World Health Organization. Western Pacific Region

Standard modules for HBV 1

HBV Module 1 Hepatitis B serological markers and virology 2

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

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

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

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

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

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

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

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

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

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

HBV Module 2 Hepatitis B transmission and prevention 13

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

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

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

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

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

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

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

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 40 49 years >90% 50 59 years >80% 21

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

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

Immunization coverage with 3 dose schedule of hepatitis B vaccine in infants in 2015 Coverage (%) 100 90 80 70 60 50 40 African American Eastern Mediterranean European South East Asia Western Pacific Global 30 20 10 24 0 1990 1995 2000 2005 2010 2015 Year Source: WHO AND UNICEF Joint Reporting

Immunization Coverage Coverage (%) 90 80 70 60 50 40 African American Western Pacific Global 30 20 10 0 2000 2005 2010 2015 Year 25 Source: WHO AND UNICEF Joint Reporting

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

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

HBV Module 3 Natural history of Hepatitis B 28

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

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 40 100% Death 30

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

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

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

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

Serological pattern of chronic HBV infection 36 GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P22

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 37

HBV Module 4 Assessment of liver fibrosis 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) + ++ 39 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)

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, F4 0.32 0.48 0.58 0.75 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 ] 40 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)

Transient elastography (Fibroscan) 41

Transient elastography (Fibroscan) Transducer sends a mechanical shearwave Monitor display of Fibroscan Large explored volume (at least 100 times more than biopsy) 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 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 44

The Child Turcotte Pugh Classification system Points 1 2 3 Encephalopathy None Minimal (grade1 or 2) Advanced (grade 3 or 4) Ascites Absent Controlled Refractory Total bilirubin <34 (<2) 34 51 (2 3) >51 (>3) (μmol/l)(mg/dl) Albumin(g/dL) >3.5 2.8 3.5 <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: 10 15 points <4 or <1.7 4 6 or 1.7 2.3 >6 or >2.3 *PT INR ; prothrombin time international normalized ratio 45

HBV Module 5 Treatment for Chronic Hepatitis B 46

WHO guidelines Assessment for treatment Monitoring Stopping treatment 47

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) 48 MONITORING AND EVALUATION FOR VIRAL HEPATITIS B AND C: RECOMMENDED INDICATORS AND FRAMEWORK (WHO 2016)

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 49 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P17 19

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 50 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)

Clinical management of HBV infection 1. Natural history of HBV infection 2. Clinical assessment of persons with chronic hepatitis B 3. Why to treat for HBV 4. Who to treat for HBV 5. How to treat for HBV 6. How to monitor during treatment for HBV 7. When to stop treatment for HBV 51

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. 52 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P36 37

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 53

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 55 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)

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 56 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P21

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 57 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)

Drug dose Adults Entecavir 0.5 mg/day oral Tenofovir 300 mg/day oral Children need dose modification 58

Drugs need dose adjustment in renal disease 59

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 60

HBV Module 6 Monitoring for Chronic Hepatitis B 61

Need for monitoring HBsAg +ve No treatment Defer treatment Start treatment All need monitoring (irrespective of need for treatment) 62

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 63 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P64

How to monitor? 64

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 65

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 66

Clinical management of HCV infection 1. Natural history of HBV infection 2. Clinical assessment of persons with chronic hepatitis B 3. Why to treat for HBV 4. Who to treat for HBV 5. How to treat for HBV 6. How to monitor during treatment for HBV 7. When to stop treatment for HBV 67

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) 68 GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P64

HBV Practical session case based learning 69

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 70

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? 71

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) 72

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 73

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 74

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 75

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 76

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? 77

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) 78

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 79

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? 80

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) 81

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? 82

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 83

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? 84

Case study 5: Questions What is the stage of liver disease? Is treatment recommended? What is the treatment? What is the monitoring required? 85

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? 86

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? 87

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 In patients with cirrhosis, antiviral treatment 90 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

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? 91

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 92

Case study 6: Questions What is the stage of liver disease? Is treatment recommended? What is the treatment? What is the monitoring required? 93

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? 94

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? 95

Case study 6: Take home messages In young patients without cirrhosis: No need for treatment, unless ALT as well as HBV DNA are high However, all patients need periodic monitoring or disease activity and for HCC HBV DNA levels should be expressed as IU/mL (if reported as copies/ml, convert before interpretation) 98

Case study 7 38 y old woman Incidentally detected HBsAg positive during treatment for primary infertility No previous hospitalization, other disease or addiction Examination: normal What tests should one order? 99

Case study 7: Test results Investigations Values Hemoglobin (g/dl) 10.8 Platelets (x 10 9 /L) 255 Total bilirubin (mg/dl) 1.2 Albumin (g/dl) 3.8 ALT (IU/L) AST (IU/L) 76 (<40 IU/L) 56 (<40 IU/L) Prothrombin time (INR) 1.2 HBV DNA (IU/ml) 123,000 USG abdomen Normal liver size and echotexture Portal vein diameter = 10 mm Normal spleen; no ascites 100

What test would you order? Case study 7 101 Investigations Values Hemoglobin 10.8 g/dl Platelets 255 x 10 9/L Total bilirubin 1.2 mg/dl Albumin 3.8 g/dl ALT AST 76 IU/L (<30 IU/L) 56 Prothrombin time INR 1.2 HBV DNA quantitative 123,000 IU/mL USG abdomen Normal size liver Portal vein diameter 10 mm No splenomegaly or ascites

Case study 7: Questions What is the stage of liver disease? Is treatment recommended? What is the treatment? What is the monitoring required? 102

Case study 7: Questions What is the stage of liver disease? APRI = [56/40] x 100/255 = ~0.6 APRI < 0.6 No cirrhosis Is treatment recommended? What is the treatment? What is the monitoring required? 103

Case study 7: Questions What is the stage of liver disease? APRI = [56/40] x 100/255 = ~0.6 APRI < 0.6 No cirrhosis Is treatment recommended? ALT high HBV DNA = 123,000 IU/mL (>20,000 IU/mL) What is the treatment? What is the monitoring required? 104

Take home messages: Case study 7 Patients with HBV infection, who have high ALT and high HBV DNA need treatment with antiviral drugs In absence of cirrhosis, either tenofovir or entecavir may be used, tenofovir is the preferred drug Such patients need periodic monitoring for drug response, toxicity and HCC 107