Management of Hepatitis B

The primary treatment goals for patients with hepatitis B (HBV) infection are to prevent progression of the disease, particularly to cirrhosis, liver failure, and hepatocellular carcinoma (HCC).

Risk factors for progression of chronic HBV include the following :
Persistently elevated levels of HBV DNA and, in some patients, alanine aminotransferase (ALT), as well as the presence of core and precore mutations seen most commonly in HBV genotype C and D infections
Male sex
Older age
Family history of HCC
Alcohol use
Elevated alpha-fetoprotein (AFP)
Coinfection with hepatitis D (delta) virus (HDV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)


A synergistic approach of suppressing viral load and boosting the patient’s immune response with immunotherapeutic interventions is needed for the best prognosis. The prevention of HCC often includes the use of antiviral treatment using pegylated interferon (PEG-IFN) or nucleos(t)ide analogues.
HBV infection can be self-limited or chronic. No specific therapy is available for persons with acute hepatitis B; treatment is supportive.

1. MANAGEMENT OF HEPATITIS B

2. BASICS OF HEPATITIS B

3. Hepatitis B Hepatitis B infection is caused by the hepatitis B virus (HBV), an enveloped DNA virus that infects the liver, causing hepatocellular necrosis and inflammation HBV infection can be either acute or chronic Associated illness ranges in severity from asymptomatic to symptomatic, progressive disease Chronic hepatitis B (CHB) – defined as persistence of hepatitis B surface antigen (HBsAg) for six months or more – is a major public health problem

4. Structure of Hepatitis B Virus – wild type (HBeAg Positive) HBs Protein ( HBsAg) HBc Protein (HBcAg) Partially double stranded DNA (HBV DNA) HBV DNA Polymerase HBe Protein (HBeAg)

5. Mutant viruses Clinically relevant mutants are : Precore mutants: abolishes HBeAg production Core mutants: down regulation of HBeAg production They do not produce HBeAg, but are capable of multiplication. This type of hepatitis is referred to as HBeAg negative hepatitis B. Mutants are also formed during treatment.eg. YMDD mutant with continued treatment using lamivudine & is believed to be defective in terms of replication.

6. Hepatitis B viral replication cycle The hepatitis B virus virion enters the hepatocyte via endocytosis . Viral nucleocapsids are uncoated and transported into the nucleus, where viral DNA is transformed into covalently closed circular DNA (cccDNA). Replication subsequently occurs through reverse transcription. The mature nucleocapsids are responsible for mediating viral persistence, and may be released to infect neighbouring hepatocytes. HBsAg: Hepatitis B surface antigen. World J Gastroenterol 2014; 20(20): 6262-6278

7. Risk groups for Hepatitis B Children of immigrants from areas where there is high prevalence of hepatitis B. Injection drug abuse. Infants born to infected mothers. History of sexually transmitted diseases, multiple sex partners, homosexual relations Sexual contacts of infected persons. Household contacts of chronically infected individuals. Healthcare & public safety workers. Hemodialysis patients.

8. Epidemiology and burden 2 billion people have evidence of past or present infection with HBV 240 million are chronic carriers of HBV surface antigen (HBsAg) Hepatitis B infection Acute hepatitis B Chronic hepatitis B C ase fatality rate of 0.5–1% 650 000 people die each year from the complications of CHB Accounts for around 45% of cases of HCC and 30% of cirrhosis

9. Global HBV prevalence WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

10. Modes of transmission HBV is transmitted via exposure to blood or mucous membranes with infectious bodily fluids In children :vertically at birth, or through iatrogenic events; folk remedies, such as acupuncture, or exposure to infected bodily fluids via person-to-person contact In adults: sexual exposure or percutaneous/mucosal exposure to infectious blood/bodily fluids (horizontal transmission), such as through needle sharing in injection drug users or exposure to infected blood or needles in the healthcare setting Direct percutaneous exposure of susceptible individuals to virus during blood transfusion or organ transplant Person-to-person transmission of HBV can also occur in settings involving close interpersonal contact over an extended period of time, such as in household contacts or developmentally disabled persons living in long-term care facilities MMWR Morb Mortal Wkly Rep. 2008;57(RR-8):1-20.

11. Outcome of hepatitis B infection by age at infection

12. Clinical presentation Acute symptomatic disease :typically begins 2-3 months after exposure and generally lasts 2-4 months Symptoms of acute HBV : fatigue, loss of appetite, nausea, arthralgias, vomiting, abdominal pain, low-grade fever, jaundice, dark urine, and light-colored stools Acute hepatitis B becomes chronic in > 90% of infants, in 25% to 50% of children aged 1-5 years, and in <5% of older children and adults Patients who are immunosuppressed, including those infected with HIV or on hemodialysis, are at increased risk of developing chronic infection 0.5% of infected patients who acquire disease early in life spontaneously resolve the infection annually Of those patients who develop chronic HBV infection as children, 25% will die from the consequences of hepatitis B, such as cirrhosis or liver cancer 1. Hepatology. 2007;45:507-539. 2. J Infect Dis. 1985;151:599-603.

13. Markers of Infection HISTOLOGICAL

14. Interpretation of Serologic Test Results for Hepatitis B Serologic Marker Interpretation HBsAg Total HBcAb IgM HBcAb HBsAb - - - - Never infected + - - - Early acute infection; transient (up to 18 days) after vaccination + + + - Acute infection - + + + or - Acute resolving infection - + - + Recovered from past infection and immune + + - - Chronic infection - + - - Past infection; false positive ( ie , susceptible); occult infection; or passive transfer of HBcAb to infant born to HBsAg-positive mother - - - + Immune if concentration is > 10 mIU /mL after vaccination series complete; passive transfer after hepatitis B immune globulin administration HBsAg = hepatitis B surface antigen; total HBcAb = total hepatitis B core antibody; IgM HBcAb = immunoglobulin M hepatitis B core antibody; HBsAb = hepatitis B surface antibody; + = positive test result; - = negative test result

15. Virologic Markers Viral load: HBV DNA: correlates with active replication; quantification of serum HBV DNA has become a pivotal tool to guide the management of the HBV carriers, to select candidates for antiviral therapy and to guide treatment with nucleoside/nucleotide analogues (NAs), which have potent direct antiviral activity HBV Genotypes Worldwide, at least nine genotypes of HBV (A through I) on basis of more than 8% difference in their genome sequences Higher rates of HCC have been found in genotypes C and F (compared with genotypes B or D), Antiviral therapy is equally effective, and the HBV vaccine protective against all HBV genotypes WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

16. Liver function tests /Histological markers Liver enzymes : One of the most important liver enzymes to look for is alanine aminotransferase (ALT). ALT levels fluctuate in persons with chronic hepatitis B and require longitudinal monitoring to determine the trend. Upper limits for normal ALT have been defined as below 30 U/L for men and 19 U/L for women During acute hepatitis B infection, ALT levels can be temporarily elevated, but this rarely leads to long-term liver problems In chronic hepatitis B, ALT levels can be either periodically or consistently increased, indicating a higher risk of long-term liver damage Serum albumin Prothrombin time Serum bilirubin

17. Histological markers Liver biopsy : invasive procedure, which is indicated only when a specific diagnosis of CHB cannot be posed or excluded using non-invasive procedures Transient elastometry (FibroScan®)- rapid, easy to perform, reproducible, non-invasive technique for the evaluation of liver stiffness The combination of serum markers has been shown to predict liver fibrosis and activity in a number of studies ;aminotransferases and indices including α(2)-macroglobulin, apolipoprotein A1, haptoglobin , γ-glutamyl transpeptidase, total bilirubin (FibroTest®) and ALT ( Actitest ) have been shown to be accurate markers of HBV-related activity

18. Non-invasive assessment of liver disease stage Presence of cirrhosis APRI ( aspartate aminotransferase [AST]-to-platelet ratio index) is recommended as the preferred non-invasive test (NIT ) Transient elastography (e.g. FibroScan ) or FibroTest preferred when available and cost not a constraint

19. Others Quantification of HBsAg Significantly improved recently by the introduction of new automated assays Potential role for quantitative serum HBsAg in on-treatment prediction of virological response to CHB therapy

20. Natural history of chronic hepatitis B CHB is dynamic and complex, and progresses non-linearly through several recognizable phases The phases are of variable duration, are not necessarily sequential, and do not always relate directly to criteria and indications for antiviral therapy.

21. Natural history of chronic hepatitis B WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1 a Not all persons after HBeAg seroconversion enter the inactive phase. Up to 20% may progress directly from HBeAg immune active to anti-HBe immune escape phase

22. Natural history of chronic hepatitis B WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

23. Natural history of chronic hepatitis B WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

24. CHRONIC HEPATITIS B

25. Acute Hepatitis Chronic Hepatitis Cirrhosis Liver transplant Death Liver Failure Liver Cancer 90% of children and <5% of adults Disease progression 15-40%

26. Chronic Hepatitis B - Diagnostic Criteria AASLD 2007 guidelines

27. Management of Chronic Hepatitis B

28. Initial evaluation of patients History and physical examination Family History of liver disease, HCC Laboratory tests to assess liver disease Tests for HBV replication—HBeAg/anti-HBe, HBV DNA. Tests to rule out viral co-infections—anti-HCV, anti-HDV, and anti-HIV in those at risk. Tests to screen for HCC–AFP at baseline and, in high risk patients-Ultrasound (USG). Consider liver biopsy to grade and stage liver disease - for patients who meet criteria for chronic hepatitis

29. Recommendations: Who to treat and who not to treat in persons with chronic hepatitis B Who to treat As a priority, all adults, adolescents and children with CHB and clinical evidence of compensated or decompensated cirrhosis (or cirrhosis based on APRI score >2 in adults) should be treated, regardless of ALT levels, HBeAg status or HBV DNA levels Treatment is recommended for adults with CHB who do not have clinical evidence of cirrhosis (or based on APRI score ≤2 in adults), but are aged more than 30 years (in particular), and have persistently abnormal ALT levels and evidence of high-level HBV replication (HBV DNA >20 000 IU/mL), regardless of HBeAg status Existing recommendation for HBV/HIV-coinfected persons1: In HBV/HIV-coinfected individuals, ART should be initiated in all those with evidence of severe chronic liver disease, regardless of CD4 count; and in all those with a CD4 count ≤500 cells/mm 3 , regardless of stage of liver disease

30. Who not to treat but continue to monitor Antiviral therapy is not recommended and can be deferred in persons without clinical evidence of cirrhosis (or based on APRI score ≤2 in adults), and with persistently normal ALT levels and low levels of HBV replication (HBV DNA <2000 IU/mL), regardless of HBeAg status or age Continued monitoring is necessary in all persons with CHB, but in particular those who do not currently meet the above-recommended criteria for who to treat or not treat, to determine if antiviral therapy may be indicated in the future to prevent progressive liver disease. These include: persons without cirrhosis aged 30 years or less, with HBV DNA levels >20 000 IU/ mL but persistently normal ALT; HBeAg-negative persons without cirrhosis aged 30 years or less, with HBV DNA levels that fluctuate between 2000 and 20 000 IU/mL, or who have intermittently abnormal ALT levels

31. Suppression of HBV replication to undetectable levels Decrease hepatic necroinflammation and fibrosis Prevent progression to cirrhosis, liver failure and HCC Goals of treatment Chronic Hepatitis B

32. Treatment Options Currently, seven antiviral agents (lamivudine, adefovir, entecavir, telbivudine, tenofovir, emtricitabine, standard and PEG-IFN) are approved for the treatment of CHB

33. Injectables in HBV treatment Immunomodulators Mode of Action Enhances phagocytic activity of macrophages Inhibits viral replication in virus-infected cells Increases cytotoxicity of lymphocytes for target cells Interferon alpha 2b Peg- interferon alpha 2a/2b IFN PEG IFN

34. Oral drugs: Nucleoside/nucleotide Analogues Mode of Action Mainly act by inhibition of HBV DNA polymerase enzyme activity resulting in decrease of viral replication Lamivudine Adefovir Entecavir Telbivudine Tenofovir 3TC/LAM ADV TDF ETV LdT

35. Antiviral agents active against hepatitis B virus infection (in order of potency and barrier to developing resistance) WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

36. Orals vs. IFN The advantage of NA therapy over IFN includes few side-effects and a one-pill-a-day oral administration. The main advantages of IFN over NAs -absence of resistance, and achievement of higher rates of HBeAg and HBsAg loss However, the disadvantages of IFN are that less than 50% of persons treated will respond, its high cost, administration by injection and common side-effects, which precludes its use in many persons, particularly in resource-limited settings. A number of relative and absolute contraindications to IFN - presence of decompensated cirrhosis and hypersplenism , thyroid disease, autoimmune diseases, severe coronary artery disease, renal transplant disease, pregnancy, seizures and psychiatric illness, concomitant use of certain drugs, retinopathy, thrombocytopenia and leucopenia IFN also cannot be used in infants less than 1 year and in pregnant women

37. WHO Recommendations: first-line antiviral therapies for chronic hepatitis B In all adults, adolescents and children aged 12 years or older in whom antiviral therapy is indicated, the nucleos(t)ide analogues (NAs) which have a high barrier to drug resistance (tenofovir or entecavir) are recommended. Entecavir is recommended in children aged 2–11 years NAs with a low barrier to resistance (lamivudine, adefovir or telbivudine) can lead to drug resistance and are not recommended Existing recommendation for HBV/HIV coinfected persons ( including pregnant women and adults with tuberculosis (TB) and HBV coinfection): In HBV/HIV-coinfected adults, adolescents and children aged 3 years or older, tenofovir + lamivudine (or emtricitabine) + efavirenz as a fixed-dose combination is recommended as the preferred option to initiate ART WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

38. National Institute for Health and Care Excellence - treatment guidelines World J Gastroenterol 2014; 20(20): 6262-6278

39. Drug doses WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

40. Comparison of antiviral agents for chronic hepatitis B World J Gastroenterol 2014; 20(20): 6262-6278

41. What is response to treatment ?

42. HBV Resistance The primary limitation of all oral antiviral agents is development of viral resistance because of mutations in the viral DNA during replication Lamivudine and telbivudine are most likely to fail because of resistance If resistance develops to one agent, the effectiveness of a second agent with the same site of action is reduced The risk of resistance increases whenever patients have persistent detectable HBV DNA levels The addition of a second agent with a different site of action or switch to a potent drug is vital in patients with detectable serum HBV DNA levels after six to 12 months of therapy

43. Antiviral resistance patterns and rescue therapy World J Gastroenterol 2014; 20(20): 6262-6278

44. WHO Recommendations: Second-line Antiviral therapies for management of treatment failure In persons with confirmed or suspected antiviral resistance (i.e. history of prior exposure or primary non-response) to lamivudine, entecavir, adefovir or telbivudine, a switch to tenofovir is recommended Primary non-response (defined as less than 1 log decrease in HBV DNA level after 3 months of treatment) is rare in persons initiating and adherent to entecavir or tenofovir treatment, but can occur in persons treated with lamivudine, adefovir or telbivudine WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

45. WHO Recommendations: when to stop treatment Lifelong NA therapy All persons with cirrhosis based on clinical evidence (or APRI score >2 in adults) require lifelong treatment with nucleos(t)ide analogues (NAs), and should not discontinue antiviral therapy because of the risk of reactivation, which can cause severe acute-on-chronic liver injury Discontinuation Discontinuation of NA therapy may be considered exceptionally in: persons without clinical evidence of cirrhosis (or based on APRI score ≤2 in adults); and who can be followed carefully long term for reactivation; and if there is evidence of HBeAg loss and seroconversion to anti-HBe (in persons initially HBeAg-positive) and after completion of at least one additional year of treatment; and in association with persistently normal ALT levels and persistently undetectable HBV DNA levels. Retreatment Relapse may occur after stopping therapy with NAs. Retreatment is recommended if there are consistent signs of reactivation (HBsAg or HBeAg becomes positive, ALT levels increase, or HBV DNA becomes detectable again) WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

46. WHO Recommendations : Monitoring for disease progression and treatment response It is recommended that the following be monitored at least annually: ALT levels (and AST for APRI), HBsAg, HBeAg, and HBV DNA levels Non-invasive tests (APRI score or FibroScan) to assess for the presence of cirrhosis, in those without cirrhosis at baseline If on treatment, adherence should be monitored regularly and at each visit WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

47. WHO Recommendations :Monitoring for disease progression and treatment response More frequent monitoring In persons who do not yet meet the criteria for antiviral therapy: persons who have intermittently abnormal ALT levels or HBV DNA levels that fluctuate between 2000 IU/mL -20 000 IU/mL and in HIV-coinfected In persons on treatment or following treatment discontinuation: More frequent on-treatment monitoring (at least every 3 months for the first year) is indicated in: persons with more advanced disease (compensated or decompensated cirrhosis) during the first year of treatment to assess treatment response and adherence where treatment adherence is a concern in HIV-coinfected persons; and in persons after discontinuation of treatment WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

48. WHO Recommendations : Monitoring for hepatocellular carcinoma (HCC) Routine surveillance for HCC with abdominal ultrasound and alpha-fetoprotein testing every six months is recommended for: persons with cirrhosis, regardless of age or other risk factors persons with a family history of HCC persons aged over 40 years without clinical evidence of cirrhosis, and with HBV DNA level >2000 IU/mL WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

49. WHO Recommendations :Monitoring for tenofovir and entecavir toxicity Measurement of baseline renal function and assessment of baseline risk for renal dysfunction should be considered in all persons prior to initiation of antiviral therapy. Renal function should be monitored annually in persons on long-term tenofovir or entecavir therapy, and growth monitored carefully in children WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

50. Recommended dosage in adults with renal impairment

51. WHO Guidelines recommendations (2015): Special Populations

52. Specific populations HBV/HDV coinfection There are limited data to inform definitive guidance on the management of persons with HDV infection Persistent HDV replication is the most important predictor of mortality and the need for antiviral therapy. PEG-IFN is the only drug effective against HDV; antiviral NAs have no or limited effect on HDV replication optimal duration of therapy is not well defined more than 1 year of therapy may be necessary most patients relapse after discontinuation of therapy New therapeutic agents and strategies are needed

53. Specific populations HBV/HCV coinfection HBV DNA levels are usually low or undetectable and as HCV is responsible for the activity of chronic hepatitis in most persons Patients should generally receive initial treatment for HCV infection The optimal regimens are uncertain, and more treatment studies are required in coinfected persons. PEG-IFN and ribavirin can be effective HBV DNA monitoring is necessary as there is a potential risk of HBV reactivation during treatment or after clearance of HCV, which can be treated with NAs

54. Specific populations HBV/Tuberculosis Groups at increased risk of infection with HBV are also at risk of infection with TB In the absence of a cough, weight loss, fever and night sweats, active TB can be confidently ruled out. Drug-induced liver injury with elevation of aminotransferases is three- to sixfold higher in persons coinfected with HBV, HCV or HIV who are receiving antituberculosis drugs, due to hepatotoxicity with isoniazid , rifampicin and pyrazinamide

55. Specific populations Extrahepatic manifestations Comparative trials of antiviral therapy are lacking, and the efficacy reported in case reports is variable. Lamivudine has been the most widely used, and entecavir and tenofovir would be expected to have enhanced efficacy in this group. PEG-IFN may worsen some immune-mediated extrahepatic manifestations and it is advisable to avoid its use.

56. Specific populations Acute hepatitis B Antiviral therapy is not necessary for uncomplicated symptomatic acute hepatitis B, as >95% of immunocompetent adults will spontaneously clear HBV infection Persons with fulminant or severe acute hepatitis may benefit from NA therapy with entecavir or tenofovir , to improve survival and reduce the risk of recurrent hepatitis B Duration of treatment is not established, but continuation of antiviral therapy for at least 3 months after seroconversion to anti-HBs or at least 12 months after anti- HBe seroconversion without HBsAg loss is generally advised

57. Specific populations Children and adolescents majority of children will not require antiviral therapy early identification and monitoring of children at risk for progression of liver disease guided by liver histology and a family history of HCC remains important Only conventional IFN, lamivudine and adefovir have been evaluated for safety and efficacy, but children generally have a similar response as adults IFN cannot be used in infants aged less than 1 year in adolescents and children above the age of 12 years tenofovir is approved for use Entecavir is approved for use in children with CHB above 2 years of age

58. Specific populations Pregnant women Indications for treatment in adults with CHB also apply to pregnant women. Tenofovir is the preferred antiviral, because it has a better resistance profile and more extensive safety data in pregnant HBV-positive women. Safety of entecavir in pregnancy is not known, and IFN-based therapy is contraindicated Prevention of mother-to-child HBV transmission deliver the first dose of hepatitis B vaccine as soon as possible after birth, preferably within 24 hours followed by at least two timely subsequent doses

59. Specific populations Dialysis and renal transplant patients persons with end-stage renal disease, including renal transplant recipients, who should be screened for HBV infection, and HBV- seronegative persons vaccinated Renal function should be monitored during antiviral therapy All Nas require dose adjustment and should be used with caution in persons with renal impairment or in renal transplant recipients Unexpected deterioration of renal function during antiviral therapy may necessitate a change of treatment or further dose adjustment. HBsAg-positive persons undergoing renal transplantation should receive prophylactic NA therapy to prevent HBV reactivation IFN-based therapy is not recommended in renal transplant recipients because of the risk of graft rejection

60. VACCINES: PREVENTION APPROACH

61. Prevention: Hepatitis B Vaccines Vaccination of infants and, in particular, delivery of hepatitis B vaccine within 24 hours of birth is 90–95% effective in preventing infection with HBV as well as decreasing HBV transmission if followed by at least two other doses WHO recommends universal hepatitis B vaccination for all infants, and that the first dose should be given as soon as possible after birth 3 doses: month 0, 1, 6. Sero -protection requires: anti HBs titer>=10 mIU /ml Factors associated with poor response: older age, chronic medical illness (cirrhosis, kidney failure, diabetes), decreased immune response, smoking, obesity, genetics WHO GUIDELINES 2015 http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf?ua=1

62. Indications for HBV Vaccines Hepatitis B immune globulin and HB vaccine to infants of HBsAg+ mothers(90% efficacy) All infants, children and adolescents who were not vaccinated at birth Vaccination of adults at risk of infection: Occupational Sexual / household contacts Injection drug users Long-term residence in high prevalence areas

63. Conclusion Chronic hepatitis B (CHB) virus infection is a global public health problem Wide clinical spectrum ranging from a subclinical inactive carrier state, to progressive chronic hepatitis, cirrhosis, decompensation, and hepatocellular carcinoma Current international guidelines recommend first-line treatment of CHB infection with pegylated interferon, entecavir, or tenofovir Future research will focus on identifying patients who can successfully stop oral therapy as well as on novel therapies or combinations of therapies that can target the HBV at various levels