Chronic HEP B


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  • Compact genomic structure of HBV. This structure, with overlapping genes, permits HBV to code for multiple proteins. The S gene codes for the "major" envelope protein, HBsAg. Pre-S1 and pre-S2, upstream of S, combine with S to code for two larger proteins, "middle" protein, the product of pre-S2 + S, and "large" protein, the product of pre-S1 + pre-S2 + S. The largest gene, P, codes for DNA polymerase. The C gene codes for two nucleocapsid proteins, HBeAg, a soluble, secreted protein (initiation from the pre-C region of the gene) and HBcAg, the intracellular core protein (initiation after pre-C). The X gene codes for HBxAg, which can transactivate the transcription of cellular and viral genes; its clinical relevance is not known, but it may contribute to carcinogenesis by binding to p53.
  • A minimum follow-up of 1 year with alanineaminotransferase (ALT) levels at least every 3–4 months and serum HBV DNA levels is required before classifying a patient as inactive HBV carrier.ALT levels should remain persistently within the normal range according to traditional cut-off values(approximately 40 IU/ml) [14] and HBV DNA should be below 2000 IU/ml.
  • Family history of hcc , persistent elevations of alt in 1-2 >normal range.
  • If NA therapy is given only for the prevention of perinatal transmission, it may be discontinued within the first 3 months after delivery.The safety of NA therapy during lactation is uncertain. HBsAg can be detected in breast milk, but breast feeding may not be considered a contraindication in HBsAg-positive mothers. Tenofovir concentrations in breast milk have been reported, but its oral bioavailability is limited and thus infants are exposed toonly small concentrations.
  • RECOMBIVAX-HB (Merck) ENGERIX-B (GlaxoSmithKline)Hemodialysispatientsb<20 years-3 doses 5 µg (0.5 mL)0, 1, 620 years-3 doses 40 µg (4 mL)0, 1, 6Hemodialysispatientsb <20 years-4 -10 g (0.5 mL) 0, 1, 2, 6 20 years-4-40 g (2 mL) 0, 1, 2, 6Hemodialysispatientsb<20 years-3 doses 5 µg (0.5 mL)0, 1, 620 years-3 doses 40 µg (4 mL)0, 1, 6
  • Some persons may test positive for anti-HBc but not HBsAg or anti-HBs. The finding of isolated anti-HBc can occur for a variety of reasons. (1) Anti-HBc may be an indicator of chronic HBV infection; in these persons, HBsAg had decreased to undetectable levels but HBVDNA often remains detectable, more so in the liver than in serum. This situation is not uncommon among persons from areas with high prevalence of HBV infection and in those with human immunodeficiency virus (HIV) or hepatitisC virus (HCV) infection.27 (2) Anti-HBc may be a marker of immunity after recovery from a prior infection. In these persons, anti-HBs had decreased to undetectable levels but anamnestic response can be observed after one dose of HBV vaccine.28 (3) Anti-HBc may be a false positive test result particularly in persons from low prevalence areas with no risk factors for HBV infection. These individuals respond to hepatitis B vaccination similar to persons without any HBV seromarkers.10,28,29 (4) Anti-HBc may be the only marker of HBV infection during thewindow phase of acute hepatitis B; these persons should test positive for anti-HBcIgM.
  • Chronic HEP B

    2. 2. OVERVIEW  Introduction and epidemiology  Virology  Pathogenesis  Natural History, Clinical features  Diagnosis  Liver Biopsy and Noninvasive Assessment of Fibrosis  Treatment
    3. 3. Introduction & Epidemiology  Definition - Chronic necroinflammatory disease of the liver caused by persistent infection with hepatitis B virus.  Approximately one third of the world’s population has serological evidence of past or present infection with HBV and 350–400 million people are chronic HBV surface antigen (HBsAg) carriers.  Up to 2 million die each year from HBV infection, making it the 9th leading cause of death worldwide.
    4. 4. Worldwide Prevalence of Chronic Hepatitis B HBsAg Prevalence (%) 8: High 2-7: Intermediate <2: Low World Health Organization Centers for Disease Control and Prevention.
    5. 5.  Hepatitis B is classified into 8 genotypes(A-H) and 8subtypes.  Genotype A & D are predominant in USA & Europe.  Genotype B & C are predominant in Asia.
    6. 6. Virology  Hepatitis B belongs to family Hepadnaviridae.  It contains circular partially single stranded & partially double stranded DNA of 3.2 kb.  HBV has compact genomic structure
    7. 7.  HBV infected cells produce 3 particulate forms 1.42nm, double shelled spherical particle(intact virion),Dane particle. 2.27nm particle (nucleocapsid core). 3.22nm (spherical and filamentous form),represent excess viral envelope protein.  Concentration of HBsAg & virus particles in blood may reach 500 µg/ml & 10 trillion particles/ml respectively.
    8. 8. MOLECULAR VARIANTS Pre -core mutant ,it occurs due to single base substitution from G to A in the second last codon of pre C gene at nucleotide 1896. This mutation prevents translation of HBeAg. 2. Mutation in core promoter region prevents transcription of the coding region of HBeAg & results in HBeAg negative phenotype. 3. Escape mutants, it occurs due to single amino acid substitution at position 145 of immunodominant a determinant common to all subtypes of HBsAg. It results in loss of neutralizing activity by anti HBs. 1.
    9. 9. PATHOGENESIS  HBV virions bind to surface receptors and are     internalized. Viral core particles migrate to the hepatocyte nucleus, where their genomes are repaired to form a covalently closed circular DNA (cccDNA) that is the template for viral messenger RNA (mRNA) transcription. The viral mRNA that results is translated in the cytoplasm to produce the viral surface, core, polymerase, and X proteins. There, progeny viral capsids assemble, incorporating genomic viral RNA (RNA packaging). This RNA is reverse-transcribed into viral DNA. The resulting cores can either bud into the endoplasmic reticulum to be enveloped and exported from the cell or recycle their genomes into the nucleus for conversion to cccDNA.
    10. 10. Natural History
    11. 11. 5 Phases of Chronic HBV Infection Current Understanding of HBV Infection HBeAg Anti-HBe ALT activity HBV DNA Phase Liver Immune Tolerant Immune Clearance Inactive Carrier State Minimal inflammation and fibrosis Chronic active inflammation Mild hepatitis and minimal fibrosis Reactivation Active inflammation Optimal treatment times Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology. 2006;43:S173-S181. Copyright © 1999–2012 John Wiley & Sons, Inc. All Rights Reserved.
    12. 12. 5 Phases of Chronic HBV Infection
    13. 13. CLINICAL FEATURES  They vary from asymtomatic infection to end     stage fatal hepatic failure. Fatigue is most common symptom. Persistent or intermitent jaundice is a feature of advanced disease. Acute exacerbations when superimposed on cirrhosis leads to decompensation. Extra hepatic manifestations include arthritis, arthralgias,iummune complex GN, generalized vasculitis (PAN).
    14. 14. LABORATORY FEATURES  Aminotransferase elevations tend to be modest for     chronic hepatitis B but may fluctuate in the range of 100–1000 units. Alanine aminotransferase (ALT) tends to be more elevated than aspartate aminotransferase (AST); however, once cirrhosis is established, AST tends to exceed ALT. Alkaline phosphatase activity tend to be normal or only marginally elevated. In severe cases, moderate elevations in serum bilirubin (3–10 mg/dL)] occur. Hyperglobulinemia and detectable circulating autoantibodies are distinctly absent in chronic hepatitis B (in contrast to autoimmune hepatitis).
    15. 15. HISTOPATHOLOGY  Histologic features in chronic hepatitis are increase in size of hepatocytes and ground glass appearance.  Abundant ground glass appearance indicates active viral replications.  Immunofluorescence and electron microscopy shows HBcAg inside hepaocyte nuclei of affected cell.
    16. 16. DIAGNOSIS Serological assays for various Hepatitis B antigens & antibodies. 2. HBV DNA by Southern hybridization, in-situ hybridization, or PCR. 3. Detection of HBsAg or hepatitis B core antigen (HBcAg) in liver tissues by immunohistochemical staining. 1.
    17. 17. Liver biopsy and non invasive monitoring of hepatic fibrosis  There are three primary reasons for performing a liver biopsy: 1) it provides helpful information on the current status of the liver injury, 2)it identifies features useful in the decision to embark on therapy, 3) it may reveal advanced fibrosis or cirrhosis that necessitates surveillance.  The biopsy is assessed for grade and stage of the liver injury, but also provides information on other histological features that might have a bearing on liver disease progression.  The grade defines the extent of necroinflammatory activity, while the stage establishes the extent of fibrosis or the presence of cirrhosis
    18. 18. Non invasive monitoring of fibrosis  aspartate aminotransferase:platelet ratio index (APRI) and  commercially available assays of : α2macroglobulin,α2-globulin, γ-globulin, apolipoprotein A-I, γ-glutamyltransferase, total bilirubin, and hyaluronic acid.  the assays are typically much better at detecting advanced fibrosis and cirrhosis than mild-to-moderate fibrosis.  Combining assays(e.g., APRI and FibroSURE or HepaScore) appears to increase the diagnostic accuracy and may eliminate the need for liver biopsy in more than half of patients.
    19. 19. TREATMENT
    20. 20. Goals and End Points of Hepatitis B Treatment  Prevention of long-term negative clinical outcomes (eg, cirrhosis, liver transplantation, HCC, death) by durable suppression of HBV DNA.  Ideal end point is induceing HBsAg loss or seroconversion.  Sustained decrease in serum HBV DNA level to undetectable.  Decrease or normalize serum ALT  Improve liver histology  Induce HBeAg loss or seroconversion in HBeAg-positive disease
    21. 21. DEFINITION OF ANTIVIRAL RESPONSE  Responses can be divided into biochemical, serological, virological and histological.  Biochemical response is defined as normalisation of ALT levels.  Serological response for HBeAg applies only to patients with HBeAg-positive CHB and is defined as HBeAg loss and seroconversion to anti-HBe.  Serological response for HBsAg applies to all CHB patients and is defined as HBsAg loss and development of anti-HBs.
    22. 22. Virological responses on IFN/PEGIFN therapy:  Primary non-response has not been well established.  Virological response is defined as an HBV DNA concentration of less than 2000 IU/ml. It is usually evaluated at 6 months and at the end of therapy as well as at 6 and12 months after the end of therapy.  Sustained off-treatment virological response is defined as HBV DNA levels below 2000 IU/ml for at least 12 months after the end of therapy
    23. 23. Virological responses on NA therapy:  Primary non-response is defined as less than 1 log10 IU/ml decrease in HBV DNA level from baseline at 3 months of therapy.  Virological response is defined as undetectable HBV DNA by a sensitive PCR assay. It is usually evaluated every 3– 6 months during therapy depending on the severity of liver disease and the type of NA.  Partial virological response is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 6 months of therapy in compliant patients.  Virological breakthrough is defined as a confirmed increase in HBV DNA level of more than 1 log10 IU/ml compared to the nadir (lowest value) HBV
    24. 24.  Histological response is defined as decrease in necroinflammatory activity (by ≥2 points in HAI or Ishak’s system) without worsening in fibrosis compared to pre-treatment histological findings.  Complete response is defined as sustained offtreatment virological response together with loss of HBsAg.
    25. 25. Indications for treatment  Serum HBV DNA levels.  Serum ALT levels.  Severity of liver disease.  May also take into account are age,health status,family history of HCC, cirrhosis & extra hepatic manifestations.
    26. 26. What Is an Elevated ALT Level?  Reference ranges for ALT laboratories  Men: 4-60 IU/L; women: 6-40 IU/L  Both AASLD and US treatment algorithms recommend lower ULN levels for ALT when making treatment-initiation decisions  30 IU/L for men  19 IU/L for women Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Prati D, et al. Ann Intern Med. 2002;137:1-10. Lok AS, et al. Hepatology. 2009;50:661-662.
    27. 27. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update
    28. 28. Current Guideline Recommendations for First-line Therapy • Peginterferon alfa-2a – Exceptions: pregnancy, chemotherapy prophylaxis, decompensated cirrhosis, acute infection • Entecavir • Tenofovir EASL. J Hepatol. 2009;50:227-242. Liaw YF, et al. Hepatol Int. 2008;2:263-283. Lok AS, et al. Hepatology. 2009;50:661-662.
    29. 29. INTERFERON -α  IFN- α was the first approved therapy for chronic hepatitis     B. It is no longer used to treat hepatitis B. For immunocompetent adults with HBeAg-reactive chronic hepatitis B, a 16-week course of IFN given subcutaneously at a daily dose of 5 million units, or three times a week at a dose of 10 million units is used. In HBeAg-negative chronic hepatitis B, more protracted courses, lasting up to 11/2 years, have been reported to result in sustained remissions documented to last for several years. Complications of IFN therapy include systemic "flu-like" symptoms; marrow suppression; emotional lability , autoimmune reactions (especially autoimmune thyroiditis); alopecia, rashes, diarrhea, and numbness and tingling of the extremities. With the possible exception of autoimmune thyroiditis, all these side effects are
    30. 30. Pegylated Interferon  PEG IFN- 2a ,is administered SC 180 µg weekly for 48 weeks.
    31. 31. When to Consider PegIFN • Favorable predictors of response In HBeAg+ve CHB – Low HBV DNA – High ALT – Genotype A or B > C or D – Not advanced disease.  Specific patient demographics – Generally young people – Young women wanting pregnancy in near future – Absence of comorbidities  Patient preference  Concomitant HCV infection 1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. Lok AS. Hepatology. 2010;52:743-747. 3. Janssen HL, et al, Lancet. 2005;365;123-129. 4. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. 5. Flink HJ, et al. Am J Gastroenterol. 2006;101:297-303.
    32. 32. Nucleos(t)ide Analogs  Lamivudine (100mg)  Adefovir (10mg)  Entecavir (0.5mg),(1mg)  Telbivudine (600mg)  Tenofovir (300mg)/(245mg)
    33. 33. Nucleos(t)ide Analogs
    34. 34. Nucleos(t)ide Analogs
    35. 35. Nucleos(t)ide Analogs
    36. 36. Nucleos(t)ide Analogs
    37. 37. Response – HBe Ag +ve
    38. 38. Response – HBe Ag +ve
    39. 39. Response – HBe Ag +ve
    40. 40. Response – HBe Ag - ve
    41. 41. • • • • • • Potential Barriers to HBV Treatments Patient resistance or cultural beliefs about treatment Potential adverse effects (particularly interferon) Challenges with long-term therapy Understanding endpoints and monitoring strategies Lack of symptoms Lack of ability to cure disease with current regimens in most patients • Adherence
    43. 43. For IFN/PEG-IFN based treatment  In HBeAg-positive CHB, predictors of anti-HBe seroconversion are low viral load (HBVDNAbelow 2000 IU/ml), high serum ALT levels (above 2–5 times ULN), HBV genotype and high activity scores on liver biopsy (at least A2). HBV genotypes A and B have been shown to be associated with higher rates of anti-HBe seroconversion and HBsAg loss than genotypes D and C, respectively, after treatment with PEGIFN.
    44. 44. For NAs treatment  In HBeAg-positive CHB, factors predictive of anti- HBe seroconversion are low viral load (HBV DNA below 2 IU/ml), high serum ALT levels, high activity scores on liver biopsy . HBVgenotype does not influence the virological response to any NA.
    45. 45. TREATMENT IN HIV CO-INFECTED Pt’S  HIV-positive patients with CHB were at increased risk of cirrhosis and HCC .  The indications for therapy are the same as in HIV- negative patients, based on HBV DNA levels, serum ALT levels and histological lesions.  In agreement with recent HIV guidelines, it is recommended that most co-infected patients should be simultaneously treated for both HIV and HBV de novo .  Tenofovir combined with emtricitabine or lamivudine plus a third agent active against HIV are indicated.
    46. 46.  In a small number of patients with CD4 count >500/ml, HBV can be treated before the institution of anti-HIV therapy; PEGIFN, adefovir and telbivudine, which are not proven to be active against HIV, should be preferred.  However, if any of these two NAs with a low barrier to resistance does not reach the goal of undetectable HBV DNA after 12 months of therapy, treatment of HIV infection should be envisaged.
    47. 47. TREATMENT IN HDV COINFECTED Pt’S  Chronic infection after acute HBV-HDV hepatitis is     less common, while chronic delta hepatitis develops in 70–90% of patients with HDV superinfection. Active co-infection with HDV is confirmed by detectable HDV RNA, immuno-histochemical staining for HDV antigen, or IgM anti-HDV. (PEG-)IFN is the only drug effective against HDV. The efficacy of (PEG-)IFN therapy can be assessed during treatment (after 3–6 months) by measuring HDV RNA levels. More than 1 year of therapy may be necessary, as there may be some benefit from treatment prolongation.
    48. 48. TREATMENT IN HCV COINFECTED Pt’S  In HBV-infected patients, HCV co-infection accelerates liver disease progression and increases the risk of HCC.  HBV and HCV replicate in the same hepatocyte without interference.  However, HBV DNA level is often low or undetectable and HCV is responsible for the activity of chronic hepatitis in most patients.  Thus, patients should usually receive treatment for HCV.
    49. 49. Treatment in Pregnant Women
    50. 50. Pre-emptive therapy before immunosuppressive therapy or chemotherapy  HBsAg-positive candidates for chemotherapy and immunosuppressive therapy should be tested for HBV DNA levels and should receive pre-emptive NA administration during therapy (regardless of HBV DNA levels) and for 12 months after cessation of therapy.  When HBV DNA levels are<2000IU/ml & finite and short duration of immunosuppression is scheduled,Lamivudine is used.otherwise Entecavir or Tenofovir are used.  HBsAg-negative, anti-HBc positive patients with detectable serum HBV DNA should be treate similarly to HBsAg positive patients.
    51. 51.  HBsAg-negative, anti-HBc positive patients with undetectable serum HBV DNA and regardless of antiHBs status who receive chemotherapy and/or immunosuppression should be followed carefully by means of ALT and HBV DNA testing and treated with NA therapy upon confirmation of HBV reactivation before ALT elevation.
    52. 52. Unresolved issues and unmet needs (1) Improve knowledge and prognosis of the natural history and indications for treatment, particularly in HBeAgpositive immunotolerant patients and HBeAg-negative patients with serum HBV DNA levels below 20,000 IU/ml. (2) Assess the role of non-invasive markers (serum and biophysical) for the evaluation of the severity of liver disease and for the follow-up of treated and untreated patients. (3) Further clarify the role of serum HBsAg levels in the evaluation of the natural history, prediction of therapeutic responses and treatment individualisation. (4) Assess host genetic and viral markers to determine prognosis and optimise patients’ management. (5) Assess the impact of early diagnosis and early treatment intervention.
    53. 53. (7) Identify markers that predict successful NA discontinuation. (8) Assess the safety and efficacy of the combination of PEGIFN with a potent NA (entecavir or tenofovir) to increase anti-HBe and anti-HBs seroconversion rates. (9) Develop and assess new drugs and therapeutic approaches, particularly immunomodulatory therapies, to enhance loss of HBeAg and HBsAg and subsequent seroconversion. (10) Assess long-term impact of therapy on the prevention of cirrhosis and its complications and HCC.
    54. 54. (12) Develop effective and optimum treatment for HDV co-infection.
    55. 55. PROPHYLAXIS
    56. 56. RECOMMENDED DOSEING RECOMBIVAX HB ENGERIX-B INFANTS &CHILDREN<11 YRS 5µg(0.5ml) 10µg(0.5ml) CHILDREN 11-19 5µg(0.5ml) 10µg(0.5ml) ADULTS >20 10µg(1ml) 20µg(1ml) HEMODIALYSIS& IMMUNOCOMPROMISE D 5µg(0.5ml) (<20 yrs) 40µg(4ml) (≥20 yrs) 10µg(0.5ml) 40µg(2ml)
    57. 57. POST EXPOSURE PROPHYLAXIS OF HB IF SOURCE IS HBSAG + Vaccination status Immune prophylaxis unvaccinated HBIG *1 dose(.06ml/kg)&initiate HBV VACCINE Previously vaccinated Known responder No treatment Known non responder HBIG *1 dose(.06ml/kg)&initiate HBV vaccine or HBIG *2 doses, revaccination Antibody response not known Test for antibodies if adequate no treatment; if inadequate HBIG *1 dose(.06ml/kg)& HBV VACCINE booster dose
    59. 59. THANK YOU
    60. 60. REFERCENCES  Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update.  EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection(2012).  HARRISONS INTERNAL MEDICINE
    61. 61. Genotypes
    62. 62.  Some persons may test positive for anti-HBc but notHBsAg or anti-HBs. The finding of isolated anti-HBc canoccur for a variety of reasons. (1) Anti-HBc may be anindicator of chronic HBV infection; in these persons,HBsAg had decreased to undetectable levels but HBVDNA often remains detectable, more so in the liver thanin serum. This situation is not uncommon among personsfrom areas with high prevalence of HBV infection and inthose with human immunodeficiency virus (HIV) or hepatitisC virus (HCV) infection.27 (2) Anti-HBc may be amarker of immunity after recovery from a prior infection.In these persons, anti-HBs had decreased to undetectablelevels but anamnestic response can be observed after onedose of HBV vaccine.28 (3) Anti-HBc may be a false positivetest result particularly in persons from low prevalenceareas with no risk factors for HBV infection. These individualsrespond to hepatitis B vaccination similar to personswithout any HBV seromarkers.10,28,29 (4) Anti-HBcmay be the only marker of HBV infection during thewindow phase of acute hepatitis B; these persons shouldtest positive for anti-HBc IgM.