Viral Hepatitis B and C Epidemiology and management to Prevention

1. Viral Hepatitis B and CEpidemiology and management to Prevention Seyed Moayed Alavian M.D. Professor of Gastroenterology and Hepatology Director of Baqiyatallah Research Center for Gastroenterology and Liver Disease Editor-in-chief of Hepatitis Monthly E mail:editor@hepatmon.com World Hepatitis Day 2012

2. B D A C E Feces Feces Source of Blood/ Blood/ Blood/ body fluids body fluids body fluids virus Childbirth, needles, sex, transfusion Needles, sex, transfusion (requires HBV co-infection) Fecal-oral Needles, transfusion, (sex, childbirth) Fecal-oral Route of transmission Yes Yes No Yes No Chronic infection Vaccine, immune globulin HBV vaccine Blood donor screening, risk management, education Ensure safe Vaccine, immune globulin, drinking water Viral Hepatitis Type of Hepatitis Prevention CDC fact sheets, available at www.cdc.gov

3. Epidemiology of Hepatitis B • Hepatitis B has a worldwide distribution and is perhaps the most common cause of chronic virus infection and the most frequent cause of chronic viral disease, cirrhosis, and hepatocellular carcinoma. Alavian SM, et al. Hepatitis B Virus Infection in Iran: A Systematic Review. Hepat Mon2008;8(4):281-94.

4. Hepatitis B Virus Infection Worldwide Disease Burden 2 billion people are infected with HBV worldwide with past infection 350 and 400 million persons are estimated suffering this infection 15%-25% will die from chronic liver disease (liver cancer or cirrhosis)

5. Geographic Distribution of Chronic HBV Infection • Many of the data relating to the global distribution of HBV are over 10 years old • More recent data suggest that this is an over-simplification • There is an increasing trend towards HBeAg-negative HBV in many areas • Global distribution of HBV is being affected by population movements from high prevalence areas Chronic infection prevalence Past infection prevalence Predominant age at infection 40– 90% 8% – High Perinatal and early childhood 16– 55% 2–7% – Intermediate Early childhood 4– 15% < 2% – Low Adult

6. HBV: A Global Problem • Hepatitis B infection is of major global importance • large pool of patients • serious nature of disease sequelae • difficult/impossible to eradicate once chronic infection established • significant economic burden • Urgent actions are needed to address the problem • immunisation programmes • therapeutic intervention for chronically-infected patients • education initiatives to prevent transmission/ infection

7. Burden of HBV • Decreased life expectancy • Loss of quality of life • High lifetime costs associated with management of liver disease and sequelae of HBV infection • HBsAg-positive patients: • more likely to be hospitalised • longer hospital stays • Healthcare costs increase with progression of CHB Pereira. Transfusion 2003; Steinke et al. Gut 2002

8. Modes of Transmission • HBV is transmitted via contact with blood or body fluids in the same way as HIV. However, HBV is50–100 times more infectious than HIV • Modes of transmission: • perinatal/vertical • child-to-child transmission • unsafe injections and transfusions • sexual contact WHO Fact Sheet 2000

9. Outcome of HBV Infection According to Age at Time of Infection % of infections with outcome Chronic infection Symptomatic acute infection Birth 1–6 months 7–12 months 1–4 years Older children and adults Age at infection WHO 2001

10. The Clinical Outcomes of HBV Infection 10–70% 95% Perinatal/childhood acute infection Adult acute infection Recovery Recovery < 1% 30–90% < 5% Fulminant hepatitis  1* Chronic infection Inactive carrier state Mild, moderate or severe chronic hepatitis  2–10* 5–50 years Cirrhosis  0.1* 2–8*  4*  3* Decompensation Transplant or HCC Death * per 100 patient-years Adapted from EASL Consensus Statement. J. Hepatol. 2003; 39 (S1):S3–25

11. Epidemiology Hepatitis B in Iran • The prevalence of hepatitis B surface antigen (HBsAg) in Iran reported between 2.5% and 7.2% in 1979. (1) • In 1980s about 3% of population was affected (from 1.7% in Fars province to 5% in Sistan-Balouchestan province). (2) The most common routes of transmission was perinatal Farzadegan H ,1979, Merat S 2000

12. Risk factors in chronic hepatitis B-Iran • Age, male sex, history of contact with hepatitis B infected subject, extramarital sexual activity, injection drug use, major surgery, experimental dentist visit and some jobs (police, barber, and driver) were found to be independent risk factors • It seems to be of great importance to pay more attention to certain jobs, life styles and cultural matters. • Sali SH, Bashtar R, Alavian SM. Risk Factors in Chronic Hepatitis B Infection: A Case-control Study. Hepat Mon2005;5(4):109-15.

13. Transmission of HBV-Iran • The seroprevalence of HBsAg positive in 1824 subjects of Nahavand of Iran in 2002 was 2.3%. History of surgery and imprisonment were the major risk factors for infection. • The most Prevalent in relatives of index cases were sons and daughters (32.2% and 23.5%), respectively. • Alizadeh AH….., Alavian SM, et al. Seroprevalence of hepatitis B in Nahavand, Islamic Republic of Iran. East Mediterr Health J2006 Sep;12(5):528-37.

14. Transmission of HBV-Iran • Among 1500 subjects attended laboratory for sexually transmitted diseases in Northeast of Iran between 1998 and 2000, the seroprevalence of HBsAg was 10% in women and 14.2% in men • Importance of Horizontal transmission in adults • Ghanaat J 2003

15. Transmission of HBV • Risk factors in Iranian blood donors (1996-2000) in 2447 HBsAg + cases: • HBsAg positivity in mother and family, transfusion history, male gender, hospital admission, sexual contact, and more age were risk factors. Alavian S,et al. Evaluation of Hepatitis B Transmission Risk Factors in Tehran Blood Donors [In Persian]. Govaresh 2004;3(9):169-75.

16. Transmission of HBV-Iran • In a study in 226 gypsies of Shahr-e-Kord, Southwest of Iran with a mean age of 20.7 years, thirty-five subjects (18%) were HBsAg positive. • Also, fifty-four persons (23.9%) had positive HBc Ab. • Tattooing and phlebotomy are common practices among our gypsies. • Hosseini Asl SK 2004

17. In I.R. Iran mass vaccination of neonates against HBV infection was started from 1993 as a national program in routine neonates care. This program is supposed to affect the prevalence rate of HBV infection thorough the country and decrease the rate of infection after awhile. Zali 2005, Alavian 2007

18. More than one billion people have been immunized in the world since the beginning of implementation globally.

19. Hepatitis B in general Population In Iran • Using survey data analysis method the HBV infection prevalence in I.R. Iran estimated 2.14 percent (95%CI: 1.92-2.35). The HBV infection prevalence in Iranian men and women estimated 2.55 percent (95%CI 2.25-2.85) and 2.03 percent (95%CI 1.6-2.46 percent) respectively. Alavian SM, Hajariazdeh B, Ahmadzad Asl M, Kabir A, Bagheri Lankarani K. Hepatitis B Virus Infection in Iran: A Systematic Review. Hepat Mon2008;8(4):281-94.

20. The distribution of HBV infection prevalence in the country showed that there are significant differences between provinces in HBV infection rates and the highest prevalence rates was in Golestan province (6.3 percent; 95%CI 3.2-9.3 percent). • Alavian SM, Hajariazdeh B, Ahmadzad Asl M, Kabir A, Bagheri Lankarani K. Hepatitis B Virus Infection in Iran: A Systematic Review. Hepat Mon2008;8(4):281-94.

21. Vaccination in adult in Iran supported by changing of transmission rout from vertical and horizontal in childhood to horizontal in adulthood due to some risk factors. Alavian SM. Ministry of Health in Iran Is Serious about Controlling Hepatitis B. Hepat Mon2007;7:3-5.

22. Vaccination against HBV in Iran • After 13 years of implementation, the coverage has reached an appropriate level from 62% in 1993 to 94% in 2005. Deputy for Health, CDC report (Iran) 2006

23. Mass vaccination in high risk group and susceptible groups, mainly women at reproductive ages, youth and high risk job workers such as health care providers, barbers, drivers and intravenous drug abusers. • Adult vaccination • People awareness • Early diagnosis

25. Hepatitis B in CRF • Hemodialysis patients are highly exposed to be infected with hepatitis B virus .Primary prevention with vaccination is the most effective strategy to reduce morbidity caused by HBV infection and hemodialysis patients are strongly recommended to be vaccinated against HBV. • The prevalence of HBsAg positivity had decreased from 3.8% in 1999 to 2.6% in 2006 in Iran. • Alavian SM, Bagheri-Lankarani K, Mahdavi-Mazdeh M, Nourozi S. Hepatitis B and C in dialysis units in Iran: Changing the epidemiology. Hemodial Int2008 Jul;12(3):378-82.

27. When should hepatitis B not be treated?

28. Clinical Case-1 -Normal ALT • A 25 years-old male, born from HBs Ag positive mother, • Diagnosed in screening for HBV due to his mother histroy • No past history of acute hepatitis or jaundice • PE: Normal • AlT: Normal, HBeAg Positive, HBV Viral Load: 2,000,000 copies/ml • What is you next plan?

29. Clinical Case-2 –Inactive carrier The patient is a 20 year old woman who is HBs Ag (+), HBe Ag (-). Her HBV DNA is 5000 copies/mL. She has mild chronic portal inflammation, no fibrosis with mild steatosis. Her serum ALT is 30 IU/L (upper limit of normal 40 IU/L). She is obese. What is your plan for this patient?

30. Characteristic phases of CHB infection Immune Immune Immune Immune tolerance clearance control escape HBeAg+ve HBeAg–ve > < > < HBV-DNA ALT HBeAg +ve chronic hepatitis HBeAg –ve/+ve active chronic hepatitis Inactive (carrier) state

31. Immune Immune Immune Immune tolerance clearance control escape HBeAg+ve HBeAg–ve > < < > HBV-DNA ALT treat treat HBeAg +ve chronic hepatitis Inactive (carrier) state HBeAg –ve/+ve active chronic hepatitis Who should be considered for treatment?

32. Immune Immune Immune Immune tolerance clearance control escape HBeAg+ve HBeAg–ve > < < > HBV-DNA ALT HBeAg +ve chronic hepatitis Inactive (carrier) state HBeAg –ve/+ve activechronic hepatitis Who should be considered for treatment? monitor monitor treat treat

33. Immune Tolerant Phase • Commonly perinatally transmitted • Frequently in Foreign-born individuals • A patient may traverse through phases • 10-30 years • Persistently elevated HBV DNA levels contribute to increased risk of HCC

34. Current AASLD Practice Guidelines • Low efficacy with current treatment • Observe, consider treatment if ALT becomes elevated • Consider biopsy: aged >40, ALT persistently elevated, family hx HCC • Consider treatment: HBV DNA >20,000 IU/mL AND biopsy shows mod/sev inflammation and significant fibrosis

35. Cut off Level for ALT & AST

36. HBeAg Positive Patients Immune-Tolerant vs HBeAg+ Active CHB

37. Role of ALT in the assessment liver disease in CHB Serum ALT level may not accurately predict histologic stage1–4 Up to 24% of patients with normal ALT have stage 2–4 fibrosis by biopsy5,6 Liver biopsies should be employed more frequently in normal ALT, especially for patients >30–40 years of age5 Treat if there is significant disease on liver biopsy7,8 1. Kim HC et al. BMJ 2004; 328: 983–6; 2. Nguyen MH et al. Hepatology 2005; 42: 593A; 3. Wang C et al. Hepatology 2005; 42: 573A; 4. Lai M et al. J Hepatol 2007; 47: 760–7; 5. Lai M et al. Hepatology 2005; 42 (Suppl 1): 720A; 6. Alberti A et al. Ann Intern Med 2002; 137: 961–4; 7. Keeffe EB et al. Clin Gastroenterol Hepatol 2006; 4: 936–62; 8. Lok ASF, McMahon B. Hepatology 2007; 45: 507–39.

38. Persistently normal ALT was associated with excellent long-term prognosis • Increasing ALT levels of at least 2 times ULN during follow-up was associated with increasing morbidity and mortality. • ALT of at least 2 times ULN is therefore an appropriate threshold for anti-HBV therapy

39. Chronic HBV: Goals of Therapy HBV is probably never cured but rather controlled by limiting viral replication Markers of treatment response Decreased serum HBV DNA to low or undetectable levels <10-15 IU/mL Decreased or normalized serum ALT levels Induce HBeAgloss or seroconversion (in HBeAg-positive patients) Induce HBsAg loss or seroconversion Improved liver histology

40. HBsAg carrier state ALT q 3 months for 1 year, if persistently normal, ALT q 6-12 months If ALT 1-2 ULN, check serum HBV DNA level and exclude other causes of liver disease. Consider liver biopsy if ALT borderline or mildly elevated on serial tests or if HBV DNA persistently 10,000 C/mL. Consider treatment if biopsy shows moderate/severe inflammation or significant fibrosis Consider screening for HCC in relevant population

41. Recommendations Any decision for treatment and/or liver biopsy in patients with CHB should be made according to • HBe Ag • ALT • Viral load • Age • Family history • Presence of comorbid diseases

42. We don’t treat patients in immune tolerance phase HBeAg +, very High HBV DNA, Persistently normal ALT, young age But, Family history is very important

43. Management of Chronic Carrier Patients (Low replicative phase) • Treatment not indicated but • Need to confirm persistently normal ALT • Need to confirm persistently HBV DNA < 2000 • Monitor for transition to reactivation with ALT measurements q3-6 months • Monitor for HCC with US and AFP • Style life modification

44. We don’t treat patients in low replicative phase (chronic carrier patients) • And think about other factors in elevated ALT such as fatty liver

45. Hepatitis C Virus Infection

46. Epidemiology of Hepatitis C • HCV infection is widespread throughout the world. • WHO estimation suggests that up to 3% of the world’s population have been infected with HCV.

47. Relative Efficiency of HBV, HCV, HIV Transmission by Type of Exposure Type of exposure Efficiency of transmission to infected sourceHBVHCVHIV Transfusion ++++ ++++ ++++ Injecting drug use ++++ ++++ ++++ Unsafe injections +++ +++ + Perinatal ++++ ++ +++ Needle stick +++ + + Sexual +++ + +++ Non-intact skin ++ +/- +/-

48. Risk Factors Associated With Acquiring HCV Infection • Transfusion, transplant from infectious donor (1992) • Injecting drug use and Incarceration • Occupational blood exposure (needle sticks) • Birth to an infected mother • Infected sex partner • Multiple heterosexual partners • Tattooing • Health-care related transmission:

49. Determining Who to Screen • Primary care offices are the frontline in identifying patients with risk factors • Anyone with a history of IDUs (even limited) should be tested • Persons with a history of no injection drug use and/or multiple sexual partners should also be screened for HCV • Persons infected with HIV should be screened for HCV • Any abnormal ALT level warrants HCV testing

50. Decrease or emerging infection? • With the implementation of mandatory HCV screening of blood and blood products in the early 1990s, the number of post-transfusion infections has already decreased dramatically. However, intravenous drug use (IDU) has accelerated in the world.