4 th PARIS HEPATITIS CONFERENCE HBeAg-negative chronic hepatitis B Why do I treat my chronic hepatitis B patients with a nucleos(t)ide analogue? George V. Papatheodoridis, MD 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital, Athens, Greece
Estimated proportions of 1 st line therapy in CHB patients in European countries 70-90% vs 10-30%
HBV-RELATED CHRONIC LIVER DISEASE THERAPEUTIC INDICATIONS NUC(s) or (Peg-)IFNa Chronic hepatitis B Only NUC(s) Decompensated HBV cirrhosis Prophylaxis in HBV transplant cases Pre-emptive therapy in inactive HBV carriers receiving immunosuppressive/chemo-therapy Pregnant women with high HBV viremia Health care workers in the HBV immunotolerant phase
TREATMENT OPTIONS IN CHB NUC(s) vs (Peg-)IFNa
3 nucleoside analogues 2 nucleotide analogues peg-ifna-2a
TREATMENT OPTIONS IN HBeAg(-) CHB NUC(s) vs (Peg-)IFNa Efficacy
Therapeutic aims in CHB Inhibition of CHB progression Change of CHB into inactive carrier state Prevention of cirrhosis HBsAg (-), HBV eradication Virological & biochemical remission Prevention of HCC Improvement of survival
Virological responses at 1 year in HBeAg-negative CHB HBV DNA drop log 10 cp/ml -4.1-4.4/-4.5 4/ 4-3.9/-4.1 41-5.0-5.2-4.5 100 93% 90% 88% 80 60 Patients with undetectable serum HBV DNA 40 at 48-52 wks, % 20 70% 63% 65% 63% 51% 0 Peg-IFNa-2a LAM ADV ETV TBV TDF HBV DNA, cp/ml <400 <300 <400 <300 <300 <400 Marcellin 2004 Tassopoulos 1999 Hadziyannis 2003 Lai 2006 Lai 2007 Marcellin 2008 Papatheodoridis 2002 Marcellin 2008 Lai 2006, Lai 2007
EFFICACY OF 12-MONTH COURSES IN HBeAg(-) CHB: Sustained off-therapy responses 100 Patients, % 80 60 40 20 0 Biochemical & virological responses (different definitions among studies) 54% End of therapy Sustained 36% 22% 25% 70% <11% 74% 78% 74% 77% IFNa Peg- LΑM ADV ETV TBV TDF IFNa 3ΜU tiw 180 μg/wk 100 mg/d 10 mg/d 0.5 mg/d 600 mg/d 300 mg/d x12 mos x12 mos x12 mos x12 mos x12 mos x12 mos x12 mos 8% 2%?? Manesis 2001 Marcellin Tassopoulos Hadziyannis Shouval Lai 2005 Marcellin 2007 2004 1999 2005 2004/2006
EFFICACY OF 12-MONTH COURSES IN HBeAg(-) CHB: Sustained off-therapy responses 12-month courses of Peg-IFNa better than 12-month courses of NUC(s) Peg-IFNa: responses in a minority of patients NUC(s) therapy: >4-5 years, indefinitely?
Resistance to oral antiviral agents in naive HBeAg(-)CHB 100 Data from different studies with different patients characteristics and methodology Pa atients with resis stance (% %) 80 60 40 20 0 25 48 66 68 60 29 18 19 16 3 6 11 0 0 0 1 1 1 4 0 0 0 0 Years 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 1 2 3 4 LAM ADV ETV TBV TDF Papatheodoridis et al. Hepatology 2002,36:219-26; 26; Hadziyannis et al. Gastroenterology 2006,131:1743-51; Liaw YF et al. Gastroenterology 2009,136:486-95; Wang Y et al. AASLD 2009, Abstr. 482; Tenney D et al. APASL 2008; Abstr. PL02; Marcellin P et al. AASLD 2010, Abstr. 476
Patient ts with με HBV DNA <300 0 cp/ml (%) 100 90 80 70 60 50 40 30 20 10 Long-term ETV (re)treatment in HBeAg(-) CHB ETV-027 ETV-901 94 93 94 98 91 83 59 4 0 n= 93/99 4/99 56/95 79/95 84/90 72/77 67/74 54/57 EOD B/L Wk Wk Wk Wk Wk Wk 12 24 48 72 96 144 Shouval et al. Hepatology 2008; 48: 722A HBsAg loss: 0%
Percen ntage % Perce centage(%) Perce entage % Per ercentage(%) 100 Study 102 - HBeAg-Negative Patients Virological i l Response: HBV DNA <400 cp/ml 90 87% 80 84% 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 ITT: LTE-TDF Analysis Weeks on Study TDF-TDF ADV-TDF 0 4 8 12 16 20 24 28 32 36 40 44 48 56 64 72 80 88 96 108 120 132 144 156 168 180 192 0 4 8 12162024283236404448 56 64 72 80 88 96 108 120 132 144 156 168 180 192 On-Treatment Analysis 0 4 8 12 16 20 24 28 32 36 40 44 48 56 64 72 80 88 96 108 120 132 144 156 168 180 192 Weeks on Study Weeks on Study 0 4 8 12162024283236404448 56 64 72 80 88 96 108 120 132 144 156 168 180 192 100% 99% Marcellin P et al. AASLD 2010, Poster #476
Long-term therapy with ETV/TDF in HBeAg(-) CHB Viral resistance: not an issue in clinical practice in 2011 Absence of virological response under ETV or TDF: check for drug compliance
Antiviral HBV drug resistance: Guideline recommendations Resistance Rescue therapy LAM-R LdT-R ETV-R ADV-R TDF-R Add TDF (or ADV if TDF is not available) Add TDF (or ADV if TDF is not available) Add TDF N236T: Add LAM or LdT or switch to TDF/FTC A181T/V: Add ETV or switch to TDF/FTC Add ETV, LdT, LAM or FTC EASL Clinical Practice Guidelines. J Hepatol 2009; 50:227-242
Long-term therapy with NUC(s) in HBeAg(-) CHB Effects on major outcomes including survival
Survival in IFN -Treated Patients with HBeAg(-)CHB Proportion of pts surviving Proportion of pts free of major complications 1.0 0.8 0.6 0.4 0.2 1.0 0.8 SR in only 20-25% 0.6 of patients P=0.027 027 SR vs non-sr 0.4 P=0.019 019 SR vs non-sr P=0.048 SR vs untreated 0.2 P=0.012 SR vs untreated 2 4 6 8 10 12 14 2 4 6 8 10 12 14 Years Years IFN treated: sustained response Untreated IFN treated: no sustained response Papatheodoridis et al. J Hepatol 2001; 34: 306-313
, patient ts grading Cha anges in Changes of necroinflammation in HBeAg(-)CHB under long-term lamivudine monotherapy 100% 80% 60% 40% 20% 0% -20% -40% -60% P=0.0202 P=0.001 No YMDD YMDD+ No YMDD YMDD+ (n=12) (n=16) (n=22) (n=26) Change of grading score of 2 points (Ishak* - HAI # ) Better Stable Worse Timing of 2 nd Bx: 26 mos 24 mos after LAM onset *Papatheodoridis et al, #Rizzetto et al, Hepatology 2002; 36: 219-26 J Hepatol 2005; 42: 173-9
fibrosis, patient ts Cha anges in 100% 80% 60% 40% 20% 0% -20% Changes of fibrosis in HBeAg(-)CHB under long-term lamivudine monotherapy No YMDD YMDD+ No YMDD YMDD+ (n=12) (n=16) (n=22) (n=26) Change of fibrosis score of 1 point (Ishak) Better Stable Worse Timing of 2 nd Bx: 26 mos 24 mos after LAM onset Papatheodoridis et al, Rizzetto et al, Hepatology 2002; 36: 219-26 J Hepatol 2005; 42: 173-9
Long-term entecavir monotherapy: Effect on necroinflammation 60,n Patients 50 40 30 20 Necroinflammation Knodell score 10 14 7 9 4 6 0 3 Missing data 10 N=57 0 Baseline Week 48 5.4 (3-7) years Chang TT et al. Hepatology 2010; 52: 886-93
Long-term entecavir monotherapy: Effect on fibrosis 60 Patients s, n 50 40 30 20 10 Fibrosis Ishak score 6 5 4 3 2 1 0 Missing data 0 Baseline Week 48 5.4 (3-7) years N=57 Chang TT et al. Hepatology 2010; 52: 886-93
Disease progression in patients with HBeAg(+)/(-) HBV cirrhosis under long-term LAM monotherapy disease e progres ssion, % 25 20 15 10 Placebo 21% (n=215) LAM-Resistant 13% (n=209) Pts with 5% 5 LAM-WT (n=221) 0 0 6 12 18 24 30 36 Months under LAM Liaw et al, NEJM 2004
vents ortion of pts without major e Prop Major event free survival under LAM ± salvage ADV 1,00 Pts in virologic remission,95,90 Pts with virologic no response or VBTHs,85,80,75 0 12 Log-rank test P=0.07 24 36 48 60 72 Papatheodoridis et al, Hepatology 2005; 42: 121-9 Follow-up (months)
10 8 6 Patients with HCC, % 4 2 HCC in CHB patients under LAM LAM Untreated P=0.003 P=0.015 Patients n: 779 534 HBeAg(-) 49% 54% Comp. Ci: 29% 39% P=0.016 FUP (mos): 32-90 32-108 6,4 Liaw et al, NEJM 2004 Papatheodoridis et al, HEP 2005 Yuen et al, AVT 2007 2,8 2,5 2,8 0 All VR BR/BTH Untreated pts LAM treated pts N 779 353 426 534 Papatheodoridis, Lampertico, Manolakopoulos, Lok. J Hepatol 2010;53:348-56
LONG-TERM ORAL ANTIVIRAL THERAPY IN HBeAg(-) CHB Can we ever stop?
Sustained off-therapy responses in patients with HBeAg(-) CHB who remained in virological i l remission i under ADV for 4-5 years 33 patients with HBeAg(-) CΗΒ & HBV DNA<400 cp/ml under ADV for 4-5 years Off-treatment F-UP: 4 years after stopping ADV Sustained biochem. & virol. off-adv response: 18/33 (55%) HBsAg clearance: 9/33 (27%) patients or 9/18 (50%) responders Hadziyannis SJ et al. AASLD 2008, Abstr. 874
HBsAg loss in patients with HBeAg(-) CHB who remained in virological i l remission i under ADV for 4-5 years 100 80 HBsAg loss, % 60 40 39 50 Total SRs 20 0 11 6 17 9 28 15 21 27 EOT Yr 1 Yr 2 Yr 3 Yr >4 Hadziyannis SJ et al. EASL 2009, Abstr. 18
HBsAg loss in patients with HBeAg(-) CHB treated t with Peg-IFNa-2a or ADV 100 80 HBsAg loss, % 60 40 Peg-IFNa-2a ADV 20 0 22 17 12 12 9 11 5 6 5 7 0 0 0 0 0 Day 0 Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Yr 7 Yr 8 Yr >9 Marcellin et al, APASL 2009. Hadziyannis et al, EASL 2009
LONG-TERM ORAL ANTIVIRAL THERAPY IN HBeAg(-) CHB Can newer, more potent NUCs (ETV/TDF) offer higher sustained off-therapy response & HBsAg loss rates after long-term virological remission?
CHRONIC HEPATITIS B Which therapy for whom? ΙFΝa (Peg-IFNa-2a) Young (reproductive) age Favorable factors of response to IFNa (low HBV DNA, high ALT, genotype Α vs D not very well defined ed in HBeAg-neg. eg CHB) Patient s preference ETV/TDF TBV, LAM, ADV Not candidates for IFNa No sustained response with IFNa Contraindication for IFNa Patient s preference
Main characteristics of patients with HBeAg(-) CHB Papatheodoridis et al, doridis et al, et al, et al, et al, J Hep 2001 Hepatol 2008 Hepatol 2003 EASL 2010 NEJM Papatheo- Lampertico Lampertico Marcellin 2004 Patients, n 209 399 101 127 177 Type of study IFNa RE Consecutive IFNa PR Peg-IFNa-2a Peg-IFNa-2a cohort patients cohort PR cohort PR cohort Origin Greeks Greeks Italians Italians Asians: 60% Age (years), mean±sd 47±11 49±14 46±10 45 40±12 Sex, M (%) 83% 77% 87% NA 85% ALT (IU/L), median 67 99 mean±sd: 204±180 95 62 Median HBV DNA 4.8 pg/ml 6.3 log 10 IU/ml NA 6log 10 IU/ml 7log 10 cp/ml RE: retrospective, PR: prospective, NA: not available
HBeAg-negative g chronic hepatitis B Why do I treat my chronic hepatitis B patients with a nucleos(t)ide analogue? No contraindication Better Tolerability & Safety On-treatment responses in almost all patients Improved histology with reversion of fibrosis Improved long-term outcomes incl. reduction in HCC Patients t preference NUC(s) even in the majority of IFNa treated patients IFNa failures