Hepatitis B virus infection. Chow Wan Cheng Dept of Gastroenterology & Hepatology Singapore General Hospital

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1 Hepatitis B virus infection Chow Wan Cheng Dept of Gastroenterology & Hepatology Singapore General Hospital

2 Chronic Hepatitis B - are we in the same situation as hepatitis C?

3 Treatment of chronic hepatitis C

4 Hepatitis B virus infection Where are we now? Is it still a problem globally?

5 Changing seroprelance of hepatitis B in Singapore Hong WW et al. Ann Acad Med 2010

6 Hepatitis B a slowly disappearing disease in Singapore Chronic HBV infection rate (HBsAg prevalence rate) Ac. hepatitis B incidence (per100,000) % (1972) 4.1 % (1999) 2.7% (2005) 10.8 (1989) 4.8 (1996) Age-standardised incidence rate of HCC per 100,000 per year (ranking of frequency of HCC amongst other cancers in males) 27.8 (6 ) ( ) 18.5 (3) ( ) Seroprevalance of HBsAg in Singapore residents between age 1 17 years was 0.3 % ( ) we met WHO goal!! Epidemio News Bulletin (MOH, Singapore) Oct Dec 2014 Singapore Cancer Registry Report No. 7 ( )

7 Etiology of HCC among patients between years (C1) & (N=1270) GBB Goh et al. Hepato Comms 2017

8 Age- & sex- specific mortality and incidence rate of chronic liver disease and HCC for birth cohorts pre- and post- vaccination programme in Taiwan CLD mortality HCC Incidence HCC mortality HBsAg prevalence among pregnant women by age at parturition & year of birth in Hong Kong ( ) CJ Chiang et al. JAMA 2013 After 20 years, HBsAg prevalence in children in Taiwan dropped from approx. 15% to < 1% S Wait & DS Chen. KJMS 2012 WHO bulletin Nov 2014; 92 (11) Similar trend in Hong KONG & Taiwan

9 Survival of carrier vs. non-carriers, Taiwan

10 Z Poh et al. Eur J Gastro Hepato % 70.4% Rate of cirrhosis and HCC in chronic hepatitis B patients in 10 year follow up (enrolled 2003/04) - N = 673 (62.6 % males); Age 56.4 (+/- 12) years - 10 year incidence of cirrhosis & HCC was 16.2 % (1.6% / year) and 7.8 % (0.8 % / year), respectively. - Rate of cirrhosis is highest among those aged > 55 years - Incidence of HCC was 29.7 % (3.0 % / year) among the cirrhotics. - HBeAg status did not affect the rate of cirrhosis

11 HBeAg positive Anti-HBe negative HBeAg negative Anti-HBe positive Natural clinical course of chronic HBV infection Pre-core mutants HBeAg-negative HBV mutants s. ALT HBV DNA Immunotolerance Immunoclearance Quiescence

12 HBV genotypes in Singapore Genotype B Genotype C Freq 80 40% 59% Genotype D % Genotype B Genotype C 1% % 37.8% 17.7% HBeAg - HBeAg + P=0.04; P=0.003 Patients with raised s. ALT

13 HBV genotypes and cirrhosis & HCC freq 38% 46.5% NON- CIRRHOTIC 53.5% 62% CIRRHOTIC Genotype B Genotype C 29.6 % % 19 Genotype B Genotype C Patient with HCC

14 Natural history of chronic hepatitis B virus infection HBsAg + ve HBeAg +ve Anti-HBe -ve HCC HBe seroconversion HBsAg +ve HBeAg -ve Anti-HBe +ve HBV DNA undetectable Immuno-tolerance phase Immuno-clearance phase Non-replicative phase Immune status Viral load

15 Past efforts & current treatment options Immunomodulation Thymosin alpha 1 Interferon alpha Pegylated interferon monotherapy Nucleos(t)ide analogue Targeting at polymerase gene Pegylated interferon NA combination Attempts to eradicate HBV from patients with chronic hepatitis B

16 Peg-IFN ALPHA 2B +/- Lam x 52 weeks Baseline HBeAg +ve patients N = 266 Follow up period: 3 +/- 0.8 years Past efforts & current treatment options Immunomodulation Thymosin alpha 1 Interferon alpha Pegylated interferon monotherapy Nucleos(t)ide analogue Targeting at polymerase gene Pegylated interferon NA combination Erik HCJ Buster et al. Gastroenterology 2008

17 Peg-IFN ALPHA 2a +/- Lam x 48 weeks Baseline HBeAg -ve patients N = 230 Follow up period: 5 years Past efforts & current treatment options Immunomodulation Thymosin alpha 1 Interferon alpha Pegylated interferon monotherapy Nucleos(t)ide analogue Targeting at polymerase gene Pegylated interferon NA combination HBsAg Loss 12 % of the overall treated population 28% (20/72) among those with low HBV DNA 1 year after EOT P Lampertico et al. Liv Int 2013

18 Patients with HBeAg seroconversion (%) Chronic hepatitis B is not a homogenous disease: HBV genotypes matter HBeAg seroconversion rates at 24 weeks after treatment according to genotypes 60 52% PEGASYS + placebo PEGASYS + lamivudine Lamivudine Prevailing genotypes in Asians: genotypes B & C % 20% 30% 29% 23% 31% 28% 18% 22% 18% 18% 0 12/23 4/18 3/15 23/76 24/82 17/73 50/162 43/156 29/162 2/9 2/11 3/17 A B C D Genotypes Cooksley et al.

19 Long term entecavir reduces incidence of HCC T. Hosaka et al. Hepatology 2013 Past efforts & current treatment options Immunomodulation Thymosin alpha 1 Interferon alpha Pegylated interferon monotherapy Nucleos(t)ide analogue Targeting at polymerase gene Pegylated interferon NA combination Treatment with Nucleos(t)ide analogues prevent / ameliorate complications of CHB, while they do not eradicate HBV definitively in the short medium term

20 Remaining problems in HBV infection Immigrant population Novel infection in the elderly HBV infection in the fertile females Hepatic complications from previously infected patients (historical cases)

21 Remaining problems in HBV infection Immigrant population Novel infection in the elderly HBV infection in the fertile females Hepatic complications from previously infected patients (historical cases)

22 Remaining problems in HBV infection Immigrant population Novel infection in the elderly HBV infection in the fertile females Impact on mothers Vaccine failure Hepatic complications from previously infected patients (historical cases) Hep B - related events Pregnant patients Control patients HBeAg positive patients N = 23 N = 92 P value HBeAg loss 3 (14.3 %) 2 (2.2 %) 0.02 Raised s. ALT pregnancy 8 (50 %) 31 (34.1 %) NS p/partum 12 (66.7 %) 14 (16.3 %) 0.01 HBeAg negative patients N = 12 N = 48 Raised s. ALT pregnancy 1 (10 %) 3 (6.4%) NS p/partum 3 (25 %) 0 (0 %) HH Tan et al. Hepatol Int (2008) 2:

23 Remaining problems in HBV infection Immigrant population Novel infection in the elderly HBV infection in the fertile females Impact on mothers Vaccine failure Hepatic complications from previously infected patients (historical cases)

24 Remaining problems in HBV infection Immigrant population Novel infection in the elderly HBV infection in the fertile females Impact on mothers Vaccine failure Hepatic complications from previously infected patients (historical cases) Complications from chronic / past HBV infection - Reactivation of HBV replication (acute exacerbation of hepatitis B) - Especially with profound / prolonged immune suppression) - Risk of HCC (with or without HCC)

25 Beware of patients hepatitis B status with use of biologics FDA-approved biologics for Crohn s disease: Adalimumab (Humira) Biosimilar to Adalimumab Adalimumab-adbm (Cyltezo), Adalimumab-atto (Amjevita), Certolizumab pegol (Cimzia) Infliximab (Remicade) Biosimilar to Infliximab Infliximab-abda (Renflexis), Infliximab-dyyb (Inflectra) Natalizumab (Tysabri) Ustekinumab (Stelara) Vedolizumab (Entyvio)

26 HBV reactivation in RA patients receiving anti-tnf F De Nard World J Hepatol 2015

27 HBV life cycle and host immune interactions

28 New therapeutic approaches against HBV

29 Summary Chronic HBV infection is much controlled in the developed countries Through successful universal vaccination programmes. Treatment to control / decrease the complications of chronic hepatitis B It is still a health threats to specific populations Past exposure will pose risks to exposed individual in various degrees Serological screening of HBV infection and appropriate prophylaxis treatment will avoid some of the complications of hepatitis B