Chronic hepatitis delta: an update:

Transcription

1 Chronic hepatitis delta: an update: Prof. Dr. Cihan Yurdaydin University of Ankara Dpt. of Gastroenterology 9 th INTERNATIONAL CONGRESS OF INTERNAL MEDICINE ATHENS, GREECE 9-11 MARCH 2017

2 DISCLOSURE I have received consultancy and/or lecture fees from AbbVie, BMS, Gilead, Roche, Merck, Boehringer Ingelheim, Janssen, and Novartis, and has received grants from BMS and Roche.

3 INTRODUCTION Chronic delta hepatitis (CDH) is the most severe form of viral hepatitis A disease of the developing or underdeveloped countries or regions Orphan disease in the EU and USA The only therapy of proven benefit is with interferons Biomedical Industry displays little interest: not cost-effective Liver injury in CDH is immune mediated

4 ACUTE HEPATITIS Simultaneous Co-Infection Acute HBV Acute HDV 95% recovery More frequent fulminant CHRONIC HEPATITIS 5% CHRONIC HDV Super-Infection Acute HDV Chronic Hepatitis B 90% chronic More severe disease

5 Proportion of patients with evidence of HDV in acute self limited vs. fulminant hepatitis B Fulminant Acute Hepatitis B Hepatitis B p value Europe 43/111 (39%) 101/532 (19%) < Smedile et al 1982 USA 24/71 (34%) 5/118 (4%) Govindarajan et al 1984 Ankara Uni.

6 Outcome in acute delta hepatitis Buti et al, J Viral Hepat acute hepatitis D 115 co-infection 23 superinfection 10 chronic hepatitis (8%) 104 resolution (90%) 23 chronic hepatitis (100%) Ankara Uni.

7 EEA HDV Prevalence Heavily impacted by Immigration and IVDU* Populations High Risk Group Proportion in HDV Population IVDU HBsAg (+) Immigrant HBsAg (+) High Risk HBsAg (+) Population 1 Population 2 Population % HDV Prevalence 3 HDV subjects in High Risk Population Spain 96% 1, , , ,786 Sweden 84% 4,466 50,593 55, ,927 France 83% 50, , , ,245 UK 74% 29, , , ,612 Germany 72% 9, , , ,082 Italy 56% 36, , , ,969 1 IVDU population figures taken from EMCDDA (European Monitoring Center for Drugs and Drug Addiction) 2 Immigrant population figures taken from Eurostat 3 HDV prevalence from post-2006 country specific literature reports High risk group proportion in HDV population is 56-96% For Spain, Sweden, France, UK, Germany, and Italy, HDV proportion of high risk groups are 96%, 84%, 83%, 74%, 72%, 56%, respectively (mean = 78%). Total HDV Population = HDV High Risk Group + HDV Low Risk Group HDV High Risk Group = [High risk group HBsAg(+) pop] x [% HDV Prevalence] HBsAg(+) High Risk Group = HBsAg(+) Immigrant Pop + HBsAg(+) IVDU Pop Spain: (Navascués et al, 1995; Buti et al, 2010], Sweden: [Ji et al, 2012], France: [Renard et al, 2011], UK: [Cross et al, 2008], Germany: [Heidrich et al, 2009; Reinheimer et al, 2012; Wedemeyer et al, 2007(a)], Italy: [Gaeta et al, 2003; Ankara Uni. Piccolo et al, 2009; Mele et al, 2007]

8 EEA HDV Prevalence Calculation Total Population (2013) Total HBsAg (+) Population High Risk HBsAg (+) Population % HDV Prevalence HDV Subjects in High Risk Population (78% HDV Population) HDV Subjects in Low Risk Population (22% HDV Population) Total HDV Population HDV Rate EEA 510,064,934 5,492,518 1,596,264 Country specific prevalence 117,265 34, , in 10,000 HDV an orphan disease in Europe Ankara Uni. 8

9 Major endemic regions for hepatitis delta Soriano V. AIDS in press

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11 Time free from liver decompensation or death in HIV infected patients Fernandez-Montero et al, Clin Infect Dis 2014

12 Estimated HCC risk in HBV, HCV and HDV infected pts in Central Africa

13 HCC in CHB vs CHD under treatment Keskin O et al, AASLD 2016

14 HBcAg IHC in CDH Nuclear localization No correlation with liver injury, even in HBV-HDV co-dominant cases Kabaçam et al, Liver Int 2013 Ankara Uni.

15 HDAg IHC in CDH HDAg display (+) correlation with ALT Kabaçam et al, Liver Int 2013 Ankara Uni.

16 DELTA HEPATITIS- DIAGNOSIS Anti HDV (IgG) Anti HDV IgM HDV RNA (qualitative, quantitative PCR) HDV Ag (immunohistochemistry) Quantitative HBsAg, HDV & HBV genotype determination Ankara Uni.

17 Female patient living in Sweden, migrated from Uzbekistan ALT: 78, AST 66 GGT and Alkalen Phosphatase: normal HBsAg (+), HBeAg negatif Anti HCV & HIV: negative HBV DNA 480 IU/mL Hb, WBC normal, platelets: Height: 1.63m; weight: 92 kg BMI: 34.6 Ankara Uni.

18 Diagnosis: İnactive HBsAg carrier + NASH Recommendation: Diet + exercise; No need to treat HBV Control visit every 3 months 3 x control visits, she loses some weight Enzymes not much affected Ankara Uni.

19 The patients is a physician (gynecologist) She decides to read, especially hepatit B On her next visit she asks for an anti HDV test Anti HDV (+) HDV RNA is positive Ankara Uni.

20 Anti HDV (or anti HDV IgG) First test to be used for searching for HDV Not a neutralizing Ab, depicts encounter with HDV HDV RNA testing necessary to establish active HDV infection Remains positive for years after successful tx including HBsAg clearance Ankara Uni.

21 Liver Int 2011

22 Anti HDV IgM titre correlate with ALT and histologic activity Wranke et al, PlosOne 2014 Ankara Uni.

23 Anti HDV IgM Suggestive of acute infection or chronic active infection Not standardized HDV RNA more sensitive Ankara Uni.

24 HDV RNA Qualitative or quantitative Surrogate marker of tx efficacy Standardization was important Now there is a WHO standard (Paul Ehrlich Institute); Labs should get it Ankara Uni.

25 28 reference lab s took part 13 lab s (46%) made correct mesurements 16 lab (57%) found 1-10 positive samples negative

26 HBsAg (log 10 copies/ml) HBsAg decline in CDH On-treatment Post-tx P= Keskin et al, Clin Gastroenterol Hepatol 2015 Ankara Uni.

27 HDV and HBV Genotypes Region HDV genotype HBV genotype Europe 1 D / A Brazil 1 / 3 F / A / D China, Taiwan, Japan 1 / 2 / 4 B / C Turkey, Romania, Albania, Iran, Pakistan, India 1 D Western Pacific 1 / 2 B / C / D Africa 1, 5-8 D / A / E 27

28 Different HDV Genotypes Are Associated With Different Clinical Outcomes Su, Wu et al., Gastroenterology

29 Non-invasive markers for differentiating cirrhosis- AUROC scores Model Luttenkort et al 1 Takyar et al 2 Kalkan et al 3 FIB APRI AAR API HUI FibroScan Liver Int 2016; 2 APT 2017; 3 EASL 2017

30 TREATMENT OF CHRONIC DELTA HEPATITIS Evidence based successful treatment : interferon High dose, long treatment period (one year, or longer) Sustained virologic response LOW NAs ineffective Ankara Uni.

31 Treatment of Hepatitis Delta With PEG-IFNα 2a: ~25% Sustained HDV RNA Clearance Wedemeyer H, et al. N Engl J Med Jan 27;364(4):

32 PEG-IFNα 2a Adefovir Combination Resulted in a More Pronounced HBsAg Suppression Wedemeyer, Yurdaydin, et al. N Engl J Med Jan 27;364(4):

33 HDV RNA Response Until Week 120 Intent-to-Treat Analysis 80 Patients HDV RNA negative (%) Treatment FU PEG-IFNα 2a + Tenofovir PEG-IFNα 2a + Placebo 60 P=.10 47% Relapse 11/25 (44%) Relapse 8/20 (40%) % P=.34 30% 23% HDV RNA Clearance after Therapy Neg post Tx, 1 patient Neg post Tx, 3 patients 0 Baseline W12 W24 W48 Wedemeyer, Yurdaydin, et al. EASL Week 96 Week w post Tx 33

34 Mean HBsAg levels [log10 IU/ml] HBsAg Response Until Week 120 Intent-to-Treat Analysis Patients with HBsAg decline >0.5 log 10 U/mL (%) PEG-IFNα 2a + Tenofovir PEG-IFNα 2a + Placebo Treatment FU HBsAg loss: 4/59 patients (6.7%) HBsAg loss: 3/61 patients (4.9%) 5 4 Mean HBsAg levels Treatment FU Wedemeyer, Yurdaydin, et al. EASL

35 Cumulative probability of development of clinical endpoints: IFN, NAs, no therapy HCC Survival Hepatic decompensation Wranke et al, Hepatology 2017

36 Cumulative event-free survival in CDH: IFN, NAs, no therapy- effect of HDV RNA levels Wranke et al, Hepatology 2017

37 Mortality/liver tx in pts with or without VR Without MVR With MVR Keskin et al, AASLD 2015

38 Overall (n:99) IFN responders (n:35) IFN nonresponders (n:64) P value Age 40.0± ± ± Gender 70 24Male/11Female 46M/18F 0.81 Male/29Female HDV RNA (log ± ± ± IU/mL) (n:59) HBVDNA (log 10 IU/mL, median (range)(n:63) 1.70 ( ) 1.67 ( ) 1.70 ( ) 0.34 HBeAg status 81 (-) / 15 (+) 29 (-) /4 (+) 52 (-) /11 (+) 0.56 ALT (U/L) 107±108 97±86 112± AST (U/L) 76±73 76±76 77± ALP (U/L) 115±52 102±52 123± GGT (U/L) 83±78 55±53 100± PT (seconds) 13.3± ± ± Total Bilirubin 1.01± ± ± (mg/dl) Platelet 161±52 181±54 150± (x10 9/ /L) HAI (n:78) 10.9± ±4.7 11± Cirrhosis 19/99 (19%) 5/35 (14%) 14/64 (22%) 0.26 present Fibrosis score 2.15± ± ± (n:78) HBsAg (log 10 IU/mL, n:49) 3.70± ± ±

39 Optimal IFN treatment duration in CDH 16 MVR (-) 16 MVR (+) 20 MVR (-) 6 MVR (+) 9 MVR (-) 2 MVR (+) 11 MVR (-) 4 MVR (+) 4 MVR (-) 3 MVR (+) 4 MVR (-) 4 MVR (+) n:99 n: 67 n: 41 n: 30 n: 15 n: m m m m m >60 m Figure 2A: Flow chart of maintained viral response and treatment duration Keskin et al, AASLD 2015

40 Cumulative probability of a maintained viral response in patients treated with interferons Keskin et al, AASLD 2015

41 Clinical event (+) Clinical event (-) P value Age 43.5± ± Gender 22 Male/10 Female 48Male/19Female 0.81 HBeAg status 28 (-) /4 (+) 53 (-)/11 (+) 0.67 ALT (U/L) 99.6± ± AST (U/L) 78.5± ± GGT (U/L) 107.7± ± ALP (U/L) 119.0± ± PT (seconds) 13.6± ± Bilirubin (mg/dl) 1.11± ± Platelet count 134±41 174±52 <0.001 (x10 9/ /L) HAI Score (n:78) 12.5± ± Fibrosis score (n:78) 2.68± ± HDV RNA (log ±1.4 (n:18) 5.85±1.4 (n:41) 0.31 IU/mL) (n:59) HBV DNA (log ± ± IU/mL (n:63) Cirrhosis present 15 (+)/ 17 (-) 4 (+) / 63 (-) <0.001 IFN response 5 (+)/27 (-) 30(+)/37(-) HBsAglog 10 IU/mL, n: ± ±

42 Cumulative probability of HBsAg clearance Without MVR With MVR Figure 4

43 HBsAg clearance No HBsAg clearance P value Treatment duration 29.4± ± (months) Gender 11 Male/3 Female 59 Male/26 Female 0.75 HBsAg (log 10 IU/Ml, 3.22± ± n:49) HBeAg status 11 (-)/2(+) 70 (-)/13(+) 0.90 HBV DNA (log ± ± IU/mL (n:63) HDVRNA (IU/ml, 6.15± ± n:59) Age 39.6± ± ALT (U/L) 102±54 108± AST (U/L) 86±86 75± GGT (U/L) 42±26 91± ALP (U/L) 115±54 115± PT (seconds) 13.8± ± T.Bil (mg/dl) 1.06± ± Platelet count 176±62 158± (x10 9/ /L) Fibrosis Score, n: ± ± HAI Score, n: ± ± Response to IFN 13 responders/1 non-responder 22 responders/63 non-responders <0.001

44 Multivariate logistic regression analysis for predicting end of treatment and post- treatment week 24 virologic response End of treatment response: OR95% CI p value HDV RNA week Baseline HAI Post-treatment week 24 response: HDV RNA week Keskin O, et al, Clin Gastroenterol Hepatol 2015 Ankara Uni.

45 N= 38, missing data= 3 Week 24 HDV RNA positive N= 33 HDV RNA negative N= 5 Week 72 Virologic Response Yes 11/33 33% Yes 5/5 100% NPV 67% PPV 100% Figure 2: Predictive value of on-treatment week 24 undetectable HDV RNA for post-treatment week 24 virologic response Keskin O, et al, Clin Gastroenterol Hepatol 2015 Ankara Uni.

46 N= 39, missing data= 11 Week 24 HDV RNA decline > 1 log decline, N=27 < 1 log decline, N= 12 Week 24 HBsAg decline Yes 21 No 6 Yes 6/12 No 6/12 Week 48 null response 2/21 9.5% 2/6 33% 3/6 50% 5/6 83% NPV 90.5% PPV 83% Figure 2D: Predictive value of on-treatment week 24 HDV RNA and HBsAg levels For EOT virologic null response (<1 log decline of HDV RNA at EOT) Keskin O, et al, Clin Gastroenterol Hepatol 2015

47 New treatments

48 Targets in HDV Treatment TLR Agonists Entry Inhibitors Nucleic Acid Polymers Prenylation Inhibitors 48

49 Effect of the hepatocyte entry inhibitor, Myrcludex in CDH 8 pts receive Myrcludex, 2mg/kg for 6 months 8 pts receive Myrcludex, 2mg/kg + Peg IFN for 6 months Daily sc injections Urban S et al, AASLD 2014, LB 20

50 6 of 7 patients experienced HDV RNA decline >1 log 10 at week 24 during Myr B monotherapy 7 of 7 patients experienced HDV RNA decline >1 log 10 at week 24 during Myr B/PEG-IFNα combination therapy HDV RNA became negative in 2 patients during MyrB monotherapy and in 5 patients in combination with PEG- IFNα Urban S et al, AASLD 2014, LB 20

51 Nucleic acid polymers for treating HBV Nucleic acid polymers (NAPs) are oligonucleotides whose biochemical function is strictly dependent on the polymer chemistry of oligonucleotides. They bind with high affinity to amphipathic protein structures These amphipathic protein structures are very rare in normal human biology (already complexed with each other inside proteins where they help stabilize the protein structure). However amphipathic targets are required for various stages of viral replication. NAPs effectively block the functions of these proteins, providing an effective, broad-spectrum antiviral activity.

52 Nucleic Acid Polymers (NAPS) for HBV/HDV Coinfection 52

53 Treatment of CDH with Lonafarnib Mean (SD) Change in HDV RNA Per Week HDV RNA Log IU/mL Placebo Lonafarnib 100mg BID Lonafarnib 200mg BID -3 Therapy Post-Therapy Follow-up Time in Weeks Time in Months Koh C et al, Lancet Infect Dis 2015

54 Mean Change in Log HDV RNA Week 4 Reduction in HDV RNA with Lonafarnib National Institutes of Health NIH POC (Lancet Infect. Dis. 2015) Ankara University LOWR-1 (EASL 2015) 0.5 Placebo Lonafarnib 100 mg BID Lonafarnib 200 mg BID Lonafarnib 100 mg TID Lonafarnib 200 mg BID Lonafarnib 300 mg BID Lonafarnib 100 mg BID + Ritonavir 100 mg QD Lonafarnib 100 mg BID + PEG IFN-α 2a 180 mcg QW Mean Log Mean Log Mean Log Mean Log Mean Log Mean Log Mean Log Mean Log N = 4 N = 6 N = 6 N = 3 N = 3 N = 3 N = 3 N = 3 54

55 Side effects LOnafarnib With Ritonavir in HDV Mainly GI side effects Observed in almost every patient Lonafarnib chronically dosed for 2 years in a pediatric population (Progeria - PNAS, 2012, 16666) 55

56 Mean log Delta Viral Load Change From Baseline Serum Concentration and Viral Load Statistically Significant Linear Relationship Koh C, et al. Lancet Infect Dis Oct;15(10): Mean Serum Lonafarnib Concentration (ng/ml) 56

57 Fig. 4 Inhibiting lonafarnib s metabolism with ritonavir increases antiviral response A) LOWR HDV 1 Results Week 4 Mean Change in HDV-RNA Viral Load -2.2 Log Week 8 Mean Change in HDV-RNA Viral Load -3.5 Log B) LOWR HDV 1 Results Elevated Liver Enzymes at Baseline Normalization of ALT on Lonafarnib + Ritonavir Lonafarnib 100 mg BID + Ritonavir 100 mg QD Lonafarnib 100 mg BID + Ritonavir 100 mg QD 250 Change in Log HDV RNA copies/ml Pa ent 1 Pa ent 2 Pa ent 3 Lonafarnib Monotherapy vs Lonafarnib + Ritonavir Week 4 Reduction in Serum HDV RNA BLQ 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week7 Week 8 C) D) 0.5 Placebo Lonafarnib 100 mg BID Lonafarnib 200 mg BID Lonafarnib 100 mg BID + Ritonavir 100 mg QD ND 1 ALT U/L Pa ent 1 Pa ent 2 Pa ent Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Sarasar (lonafarnib) PK Boosted by Ritonavir Serum Concentration Increased 4-5 Fold Normal U/L 1 Change in Log HDV RNA copies/ml Mean = Log Mean = Log Mean = Log -2.5 Mean = Log N = 4 N = 6 N = 6 N = 3 1 1

58 LOWR HDV 2: Dose Finding Study Tolerability, Longer Dosing, and Triple Combination High Dose Months 1-3 Months 4-6 N=15 LNF 75 mg BID + RTV N=19 Low Dose LNF 50 mg BID or LNF 25 mg BID + RTV 100 mg BID Low Dose: Triple Combination N=12 LNF 50 mg BID or LNF 25 mg BID + RTV 100 mg BID + PEG IFN α 180 mcg QW N=46 58

59 LOWR HDV 2: Dose Finding Study Tolerability, Longer Dosing, and Triple Combination High Dose Months 1-3 Months 4-6 N=15 LNF 75 mg BID + RTV N=19 Low Dose LNF 50 mg BID or LNF 25 mg BID + RTV 100 mg BID Low Dose: Triple Combination N=12 LNF 50 mg BID or LNF 25 mg BID + RTV 100 mg BID + PEG IFN α 180 mcg QW N=46 59

60 Summary and Conclusion- 1 The only effective treatment is with interferons Treatment beyond 1 year needed in a sizeable proportion of patients Until new therapies are available IFN treatment duration has to be decided on an individual basis In order to treat CDH, it needs to be diagnosed Beware of certain risk populations (immigrants, IVDUs)

61 Summary and Conclusion- 2 The future: There is now hope: Hepatocyte entry inhibitors Prenylation inhibitors Nucleic acid polymers sirnas Stay tuned