HCC
PAGE-B
*While 5-year projections are available for the CU-HCC, GAG-HCC, and PAGE-B scores, yearly incidence data were available for calculations of REACH-B as well as actual observed HCC incidence data through 8 years in Studies 102 and 103.
All four risk scores predicted similar number of patients experiencing HCC at the end of 5 years, which was higher than what was observed in TDF-treated patients
Kim R et al, EASL 2015, P0644 19

20. HCC in patients with chronic hepatitis or compensated cirrhosis on TDF
320 NUC experienced treated with TDF for 69 months 2
1.5
1.3%
HCC per year (%) 1
0.5
0.2%
1/119
11/155
Chronic hepatitis
Compensated cirrhosis
HCC/yr in untreated HBV (Europe): 0.3% (CH) and 2.2% (Cirr)
(Fattovich G et al, J Hepatol 2008)
Lampertico P et al, EASL 2015

21. Incidence of HCC in CHB patients treated with ETV or TDF - A multicenter European study
N=1666 patients on ETV or TDF
36% (7.2%/yr)
P<0.001
17% (3.4%/yr)
3.7% (0.7%/yr)
Papatheodoridis G et al, J Hepatol 2015

22. HCC free survival in cirrhotic patients with or without HDV
coinfection treated with NA
Matched 1:1 by age, gender, serum albumin level, platelet count, bilirubin values
HBV monoinfected
HDV coinfected
Manuscript in preparation

23. Recommendations for HCC surveillance in HBV
AASLD [1]
APASL [2]
EASL-EORTC [3]
Cirrhosis
Asian males over age 40
Asian females over age 50
Family history of HCC
African/ North American blacks
Non-cirrhotic HBV carriers with active hepatitis
Surveillance: 6-month US for AASLD and EASL (+ AFP for APASL)
[1] Bruix J, Sherman M, AASLD: Management of hepatocellular carcinoma: an update. Hepatology
2011;53: [2] Omata M, et al. APASL. Hepatol Int 2010;4: [3] EASL-EORTC. Clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:

24. Construction of the PAGE-B HCC risk score
A score was attributed to each variable according to its relative contribution in the Cox proportional hazards model
Age
(years)
Sex
(F/M)
Platelets
(/mm3)
16-29: -4
30-39: -2
40-49: 0
50-59: 2
60-69: 4
>70: 6
Female: 0
Male: 6
>200,000: 0
100,000 – 199,999: 6
<100,000: 9
PAGE-B HCC score range: -4 to 21
(AUROC, c-index=0.82)
Papatheodoridis G etal, EASL 2014, submitted 2015

25. Cumulative 5-year HCC in relation to the PAGE-B HCC risk score
High (17%)
High
Intermediate (3%)
Intermediate
Low
low (0%)
Moderate to high HCC risk (PAGE-B score ≥6):
males ≥40 yrs, females ≥70 yrs, PLT <200,000/mm3
5-year HCC: 0%, 3% 17%
HCC/year: 0%, 0.6%, 3.4%
Patients: 25%, 47%, 28%
Cirrhosis: 4%, 18%, 41%
5-year HCC: 0%, 4% 16%
HCC/year: 0%, 0.8%, 3.2%
Patients: 11%, 48%, 41%
Cirrhosis: 15%, 41%, 66%
Papatheodoridis G et al, EASL 2014, submitted 2015

26. Key points of the presentation
Limited stopping rules with NA
HCC risk
Can we combine NA and Peg-IFN ?
New therapies

27. Randomized, controlled, open-label study (N=740)
Stratified by screening HBeAg status and HBV genotype
Inclusion criteria
HBeAg+ and HBV DNA ≥20,000 IU/mL; HBeAg- and HBV DNA ≥2,000 IU/mL
ALT >54 and ≤400 U/L (men); ALT >36 and ≤300 U/L (women)
No bridging fibrosis or cirrhosis on liver biopsy or by transient elastography
Gastroenterology, ePub 2015

28. Start TDF during follow-up if prespecified safety criteria met
Study Design
Week 16 24 48 72
120
n=186
TDF + PEG
Start TDF during follow-up if prespecified safety criteria met
n=184
TDF+PEG → TDF
n=185
TDF
n=185
PEG
Gastroenterology, ePub 2015

29. Results: HBsAg Loss Over Time (Week 72)
0.15
0.14
0.13
0.12
0.11
48 weeks
72 weeks
0.10
0.09
0.08
0.07
0.06
0.05
0.04
TDF + PEG 48 wk
9.0%
Patients with HBsAg Loss,
Kaplan-Meier Estimate (%)
p=0.003
PEG 48 wk
2.8%
p<0.001
p=NS
TDF + PEG 16 wk →TDF 32 wk
2.8%
0.03
0.02
p=NS
0.01
TDF 120 wk 0%
0.00 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Week
7 patients had HBsAg seroreversion on or after Week 48 (4 [TDF + PEG 48 wk], 3 [TDF + PEG 16 wk →TDF 32 wk])
5/7 had ≤1 week of therapy after HBsAg loss
Gastroenterology, ePub 2015

30. Efficacy: On-Treatment Changes in HBsAg Levels at Week 48
Results: Change in Serum HBsAg Levels 48
TDF 120 wk
-0.3 log
p<.001
TDF+PEG 16 wk →TDF 32 wk
-0.5 log
p<.001
Mean Change From Baseline(log10 IU/mL)
PEG 48 wk
-0.8 log
p=.016
TDF + PEG 48 wk
-1.1 log
Error bars represent 95% confidence intervals.
Gastroenterology, ePub 2015

31. Early HBsAg Kinetic Predictors of HBsAg Loss
Chan, AASLD 2015

32. Add-on Peginterferon Alfa-2a significantly reduces HBsAg levels in HBeAg-negative, genotype D chronic hepatitis B patients fully suppressed on nucleot(s)ide analogue treatment. The HERMES Study
Pietro Lampertico1, Maurizia R. Brunetto2, Antonio Craxì3, Giovanni B. Gaeta4, Mario Rizzetto5, Giulio Palmieri6, Massimo Colombo1 on behalf of the HERMES Study Team
Phase II b, open label, single arm , multicenter study
To evaluate whether add-on Peg-IFN for 48 weeks foster HBsAg kinetics
70 HBeAg negative CHB patients, genotype D
Median viral suppression 3.2 years ( y)
Median HBsAg levels at screening IU/ml ( IU/ml)
EASL 2015

33. Add-on Peg-IFN significantly reduces HBsAg levels in HBeAg negative, genotype D CHB patients fully suppressed on NUCs treatment - The HERMES Study
Median HBsAg levels decreased significantly from BL to w48 (p<0.0001).
Median change was IU/ml at w 24 and IU/ml at w 48.
At week 48 serum HBsAg decreased ≥ 50% from BL in 30 patients (42.9%)
3 patients lost HBsAg
1160 IU/ml
743 IU/ml
308 IU/ml
EASL 2015

34. Key points of the presentation
Limited stopping rules with NA
HCC risk
Can we combine NA and Peg-IFN ?
New therapies

35. Emerging antiviral approaches
From: Nassal et al. (2008)

36. New anti-HBV drugs Non-nucleosides ARC-520 RNAi gene silencer
Mechanisms
Company
Status
Non-nucleosides
ARC-520
RNAi gene silencer
Arrowhead Res
Phase 2a
BI-25
cccDNA inhibitor
Blumberg Institute
Preclinical
TKM-HBV
Tekmira
Myrcludex B
Entry inhibitor
Hepatera
Phase 2
Bay
Inhibitor viral nucleocapsid
AiCuris, Germany
Phase 1
Immune enhancers
GS-4774
Therapeutic vaccine
Gilead Sciences
Interleukin-7
Immunomodulator
Dynavax
Phase 1b
HBV core vaccine
Emergent Europe
GS-9620
TLR7 agonist

39. Basic scientific research has identified the viral
myristoylated preS1 subdomain and the NTCP as the host receptor
to which it binds – an interaction that is essential for specific
HBV binding to the hepatocyte

40. HCC rates in ETV treated cirrhotics from Hong Kong a retrospective study
(482 ETV treated, 55 yrs, 72% HBeAg negative, 80% naive, 77% compensated)
P=0.036
Untreated
26%
ETV
14%
*“cirrhosis” was a radiological definition (US)
Wong et al, Hepatology 2013

41. Chronic hepatitis without cirrhosis Compensated cirrhosis
HCC rates in ETV and LAM treated compensated cirrhotics from Korea - a PS matched study
Chronic hepatitis without cirrhosis
Compensated cirrhosis
HCC/yr: ~0.7%
HCC/yr: ~3.4%
P=0.46
P=0.66
LAM
~20%
ETV
ETV
~4.7%
LAM
Lim YS et al, Gastroenterology 2014

42. ARES Study: add-on of Peg-IFN in ENT suppressed patients
Adults with HBeAg-positive CHB,
compensated liver disease, ALT >1.3 x
Response?
Randomisation
Responders stop treatment at week 72
Yes 16
ETV 0.5mg/day
Follow-up
PEG-IFN 180µg/week
N=85
ETV 0.5mg/day
ETV 0.5mg/day no
ETV 0.5mg/day
Responders stop treatment at week 72
Yes 9
ETV 0.5mg/day
Follow-up
ETV 0.5mg/day
N=90
ETV 0.5mg/day no 24 48 72 96
weeks

43. p=0.049 p=0.076 Sustained HBeAg loss & HBV DNA <200 IU/mL
Sustained HBeAg seroconversion

44. PEG-IFN add-on results in more sustained off-treatment response
Sustained HBeAg loss
& HBV DNA <200 IU/mL
p=0.049
Sustained HBeAg seroconversion
p=0.014
2/8
9/14
2/8
9/13
2/8
11/14
Normal ALT &
HBV DNA <2000 IU/mL

45. PEG-IFN add-on leads to sustained response
ETV PEG-IFN add-on
81%
No further treatment required*
21%
79%
19%
Stop Rx
Continue ETV therapy
ETV monotherapy
No further treatment required*
90%
10%
25%
Stop Rx
Continue ETV therapy
75%
* Normal serum ALT and HBV DNA <2000 IU/mL

46. HBeAg negative chronic hepatitis B
Cirrhosis
Decompensated cirrhosis
Fibrosis No
Mild
Moderate
Severe
METAVIR
Ishak’s F0 S0 F1
S 1-2 F2 S3 F3 S4 F4
S5-6
INDEFINITE Treatment with NAs
PEG IFN
Necroinflamm.
activity
> A2 (METAVIR
ANY
HBVDNA : > 2000 UI/mL > 15 UI/mL
ALT: > UNL ANY ALT
Consider
treatment
Treat
Carosi G, Rizzetto M et al, DLD 43 (2011) 46 46