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Hepatitis b

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Hepatitis B...everything u need to know...in and out...take ur time to read...wont disappoint

Publicada em: Saúde e medicina
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Hepatitis b

  1. 1. Management of Hepatitis B Ajay Kumar Yadav PGY2,Internal medicine IOM-TUTH, Kathmandu 2074/11/09
  2. 2. Hep-B virus  Hepadnaviridae family  Enveloped  Primarily hepatotropic  DNA viruses : Small - 3.2 kb : partially ds : relaxed circular(rc) --> HBV nucleocapsid is transported to the nucleus to release the rcDNA genome  rcDNA is converted into a covalently closed circular DNA (cccDNA) : transcription template for all viral transcripts  viral proteins.  lack of reverse transcriptase proofreading activity : HBV mutants  Nine genotypes (A-I) and several sub-genotypes
  3. 3. Hep-B cont..  Encode 7 proteins: • HBeAg • HBcAg • HBV Pol/RT • PreS1/PreS2/HBsAg (large, medium, and small surface envelope glycoproteins) • HBxAg : regulator of transcription required for the initiation of infection).  Immunity • Acute infections : immune response efficient and timely • Chronic infections : impairment of T cell immunity
  4. 4. Epidemiology  Approx. 240 million people are chronic HBsAg carriers
  5. 5. Serology in Hep-B
  6. 6. Serology cont..
  7. 7. Natural history of Hep-B
  8. 8. Natural history cont..
  9. 9. Natural history cont.. • Infection at birth is associated with clinically silent acute infection but a 90% chance of chronic infection. • Infection in young adulthood in immunocompetent persons is typically associated with clinically apparent acute hepatitis but a risk of chronicity of only approx. 1%. • The likelihood in a patient with HBeAg-reactive chronic hepatitis B of converting spontaneously from relatively replicative to nonreplicative infection is approx. 10−15% per year
  10. 10. Natural history cont..  The 5 yr cumulative incidence of cirrhosis in untreated CHB : 8% to 20%  The 5-year cumulative risk of hepatic decompensation among those with cirrhosis is 20%.  The annual risk of HCC in patients with cirrhosis has been reported to be 2–5%.  Hepatitis B responsible for 80% of primary liver cancer globally  In Asia, upto 40% of HCC related to Chronic HBV infection without cirrhosis
  11. 11. Natural history cont.. • The risk of developing HCC is higher in patients with one or more factors that relate to the host :  Cirrhosis  Chronic hepatic necroinflammation on tissue biopsy  Older age  Male sex  African origin  Alcohol abuse  Chronic co-infections with other hepatitis viruses or HIV  Diabetes or metabolic syndrome  Active smoking  Positive family history  High HBV DNA and/or HBsAg levels  HBV genotype C > B  Specific mutations
  12. 12. Goals of treatment  Main goal • improve survival and quality of life by preventing disease progression, and consequently HCC development.  Additional goals • Prevent mother to child transmission • Prevent hepatitis B reactivation • Prevention and treatment of HBV-associated extrahepatic manifestations.
  13. 13.  HBV-induced HCC • Suppress HBV replication to induce the stabilisation of HBV-induced liver disease and to prevent disease progression • Reduce the risk of HCC recurrence after potentially curative HCC therapies.  Acute hepatitis B • Preventing the risk of acute or subacute liver failure
  14. 14. Initial assessment in pts with chronic Hep-B infection History/physical examination Routine lab tests Serology/Virology studies Imaging/Staging studies All pts. Symptoms/signs of cirrhosis Alcohol and metabolic risk factors Family history of HCC Vaccination status CBC including platelet count, AST, ALT, total bilirubin, alkaline phosphatase, albumin, INR HBeAg/anti-HBe HBV DNA quantitation Anti-HAV to determine need for vaccination Abdominal ultrasound Vibration-controlled transient elastography or serum fibrosis panel (APRI, FIB-4, or FIbroTest) Selected pts. Tests to rule out other causes of chronic liver diseases if elevated liver test(s) AFP, GGT HBV genotype Anti-HDV Anti-HCV Liver biopsy
  15. 15. Initial assessment cont..  The diagnostic accuracy of all non-invasive methods is better at excluding than confirming advanced fibrosis or cirrhosis  HBeAg and anti-HBe detection are essential for the determination of the phase of chronic HBV infection.  Measurement of HBV DNA serum level is essential for the diagnosis, establishment of the phase of the infection, the decision to treat and subsequent monitoring of pts.  Sr. HBsAg quantification can be useful, particularly in HBeAg-negative chronic HBV infection and in patients to be treated with interferon-alfa (IFNa).  HBV genotype is not necessary in the initial evaluation : selected pts to be treated with IFNa : prognostic information : response to IFNa therapy and the risk of HCC.  Pts with negative anti-HAV should be advised to be vaccinated against HAV.
  16. 16. Candidates of treatment AASLD (2015) APASL (2015) EASL (2017) HBeAg-positive HBV DNA > 20,000 20,000 2000 HBeAg-negative 2000 2000 2000 ALT cutoff level U/L 30 for men 19 for women Traditional cutoff value of 40 U/L Traditional cutoff value of 40 U/L
  17. 17. T/t of HBeAg (+) CHB AASLD (2015) APASL (2015) EASL (2017) HBV DNA>20,000 IU/mL, ALT >2xULN Monitor for 3-6months. Treat if no spontaneous HBeAg loss. Liver biopsy before treatment is optional HBV DNA>20,000 IU/mL ,ALT >2xULN Monitor for 3months. Treat if no spontaneous HBeAg loss. Histology should be obtained or assessed noninvasively HBV DNA>20,000 IU/mL, ALT >ULN) : Treat HBV DNA>2000 IU/mL, ALT >ULN : Monitor for 3-6months. Liver biopsy (or noninvasive markers of fibrosis) is recommended. Treat if no spontaneous HBeAg loss and biopsy shows moderate-severe inflammation HBV DNA>20,000 IU/mL, ALT≤2xULN : Monitor every 3- 6months. Consider biopsy (>40 years, ALT persistently 1- 2ULN,or family h/o of HCC). Treat if moderate/severe inflam. or significant fibrosis Similar to AASLD except age cut off for biopsy > 35 years HBV >20,000 IU/mL, ALT persistently Normal : May be treated if age > 30 years depending on underlying liver injury. <30 yrs : monitor 3 – 6 months
  18. 18. T/t of HBeAg (-) CHB AASLD (2015) APASL (2015) EASL (2017) HBV DNA>20,000 IU/mL, ALT >2xULN : Treat Biopsy optional . HBV DNA>20,000 IU/mL ,ALT >2xULN :Treat Biopsy optional HBV DNA>20,000 IU/mL, ALT >ULN : Treat Biopsy optional HBV DNA 2000-20,000 IU/mL, ALT 1-2xULN : Consider liver biopsy. Treat if liver biopsy shows moderate/severe inflammation or significant fibrosis. HBV DNA >2000IU/mL, ALT 1- 2xULN : Monitor ALT and HBV DNA every 1-3 months. Biopsy if ≥40years. Treat if moderate/severe inflammation or fibrosis. HBV DNA >2000IU/mL, ALT> ULN Liver biopsy(or non invasive markers of fibrosis) is recommended Treat if biopsy shows moderate- severe inflammation and/or at least moderate fibrosis. HBV DNA≤2000 IU/mL, ALT≤ULN : Monitor HBV DNA≤2000 IU/mL, ALT≤ULN : Monitor HBV DNA≤2000 IU/mL, ALT≤ULN : Monitor
  19. 19. T/t of HBV induced cirrhosis Cirrhosis AASLD (2015) APASL(2015) EASL (2017) Compensated HBV DNA>2000IU/mL: Treat regardless of ALT level HBV DNA<2000IU/mL : Treat regardless of ALT level HBV DNA>2000IU/mL : Treat regardless of ALT level HBV DNA<2000IU/mL : Treat if ALT >ULN. HBV DNA detectable : Treat regardless of ALT level Decompensated Regardless of HBV DNA or ALT level Treat and refer for liver transplantation Same Same HCC surveillance US every 6 months US and AFP every 6 months US every 6 months Presence of extrahepatic manifestations: treatment irrespective of liver disease severity
  20. 20. How long treatment s/b continued?  At least four to five years of treatment  Cirrhotic patients: • life-long therapy with oral agents is typically administered to reduce the risk of clinical decompensation if a relapse occurs  Non Cirrhotic: • HBeAg-positive : o At least 12 months after HBeAg seroconversion o Some advice treatment until loss of HbsAg • HBeAg-Negative : confirmed loss of HBsAg
  21. 21. Just for fun !!!
  22. 22. Drugs for treatment of Hep-B • 1992 : Conventional IFN-α • 1998 : Lamivudine • 2002 : Adefovir disoproxil • 2005 : Entecavir; Pegylated IFN-α • 2006 : Telbuvidine • 2008 : Tenofovir DF • 2016 : Tenofovir AF • Newer antivirals and immunotherapeutics
  23. 23. Drug Dose in adults Dose in children Potential A/E Monitoring Peg-IFN-2a(adult) IFN-a-2b (children) 180 mcg weekly ≥ 1 year Dose: 6 million IU/m2 Flu-like symptoms, fatigue, mood disturbances, cytopenias, autoimmune disorders in adults Anorexia and weight loss in children CBC (monthly to every 3 months) TSH (every 3 months) Clinical monitoring for autoimmune, ischemic, neuropsychiatric, and infectious complications Lamivudine 100 mg daily ≥ 2 years Dose: 3 mg/kg daily to max 100 mg Pancreatitis Lactic acidosis Amylase if symptoms Lactic acid levels if clinical concern Telbivudine 600 mg daily Creatine kinase elevations and myopathy Peripheral neuropathy Lactic acidosis Creatine kinase if symptoms Cinical evaluation if symptoms Lactic acid levels if clinical concern
  24. 24. Drug Dose in adults Dose in children Potential A/E Monitoring Entecavir 0.5 or 1.0 mg daily ≥ 2 years Dose: weight-based to 10-30 kg; above 30 kg : 0.5 mg daily Lactic acidosis Lactic acid levels if clinical concern Adefovir 10 mg daily ≥ 12 years 10 mg daily Acute renal failure Fanconi syndrome Nephrogenic diabetes insipidus Lactic acidosis Creatinine clearance at baseline If at risk for renal impairment, creatinine clearance, serum phosphate, urine glucose, and protein at least annually Consider bone density study at baseline and during treatment in persons with history of fracture or risks for osteopenia Lactic acid levels if clinical concern Tenofovir 300 mg daily ≥ 12 years 300 mg daily Nephropathy, Fanconi syndrome Osteomalacia Lactic acidosis As above
  25. 25.  PEG IFN, entecavir, or tenofovir are recommended as first-line therapy  PEG IFN requires finite-duration therapy, achieves the highest rate of HBeAg responses after a year of therapy, and does not support viral mutations, but it requires subcutaneous injections and is associated with inconvenience and intolerability  Oral nucleoside analogues require long-term therapy in most patients, and when used alone, lamivudine and telbivudine foster the emergence of viral mutations, adefovir somewhat less so, and entecavir (except in lamivudine-experienced patients) and tenofovir rarely at all.  Oral agents do not require injections, are very well tolerated, lead to improved histology in 50−90% of patients, suppress HBV DNA more profoundly than PEG IFN, and are effective even in patients who fail to respond to IFNbased therapy.
  26. 26. Peg Inteferon 2 alpha  Short fixed duration therapy ( 48-52 wks)  No renal toxicity  Ideal patients with high ALT and medium to low DNA  Has stopping rules and continuation rules  Chance of DNA suppression long term in less than 20%  Loss of HBsAg less than 10% • Interferons have antiproliferative properties and should not be used during pregnancy • PEG IFN should not be used in patients with compensated or decompensated cirrhosis
  27. 27. Entecavir  Nucleoside analogue, inhibits reverse transcriptase  0.5 mg/day : 1 mg/day in lamivudine or telbivudine exposed and decompensated COL  Over 97% of treatment-naıve patients could achieve maintained HBV DNA suppression on entecavir after 2–3 years
  28. 28. Advantages of TAF over TDF  Greater plasma stability than TDF  Efficient delivery of active drug to hepatocytes at reduced systemic tenofovir exposures  Safe and well tolerated; declines in HBV DNA similar to TDF at all doses evaluated  Less renal and bone toxicity
  29. 29. Indications for selecting ETV or TAF over TDF  Age >60 years  Bone disease • Chronic steroid use or use of other medications that worsen BMD • History of fragility fracture • Osteoporosis  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
  30. 30. Definition of responses  Responses • Virological • Serological • Biochemical • Histological
  31. 31. Responses cont.. • Virological responses • NA therapy  Virological response : Undetectable HBV DNA by a sensitive PCR assay with a limit of detection of 10 IU/ml.  Primary nonresponse : defined by a less than one log10 decrease of serum HBV DNA after 3 months of therapy.  Partial virological response : defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 12 months of therapy in compliant patients.  Virological breakthrough : defined as a confirmed increase in HBV DNA level of more than 1 log10 IU/ml compared to the nadir(lowest value) HBV DNA level on-therapy • PegIFNa therapy  Virological response : defined as serum HBV DNA levels <2,000 IU/ml : evaluated at 6 months and at the end of therapy.  Sustained off-therapy virological response : defined as serum HBV DNA levels <2,000 IU/ml for at least 12 months after the end of therapy.
  32. 32. Responses cont.. • Serological responses for HBeAg :  HBeAg loss and HBeAg seroconversion • Serological responses for HBsAg :  HBsAg loss and HBsAg seroconversion • Biochemical response :  Normalisation of ALT • Histological response :  Defined as a decrease in necroinflammatory activity (by P2 points in histologic activity index or Ishak’s system) without worsening in fibrosis compared to pretreatment histological findings.
  33. 33. Antiviral resistance
  34. 34. Antiviral Options for Management of Antiviral Resistance Antiviral Resistance Switch Strategy Add Strategy: 2 Drugs Without Cross-Resistance Lamivudine-resistance Tenofovir Continue lamivudine : add tenofovir (or alternative emtricitabine-tenofovir) Telbivudine-resistance Tenofovir Continue telbivudine : add tenofovir Adefovir-resistance Entecavir Continue adefovir : add entecavir Entecavir-resistance Tenofovir Continue entecavir : add tenofovir (or alternative emtricitabine- tenofovir) Multi-drug resistance Tenofovir Combined tenofovir and entecavir
  35. 35. Monitoring of Patients • HBV DNA : every three months until undetectable for at least two consecutive visits, then decrease the frequency to every six months. • ALT : every three months, the frequency can be decreased to every six months in patients with an undetectable HBV DNA or normalized ALT. • HBeAg and anti-HBe : every six months in HBeAg-positives to determine if seroconversion has occurred. If HBeAg seroconversion has occurred test is repeated to confirm the result. • HBsAg : be tested yearly. • Screening for HCC : USG and AFP • Adverse reactions to drugs
  36. 36. Endpoints in therapy Ideal endpoint : sustained off- therapy HBsAg loss, with or without seroconversion to anti-HBs More realistic endpoint : induction of sustained or maintained off therapy virological remission Sustained or maintained on therapy virological remission
  37. 37. Treatment in special patient groups with HBV infection  HIV co-infected patients • All HIV-positive patients with HBV co-infection should start ART irrespective of CD4 cell count • HIV-HBV co-infected patients should be treated with a TDF- or TAF-based ART regimen • Entecavir may generate HIV mutations  HDV co-infected patients • PegIFNa for at least 48 weeks is the current treatment of choice in HDV-HBV co-infected patients with compensated liver disease. • In HDV-HBV co-infected patients with ongoing HBV DNA replication, NA therapy should be considered • PegIFNa treatment can be continued until week 48 irrespective of on-treatment response pattern if well tolerated
  38. 38.  HCV co-infected patients • 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 s/b 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
  39. 39.  Acute hepatitis B • More than 95% of adults with acute HBV hepatitis do not require specific treatment, because they will fully recover spontaneously • Only patients with severe acute hepatitis B, characterised by coagulopathy or protracted course(i.e., persistent symptoms or marked jaundice for [4 weeks), or signs of ALF s/b treated with NA and considered for liver transplantation  Children • In children, the course of the disease is generally mild, and most of the children do not meet standard treatment indications. Thus, treatment should be considered with caution • In children or adolescents who meet treatment criteria, ETV, TDF, TAF, and PegIFNa can be used in this population
  40. 40.  Healthcare workers • HBV infection alone should not disqualify infected persons from the practice or study of surgery, dentistry, medicine, or allied health fields • Healthcare workers performing exposure prone procedures with serum HBV DNA >200 IU/ml may be treated with NA to reduce transmission risk
  41. 41.  Pregnancy • 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 s/b continued while ETV or other NA s/b 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 24–28 wop and continue for up to 12 weeks after delivery • The infants of all HBsAg-positive women should receive immunoprophylaxis (HBV vaccination and/or hepatitis B immunoglobulin ) • Breast feeding is not contraindicated in HBsAg-positive untreated women or on TDF-based treatment or prophylaxis
  42. 42. • Patients undergoing immunosuppressive therapy or chemotherapy • All candidates for chemotherapy and immunosuppressive therapy s/b tested for HBV markers prior to immunosuppression • 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
  43. 43.  Dialysis and renal transplant patients • HBsAg-positive dialysis patients who require treatment should receive ETV or TAF • All HBsAg-positive renal transplant recipients should receive ETV or TAF as prophylaxis or treatment • HBsAg-negative, anti-HBc positive subjects s/b monitored for HBV infection after renal transplantation  Extrahepatic manifestations • Pts with replicative HBV infection and extrahepatic manifestations should receive antiviral treatment with NA • PegIFNa should not be administered in patients with immune-related extrahepatic manifestations
  44. 44. Experimental immunotherapeutics
  45. 45. Thank you !!!