Hepatitis Delta. Vicente Soriano Infectious Diseases Unit La Paz University Hospital & IdiPAZ Madrid, Spain

Transcription

1 Hepatitis Delta Vicente Soriano Infectious Diseases Unit La Paz University Hospital & IdiPAZ Madrid, Spain

2 Disclosures Member of speaker bureau and advisory board for: Roche, Boehringer, Gilead, Viiv, Abbott, Siemens, Janssen

3 To which viral hepatitis applies it? Neglected disease Virus of virus Trojan horse Most severe form of chronic viral hepatitis No licensed treatment Not approved viral load test A vaccine can prevent it Hepatitis E Hepatitis GB Hepatitis D

4 Hepatitis delta virus 1700-nt circular single-stranded RNA Defective virus that requires HBsAg (virus of virus!) Replicates in the nucleus of infected hepatocytes. 15 million infected persons worldwide Only in humans - No animal reservoir Most severe form of chronic viral hepatitis No FDA or EMA approved treatment No FDA or EMA licensed viral load test Diagnosis (HDV-Ab) often missed in HBsAg+ pts The best strategy to prevent hep D is HBV vaccine

5 Genome size of living organisms nt EBV 1,7 x 10 5 Ebola 1,9 x 10 4 E. Coli 4,6 x 10 6 Tuberculosis 4,4 x 10 6 Pneumococcus 2 x 10 6 Plasmodium 2,3 x 10 7 Humans 3,3 x 10 9 HIV 9,2 x 10 3 HBV 3,2 x 10 3 HCV 9,5 x 10 3 HDV 1,7 x 10 3 Influenza 2,3 x 10 3 VIRUS BACTERIA EUCHARIA

6 HDV replication HDV HBV HBsAg NCTP Rolling circle replication RNA Celular RNA POL II HDV-Ag 800bp mrna Small Large Hepatocyte 1700bp mrna

7 Hepatitis delta Romania Turkey Mongolia Taiwan Gt Location Amazonian Ubiquitous Japan, Taiwan, Rusia Amazonian Taiwan, Japan Africa 15 million

8 Delta hepatitis - Transmission Mainly throughout parenteral and sex. Major risk groups: IDUs Multiple sex partners Transfusions Foreigners from endemic regions.

9 Overlapping HBV, HDV & HCV Epidemics HCV Hep B HBsAg+ 80 million Hep D 240 million 15 million WHO. April 2015

10 Delta Coinfections Coinfection of HDV with HCV is associated with increased risk of advanced liver disease, including HCC. The most recently acquired virus tends to suppress the pre-existing virus. However, overall HCV tends to suppress HBV, but HDV tends to overtake any other viruses. The dominant virus must be identified in order to make appropriate treatment decisions: If HDV-RNA-pos and HCV-RNA-neg: consider pegifn with null/minimal risk of HCV relapse 1 If HCV-RNA-pos and HDV-RNA-neg/HBV-DNA-neg: consider DAA, but close monitoring of HBV/HDV relapse 2 Loss of serum HBsAg is rare with pegifn therapy in Delta hepatitis and very rare spontaneously. Overall, 12/188 (6%) in an Italian cohort 3 1. Soriano et al. J Infect Dis 2007; 195: Liu et al. Hepatology 2003; 37: Niro et al. J Hepatol 2010; 53:

11 HBV/HDV HCV coinfections 21 HIV / HBsAg+ / HCV Ab+ patients exposed to treatment for either HBV or HCV. Soriano et al. J Infect Dis 2007; 195:

12 Prevalence of anti-hdv Ab in HBsAg+ patients EuroSIDA North Central East South 14.5% of HBsAg+ Soriano et al. AIDS 2011; 25:

13 Delta hepatitis in HIV The incidence and prevalence of delta hepatitis and HDV-related liver disease in the HIV population has dramatically declined since year 2006 (HAART): Broader HBV vaccination Decline in IDU Closer medical follow-up: no alcohol, early diagnosis, proper follow-up of cirrhotics, etc. New incident HDV cases are mainly immigrants from Central-West Africa, Eastern Europe, Northern part of Latin America, and Middle East and Central Asia.

14 Clinical Infectious Diseases 2014; 58: Variables Total HIV monoinfection Hepatitis B Hepatitis C Hepatitis D No. 1, Mean age (years) 42.1± ± ± ± ±4.5 Male gender (%) Intravenous drug use (%) Mean body mass index (Kg/m 2 ) 24.1± ± ± ± ±4 Alcohol intake >60 g/day (%) Baseline advanced liver fibrosis (%) Mean baseline CD4 count (cells/μl) 566± ± ± ± ±146 Mean baseline ALT (IU/mL) 53.6± ± ± ± ±71 Antiretroviral therapy (%)

15 Predictors of liver decompensation or death in HIV+ patients Univariate analysis (HR, 95% CI, p) Multivariate analysis (HR, 95% CI, p) Age 1.01 ( , 0.7) --- Male gender 1 ( , 1) --- Alcohol abuse 0.93 ( , 0.92) --- Reactive HCV antibody 4.27 ( , 0.001) --- Positive HBsAg 1.89 ( , 0.24) --- Reactive HDV antibody 8.43 ( , 0.001) 7.5 ( , 0.005) Baseline liver stiffness 1.09 ( , <0.0001) 1.1 ( , <0.0001) SVR after HCV treatment 0.14 ( , 0.06) 0.11 ( , 0.03) Baseline ALT 1.01 (1-1.01, 0.03) --- Baseline total cholesterol 0.99 (0.98-1, 0.08) --- Baseline glucose 1.01 (1-1.02, 0.06) ---

16 Time free from liver decompensation events or death in HIV+ patients Patients (%) HIV-monoinfected (n=524) HIV/HCV-coinfected with SVR (n=106) HIV/HCV spontaneous seroconverters (n=21) HIV/HBV-coinfected (n=85) HIV/HCV untreated (n=258) HIV/HCV non-responders (n=127) HIV/delta (n=17) p=0.002 p< p< Months

17 Anti-HBV Nucleos(t)ides in HIV with Delta HDV-RNA 6.9 3TC/FTC +/- TDF HBV-DNA ALT delta HIV patients years Sheldon et al. Antivir Ther 2008; 13:

18 3TC do not inhibits HDV-RNA replication or improve HDV-related liver disease (Lau et al. Hepatology 1999; 30: 546-9) Selection of rtm204i, which results in change sw196l/s, may abrogate HDV packaging and release in chronic hepatitis delta patients. Any role for telbivudine in delta hepatitis?

19 47 years-old male From Dagestan, East Asia HBsAg, HBeAg, and anti-delta Ab (IgG) positive Serum HBV-DNA >9 log cop/ml Serum HDV-RNA 5.6 log cop/ml HBV-D and HDV-1 Liver biopsy A2F2 Treatment with pegifn + TDF + FTC Clearance of serum HBsAg with seroconversion to anti-hbs, along with clearance of HBV-DNA and HDV-RNA after 10 months of therapy.

20 Median log HDV-RNA (cop/ml) HBsAg (IU/mL) HBV-DNA (cop/ml) HDV-RNA 10 neg 9 pos Follow-up (months)

21 Main baseline characteristics Variable HDV-RNA-neg n=10 HDV-RNA-pos n=9 p Male gender, n (%) 10 (100) 8 (89) 0.28 Median age, years (IQR) 47 (46-53) 49 (44-49) 0.66 Median CD4 count, cells/ L (IQR) 284 (95-523) 294 ( ) 0.72 Median HDV-RNA, log IU/mL (IQR) 5.85 ( ) 6.17 ( ) 0.32 Serum HBV-DNA <10 IU/mL, n (%) 4 (40) 4 (44) 0.67 Median HBsAg, log IU/mL (IQR) 2.90 ( ) 3.57 ( ) 0.77 HBV genotype, n (%) A D 2 (22) 7 (78) 3 (43) 3 (43) Reactive HCV antibodies, n (%) 8 (80) 8 (89) 0.59 Advanced liver fibrosis (>9.5 kpa), n (%) (50) 6 (67) 0.46 IL28B CC alleles, n (%) 4 (57) 4 (67) 0.72

22 Predictors of serum HDV-RNA suppression on long-term tenofovir therapy Univariate analysis OR [95% CI] p Multivariate analysis OR [95% CI] p Age (per year) 1.08 [ ] Baseline HBV-DNA <10 IU/mL 0.67 [ ] HBsAg concentration (per log IU/mL) 0.61 [ ] Baseline CD4 count (per cells/ L) 1.01 [ ] Advanced liver fibrosis (>9.5 kpa) 0.62 [ ] Baseline HDV-RNA (per log IU/mL) 0.63 [ ] [ ] 0.36 Reactive HCV antibodies 0.50 [ ] HBV genotype (A vs D) 0.38 [ ] IL28B alleles (CC vs CT/TT) 0.67 [ ] 0.72 Baseline ALT (per IU/L) 0.99 [ ] *In bold variables that entered the multivariate analysis.

23 Changes in liver fibrosis according to HDV-RNA suppression Median liver fibrosis (kpa) p = Follow-up (months) 84

24 Long-term effect of TDF on hepatitis delta 34-year old male with advanced cirrhosis due to HDV. HIV-negative Experienced clinical improvement, normalization of liver enzymes, suppression of serum HDV-RNA and HBsAg clearance after two years of oral TDF monotherapy. No development of anti-hbs Conclusion: TDF should be tried in patients with hepatitis delta with contraindications for interferon use. James et al. Hepatology (in press)

25 Long-term effect of TDF on hepatitis delta 19 individuals with hepatitis delta treated with TDF for an average of 58 months, as part of their antiretroviral combination for HIV infection. All experienced significant declines in serum HDV-RNA and 10 (53%) achieved undetectable viral load. Hepatic fibrosis as measured using elastometry, significantly improved in the subset of individuals that reached complete HDV suppression. Serum HBsAg became negative in 3 patients but none of them seroconverted to anti-hbs. We then decided to give 4 double-doses of the HBV vaccine to these three patients, but none elicited an anti-hbs response. Given that removal of tenofovir could be risky, we have decided to keep on TDF all our patients. Soriano et al. Hepatology (in press)

26 Hepatitis Delta - Treatment Pegylated interferon Anti-HBV nuc /TDF) Myrcludex B Prenylate inhibitors Lonafarnib

27 HDV replication HDV NCTP HBV Myrcludex (entry inhibitor) Rolling circle replication HBsAg Lonafarnib (assembly inhibitor) RNA Celular RNA POL II HDV-Ag 800bp mrna Small Large Hepatocyte 1700bp mrna

28 Lonafarnib Inhibitor of farnesyl-transferase. Prior clinical experience in the treatment of progeria Blocks virus assembly and packaging No selects for drug resistance Phase 2 comparing dosing in 15 pts. Ritonavir increases 5-fold lonafarnib exposure Recognition of dose-response Lonafarnib 200 mg BID plus ritonavir 100 mg QD produced >1 log drop in all treated pts: Mean drop week 4: -2.2 log Mean drop week 8: -3.2 log Yurdaydin et al. EASL 2015, abstract O118

29 Acknowledgments Clinic Pablo Labarga Pablo Barreiro Laura Benitez Jose V. Fernandez-Montero Laboratory Carmen de Mendoza Ana Treviño Isabella Esposito Collaborators: Ivana Maida (Italy), Giovanni Gaeta (Italy), Antonio Aguilera (Spain), Paula Tuma (Brazil) & Carmen Rodriguez & Jorge del Romero (Spain)