World Health Organization. Western Pacific Region

Transcription

1 Advanced modules for HBV 1

2 HBV Module 1 Hepatitis B serological markers and virology 2

3 Acute hepatitis HAV HBV HCV HDV HEV Case fatality Case fatality Uncommon increases with increases with age age Superinfection in HBV may lead to fulminant disease Higher case fatality in pregnant women Chronic No 5% (adults) 55 85% Very rare infection 90% (children) Complicates hepatitis B HCC* No Yes Yes No Route of transmission Waterborne Foodborne Person to person Main hepatitis viruses Perinatal Bloodborne Sexual Bloodborne Perinatal Sexual Bloodborne Waterborne Foodborne Vaccine Yes Yes No HBV vaccine No Treatment None options None Available Available Modified treatment of HBV *HCC; hepatocellular carcinoma 3

4 Populations at higher risk for hepatitis B and C HBV HCV Persons who injected drugs Sex workers Men who have sex with men Health care workers Persons in long term care facilities Persons on chronic dialysis treatment Prisoners and other persons in closed setting Persons who frequently receive blood/blood products Children born to mother infected with HBV / HCV 4 TECHNICAL CONSIDERATIONS AND CASE DEFINITIONS TO IMPROVE SURVEILLANCE FOR VIRAL HEPATITIS. (WHO 2016) P9

5 Who is at risk for chronic HBV infection? Age is a key factor in determining the risk of chronic hepatitis B infection 80 90% of infants infected during the first year of life 30 50% of children infected before the age of 6 years Less than 5% of otherwise healthy persons who are infected as adults 20 30% of adults who are chronically infected will develop cirrhosis and/or liver cancer. 5 WHO guideline 2015

6 Who is at risk for chronic HBV infection? 6 WHO guideline 2015

7 Who to test for chronic HBV and HCV infection There are several possible approaches to testing for HBV and HCV infection General population testing Focused or targeted testing of specific high risk groups Routine antenatal clinic (ANC) testing Birth cohort testing Blood donor screening 7 GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P38 39

8 Who to test for chronic HBV infection Testing approach and population General population testing Routine testing in pregnant women Focused testing in most affected populations Blood donors Recommendations In settings with a 2% or 5% HBsAg seroprevalence,all adults have routine access to and be offered HBsAg serological testing In settings with a 2% or 5% HBsAg seroprevalence, HBsAg serological testing be routinely offered to all pregnant women in antenatal clinics In all settings, HBsAg serological testing be offered to the following individuals Adults and adolescents from populations most affected by HBV infection Adults, adolescents and children with a clinical suspicion of chronic viral hepatitis Sexual partners, children and other family members, and close household contacts of those with HBV infection Health care workers In all settings, screening of blood donors should be mandatory 8 GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P36

9 Initial assessment for chronic hepatitis B and C HBV HCV Chronic infection HBsAg Anti HCV Acute infection Anti HBc IgM HCV RNA, HCcAg etc. (without anti HCV antibody, excluding other hepatitis viruses) 9

10 Additional assessment for chronic hepatitis Serological markers Severity Staging HBV Anti HBs/anti HBc antibodies HBe antigen, Anti HBe, HBV DNA HCV HCV RNA HCV genotype Aminotransferase (AST/ALT) Bilirubin, albumin, alkaline phosphatase (ALP) Liver biopsy Non invasive tests APRI, FIB 4, FibroTest, Transietn elastography 10

11 Serological pattern of chronic HBV infection 11 GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P22

12 How to test for chronic HBV infection (A) Single assay (HBs seroprevalence 0.4%) (B) Two assays (HBs seroprevalence <0.4%) 12 GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P53

13 HBV Module 2 Hepatitis B transmission and prevention 13

14 Transmission routes of HBV Vertical: Mother to child Horizontal: Young children, household contacts Sexual Health care associated Blood products Unsafe injections Medical procedure (i.e. Needle stick injury) Persons who inject drugs (PWID) Organs and tissue transplantation 14

15 HBV infection and age at acquisition Infections during infancy and early childhood are particularly likely to lead to chronic infection, with risk of cirrhosis and death (a public health problem) 15

16 Prevention of HBV infection Vaccination* Childhood vaccination Primary 3-dose vaccination Timely birth dose High risk groups Catch up programs * Is the key intervention to prevent chronic HBV infection (occurs following infection during infancy and childhood) Other measures Screening of blood and blood products Injection safety Occupational safety Harm reduction interventions Safe sex 16

17 Infant and neonatal hepatitis B vaccination Vaccination is the mainstay of Hepatitis B prevention Infant and neonatal hepatitis B vaccination The hepatitis B vaccination is the mainstay of hepatitis B prevention WHO recommends birth dose (BD) and 3rd dose (B3) of hepatitis B vaccination The complete vaccine series induces protective antibody levels in >95% of infants and children. 17

18 Hepatitis B vaccine Contains a viral protein: HBsAg = Hepatitis B surface antigen Originally produced from plasma of persons with chronic HBV infection, but now only recombinant protein is used Recombinant vaccine Gene for HBsAg is inserted into yeast or mammalian cells The cells are cultured to produce an excess of protein The protein is purified and adsorbed on the surface of an adjuvant (alum) Used as intramuscular injection 18

19 Hepatitis B vaccines Storage at 2 8 C Stability and storage Relatively heat stable remains effective even after several days at room temperature However, very sensitive to freezing Avoid freezing at all costs 19

20 Protection* in Infants by HBV Vaccination Dose Dose Protection 1 16% 40% 2 80% 95% 3 98% 100% * Protection defined as anti HBs antibody titer of 10 miu/ml or higher Note: Preterm infants less than 2 kg respond to vaccination less often 20

21 Hepatitis B vaccine response rates A 3 dose series induces protective antibody concentrations in >95% of healthy infants, children and young adults (<40 years) Lower response rates in older adults (>40 years), obesity, smoking, chronic systemic illnesses Seroprotection rates following vaccination in older persons years >90% years >80% 21

22 Vaccine non responders 5 10% people may not respond to 3 dose schedule Most of the non responders do respond to an additional 3 dose vaccination series Alternative options for non responders Double dose Four dose schedule Intradermal administration Newer vaccines 22

23 Global health sector strategy on hepatitis Targets Interventions 2020 target 2030 target 1. Hep B3 vaccine 90% 90% 2. HBV PMTCT 50% 90% 1. Service coverage 2. Impact 3. Blood and injection safety 95 % screened donations 100 % screened donations 50% RUP devices 90% RUP devices 4. Harm reduction 200 injection sets / PWID 300 injection sets / PWID 5. Treatment A. Incidence 30% diagnosed 90% diagnosed 5M and 3M treated for HBV and HCV 30% (1% HBsAg in children ) 80% eligible treated 90% (0.1% HBsAg in children) B. Mortality 10% 65% 23 PMTCT: Prevention of mother to child transmission PWID: Person who injects drugs

24 Immunization coverage with 3 dose schedule of hepatitis B vaccine in infants in 2015 Coverage (%) African American Eastern Mediterranean European South East Asia Western Pacific Global Year Source: WHO AND UNICEF Joint Reporting

25 Immunization Coverage Coverage (%) African American Western Pacific Global Year 25 Source: WHO AND UNICEF Joint Reporting

26 Regional vaccination coverage Hepatitis B vaccine 3rd dose Hepatitis B vaccine birth dose Chronic infections 26 Eric Wiesen et al,vaccine 2016 WPRO

27 Catch up hepatitis B vaccination strategies All children and adolescents younger than 18 yearsold and not previously vaccinated should receive the vaccine if they live in countries where there is low or intermediate endemicity. Higher dose of vaccination might improve the lower response in persons with HIV or with a low CD4 count. Safer sex practices also protect against transmission including minimizing the number of partners and using barrier protective measures. 27

28 HBV Module 3 Natural history of Hepatitis B 28

29 Consequences of HBV infection Hepatitis B virus infection Acute infection (short duration: <6 mo) Chronic infection (duration >6 mo) Asymptomatic Chronic hepatitis B Acute viral hepatitis Cirrhosis: compensated Acute liver failure Cirrhosis: decompensated 29

30 Natural history of HBV infection (Acute phase) Acute HBV infection HBsAg (+) IgM anti HBc (+) HBV DNA(+), HBeAg(+/ ), Anti HBs( ) *: IgM anti HBc(+) can distinguish acute infection from chronic infection 95% in adults 5 30% in children Infection resolved HBsAg ( ), Anti HBs (+) IgM anti HBc( ), Anti HBc (+), HBV DNA( ), HBeAg( ) 3 5% (10% in Gt. A) in adults 70 95% in children Infection persistent HBsAg (+), Anti HBs ( ) IgM anti HBc( ), Anti HBc(+) HBV DNA(+), HBeAg(+/ ) Rare, but to take care Fulminant hepatitis *: Anti HBs (+) can distinguish resolved state from chronic infection next slide % Death 30

31 Serological pattern of acute HBV infection 31 GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P22

32 Natural history of HBV infection (chronic phase) Infection persistent HBe(+) chronic hepatitis HBsAg (+), Anti HBc (+) HBeAg (+), HBV DNA high ALT high HBe( ) chronic hepatitis HBsAg (+), Anti HBc (+) HBeAg ( ), HBV DNA low( high) ALT normal high Liver cirrhosis Liver failure Liver cancer Death Inactive carrier HBsAg (+), Anti HBc (+) HBeAg ( ), HBV DNA ( ) low ALT normal Clinical clearance HBsAg ( ), Anti HBs ( ) Anti HBc (+), HBV DNA ( ) ALT normal 32

33 Natural history of chronic hepatitis B Chronic hepatitis B Immunetolerant phase Immune active phase Immune control phase Immune clearance (cure) Reactivation phase 33

34 Natural history of chronic hepatitis B Chronic hepatitis B Immunetolerant phase Immune active phase Immune control phase Immune clearance (cure) Cirrhosis with any of the phases Phases that need anti viral drug treatment Phases that DO NOT need anti viral drug treatment Reactivation phase 34

35 Serological pattern of chronic HBV infection 35 GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P22

36 Atypical clinical course of HBV infection HBeAg negative chronic hepatitis Seroconversion commonly means HBV replication Mutations in pre core or core promotor region Rapid progression to cirrhosis HBV reactivation in immuno deficient state De novo hepatitis Hematopoietic stem cell transplant, rituximab, Chronicity rate in new adults infection Difference in geographical distribution and chronicity 36

37 HBV Module 4 Assessment of liver fibrosis 37

38 Assessing the degree of liver fibrosis Non invasive tests Components Requirements Cost APRI AST, platelets Simple serum and FIB 4 Age, AST, ALT, Platelets hematology test FibroTest ggt, haptoglobin, bilirubin, A1apoprotein, α2 macroglobulin AST; aspartate aminotransferase ALT; alanine aminotransferase APRI; aspartate aminotransferase to platelet ratio index FIB 4; fibrosis 4 score Specialized tests at designed laboratories Fibroscan Transient elastography Dedicated equipment +++ Fibroscan (http.myliverexam.com/en/lexamen fibroscan.html) GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)

39 Assessing the degree of liver fibrosis by NITs Fibrosis stages assessed Cut off values for the detection of fibrosis Cirrhosis (METAVIR F4) Significant fibrosis (METAVIR F2) APRI F2, F4 High cut off 2.0 High cut off 1.5 FIB 4 F3 High cut off 3.25 FibroTest F2, F3, F Fibroscan F2, F3, F4 >11 14 kpa >7 8.5 kpa APRI = [ (AST(IU/L)/ AST_ULN(IU/L)) x 100 ] / platelet count (10 9 /L) ULN signifies the upper limit of normal for AST in the laboratory where these investigations were undertaken FIB 4 = age(yr) x AST(IU/L)/platelet count(10 9 /L) x [ALT(IU/L) 1/2 ] 39 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)

40 Transient elastography (Fibroscan) 40

41 Transient elastography (Fibroscan) Transducer sends a mechanical shearwave Monitor display of Fibroscan Large explored volume (at least 100 times more than biopsy) 41

42 Transient elastography (Fibroscan) Median Calculated from 10 valid measurement Is used as the final result Inter quartile range (IQR) Spread of the middle half of observations Should be small IQR/median Ratio of IQR to median Indicates variability in different reading High values means large variation If > 30%, implies no reliability 42

43 Fibroscan Advantages Easy, non invasive Can be done in outpatient or community settings Takes <10 minutes to perform Health care staff can be easily trained Limiting factors High cost of equipment Equipment needs regular maintenance/calibration by trained personnel No universal cut off values for specific stages of fibrosis Difficult to measure in very obese 43

44 The Child Turcotte Pugh Classification system Points Encephalopathy None Minimal (grade1 or 2) Advanced (grade 3 or 4) Ascites Absent Controlled Refractory Total bilirubin <34 (<2) (2 3) >51 (>3) (μmol/l)(mg/dl) Albumin(g/dL) > <2.8 Prothrombin time (seconds) or PT INR* Child Pugh Class A: 5 6 points Child Pugh Class B: 7 9 points Child Pugh Class C: points <4 or < or >6 or >2.3 *PT INR ; prothrombin time international normalized ratio 44

45 HBV Module 5 Treatment for Chronic Hepatitis B 45

46 46

47 Other international treatment Guidelines American Association Liver disease 2018 European Association in the Study of Liver disease 2017 Asian Pacific Association for the Study of Liver 2016 Country specific Treatment and Care guidelines 47

48 WHO guidelines Assessment for treatment Monitoring Stopping treatment 48

49 Initial assessment for hepatitis B and C HBV HCV Chronic infection HBsAg Anti HCV Acute infection Anti HBc IgM HCV RNA, HCcAg etc. (without anti HCV antibody, excluding other hepatitis viruses) 49 MONITORING AND EVALUATION FOR VIRAL HEPATITIS B AND C: RECOMMENDED INDICATORS AND FRAMEWORK (WHO 2016)

50 Additional assessment for chronic hepatitis Serological markers Severity Staging HBV Anti HBs/anti HBc antibodies HBe antigen, Anti HBe, HBV DNA HCV HCV RNA Aminotransferase (AST/ALT) Bilirubin, albumin, alkaline phosphatase (ALP) Liver biopsy Non invasive tests APRI, FIB 4, FibroTest, Transietn elastography 50 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P17 19

51 Why should we treat HBV infection Delay the progression of cirrhosis (Improve liver fibrosis) Reduce the incidence of hepatocellular carcinoma Improve long term survival and QOL Key outcomes Sustained ALT normalization Sustained undetectable HBV DNA HBeAg seroconversion / HBsAg seroconversion Reversion of fibrosis stage 51 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)

52 Effects of antiviral therapy Sustained ALT normalization Sustained undetectable HBV DNA HBeAg seroconversion HBsAg seroconversion HBsAg seroconversion and development of HBsAb = functional cure.. uncommon Resulting in Lim YS, et al. Gastroenterology. 2014;147: Chang TT, et al. Hepatology. 2010;51: Zoutendijk R, et al. Gut. 2013;62: Marcellin P, et al. Lancet. 2013;381: Papatheodoridis GV, et al. J Hepatol. 2015;62: Papatheodoridis GV, et al. Hepatol. 2016;63:

53 Effects of antiviral therapy Prevention of fibrosis progression Promoting fibrosis regression, even in cirrhosis Prevents or even reverses hepatic decompensation Reduces, but does not eliminate the risk of HCC Reduce risk of transmission Improve long term survival and quality of life Fibrosis Reversal after antiviral 53

54 Cure as a Goal of Therapy Actual cure True cure = all traces of HBV gone from the liver (like HCV) VERY difficult due to presence of HBV cccdna Functional cure Use the markers of pts who do well: 1. HBsAg loss (ideally with anti-hbs) 2. Possibly sustained off-treatment inactive disease without HBsAg loss (HBeAg negative, DNA undetectable, normal ALT, normal histology) Cure not so simple... reasons lie in the virology 54

55 Why Is Cure Rare With Nucleos(t)ide Therapy? Attachment and penetration Transport to cell nucleus Uncoating DNA repair cccdna HBsAg HBV virion Golgi complex Release Envelope proteins S, M, L Pregenomic RNA Core protein DNA synthesis HBV RNA transcripts Encapsidation of pg RNA HBeAg Polymerase protein Oral anti-hbv therapy O- Translocation HBeAg new (-) strand DNA 5 Cap synthesis dadadg (A)n 3 pgrna Grimm D, et al. Hepatol Int. 2011;5:

56 REVEAL: HBV DNA Level and Risk of Cirrhosis Long-term (mean follow-up: 11.4 yrs) cohort study to determine risk of cirrhosis and HCC in untreated, HBsAg-positive individuals in Taiwan (N = 3582) Cumulative Incidence of Liver Cirrhosis Iloeje UH, et al. Gastroenterology. 2006;130: Baseline HBV DNA Level (copies/ml) 1 million 100, ,999 10,000-99, < Follow-up (Yrs) 56

57 REVEAL: HBV DNA Level and Risk of HCC Prospective study in same REVEAL cohort (N = 3653) Cumulative Incidence of HCC (%) Baseline HBV DNA (copies/ml) 1 million 100, ,999 10,000-99, < 300 Increased HCC incidence with increasing DNA levels (P <.001) HCC can occur in the absence of cirrhosis Chen CJ, et al. JAMA. 2006;295: Follow-up (Yrs) 57

58 HBV Treatment Reduces Risk of Disease Progression Including Decompensation Placebo-controlled, double-blind, parallel group study of pts with chronic HBV infection and cirrhosis (F4) (N = 651) followed until HBeAg seroconversion or disease progression* 25 Pts With Disease Progression (%) Placebo P =.001 n = 173 n = 198 Lamivudine n = 122 n = 417 n = Mos *Hepatic decompensation, HCC, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease. Liaw YF, et al. N Engl J Med. 2004;351:

59 Annual Incidence of HCC HCC Incidence in Pts with Chronic HBV n = Wong GL, et al. Hepatology. 2013;5: Wu CY, et al. Gastroenterology. 2014;147: Hosaka T, et al. Hepatology. 2013;58: Infection and Cirrhosis 7.8 ahr: 0.55 (95% CI: ) ahr: 0.72 Nucleos(t)ide (95% CI: ) analogues 5.3 Control Hong Kong [1] Taiwan [2] Japan [3] 59

60 HBV Treatment Reduces Risk of Liver Transplant Prospective cohort study in pts with HBV and first-onset complications of decompensated cirrhosis (N = 707) LT-Free Survival (%) Bonferroni-adjusted P < Mos Treated,* responder (n = 245) Treated,* nonresponder (n = 178) Untreated (n = 284) *Treated predominantly with lamivudine (n = 203) or entecavir (n = 198). Antiviral therapy improved transplant-free survival over 5 yrs (P =.0098 vs untreated) Jang JW, et al. Hepatology. 2015;61:

61 Long term TDF in Pts With HBV: Regression of Fibrosis, Cirrhosis Overall regression of fibrosis in 51% of pts through 5 yrs (176/348 pts with matched biopsies) Reversal of cirrhosis in 74% of pts through 5 yrs (71/96 pts with cirrhosis at baseline) Marcellin P, et al. Lancet. 2013;381:

62 Reduction in HCC Mortality Through National Viral Hepatitis Therapy Program Pts receiving treatment for chronic hepatitis after start of program in 2003 in Taiwan: 157,570 (HBV) and 61,823 (HCV) Reduced rate of HCC mortality in all age cohorts by 5-8 yrs after introduction of national therapy program Sex-Adjusted HCC Mortality Rate Ratio * * * *P <.01 vs P <.005 vs Age Group (Yrs) Chiang CJ, et al. Hepatology. 2015;61:

63 5 Year Follow Up Study: CHB patients on Tenofovir DF 63 Multicenter, 3 year retrospective, 2 year prospective study (n=357) Males (69%) Mean age: 48 years Cirrhotics (n=7) Follow up: 65 months Cirrhosis progression No progression among baseline cirrhotics New cirrhosis (n=7) No development of HCC Ormeci N, et al. Hepatol Int. 2016;10(suppl 1):48. Abstract O-115. Patients (%) % 5-Year Outcomes 83% 92% 0 HBV DNA ALT AST Suppression Normalizatio n 2% New Cirrhosis Cases Absence of cirrhosis defined by: Liver biopsy (Metavir F0-F3); or transient elastography (<12.5 kpa); or FibroTest or FibroSure (<0.48 with APRI <1).

64 Long term TDF in Pts With HBV: Reversal of Inflammation Open-label study of TDF in pts with chronic HBV infection (N = 585) Parameter Outcome at 7 Yrs [1] Normalized ALT, % (n/n) ITT* On-treatment HBV DNA < 29 IU/mL, % (n/n) ITT On-treatment 57.1 (323/566) 80.0 (328/410) 70.1 (418/596) 99.3 (430/433) HBeAg loss, % (n/n) 54.5 (84/154) HBe seroconversion, % (n/n) HBsAg loss, K-M % (95% CI) HBs seroconversion, K-M % (95% CI) 39.6 (61/154) 11.8 (8.1, 16.9) 9.7 (6.4, 14.6) Necroinflammation improved over 5 yrs (n = 348 matched biopsies) [2] HBeAg-positive population. 1. Buti, M et al. Dig Dis ci. 2015;60: Marcellin P, et al. Lancet. 2013;381: Pts (%) Knodell Necroinflammatory Score P <.001 P <.001 8% Baseline Yr 1 Yr 5 80% 64

65 Is HBV Suppression the Same as Inactive Disease? Retrospective cohort study of treatment-naive pts with HBV starting oral nucleos(t)ide analogues (n = 1378) vs HBeAgnegative pts with inactive CHB (n = 1014) Group receiving nucleos(t)ide analogues divided by continuous viral suppression (complete vs incomplete responder) Spontaneous control better than treatment Cho JY, et al. Gut. 2014;63: Cumulative Incidence of HCC (%) Pts at Risk, n NUC CR Inactive CHB P <.001 Complete responders Mos Inactive CHB

66 Who Should Be Treated? All people with CHB are potential treatment candidates Not a question of who to treat, but when: treat now or monitor and treat later when indicated A person who is not a treatment candidate now can be a treatment candidate in the future Changes in HBV replica on status and/or ac vity/stage of liver disease Availability of new or improved treatments 66

67 All Patients with cirrhosis should be treated All patients with cirrhosis should be treated Life long treatment Treat with antivirals (Tenofovir or entecavir) Decompensated cirrhosis based on clinical findings or history Compensated cirrhosis based on Transient elastography (in clinical context), APRI or FIB 4. Irrespective of ALT, Hepatitis BeAg status, or HBV viral load 67

68 Who should be treated High risk of disease progression to cirrhosis and hepatocellular carcinoma, such as Older than 30 years Persistently abnormal ALT levels High level HBV replication Special populations Pregnant mothers with high viral load??? Coinfection with HCV, HIV Undergoing immunosuppressive therapy 68

69 Which patients should we treat for HBV HBV Cirrhosis High risk of disease progression to cirrhosis and hepatocellular carcinoma, such as Older than 30 years Persistently abnormal ALT levels High level HBV replication HCV All patients Optimal timing of treatment for HBV is still debated. 69 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P36 37

70 Summary of WHO Recommendation HBsAg CIRRHOSIS ALT HBV DNA Cirrhotic patients or APRI >2 Treatment Recommended >20,000 Treatment Recommended Persistently elevated 2,000 20,000 Treatment Deferred Non cirrhotic patients aged >30 <2,000 Treatment Deferred HBsAg+ Fluctuating Normal (<19 F, <30 M) Treatment Deferred Treatment Deferred Populaiton Non cirrhotic patients aged <30 Treatment Deferred HBsAg No Treatment Required 70

71 Young patients Persistently normal ALT Who not to treat now No features of advanced fibrosis on APRI or Transient Elastography No family history of liver disease If viral load available HBV DNA <2000 and no fibrosis and normal ALT 71

72 Phases of CHB infection 72 Initiate treatment Initiate treatment

73 How to treat HBV infection Antiviral agents Interferon (IFN), Pegylated (PEG) IFN Nucleos(t)ide analogue (NA) Tenofovir, Entecavir Lifelong treatment is generally required Clearance of HBsAg (=Cure) is rare High rate recurrence in treatment discontinuation Optimal timing of discontinuation remains unclear Patient s motivation is essential 73 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)

74 How to Treat HBV infected People Antiviral agents: Nucleos(t)ide analogue (NA) Tenofovir, Entecavir Long term Rx required, often life long (all patients with cirrhosis) Functional cure (loss of HBsAg uncommon 1% per year) High rates of relapse after stopping Rx Interferon therapy Pegylated (PEG) IFN or standard IFN Limited role in resource poor setting Finite duration of Rx 12m, Stopping rules Role in coinfection with HBV and HDV 74 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)

75 Advances in HBV treatment 1957 Discovery interferon 1990 Discovery PMEA 1991 Discovery lamivudine (3TC) 1998 Discovery entecavir 2001 Discovery telbivudine 2005 Peginterferon alfa- 2a Peginterferon alfa- 2b * licensed 2008 Tenofovir disoproxil fumarate licensed 2017 Tenofovir alafenamide licensed 1991 Interferon alfa-2b licensed 2003 Adefovir dipivoxil (PMEA prodrug) licensed 2007 Telbivudine licensed 75 ted from: ClinicalCareOptions.com 1999 Lamivudine (3TC) licensed 2006 Entecavir licensed * Specific countries only

76 Antiviral agents for HBV Antiviral agent Potency against HBV Resistance barrier Antivity against HIV Cost Interferons Moderate Not applicable Moderate High Tenofovir High High High Low (high in Hong Kong and other Asian countries) Entecavir High High Weak High Emtricitabine Moderate Low High Low Telbivudine High Low Unclear High Lamivudine Moderate high Low High Low Adefovir Low Moderate None (at 10mg dose) High 76 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P21

77 The replication cycle of HBV and sites of action of NAs 77

78 WHO recommendation: choice of drug In all adults, adolescents and children aged 12 years or older in whom antiviral therapy is indicated, the nucleos(t)ide analogues which have a high barrier to drug resistance (tenofovir or entecavir) are recommended. Entecavir is recommended in children 78 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)

79 WHO Recommended First line HBV Treatment: Essential Medicines List Nucleoside/Nucleotide reverse transcriptase inhibitors entecavir Oral liquid: 0.05 mg/ ml Tablet: 0.5 mg or 1 mg Remarks - Oral liquid for children (weight-based dose) up to 30 kg. Entecavir approved for children age 2 years. - Usual dose (adults): 0.5 mg/d oral for compensated liver disease. 1 mg/d for decompensated liver disease (0.5 mg x 2 pills daily) tenofovir disoproxil fumarate (TDF) Tablet: 300 mg (tenofovir disoproxil fumarate equivalent to 245 mg tenofovir disoproxil) - Listed in the adult WHO EML for hepatitis B: standard dose. - NOT listed in the WHO EML for hepatitis B for children and adolescent. - Approved by US FDA in 2012: 300 mg once daily oral for 12 years of age ( 35kg) with hepatitis B EML: essential medicines list 79 WHO Model List of Essential Medicines 20th List (March 2017) (Amended August 2017): adults, children

80 Choosing Among Nucleos(t)ide Analogues If no comorbidities (for most pts) If risk of or preexisting bone or renal disease, prioritize ETV or TAF [2] Age > 60 yrs Bone disease Chronic steroids or other meds that affect bone History of fragility fracture Osteoporosis Renal abnormalities egfr < 60 ml/min/1.73 m 2 Albuminuria > 30 mg or moderate proteinuria Low phosphate (< 2.5 mg/dl) Hemodialysis Monotherapy with ETV, TDF, or TAF [1,2] When to prioritize TAF over ETV Previous nucleoside exposure [2] Lamivudine with or without adefovir resistance HIV/HBV coinfection No dose adjustment for CrCl 15 ml/min When to prioritize ETV over TAF If less expensive (generic available) Dosing guidelines for CrCl < 15 ml/min 1. Terrault NA, et al. Hepatology. 2016;63: EASL. J Hepatol. 2017;67:

81 Entecavir dosing in children Group Drug and dose Children 2 12 years of age and weighing 10 Kg Entecavir once daily as oral solution* (ml) if available Body weight (Kg) Dose (ml)* once daily >11 to 14 4 >14 to 17 5 >17 to 20 6 >20 to 23 7 >23 to 26 8 >26 to 9 30 >30 10 *Solution containing 0.05 mg/ml (or 0.5 mg in 10 ml) 81

82 Tenofovir: adverse effects in the trials >10% Asthenia (11%) Diarrhoea (16%) Nausea (11%) Pain (12%) 1 10% Anorexia Depression Myalgia Peripheral neuropathy Dyspepsia Rash Headache Vomiting Flatulence Abdominal pain Neutropenia Increased transaminases 82

83 Tenofovir Disoproxil Fumarate: Dose in renal impairment 83

84 Chronic HBV Infection: Management of Pts With Renal Impairment All pts receiving TDF should undergo periodic monitoring of renal function, including phosphate levels [1] Entecavir [2] Reduce dose if CrCl < 50 ml/min Tenofovir Disoproxil Fumarate [3] Reduce dose if CrCl < 50 ml/min No dose recommendation at CrCl < 10 ml/min without dialysis Tenofovir Alafenamide [4] No dose reduction if CrCl 15 ml/min Not recommended at CrCl < 15 ml/min 1. EASL. J Hepatol. 2017;67: Entecavir [package insert] Tenofovir disoproxil fumarate [package insert] Tenofovir alafenamide [package insert]

85 Tenofovir Alafenemide (TAF) vs TDF: Mechanism of Action GI tract Plasma Renal tubular cell TDF 300 mg TAF 25 mg 90% lower plasma TFV than with TDF TFV Renal tubular cell TFV Hepatocyte HBV TAF: novel prodrug of TDF TAF: no dose adjustment needed in pts with CrCl > 15 ml/min Arribas JR, et al. CROI Abstract 453. Duarte-Rojo A. Therap Adv Gastroenterol. 2010;3: Murakami E, et al. Antimicrob Agents Chemother. 2015;59: Tenofovir disoproxil fumarate [package insert] Tenofovir alafenamide [package insert]

86 TAF vs TDF in Pts with HBV Infection: Efficacy Multicenter phase III studies in pts with chronic HBV infection (N = 1298), including pts with compensated cirrhosis HBeAg-Positive Pts [2] (N = 873) HBeAg-Negative Pts [3] (N = 425) Outcome, % TAF TDF P Value TAF TDF P Value HBV DNA < 29 IU/mL at Wk 72 [1] ALT normalization at Wk 48 Central laboratory criteria* AASLD laboratory criteria <.001 HBeAg Loss at Wk 48 Seroconversion at Wk HBsAg Loss at Wk 48 Seroconversion at Wk 48 <1 <1 < *ULN for men, 43 U/L ( 35 U/L if age 69 yrs); for women, 34 U/L ( 32 U/L if age 69 yrs). ULN for men, 30 U/L; for women, 19 U/L. 1. Seto WK, et al. AASLD Abstract Chan HL, et al. EASL Abstract GS Buti M, et al. EASL Abstract GS06. 86

87 TAF vs TDF in Pts With HBV Infection: Safety Multicenter phase III studies in pts with chronic HBV infection (N = 1298), including pts with compensated cirrhosis Outcome TAF TDF P Value Mean change in BMD at Wk 72, % [1] Hip Spine <.001 <.001 Median change in serum creatinine at Wk 48, mg/dl [2] Median change in egfr at Wk 48, ml/min [2] <.001 Mean change in FibroTest score at Wk 48 [3] HBeAg-positive pts HBeAg-negative pts Seto WK, et al. AASLD Abstract Agarwal K, et al. AASLD Abstract Izumi N, et al. AASLD Abstract

88 Chronic HBV Infection: Management of Pts With NA Resistance Resistance Switch Strategy Add Strategy Adefovir Entecavir [1] Entecavir [1] Entecavir Tenofovir* [1,2] Tenofovir (or emtricitabine/tenofovir*) [1] Lamivudine Tenofovir* [1,2] Tenofovir (or emtricitabine/tenofovir*) [1] Telbivudine Tenofovir* [1,2] Tenofovir [1] Multidrug Tenofovir* [1] Tenofovir* + entecavir [1,2] *Includes either TDF or TAF in EASL guidelines; AASLD guidelines not yet updated since approval of TAF. 1. Terrault NA, et al. Hepatology. 2016;63: EASL. J Hepatol. 2017;67:

89 Simplified guidelines on selection of patients for Treatment of patients with Chronic hepatitis B 89

90 Duration of treatment Cirrhosis or APRI >2.0 Lifelong treatment Discontinuation may be considered exceptionally in those without cirrhosis (or APRI < 2.0 in adults) and all of the following: Can be followed carefully long term for reactivation If HBeAg loss and seroconversion to anti HBe, and maintained for one year Persistently normal ALT Persistently undetectable HBV DNA 90

91 Drug dose Adults Entecavir 0.5 mg/day oral Tenofovir 300 mg/day oral Children need dose modification 91

92 Drugs need dose adjustment in renal disease 92

93 Duration of treatment Cirrhosis or APRI >2.0 Lifelong treatment Discontinuation may be considered exceptionally in those without cirrhosis (or APRI < 2.0 in adults) and all of the following: Can be followed carefully long term for reactivation If HBeAg loss and seroconversion to anti HBe, and maintained for one year Persistently normal ALT Persistently undetectable HBV DNA 93

94 HBV Module 6 Monitoring for Chronic Hepatitis B 94

95 Need for monitoring HBsAg +ve No treatment Defer treatment Start treatment All need monitoring (irrespective of need for treatment) 95

96 Monitoring patients with CHB All patients infected with HBV More frequent monitoring recommended for: Persons who do not yet meet the criteria for treatment Persons on treatment or following treatment cessation Monitoring is essential to confirm Adherence, toxicities Treatment effect - ALT, HBsAg, HBeAg, HBV DNA Hepatocellular carcinoma Ultrasound and AFP testing 96 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P64

97 Who should we monitor and why All patients with chronic HBV and HCV infection More frequent monitoring is recommended for: Persons who do not yet meet the criteria for treatment Persons on treatment or following treatment cessation Monitoring is essential to confirm Adherence, toxicities Treatment effect ALT, HBsAg, HBeAg, HBV DNA Hepatocellular carcinoma Ultrasound and AFP testing 97 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P64

98 How to monitor? 98

99 How to monitor? At least annually: ALT HBsAg, HBeAg, HBV DNA level APRI Adherence to treatment Drug adverse events (renal function) More frequent In those who do not clearly meet criteria for treatment Following treatment discontinuation Surveillance for hepatocellular cancer 99

100 How to monitor HBV infected patients : every 12 mos Disease progression / treatment response : every 12 months Monitoring for treatment toxicities Adherence Renal function Ultrasound : every 6 months Detection of liver cancer (cirrhosis / family history) ALT, HBV DNA, HBeAg Risk factors for renal dysfunction α fetoprotein Non invasive test Baseline 6month 12month 18month 24month 100

101 When to stop treatment of HBV Possible discontinuation (Persons without cirrhosis) who can be followed carefully long term for reactivation HBeAg seroconversion to anti HBe and after completion of at least one additional year of treatment in association with persistently normal ALT levels persistently undetectable HBV DNA levels Retreatment is recommended if there are consistent sign of reactivation (HBsAg / HBeAg becomes positive, ALT levels increase, or HBV DNA becomes detectable again) 101 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P64

102 Therapeutic endpoints over time HBeAg decline HBV DNA suppression HBeAg to Anti-HBe seroconversion Improved histology and survival Loss of HBsAg Anti-HBs+ = HBsAg seroconversion Cure 102 TIME

103 Why hepatitis B is not curable: A Key Difference Between HCV & HBV Nuclear cccdna 103

104 Minimise other hepatic insults Stop/reduce alcohol intake Stop/reduce smoking Stop recreational drug use Monitor medications Assess for co infections: HIV, HAV (vaccinate), HCV, HDV Eat a balanced healthy diet Maintain a healthy body weight Exercise regularly 104 Manage stress

105 Duration of treatment Cirrhosis or APRI >2.0 Lifelong treatment Discontinuation may be considered exceptionally in those without cirrhosis (or APRI < 2.0 in adults) and all of the following: Can be followed carefully long term for reactivation If HBeAg loss and seroconversion to anti HBe, and maintained for one year Persistently normal ALT Persistently undetectable HBV DNA 105

106 HBV Module 7 Special population for Chronic Hepatitis B 106

107 Who are specific populations Coinfections HBV and HCV coinfection HBV and HDV coinfection HBV coinfected with HIV HBV coinfected with Tuberculosis Pregnant women Children and adolescents 107 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P98 GUIDELINES FOR THE CARE AND TREATMENT OF PERSONS DIAGNOSED WITH CHRONIC HEPATITIS C VIRUS INFECTION P37, P51

108 HBV and HCV coinfection 3 18% of people who are HBsAg(+) are also HCV infected, and up to 25% of HCV infected persons are HBV infected. Coinfection with HBV/HCV promotes rapid progression of liver diseases, and increases the risk of HCC. Indications for treatment of HBV infection in patients with HBV/HCV coinfection are same as those with HBV monoinfection. HBV DNA monitoring may be necessary as there is a 108 potential risk of HBV reactivation during DAA treatment. GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P103 GUIDELINES FOR THE CARE AND TREATMENT OF PERSONS DIAGNOSED WITH CHRONIC HEPATITIS C VIRUS INFECTION P38

109 HBV and HDV coinfection The routes of HDV transmission are the same as for HBV but vertical transmission is rare. 5% of HBsAg(+) are coinfected with HDV. Vaccination against HBV prevents HDV coinfection. Fulminant hepatitis is more frequently observed in HBV/HDV coinfection compared to HBV monoinfection. PEG IFN is the only drug effective against HDV; TDF/ETV are not effective in HBV/HDV coinfection. 109 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P23, 102

110 HBV and HIV coinfection HBV/HIV coinfection results in Higher rates of chronicity after acute HBV infection Higher levels of HBV replication and rates of reactivation Less spontaneous clearance More rapid progression to cirrhosis Higher liver related mortality Decreased treatment response (compared with persons without HIV coinfection) 110 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P22

111 HBV and HIV coinfection 5 15% of HIV infected persons are coinfected with HBV All HIV infected individuals should be recommended on ART, regardless of CD4 count. Patients should be simultaneously treated for HBV/HIV. Choice of ART should be based on drugs that are active against both HIV and HBV Tenofovir (TDF) Lamivudine (3TC) Efavirenz (EFV) 111 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P22

112 HBV and HIV coinfection Several challenges with HBV/HIV coinfection Cross resisitance between HIV and HBV drugs Increased risk of liver injury ART related immune reconstitution can lead to increased hepatocyte killing Anti HIV drugs can induce direct hepatotoxicity Severe liver injury may lead to fulminant hepatitis and death 112 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P99

113 HBV and tuberculosis (TB) coinfection Persons at increased risk of infection with HBV are also at increased risk of infection with TB. Drug induced liver injury with elevation of aminotransferase is three to six fold higher in persons coinfected with HBV who are receiving antituberculosis drugs, due to hepatotoxicity with isoniazid, rifampicin and pyrazinamide. 113 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P103

114 HBV infection in pregnant women Mother to child HBV transmission must be prevented through a birth dose of hepatitis B vaccine followed by two or three doses as EMTCT strategies (Module 4) Indication for treatment in adults with CHB also apply to pregnant women; however, WHO makes no recommendation on the routine use of NAs. Tenofovir may be recommended for pregnant women based on safety data and resistance profile. IFN based therapy is contraindicated. 114 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P106

115 Children and adolescents with HBV infection The majority of children with HBV infection will not require antiviral therapy because They are usually in the immune tolerant phase. Curative response rates with NAs and IFN are low. There are concerns over long term safety and risks of drug resistance. The FDA has approved; Tenofovir for children with HBV above 12 years. Entecavir for children with HBV above 2 years. 115 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P105

116 HBV Practical session case based learning 116

117 A 52 year old male presents with malaise History: no previous hospitalization Social: 120g alcohol/day (30 years), no tobacco, no records of substance abuse Examination: unremarkable Laboratory data: AST 78 U/L (ULN 30), ALT 64 U/L HBsAg positive, Anti HCV negative Clinical Question What test do you order? Case study 1 117

118 What test do you order? HBV DNA 2.8 x10 8 IU/mL, HIV rapid diagnostic test negative Hb 11.8 g/dl, Neutrophil 2.5 x10 9 /L, PLT 98 x10 9 /L Alb 3.4 g/dl, T Bil 1.2 mg/dl, PT INR 1.6 Cre 1.0 mg/dl Ultrasound: chronic liver disease, mild splenomegaly Clinical Question What is the stage of liver disease? Is treatment recommended? Case study 1 What monitoring do you require? 118

119 What is the stage of liver disease? APRI 2.6; [78/30]x100/98 > 2.0; Liver cirrhosis (compensated) Is treatment recommended? Diagnosis: Liver cirrhosis B Select recommended preferred regimen: Tenofovir 300mg once daily or Entecavir 0.5mg once daily Lifelong treatment Case study 1 Assist for treatment: reduce alcohol intake What monitoring do you require? Monitor for efficacy and toxicity (baseline and every 12 months) Long life screening for HCC (every 6 months) 119

120 A 28 year old female presents for a health check up Complaints: not any symptoms History: no previous hospitalization Social: no records of alcohol, tobacco and substance Examination: unremarkable Laboratory data: She has found to be 24 weeks of gestation HBsAg positive, Anti HCV negative, HIV RDT negative Clinical Question What test do you order? Case study 2 120

121 What test do you order? HBV DNA 1.7 x10 8 IU/mL Hb 9.8 g/dl, Neutrophil 2.8 x10 9 /L, PLT 188 x10 9 /L AST 58 U/L (ULN 30), ALT 62 U/L Alb 4.0 g/dl, T Bil 0.9 mg/dl, PT INR 1.4 Cre 0.8 mg/dl, normal urine Ultrasound: normal liver, no ascites, no hepatoma Clinical Question What is the stage of liver disease? Is treatment recommended? Case study 2 121

122 What is the stage of liver disease? APRI 1.0; [58/30]x100/188 < 2.0; not liver cirrhosis Is treatment recommended? Diagnosis: chronic hepatitis B, 24 weeks of gestation Infant and neonatal hepatitis B vaccination: All infants should receive their first dose of hepatitis B vaccine as soon as possible after birth, preferably 24 hours, followed by two or three doses. Prevention of mother to child HBV transmission no recommendation Breast feeding is safe. Case study 2 122

123 A 45 year old female presents with insomnia History: no previous hospitalization Social: no records of alcohol, tobacco and substance Examination: unremarkable Laboratory data: Hb 12.6 g/dl, AST 34 U/L (ULN 30), ALT 40 U/L HBsAg positive, Anti HCV negative Clinical Question What test do you order? Case study 3 123

124 What test do you order? HBV DNA 1.2 x10 8 IU/mL Neutrophil 3.0 x10 9 /L, PLT 218 x10 9 /L Alb 4.0 g/dl, T Bil 0.8 mg/dl, PT INR 1.5 Cre 0.8 mg/dl Ultrasound: normal liver, no ascites, no hepatoma Clinical Question Case study 3 What is the stage of liver disease? Is treatment recommended? What monitoring do you require? 124

125 What is the stage of liver disease? APRI 0.5; [34/30]x100/218 < 2.0; not liver cirrhosis Is treatment recommended? Diagnosis: Chronic hepatitis B Select recommended preferred regimen: Tenofovir 300mg once daily or Entecavir 0.5mg once daily Lifelong treatment Case study 3 What monitoring do you require? Monitor for efficacy and toxicity (baseline and every 12 month) 125

126 A 26 year old male presents with low grade fever History: no previous hospitalization Social: 60g alcohol/day (6 years), there are records of substance abuse, Sexually active with several partners Examination: injection scar of arm Laboratory data: Hb 13.0 g/dl, Neutrophil 2.8 x10 9 /L, PLT 282 x10 9 /L AST 112 U/L (ULN 30), ALT 120 U/L, HBsAg positive Clinical Question What test do you order? Case study 4 126

127 What test do you order? HBV DNA 3.5 x10 8 IU/mL Alb 4.1 g/dl, T Bil 1.0 mg/dl, PT INR 1.4 Cre 0.8 mg/dl Anti HCV negative, HIV RDT negative Ultrasound: normal liver, no ascites, no hepatoma Clinical Question What is the stage of liver disease? Is treatment recommended? Case study 4 What monitoring do you require? 127

128 What is the stage of liver disease? APRI 1.3; [112/30]x100/282 < 2.0; not liver cirrhosis Is treatment recommended? Diagnosis: chronic hepatitis B Select recommended preferred regimen: Tenofovir 300mg once daily or Entecavir 0.5mg once daily Lifelong treatment Case study 4 Assist for treatment: alcohol sobriety, drug abstinence What monitoring do you require? Monitor for efficacy and toxicity (baseline and every 12 month) 128

129 Case study 5 52 year old man Planned for laparoscopic cholecystectomy Detected to have HBsAg positive on evaluation History No previous hospitalization No addiction Examination: unremarkable What tests should one order? 129

130 Case study 5: Test results Investigations Values Hemoglobin (g/dl) 11.8 Platelets (x 10 9 /L) 98 Total bilirubin (mg/dl) 1.2 Albumin (g/dl) 3.4 ALT (IU/L) AST (IU/L) 66 (<40 IU/L) 98 (<40 IU/L) Prothrombin time (INR) 1.6 HBV DNA (IU/L) 1,120 USG abdomen Coarse echo texture of liver Portal vein diameter = 14 mm Splenomegaly, no ascites 130

131 Case study 5: Issues in management What is the stage of liver disease? Cirrhosis versus no cirrhosis Compensated versus decompensated Is treatment recommended? What drug? How long? How would you monitor the person during treatment? 131

132 Case study 5: Questions What is the stage of liver disease? Is treatment recommended? What is the treatment? What is the monitoring required? 132

133 Case study 5: Questions What is the stage of liver disease? APRI = [98/40] x 100/98 = ~2.5 APRI > 2.0 Liver cirrhosis (compensated) Is treatment recommended? What is the treatment? What is the monitoring required? 133

134 Case study 5: Questions What is the stage of liver disease? APRI = [98/40] x 100/98 = ~2.5 APRI > 2.0 Liver cirrhosis (compensated) Is treatment recommended? HBV DNA is detectable: Those with cirrhosis need treatment (irrespective of DNA level) What is the treatment? What is the monitoring required? 134

135 Case study 5: Questions What is the stage of liver disease? APRI = [98/40] x 100/98 = ~2.5 APRI > 2.0 Liver cirrhosis (compensated) Is treatment recommended? HBV DNA is detectable: Those with cirrhosis need treatment (irrespective of DNA level) What is the treatment? Entecavir 0.5 mg, once daily, oral, life-long What is the monitoring required? 135

136 Case study 5: Questions What is the stage of liver disease? APRI = [98/40] x 100/98 = ~2.5 APRI > 2.0 Liver cirrhosis (compensated) Is treatment recommended? HBV DNA is detectable: Those with cirrhosis need treatment (irrespective of DNA level) What is the treatment? Entecavir 0.5 mg, once daily, oral, life-long 136 What is the monitoring required? Monitor for efficacy, decompensation and liver cancer Lifelong

137 Case study 5: Take home messages Cirrhosis must be looked for in all HBsAg positive patients In patients with cirrhosis and detectable HBV DNA Antiviral drugs should be started (regardless of HBV DNA level) Serum ALT level has no role in deciding the need for treatment 137 In patients with cirrhosis, antiviral treatment Should be continued for life Entecavir is preferred over tenofovir (the latter has renal toxicity) Usual dose of entecavir is 0.5 mg/d even in compensated cirrhosis, but is 1.0 mg/d in decompensated cirrhosis

138 Case study 6 25 y old woman Detected HBsAg positive during blood donation screening Asymptomatic, good health No previous hospitalization, no morbidity, no addiction Examination: unremarkable What test should one order? 138

139 Case study 6: Test results Investigations Values Hemoglobin (g/dl) 12.8 Platelets (x 10 9 /L) 218 Total bilirubin (mg/dl) 0.8 Albumin (g/dl) 4.0 ALT (IU/L) AST (IU/L) 34 (<40 IU/L) 28 (<40 IU/L) Prothrombin time (INR) 1.1 HBV DNA (copies/ml) 8000 USG abdomen Normal liver size and echotexture Portal vein diameter = 10 mm Normal spleen; no ascites 139

140 Case study 6: Questions What is the stage of liver disease? Is treatment recommended? What is the treatment? What is the monitoring required? 140

141 Case study 6: Questions What is the stage of liver disease? APRI = [28/30] x 100/218 = ~0.4 APRI < 2.0 No cirrhosis Is treatment recommended? What is the treatment? What is the monitoring required? 141

142 Case study 6: Questions What is the stage of liver disease? APRI = [28/30] x 100/218 = ~0.4 APRI < 2.0 No cirrhosis Is treatment recommended? ALT normal HBV DNA = 8000 copies/ml = ~ 8000/5 or 1600 IU/mL What is the treatment? What is the monitoring required? 142

143 Case study 6: Questions What is the stage of liver disease? APRI = [28/30] x 100/218 = ~0.4 APRI < 2.0 No cirrhosis Is treatment recommended? ALT normal HBV DNA = 8000 copies/ml = ~ 8000/5 or 1600 IU/mL What is the treatment? No treatment (immune control phase) What is the monitoring required? 143