2. Iranian College of Internal Medicine Hamid Kalantari MD Professor of Gastroenterology Isfahan University of Medical Sciences Management of Hepatitis B Questions & Answers

5. Goals of Presentation Understand natural history of chronic HBV infection. HBV and perinatal transmission. Discuss management of HBV. Discuss antiviral agents used in adults.

6. Geographic Distribution of Chronic HBV Infection

7. What is natural history of HBV infection?

9. What are the modes of HBV transmission?

10. Vertical transmission Infants born to HBV+ mothers Vertical transmission is responsible for approximately one-half of chronic infection worldwide.

11. What is the chance of HBV transmission during pregnancy? (Based on time of acquired infection)

12. What is the chance of HBV transmission during pregnancy? Acute HBV occurring early in the pregnancy has been associated with a 10 percent perinatal transmission rate. Transmission rates significantly increase if acute infection occurs at or near the time of delivery, with rates reported as high as 60 percent.

13. How you can reduce perinatal transmission rate of maternal HBV?

14. Administration of prophylaxis: –The high protective efficacy (95 percent) of neonate –HBIG –First dose of HBV vaccine given within 12 hours of birth and completion of HBV vaccine series.

15. What is perinatal transmission rate of maternal HBV without prophylaxis?

16. 90 percent in infants born to HBeAg-positive mothers and 32 percent in infants born to HBeAg-negative mothers in the absence of prophylaxis. Children born to HBeAg-positive mothers remain at risk for HBV infection, even if they receive vaccination and HBIG (approximately 9 percent in one large cohort study). Maternal-infant transmission can occur in utero, at birth, or after birth.

17. What are risk factors for perinatal transmission?

18. The most important risk factor: –High maternal HBV viral load The risk of transmission is increased in women who have active HBV replication. Transplacental transmission and transmission due to obstetrical procedures are less frequent causes.

19. What are not risk factors for perinatal transmission?

20. Breast feeding does not appear to pose a substantial risk. The benefit of cesarean delivery in protecting against transmission has not been clearly established. The obstetrical approach should not be influenced by the HBV status of the mother.

21. Horizontal Transmission

22. Household contacts of chronically infected persons Hemodialysis patients Healthcare workers Sexual partners of HBV carriers People with sexually transmitted diseases Injection drug users who share contaminated needles people with multiple sexual partners Adoptive families of children born in endemic areas

23. Who should be screened for HBV infection?

24. US born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity (≥8 percent) Household and sexual contacts of HBsAg-positive persons Persons who have ever injected drugs Persons with multiple sexual partners or history of sexually transmitted disease Men who have sex with men Inmates of correctional facilities Individuals with chronically elevated ALT or AST Individuals infected with HCV or HIV Patients undergoing renal dialysis All pregnant women Persons needing immunosuppressive therapy

25. Tattoo

26. Who Should Be Vaccinated for HBV?

27. Residents/staff in certain settings with clients with known HBV risk factors Persons with end-stage renal disease, chronic liver disease, or HIV infection Persons with behavioral or occupational exposures Persons seeking evaluation or treatment for an STD Susceptible sex partners and household contacts of HBsAg-positive persons Travelers to regions of intermediate/high endemicity

28. What should be considered by persons who are HBsAg positive?

29. Persons who are HBsAg positive should: Have sexual contacts vaccinated Use barrier protection during sexual intercourse if partner not vaccinated or naturally Not donate blood, organs, or sperm Clean blood spills with detergent or bleach Cover open cuts and scratchesp Not share toothbrushes or razors

31. Case one A 30 year old man is referred to you with low grade fever, nausea, vomiting, jaundice, dark urine and RUQ pain. He has past history or needle stick 8 weeks ego. Serologic evaluation reveals: –HBsAg + –Alt: 1000 U/L –HBeAg + –INR: ½ –IgM anti HBC + –Total Bilirubin: 10 mg/dl

32. What is your management?

33. Acute infection of HBV Treatment is mainly supportive All patients with acute HBV don’t require antiviral treatment since: Liver failure from acute hepatitis B is less than 1 percent Progression to chronic HBV infection is less than 5 percent

34. Case two A 70 year old man who is hospitalized with drowsiness, low grade fever, abdominal pain, anorexia, and deep jaundice up to four weeks. Serologic evaluation reveals: –HBsAg+ -INR =2 –IgM anti-HBc+ –HBV DNA: 300,000 IU/cc –ALT is 2000 U/L –Total bilirubin is 10 mg/dL

35. What is your management?

36. Acute infection of HBV Who is recommended treated? Patients with a severe (such as those who develop a coagulopathy {INR >1.5}) or a protracted course (such as persistent symptoms or marked jaundice {bilirubin >10 mg/dL} for more than four weeks after presentation). Acute liver failure due to hepatitis B to reduce the likelihood of reinfection post-liver transplant.

37. Acute infection of HBV Which Drugs is recommended? Telbivudine, lamivudine, adefovir, tenofovir, or entecavir would all be acceptable options given as monotherapy as the duration of treatment should be short. Treatment can be stopped after confirmation (two consecutive tests four weeks apart) that the patient has cleared HBsAg.

38. Acute infection of HBV Which Drug is not recommended?

39. Interferon should be avoided because of the risk of infection and a further increase in hepatic necroinflammation in patients with severe hepatitis or acute liver failure

40. Case three A 25 year old woman is HBSAg+ from 6 months ego was referred to you with –HBeAg+ –HBV DNA of 200 M IU/cc –ALT: 200 U/L She is planning to be pregnant within the next two years.

41. What is your management?

42. The main role of interferon Primarily treatment of young patients with well compensated liver disease Who do not wish to be on long-term treatment In patients which planning to be pregnant within the next two to three years In whom drug resistance may limit their treatment options in the future Interferon is also an attractive option for patients with HBV genotype A infection

43. What are advantages & disadvantages of Interferon?

44. Interferon Advantages Its finite duration of treatment The absence of selection of resistant mutants More durable response Disadvantages Side effects from interferon are troubling for many patients, and (less commonly) can be severe Interferon cannot be used in patients with decompensated disease

45. Standard interferon For adults: 5 MU daily or 10 MU three times a week by subcutaneous injection For children: 6 MU/M(2) three times weekly with a maximum of 10 MU Treatment duration for HBeAg positive chronic hepatitis is 16 to 32 weeks Treatment duration for HBeAg negative hepatitis is 12 to 24 months

46. Peginterferon alfa-2a (Pegasys) For adults: 180 μg once weekly For children: Not approved The manufacturer recommends 48 weeks of treatment for HBeAg positive or negative chronic HBV

47. What is definition of chronic hepatitis B?

48. What factors are associated with progression of chronic HBV?

49. Demographic: –Male Sex Increase incidence HCC in males (1a) –Age Increasing incidence of HCC with age (1a) –Family history (1b) Environmental and Social: –Alcohol: Increase risk for HCC and cirrhosis (2c) –Aflatoxin exposure: increase risk of HCC (2c) –Tobacco: Increased risk for HCC (2c) –NAFLD: limited conflicting data (3)

50. Factors Associated with Progression of Chronic HBV: Viral Genotype Other viral co-infections: –HIV: Increase HBV DNA levels High HBV DNA level over time (>5 log copies or 20,000 IU/ml) in persons > 40 years

51. What are recommendations for treatment of Chronic HBV Infection? (HBeAg+)

52. What are recommendations for treatment of Chronic HBV Infection? (1)

53. What are recommendations for treatment of Chronic HBV Infection? (HBeAg-)

54. What are recommendations for treatment of Chronic HBV Infection? (2)

55. Case four A 70 year woman is brought in by her son after she was found wandering the streets. She has progressively disoriented, confused, and forgetful over the last 2 weeks. A routine health check up revealed normal except liver tests dysfunction: –ALT: 100 IU/cc –HBsAg (+) –HBeAg (-) –HBV DNA = 100.000 IU/cc Fibro scan showed moderate fibrosis.

56. What is your suggestion?

57. What are the advantages of Tenofovir?

58. Tenofovir Advantages Tenofovir may be used as first line treatment in treatment-naive patient. In patients with lamivudine, telbivudine or entecavir resistance, preferably as additional treatment in these patients Preliminary data indicate that resistance to tenofovir is rare after up to four years of treatment.

59. Tenofovir Tenofovir is given at a dose of 300 mg daily. The dose needs to be adjusted in renal impairment.

60. What are the advantages of Entecavir?

61. Entecavir Advantages Its potent antiviral activity Low rate of drug resistance (approximately 1 percent with up to five years of treatment) Entecavir may also have an important role in patients with decompensated cirrhosis because of its potent antiviral activity and low rate of drug resistance. Resistance has been observed in up to 50 percent of lamivudine-refractory patients after five years of treatment.

62. Entecavir Entecavir is administered orally. The recommended dose is 0.5 mg once daily for nucleoside-naive adults and adolescents older than 16. It is 1 mg daily for those who have lamivudine resistance. The dose should be adjusted in patients with a creatinine clearance of <50 mL/min.

63. In patients with renal insufficiency which drug may be a better option?

64. Renal insufficiency Entecavir may be a better option than adefovir or tenofovir in patients with renal insufficiency and in those who are at risk for renal insufficiency. Entecavir has not been reported to cause renal impairment. While all of these medications require dose reduction according to renal function.

65. What are the advantages of Lamivudine?

66. The main disadvantage of lamivudine are its lower cost compared to the other oral agents. The many years of experience confirming its safety, including its use during pregnancy. Compared to adefovir, lamivudine has more rapid and more potent virus suppression, but entecavir, telbivudine, and tenofovir are superior to lamivudine in suppressing viral replication. Lamivudine may still have a role in patients coinfected with HIV (in whom lamivudine may be part of the antiretroviral regimen).

67. What is the disadvantage of Lamivudine?

68. Lamivudine The main disadvantage of lamivudine: high rate of drug resistance

69. Lamivudine Lamivudine is administered orally. The recommended dose for adults with normal renal function without concomitant HIV infection is 100 mg daily. Dose adjustment is required in those with decreased renal function.

70. Lamivudine The recommended dose for children is 3 mg/kg per day with a maximum of 100 mg/day. The recommended dose for those who are coinfected with HIV is 150 mg twice daily (along with other anti-retroviral drugs).

71. What are the advantages of Adefovir?

72. The main advantage of adefovir is its activity against lamivudine-resistant HBV. Lower rate of drug resistance compared to lamivudine. Virus suppression is slow at the approved dose and up to 25 percent of patients experience minimal or no viral suppression.

73. Adefovir Adefovir resistance was not detected after one year of treatment but the rate of drug resistance has been reported to be as high as 29 percent after five years of treatment. With the approval of tenofovir, which is more potent, the role of adefovir is rapidly diminishing.

74. Adefovir Adefovir at high doses has been associated with nephrotoxicity At the approved dose of 10 mg daily, reversible increase in serum creatinine has been reported in 3 to 9 percent of patients after four to five years of treatment

75. Adefovir Adefovir is administered orally. The dose is 10 mg daily. Patients with impaired renal function should have the dosing interval adjusted.

76. What are the advantages of Telbivudine?

77. Telbivudine Telbivudine appears to have slightly more potent antiviral effects compared with lamivudine and adefovir. It selects for the same resistant mutants as lamivudine and is more expensive. Its role as primary therapy is limited. Furthermore, there have been rare cases of myopathy and peripheral neuropathy.

78. Telbivudine Telbivudine is administered orally. The recommended dose is 600 mg once daily.

79. What is endpoint of treatment in HBeAg-positive chronic hepatitis?

80. HBeAg seroconversion

81. Endpoint of treatment in HBeAg-positive chronic hepatitis HBeAg seroconversion has been confirmed (by testing on two occasions at least two months apart) to reduce the rate of relapse. All patients should be closely monitored after discontinuation of treatment as viral relapse may lead to hepatitis flares and hepatic decompensation.

82. How long treatment should the continued after HBeAg seroconversion?

83. After HBeAg seroconversion has occurred and serum HBV DNA has become undetectable treatment should be continued for at least 6-12 more months after HBeAg seroconversion.

84. What is endpoint of treatment in HBeAg-negative chronic hepatitis?

85. Endpoint of treatment in HBeAg-negative chronic hepatitis (1) The endpoint of treatment has not been established. Treatment may be discontinued in patients who have confirmed loss of HBsAg (by testing on two occasions at least two months apart)

86. Endpoint of treatment in HBeAg-negative chronic hepatitis (2) Approximately 5 percent of patients lose HBsAg after five years of continued therapy. Most patients with HBeAg-negative chronic hepatitis will require many years of treatment with its associated risks of adverse events, drug resistance, and costs.

87. What is the aim of treatment in patients with compensated cirrhosis?

88. Aim of treatment in patients with compensated cirrhosis Prevent liver failure and HCC. Life-long treatment is generally recommended. It is possible that treatment may be discontinued in those who have lost HBsAg.

89. How long treatment should the continued in patients with decompensated cirrhosis?

90. Life-long treatment is recommended.

93. What is treatment of acute HBV during pregnancy?

94. Treatment of acute infection during pregnancy is mainly supportive. Liver biochemical tests and prothrombin time should be monitored. Antiviral therapy is usually unnecessary, except in women who have acute liver failure or protracted severe hepatitis. Lamivudine (100 mg daily) is a reasonable option since it has been used safely during pregnancy and the anticipated duration of treatment is short. Telbivudine or tenofovir (both considered pregnancy class B drugs [FDA]) are acceptable alternatives.