Introduction to hepatitis B and C for healthcare workers

1. Introduction to hepatitis B and C for healthcare workers ศตวรรษ ทองสวัสดิ์ ภาควิชาอายุรศาสตร์

3. 1910.1030(f) Hepatitis B Vaccination and Post-exposure Evaluation and Follow-up -- ..1910.1030(f)(1) 1910.1030(f)(1) General. 1910.1030(f)(1)(i) The employer shall make available the hepatitis B vaccine and vaccination series to all employees who have occupational exposure, and post-exposure evaluation and follow-up to all employees who have had an exposure incident.

4. 1910.1030(f)(2) Hepatitis B Vaccination. 1910.1030(f)(2)(i) Hepatitis B vaccination shall be made available after the employee has received the training required in paragraph (g)(2)(vii)(I) and within 10 working days of initial assignment to all employees who have occupational exposure unless the employee has previously received the complete hepatitis B vaccination series, antibody testing has revealed that the employee is immune, or the vaccine is contraindicated for medical reasons.

5. Acute hepatitis Resolution Chronic hepatitis cirrhosis Hepatocellular carcinoma Death

6. Prevalence among blood donors in Chiang Mai

7. Hepatitis B • Incomplete circular DNA virus • Four overlapping genes: S, C,P and X • Family: Hepadna virus • Human, woodchuck, squirrel, Peking duck • Replicate as the retrovirus

8. Hepatitis B A. The HBV invades the cell by binding to surface receptors B. the virus is taken up by the cell C. enzymes extend the S(+) strand to form a covalently closed circular double-stranded DNA (CCC-DNA) D. The HBV genome in its core migrates to the nucleus E.& F. Additional viral structural protein messenger RNAs pass into the cytoplasm and are translated G. The pregenome and viral DNA polymerase are packaged into new capsids H.& I. The pregenome is then destroyed. The L(−) strand (H) is then used as a template for formation of the S(+) strand J. the mature cores (I) are packaged into HBsAg particles, which accumulate in the endoplasmic reticulum and exit the cell

9. Symptoms anti-HBe HBeAg Total anti-HBc Titer anti-HBs IgM anti-HBc HBsAg 0 4 8 12 16 24 28 32 52 100 20 36 Weeks after Exposure Hepatitis B acute infection and resolution

10. Typical Serologic Course Acute (6 months) Chronic (Years) HBeAg anti-HBe HBsAg Total anti-HBc Titer IgM anti-HBc Years 0 4 8 16 20 24 28 36 12 32 52 Hepatitis B acute infection turn into chronicity Weeks after Exposure

11. Hepatitis B • Incubation period 30-180 days, mean 60-90 • Perinatal transmission and intimate contact between toddlers are the important transmission routes • 350 million HBsAg carriers worldwide

12. HBsAg Prevalence ³8% - High 2-7% - Intermediate <2% - Low Prevalence of chronic hepatitis B

13. Chronic HBV Asymptomatic with normal ALT HBe +, HBV DNA + Spontaneous HBe to Anti-HBe: rare Immune tolerance 15-35 yr. Adult acquired Symptoms + Increase ALT with active histology HBV DNA + but usually low HBe to Anti-HBe : 2.7-25% /year Immune clearance rapid silence prolonged fluctuating No symptom with normal ALT HBeAg -, HBsAg + (cytoplasm), HBV DNA (host DNA) Nonreplicative

14. Natural History of Chronic HBV Infection CompensatedCirrhosis 90-95% Resolution Stabilisation 15-25% Liver Cancer AcuteInfection ChronicHepatitis Cirrhosis Death DecompensatedCirrhosis (Death) 5-10% Chronic Carrier Progression 30–50 Years Adapted from Feitelson, Lab Invest 1994

15. The new concept of ‘carrier’ • All with HBsAg-positive should be called chronic hepatitis B (CHB), with consideration of • Virologic (HBeAg status, viral load) • Biochemical (ALT level) • Histological status • Then consider as “active” or “inactive carrier state” • “Inactive carrier state” is • HBeAg-negative • Normal ALT, viral load < 105 • Very mild necroinflammation (HAI score < 3), no fibrosis

16. Carrier vs chronic hepatitis Depends on ALT • Carrier has normal ALT at every 6 months for at least 3 years (6 tests) • Chronic hepatitis • HBsAg-positive for more than 6 months • High ALT (preferably >1.5x) two times six months apart • Biopsy reveals moderate necroinflammation

17. Whom should we treat? Chronic hepatitis • Documented HBsAg+ >6 month • Either HBeAg +, (antiHBe -) or HBeAg - (precore mutant) • HBV-DNA +, but not very high • Moderately increased ALT, >2x but <10x • Documented necroinflammation and fibrosis by biopsy

18. Why biopsy needed? • Confirm the need to be treated • No ideal treatment exists • Treatments are with certain risks, including resistance and flares both during and after treatment failure • Uncontrolled treatment means uncontrolled infection

19. Should we treat the CARRIERS? • Carriers also carry the certain risk of developing cirrhosis and hepatocellularcarcinoma • No study on the incidence risk, but very low • Surveillance is not recommended, but may be considered if affordable • Treatment for carrier (eradication of the virus) is not available now • Current treatment relies on activated immune status • No treatment that can eradicate the virus • Carriers should have regular follow up, avoid alcohol and other liver injury

20. Current treatment • Interferonalpha • 5-10 million units qd or tiw for 16-24 weeks • Pegylated interferon • Only pegylated interferon alpha-2a • 180 mcg qw for 48 weeks • Antivirals • Lamivudine • Adefovir dipivoxil

21. Seroconversion = HBeAg-ve and anti-HBe+ve 100 ALT > 1 x ULN (n=41) 77% ALT > 2 x ULN (n=26) 80 69% 65% 63% 56% 54% 60 Patients (%) 42% 38% 37% 40 27% 20 0 1 2 3 4 5 Duration of Therapy (years) Response to lamivudine treatment Guan R . J. Gast. Hep. 2001; 16 Suppl.: Abs 160

22. Emerging of YMDD resistance % Incidence of YMDD mutant HBV 69 - 75% 47 - 56% 16 - 32% 2 year 3 year 1 year At year of Lamivudine therapy Atkins M. et al. Hepatology. 1998.

23. 55 CH-B patients treated uninterruptedly for a minimum of 2 years (Lam 100 mg: 38 pts, Lam 25 mg: 7 pts, Lam 25 100 mg: 10 pts) 13/32 (40.6%) Occurred 4-94 weeks (median 24 wks) after emergence of the YMDD mutant Acute exacerbation* 1/23 3/32 (9.4%) (4.3%) 3/13 decompensation (23%) With YMDD Without YMDD Mean Fu = 104 wks 62 wks * abrupt increase of ALT by 2 folds and to a level greater than 5 x ULN or to a level > 300 IU/L Hepatitis flare from YMDD resistance Liaw YF. et al. Hepatology. 1999.

24. Treatment of chronic disease • Long term treatment • Increasing cost in progressing disease • Even sky high cost for end stage • Supportive treatment • Organ replacement therapy • Transplantation • Cancer prevention and treatment

25. What do we expect from chronic hepatitis B? • Cirrhosis • Compensated • Decompensated • Complication of cirrhosis • Ascites • Variceal bleeding • Hepatic encephalopathy • Hepatocellular carcinoma

26. Is treatment of chronic hepatitis B cost-effective? • Relatively low effectiveness as compared to hepatitis C (20-40% vs. 80-90%) • Treatment is considerably expensive • Undesirable side effects with high dose interferon • Treatment with antiviral may result in flare or resistance • No firm data on prevention of cirrhosis and HCC

27. Viral entry Uncoating Assembly & budding ER Positive strand synthesis LAM, ADV, and TDF pol Inhibitors HBsAg Nuclear import HBV Polymerase ? Removal of pregenome cccDNA Repair Transcription Negative strand synthesis 5’ 3’ 2.4/2.1 kb RNA 5’ 3’ Translation 3.5 kb RNA Encapsidation Role of oral antivirals

28. Hepatitis B vaccination • First anti-cancer Vaccine • Hepatitis B vaccine prevents hepatitis B disease and its serious consequences like hepatocellular carcinoma. Therefore, this is the first anti-cancer vaccine. • Safe and effective • Medical, scientific and public health communities strongly endorse using hepatitis B vaccine as a safe and effective way to prevent disease and death. • Scientific data show that hepatitis B vaccines are very safe for infants, children, and adults. • There is no confirmed evidence indicating that hepatitis B vaccine can cause chronic illnesses.

30. * The schedule for hepatitis B vaccination is flexible and varies. Consult the ACIP statement on hepatitis B (11/91), AAP's 2003 Red Book, or the package insert for details.Note: For adult dialysis patients, the Engerix-B dose required is 40µg/2.0ml (use the adult 20µg/ml formulation) on a schedule of 0, 1, 2, and 6 months. For Recombivax HB, a special formulation for dialysis patients is available. The dose is 40µg/1.0ml and it is given on a schedule of 0, 1, and 6 months.

31. Vaccine interruption • If the vaccination series is interrupted after the first dose, the second dose should be administered as soon as possible. The second and third doses should be separated by an interval of at least 2 months. If only the third dose is delayed, it should be administered when convenient. Booster doses • Current data show that vaccine-induced hepatitis B surface antibody (anti-HBs) levels may decline overtime; however, immune memory (anamnestic anti-HBs response) remains intact indefinitely following immunization. Persons with declining antibody levels are still protected against clinical illness and chronic disease. • For health care workers with normal immune status who have demonstrated an anti-HBs response following vaccination, booster doses of vaccine are not recommended nor is periodic anti-HBs testing.

32. Post-vaccination Testing • After routine vaccination of infants, children, adolescents, or adults post-vaccination testing for adequate antibody response is not necessary. • Post-vaccination testing IS recommended for persons whose medical management will depend on knowledge of their immune status. • This includes persons who: • are immunocompromised (e.g., hemodialysis patients) • received the vaccine in the buttock • are infants born to HBsAg (hepatitis B surface antigen)-positive mothers • are healthcare workers who have contact with blood • are sex partners of persons with chronic hepatitis B virus infection • Post-vaccination testing should be completed 1-2 months after the third vaccine dose for results to be meaningful. A protective antibody response is 10 or more milliinternational units (>=10mIU/mL).

33. Hepatitis C • Linear single -stranded RNA virus • Family: Flaviviridae • Anti-HCV is not neutralizing antibody • Neutralizing antibody can be demonstrated but short-lived

34. Hepatitis C • HCV is a positive sense, single-stranded RNA virus, with an estimated diameter of 36 to 72 nm. • HCV is believed to represent a distinct genus in the Flaviviridae family • A viral envelope comprising a lipid layer and envelope proteins, surrounds a core (capsid) structure enclosing the viral nucleic acid • HCV RNA is 9.4 kb in length and consists of a 5′nontranslated region, followed by core (C), envelope (E), and nonstructural (NS) protein encoding regions

35. Hepatitis C • Incubation period 15-160 days,mean 50 • Transmitted mostly by blood and blood products • The second generation test in 1992 reduced the infection to near zero • Perinatal and sexual transmission is also possible but with rather low incidence

36. HCV infection 2-20 wks All abnormal ALT 1/3 jaundice 15% Resolved 85% chronic 1/3 2/3 All abnormal pathology normal ALT Abnormal ALT cirrhosis 20-30% in 10-20 yr. HCC 3%/yr.

37. Different in Disease Progression of HCV 100 Medium rate 0.133 /y Very rapid fibrosis 0.36/y 30 years to cirrhosis % cirrhosis 11 years to cirrhosis 50 Very slow fibrosis 0.04/y 100 years to cirrhosis

38. 2 5 1 4 3 6 HCV genotypes and subtypes P. Simmonds, Philos Trans R Soc Lond B Biol Sci 2001;356:1013-26

39. Geographic distribution of hepatitis C genotypes 1b2a, 2b, 2c, 3a 1b 1a, 1b2a, 2b, 3a 2a 4 1b, 3a 1b, 3, 6 4 3b 1b, 3a 5a Adapted from Fang J Clin Liver Dis 1997;1:503.

40. Current treatment Pegylated-interferon alfa + ribavirin • Pegylated interferon qw, 24-48 weeks • Ribavirin according to body weight and genotypes • <70 kg, or genotypes non-1, 800 mg/day • >=70 kg, 1,000-1,200 mg/day • All cases that have undetectable HCV-RNA at the end of treatment need to have it checked again 6 months later • Undetectable HCV-RNA at 6 months after completion of treatment means complete eradication

41. Benefit from treatment • Eradication, 60-90%Termination of disease course and even with regression of fibrosis • Non sustained remission, 20+%Retardation of disease progression • Less than 10% will not benefit from treatment

42. Fibrosis regression or retardation in CH-C patients treated with interferon (IFN) IFN Fibrosis stage Fn+1 untreated (+0.10 unit/year) Fibrosis progression Fn non-SR (+0.024 unit/year) Fn-1 Fibrosis resolution SR (-0.28 unit/year) 0 5 10 -10 -5 (Years) After IFN treatment

43. Screening for HCC