hepatitis b (and d) cure strategies: how far are...

Heiner WedemeyerDept. of Gastroenterology and Hepatology

Essen University Hospital

Hepatitis B (and D) Cure Strategies: How far are we?

H. Wedemeyer 8-2018 Hepatitis Viruses

International Hepatitis E Symposium February 14-16, 2019

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H. Wedemeyer 10-2018 HBV cure

HBV is present in humans since >5.000

years (maybe 100.000 years) !

(isolation of HBV Genotype C2 from a

korean mummy 15th centruy)

Bar-Gal et al., Hepatology 2012

Paraskevis, Hatzakis et al.: Hepatology 2013 Mar;57(3):908-916

HBV Diversity in comparision to human evolution:

HBV infection of humans longer than 33.000 years!

Nature. 2018 May;557(7705):418-423. Ancient hepatitis B viruses from the Bronze Age to the Medieval period.

https://www.ncbi.nlm.nih.gov/pubmed/29743673


Hepatitis B Virus: Co-evolution over more than 400 Million years!

Lauber, Seitz, …. Bartenschlager; Cell Host Microbe 2017


The hepatitis B-associated disease burden is still increasing!

HBV-Cirrhosis Mortality

Increase 36%

HBV-HCC Mortality

Increase 51%

GBD-Study: Lancet Jan 2015

Cowie et al.: EASL 2015

Mortality due to HBV 2013~ 650.000


Hepatitis B ≠

Hepatitis B


Different phases of HBV infection

Lok, Zoulim et al., J Hepatology 2017


1Chang et al., Hepatology 2010 2Marcellin et al., Lancet. 2013 3Hosaka et al., Hepatology 2013, Kwon and Lok, Antivir Ther 2011Glebe & Bremer, Semin Liver Dis. 2013

Improvement of fibrosis1,2

NUCs

Suppression of HBV DNA in >95%

Reduction of risks for HCC and decompensation3

NA treatment of chronic hepatitis B


Papatheodoridis, GV et al., J. Hepatol. 2018; 68: 1129-1136

HBV NA-treated patients have an excellent longterm outcome!


Do we really need new therapies for hepatitis B?


➢HBsAg-positive patients have an increased risk to develop hepatocellular carcinoma

➢ Long-term treatment is associated with costs and may cause side-effects

➢ Immunosuppression may lead to severe HBV reactivation

➢Very limited treatment options for HDV coinfection

Why would “curative” therapies for HBV be useful?


Heterogeneity of hepatitis delta world-wide: the HDIN network

Hepatic clinical complications

➢ The Hepatitis Delta International Network (HDIN)➢ 1579 anti-HDV+ or HDV-RNA+ patients from 15 countries

Wranke et al., Liver International 2018


HDV infection increases the risk for liver-related clinical events

Beguelin et al., J Hepatol 2017 (66:297-303)

Anti-HDV+vs. anti-HDV(-)

HDV-RNA+vs. HDV-RNA(-)


PEG-IFNa leads to HDV RNA suppression in ~25% of cases

Wedemeyer, Yurdaydin et al. NEJM 2011


New treatments aiming for HBV cure

H. Wedemeyer 10-2018 HBV cureLok, Zoulim et al., J Hepatology 2017


Source: Durantel & Zoulim. J Hepatol 2016; 64:117-131

DAA

HTA


HBV-specific T cells kill HBV infected cells

Kah, ..., Bertoletti, Dandri. Journal of Clinical Investigation 2017


Wooddell et al., Sci. Transl. Med. 2017

HBsAg-Reduction by siRNAs


Bazinet et al. Lancet G&H 2017

Nucleic Acid Polymers to block HBV release


Median HDV RNA levels

HBV-HDV Entry Inhibition

Wedemeyer et al., EASL 2018


The virological endpoint of novel therapies

HBsAg loss


Is HBsAg loss a reliable surrogate endpoint?


Jaroszewicz et al., Antiviral Therapy 2011

Loss of HBsAg during Nuc-Therapy can be predicted by HBsAg kinetics


HBsAg loss after 12 years of therapyJaroszewicz, Cornberg et al., AVT 2011

HCC2 years after HBsg loss

Is HBsAg loss a reliable surrogate endpoint?


HBsAg loss was not associated with a lower HCC incidence in Alaska!

Gounder et al., AP&T 2016


HCC rate / 100.000 person years:

HBsAg loss: 132

no HBsAG loss: 178

HR 0.7 (0.2-2.4); p=0.65

HBsAg loss was not associated with a lower HCC incidence in Alaska!

Gounder et al., AP&T 2016


Yuen et al., Gastroenterology 2008

Risk of HCC After HBsAg Loss

Follow-up (month)

Early loss of HBsAg is important



Potential Surrogate Markers for HBV: HBsAg


Different sources of HBsAgCornberg et al., J Hepatol 2017; 66:398-411

16


HBV-IntegrationMason et al., Gastroenterology 2016; 151: 986-998

• Integration randomly across chromosomes

• clonal hepatozyte-expansion high in high viremic infection

Similar data:Urban-lab (J Virol 2018)



Potential Surrogate Markers for HBV: HBV-RNA


Me

an

ch

an

ge

fro

m b

ase

line

(lo

g10

co

pie

s/m

L)

-2.0

-1.0

-0.5

0.0

0.5

-1.5

Cohort J(peg-IFN alpha-

2a +600 mg BD)

- 1.51

Cohort K(peg-IFN alpha-2a

+ placebo)

- 0.73

Cohort I(600 mg BD)

- 0.82

Placebo

HBV-RNA is induced by NVR 3-778

Yuen et al., EASL 2016 (LB06)



Potential Surrogate Markers for HBV: HBcrAg


HBcrAg in different phases of HBV infection

Higher Risk for reactivation?

Maasoumy, Cornberg et al., CMI 2015



Potential Surrogate Markers for HBV: cccDNA


Immunotherapies

New treatments for HBV

Host targeting agents Direct acting antivirals


…or simply to stop NA therapy?

New treatments for HBV


Stopping TDF-Treatment: The Gemran FINITE-StudyBerg, T et al., J. Hepatol. 2017; 67: 918–924

40


Induction of IP-10, IL12, TNFa, IL-10 and T-cell responses after cessation of therapy

Hoener zu Siederdissen, Rinker, et al. JID 2016


Stopping NA-Therapy leads to an immune induction„auto-vaccination“

Höner zu Siederdissen et al., J infect Dis 2016; 214: 1492-97Zimmer et al., J Infect Dis 2018; epub

Rinker et al., J Hepatol 2018 epub

43


How to use a new drug against HBV?

Putative Target Profile for a New Curative Therapy for Hepatitis B

“The musts”

➢No major safety signal

➢Finite therapy ideally 12 weeks – 48 weeks (max)

➢Endpoint: HBsAg loss> 30% of patients (HBsAg decline sufficient?)

HBsAg kinetics have to be consideredin the development of novel curative therapies

Antiviral Therapy

HBV DNA

HBsAgeraBicate

Antiviral Therapy

HBV DNA

HBsAg

HBsAg kinetics have to be consideredin the development of novel curative therapies

Continue Therapy?Is this clinically meaningful?

eraBicate

HBV DNA

HBsAg

Novel curative therapies as first line treatment?

Continue Therapy?Is this clinically meaningful?

eraBicate

H. Wedemeyer: 02-2018

NK cells and T cells and HCV Therapy

Was kann der Patient noch tun?

Kaffee ist

gut

für die Leber

H. Wedemeyer: 02-2018

NK cells and T cells and HCV Therapy

Is Aspirin good or bad?

Original InvestigationOctober 4, 2018

Association Between Aspirin Use and Riskof Hepatocellular Carcinoma

TraceyG. Simon, MD; Yanan Ma, PhD;Jonas F. Ludvigsson, MD, PhD;

et al

JAMA Oncology

Good: Lower HCC Incidence! Bad: Aspirin may cause cancer!

NEJM Sept 16 2018Effect of Aspirin on All-CauseMortality in the Healthy ElderlyJohn J. McNeil, et al.,for the ASPREE Investigator Group

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