Chronic Hepatitis B. What every GP should know. Prof Ed Gane NZ Liver Unit

Transcription

1 Chronic Hepatitis B What every GP should know Prof Ed Gane Z Liver Unit

2 Case 1 55 Yr old Tonga male»well but dad died of liver cancer»lfts: ALT 85, GGT 60; ALP 75; bilirubin 12 What next?

3 Case 1 55 Yr old Tonga male»well but dad died of liver cancer»lfts: ALT 85, GGT 60; ALP 75; bilirubin 12 HBsAg + HBeAg neg What next?

4 Case 1 55 Yr old Tonga male»well but dad died of liver cancer»lfts: ALT 85, GGT 60; ALP 75; bilirubin 12 HBsAg + HBeAg neg HBV DA 6,500,000 IU/mL What next?

5 Case 1 55 Yr old Tonga male»well but dad died of liver cancer»lfts: ALT 85, GGT 60; ALP 75; bilirubin 12 HBsAg + HBeAg neg HBV DA 6,500,000 IU/mL Referred to Hospital Fibroscan cirrhosis Treat?

6 Case 2 35 Yr old European male»2 weeks malaise, anorexia»ow dark urine, RUQ abdo pain,»previously well, no family history»lfts: ALT 1600, GGT 160; ALP 95; bilirubin 122 ew partner Chinese tertiary student who has strong family history of liver cancer What next?

7 Case 2 35 Yr old European male»2 weeks malaise, anorexia»ow dark urine, RUQ abdo pain,»previously well, no family history»lfts: ALT 1600, GGT 160; ALP 95; bilirubin 122 ew partner Chinese tertiary student who has strong family history of liver cancer Anti-HAV IgM neg Anti-HCV neg HBsAg neg; anti-hbs neg What next?

8 Case 2 35 Yr old European male»2 weeks malaise, anorexia»ow dark urine, RUQ abdo pain,»previously well, no family history»lfts: ALT 1600, GGT 160; ALP 95; bilirubin 122 ew partner Chinese tertiary student who has strong family history of liver cancer Anti-HAV IgM neg Anti-HCV neg HBsAg neg; anti-hbs neg Anti-HBcore IgM ++ What next?

9 window Diagnosis of Acute Hepatitis B Symptoms anti-hbs Titre HBsAg IgM anti-hbc Total anti-hbc Weeks after Exposure

10 Diagnosis of Chronic Hepatitis B Acute (6 months) HBeAg HBsAg Chronic (Years) Titre Total anti-hbc IgM anti- HBc Years Weeks after Exposure

11 ACUTE HBV early window late HB s Ag anti-hbs HB e Ag anti-hbe anti-hb c IgM anti-hb c IgG Serum ALT >5x UL HBV DA /- /-

12 ACUTE HBV CHROIC HBV early window late eag+ eag - HB s Ag anti-hbs HB e Ag anti-hbe anti-hb c IgM anti-hb c IgG Serum ALT >5x UL >UL HBV DA /- /-

13 ACUTE HBV CHROIC HBV IMMUE early window late eag+ eag - past HBV vaccine HB s Ag anti-hbs /- /- HB e Ag anti-hbe anti-hb c IgM anti-hb c IgG Serum ALT >5x UL >UL < UL HBV DA /- /-

14 Route of acquisition of Chronic HBV infection in Z Adult to Adult 1% Maternal 10% Playground 89% Vaccine available, cheap, >99% effective

15 Control of HBV in ew Zealand eonatal Vaccination Program (1987) % HBsAg+ in 12 yr olds Lucas et al. Z Med J 1994; 107: % 15% 10% 10% 6% 5% 0% (total) 0% 1992 (vaccinated)

16 HCC incidence in children (<14yrs) (100,000 person yrs) Prevention of HBV-related Hepatoma Vaccination in Taiwan neonatal vaccine school vaccine '75 '76 '77 '78 '79 '80 '81 '82 '83 '84 '85 '86 '87 Birth Year Chang,1997

17 Cost/QALYS HCC Surveillance in Chronic HBV Infection Cost-Effectiveness Comparison $ 50,000 $ 40,000 $38,000 $ 30,000 $ 30,000 $ 25,000 $23,000 $ 20,000 $ 10,000 $ 0 $200 Cervical Cancer Screen Breast Cancer Screen Colonic Cancer Screen HCC screening in HBsAg+ HBV Vaccine

18 HBV Status ational HBV Screening Programme Target Maori, Pacific and Asians >15 yrs 177,292 screened July July ,300 HBsAg+ identified 100% 75% 50% 54% 59% 59% 45% HBsAg(-)/anti-HBs(-) = HBV naïve anti-hbs(+) = immune to HBV 25% 0% 6.5% 5.8% 7.3% 6.2% 9% 1% Overall Maori Pacifican Asian European HBsAg+ = chronic HBV

19 Maori Cook Is iuean Tongan Indian (50,000) SE Asian (20,000) Chinese (72,500) % HBsAg+ ational HBV Screening Programme Prevalence according to Ethnicity 20% 15% 13.3% 10% 5% 5.8% 7.4% 9.1% 9.3% 9.4% 0% 0.6%

20 ational HBV Screening Programme : MoH-funded screening programme»enrolled 11,300 HBsAg+ Since 2002: MoH surveillance programme»lost 3100 from original cohort»gained 4100 from opportunistic screening»currently 12,234 enrolled

21 umbers lost from f/u ational HBV Screening Programme Lost from Surveillance Programme sag loss 300 Emigrated Died 0 Refused

22 ational HBV Screening Programme What is the future? Estimated 100,000 ew Zealnders have HBV Only 12,000 in the Surveillance Programme eed to increase screening and follow-up Target Maori, Pacific Islanders and Asians 1. GPs opportunistic screening 2. Reopen ational Screening Program Demonstrate need Demonstrate benefits of screening

23 Demonstrate eed 2006 Census 9.3% HBsAg+ =36, % HBsAg+ =21, % HBsAg+ 36,250 Pacific Asian, 395,000 Asia-Pacific 1% HBsAg =22,000 Maori, European 2.7million Estimated 100,000 HBsAg+ cases in Z >60,000 cases OT YET DETECTED (assumed O childhood infections since 1987)

24 The HBV population is OT declining Projected Ethnic Populations (i) Maori (ii) Pacific (iii) Asian (iv) European

25 Re-open ational Screening Demonstrate Benefit All HBsAg+ offered 6 monthly surveillance for chronic hepatitis and liver cancer (HCC)»Safe, effective surveillance tests (AFP, ALT)»Effective treatments available HCC ablation/resection Chronic hepatitis antiviral therapy»do treatments improve survival?

26 ational HBV Surveillance Improves survival

27 ational HBV Follow-up Programme Surveillance for Hepatoma 90% HBsAg+ o cirrhosis o family Hx LOW RISK 6 mthly AFP ALL HBsAg+ 10% HBsAg+ Cirrhosis or Family Hx HIGH RISK 6 mthly AFP and U/S

28 ational HBV-HCC Surveillance Programme Outcomes to date ( ) Patients in the Z HBV Screening Program 190 HCCs Detected at screening visit Detected between visits Patients OT enrolled in HBV Screening Program 375 on-screened HCCs All symptomatic

29 % of patients treated Surveillance in HBV increases chance of curative treatment for HCC Surveillance detects HCC earlier 80 and increases treatment options Screened HBV-HCC (n=190) on-screened HBV-HCC (n=375) 79% P< % 25% 17% 13% 9% 5% 4% 1% 0% TACE/TAE RFA Resection Liver Tx Overall Treatment Modality

30 Cumulative Survival Surveillance in HBV increases survival % 54% Screened HBV group Median survival = 2054 days n = Surveillance Log-rank: P< increases survival 20 21% 3% on-screened HBV group Median survival = 99 days n = Survival (Years)

31 ational HBV Surveillance Improves survival

32 Goals of treatment in CHB: APASL Consensus Statement 2005 The ultimate long-term goal is prevention of cirrhosis, decompensation and HCC, and prolong survival. Sustained viral suppression is the key to the reduction or prevention of hepatic injury and disease progression. Therefore, the primary goal of treatment for chronic hepatitis B is to eliminate or permanently suppress HBV.. Liaw YF et al. Liver Int 2005

33 ATIVIRAL THERAPY ational HBV Follow-up Programme Surveillance for Chronic Hepatitis ALL HBsAg+ 6 monthly ALT ALT>UL Repeat in 3 months ALT>UL Refer to Clinic HBV DA >4 log IU/mL

34 Lai et al., J Med Virol 2000 Replication Cycle of Hepatitis B Virus; Mechanism of Action of Lamivudine Infectious HBV virion Lamivudine Infectious HBV virion Partially doublestranded DA DA pol (-)- DA RT HBsAg envelopes cccda A(n) mra Encapsidated pregenomic mra

35 Treatment in HBV prevents and reverses cirrhosis Pre-treatment Cirrhosis After 3 years Lamivudine Mild Fibrosis Dienstag,2003

36 Viral Suppression with Lamivudine may prevent Liver Failure Cirrhosis Asian Lamivudine Multicenter study RCT of 651 Pts with compensated HBV-cirrhosis 25% % with liver failure 20% 15% 10% Placebo p< % 9% 5% Lamivudine 0% Months of therapy Liaw YF. EJM. 2004;351:

37 Viral Suppression with Lamivudine may prevent Hepatocellular Carcinoma.5 Korean Study Cumulative incidence of HCC Log Rank p<0.001 Control (n=385) Follow-up duration (years) Lamivudine (n=561) Eun JR et al. J Hepatol 2010; 53:

38 Viral Suppression with Lamivudine may prevent Liver Transplantation Annual umber of Transplants Transplants for Decompensated CHB Lamivudine Adefovir Entecavir Tenofovir ZLTU data

39 Genotypic Lamivudine Resistance Lamivudine Lamivudine M552 M204V/I L180M L528

40 Rate of Lamivudine resistance Lamivudine in Z Auckland HBV Clinic ( ) 1254 treated with Lamiv Breakthrough in 422 ( DA >1 log) % 57% 25 34% 5% Duration of LAM (Yrs)

41 Options for Lamivudine-resistant CHB (a) L-ucleosides H 2 H O C H 3 H 2 F HO S O O O O H O O O H Lamivudine O H Telbivudine S Emtricitabine (b) D-Cyclopentane (c) Acyclic Phosphonate H 2 H O H Entecavir H 2 H 2 O O O P O H O H Adefovir O O P O H O H O H Tenofovir

42 Options for Lamivudine-resistant CHB (b) D-Cyclopentane (c) Acyclic Phosphonate H 2 H O H H 2 H 2 O O O P O H O H O O H O P O H O H Entecavir Adefovir Tenofovir

43 Options for Lamivudine-resistant CHB (c) Acyclic Phosphonate H 2 H 2 O O O P O H O H O O H O P O H O H Adefovir Tenofovir

44 Resistance to ucleoside Analogues

45 Management of CHB in Z Summary >100,000 ew Zealanders have chronic HBV»>10,000 ew Zealanders have HBV-cirrhosis»200 die each year from HCC/liver failure Suppression of HBV with antiviral therapy prevents disease progression and reverses liver cirrhosis Current treatments (entecavir, tenofovir) are safe and 100% effective and fully funded for life Life-long antiviral therapy prevents disease progression and reverses liver cirrhosis Earlier diagnosis and treatment will prevent liver cancer, liver failure, transplant and death

46 Management of CHB in Z Challenges < 25% all HBsAg+ patients have been recruited into regular follow-up <5% all active CHB receive antiviral Rx Most cases of liver cancer and cirrhosis present late with symptoms of advanced disease, when therapeutic options are limited and survival poor (<3 months) Outcomes can only be improved from earlier diagnosis and surveillance

47 Hepatitis Foundation of ew Zealand The Story So Far?

48 History so far Established 30 years ago Charitable Trust Head office in Whakatane Largest HBV follow-programme globally Employs 22 staff Works in partnership with the Z Liver Unit Has over 12,000 clients enrolled in longterm follow-up

49 Why use the Hepatitis Foundation? Expertise in HBV management & education Better outcomes for HBV patients enrolled into national follow-up programme Community Service Advice line up-to-date information Safety net for both patients & GP ational HBV Patient Management System

50 How to refer from Primary Care Letter Telephone Fax Hep Foundation Community urse Hep Foundation webpage Self referral

51 ational HBV Surveillance Program Contracted to Hepatitis Foundation since 2002 Still GP-based but community nurse available to chase repeated nonresponders to recall Facilitated collection Preprinted blood forms or HepBFree stickers Central database (updated SQL) Efficiency Quality assurance; effectiveness analysis

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57 HBV the solution Universal neonatal vaccination will prevent all infections HBV should be eradicated within next 50 years. For those who are already infected, longterm antiviral therapy will prevent all liverrelated complications and is safe Early detection and long-term surveillance will improve survival

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