Ηπαηίηιδα Β:Σύγτρονη θεραπεσηική προζέγγιζη κιρρωηικού αζθενούς

Transcription

1 Ηπαηίηιδα Β:Σύγτρονη θεραπεσηική προζέγγιζη κιρρωηικού αζθενούς Γεώργιος Γερμανίδης, Επίκοσρος Καθηγηηής Γαζηρενηερολογίας Α.Π.Θ., Α Παθολογική Κλινική Α.Π.Θ., ΠΓΝΘ Α.Χ.Ε.Π.Α

2 2

3 3

4 HBV CIRRHOSIS Cheng-Yuan Peng ET AL., Journal of Hepatology 2012 HBV CIRRHOSIS : 5y survival rate 84% in compensated but only 14-35% in decompensated Journal of Hepatology 2012; 57: (DOI: /j.jhep ) 4

5 HBV CIRRHOSIS Cheng-Yuan Peng ET AL., Journal of Hepatology 2012 Journal of Hepatology 2012; 57: (DOI: /j.jhep ) 5

6 Τι προηείνοσν οι Καηεσθσνηήριες Οδηγίες; Compensated cirrhosis Patients with compensated cirrhosis and detectable HBV DNA must be considered for treatment even if ALT levels are normal (B1). Decompensated cirrhosis Patients with decompensated cirrhosis and detectable HBV DNA require urgent antiviral treatment with NA(s). Significant clinical improvement can be associated with control of viral replication. However, antiviral therapy may not be sufficient to rescue some patients with very advanced liver disease who should be considered for liver transplantation at the same time (A1). 6 months mortality: Baseline CPT score >11, MELD score in 3 months >17.5 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. J Hepatol (2012), 6

7 Τι προηείνοσν οι Καηεσθσνηήριες Οδηγίες; ΚΕΕΛΠΝΟ 2013 Σε ηπαηολογικά κένηρα επείγοσζα καηάζηαζη Κύριος ζηότος: ζηαθεροποίηζη ή βεληίωζη κλινικής καηάζηαζης (CPT score) και η ζσνδσαζμένη βιοτημική ιολογική ανηαπόκριζη Nοσκλεοζ(η)ιδικό Ανάλογο με πολύ μικρό κίνδσνο ανηοτής, (Eνηεκαβίρη ή Τενοθοβίρη) 7

8 Study Design of Phase 3 Tenofovir DF Pivotal Studies 102 (HBeAg- Patients) and 103 (HBeAg+ Patients) Double Blind Year 1 Open-label Year 8 RANDOMIZATIO N 2:1 Tenofovir DF 300 mg N=250 & N=176 Adefovir Dipivoxil 10 mg N=125 & N=90 N=235 N=154 N=112 N=84 Tenofovir DF 300 mg Tenofovir DF 300 mg Pre-treatment Liver Biopsy Year 1 Liver Biopsy 1 Year 5/ Week 240 Week 72 Year 3 2 Liver Biopsy Year 8 At Week 72, patients with HBV DNA 400 copies/ml had the option at the discretion of the investigator to add emtricitabine (FTC)* Retention rate at Week 240: 81% for HBeAg-, 70% for HBeAg+ Patient retention rates at Year 7: Study 102 (HBeAg-): 74%; Study 103 (HBeAg+): 61% Marcellin, P, et al. Lancet Feb 9;381(9865): *Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV 1 Marcellin et al NEJM; 359: Heathcote et al Gastroenterology; 140:

9 Σηαηιζηική ανάλσζη- Τροποποιημένη ΙΤΤ (intent-to-treat) A modified last observation carried forward (mlocf) analysis was implemented, -that carried forward year 1 results if year 5 results were missing, -and for those missing data at years 1 and 5, it was assumed that their disease progressed to cirrhosis at year 5. 9

10 Knodell necroinflammatory scores at baseline, year 1 and year 5 Percentage 2A. P <0.001 P < Series Series Series Series Baseline Year 1 Year 5 Progressive reductions in Knodell scores were evident with 8% (27/348) at baseline, this increased to 49% at year 1 and further increased to 80% at year 5 (P <0.001) (278/348) of patients at year 5 having mild to no evidence of necroinflammation (Knodell score 0-3; P <0.001, sign test) 10

11 Percentage Percentage of of Patients Patient s Distribution of Ishak Fibrosis Scores at Baseline, Year 1, and Year 5 Marcellin, P, et al. Lancet ;381: P < % 90% 80% 70% 60% 50% 40% 30% 20% 10% Ishak Fibrosis Score Baselin e Year 1 Year 5 344/348 patients had liver biopsy data available at all three time points Percentage of the population with cirrhosis (Ishak Score 5) progressively decreased from 28% at baseline to 8% at Year 5 38% (133/348) had Ishak scores 4 (changes ranging from marked bridging fibrosis to cirrhosis), this declined to 28% and 12% at years 1 and 5 Over time, an increasing proportion of patients had regression of fibrosis as reflected in 63% (219/348) of patients having Ishak scores 2 at year 5 vs 39% baseline &43% at year 1 P <0.001, sign test) 11

12 Collagen (%) Studies 102/103 Morphometric Assessment of Liver Biopsies Percent collagen area (PCA) measurement in liver biopsies at Baseline, Week 48 and Week 240 in subjects treated with TDF 1 Biopsy slides were stained with Sirius red: Digital image analysis used to calculate relative collagen content of each biopsy Slides with < 5 mm 2 tissue and slides with < 3% collagen at baseline were excluded Mean PCA decreased over time: 7.1% at Baseline 5.3% at Week % at Week Change in PCA* P<0.001 P<0.005 P<0.005 Baseline Week 48 Week Histology described previously: Marcellin P, et al. The Lancet 2013;381(9865): Goodman Z, et al. AASLD Washington, DC. #820 12

13 Change from Baseline in Fibrosis Score Change in Ishak Fibrosis Scores at Year 5 for Patients with Cirrhosis at Baseline Change from Baseline in Fibrosis Score n = 15 n = 41 n = 14 n = 1 n = 24 n = 1 96/348 (28%) patients with cirrhosis at baseline (Ishak fibrosis score 5) had paired BL and Year 5 biopsies 74% (n=71) of patients had cirrhosis reversed (Ishak fibrosis score <5) at Year 5, and 73% (n= 70) had decreases of 2 points at Year 5; 58%, (56 patients) experiencing a 3 unit decrease ; 25% (n=24) did not change Of 94 patients who did not add FTC, 73% had cirrhosis reversed; 26% showed no change Marcellin, P, et al. Lancet Feb 9;381(9865): Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use in HBV 13

14 Collagen (%) Studies 102/103 Morphometric Assessment of Liver Biopsies Among 344 subjects with biopsies, 71/96 had histologic regression of cirrhosis by Week under TDF treatment For cirrhotics, mean PCA decreased from 7.8% at Baseline to 4.1% at Week 240 (P<0.001) Those with persistent cirrhosis by Ishak stage had significantly higher mean collagen in their baseline biopsies Patients with regression of histologic cirrhosis had a 42% mean reduction in collagen while those with persistent cirrhosis had a mean reduction of 17% PCA in Cirrhotic Patients Persistent Cirrhosis Regression of Cirrhosis P=0.04 P=0.17 P=0.03 B aseline Week 48 Week Marcellin P, et al. The Lancet 2013;381(9865): Goodman Z, et al. AASLD Washington, DC. #820 14

15 Studies 102/103 Morphometric Assessment of Liver Biopsies An example of liver biopsies in a TDF-treated subject with histological regression of cirrhosis at Week 240 shows a marked decrease in PCA over time Percent collagen area decreased by 79% from Baseline to Week 240 Week 240 Goodman Z, et al. AASLD Washington, DC. #820 15

16 Multivariable Logistic Regression Identifying Factors Associated with Reversal of Cirrhosis Variable Level Odds Ratio Estimate BMI (kg/m 2 ) BMI < (normal) BMI 25 to (overweight) Years Positive for HBV Baseline platelet count (/mm3) 95% CI P-value (3.570, ) (1.071, ) < BMI 30 (Obese - Reference) (0.988, 1.177)

17 Multivariable Logistic Regression Identifying Factors Associated with Reversal of Fibrosis Variable Odds Ratio Estimate 95% CI P-value Baseline Ishak fibrosis score Baseline platelet count (/mm 3 ) (4.162, ) < (1.003, 1.015) Baseline HBV DNA (log 10 IU/ml) (0.993, 1.548)

18 Studies 102/103 Virologic Suppression at Year 7 Response HBeAg- Patients (Study 102) HBeAg+ Patients (Study 103) Year 6 Year 7 Year 6 Year 7 HBV DNA < 400 copies/ml Intent-to-treat *, % (n/n) 81.4 (281/345) 77.3 (269/348) 62.5 (157/251) 60.3 (149/247) HBV DNA < 400 copies/ml On-treatment, % (n/n) 99.6 (283/284) 99.3 (271/273) 96.8 (167/169) 99.4 (159/160) HBV Resistance * LTE-TDF (missing = failure; addition of FTC = failure) Observed (missing = excluded/addition of FTC = included) HBeAg loss/seroconversion rates of 55% and 40%, respectively, through 7 years 12% of HBeAg+ patients had confirmed HBsAg loss (10% with seroconversion) Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use to treat CHB Marcellin P, et al. AASLD Washington, DC. #926 18

19 Studies 102/103 No Resistance to TDF Observed Through Year 7 Genotypic changes in HBeAg and HBeAg+ Patients during Year 7 n=1 Conserved site change n=2 n=1 No change Polymorphic site change Unable to genotype 4 patients qualified for genotypic analysis during Year 7 1 polymorphic site change (rtl91i/l) detected: sensitive to TDF by phenotypic testing 3 of the 4 patients were confirmed to be non-adherent (undetectable TDF levels in plasma) No resistance to TDF detected Marcellin P, et al. AASLD Washington, DC. #926 19

20 Studies 102/103 Safety Summary During the Open-Label Period By Initial Treatment Assignment TDF-TDF (n=389) ADV-TDF (n=196) Total (N=585) AEs leading to drug discontinuation, n (%) 11 (2.8) 2 (1.0) 13 (2.2) Deaths, n (%) 9 (2.3) 3 (1.5) 12 (2.1) Serious AEs*, n (%) 5 (1.3) 2 (1.0) 7 (1.2) Grade 3 or 4 AEs*, n (%) 3 (0.8) 3 (1.5) 6 (1.0) scr 0.5 mg/dl above baseline, n (%) 6 (1.5) 4 (2.0) 10 (1.7) PO 4 < 2 mg/dl, n (%) 5 (1.3) 4 (2.0) 9 (1.5) CrCl < 50 ml/min, n (%) 3 (0.8) 3 (1.5) 6 (1.0) * Study drug related Confirmed upon retest Marcellin P, et al. AASLD Washington, DC. #926 20

21 Mean egfr (ml/min) Mean egfr (ml/min) VIREAL Study TDF in CHB Patients with Older Age and Comorbidities 2-year efficacy and tolerability data of TDF treatment in real-life patients (N=441), with a subgroup analysis of elderly patients (age 65 years; n=49) 100 Mean egfr (by CKD-EPI) in Elderly Patients by Hypertension (HTN) 100 Mean egfr (by CKD-EPI) in Elderly Patients by Diabetes In real-life practice, TDF presented a favorable safety profile in older patients with Zoulim F, et al. AASLD Washington, DC. # Elderly (n=45) HTN (n=16) No HTN (n=29) Baseline W48 W96 (n=45) (n=42) (n=35) comorbidities, such as hypertension and diabetes Elderly (n=45) Diabetes (n=8) No Diabetes (n=37) Baseline W48 W96 (n=45) (n=42) (n=35) TDF has not been studied in patients over age of 65yrs. Elderly patients are more likely to have decreased renal function, therefore caution should be exercised when treating elderly patients with TDF (Viread SPC, Oct 2013) 21

22 TDF, Emtricitabine/TDF, and Entecavir in Patients with Decompensated Chronic Hepatitis B Liver Disease Liaw YF et al HEPATOLOGY 2011;53:62-72 Efficacy Results at Week 48 Tolerability failure was infrequent across arms: 6.7% TDF, 4.4% FTC/TDF, and 9.1% ETV (P = 0.622) as were confirmed renal parameters meeting threshold 8.9%, 6.7%, and 4.5% (P = 1.000), respectively 22

23 Percentage of patients with HBV DNA <400 copies/ml (95% CI) at weeks 12, 24, and 48 23

24 Median (IQR) calculated creatinine clearance (ml/min) over time 24

25 Conclusions All treatments were well tolerated in patients with decompensated liver disease due to CHB with improvement in virologic, biochemical, and clinical parameters 25

26 Incidence of HCC among patients treated with TDF over 6 years Aim: to examine impact of long-term TDF therapy on HCC incidence 641 patients from TDF Phase III registration studies 102 and 103 TDF treatment for 6 years Observed HCC incidence compared with HCC risk predicted risk using REACH-B risk calculator Standardized incidence ratios (SIR) = observed/expected HCC cases Over 6 years 13 cases of HCC reported 9 HBeAg-negative (3 cirrhotic) 4 HBeAg-positive (3 cirrhotic) Kim WR, et al. EASL Oral

27 Reach B HCC risk score 17-point score to predict 3-, 5- and 10-year HCC risk Based on data from Asian patient cohorts All patients were non-cirrhotic 3584 patients in training cohort (from the Taiwanese REVEAL study) 131 developed HCC during follow-up 1505 patients in validation cohort (from two Hong Kong hospital cohorts and one Korean hospital cohort) 111 developed HCC during follow-up Components Sex, age, serum ALT, HBeAg status and serum HBV DNA Yang HI, et al. Lancet Oncol 2011;12:

28 HCC (%) HCC incidence based on cirrhosis status at baseline 5 4 Cirrhotics 3 2 Non-cirrhotics Week Non-cirrhotic * Cirrhotic * *Patients completing 336 weeks in study as defined by protocol: 4/437 patients completing Week 336 did not have baseline biopsy data Kim WR, et al. EASL Oral

29 Cumulative no. of HCC cases Observed vs predicted HCC cases: non-cirrhotics Predicted Observed p< Patients with VR (n=278) Patients without VR (n=46) 5 SIR = 0.45* 95% CI (0.227, 0.909) Kim WR, et al. EASL Oral *Statistically significant at nominal -level of CI, confidence interval; SIR, standardized incidence ratio. 1 st significant difference Week 29

30 Cumulative no. of HCC cases Observed vs predicted HCC cases: cirrhotics Predicted Observed p< LOCF Week Kim WR, et al. EASL Oral

31 Cumulative no. of HCC cases Observed vs predicted HCC cases: combined Predicted Observed p< SIR = 0.50* 95% CI (0.294, 0.837) Kim WR, et al. EASL Oral *Statistically significant at nominal -level of CI, confidence interval; SIR, standardized incidence ratio Week 1 st significant difference 31

32 Authors summary/conclusions The incidence of HCC in patients on TDF in studies 102 and 103 was lower than predicted by the REACH-B model In non-cirrhotic patients, the effect of TDF becomes noticeable at approximately 2 years of therapy and became significant (55% reduction) at 6 years of therapy TDF effect was less pronounced in cirrhotic patients; however the number of cirrhotics with HCC was small and may not rule out longer-term benefits Conclusion Potent antiviral therapy with TDF may reduce the risk of HCC Kim WR, et al. EASL Oral

33 190. Risk and Risk Factors of Hepatocellular Carcinoma (HCC) in Caucasian Chronic Hepatitis B (CHB) Patients with or Without Cirrhosis Treated with Entecavir (ETV) or Tenofovir (TDF) George V. Papatheodoridis, 1,2 George N. Dalekos, 3 Cihan Yurdaydin, 4 Ioannis Goulis, 5 Pauline Arends, 6 Maria Buti, 7 Vana Sypsa, 8 Spilios Manolakopoulos, 1 Giampaolo Mangia, 9 Nikolaos Gatselis, 3 Onur Keskin, 4 Savvoula Savvidou, 5 Bettina E. Hansen, 6 Christos Papaioannou, 1 Kostas Galanis, 3 Ramazan Idilman, 4 Massimo Colombo, 9 Rafael Esteban, 7 Harry L. Janssen, 6,10 Pietro Lampertico nd Academic Department of Internal Medicine, Hippokratio Hospital of Athens, Greece; 2. Academic Dept of Gastroenterology, Laiko Hospital of Athens, Greece; 3. Dept of Internal Medicine, Thessalia Univ. Medical School,Greece; 4. Dept of Gastroenterology, Univ. Of Ankara Medical School, Ankara, Turkey; 5. 4th Dept of Internal Medicine, Aristotle Univ. of Thessaloniki Medical School, Greece; 6. Dept of Gastroenterology and Hepatology, ErasmusMC, Rotterdam, The Netherlands; 7. Hospital General Universitario Valle Hebron and Ciberend, Barcelona, Spain; 8. Dept of Hygeine and Epidemiology, Athen Univ. Medical School, Greece; 9. 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Universita degli Studi di Milano, Milano, Italy; 10. Liver Clinic, Toronto Western & General Hospital, Univ. Health Network, Toronto, Canada. 33

34 Main Patient Characteristics at Baseline (Before ETV/TDF) Characteristic at Baseline Patients, n 1231 Mean±SD age, years 52±15 Sex, males 883 (72%) Caucasians 1214 (98.6%) HBeAg(+) patients 168 (14%) Patients with normal ALT 613/1138 (54%) Median ALT in cases with abnormal ALT, IU/L 84 (IQR: 89) Patients with HBV DNA <80 IU/mL 448/1047 (43%) Median HBV DNA in cases with DNA >80 IU/mL 210,000 (IQR: 5,187,000) Disease severity (unclassified: 49) CHB without Ci Compensated Ci Decompensated Ci 780 (66%) 359 (30%) 43 (4%) Mean±SD follow-up under therapy, months 39±17 Papatheodoridis GV, et al. AASLD 2013, Washington, DC. Oral

35 Current Antiviral Therapy in the 1231 Patients Current antiviral therapy in the 1231 patients ETV monotherapy 516 (42%) ETV + ADV 14 (1%) ETV + TDF 25 (2%) TDF monotherapy 369 (30%) TDF + LVD 305 (25%) ETV-based therapy*: 530 (43%) TDF-based therapy*: 676 (55%) ETV + TDF: 25 (2%) TDF + LdT 2 (0.2%) *Excluding ETV + TDF. Papatheodoridis GV, et al. AASLD 2013, Washington, DC. Oral

36 Cumulative probability of HCC Cumulative Probability of HCC by Disease Severity Annual HCC rate No cirrhosis 0.5% Cirrhosis 4% 0.40 Log rank test: P<0.001 Dec. cirrhosis 6% % 23.8% 20.9% % % 2.5% 1.2% 2.5% % Years since NUC initiation Papatheodoridis GV, et al. AASLD 2013, Washington, DC. Oral

37 HCC Risk Factors in 1231 Caucasian Patients with CHB ± Cirrhosis Treated with ETV/TDF HCC risk factor Non-cirrhotics Cirrhotics Univar.- P Multivariate-HR, P Univar.- P Multivariate-HR, P Age, year NS ( ), Sex, male NS NS BMI, kg/m 2 NS ( ), (Peg-)IFNa in the past NS NS Prior NA(s) therapy NS ( ), ALT, IU/L NS NS Platelets, 10 3 /mm ( ), NS HBeAg(+) NS NS HBV DNA, log 10 IU/mL NS NS Decompensation ( ), Virological remission NS NS ETV vs TDF NS NS GAG-HCC NS NS REACH-B NS NS Papatheodoridis GV, et al. AASLD 2013, Washington, DC. Oral

38 Cumulative probability of HCC Cumulative Probability of HCC by REACH-B Score All Patients (AUROC=0.59) < Log rank test: P= Years since NUC initiation Papatheodoridis GV, et al. AASLD 2013, Washington, DC. Oral

39 Conclusions Data from this large multicenter study in predominantly Caucasian patients indicate that the HCC risk remains increased in ETV/TDF treated CHB patients, particularly those with advanced disease The severity of liver disease (decompensated > compensated cirrhosis > CHB only and lower platelet counts in non-cirrhotic patients) together with age represent the strongest HCC risk factors The applicability of HCC risk scores developed in Asians seems to be modest in Caucasian CHB patients, for whom different risk scores are required Papatheodoridis GV, et al. AASLD 2013, Washington, DC. Oral

40 CHB and cirrhosis: Conclusions and perspectives HBsAg seroconversion, low/nd virus levels and normal ALT levels are the current goals of treatment in CHB Associated with reduced risk of cirrhosis and HCC Reductions in HBsAg levels are comparable between NUCs but decrease slowly Long-term viral suppression is achieved on treatment, but immune control following treatment cessation is limited Persistence of cccdna is a barrier to cure future therapies may increase depletion rates Future treatments harnessing the innate and adaptive immune responses might offer increased or longer-lasting efficacy compared with current treatments Further research is necessary to achieve full cure in HBV, in cirrhosis non-regressors and involvement in mechanisms of liver carcinogenesis to reduce the incidence of liver cancer in treated with NUCs cirrhosis 40

41 41

42 Future directions: drugs in development Immune modulation Toll-like receptors agonists, e.g. GS-9620 Anti-PD-1 mab, e.g. BMS CYT107 GI13000 RNA interference, e.g. ARC-520 HBx cccdna Inhibitors of HBsAg release, e.g. REP 9AC Surface proteins Polymerase Core pgrna Polymerase inhibitors Nucleoside analogues, e.g. emtricitabine, am doxovir, MIV-210 Nonnucleoside, e.g. LB80380 rcdna Entry inhibitors Lipopeptides, e.g. Myrcludex-B Endosome Inhibition of cccdna formation Inhibition of nucleocapsid assembly, e.g. Bay , NVR1221 Development stage: preclinical, clinical Zoulim F, et al. Antiviral Res 2012;96(2):256 9; HBF Drug Watch, Available at: Accessed 15 Aug Zoulim F, et al. Gastroenterology 2013;144: