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

- Hepatitis B - Resistence management in the clinical setting Priv.-Doz. Dr. A. Erhardt Klinik für Gastroenterologie, Hepatologie und Infektiologie Universitätsklinikum Düsseldorf

Aims of HBV Therapie • Effektive therapy - HBsAg seroconverion - HBeAg seroconversion - DNA suppression • Avoiding resistence

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

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

Indication for treatment

IFN-Response and HBV-Genotyp – Literature; HBeAg-positive patients – Respnse (%) Janssen et al . Lancet 2005 Erhardt et al . Gut 2005 60 Lau et al . NEJM 2005 Wai et al . Hepatology 2002 50 Kao et al. J Hepatol 2000 40 30 20 10 0 A B C D HBV-Genotype

Genotype and Response N= 399 Patienten; IFN/ PEG-IFN 4–12 months p < 0,003 p < 0,001 SR [%] 60 50 40 43 36 36 30 29 22 20 22 20 10 0 Genotype A Genotype D HBeAg+ HBeAg- n=141 n=258 n=222 n=177 Erhardt, Ludwig, Brunetto et al , AASLD 2007

HBeAg-Status and Genotype N= 399 patients; IFN/ PEG-IFN 4–12 months n.s . n.s. SR [%] 60 50 45 45 40 39 39 30 29 20 21 19 10 0 HBeAg+ HBeAg- HBeAg+ HBeAg- Genotype A Genotype D Erhardt, Ludwig, Brunetto et al , AASLD 2007

Antiviral Potency DNA-suppression below 300/400 Cop/ml after 48/52 Wo 1 0 0 DNA Negativierung [%] 9 0 9 0 9 3 8 0 7 0 7 6 7 2 7 4 Adefovir 6 0 6 7 6 0 Lam ivudine 5 0 Telbivudine 5 1 4 0 Entecavir 3 0 Tenofovir 3 6 2 0 2 1 1 0 0 HBeAg+ HBeAg- 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

Secundary resistence - Nucleos(t)idanaloga % Resistenz HBV/HIV HBV 100 70 90 80 67 69 60 49 40 50 28 38 18 20 22 17 19 19 11 5. 9 11 4 12 3. 5 5 0 1 1. LAM/PEG e- LDT/LAM ETV/LAM-R ADV/LAM TDF/LAM LAM LAM/PEG e+ ADV FTC LDT ETV LAM 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

Combination therapy Kombination Literatur Patienten Virologisches Resistenzen Ansprechen [%] FTC+Clevudine Lim et al, 2006 163; naiv HBV idem 7 vs. 10 vs. FTC Lai et al, 2005 LDT+LAM vs. 104; naiv HBV idem 12,2 vs. 4,5 vs LDT vs. LAM 15,8 Schmutz et al, TDF+LAM vs. 75 LAM-R; idem k.A. 2006 TDF HBV/HIV ADV+LAM vs. Peters et al, 2004 59; LAM-R idem keine LAM ADV+LAM vs. Lampertico et al, 588; LAM-R idem 2 vs. 9 (0,001) 2006 LAM ADV+LAM Lampertico et al, 145; LAM-R 80% 4% after 4 2007 years

Resistence profile of nucleos(t)idanaloga S 5 A 1 5 2 8 Q S T I S / / / / V V M V G A I L T T / / M I 4 0 V 3 1 4 2 4 6 0 4 8 0 3 5 4 7 9 0 1 0 8 8 2 2 1 1 2 8 8 1 1 1 2 2 M M V V A A S V N L L T X Lamivudine M204I Telbivudine Clevudine Emtricitabine Entecavir Adefovir X X Tenofovir X Crossresistance; Villet et al, J Hepatol 2008

Adapting therapy

Tenofovir 108 patients; multizentrisch; 6 naive Patienten, 102 pretreated mit Lamivudine und Adefovir 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 % ) p=n.s HBeAg negative 2 4 / 2 5 ( 9 6 % ) p=n.s ADV pretreatm ent 6 5 / 7 3 ( 8 9 % ) no ADV pretreatm ent 1 8 / 2 0 ( 9 0 % ) p=n.s. 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 % ) p=0.01 . HBV DNA < 1 0 7 at TDF BL 4 2 / 4 2 ( 1 0 0 % ) p=n.s HBV DNA > 1 0 7 at TDF BL 3 9 / 5 1 ( 7 6 % ) liver cirrhosis 1 7 / 1 9 ( 8 9 % ) end of Norm al ALT 7 0 / 9 3 ( 7 5 % ) obsveration: HBeAg serovonversion 16/ 75 (21% ), mean 11month [ 2-34] HBsAg loss 3/ 108 (2.7% , mean 17month [ 9-25] van Bömmel, deMan, Erhardt, et al , AASLD 2007

Primary resistence N= 212; naive Patienten Patients A defovir L 1 8 0 M La m ivudine M 2 04 I/V V 1 7 3 L 4 A 1 8 1 S I2 3 3 V T enofo vir Anzahl Patienten E ntecavir 3 3 3 2 1 2 5 2 A 19 4 T N 2 3 6 D T184A /S 1 0 Primary resistence in 5,2% of patients I233V A181A/S N236N/D M204I V173V/L A194A/T Ludwig et al, EASL 2008

Primary resistence and genotype N= 212; naive patients Nukleos(t)ide Number of Geno- Detected mutations 70 patients type Distribution of H BV Adefovir 6 D I233V (4x), A181A/S (1x), 60 genotypes for all patients N236N/D (possible resistance,1x) n=212 (in percent, y-axis) 50 Lamivudine 1 A M204I Percent [% ] Lamivudine 1 B M204V+L180M 40 Lamivudine 1 D V173V/L (possible Percentage of patients with resistance) primary resistance mutations 30 Tenofovir 1 A A194A/T per genotype for all patients Entecavir 1 D T184I/T (possible (in percent, y-axis) and for resistance) 20 patients with genotype A or D 10 (indicated as number). 6,8% 3,6% 0 A B C D E G HBV genotypes Ludwig et al, EASL 2008

Genotype and Nucleosideanaloga N=53; Adefovir for 48 Wo; n=40 genotype D; n=13 genotyp A Where is the diference? 6 0 Nonresponse [%] 5 0 Genotyp A2: rtL217R 4 0 3 0 < o HBV Genotyp A2 Nonresponder: 2 0 rt122N/rt126Y HBV Genotyp A2 Responder: 1 0 rt122H/rt126H 0 D A2 A1 HBV Genotyp Chueca et al, EASL 2007

Therapy

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

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

HBV-Genotyp -weltweite Verteilung- B A D D A D A D B D D D C HF D B D D D G E C F 1 E D H C B F 2 F 1 A afr F 2 C aus A afr F Erhardt; In: Hepatitis B, 2006

Seltene Genotypen – IFN n=28 (E: 21; F :3; H: 4); n=15 mit IFN; 4 mit NA; 9 keine Therapie SVR ETR % Response 50 50 40 40 40 30 33 33 33 20 10 0 Alle Genotyp E Alle Genotyp E Data unpublished

Wichtige Bereiche für Replikation und IFN-Response Schaefer und Gerlich, 2007

Therapieziel: Überleben Komplikationsfreies Überleben (%) 100 HBe-Ag negativ HBe-Ag negativ 80 60 HBe-Ag positiv 40 HBe-Ag positiv 20 Interferon-Gruppe (n = 103) Kontroll-Gruppe (n = 53) 0 12 24 36 48 60 72 84 96 Zeit (Monate) Niederau et al, NEJM 1996

Yang et al, NEJM 2002 RR: 60,2 RR: 1,0 RR: 9,6 HBsAg+ , HBeAg+ HBsAg+ , HBeAg- Therapieziel: HCC Inzidenz HBsAg- ,HBeAg+ (11.893 Männer)

+/- Therapie + - Definitionen

Chen et al, JAMA 2006 HBV – HCC Inzidenz und Viruslast Kohorte, N= 3653, Asien

Langzeit-Lamivudine bei Zirrhose RCT, Taiwan, N = 651, Follow-up 32,4 Monate Liaw et al, NEJM, 2004

Leberzirrhose –Lamivudine Bedeutung von Resistenzen für Progress Liver cirrhosis complications

Laboruntersuchungen vor Therapie • HBV-DNA quantitativ • HBV-Genotypisierung (bei klinischer Relevanz) • Klinisch-chemische Labortests

IFN-Response und HBV-Genotyp Genotyp Genotyp p-W ert A D N 78 66 Kumulative IFN-Dosis [ MU] 418±21 447±20 n.s. Behandlungsdauer 6.7 6.2 n.s. [ Monate] ETR [ % ] 59 46 n.s. Relapse [ % of ETR] 17 43 < 0.02 SVR [ % ] 4 9 2 6 < 0 .0 0 5 Erhardt et al , Gut 2005

IFN-Response und HBV-Genotyp – Literaturübersicht; HBeAg-positive Patienten – Ansprechen (%) Janssen et al . Lancet 2005 Erhardt et al . Gut 2005 60 Lau et al . NEJM 2005 Wai et al . Hepatology 2002 50 Kao et al. J Hepatol 2000 40 30 20 10 0 A B C D HBV-Genotyp

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

Wirksamkeit von Nukleos(t)idanaloga DNA-Suppression unter 300/400 Kop/ml nach 48/52 Wo 1 0 0 DNA Negativierung [%] 9 0 9 0 9 3 8 0 7 0 7 6 7 2 7 4 Adefovir 6 0 6 7 6 0 Lam ivudine 5 0 Telbivudine 5 1 4 0 Entecavir 3 0 Tenofovir 3 6 2 0 2 1 1 0 0 HBeAg+ HBeAg- 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

* * Nukleos( t) idanaloga * zugelassene Medikamente * *