chronic hepatitis delta: an update · chronic hepatitis delta: an update: prof. dr. cihan yurdaydin...
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Chronic hepatitis delta: an update:
Prof. Dr. Cihan YurdaydinUniversity of AnkaraDpt. of Gastroenterology
9th INTERNATIONAL CONGRESSOF INTERNAL MEDICINEATHENS, GREECE9-11 MARCH 2017
I have received consultancy and/or lecture fees from
AbbVie, BMS, Gilead, Roche, Merck, Boehringer Ingelheim, Janssen, and Novartis, and has received grants from BMS and
Roche.
DISCLOSURE
INTRODUCTION
Chronic delta hepatitis (CDH) is the most severe form of viral hepatitis
A disease of the developing or underdeveloped countries or regions
Orphan disease in the EU and USA
The only therapy of proven benefit is with interferons
Biomedical Industry displays little interest: “not cost-effective”
Liver injury in CDH is immune mediated
Acute HDV
95% recoveryMore frequent fulminant
Acute HBV
Simultaneous Co-Infection
Acute HDV
Chronic Hepatitis B
HDV Super-Infection
ACUTE HEPATITIS
5% CHRONIC
CHRONIC HEPATITIS
90% chronicMore severe disease
Europe 43/111 (39%) 101/532 (19%) <0.000001Smedile et al 1982
USA 24/71 (34%) 5/118 (4%) 0.000016Govindarajan et al 1984
Fulminant AcuteHepatitis B Hepatitis B p value
Proportion of patients with evidence of HDV in acute self limited vs. fulminant hepatitis B
Ankara Uni.
138 acute hepatitis D
23 superinfection115 co-infection
104 resolution(90%)
10 chronic hepatitis (8%)
Outcome in acute delta hepatitisButi et al, J Viral Hepat 2011
23 chronichepatitis (100%)
Ankara Uni.
EEA HDV Prevalence Heavily impacted by Immigration and IVDU* Populations
High Risk Group Proportion in HDV
PopulationIVDU HBsAg (+)
Population1
Immigrant HBsAg (+) Population2
High Risk HBsAg (+) Population
% HDVPrevalence3
HDV subjects
in High RiskPopulation
Spain 96% 1,686 155,459 157,145 6-9 11,786
Sweden 84% 4,466 50,593 55,059 2-5 1,927
France 83% 50,562 112,704 163,266 6-9 12,245
UK 74% 29,367 192,128 221,495 6-9 16,612
Germany 72% 9,394 282,256 291,650 10-12 32,082
Italy 56% 36,940 202,648 239,588 6-9 17,9691 IVDU population figures taken from EMCDDA (European Monitoring Center for Drugs and Drug Addiction)2 Immigrant population figures taken from Eurostat3 HDV prevalence from post-2006 country specific literature reports
• High risk group proportion in HDV population is 56-96%For Spain, Sweden, France, UK, Germany, and Italy, HDV proportion of high risk groups are 96%, 84%, 83%, 74%, 72%, 56%, respectively (mean = 78%).
• Total HDV Population = HDV High Risk Group + HDV Low Risk Group• HDV High Risk Group = [High risk group HBsAg(+) pop] x [% HDV Prevalence]
HBsAg(+) High Risk Group = HBsAg(+) Immigrant Pop + HBsAg(+) IVDU Pop
Spain: (Navascués et al, 1995; Buti et al, 2010], Sweden: [Ji et al, 2012], France: [Renard et al, 2011], UK: [Cross et al, 2008], Germany: [Heidrich et al, 2009; Reinheimer et al, 2012; Wedemeyer et al, 2007(a)], Italy: [Gaeta et al, 2003; Piccolo et al, 2009; Mele et al, 2007]
Ankara Uni.
EEA HDV Prevalence Calculation
8
TotalPopulation
(2013)
TotalHBsAg (+)
Population
High RiskHBsAg (+)
Population
% HDVPrevalence
HDV Subjects in High Risk
Population (78% HDV
Population)
HDV Subjects in Low Risk
Population (22% HDV
Population)
Total HDV Population
HDV Rate
EEA 510,064,934 5,492,518 1,596,264Country specific
prevalence117,265 34,045 151,310
2.97 in10,000
HDV an orphan disease in Europe
Ankara Uni.
Soriano V. AIDS in press
Major endemic regions for hepatitis delta
Time free from liver decompensation or death in HIV infected patients
Fernandez-Montero et al, Clin Infect Dis 2014
Estimated HCC risk in HBV, HCV and HDV infected pts in Central Africa
HCC in CHB vs CHD under treatment
Keskin O et al, AASLD 2016
Nuclear localization
No correlation with liver
injury, even in HBV-HDV
co-dominant cases
Kabaçam et al, Liver Int 2013Ankara Uni.
HBcAg IHC in CDH
HDAg IHC in CDH
HDAg display (+)
correlation with ALT
Ankara Uni.Kabaçam et al, Liver Int 2013
DELTA HEPATITIS- DIAGNOSIS
• Anti HDV (IgG)
• Anti HDV IgM
• HDV RNA (qualitative, quantitative PCR)
• HDV Ag (immunohistochemistry)
• Quantitative HBsAg,
• HDV & HBV genotype determination
Ankara Uni.
Female patient living in Sweden, migrated from Uzbekistan
• ALT: 78, AST 66
• GGT and Alkalen Phosphatase: normal
• HBsAg (+), HBeAg negatif
• Anti HCV & HIV: negative
• HBV DNA 480 IU/mL
• Hb, WBC normal, platelets: 176 000
• Height: 1.63m; weight: 92 kg
• BMI: 34.6
Ankara Uni.
Diagnosis:
İnactive HBsAg carrier + NASH
Recommendation:Diet + exercise; No need to treat HBV
Control visit every 3 months
3 x control visits, she loses some weightEnzymes not much affected
Ankara Uni.
The patients is a physician (gynecologist)
She decides to read, especially hepatit B
On her next visit she asks for an anti HDV test
Anti HDV (+)
HDV RNA is positive
Ankara Uni.
Anti HDV (or anti HDV IgG)
• First test to be used for searching for HDV
• Not a neutralizing Ab, depicts encounter withHDV
• HDV RNA testing necessary to establish activeHDV infection
• Remains positive for years after successful txincluding HBsAg clearance
Ankara Uni.
Liver Int 2011
Wranke et al, PlosOne 2014
Anti HDV IgM titre correlate with ALT
and histologic activity
Ankara Uni.
Anti HDV IgM
• Suggestive of acute infection or chronic active infection
• Not standardized
• HDV RNA more sensitive
Ankara Uni.
HDV RNA
• Qualitative or quantitative
• Surrogate marker of tx efficacy
• Standardization was important Now there is a WHO standard (Paul Ehrlich Institute); Labsshould get it
Ankara Uni.
28 reference lab’s took part13 lab’s (46%) made correct mesurements16 lab (57%) found 1-10 positive samples negative
HB
sA
g (
log
10co
pie
s/m
L)
P= 0.024
On-treatment Post-tx
Keskin et al, Clin Gastroenterol Hepatol 2015
HBsAg decline in CDH
Ankara Uni.
HDV and HBV Genotypes
RegionHDV
genotypeHBV
genotype
Europe 1 D / A
Brazil 1 / 3 F / A / D
China, Taiwan, Japan 1 / 2 / 4 B / C
Turkey, Romania, Albania, Iran, Pakistan, India
1 D
Western Pacific 1 / 2 B / C / D
Africa 1, 5-8 D / A / E
27
Su, Wu et al., Gastroenterology 2006
Different HDV Genotypes Are Associated With Different Clinical Outcomes
28
Non-invasive markers for differentiating cirrhosis-AUROC scores
Model Luttenkort et al1 Takyar et al2 Kalkan et al3
FIB-4 0.65 0.83 0.78
APRI 0.60 0.76 0.69
AAR 0.62 0.70 0.65
API 0.80 0.77
HUI 0.70 0.84
FibroScan 0.87
1Liver Int 2016; 2APT 2017; 3EASL 2017
TREATMENT OF CHRONIC DELTA
HEPATITIS
• Evidence based successful treatment : interferon
• High dose, long treatment period (one year,
or longer)
• Sustained virologic response LOW
• NAs ineffective
Ankara Uni.
Wedemeyer H, et al. N Engl J Med. 2011 Jan 27;364(4):322-331.
Treatment of Hepatitis Delta With PEG-IFNα 2a: ~25% Sustained HDV RNA Clearance
31
PEG-IFNα 2a – Adefovir Combination Resulted in a More Pronounced HBsAg Suppression
32Wedemeyer, Yurdaydin, et al. N Engl J Med. 2011 Jan 27;364(4):322-331.
Baseline W12 W24 W48
PEG-IFNα 2a + Tenofovir
PEG-IFNα 2a + PlaceboPatients HDV RNA negative (%)
0
20
40
60
80
P=.10
Week 96
47%
33%
Relapse 11/25 (44%)
Relapse 8/20 (40%)
Neg post Tx, 1 patient
Neg post Tx, 3 patients
HDV RNA Clearance after Therapy
Treatment
P=.34
30%
23%
Week 12024 w post Tx
FU
Wedemeyer, Yurdaydin, et al. EASL 2014.
HDV RNA Response Until Week 120Intent-to-Treat Analysis
33
Patients with HBsAg decline >0.5 log10 U/mL (%)
PEG-IFNα 2a + Tenofovir
PEG-IFNα 2a + Placebo
Mea
n H
BsA
g le
vels
[lo
g10
IU/m
l]
Mean HBsAg levels
0
20
40
60
80Treatment FU
1
2
3
4
5Treatment FU
HBsAg loss: 4/59 patients (6.7%)
HBsAg loss: 3/61 patients (4.9%)
HBsAg Response Until Week 120Intent-to-Treat Analysis
34
Wedemeyer, Yurdaydin, et al. EASL 2014.
Cumulative probability of development of clinical endpoints: IFN, NAs, no therapyHCC Survival
Hepatic decompensation
Wranke et al, Hepatology 2017
Cumulative event-free survival in CDH: IFN, NAs, no therapy- effect of HDV RNA levels
Wranke et al, Hepatology 2017
With MVR
Without MVR
Keskin et al, AASLD 2015
Mortality/liver tx in pts with or without VR
Overall(n:99) IFNresponders(n:35)
IFNnon-responders
(n:64)
Pvalue
Age 40.0±10.6 41.6±9.4 39.2±11.2 0.28
Gender 70
Male/29Female
24Male/11Female 46M/18F 0.81
HDVRNA(log10
IU/mL)(n:59)
5.98±1.4 6.1±1.6 5.9±1.3 0.6
HBVDNA(log10IU/mL,median
(range)(n:63)
1.70(1.0-7.62) 1.67(1.0-4.90) 1.70(1.0-7.62)
0.34
HBeAgstatus 81(-)/15(+) 29(-)/4(+) 52(-)/11(+) 0.56
ALT(U/L) 107±108 97±86 112±119 0.53
AST(U/L) 76±73 76±76 77±71 0.9
ALP(U/L) 115±52 102±52 123±51 0.07
GGT(U/L) 83±78 55±53 100±86 0.007
PT(seconds) 13.3±1.4 13.2±1.4 13.3±1.4 0.6
TotalBilirubin
(mg/dL)
1.01±0.5 0.89±0.5 1.08±0.6 0.12
Platelet(x10
9//L)
161±52 181±54 150±48 0.004
HAI(n:78) 10.9±3.9 10.5±4.7 11±3.5 0.56
Cirrhosispresent
19/99(19%) 5/35(14%) 14/64(22%) 0.26
Fibrosisscore(n:78)
2.15±1.4 1.97±1.4 2.26±1.3 0.36
HBsAg(log10IU/mL,n:49)
3.70±0.66 3.40±0.79 3.96±0.35 0.004
n:99 n: 67 n: 41 n: 30 n: 15 n: 8
6-12 m 13-24 m 25-36 m 37-48 m 49-60 m
9 MVR (-)2 MVR (+)
20 MVR (-)6 MVR (+)
16 MVR (-)16 MVR (+)
11 MVR (-)4 MVR (+)
4 MVR (-)3 MVR (+)
4 MVR (-)4 MVR (+)
>60 m
Figure 2A: Flow chart of maintained viral response and treatment duration
Keskin et al, AASLD 2015
Optimal IFN treatment duration in CDH
Cumulative probability of a maintained viral response in patients treated with interferons
Keskin et al, AASLD 2015
Clinicalevent(+) Clinicalevent(-) Pvalue
Age 43.5±10.1 38.3±10.5 0.02Gender 22Male/10Female 48Male/19Female 0.81
HBeAgstatus 28(-)/4(+) 53(-)/11(+) 0.67
ALT(U/L) 99.6±69.5 111.1±124 0.56
AST(U/L) 78.5±47.0 75.9±83 0.84
GGT(U/L) 107.7±68.8 71.9±81 0.03
ALP(U/L) 119.0±43.7 114.0±56.2 0.65
PT(seconds) 13.6±1.5 13.1±1.3 0.19
Bilirubin(mg/dL) 1.11±0.63 0.96±0.53 0.23
Plateletcount
(x109//L)
134±41 174±52 <0.001
HAIScore(n:78) 12.5±3.3 10.2±4.0 0.02
Fibrosisscore(n:78) 2.68±1.35 1.95±1.3 0.04
HDVRNA(log10
IU/mL)(n:59)
6.26±1.4(n:18) 5.85±1.4(n:41) 0.31
HBVDNA(log10
IU/mL(n:63)
2.57±1.5 2.0±1.3 0.2
Cirrhosispresent 15(+)/17(-) 4(+)/63(-) <0.001
IFNresponse 5(+)/27(-) 30(+)/37(-) 0.006HBsAglog10IU/mL,
n:49
9239±6757 9252±7965 0.9
Figure 4
With MVR
Without MVR
Cumulative probability of HBsAg clearance
HBsAgclearance NoHBsAgclearance Pvalue
Treatmentduration(months)
29.4±21.2 31.8±24.4 0.70
Gender 11Male/3Female 59Male/26Female 0.75
HBsAg(log10IU/Ml,n:49)
3.22±0.88 3.84±0.52 0.005
HBeAgstatus 11(-)/2(+) 70(-)/13(+) 0.90
HBVDNA(log10IU/mL(n:63)
2.47±1.8 2.4±1.5 0.90
HDVRNA(IU/ml,
n:59)
6.15±1.5 5.95±1.4 0.70
Age 39.6±6.8 40.1±11.1 0.87
ALT(U/L) 102±54 108±115 0.86
AST(U/L) 86±86 75±71 0.58
GGT(U/L) 42±26 91±82 0.03
ALP(U/L) 115±54 115±52 0.98
PT(seconds) 13.8±2.2 13.2±1.2 0.38T.Bil(mg/dL) 1.06±0.8 1.01±0.5 0.75
Plateletcount(x109//L)
176±62 158±50 0.32
FibrosisScore,n:78 2.18±1.1 2.14±1.4 0.92
HAIScore,n:78 11.0±5.0 10.8±3.8 0.85ResponsetoIFN 13responders/1
non-responder
22responders/63
non-responders
<0.001
End of treatment response:
OR95% CI p value
HDV RNA week 24 1.627 1.070 – 2.474 0.023
Baseline HAI 0.586 0.366 – 0.937 0.026
Post-treatment week 24 response:
HDV RNA week 24 2.538 1.347 – 4.782 0.004
Multivariate logistic regression analysis for predicting end of treatment and post- treatment week 24 virologic response
Keskin O, et al, Clin Gastroenterol Hepatol 2015Ankara Uni.
N= 38, missing data= 3
Week 24 HDV RNA positive
N= 33
HDV RNA negative
N= 5
Week 72
Virologic ResponseYes
11/33
33%
Yes
5/5
100%
Figure 2: Predictive value of on-treatment week 24 undetectable
HDV RNA for post-treatment week 24 virologic response
NPV 67% PPV 100%
Ankara Uni.Keskin O, et al, Clin Gastroenterol Hepatol 2015
N= 39, missing data= 11
Week 24 HDV RNA
decline
< 1 log decline,
N= 12
> 1 log decline,
N=27
Week 24 HBsAg
declineYes
6/12
Yes
21No
6/12
No
6
Figure 2D: Predictive value of on-treatment week 24 HDV RNA and HBsAg levels
For EOT virologic “null response” (<1 log decline of HDV RNA at EOT)
Week 48 “null”response
3/6
50%
5/6
83%
2/6
33%
2/21
9.5%
PPV 83%NPV 90.5%
Keskin O, et al, Clin Gastroenterol Hepatol 2015
New treatments
Prenylation Inhibitors
Entry Inhibitors
TLR Agonists
Nucleic Acid Polymers
Targets in HDV Treatment
48
Effect of the hepatocyte entry inhibitor,
Myrcludex in CDH
8 pts receive Myrcludex, 2mg/kg for 6 months
8 pts receive Myrcludex, 2mg/kg + Peg IFN for 6 months
Daily sc injections
Urban S et al, AASLD 2014, LB 20
.
• 6 of 7 patients experienced HDV RNA decline >1 log10 at week 24 during Myr B monotherapy
• 7 of 7 patients experienced HDV RNA decline >1 log10 at week 24 during Myr B/PEG-IFNα combination therapy
• HDV RNA became negative in 2 patients during MyrBmonotherapy and in 5 patients in combination with PEG-IFNα
Urban S et al, AASLD 2014, LB 20
Nucleic acid polymers for treating HBVNucleic acid polymers (NAPs) are oligonucleotides whose biochemical function is strictly dependent on the polymer chemistry of oligonucleotides.
They bind with high affinity to amphipathic protein structures
These amphipathic protein structures are very rare in normal human biology (already complexed with each other inside proteins where they help stabilize the protein structure).
However amphipathic targets are required for various stages of viral replication. NAPs effectively block the functions of these proteins, providing an effective, broad-spectrum antiviral activity.
.
Nucleic Acid Polymers (NAPS)
for HBV/HDV Coinfection
52
-3
-2
-1
0
1
2
HD
V R
NA
Lo
g IU
/mL
Mean (SD) Change in HDV RNA Per Week
Lonafarnib 100mg BID
Lonafarnib 200mg BID
Placebo
Therapy Post-Therapy Follow-up
Time in Weeks Time in Months
Treatment of CDH with Lonafarnib
Koh C et al, Lancet Infect Dis 2015
.
Week 4 Reduction in HDV RNA with Lonafarnib
Lonafarnib
100 mg BIDPlacebo
Lonafarnib
100 mg BID
+
Ritonavir
100 mg QD0.5
0
-0.5
-1
-1.5
-2
-2.5
Mean ∆
- 0.74 Log
Mean ∆
- 2.4 Log
Mean ∆
- 0.2 Log
N = 4 N = 6 N = 3
Me
an
Ch
an
ge
in
Lo
g H
DV
RN
A
Mean ∆
- 1.8 Log
Lonafarnib
100 mg BID
+
PEG IFN-α 2a
180 mcg QW
N = 3
Lonafarnib
200 mg BID
Mean ∆
- 1.6 Log
N = 6 N = 3
Lonafarnib
300 mg BID
Mean ∆
- 2.0 Log
Lonafarnib
200 mg BID
Mean ∆
- 1.6 Log
N = 3
National Institutes of Health
NIH POC (Lancet Infect. Dis. 2015)
N = 3
Lonafarnib
100 mg TID
Mean ∆
- 1.2 Log
Ankara University
LOWR-1 (EASL 2015)
54
Side effectsLOnafarnib With Ritonavir in HDV
55
• Mainly GI side effects
• Observed in almost every patient
• Lonafarnib chronically dosed for 2 years in a pediatric
population (Progeria - PNAS, 2012, 16666)
✔ ✔ ✔ ✔
✔ ✔ ✔ ✔
✔ ✔ ✔ ✔
✔ ✔ ✔ ✔
✔
Me
an
lo
g D
elta
Vira
l L
oa
d C
ha
ng
e F
rom
Ba
se
line
Mean Serum Lonafarnib Concentration (ng/mL)
Serum Concentration and Viral LoadStatistically Significant Linear Relationship
56Koh C, et al. Lancet Infect Dis. 2015 Oct;15(10):1167-1174.
Sarasar (lonafarnib) PK Boosted by Ritonavir Serum Concentration Increased 4-5 Fold
1
1
0
50
100
150
200
250
0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8
ALT
U/L
Lonafarnib 100 mg BID + Ritonavir 100 mg QD
LOWR HDV – 1 Results Elevated Liver Enzymes at Baseline
Normalization of ALT on Lonafarnib + Ritonavir
Normal10-40U/L
Pa ent1Pa ent2Pa ent3
LOWR HDV – 1 Results Week 4 Mean Change in HDV-RNA Viral Load -2.2 Log
Week 8 Mean Change in HDV-RNA Viral Load -3.5 Log
1
-5.5
-4.5
-3.5
-2.5
-1.5
-0.5
Ch
an
ge in
Lo
g H
DV
RN
A c
op
ies/m
L
0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week7 Week 8
BLQ
ND
Lonafarnib 100 mg BID + Ritonavir 100 mg QD
Pa ent1Pa ent2Pa ent3
Fig. 4 Inhibiting lonafarnib’s metabolism with ritonavir increases antiviral response
1
Lonafarnib Monotherapy vs Lonafarnib + Ritonavir Week 4 Reduction in Serum HDV RNA
Lonafarnib
100 mg BID Placebo
Lonafarnib 100 mg BID +
Ritonavir 100 mg QD
Lonafarnib
200 mg BID 0.5
0
-0.5
-1
-1.5
-2
-2.5
Mean ∆ = - 0.74 Log
Mean ∆ = - 1.60 Log
Mean ∆ = - 2.2 Log
Mean ∆ = - 0.2 Log
N = 4 N = 6 N = 6 N = 3
Ch
an
ge i
n L
og
HD
V R
NA
co
pie
s/m
L
A)B)
C) D)
High Dose
Months 4-6Months 1-3
LNF 50 mg BID
or
LNF 25 mg BID
LNF ≥ 75 mg BID + RTV
LNF 50 mg BID
or
LNF 25 mg BID
+ RTV 100 mg BID
+ RTV 100 mg BID + PEG IFN α 180 mcg QW
Low Dose
Low Dose: Triple Combination
N=19
N=15
N=12
N=46
LOWR HDV – 2: “Dose Finding” StudyTolerability, Longer Dosing, and Triple Combination
58
High Dose
Months 4-6Months 1-3
LNF 50 mg BID
or
LNF 25 mg BID
LNF ≥ 75 mg BID + RTV
LNF 50 mg BID
or
LNF 25 mg BID
+ RTV 100 mg BID
+ RTV 100 mg BID + PEG IFN α 180 mcg QW
Low Dose
Low Dose: Triple Combination
N=19
N=15
N=12
N=46
LOWR HDV – 2: “Dose Finding” StudyTolerability, Longer Dosing, and Triple Combination
59
Summary and Conclusion- 1
The only effective treatment is with interferons
Treatment beyond 1 year needed in a sizeable
proportion of patients
Until new therapies are available IFN treatment
duration has to be decided on an individual basis
In order to treat CDH, it needs to be diagnosed
Beware of certain risk populations (immigrants,
IVDUs)
.
Summary and Conclusion- 2
The future:
There is now hope:
Hepatocyte entry inhibitors
Prenylation inhibitors
Nucleic acid polymers
siRNAs
.
Stay tuned