Hepatitis B and C - Approach and Management : Updates 2020

Hepatitis B and C - Approach and Management : Updates 2020

1. HEPATITIS B Chair person: Dr Ram S K Associate professor Dept of General Medicine Student :Dr Tousif

2. HEPATITIS B INTRODUCTION 1965 Baruch Samuel Blumberg Discovered hepatitis B surface antigen(HBs AG) Autralia Ag, now a days known as Hepatitis surface antigen 1970,Dane Cameron and Briggs Visualized the hepatitis B virus (HBV) virion -Dane particle Block Tmet et al A historical perspective on the discovery and elucidation of the hepatitis B virus. Antiviral Research. 2016 Jul

3. Baruch Samuel Blumberg was an American physician,  geneticist, and co-recipient of the 1976 Nobel Prize in Physiology or Medicine  (with Daniel Carleton Gajdusek) for his work on the hepatitis B virus while an investigator at the NIH (National Institute of health ,USA)

4. Introduction Hepatitis b virus is an hepadnavirus , Has a circular genome composed of partially double standed DNA. The virus replicate through an RNA intermediate form by reverse transcription Zlotnick A, et al A theoretical model successfully identifies features of hepatitis B virus capsid assembly . Biochemistry. 1999

5. Continue Hepatits B virus(HBV) has been classified into ten genotypes (A-J) based on genomic sequence divergence. HBeAg expression last longer and liver disease is more severe with graver outcome in carriers of genotype C than B in Asia. Evidence indicate a better response to interferon and lamivudine in patients with chronic hepatitis B genome b rather than genome c Pujol F, et al Hepatitis B virus American genotypes: Pathogenic variants?. Clinics and Research in Hepatology and Gastroenterology . 2020 Jun 15.

6. Prevalence 400 to 500 million carriers of HBV worldwide, with chronic HBV infection at a rate of 5%. WHO report, HBsAg prevalence between 2% and 8% in most studies. India, prevalence in general population appears to less than 3-4% Jha AK et al Seroprevalence of Hepatitis B and C in the Eastern Himalayan Region of India: A Population-Based Study. Tropical Gastroenterology. 2020 Jun

7. Morphological characteristics Lipid envelope Icosahedral nucleocapsid Core composed of proteins The nucleocapsid encloses the viral DNA DNA polymerase that has reverse transcriptase activity. The outer envelope contains embedded proteins helps entry into, susceptible cells. The virus is one of the smallest enveloped viruses 42nm

8. Liu H, Shen L, Zhang S, Wang F, Zhang G, Yin Z, Qiu F, Liang X, Wang F, Bi S. Complete genome analysis of hepatitis B virus in Qinghai-Tibet plateau: the geographical distribution, genetic diversity, and co-existence of HBsAg and anti-HBs antibodies. Virology Journal. 2020 Dec;17(1):1-2.

9. Gene Regions Antigens S (Having three regions S, Pre -S1 and Pre-S2) S S + Pre S2 S + Pre S1 & S2 Small protens (S) surface antigen Middle protein (M) Large protein (L)-present only in virion C (having regions C and Pre –C) C C +Pre -C Core antgen HBeAg P Dna polymerase(DNA dependent DNA polymerases) X HBXAg ( nonparticulate antigen which leads to enhance replication of HBV Liu H et al Complete genome analysis of hepatitis B virus in Qinghai-Tibet plateau: the geographical distribution, genetic diversity, and co-existence of HBsAg and anti-HBs antibodies. Virology Journal. 2020

10. Route of transmission Contaminated needles Sexual transmission Blood and blood products Vertical transmission Hahné S et al Incidence and routes of transmission of hepatitis B virus in England and Wales, 1995–2000: implications for immunisation policy. Journal of clinical virology. 2004 Apr 1

11. High risk groups Multiple sex partners (>1 partner/6 months); men who have sex with men; injecting drug users; imprioned persons; household and sex contacts of HBV-infected persons; healthcare and public safety workers who have exposure to blood in the workplace; and haemodialysis patients Mast EE et al Hepatitis B vaccination of adolescent and adult high-risk groups in the United States. Vaccine. 1998 Nov

12. Acute Viral Hepatitis Incubation period is prolonged than Hep A lasting for 30-180 days (8-12weeks) CLINICAL FEATURES divided into Preicteric phase Icteric phase Post icteric phase or recovery phase

13. 1.Pre-icteric Phase/ prodromal stage: 3-9 days anorexia, nausea and vomiting, fatigue, malaise, arthralgias , myalgias , headache, photophobia, pharyngitis , cough, and coryza may precede the onset of jaundice by 1–2 weeks , Examination; fever with relative bradycardia + enlarged liver

14. 2.Icteric Phase: 2-4 weeks Increase jaundice with decrease fever and improvement of general condition and constitutions symptoms Dark coloured urine due to bilirubinuria Clay coloured stools due to cholestasis Loss of weight Pruritis as a result of elevated serum bile acid/salt (Large percentage of patient never become icteric )

15. 3. Post- icteric Phase (recovery phase) disappearance of jaundice urine and stools colour become normal appetite improve GI symptoms disappears Complete recovery of liver may take up to 6months

16. Laboratory features The serum AST and ALT increase to a variable degree during the prodromal phase, and precede the rise in bilirubin level. these enzymes does not correlate  degree of liver cell damage. levels vary from 400–4000 IU or more; these levels are usually reached at the time the patient is clinically icteric and diminish progressively during the recovery phase of acute hepatitis.

17. Bilirubin -> 2.5 mg/ dL . When jaundice appears levels will ranging 5–20 mg/ dL which may continue to rise despite falling serum aminotransferase levels. In most instances, the total bilirubin is equally divided between the conjugated and unconjugated fractions. Bilirubin levels >20 mg/ dL is associated with severe disease Harrison 20 th Edition

18. Neutropenia and lymphopenia Lymphocytosis Prolong prothrombin time Hypoglycemia Steatorrhea slight microscopic hematuria and minimal proteinuria .

19. >1000 At 6 month 95% becomes HBsAg negative Window period

20. Wai CT et al US Acute Liver Failure Study Group. Clinical outcome and virological characteristics of hepatitis B‐related acute liver failure in the United States. Journal of viral hepatitis. 2005 Mar >95%

21. Management When to give AntiVIRAL treatment ? Fulminant hepatitis Severe hepatitis – defined as 2 of the following 3 criteria bilirubin >5.8mg/dl PT(INR) 1.6 liver encephalopathy Long-lasting symptoms or increased bilirubin for over 4 weeks Immunocompromized patients active viral replication (documented by measurable HBVDNA C1 9 104 copies/ml);

22. Fulminant hepatitis Diagnosis of fulminant hepatitis B was based on the following criteria: (a) histologically proven acute hepatitis (b) severe coagulation disorders; (c) hepatic encephalopathy within 2 months after the onset of jaundice (d) presence of IgM anti- HBc in the earliest serum sample collected after the onset of hepatic encephalopathy Bernuau J et al Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology . 1986 Jul

23. How long we should continue teatment Treatment with ETV, TDF or TAF is primarily recommended until HBsAg is undetectable. If HBsAg is still detectable, treatment should be discontinued after 6-12 months. Future need of treatment should then be assessed according to the same guidelines as for chronic hepatitis B. Interferon is contraindicated in acute hepatitis B, due to the risk of liver decompenzation . Flisiak R et al Recommendations for the treatment of hepatitis B in 2017. Clinical and experimental hepatology . 2017 Jun.

24. At present, there are no unambiguous results from controlled trials on the effectiveness of NA therapy in acute hepatitis B with a severe (including fulminant ) course. NA therapy may be considered only if liver transplantation is an option. Treatment should be started with NA drugs which show potent antiviral activity and high genetic barrier: ETV, TDF or TAF . However, patient management should be oriented primarily toward actions leading to liver transplantation. Flisiak R et al Recommendations for the treatment of hepatitis B in 2017. Clinical and experimental hepatology . 2017

25. Chronic Hepatitis B

26. Immune tolerant phase The AASLD suggests that ALT levels be tested at least every 6months for adults with immunotolerant CHB to monitor for potential transition to immune-active or inactive CHB. Antiviral treatment is usually not recommended. The patient should be monitored one to two times per year ( The AASLD suggest antiviral therapy in selected group of Adults >40 yr of age with normal ALT Elevated HBV DNA (1,000,000 IU/ mL ) Liver biopsy showing significant necroinflammation or fibrosis Management of hepatitis B virus infection, updated Swedish guidelines by Johan Westin, infectous disease American Association for the study of Liver diasease

27. Immune tolerance phase HBsAg + ve HBeAg + ve HBV DNA –elevated ALT-normal Asymptomatic

28. Immune clearance phase Seroconversion of HBeAg HBV DNA fluctuation ALT-elevated Active inflammation

29. Inactive carrier state Anti HBe + ve HBV DNA-low ALT-normal Mild inflammation and minimal fibrosis

30. Immune active phase Immune Active CHB is defined by An elevation of ALT >2 ULN OR evidence of significant histological disease plus Elevated HBV DNA above 20,000 IU/ mL ( HBeAg positive) AASLD recommends Peg-INF , Entecavir,or Tenofovir as prefered initial therapy for adults with immune-active CHB.

31. Additional factors included in the decision to treat persons with immune active CHB but ALT <2 ULN and HBV DNA below thresholds are: Age: Older age (>40 years ) is associated with higher likelihood of significant histological disease. Family fistory of HCC Presence of extra hepatic manifestation

32. Extrahepatic manifestation Vasculitis ( polyarteritis nodosa ) skin rash ( purpura ), joint pain, peripheral neuropathy,Acute dorsal myelitis Glomerulonephritis leading to chronic kidney disease ( HBsAg,immunoglobulina,C3 deposition ) Cryoglobinemia Han SH et al Extrahepatic manifestations of chronic hepatitis B. Clinics in liver disease. 2004 May

33. Polyarteritis nodusa

34. Cryoglobulinemia Essential mixed cryoglobulinemia reported initially to be associated with hepatitisB . arthritis, cutaneous vasculitis (palpable purpura ), glomerulonephritis (AKI) presence of circulating cryoprecipitable immune complexes of more than one immunoglobulin class( LOW C4 and LOW C3) Type 1 MPGN 75% presented after >10 years of HBV infection Predominantly type 3 cryoglobulinemia (polyclonal IgM -polyclonal IgG )

35. Treatment options Eligibility of chronic hepatitis B infections HBsAg must be consistently detectable for at least six months, and at least two out of the three criteria below (evaluated concurrently) must be met: 1) HBV-DNA > 2,000 IU/ml; 2) ALT level exceeding the upper limit of normal; 3) signs of liver inflammation or fibrosis. Inflammation should be evaluated by histological examination of liver biopsy specimens, Flisiak R et al Recommendations for the treatment of hepatitis B in 2017. Clinical and experimental hepatology . 2017 Jun

36. Treatment in CIRRHOSIS Entecavir and tenofovir are preferred drugs. Peg-IFN is contraindicated in persons with decompensated cirrhosis owing to safety conserns . Concurrent consideration for liver transplantation is indicated in eligible persons. Treatment with antivirals does not eliminate the risk of HCC and survellance for HCC should be continued .

37. All individuals must evaluated at least every 6 months for a history and examination , metabolic panel with renal and liver function tests, CBC, HBV DNA level, and serological tests for HBeAg and HBsAg . Patients with increasing HBV DNA and ALT levels should be evaluated more frequently Tang LS et al. Chronic hepatitis B infection: a review. Jama . 2018 May

38. Duration of treatment The AASLD suggest that HBeAg -positive adult without cirrhosis with CHB who seroconvert to anti- Hbe on therapy discontinued NAs after period of treatment consolidation. The period of consolidation therapy generally involves treatment for at least 12months of persistently normal ALT levels and undetectable serum HBV DNA levels

39. Persons with cirrhosis who stop antiviral therapy should be monitored closely ( e.g montly first 6 months ,then every 3 montly ) for recurrrent viremia , ALT flares, seroreversion,and clinical decompensation . Tang LS et al Chronic hepatitis B infection: a review. Jama . 2018 May

40. Pharmacological management There are currently two main options for treating chronic HBV infection: Nucleos (t) ide analogues (NA) or Alpha-interferon (IFN)

41. Nucleoside/nucleotide Analogues Six different NAs are approved for the treatment of HBV: lamivudine (LAM), adefovir (ADV), telbivudine (TBV), (2 nd line Treatment) entecavir (ETV), tenofovir disoproxil fumarate (TDF) tenofovir alafenamide (TAF)

42. ETV, TDF or TAF, which all have a high barrier to drug resistance, are recommended as preferred treatments of HBV infection, while LAM, ADV, TBV (which have a low barrier to drug resistance) are no longer recommended NAs are used in 90% of the cases internationally. ongoing therapy most patients achieve non-detectable HBV-DNA levels, histological improvement, and normalization of ALT values effect of the treatment is usually not persistent and lifelong treatment required

43. Nucleos (t) ide Analogue The nucleos (t) ide analogues inhibit the RNA-dependent DNA polymerase reverse transcriptase Adverse effects The most common adverse effects were fatigue (3.3%-10.4%), dizziness (5.0%-6.6%), headache (4.9%-15.5%), and nausea(3.0%-10.0%) lactic acidosis and severe hepatomegaly Gilead Sciences. VIREAD ( tenofovir disoproxil fumarate ) package insert. https://www.accessdata . fda.gov / drugsatfda_docs /label/2012 /021356s042,022577s002lbl.pdf. Accessed June 20, 2017 .

44. Lamivudine Seroconversion in 20% of patients Delaying of Fibrosis and HCC Useful in HBe Ag – ve CHB Useful in decompensated hepatitis YMDD mutation in virus leads to 70%of patient after 5yeasr become resistance Haptavir (100mg) brand name Cost ~3000/ anum

45. Entecavir (ETV) Dose 0.5mg OD in HBeAg postive patients, 6 log10 units reduction in HBV DNA after 48 weeks of treatment HBeAg -negative patients, a reduction of HBV DNA by more than 5 log10 units is achieved at week 48 less than 1% of previously untreated patients, resistance to ETV has developed after 3 years of treatment. Cross resistance exsist with those who developed resistance againt LAM

46. The ETV dose should be reduced in patients with renal impairment ( creatinine clearance <50 mL /min). Prefered in patients resistance to Adefovir Yearly cost is nearly ~13,200/-INR or more (X-VIR Brand ) Johan Westin, et al ;Management of hepatitis B virus infection,updated Swedish guidelines 2019

47. Tenofovir disoproxil fumarate (TDF) Monotherapy Approved for HBV and in combination therapy is approved for HIV. Dose 300mg OD 4-6 log10 reduction of HBV DNA after 48 weeks of treatment Nephrotoxic ,so RFT should be monitored every 6 months Crcl 30-49 300mg in 48hrs Crcl 10-29 300mg in 72-96hr If patient on hemodialysis 300mg in 7days is recommended

48. TDF also has an impact on bone density; hence, patients with increased risk of pathological fractures (high age, post-menopausal women, steroid treatment, impaired renal function) should be monitored regarding bone density Cost per anum ~18,000/-INR( TENVIR brand CIPLA) Johan Westin, et al ;Management of hepatitis B virus infection,updated Swedish guidelines 2019

49. Tenofovir alafenamide (TAF) Recently approved for CHB Dose 25mg OD dose does not need to be adjusted for patients with renal insufficiency, but is not recommended in patients with creatinine clearance below 15 mL /min, who are not on haemodialysis

50. Expenditure per anum ~18,000/-INR (TENVIR AF 25mg brand CIPLA) Johan Westin, et al ;Management of hepatitis B virus infection,updated Swedish guidelines 2019

51. Alpha-interferon (IFN) weaker antiviral effect Approximately 11% of HBeAg -positive patients and 6% of HBeAg -negative patients achieve HBsAg clearance important advantage is that a persistent effect can be achieved with a finite treatment 48 weeks of treatment is given by subcutaneous injections once per week, No role in Asian population, immunosuppresed , decompensated CHB,minimal ALT,HbeAg neagtive patient

52. Efficacy of Pegylated Interferon | In randomized clinical trials, pegylated interferon achieved higher rates of HBeAg loss (30% vs 21% with lamivudine, P < .001). and higher incidence of HBsAg loss,improved liver histology, and a reduction in cirrhosis and hepatocellular carcinoma compared with untreated controls. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine , and the combination for HBeAg -positive chronic hepatitis B. N Engl J Med. 2005;352(26):2682-2695 .

53. However, overall responses remain suboptimal in that only approximately one-third of patients achieve HBeAg loss and fewer achieve HBsAg loss. For HBeAg -positive patients, factors indicating good probability of response are genotype A or B (vs. C and D), high ALT levels, low viral load, apparent necroinflammatory activity, and low HBsAg levels, Cost per anum is ~4,00,000/-INR (brand name EXXURA 180mcg/0.5mL)

54. Myrcludex B/ Bulevirtide (BLV) Myrcludex B/ Bulevirtide (BLV) is a first-in-class entry inhibitor to treat HBV/HDV co-infected patients. BLV monotherapy / combination with Tenofovir (TDF) or PEG-interferon α-2 a (PEG-IFN α) induced serum and intrahepatic HDV RNA decline in two phase 2 clinical trials . In a substantial number of patients HBsAg was undetectable and seroconversion occurred Results in study shows HBsAg declined by > 1log10 IU/ml in two patients but was detectable further on. Wedemeyer H et al ;Safety and Efficacy of 10 mg Myrcludex B/ IFNa Combination Therapy in Patients with Chronic HBV/HDV Co-Infection. Zeitschrift für Gastroenterologie . 2020 Jan

55. Treatment of CHB in pregnancy Telbivudine and Tenfovir are the safest. to reduce the risk of perinatal transmission in HBsAg positive pregnant women with an HBV DNA levels >200,000 IU/ mL. 28-32 weeks of gestation. discontinued at birth to 3 months post partum discontinuation of treatment , women should be monitored for ALT flares every 3 months for 6 months. Breastfeeding is not contraindicated.

56. Neonates born to hepatitis B infected mothers should be immunised at birth and immunoglobulin is given.

57. Combination therapy Studies of combination therapy of IFN-a or Peg IFN-a and lamivudine compared with IFN-a or Peg IFN-a alone or lamivudine alone in viral suppression and a higher rate of sustained response than lamivudine alone , but no difference in sustained off-treatment response To date , there has been no large clinical trial that confirms the benefits of Peg IFN-a plus lamivudine therapy over Peg IFN-a monotherapy . Piratvisuth et al Reviews for APASL guidelines: immunomodulator therapy of chronic hepatitis B. Hepatology international.

58. Vaccination Unvaccinated persons ----0,1,6 months Perinatal exposure----HBIG 0.5 ml immediately after BIRTH , Hep B vaccine started within 12 hrs Percutaneus / Transmucosal ----HBIG 0.06 ml/kg, plus HEP B vaccine within week Sexual contact---- HBIG 0.06 ml/kg within 14 days + HEP B vaccine

59. Vaccination A series of 3 doses (0.5 ml each) on a 0,1,6 month schedule. Alternative doseage shedule 0,1,2 and 12 months if there is an interruption between doses of hepatitis B vaccine no need to restart, Interruption after 1 st dose ,2 nd dose should be given as soon as possible and 3 rd should be given at least 8weeks after 2 nd dose If 3 rd dosed missed it should be given as soon as possible

60. Booster doses of vaccine For hemodialysis patient immunocompromised persons (HIV-infected persons, hematopoitic stem-cell transplant recipient,and persons receiving chemotherapy) A booster dose should be administered when anti-HBs levels decline to <100mIu/ml Jia Q et al ;Predictive effect of five hepatitis B virus markers on re-vaccination time of hepatitis B vaccine. Experimental and Therapeutic Medicine.2017

61. POST exposure prophylaxis Unvaccinated persons /incomplete hepatitis B vaccine series/ANTI-HBS <100 should receive both hepatitis B immunoglobulin and Hepatitis B as soon as possible.(preferably<24hrs). For sexual exposures,HBIG should not be be administered more than 14 days after exposure. Hepatitis B vaccine is administered simultaniously with HBIG in a separate injection site.

62. Thanking you Thanking you Be careful while handling blood products