18.0.2012 C‐Hep Meeting Berlin
Is there a need for combination treatment ?
Yes!
Florian van Bömmel
University Hospital Leipzig
Hepatology Section
Germany
Most patients respond to monotherapy with entecavir or tenofovir ‐
- however, response can be decreased by
HBV resistance
OptiB – Response to TDF monotherapy by baseline ADV resistance
p<0.05
100
NS
94%
SORs*
ADV‐Rs
85%
81%
80
Patients %
67%
61%
60
55%
55%
45%
37%
40
27%
20
0%
0
Baseline
All Patients
ADV‐Rs
SORs
73
30
43
Levrero M, et al. EASL 2011; Poster #732.
4
12
24
48
96
73
30
43
71
29
42
67
27
40
66
26
40
63
26
37
Weeks
*suboptimal responders
Background: Currently available HBV polymerase inhibitors and HBV resistance mutations HBV variant
Resistant against
Lamivudin Telbivudin Entecavir
Adefovir
Tenofovir
Wildtyp
S
S
S
S
S
M204I
R
R
I
S
S
L180M + M204V
R
R
I
S
S
A181T/V
I
S
S
R
S
N236T
S
S
S
R
I
L180M + M204V/I ± I169T ± V173L
± M250V
R
R
R
S
S
L180M + M204V/I ± T184G ±
S202I/G
R
R
R
S
S
EASL Clinical Practice Guideline CHB. J Hepatol. 2009;50:227‐242
EASL Clinical Practice Guideline CHB. J Hepatol. 2009;50:227‐242
HBV DNA < 400 cop/mL
Efficacy of TDF monotherapy against different resistance mutations
p<0.0001
months
patients under observation (n): ADV‐resistance 21 15 3
ADV=adefovir dipivoxil
LAM‐resistance 70 54 25
LAM=lamivudine
no genotypic resistance 22 18 12 van Bömmel et al., Hepatology 2010
Response to ETV monotherapy in patients with resistance to ADV
ADV‐naive ADV‐experienced without development of ADV‐resistance ADV‐experienced with ADV‐resistant mutations at baseline 100
80
% Cumulated response
P = NS
60
40
Nucleos(t)ide naive patients n=104
Patients previously treated with ADV n=42
Median duration (months) 19 [2‐55]
20
0
0
2
4
6
8
10
12
Treatment month
Reijnders J et al. J Hepatol 2010
Why combination treatment?
• combination treatment may be needed in patients with drug resistance and incomplete response to monotherapy
What about pretreated patients with incomplete response to second/third line treatment?
Response to third line entecavir monotherapy in patients with previous failure to lamivudine and adefovir treatment
Entecavir 1 mg/day
Herber A, et al. DGVS 2011
Incomplete response to TDF monotherapy acording to baseline adefovir resistance mutations – an Australian perspective Patterson S J et al. Gut 2011;60:247-254
HBV DNA level and incidence of HCC
R.E.V.E.A.L. – HBV Study
Chen et al; JAMA 2006
Combination treatment can be effective to induce complete response in patients with residual viremia
Patients with HBV DNA > 400 cp/mL (n=9)
HBV DNA log10 copies/mL
TDF 245 mg monotherapy
ADV resistance (N236T or/and A181T/V) at start of TDF
HBV wildtype at start of TDF
TDF 245 mg + lamivudine 100 mg
lower limit of detection
months of treatment
van Bömmel et al., AASLD 2009
Why combination treatment?
• Combination of nucleos(t)die analogues is safe and effective, also in patients with advanced fibrosis
Combination treatment is safe and effective
Petersen J et al
2012.
JHepatol;56:520-526
Petersen J et al
2012.
JHepatol;56:520-526
Probability of HBV DNA Below LLoD (<80 IU/ml)
Petersen, J et al. 2012. Jhepatol;56:520-526
ETV‐110: Study Design
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 Week 96 in HBeAg(+) Patients: By Baseline HBV DNA Stratum
Difference 16.8%
(95% CI 2.9, 30.7)
All HBeAg(+)
Number of
patients:
88 111
126 138
Lok, AS, et al. AASLD 2011; Oral #223.
B/L HBV DNA
<108 IU/mL
39 44
47 53
B/L HBV DNA
≥108 IU/mL
49 67
79 85
Non-completer = failure
Why combination treatment?
• combination treatment with NUCs and pegylated interferon alpha may increase the rate of HBsAg loss
10.8% HBsAg loss after 4 years of tenofovir: cumulative probability – Study 103
0.12
HBeAg+ve patients
Cumulative probability*
function estimate
0.11
10.8%
0.10
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
TDF-TDF
0.01
0.00
0
12
24
36
48
64
N=154
80
96
108
120
132
144
156
168
180
192
Weeks
Cumulative probability* of seroconversion to anti-HBs: 7.7%
*Kaplan-Meier
1. Adapted from Heathcote EJ, et al. AASLD 2010; Poster #477.
Rapid and continuous decline of HBsAg observed in patients with HBsAg loss: Study 103
HBeAg+ve: HBsAg loss vs. NO loss
Median HBsAg (lU/mL)
1,000,000
No HBsAg Loss:
Genotype A
Genotype B
100,000
Genotype C
Genotype D
10,000
1,000
HBsAg Loss:
Genotype A
Genotype B
100
Genotype D
10
1
0
TDF-TDF arm
12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192
Weeks
1. Adapted from Marcellin P, et al. EASL 2011; Poster #740.
OSST-Study: Add-On PegIFN may reduce HBsAg
in NUC responders
Q. Ning et al., AASLD 2011
Q. Ning et al., AASLD 2011
OSST-Study: Serologic Response
Q. Ning et al., AASLD 2011
OSST-Study: Serologic Response
Q. Ning et al., AASLD 2011
OSST-Study: Reduktion of HBsAg levels
Q. Ning et al., AASLD 2011
Why combination treatment?
• not big evidence, but:
• are there pathogenic HBV variante beeing selected during treatment?
• Can combination treatment possibly prevent selection of pathogenic HBV variants?
Resistance mutations may become increasingly selected although HBV replication decreases
a)
TDF
HBV DNA log10 copies/mL
8
TDF + LAM
7
6
5
4
3
2
lower limit of detection
1
0
3
6
9
12
15
18
months
% HBV variants
100
50
12
9
5
14
12
6
WT
N236T
0
A181T+N236T
van Bömmel et al, Antiviral Therapy 2012
HBsAg mutations:
selected by NUCs and cancerogenous?
Tenofovir,
Lamivudine,
Adefovir,
Telbivudine,
Clevudine
A181T
Polymerase
gene
Terminal Protein
Spacer
Reverse transcriptase
G FA
Surface gene
PreS1
Pre
S2
RNAse H
B C DE
S
W172*
L
M
S
Surface
proteins
Surface proteins
X
ER lumen/virion surface
membrane
Cytosol/virion interior
Transactivation and HCC ?
Warner N, et al. Hepatology 2008
Truncated s‐antigens may accumulate in the hepatocytes
HBVwt
HBV172*
1:1 mixture of both.
Surface proteins are shown as brown staining.
Cell nuclei are stained in blue.
Warner N, et al. Hepatology 2008
Pre‐S Mutations and Long Term Outcome
141 HBeAg negative patients
Progression to Cirrhosis
Followed up for at least 36 months
Incidence of Pre‐S mutation at baseline
27/141 (19.1%)
Chen et al, Gastroenterology 2007
Increased HCC risk in patients with prior LAM resistance
Papatheodoridis GV et al, J Hepatol 2010
Conclusion
• Monotherapy with nucleos(t)ide analogues is safe and very effective in the majority of cases
• However, some patients with previous resistance to nucleos(t)ide analogues may show resistance or incomplete response to following treatments with nucleos(t)ide analogues and may require combination treatment (especially patients with cirrhosis/advanced fibrosis)
• Combination treatment with pegylated interferon may increase HbsAg loss rates in future treatment regimes (ongoing studies)
• It needs to be investigated if pathogenic HBV mutations can be selected by monotherapy with nucleos(t)ide analogues in multiresistant patients (not prooven! ongoing research)