Hepatitis -B implications , investigations and management

Hepatitis B infection , medicine presentation

1. Hepatitis -B Diagnosis and Management

2. Hepatitis B Virus Member of Hepadnaviridae Family Virus particle – Dane particle ( virion) – contains outer lipid envelope Icosahedral nucleocapsid core composed of protein which encloses viral dna and DNA polymerase with reverse transcriptase activity. Envelope protein expressed on the outer surface of virion – HBsAg Partially double stranded DNA

3. Genome

4. Serological Markers HBsAg Appears about 6 weeks after infection and usually disappears by 3 months after clinical illness Persistance > 6 months - carrier state or chronicity Diagnosis of HBV infection can usually be made by detection of HBsAg in serum Rarely, levels of HBsAg are too low to be detected during acute HBV infection , even with contemporary, highly sensitive immunoassays

5. HBsAg and Degree of Liver Damage An inverse correlation exists between the serum concentration of HBsAg and the degree of liver cell damage. For example, titers are highest in immunosuppressed patients , lower in patients with chronic liver disease, and very low in patients with acute fulminant hepatitis . These observations suggest that, in hepatitis B, the degree of liver cell damage and the clinical course are related to variations in the patient’s immune response to HBV rather than to the amount of circulating HBsAg

6. Anti - HBc (Antibody to HBV core antigen) Total - indicates past or active infection; Specificity = 99.8% to 99.9% IgM - early indicator of acute infection In patients with hepatitis B surface antigenemia of unknown duration testing for IgM anti-HBc may be useful to distinguish between acute or recent infection (IgM anti-HBc-positive) and chronic HBV infection (IgM anti- HBc-negative, IgG anti-HBc-positive). A false-positive test for IgM anti-HBc may be encountered in patients with high-titer rheumatoid factor. IgG False positivity in patients receiving IV Ig

7. HBeAg HBeAg correlates with ongoing viral synthesis and with infectivity . It is transiently present during the acute attack. It is present for a shorter time than HBsAg. Persistence for more than 10 weeks strongly suggests the development of chronicity. Its principal clinical usefulness is as an indicator of relative infectivity. Selecting patients for therapy. V iral mutations in precore and basal core promoter regions result in eAg -negative hepatitis

8. Pre core mutants Chronic hepatitis due to pre-core hepatitis B virus (HBV) mutants presents as hepatitis B e antigen ( HBeAg )-negative chronic hepatitis B (CHB). HBeAg -negative CHB represents a late phase in the natural course of chronic HBV infection that develops after HBeAg loss and seroconversion to anti- Hbe .  Interferon-alpha (IFN-alpha) and lamivudine are the two drugs that have been tried, mainly in the management of HBeAg -negative CHB

9. Anti- HBe (Antibody to HBVe Antigen) Prognostic for resolution of infection Less infectious The appearance of Anti- Hbe is strong evidence that the patient will recover completely

10. Anti HBs Anti-HBs is rarely detectable in the presence of HBsAg in patients with acute hepatitis B, but 10–20% of persons with chronic HBV infection may harbor low-level anti-HBs. After immunization with hepatitis B vaccine, which consists of HBsAg alone, anti-HBs is the only serologic marker to appear. Anti-HBs >10mIu – Protective.

11. HBV DNA HBV DNA is the most sensitive index of viral replication . It is a good marker of the level of viraemia , can be correlated with serum transaminase levels and parallels the presence of HBsAg in serum. Patients with an HBV pre-core mutant are HBeAg negative and HBV DNA positive

12. Liver Biopsy Liver biopsy has been used to ascertain the degree of necroinflammation and fibrosis, and to help guide the decision to treat. Hepatic histology varies widely and includes chronic hepatitis, active cirrhosis and hepato-cellular carcinoma. The amount of replicating virus in the serum does not correlate with the degree of histological activity

13. Fibroscan More recently, new techniques that measure liver stiffness have been developed based on ultrasound technology. Transient elastography performed with FibroScan has been the most widely evaluated. >90% accuracy for early Fibrosis and Cirrhosis.

14. Serological Patterns of Hepatitis B

15. Acute hepatitis B Diagnosis HBsAg and IgM Anti HBc HBsAg positive in both acute and chronic HBV infection IgM anti HBc – diagnostic of acute or recently acquired infection Absence of IgM anti HBc – chronic HBV infection Pressence of anti HBc alone – acute/ resolved(Anti HBsAg)/Chronic / false positive

16. Acute hepatitis B- Management “ More than 95% of adults with acute HBV hepatitis do not require specific treatment, because they will fully recover spontaneously (Evidence level II-2, grade of recommendation 1) “ In patients with acute hepatitis B, preventing the risk of acute or subacute liver failure is the main treatment goal . Improving quality of life by shortening the disease associated symptoms as well as lowering the risk of chronicity can be also regarded as relevant goals of treatment

17. When to treat ? “ Only patients with severe acute hepatitis B , characterised by coagulopathy or protracted course, should be treated with NA and considered for liver transplantation (Evidence level II-2, grade of recommendation 1).” A potentially life-threatening disease manifestation is severe or fulminant acute hepatitis B . Characteristics of severe acute hepatitis B are coagulopathy (most studies defined this as international normalised ratio [INR] >1.5), or a protracted course (i.e., persistent symptoms or marked jaundice for [4 weeks), or signs of acute liver failure The early antiviral therapy with highly potent NAs can prevent progression to acute liver failure and subsequently liver transplantation or mortality. This effect, however, is not seen if antiviral therapy is initiated late in the course of severe acute hepatitis B in patients with already manifested acute liver failure and advanced hepatic encephalopathy . Data supports the use of TDF, ETV or even LAM

18. Chronic HBV Infection - Phases

19. Management of CHB The currently approved treatment options include immunomodulatory therapies ( including conventional interferon alpha IFN α, Pegylated Interferon α ) and Nucleoside/Nucleotide Analogs (NA’s). The nucleoside analogs include ( lamivudine, entecavir , telbivudine and emtricitabine) and nucleotide analogs include ( adefovir and tenofovir ) The long-term administration of a potent NA with high barrier to resistance is the treatment of choice regardless of the severity of liver disease (Evidence level I, grade of recommendation 1). The preferred regimens are ETV, TDF and TAF as monotherapies (Evidence level I, grade of recommendation 1).

20. Tenofovir

21. Indications for treatment All patients with HBeAg -positive or -negative chronic hepatitis B , defined by HBV DNA >2,000 IU/ml , ALT >ULN and/or at least moderate liver necroinflammation or fibrosis , should be treated Patients with compensated or decompensated cirrhosis need treatment, with any detectable HBV DNA level and regardless of ALT levels . Patients with HBV DNA>20,000 IU/ml and ALT>2xULN should start treatment regardless of the degree of fibrosis . Patients with HBeAg -positive chronic HBV infection , defined by persistently normal ALT and high HBV DNA levels, may be treated if they are older than 30 years regardless of the severity of liver histological lesions . Patients with HBeAg -positive or HBeAg -negative chronic HBV infection and family history of HCC or cirrhosis and extrahepatic manifestations can be treated even if typical treatment indications are not fulfilled (Evidence level III, grade of recommendation 2).

22. Monitoring

23. Discontinuation NAs should be discontinued after confirmed HBsAg loss , with or without anti-HBs seroconversion . NAs can be discontinued in non-cirrhotic HBeAg positive CHB patients who achieve stable HBeAg seroconversion and undetectable HBV DNA and who complete at least 12 months of consolidation therapy. Close post-NA monitoring is warranted . Discontinuation of NAs in selected non-cirrhotic HBeAg -negative patients who have achieved longterm (P3 years) virological suppression under NA(s) may be considered if close post-NA monitoring can be guaranteed .

24. Indications for selecting ETV or TAF over TDF. 1. Age >60 years 2. Bone disease Chronic steroid use or use of other medications that worsen bone density History of fragility fracture Osteoporosis 3. Renal alteration eGFR \60 ml/min/1.73 m2 Albuminuria >30 mg/24 h or moderate dipstick proteinuria Low phosphate (<2.5 mg/dl) Hemodialysis ETV dose needs to be adjusted if eGFR \50 ml/min; No dose adjustment of TAF is required in adults or adolescents (aged at least 12 years and of at least 35 kg body weight) with estimated creatinine clearance ( CrCl ) >15 ml/min or in patients with CrCl <15 ml/min who are receiving haemodialysis .

25. TREATMENT RECOMMENDATIONS

26. Decompensated cirrhosis Patients with decompensated cirrhosis should be referred for liver transplantation and treated with NAs as early as possible, with the goal of achieving complete viral suppression in the shortest time possible. ETV or TDF are the preferred treatment options and both drugs have been shown to be effective but also generally safe in patients with decompensated disease. The licensed ETV dose for patients with HBV decompensated cirrhosis is 1 mg (instead of 0.5 mg for patients with compensated CLD) PegIFNa is contraindicated in patients with decompensated liver disease Main goal of NA treatment in patients with decompensated liver disease is to achieve clinical recompensation and to avoid liver transplantation. There is strong evidence that antiviral therapy significantly modifies the natural history of decompensated cirrhosis, improving liver function and increasing survival Lifelong treatment is recommended for all patients with decompensated disease. Even under effective NA therapy, the risk of developing HCC is high in these patients, and therefore careful long-term HCC surveillance is mandatory.

27. P reventing Reactivation All candidates for chemotherapy and immunosuppressive therapy should be tested for HBV markers prior to immunosuppression .( HBsAg, anti-HBc, and anti-HBs +HBV DNA in case of positive results) All HBsAg-positive patients should receive ETV or TDF or TAF as treatment or prophylaxis HBsAg-negative, anti-HBc positive subjects should receive anti-HBV prophylaxis if they are at high risk of HBV reactivation

28. Inactive Carriers The inactive HBsAg carrier state is diagnosed by absence of HBeAg and presence of anti- HBe , undetectable or low levels of HBV DNA in PCR-based assays, repeatedly normal ALT levels, and minimal or no necroinflammation, slight fibrosis, or even normal histology on biopsy. Advice : Regular monitoring of ALT, avoid use of alcohol and protected sexual intercourse

29. HBV-HIV coinfection All HIV-positive patients with HBV co-infection should start antiretroviral therapy (ART) irrespective of CD4 cell count (Evidence level II-2, grade of recommendation 1). HIV-HBV co-infected patients should be treated with a TDF- or TAF-based ART regimen (Evidence level I for TDF, II-1 for TAF, grade of recommendation 1).

30. HBV-HCV Co-Infection Treatment of HCV with direct-acting antivirals (DAAs) may cause reactivation of HBV. Patients fulfilling the standard criteria for HBV treatment should receive NA treatment ). HBsAg-positive patients undergoing DAA therapy should be considered for concomitant NA prophylaxis until week 12 post DAA, and monitored closely . HBsAg-negative, anti-HBc positive patients undergoing DAA should be monitored and tested for HBV reactivation in case of ALT elevation .

31. Extrahepatic manifestations HBV related extrahepatic manifestations include vasculitis, skin manifestations (purpura), polyarteritis nodosa, arthralgias, peripheral neuropathy and glomerulonephritis. Mixed cryoglobulinemias , positive rheumatoid factor or inflammatory markers (complement factors C3/C4, C-reactive protein, blood sedimentation rate) may be found in these patients. HBsAg-positive patients with extrahepatic manifestations and active HBV replication may respond to antiviral therapy PegIFNa should not be administered in patients with immune-related extrahepatic manifestations .

32. Liver Transplantation Liver transplantation is currently a successful therapy for end-stage chronic HBV-associated liver disease. Until early 1990s, transplantation resulted in an 80% rate of re-infection in the absence of prophylaxis. The use of high dose HBIG ( Hepatitis B immunoglobulin ) peri-operatively and post-operatively, combined with treatment of heptitis B with entecavir or tenofovir are favored to prevent recurrent HBV infection posttransplantation .

33. Screening for HCC Patients who are HBsAg positive with chronic hepatitis or cirrhosis, especially if male and more than 45 years old, should be screened regularly so that hepato-cellular carcinoma may be diagnosed early when surgical resection may prove possible. Serum α-fetoprotein should be measured and ultrasound examination performed at 6-monthly intervals.

34. Pregnancy Screening for HBsAg in the first trimester of pregnancy is strongly recommended. In a woman of childbearing age without advanced fibrosis who plans a pregnancy in the near future, it may be prudent to delay therapy until the child is born . Pregnant women with CHB and advanced fibrosis or cirrhosis, therapy with TDF is recommended In pregnant women already on NA therapy, TDF should be continued while ETV or other NA should be switched to TDF . In all pregnant women with high HBV DNA levels >200,000 IU/ml or HBsAg levels >4 log10 IU/ml, antiviral prophylaxis with TDF should start at week 24–28 of gestation and continue for up to 12 weeks after delivery . Breast feeding is not contraindicated in HBsAg-positive untreated women or on TDF-based treatment or prophylaxis (

35. Healthcare workers- Recommendations Healthcare workers performing exposure prone procedures with serum HBV DNA >200 IU/ml may be treated with NA to reduce transmission risk . Healthcare workers, including surgeons, gynaecologists and dentists, who are HBsAg-positive with HBV DNA >200 IU/ml may be treated with a potent NA (i.e., ETV, TDF, TAF) to reduce levels of HBV DNA ideally to undetectable or at least to<200 IU/ml (CDC recommendation: <1,000 IU/ml

36. PEP Vaccine status Unvaccinated - HBIG – 0.06 ml/kg and initiate HB vaccination series Previously vaccinated Known responder- no action required Known nonresponder – HBIG – 2 doses 1 month apart or HBIG 1 dose and revaccination Antibody response unknown – Test for Anti HBs > 10mIU – no action required < 10 mIU - HBIG 1 dose and booster dose vaccine

37. Assessment 1 Is breast feeding contraindicated in HBsAg positive mothers not on Tenofovir ? 2 What interval should patient with hepatitis B related CLD undergo screening for HCC ? 3 what are the investigations to be done prior to immunosuppressive therapy to check for latent HBV infection? 4 Duration of treatment in decompensated liver disease ?

38. Thank you