Hepatitis delta: often forgotten?

Transcription

1 15 th Annual Resistance and Antiviral Therapy Meeting Dr Sarah Hughes King s College Hospital, London Thursday 29 September 2011, Royal College of Physicians, London Hepatitis delta: often forgotten? Dr Sarah Hughes Institute of Liver Studies, King s College Hospital 1

2 Hepatitis delta: often forgotten? Dr Sarah Hughes Institute of Liver Studies, King s College Hospital Aims What is HDV? Why test? How and when to test for HDV Therapy for HDV 2

3 24 year old twins Case Illustration Known to have hepatitis B Low risk carrier Not previously treated Born in Romania to HBsAg negative mother Both diagnosed HBsAg +ve aged 5 hospitalised in Bucharest for episode of icteric hepatitis after being subject to group vaccination practice Referred to King s Hepatitis Service during first trimester of first pregnancy of twin 1 Investigations Twin 1 Twin 2 HBsAg + + HBeAg - - Anti-HBe + + HBV DNA (IU/mL) <20 <20 Anti-HCV IgG - - Anti-HIV ALT (IU/L)(5-55)

4 Investigations Twin 1 Twin 2 HBsAg + + HBeAg - - Anti-HBe + + HBV DNA (IU/mL) <20 <20 Anti-HCV IgG - - Anti-HIV ALT (IU/L)(5-55) Anti-HD IgG + + Anti-HD IgM + + HDV RNA (qual) Detectable Detectable HDV RNA (quant) 5 log copies/ml 5 log copies/ml HDV genotype 1 1 Case History - Histology 4

5 Management Pegylated Interferon alpha 2a 180mcg/week via subcutaneous injection Twin 1: Responder-relapser Twin 2: Non-responder Disease evolution Spleen size (cm) Twin 1 Twin Time (months) 5

6 MRI: cirrhosis with portal hypertension HDV What is it? Outbreak of cases of Hepatitis B with severe clinical course in Mediterranean basin in mid-1970s Novel (non-hbv) antigen in hepatocyte nuclei detected by immunofluorescence 1 Recognised to be a specific marker ofanovelhumanpathogen 2 1 Rizetto et al Gut Rizetto et al Proc Natl Acad Sci

7 HDV - Virology Small single stranded RNA virus: 36 nm diameter 1700 nucleotide genome Defective: Only infects those with hepatitis B virus Requires helper function of HBV to provide envelope proteins for assembly and transmission HDV -Life Cycle Hughes et al Lancet

8 HDV - Epidemiology 1/3 world population (2 billion) exposed to HBV million chronic carriers 1 Average estimated 5% seroprevalence for HDV Ab amongst HBV carriers million worldwide infected with HDV 1 WHO fact sheets at 2 Farci J Hepatol 2003 HDV Modes of transmission Parenteral transmission infected blood/body fluids Highly contagious Tiny innoculum required for infection (<10-8 ul) 1 Vertical transmission uncommon Evidence for sexual transmission Familial spread inapparent parenteral transmission 2 High risk groups IVDU Prostitutes 1 Ponzetto J Infect Dis Niro et al J Hepatol

9 HDV - Viral Heterogeneity High variability of genome sequence 8 different genotypes so far identified Genotypes 5-8 of exclusively African origin % sequence divergence between genotypes 2 Vary in geographical distribution Differ in clinical course 3 1 Le Gal et al Emerg Infect Dis Deny Curr Top Micro Immunol Su et al Gastro 2006 Global prevalence of HDV infection Hughes et al Lancet

10 Global prevalence of HDV infection HBsAg 19% HDV Ab1.3% Hughes et al Lancet 2011 Global prevalence of HDV infection HDV Ab<0.5% Hughes et al Lancet

11 Global prevalence of HDV infection 0 4% 13% 0 3.5% Hughes et al Lancet 2011 Prevalence of anti-hd in HBsAg carriers with liver disease in Italy Younger Severe hepatitis Older Cirrhosis 11

12 HDV infection South London 8.5% vs 2% in Cases HDV HBV Cross et al. J Med Virol 2008 & Harrison unpublished data Year 12

13 Global Migration in 21 st Century Change in epidemiology in N Europe Le Gal et al Hepatology

14 HDV Natural History Increased prevalence of cirrhosis compared with HBV mono-infection OR2.64 ( ) p< % with cirrhosis /840 22/ HBV HBV/HDV Data from Cross et al JVH

15 Influence of HDV on outcome of cirrhosis in HBV Decompensation HCC Survival Increased risk of decompensation, HCC and death compared with HBV monoinfection RR Decompensation 2.2 HCC 3.2 Death 2.0 Fattovich Gut 2000 Co-infection and Viral Dominance 70 90% of those with HDV are HBeAg-ve HDV suppresses HBV replication HDAg altering gene expression to interfere with HBV mrna export from nucleus thereby inhibiting HBV replication High rate of HCV co-infection but replication also suppressed HDV>HBV>HCV HIV co-infection common Heidrich JVH

16 HIV and HBV/HDV co-infection EuroSIDA cohort 16,597 HIV patients 7.9% HBsAg + ever reported Substudy of 422 HBsAg + individuals 61/422 anti-hd IgG + (14.5%) 87% of those HDV RNA + HDV predominated in IVDU Inhibitory effect of HDV on HBV seen in all but HBV genotype D Not associated with progression to AIDS Increased risk of liver-related death and overall mortality Soriano et al AIDS 2011 HDV - Diagnosis Anti-HDV IgG Indicates exposure to HDV should be performed in all HBsAg-positive patients Anti-HDV IgM Indicates acute HDV infection or chronic HDV infection with ongoing replicative activity Serum HDV RNA Indicates active infection No internationally standardised assay Quantitation (in-house) on-treatment monitoring No association between HDV RNA level and grade or stage of liver disease Liver biopsy 16

17 Challenge HDV - Treatment To target two co-existing viruses Highly pathogenic virus Unconventional life cycle No viral polymerase to target Interferon monotherapy trials 17

18 The Hep-Net/International Delta Hepatitis Intervention Trial (HIDIT-1) N=32* PEG-IFNa-2a (180 µg oiw) Adefovir dipivoxil 10 mg daily N=91 N=29 PEG-IFNa-2a (180 µg oiw) Placebo N=30 Adefovir dipivoxil 10mg daily Screening TW0 TW24 TW48 F24 * 1 patient withdrew informed consent after randomization Wedemeyer et al NEJM 2011 Significant decline of HDV-RNA with PEG-IFN ** Patients (%) with negative HDV-RNA (ITT) TW ADV PEG-IFN / P PEG-IFN / ADV ** * TW0 TW24 TW48 F24 *p<0.02 vs TW0; ** p<0.001 vs. TW0 F 24 PEG-IFN / ADV PEG-IFN / P ADV 18

19 PEG-IFN & ADV combination resulted in a more pronounced decrease of HBsAg levels 5 ADV PEG-IFN / P PEG-IFN / ADV Clearance of HBs-Ag in 2 patients treated with PEG-IFN & ADV HBs-Ag (IU/ml) 4,5 4 3, ,5 W0 W24 W48 F24 Baseline predictors of response to therapy p=0.021 % of patients SVR No SVR 0 Genotype 1 Genotype non-1 Hughes et al Unpublished 19

20 HDV Treatment recommendations PEG-IFN α2a 180 mcg/week sc for 48 weeks detectable serum HDV RNA any degree of liver disease histologically compensated liver disease no contraindications to interferon Insufficient data for early stopping rules Individualised approach to those who remain HDV RNA +ve at 48 weeks sag quantification Baseline characteristics viral load, genotype Insufficient data as yet to support combination Rx HDV Treatment recommendations Liver transplantation Treatment of choice End-stage decompensated liver disease Fulminant liver failure meeting criteria for poor prognosis 1 Good long-term outcome with administration of HBIg 5-year survival c.80% 2 1 O Grady Gastroenterology Samuel Hepatology

21 Prenylation inhibitors Entry Uncoating Editing + UAG + UIG - AUC + UGG - ACC + UAG + UGG Small δ Large δ Small δ Large δ HBsAg Rolling circle replication Transcription and linearization Translation Prenylation Assembly HDV HBV HDV virion assembly -critically dependent on prenylation of large delta Ag Prenylation of large δcreates a hydrophobic/lipophilic molecule that binds both to HDV RNA and to HBsAg, leading to packaging and export Inhibition of prenylation interferes with HDV assembly and release Inhibitors in use as anti-cancer agents; good safety profile Virion release Heller and Hoofnaggle. J Clin Invest 2003 Prenylation inhibitor in mouse model control prenylation inhibitor Decline in HDV RNA associated with clearance of pre-existing pool of prenylated large DAg Bordier et al. J Clin Invest

22 Summary The most severe form of chronic viral hepatitis Remains underdiagnosed but still represents a significant global health burden Easy to miss, easy to screen for Test all HBsAg+ individuals for HDV IgG antibodies At presentation Unexplained flare in transaminases In those with detectable serum HDV RNA Evaluate stage of liver disease with biopsy Assess for anti-viral therapy with PEG-IFN 22