TERAPIA PER LA EPATITE DA HBV
IFN, LAMIVUDINA, ADEFOVIR
ed oltre…….
Felice Piccinino
Dipartimento Malattie infettive
II Università Napoli
HBV: End points of treatment
e Ag Neg
ALT NORMAL
DNA(HYB.) neg
Anti e Pos
“HARD”
PREVENT FIBROSIS
CIRRHOSIS, HCC AND
LIVER FAILURE
DNA(PCR) neg
Methods???
ERADICATION
ccc DNA ?
Anti HBs Pos
HBsAg Neg
Serum HBV DNA and Liver Inflammation
in Chronic Hepatitis B
Median improvement in HAI
Histology Activity Index (HAI)
Review of 26 prospective studies
HBV DNA level (log10 c/mL)
Correlation between HAI and HBV DNA
in untreated patients (r=0.78; P=0.0001)
Median log10 HBV DNA decrease
Correlation between change in HBV DNA
and HAI with treatment (r=0.96; P<0.0000)
Mommeja-Marin H, et al. Hepatology. 2003:37:1309-1319.
Level of DNA suppression
 < 50
g/ml
 < 1000 g/ml
 < 10 4
g/ml
 < 10 5 g/ml
1 UI = 5 g
INTERFERONE
Interferon in HBeAg-negative CHB:
Sustained Response and HBsAg Clearance
SR-12 (ALT normal/HBV-DNA negative by non-PCR assay)
HBsAg clearance (with or without anti-HBs)
50
% Patients
26% to 67% of sustained responders
40
30
20
27%
32%
30%
23%
15%
10
15%
9%
0
Manesis,
Papatheodoridis
(209 cases)
10%
Lampertico
Colombo
(101 cases)
Brunetto
Bonino
(103 cases)
10%
Fattovich
Alberti
(88 cases)
6%
Santantonio
Pastore
(81 cases)
GLI ANALOGHI
HBV DNA e ALT dopo un anno di terapia
con LAM in pazienti HBeAg neg
80
70
Patients
(%)
65%
60
50
40
28%
30
20
7%
10
Missing
Data
0
HBV DNA -ve,
ALT Normal
Responders
Tassopoulos et al. Hepatology 1999
HBV DNA -ve,
ALT elevated
Partial responders
HBV DNA and ALT
elevated
Non-responders
Attività istologica (HAI) dopo un anno di terapia con
LAM in pazienti HBeAg neg
Improved
12%
29%
 2 point reduction
No Change
 1 point change
Worsened
 2 point increase
60%
Tassopoulos et al. Hepatology 1999
Missing data excluded (n=42)
Adefovir in naïve HBeAg-neg CHB
Median Change of HBV DNA Through 48 Weeks
Placebo =61 pts
Adefovir Dipivoxil 10 mg/daily = 123 pts
Change in HBV DNA
(log copies/ml)
0
- 1.35 log10
copies/ml
PLB
-1
-2
-3
0%
HBV DNA
< 400 copies/ml
p < 0.001
- 3.91 log10
copies/ml
ADV
-4
0
44
Base
line
51%
88 12
12 1616 2020 24
24 28
28 32
32 36
36 40
40 44
44 48
48
Week of study
(Hadziyannis et al., NEJM 2003)
48 weeks of Adefovir dipivoxil (ADV)
significantly reduces cccDNA
Design:
p=0.002
ADV n=22
2
Baseline
Biopsy
Week 48
Biopsy
cccDNA in biopsies
measured by
quantitative real-time
PCR
Werle, Petersen, Locarnini, Zoulim Gastroenterology 2004
D cccDNA (Log10)
PLB n=10
1
0
Median
-0,8 log
reduction
from
-1
baseline
-2
PBO
ADV
HBV-CH: Cinetica antivirale di LAM ed ADV
LAM
TERAPIA
8
ADV
HBV DNA Log
7
6
5
4
3
2
1
0
6
12
18
MESI
24
Response to antiviral therapy in
HBeAg-negative chronic hepatitis B
Treatment
Interferon
>12 months
Lamivudine
12 months
24 months
>36 months
Adefovir
12 months
On-Therapy
Response
Sustained
Response
HBsAg
loss
50-75%
20-30%
10-15%
60-80%
~10%
-
50-60%
30-40%
?
?
-
70%
?
-
(modified from EASL HBV Consensus, J Hepatol 2003)
Long Term Benefit with Adefovir therapy over
Time in HBeAg-negative patients
Percentage of Patients
HBV DNA < 1000 c/ml
90
80
70
60
50
40
30
20
10
0
ALT Normal
83%
73%
88%
79%
71%
64%
0%
3%
Week 0
Week 48
Week 96
Week 144 (3 Yr)
Hadziyannis et al., EASL 2004
IL PROBLEMA DELLE
RESISTENZE
Limits of new treatments for HBV chronic
hepatitis: viral resistance mutations
Lamivudine
Y
inhibition
Nucleotides
ss (-) DNA
high affinity M
D
D
Y = Tyrosine
M = Methionine
D = Aspartate
HBV polymerase
(wild type)
I = isoleucine or V = valine
Terapia con LAM:Cinetica della resistenza virale
Riattivazione
Da 5 a 30 mesi
LAMIVUDINA
90%
Virologica
ALT
Biochimica
HBV DNA
Hybridization assay
1 log
PCR assay
6
12
mesi
Resistenza Genotipica
LiPA
+
RLFP
+
Direct sequencing -
+
+
+
+
+
+
(Santantonio et al, 2002)
Risposta ad ADV in pazienti con epatite cronica da HBV
resistenti alla LAMIVUDINA
+0.3 log
Median HBV DNA
(log10 copies/ml)
Lamivudine + Placebo (compensated) 49 pts
Lamivudine + Adefovir (compensated) 46 pts
Lamivudine + Adefovir (decompensated)
40 pts
-4.6 log
weeks
Perrillo et al. Gastroenterology 2004
Livelli di DNA e risposta virologica ad ADV in
pazienti Anti- e con resistenza alla LAMIVUDINA
3-6 log HBV-DNA
100
6-8 log HBV-DNA
80
60
>8 log HBV DNA
40
p<0.0001
20
0
Patients
still at
risk
0
3
6
9
12
15
18
21
28
32
3
22
1
14
0
10
0
9
0
6
0
5
0
4
14
13
12
11
10
9
6
4
24 Months
0
2
3
(Lampertico et al., Hepatology 2005, in press)
Therapeutic strategies in HBV
Nucleos(t)ide-based treatment 
Extended/lifelong treatment
On treatment
response
1
Lamivudine
2
3
Adefovir dipivoxil
Antiviral C
Antiviral with a low frequency of resistance (ADV)
Combination of 2 antivirals
Years
Reported HBV Polymerase Mutations by
Treatment
Resistance mutations associated with viral rebound in patients on treatment
LAM
ADV
ETV
LdT
FTC
Selection of YMDD mutants affects
future treatment options
Treatment of HBV Resistance
Lamivudine
resistant
Lamivudine
Entecavir
YES
Low efficacy
Adefovir
YES
(TDF)
Entecavir
resistant
Adefovir
resistant
NO
YES
PROBABLY
( TDF )
PROBABLY
(TDF)
POTENZA
Rapidità + Efficacia
HBV – CH : Azione Analoghi nucleos(t)idici
ETV
TEL
LdT
LAM
3TC
EMT
FTC
TDV
PMPA
ADV
PMEA
BARRIERA GENETICA
LE COMBINAZIONI
HCV-CH: Presupposti alla terapia di
combinazione
● Mutazioni virali preesistono alla terapia
● Il cccDNA è l’archivio genetico delle
mutazioni resistenti
● Il ritrattamento provoca una rapida
riemergenza delle mutazioni
● Sotto pressione antivirale combinata le
varianti genetiche hanno meno
probabilità di emergere
Zhu AAC 1999; Werle, Gastroenterology 2004; Villeneuve J Hepatol 2003; Richman AASLD 2004;
Durantel Hepatology 2004
Prevenzione delle resistenze con terapia
di combinazione: la teoria
Wild type
v
LAMIVUDINE
Lam-R
ADEFOVIR
ADF-R
Frequency ??
Lam + ADF -R
Zoulim, Antiviral research, 2004
Incidence of resistance* (%)
Prevenzione della resistenza alla LAM
con terapie di combinazione
100
80
60
34%
40
20%
20
11%
2%
0
21%
18%
LAM
LAM+ADV
Sung 1
12%
5%
1%
LAM
LAM+Peg
Marcellin 2
LAM LAM+Peg
LAM LAM+LdT LdT
Lau 3
Lai 4
* After 1- year therapy
1 Sung et al. J Hepatol 2003 ;38 (suppl 2):25-26
2 Marcellin et al. N Engl J Med 2004; 351: 1206-17
3 Lau et al. Hepatology 2004;40:171A
4 Lai et al. Hepatology 2003;38:262A
TERAPIA EPATITE CRONICA DA HBV
Conclusioni 1
 IFN in prima scelta (PEG IFN > IFN St)
 Soppressione stabile dopo sospensione
 Possibile perdita HBsAg ( Anti- HBs+ )
 Meno tollerato degli analoghi
 Non dà resistenze
TERAPIA EPATITE CRONICA DA HBV
conclusioni 2
 Nei non responders o non tolleranti ad IFN terapia
continua con LAM o ADV o combinazione.
 Nel cirrotico avanzato ADV- monoterapia o
combinazione
 Nei pazienti in terapia con LAM attento
monitoraggio, se riattiva, immediatamente ADV
 Nei resistenti ad ADV,LAM o altri analoghi. ???
 Entecavir ! Tenofovir !
GRAZIE DELL’ASCOLTO