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