- Hepatitis B - Resistence management in the clinical setting - - PowerPoint PPT Presentation

▶
hepatitis b resistence management in the clinical setting
SMART_READER_LITE
LIVE PREVIEW

- Hepatitis B - Resistence management in the clinical setting - - PowerPoint PPT Presentation

Sep 18, 2023 282 likes •711 views

- Hepatitis B - Resistence management in the clinical setting Priv.-Doz. Dr. A. Erhardt Klinik fr Gastroenterologie, Hepatologie und Infektiologie Universittsklinikum Dsseldorf Aims of HBV Therapie Effektive therapy - HBsAg

slide-1
SLIDE 1
  • Hepatitis B -

Resistence management in the clinical setting

Priv.-Doz. Dr. A. Erhardt Klinik für Gastroenterologie, Hepatologie und Infektiologie Universitätsklinikum Düsseldorf

slide-2
SLIDE 2

Aims of HBV Therapie

  • Effektive therapy
  • HBsAg seroconverion
  • HBeAg seroconversion
  • DNA suppression
  • Avoiding resistence
slide-3
SLIDE 3

HBV Therapy

  • available medications -
  • Interferone
  • Pegylated interferons
  • Interferon-alfa2b and interferon-alfa2a
  • Nukleos(t)idanaloga
  • Lamivudine
  • Adefovir
  • Entecavir
  • Telbivudine
  • Tenofovir (HIV)
  • Emtircitabine (HIV)
slide-4
SLIDE 4

Avoiding resistence

  • Correct indication
  • Role of interferons
  • Antiviral potency of nucleosidanaloga
  • Resistence barrier
  • Resistence profile
  • Virus kinetiks „on treatment“
  • Secundary resistence
  • Primary resistence
slide-5
SLIDE 5

Indication for treatment

slide-6
SLIDE 6

IFN-Response and HBV-Genotyp

– Literature; HBeAg-positive patients –

40 20

A

60

HBV-Genotype

50 30 10

B C D Respnse (%) Janssen et al. Lancet 2005 Erhardt et al. Gut 2005 Lau et al. NEJM 2005 Wai et al. Hepatology 2002 Kao et al. J Hepatol 2000

slide-7
SLIDE 7

Genotype and Response

N= 399 Patienten; IFN/ PEG-IFN 4–12 months

40 20 60 50 30 10

36 36 22 22 Genotype A n=141

p < 0,003

43 29 SR [%] 20

p < 0,001

Genotype D n=258 HBeAg+ n=222 HBeAg- n=177

Erhardt, Ludwig, Brunetto et al, AASLD 2007

slide-8
SLIDE 8

HBeAg-Status and Genotype

N= 399 patients; IFN/ PEG-IFN 4–12 months

Erhardt, Ludwig, Brunetto et al, AASLD 2007 40 20 60 50 30 10

45 45 39 39 HBeAg+

n.s.

19 29 SR [%] 21 n.s. HBeAg- HBeAg+ HBeAg-

Genotype A Genotype D

slide-9
SLIDE 9

Antiviral Potency

DNA-suppression below 300/400 Cop/ml after 48/52 Wo

2 1 3 6 6 0 6 7 7 6 5 1 7 2 7 4 9 0 9 3 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 HBeAg+ HBeAg-

Adefovir Lam ivudine Telbivudine Entecavir Tenofovir

DNA Negativierung [%]

Dienstag et al, NEJM 1999; Lai et al, NEJM 1998; Chang et al, NEJM 2006; Lai et al, NEJM 2006; Lai et al, AASLD 2006; Lai et al AASLD 2005; Marcellin et al, NEJM 2003; Hadziyannis et al, NEJM 2003; Heathcote et al, AASLD 2007; Marcellin et al, AASLD 2007

slide-10
SLIDE 10

20 40 60 80 100

LAM LAM/PEG e- LAM/PEG e+ ADV FTC LDT LDT/LAM ETV ETV/LAM-R LAM ADV/LAM TDF/LAM

1. 5. 19 69 90 67 38 50 49 70 4 11 18 28 22 5 19 11 12 5 1 9 17 3.

Hadziyannis et al, NEJM 2005; Lai et al, Clin Inf Dis 2003; Qi et al, J Hepatol 2004; Hadziyanniset al, AASLD 2005; Colonno et al, AASLD 2006; Benhamou et al, Hepatology 1999

Secundary resistence - Nucleos(t)idanaloga

HBV HBV/HIV

% Resistenz

slide-11
SLIDE 11

Combination therapy

Kombination Literatur Patienten Virologisches Ansprechen Resistenzen [%] FTC+Clevudine

  • vs. FTC

Lim et al, 2006

163; naiv HBV idem 7 vs. 10 LDT+LAM vs. LDT vs. LAM

Lai et al, 2005

104; naiv HBV idem 12,2 vs. 4,5 vs 15,8 TDF+LAM vs. TDF

Schmutz et al, 2006

75 LAM-R; HBV/HIV idem k.A. ADV+LAM vs. LAM

Peters et al, 2004

59; LAM-R idem keine ADV+LAM vs. LAM

Lampertico et al, 2006

588; LAM-R idem 2 vs. 9 (0,001) ADV+LAM

Lampertico et al, 2007

145; LAM-R 80% 4% after 4 years

slide-12
SLIDE 12

Resistence profile of nucleos(t)idanaloga

M204I

Lamivudine Telbivudine Clevudine Entecavir Tenofovir Adefovir Emtricitabine

M 2 4 V / I L 1 8 M N 2 3 6 T A 1 8 1 V / T T 1 8 4 G / S S 2 2 I M 2 5 V V 2 1 4 A / Q 2 1 5 S V 1 7 3 L L 8 V / I A 1 9 4 T V 8 4 M / S 8 5 A

X X X

X Crossresistance; Villet et al, J Hepatol 2008

slide-13
SLIDE 13

Adapting therapy

slide-14
SLIDE 14

Tenofovir

108 patients; multizentrisch; 6 naive Patienten, 102 pretreated mit Lamivudine und Adefovir

van Bömmel, deMan, Erhardt, et al, AASLD 2007 m onth 1 2 of TDF treatm ent ( n= 93 ) HBV DNA < 4 0 0 c/ m L:

total 84/ 93 (90% )

HBeAg positive 5 8 / 6 8 ( 8 5 % ) HBeAg negative 2 4 / 2 5 ( 9 6 % ) ADV pretreatm ent 6 5 / 7 3 ( 8 9 % ) no ADV pretreatm ent 1 8 / 2 0 ( 9 0 % ) YMDD m utations at TDF BL 5 1 / 5 7 ( 8 9 % ) HBV w ild type at TDF BL 3 3 / 3 6 ( 9 2 % ) HBV DNA < 1 0 7 at TDF BL 4 2 / 4 2 ( 1 0 0 % ) HBV DNA > 1 0 7 at TDF BL 3 9 / 5 1 ( 7 6 % ) liver cirrhosis 1 7 / 1 9 ( 8 9 % ) Norm al ALT 7 0 / 9 3 ( 7 5 % ) HBeAg serovonversion 16/ 75 (21% ), mean 11month [ 2-34] HBsAg loss 3/ 108 (2.7% , mean 17month [ 9-25]

end of

  • bsveration:

p=n.s p=n.s p=n.s. p=0.01. p=n.s

slide-15
SLIDE 15

Primary resistence

N= 212; naive Patienten

Ludwig et al, EASL 2008

1 2 3 4

I233V A181A/S N236N/D M204I V173V/L A194A/T

Anzahl Patienten

Primary resistence in 5,2% of patients

M 2 04 I/V A 1 8 1 S I2 3 3 V L 1 8 M V 1 7 3 L 3 3 2 1 2 5 N 2 3 6 D A 19 4 T T184A /S

La m ivudine A defovir T enofo vir E ntecavir

Patients

slide-16
SLIDE 16

Primary resistence and genotype

N= 212; naive patients

Ludwig et al, EASL 2008

A B C D E G 10 20 30 40 50 60 70 Percentage of patients with primary resistance mutations per genotype for all patients (in percent, y-axis) and for patients with genotype A

  • r D

(indicated as number). Distribution of H BV genotypes for all patients n=212 (in percent, y-axis)

3,6% 6,8%

HBV genotypes

Percent [% ]

T184I/T (possible resistance) D 1 Entecavir A194A/T A 1 Tenofovir V173V/L (possible resistance) D 1 Lamivudine M204V+L180M B 1 Lamivudine M204I A 1 Lamivudine I233V (4x), A181A/S (1x), N236N/D (possible resistance,1x) D 6 Adefovir

Detected mutations Geno- type Number of patients Nukleos(t)ide

slide-17
SLIDE 17

Genotype and Nucleosideanaloga

N=53; Adefovir for 48 Wo; n=40 genotype D; n=13 genotyp A

Chueca et al, EASL 2007

1 0 2 0 3 0 4 0 5 0 6 0 D A2 A1 < o

HBV Genotyp Nonresponse [%]

Where is the diference? Genotyp A2: rtL217R HBV Genotyp A2 Nonresponder: rt122N/rt126Y HBV Genotyp A2 Responder: rt122H/rt126H

slide-18
SLIDE 18

Therapy

slide-19
SLIDE 19

Conclusion

  • HBV-DNA of 2.000 IU/ ml (10.000 Kop/ ml) important for

treatment indication and natural course of HBV

  • HBV-DNA von 200 IU/ ml (1000 Kop/ ml) important for

determining treatment response at month 6

slide-20
SLIDE 20

Conclusion

  • Etermination of HBV-enotype, Hepatitis-B-viral load and virus kinetiks

importat and for the treatment choice and treatment monitoring

  • Resistance determination before therapy?
  • Consider Interferons as first line therapy
  • Therapy

with nucleos(t)idanaloga considering antiviral efficacy, resistence barrier and resistence profile

  • Add-On vs. switch
slide-21
SLIDE 21
slide-22
SLIDE 22

HBV-Genotyp

  • weltweite Verteilung-

Erhardt; In: Hepatitis B, 2006

B HF G

F1 H F1 F2 F2 F

A A A D D D D D D B C B C D D D C B Caus Aafr Aafr D E E D D

slide-23
SLIDE 23

Seltene Genotypen – IFN

n=28 (E: 21; F :3; H: 4); n=15 mit IFN; 4 mit NA; 9 keine Therapie

40 20 50 30 10

40 40 33 33 Alle 50 33

% Response

Genotyp E Alle Genotyp E

ETR SVR

Data unpublished

slide-24
SLIDE 24

Schaefer und Gerlich, 2007

Wichtige Bereiche für Replikation und IFN-Response

slide-25
SLIDE 25

Therapieziel: Überleben

20 40 60 80 100 Zeit (Monate) 12 24 36

48 60 72 84 96

HBe-Ag negativ HBe-Ag negativ HBe-Ag positiv HBe-Ag positiv

Komplikationsfreies Überleben (%) Interferon-Gruppe (n = 103) Kontroll-Gruppe (n = 53)

Niederau et al, NEJM 1996

slide-26
SLIDE 26

Therapieziel: HCC Inzidenz

(11.893 Männer)

Yang et al, NEJM 2002

RR: 60,2 RR: 1,0 RR: 9,6

HBsAg+ , HBeAg+ HBsAg+ , HBeAg- HBsAg- ,HBeAg+

slide-27
SLIDE 27

Definitionen

Therapie

+/-

  • +
slide-28
SLIDE 28

Chen et al, JAMA 2006

HBV – HCC Inzidenz und Viruslast Kohorte, N= 3653, Asien

slide-29
SLIDE 29

Langzeit-Lamivudine bei Zirrhose

RCT, Taiwan, N = 651, Follow-up 32,4 Monate

Liaw et al, NEJM, 2004

slide-30
SLIDE 30

Leberzirrhose –Lamivudine

Bedeutung von Resistenzen für Progress

Liver cirrhosis complications

slide-31
SLIDE 31

Laboruntersuchungen vor Therapie

  • HBV-DNA quantitativ
  • HBV-Genotypisierung (bei klinischer Relevanz)
  • Klinisch-chemische Labortests
slide-32
SLIDE 32

IFN-Response und HBV-Genotyp

Erhardt et al, Gut 2005

Genotyp A Genotyp D p-W ert N 78 66 Kumulative IFN-Dosis [ MU] 418±21 447±20 n.s. Behandlungsdauer [ Monate] 6.7 6.2 n.s. ETR [ % ] 59 46 n.s. Relapse [ % of ETR] 17 43 < 0.02 SVR [ % ] 4 9 2 6 < 0 .0 0 5

slide-33
SLIDE 33

IFN-Response und HBV-Genotyp

– Literaturübersicht; HBeAg-positive Patienten –

40 20

A

60

HBV-Genotyp

50 30 10

B C D Ansprechen (%) Janssen et al. Lancet 2005 Erhardt et al. Gut 2005 Lau et al. NEJM 2005 Wai et al. Hepatology 2002 Kao et al. J Hepatol 2000

slide-34
SLIDE 34

Laboruntersuchungen unter Therapie

  • HBV-DNA quantitativ nach 4-6 Wo
  • HBV-DNA anschliessend alle 3 (-6) Monate
  • Bestimmung von Resistenzmutationen bei
  • Anstieg der Virämie (> 1 log Anstieg im Vgl. zu Nadir)
  • fehlendem primärem Ansprechen (< 1 log Abfall zu Mo 3)
  • Klinisch-chemische Labortests
slide-35
SLIDE 35

Wirksamkeit von Nukleos(t)idanaloga

DNA-Suppression unter 300/400 Kop/ml nach 48/52 Wo

2 1 3 6 6 0 6 7 7 6 5 1 7 2 7 4 9 0 9 3 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 HBeAg+ HBeAg-

Adefovir Lam ivudine Telbivudine Entecavir Tenofovir

DNA Negativierung [%]

Dienstag et al, NEJM 1999; Lai et al, NEJM 1998; Chang et al, NEJM 2006; Lai et al, NEJM 2006; Lai et al, AASLD 2006; Lai et al AASLD 2005; Marcellin et al, NEJM 2003; Hadziyannis et al, NEJM 2003; Heathcote et al, AASLD 2007; Marcellin et al, AASLD 2007

slide-36
SLIDE 36

Nukleos( t) idanaloga

* * * * * zugelassene Medikamente

slide-37
SLIDE 37

Tenofovir

108 Patienten; multizentrisch; 6 naive Patienten, 102 vorbehandelt mit Lamivudine und Adefovir

van Bömmel, deMan, Erhardt, et al, AASLD 2007

slide-38
SLIDE 38

Hepatitis D

  • Pegyliertes IFN
  • Dauer mindestens 12 Monate
  • Nukleot(s)idanaloga oder Kombination von IFN und

Nukleot(s)idanaloga unwirksam gegenüber HDV

  • Nukleot(s)idanaloga indiziert bei persistierender HBV

Infektion (> 2000 IU/ ml)

slide-39
SLIDE 39

Hepatitis D

pegyliertes Interferon

N Medikation Dauer [ W o] GPT SR HDV RNA SVR Castelneau et al Hepatol 2006 14 PegIFN alfa2b 48 57% 43% Niro et al Hepatol 2006 38 PegIFN alfa2b

  • vs. PegIFN alfa2b

+ RBV (48wk) 72 25% 27% 25% 18% Erhardt et al Liver Int 2006 12 PegIFN alfa2b 48 27% 17% W edem eyer et al EASL 2007 91 PegIFN alfa2a vs. PegIFN alfa2a + ADV

  • vs. ADV

48 24% 30 vs. 21

  • vs. 8 %
slide-40
SLIDE 40
  • Z. Gastroenterol, 2007, 45:1-50
slide-41
SLIDE 41

Akute Hepatitis B

  • Hohe Spontanheilungsrate – keine Therapieindikation

Randomisierte Studie; n= 71;

  • Therapieindikation bei fulminanter Hepatitis

Kumar et al, Hepatology 2007

9 3 ,5 9 6 ,7 9 2,5 97 ,5 67 ,7 8 5

1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 H BsAg loss Mo 1 2 H BsAg loss Mo 1 8 ant i- H Bs Mo 1 2 LAM Kont rolle

[%]

slide-42
SLIDE 42

Empfehlung Fachgesellschaften

  • HBeAg-positiv:

GPT 2 bis 5 -fache der Norm : 1) Interferon 2) Nukleos(t)idanaloga EASL Interferon oder Nukleos(t)idanaloga DGVS, AASLD GPT > 5 -fache der Norm : 1) Interferon 2) Nukleos(t)idanaloga DGVS, EASL

  • HBeAg-negativ, GPT > 2 -fache Norm :

1) Interferon 2) Nukleos(t)idanaloga EASL, AASLD Nukleos(t)idanaloga DGVS

  • Kom pensierte Zirrhose:

– Interferon oder Nukleos(t)idanaloga DGVS, EASL – Nukleos(t)idanaloga AASLD