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 NZ 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 DNA 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 DNA 6,500,000 IU/mL Referred to Hospital Fibroscan cirrhosis Treat?

6 Case 2 35 Yr old European male» 2 weeks malaise, anorexia»now dark urine, RUQ abdo pain,» Previously well, no family history»lfts: ALT 1600, GGT 160; ALP 95; bilirubin 122 New 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»now dark urine, RUQ abdo pain,» Previously well, no family history»lfts: ALT 1600, GGT 160; ALP 95; bilirubin 122 New 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»now dark urine, RUQ abdo pain,» Previously well, no family history»lfts: ALT 1600, GGT 160; ALP 95; bilirubin 122 New 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 IgM anti-hbc Total anti-hbc HBsAg 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 ULN HBV DNA /- /-

12 ACUTE HBV CHRONIC 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 ULN >ULN HBV DNA /- /-

13 ACUTE HBV CHRONIC HBV IMMUNE 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 ULN >ULN < ULN HBV DNA /- /-

14 ACUTE HBV CHRONIC HBV IMMUNE 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 ULN >ULN < ULN HBV DNA /- /-

15 ACUTE HBV CHRONIC HBV IMMUNE 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 ULN >ULN < ULN HBV DNA /- /-

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

17 Control of HBV in New Zealand Neonatal Vaccination Program (1987) % HBsAg+ in 12 yr olds 20% 15% 10% 10% 5% 0% 0% (vaccinated) Lucas et al. NZ Med J 1994; 107:266-8

18 HCC incidence in children (<14yrs) (100,000 person yrs) Childhood Vaccination in Taiwan reduces incidence of Liver Cancer 0.8 neonatal vaccine '75 '76 '77 '78 '79 '80 '81 '82 '83 '84 '85 '86 '87 Birth Year Chang,1997

19 Cost/QALYS Childhood Vaccination is the most costeffective health intervention $ 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

20 Roll out of HBV Vaccination: Milestones 1985: International Vaccination Workshop» Saul Krugman, Palmer Beazley, Ron Lucas, Mary Dimitrikakas, Brian McMahon, Jim Maynard 1986: Vaccinate infants of HBsAg+ mothers 1987: Vaccinate all infants (80,000/year) 1988: Catch-up vaccination in all 12 yr olds What about those already infected?

21 Impact of Endemic HBV Infection in New Zealand LIVER MORTALITY HEPATOMA CLINIC Alcohol 31% Other 4% HCV 21% Alcohol 9% NASH 7% Other 3% HCV 8% \ HBV 63% HBV 60% 200 cases per annum 120 cases per annum Weir,R, et al. J Gastro Hepatol 2002;17: Fung J, et al. Hepatology 2005; 42:258A

22 NZ Maori Cook Islands Fiji W. Samoa Niue Tonga Hong Kong Taiwan SE China Prevalence of HBsAg Who should be included in a National HBV Screening Programme? Prevalence of HBV Incidence of HCC 25% 20% 15% 10% 5% China Middle Africa Japan Eastern Africa Southern Europe Caribbean Southern Africa Western Europe Eastern Europe Northern America Central America Western Asia Northern Africa Australia South America Northern Europe Males Females 0% NZ Maori NZ Asian NZ Pacifican HCC Age Standardized Incidence per 100,000 Parkin D, et al. CA Cancer J Clin. 2005;55; Tuikitonga C, et al. NZMJ 1992.

23 Projected Ethnic Populations (i) Maori (ii) Pacific (iii) Asian (iv) European

24 National HBV Screening Programme June 1998: Pilot programme scrapped National screening programme funded from July 1999 until June 2002 Targeting at-risk adults» Asian, Pacific Islander, Maori» 15 years old (post vaccination) Total to be screened= 566,000 All HBsAg+ offered life-long follow-up

25 HBV Status National HBV Screening Programme July July 2002» 177,292 Screened 75% 50% 25% 0% 11,936 HBsAg+ identified 54% 59% 59% 45% 6.5% 5.8% 7.3% 6.2% 9% 1% Overall Maori Pacifican Asian European anti-hbs(+) = immune to HBV HBsAg+ = chronic HBV Robinson T, et al. NZ Med J. 2005; 118: No. 1211

26 Maori Cook Is Niuean Tongan Indian (50,000) SE Asian (20,000) Chinese (72,500) % HBsAg+ National HBV Screening Programme Prevalence according to Ethnicity 20% 15% 13.3% 10% 5.8% 7.4% 9.1% 9.3% 9.4% 5% 0% 0.6% Robinson T, et al. NZ Med J. 2005; 118: No. 1211

27 National HBV Follow-up Programme Opportunistic screening in Primary Care Total enroled pre

28 Numbers lost from f/u Numbers exiting from the National HBV Surveillance Programme sag loss Emigrated Died Refused

29 National HBV Screening Programme : MoH-funded screening programme»enrolled 11,300 HBsAg+ Since 2002: MoH surveillance programme»lost 3500 from original cohort»gained 6000 from opportunistic screening»currently 18,000 enrolled

30 NZ Hepatitis B Screening and Follow-up Programme HBsAg Negative Immune Nonimmune DISCHARGE VACCINATE HBsAg Positive THF Follow-up Programme 6 mthly surveillance for CHB and HCC Robinson T, et al. NZ Med J. 2005; 118: No. 1211

31 National HBV Follow-up Programme Surveillance for Hepatoma Screening Programme Regular surveillance 6 monthly AFP ± U/S ALL HBsAg+ Not Screened No surveillance Present with symptoms

32 National HBV-HCC Surveillance Programme Outcomes to date ( ) Patients in the NZ HBV Screening Program 284 HCCs Detected at screening visit Detected between visits Patients NOT enrolled in HBV Screening Program 374 Non-screened HCCs All symptomatic

33 % of patients treated National HBV-HCC Surveillance Programme Increase in curative treatment for HCC Surveillance detects HCC earlier 80 and increases treatment options Screened HBV-HCC (n=190) Non-screened HBV-HCC (n=375) 79% P< % 25% 17% 13% 9% 5% 4% 1% 0% TACE/TAE RFA Resection Liver Tx Overall Treatment Modality

34 Cumulative Survival National HBV-HCC Surveillance Programme Increase in survival for HCC % 54% Screened HBV group Median survival = 2054 days n = Surveillance Log-rank: P< increases survival 20 21% 3% Non-screened HBV group Median survival = 99 days n = Survival (Years)

35 ANTIVIRAL THERAPY National HBV Follow-up Programme Surveillance for Chronic Hepatitis B ALL HBsAg+ 6 monthly ALT ALT>ULN Repeat in 3 months ALT>ULN Refer to Clinic HBV DNA >4 log IU/mL

36 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

37 (a) L-Nucleosides NH 2 Options for Treating CHB O N N CH HN 3 N NH 2 F HO S N O O N O OH O N O OH S Lamivudine OH Telbivudine Emtricitabine (b) D-Cyclopentane (c) Acyclic Phosphonate NH 2 HO HN N N N N Entecavir NH 2 N NH 2 N N N O Adefovir O O P OH OH N N O O P OH OH Tenofovir OH

38 Resistance to nucleoside analogues Treatment-naive % resistant LAM ADV LdT ETV TDV Year 6 Year 5 Year 4 Year 3 Year 2 Year 1 0 0

39 Proportion of Subjects, % Benefits of Long-term Oral Antiviral Therapy Suppression of HBV Replication HBeAg- Patients HBeAg+ Patients % % 90 TDF-TDF 80 TDF-TDF 70 ADV-TDF 60 ADV-TDF Weeks Weeks 99.6% overall response at Year 8 98% overall response at Year 8 1. Marcellin P, et al. J Hepatol Jul 18; DOI: /j.jhep (epub ahead of print). 39

40 Benefits of Long-term Oral Antiviral Therapy Reversal of Fibrosis Pre-treatment Cirrhosis After 3 years Tenofovir Mild Fibrosis Dienstag,2003

41 HCC Incidence (%) Benefits of Long-term Oral Antiviral Therapy Prevention of Liver Cancer Case-control Korean study (2518 patients): 0.4 Control Group P = Suppressed on Lamivudine Years Follow-up Eun JR et al. J Hepatol 2010; 53:

42 Number of Transplants Benefits of Long-term Oral Antiviral Therapy Demand for Liver Transplantation NZLTU Trends in HBV Transplants ( ) 602 liver transplants; 121 (20%) for HBV Decomp 15 Lamivudine Adefovir Tenofovir / /2 2003/4 2005/6 2007/8 2009/ / /4 NZLTU data

43 Benefits of Long-term Oral Antiviral Therapy for CHB Mortality reduction Transplant need reduction HCC reduction Cirrhosis reduction Histological response Serological response Histological response Serological response Virological response Biochemical response Fibrosis regression HBsAg seroclearance Histological improvement HBeAg loss-seroconversion (HBeAg(+) patient only) HBV DNA negativity ALT normalisation Short-term goal Medium-term goal Long-term goal Treatment start Su TH, et al. Expert Rev Gastroenterol Hepatol 2014; doi: /

44 Management of HBV in NZ Summary 100,000 infected here in NZ»Only 1/3 are aware of their status»only 20% in long-term surveillance 300+ deaths/yr 1000/yr by 2030»Most due to HCC (liver cancer)»all preventable by earlier diagnosis Need to restart targeted HBV screening in all adult Maori, Pacific, Asian New Zealanders»Opportunistic screening in primary care»open national screening programme?

45 Management of HBV in NZ Summary Suppression of HBV with antiviral therapy prevents disease progression and reverses liver cirrhosis thereby reducing liver cancer Current treatments (entecavir, tenofovir) are safe and 100% effective and fully funded for life Regular surveillance and monitoring of patients with HBV will provide earlier detection of liver cancer and improved chance of cure

46 Number of HBV-HCC Management of HBV in NZ Unresolved issues Almost 50% HCCs are only diagnosed when symptoms develop, when cure is not possible Not screen-detected Screen-detected 50 Need to increase recruitment into followup programme through primary care Need to improve the effectiveness of 20 surveillance, by using new predictors of 10 HCC to individualise monitoring strategies

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48 Hepatitis Foundation of New Zealand The Story So Far?

49 History so far Established 31 years ago Charitable Trust Head office in Whakatane Largest HBV follow-programme globally Employs 28 staff Has over 18,000 clients registered in long-term follow-up Works in partnership with the NZ Liver Unit Provides community Fibroscan Service

50 Liver biopsy Day off work in 100% Pain, tenderness in 100% Haemorrhage in 1% Bile leak in 0.5% Overnight admission in 5% Surgery in 1% Death in 0.3% van der Poorten E, et al. Int Med J 2006; 36:

51 Fibroscan No days off work Non-invasive» Painless» No admissions/deaths Bedside/clinic Immediate result Inexpensive Reproducible

52 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 National HBV Patient Management System

53 National HBV Surveillance Programme Hep Foundation contracted by MoH 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 GPs can now e-refer to the Foundation via Medtech, Best Practice and Care Select

54 How to refer from Primary Care Letter Telephone Fax Hep Foundation Community Nurse Hep Foundation e-referral via Medtech Best Practice Care Select Self referral

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57 HBV the solution Universal neonatal vaccination will prevent >99% new infections and will lead to global eradication of HBV within the next 50 years For those who are already infected, long-term antiviral therapy will prevent all liver-related complications and is safe In near future, the addition of short-term HBV CURE therapies will induce HBsAg loss and allow cessation of long-term therapy