Lessons learned during the HOPE-Project - which role have HBV - - PowerPoint PPT Presentation

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Lessons learned during the HOPE-Project - which role have HBV - - PowerPoint PPT Presentation

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11.04.2013 AREVIR Meeting Kln Lessons learned during the HOPE-Project - which role have HBV mutations in the times of tenofovir and entecavir? Florian van Bmmel University Hospital Leipzig Hepatology Section Germany Current

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SLIDE 1

Lessons learned during the HOPE-Project

  • which role have HBV mutations

in the times of tenofovir and entecavir?

Florian van Bömmel University Hospital Leipzig Hepatology Section Germany 11.04.2013 AREVIR Meeting Köln

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SLIDE 2
  • Current treatment of chronic HBV with

nucleos(t)die analogues

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SLIDE 3

3 Click to edit Footnote

Virological Response to ETV in treatment-naïve patients by HBeAg Status (undetectable HBV DNA)

Patients % HBeAg(-)

20 40 60 80 100

6 38% 63% 12

67 66

88%

48

Months

24

20 40 60 80 100

6 74%

Patients %

90% 12

338 327 Patients

  • n follow-up

96%

296

24

HBeAg(+ )

88%

42

36 98%

265

36 97%

32

48 98%

227

48 100%

11

60 100%

86

60

Lampertico P, et al. AASLD 2012, Boston, MA. Poster 366.

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SLIDE 4

Response to third line entecavir monotherapy in patients after previous consecutive failure to lamivudine and adefovir treatment

Herber A, van Bömmel F et al. DGVS 2011

Entecavir 1 mg/day

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SLIDE 5

Tenofovir

Marcellin et al., AASLD 2011, Abstract 238 u. 1375

Suppression of HBV DNA under the detection limit during long term treatment with TDF

Marcellin et al., AASLD 2011, Abstract 238

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SLIDE 6

LAM-resistance 70 54 25 ADV=adefovir dipivoxil LAM=lamivudine

van Bömmel et al., Hepatology 2010

ADV-resistance 21 15 3 no genotypic resistance 22 18 12 patients under observation (n):

months

p<0.0001

HBV resistance against ADV decreases efficacy of TDF monotherapy

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SLIDE 7

Response to TDF monotherapy acording to baseline resistance mutations – an Australian perspective

Patterson S J et al. Gut 2011;60:247-254

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SLIDE 8

Response to TDF monotherapy acording to baseline resistance mutations – an Australian perspective

Patterson S J et al. Gut 2011;60:247-254

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SLIDE 9

TDF monotherapy in a patient with ADV resistance

a)

% HBV variants N236T WT A181T+N236T

12 9 6 100 50 5 12 14

3 6 9 12 15 18 1 2 3 4 5 6 7 8

lower limit of detection

3 6 9 12 15 18 1 2 3 4 5 6 7 8

lower limit of detection

TDF LAM

months HBV DNA log

10 copies/mL

TDF +

van Bömmel et al, Antiviral Therapy 2012

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SLIDE 10

Background: Currently available HBV polymerase inhibitors and HBV resistance mutations

EASL Clinical Practice Guideline CHB. J Hepatol. 2009;50:227-242

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

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SLIDE 11
  • Beyond the „own“ reading frame

mutations in the HBV s-gene

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SLIDE 12

HBV Genome

The HBV genome is compact (3.2kb) and contains four overlapping reading frames, encoding seven proteins Surface proteins L M S Polymerase Core Precore X

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SLIDE 13

Pre-S Mutations

Naturally occurring (B cell responses) Antiviral drug selected (POL/envelope overlap)

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SLIDE 14

Pre-S function

Important regulatory function of surface protein (transcription)

Summers et al 1990

Attachment of HBV to the hepatocytes surface for initiating infection

Neurath 1989, Ishikawa & Ganem 1995

T and B cell recognition sites

Chisari and Ferrari 1995

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SLIDE 15

LHBs MHBs SHBs S

Pre-S1/Pre-S2/S ORF

Pre-S1 RNA (2.4kb)

S S S PreS2 PreS2 PreS1

Pre-S2/S RNA (2.1kb)

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SLIDE 16

LHBs GP33 (GP36) MHBs SHBs S

Pre-S1 RNA (2.4kb)

S S S PreS2 PreS2 PreS1 Pre-S2/S RNA (2.1kb) CHO CHO CHO CHO P39 (GP42) P24 (GP27)

Pre-S2 Deletion Mutant

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SLIDE 17

LHBs SHBs

Pre-S1 RNA (2.4kb)

S S PreS1 Pre-S2/S RNA (2.1kb) CHO CHO Truncated Pre-S1(L) P24 (GP27)

Pre-S2 Deletion Mutant

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SLIDE 18

Pre-S Mutations

Yoo BC et al, J Viral Hepatitis 2007

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SLIDE 19

Terminal Protein Spacer RNAse H Polymerase gene Surface gene PreS1 Pre S2 S A1 8 1 T

A B C D F G

Reverse transcriptase

E

W 1 7 2 * Lam ivudine, Adefovir, Telbivudine, Clevudine L M S Surface proteins

ER lumen/virion surface Cytosol/virion interior

Surface proteins

membrane

X

Transactivation and HCC

Tenofovir,

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SLIDE 20

Truncated s-antigens may accumulate in the hepatocytes

Surface proteins are shown as brown staining. Cell nuclei are stained in blue. 1:1 mixture of both. HBVwt HBV172*

Warner N, et al. Hepatology 2008

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SLIDE 21

Monat Probe M204I M204V L80V V173L L180M A181V A181T N236T A194T I169T Varianten E164D I195M W196S/* W172* W182* W199*/L BL M204I M204V WT V173/WT L180M/WT WT WT WT WT WT V84M/WT, N122T/WT, Q130H/WT, V208I/WT, R217L/WT,M335L/WT E164D/WT I195M/WT W196*/WT WT WT W199*/WT 5 M204I/WT WT WT WT L180M/WT WT WT WT WT WT V84M/WT, N122T, S143F/WT, Q130H/WT, V208I/WT, R217L,M335L/WT WT WT W196*/WT WT WT W199*/WT 11 M204I/WT WT WT WT WT WT WT WT WT WT V84M, N122T, Q130H, V208I, R217L/WT,M335L/WT WT WT W196*/WT WT WT WT 21 M204I M204V WT WT L180M/WT WT WT WT WT WT WT, N122T/WT, N123T/WT, Q130H/WT, V208I/WT, R217L/WT,M335L/WT WT I195M/WT W196*/WT WT WT W199*/WT 29 M204I M204V WT V173/WT L180M/WT WT WT WT WT WT WT, N118T/WT, N122T/WT, Q130H/WT, V208I/WT, R217L/WT,M335L/WT E164D/WT I195M/WT W196*/WT WT WT W199*/WT 50 M204I M204V WT WT L180M/WT WT WT WT WT WT WT, N122T/WT, Q130H/WT, V208I/WT, R217L/WT,M335L/WT WT I195M/WT W196*/WT WT WT W199*/WT

Examples for persistance of stop codons within the s-gene during TDF treatment

Schmalbrock, van Bömmel, submitted 2013

Monat Probe M204I M204V L80V V173L L180M A181V A181T N236T A194T I169T Varianten E164D I195M W196S/* W172* W182* W199* BL WT WT WT WT WT WT WT WT WT WT Y124H, R266I, E271D, V282I, M309K WT WT WT WT WT WT 5 WT WT WT WT WT WT WT/A181T WT WT WT Y124H, R266I, E271D, V282I, M309K, V191I/WT WT WT WT WT/W172* WT/sagW1 82* 12 WT WT WT WT WT WT WT WT WT WT Y124H, V282I WT WT WT WT WT WT 25 WT WT WT WT WT WT WT WT WT WT Y124H, R266I, E271D, V282I, M309K WT WT WT WT WT WT 33 WT WT WT WT WT WT WT WT WT WT Y124H, R266I, E271D, V282I, M309K WT WT WT WT WT WT 46 WT WT WT WT WT WT WT WT WT WT S74A, Y124H, E271D, I278V, V282I, M309K WT WT WT WT WT WT

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SLIDE 22
  • HBsAg mutations caused by HBV polymerase

gene mutants – any clinical impact?

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SLIDE 23

HBV leading to HCC Development?

Multi-factorial process

  • 1. Inflammation, damage & regeneration
  • 2. Increase in chromosomal instability
  • a. Integration
  • b. Oxidative stress
  • 3. Direct effect of the virus or viral proteins
  • a. HBx
  • b. PreS2 deletion mutants
  • c. PreS2 C-terminal truncation (integrants)
  • c. HBSP (splice protein)
  • e. Basal Core Promoter/pre-C stop codon mutations

Hino 2002, Warner & Locarnini 2009

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SLIDE 24
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SLIDE 25

Reference HCC (n, %) Control (n, %) Odd ratio 95% CI P value Lin et al1 19/64 (29.7%) 25/202 (12.4%) 3.72 1.44-9.65 0.007 Yeung et al2 23/69 (33.3%) 11/69 (15.9) 2.64 1.17-5.96 0.018 Qu et al3 32/134 (23.9%) 14/114 (12.3%) 2.22 1.03-4.76 0.041 Chen et al4 28/80 (35.0%) 27/160 (16.9%) 2.17 1.13-4.19 0.021

Pre-S mutation and HCC

1Lin et al, J Gastroenterology 2007; 22:1098 2Yeung et al, J Infectious Dis 2011; 203:646 3Qu et al, Hepatol Research 2011; 41:54 4Chen et al, J Infectious Dis 2008; 198:1634

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SLIDE 26

Pre-S Mutation & Long Term Outcome

141 HBeAg negative patients Followed up for at least 36 months Incidence of Pre-S mutation at baseline 27/141 (19.1%) Chen et al, Gastroenterology 2007

Progression to Cirrhosis

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SLIDE 27

Increased HCC risk in patients with prior LAM resistance

Papatheodoridis GV et al, J Hepatol 2010

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SLIDE 28

Hepatocarcinogenic effects

PreS1 and PreS2 mutations cause over production and accumulation of LHBs in the endoplasmic reticulum Resulting in significant ER stress Induce DNA damage & genomic instability

Bock et al, Hepatology 2007

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SLIDE 29
  • the remains of the day
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SLIDE 30

Marcellin et al. The Lancet Volume 381, Issue 9865 2013 468 - 475

Development of liver histology in 348 patients during 5 years tenofovir treatment

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SLIDE 31

Does NA Therapy Prevent HCC?

YES!

2010 Journal of Hepatology vol. 53

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SLIDE 32

32 Click to edit Footnote

Long-term treatment with ETV reduces HCC incidence

Hosaka T, et al. AASLD 2012, Boston, MA. Poster 357.

Figure 3. Comparison of hepatocellular carcinoma cumulative incidence rates between the ETV-treated group and the non-treated control group after propensity score matching

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SLIDE 33

Summary

  • Long term treatment with NUCs is safe and

effective in preventing HCC and reversing fibrosis

  • HBsAg mutations are beeing selected and

persist during NUC treatment

  • liver damage or HCC by defective HBsAg

secretion must be assumed for individual patients