standard modules for hbv · hepatitis b vaccine contains a viral protein: ‘hbsag= hepatitis b...
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1 |World Health Organization
Western Pacific Region
Standard modules for HBVStandard modules for HBV
2 |World Health Organization
Western Pacific Region
HBV Module 1Hepatitis B serological markers
and virology
HBV Module 1Hepatitis B serological markers
and virology
3 |World Health Organization
Western Pacific Region
HAV HBV HCV HDV HEVAcute hepatitis
Case fatality increases with age
Case fatality increases with age
Uncommon Superinfection in HBV may lead to fulminant disease
Higher case fatality in pregnant women
Chronic infection
No 5% (adults)90% (children)
55‐85%Complicates hepatitis B
Very rare
HCC* No Yes Yes NoRoute of transmission
WaterborneFoodbornePerson‐to person
PerinatalBloodborneSexual
BloodbornePerinatalSexual
Bloodborne WaterborneFoodborne
Vaccine Yes Yes No HBV vaccine NoTreatment options
None Available Available Modified treatment of
HBV
None
Main hepatitis virusesMain hepatitis viruses
*HCC; hepatocellular carcinoma
4 |World Health Organization
Western Pacific Region
TECHNICAL CONSIDERATIONS AND CASE DEFINITIONS TO IMPROVE SURVEILLANCE FOR VIRAL HEPATITIS. (WHO 2016) P9
HBV HCVPersons 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 ● ●
Populations at higher risk for hepatitis B and CPopulations at higher risk for hepatitis B and C
5 |World Health Organization
Western Pacific RegionWHO guideline 2015
Who is at risk for chronic HBV infection ?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.
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Western Pacific Region
Who is at risk for chronic HBV infection ?Who is at risk for chronic HBV infection ?
WHO guideline 2015
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Western Pacific Region
Who to test for chronic HBV and HCV infectionWho 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
GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P38‐39
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Western Pacific Region
Who to test for chronic HBV infectionWho to test for chronic HBV infectionTesting approach and population Recommendations
General population testing
In settings with a ≥2% or ≥5% HBsAg seroprevalence,all adults have routine access to and be offered HBsAg serological testing
Routine testing in pregnant women
In settings with a ≥2% or ≥5% HBsAg seroprevalence, HBsAgserological testing be routinely offered to all pregnant women in antenatal clinics
Focused testing in most affected populations
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
Blood donors In all settings, screening of blood donors should be mandatory
GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P36
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Western Pacific Region
Initial assessment for chronic hepatitis B and CInitial assessment for chronic hepatitis B and C
HBV HCVChronic infection HBsAg Anti‐HCVAcute infection Anti‐HBc IgM HCV RNA, HCcAg etc.
(without anti‐HCV antibody, excluding other hepatitis viruses)
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Western Pacific Region
Additional assessment for chronic hepatitisAdditional assessment for chronic hepatitis
HBV HCVSerological markers
Anti‐HBs/anti‐HBc antibodiesHBe antigen, Anti‐HBe,
HBV DNA
HCV RNAHCV genotype
Severity Aminotransferase (AST/ALT)Bilirubin, albumin, alkaline phosphatase (ALP)
Staging Liver biopsyNon‐invasive tests
‐APRI, FIB‐4, FibroTest, Transietn elastography
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Western Pacific Region
Serological pattern of chronic HBV infectionSerological pattern of chronic HBV infection
GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P22
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Western Pacific Region
How to test for chronic HBV infectionHow to test for chronic HBV infection(A) Single assay
(HBs seroprevalence ≥0.4%)
(B) Two assays(HBs seroprevalence <0.4%)
GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P53
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Western Pacific Region
HBV Module 2Hepatitis B transmission and
prevention
HBV Module 2Hepatitis B transmission and
prevention
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Western Pacific Region
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
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Western Pacific Region
HBV infection and age at acquisitionHBV 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)
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Prevention of HBV infectionPrevention of HBV infectionVaccination*
Childhood vaccination• Primary 3-dose vaccination• Timely birth dose
High risk groups Catch‐up programs
Other measures Screening of blood and blood products Injection safety Occupational safety Harm reduction interventions Safe sex
* Is the key intervention to prevent chronic HBV infection(occurs following infection during infancy and childhood)
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Infant and neonatal hepatitis B vaccinationInfant 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.
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Western Pacific Region
Hepatitis B vaccineHepatitis 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
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Stability and storage Stability and storage
Hepatitis B vaccines
Storage at 2‐8°C
Relatively heat stable – remains effective even after several days at room temperature
However, very sensitive to freezing
Avoid freezing at all costs
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Western Pacific Region
Dose Protection
1 16%‐40%2 80%‐95%3 98%‐100%
Protection* in Infants by HBV Vaccination DoseProtection* in Infants by HBV Vaccination Dose
* Protection defined as anti‐HBs antibody titer of 10 mIU/mL or higherNote: Preterm infants less than 2 kg respond to vaccination less often
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Western Pacific Region
Hepatitis B vaccine response ratesHepatitis 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%
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Vaccine non‐respondersVaccine 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
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Western Pacific Region
Global health sector strategy on hepatitisTargets Interventions 2020 target 2030 target
1. Service coverage
1. Hep B3 vaccine 90% 90%
2. HBV PMTCT 50% 90%
3. Blood and injection safety95 % screened donations 100 % screened donations
50% RUP devices 90% RUP devices
4. Harm reduction 200 injection sets / PWID 300 injection sets / PWID
5. Treatment30% diagnosed 90% diagnosed
5M and 3M treated for HBV and HCV 80% eligible treated
2. ImpactA. Incidence ‐30%
(1% HBsAg in children )‐90%
(0.1% HBsAg in children)
B. Mortality ‐10% ‐65%
PMTCT: Prevention of mother to child transmissionPWID: Person who injects drugs
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Western Pacific Region
0
10
20
30
40
50
60
70
80
90
100
1990 1995 2000 2005 2010 2015
Coverage (%
)
Year
AfricanAmericanEastern MediterraneanEuropeanSouth East AsiaWestern PacificGlobal
Source: WHO AND UNICEF Joint Reporting
Immunization coverage with 3‐dose schedule of hepatitis B vaccine in infants in 2015
Immunization coverage with 3‐dose schedule of hepatitis B vaccine in infants in 2015
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Western Pacific Region
0
10
20
30
40
50
60
70
80
90
2000 2005 2010 2015
Coverage (%
)
Year
African
American
Western Pacific
Global
Source: WHO AND UNICEF Joint Reporting
Immunization CoverageImmunization Coverage
26 |World Health Organization
Western Pacific RegionEric Wiesen et al,Vaccine 2016WPRO
Regional vaccination coverageRegional vaccination coverage
Hepatitis B vaccine 3rd doseHepatitis B vaccine birth dose
Chronic infections
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Western Pacific Region
Catch‐up hepatitis B vaccination strategiesCatch‐up hepatitis B vaccination strategies All children and adolescents younger than 18 years‐
old 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.
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Western Pacific Region
HBV Module 3Natural history of Hepatitis B
HBV Module 3Natural history of Hepatitis B
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Consequences of HBV infectionConsequences of HBV infectionHepatitis B virus infection
Acute infection(short duration: <6 mo)
Chronic infection(duration >6 mo)
Asymptomatic
Acute viral hepatitis
Acute liver failure
Chronic hepatitis B
Cirrhosis: compensated
Cirrhosis: decompensated
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Fulminant hepatitis
Rare, but to take care
40‐100%Death
*: IgM anti‐HBc(+) can distinguish acute infection from chronic infection
3‐5% (10% in Gt. A) in adults70‐95% in children
next slide
Acute HBV infectionHBsAg (+)
IgM anti‐HBc (+)HBV DNA(+), HBeAg(+/‐), Anti‐HBs(‐)
95% in adults5‐30% in children
Infection persistentHBsAg (+), Anti‐HBs (‐)
IgM anti‐HBc(‐), Anti‐HBc(+)HBV‐DNA(+), HBeAg(+/‐)
Infection resolvedHBsAg (‐), Anti‐HBs (+)
IgM anti‐HBc(‐), Anti‐HBc (+), HBV DNA(‐), HBeAg(‐)
*: Anti‐HBs (+) can distinguish resolved state from chronic infection
Natural history of HBV infection (Acute phase)Natural history of HBV infection (Acute phase)
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Serological pattern of acute HBV infectionSerological pattern of acute HBV infection
GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P22
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Infection persistent
HBe(+) chronic hepatitis HBsAg (+), Anti‐HBc (+)
HBeAg (+), HBV DNA highALT high
HBe(‐) chronic hepatitis HBsAg (+), Anti‐HBc (+)
HBeAg (‐), HBV DNA low(‐high)ALT normal‐high
Inactive carrierHBsAg (+), Anti‐HBc (+)
HBeAg (‐), HBV DNA (‐)‐lowALT normal
Liver cirrhosis
Liver failureLiver cancer
Death
Clinical clearanceHBsAg (‐), Anti‐HBs (‐)
Anti‐HBc (+), HBV DNA (‐)ALT normal
Natural history of HBV infection (chronic phase)Natural history of HBV infection (chronic phase)
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Natural history of chronic hepatitis BNatural history of chronic hepatitis B
Chronic hepatitis B
Immune‐tolerant phase
Immune‐active phase
Immune‐control phase
Reactivation phase
Immune clearance (cure)
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Natural history of chronic hepatitis BNatural history of chronic hepatitis B
Chronic hepatitis B
Immune‐tolerant phase
Immune‐active phase
Immune‐control phase
Reactivation phase
Immune clearance (cure)
Phases that need anti‐viral drug treatment
Phases that DO NOT need anti‐viral drug treatment
Cirrhosis with any of the phases
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Infection persistent
HBe(+) chronic hepatitis HBsAg (+), Anti‐HBc (+)
HBeAg (+), HBV DNA highALT high
HBe(‐) chronic hepatitis HBsAg (+), Anti‐HBc (+)
HBeAg (‐), HBV DNA low(‐high)ALT normal‐high
Inactive carrierHBsAg (+), Anti‐HBc (+)
HBeAg (‐), HBV DNA (‐)‐lowALT normal
Liver cirrhosis
Liver failureLiver cancer
Death
Clinical clearanceHBsAg (‐), Anti‐HBs (‐)
Anti‐HBc (+), HBV DNA (‐)ALT normal
Natural history of HBV infection (chronic phase)Natural history of HBV infection (chronic phase)
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Serological pattern of chronic HBV infectionSerological pattern of chronic HBV infection
GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P22
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Atypical clinical course of HBV infectionAtypical 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
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HBV Module 4Assessment of liver fibrosis
HBV Module 4Assessment of liver fibrosis
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Fibroscan®(http.myliverexam.com/en/lexamen‐fibroscan.html)
AST; aspartate aminotransferase ALT; alanine aminotransferaseAPRI; aspartate aminotransferase‐to‐platelet ratio indexFIB‐4; fibrosis‐4 score
Assessing the degree of liver fibrosisAssessing the degree of liver fibrosis Non‐invasive tests
Components Requirements Cost
APRI AST, platelets Simple serum andhematology test +
FIB‐4 Age, AST, ALT, Platelets
FibroTest gGT, haptoglobin, bilirubin,A1apoprotein, α2‐macroglobulin
Specialized tests atdesigned laboratories ++
Fibroscan ® Transient elastography Dedicated equipment +++
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)
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Assessing the degree of liver fibrosis by NITsAssessing the degree of liver fibrosis by NITs
APRI = [ (AST(IU/L)/ AST_ULN(IU/L)) x 100 ] / platelet count (109/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(109/L) x [ALT(IU/L)1/2]
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 1.5FIB‐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
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)
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Transient elastography (Fibroscan)Transient elastography (Fibroscan)
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Transient elastography (Fibroscan)Transient elastography (Fibroscan)
Transducer sends a mechanical shearwave
Large explored volume(at least 100 times more than biopsy)
Monitor display of Fibroscan
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Transient elastography (Fibroscan)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
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FibroscanFibroscan
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
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Western Pacific Region
The Child‐Turcotte‐Pugh Classification systemThe Child‐Turcotte‐Pugh Classification systemPoints 1 2 3
Encephalopathy None Minimal(grade1 or 2)
Advanced(grade 3 or 4)
Ascites Absent Controlled Refractory
Total bilirubin(μmol/L)(mg/dL)
<34 (<2) 34‐51 (2‐3) >51 (>3)
Albumin(g/dL) >3.5 2.8‐3.5 <2.8
Prothrombin time (seconds) or PT‐INR*
<4 or <1.7 4‐6 or 1.7‐2.3 >6 or >2.3
Child‐Pugh Class A: 5‐6 pointsChild‐Pugh Class B: 7‐9 pointsChild‐Pugh Class C: 10‐15 points
*PT‐INR ; prothrombin time international normalized ratio
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HBV Module 5Treatment for Chronic Hepatitis B
HBV Module 5Treatment for Chronic Hepatitis B
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WHO guidelinesWHO guidelinesAssessment for treatment
Monitoring
Stopping treatment
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Initial assessment for hepatitis B and CInitial assessment for hepatitis B and C
HBV HCVChronic infection HBsAg Anti‐HCVAcute infection Anti‐HBc IgM HCV RNA, HCcAg etc.
(without anti‐HCV antibody, excluding other hepatitis viruses)
MONITORING AND EVALUATION FOR VIRAL HEPATITIS B AND C: RECOMMENDED INDICATORS AND FRAMEWORK (WHO 2016)
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Additional assessment for chronic hepatitisAdditional assessment for chronic hepatitis
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P17‐19
HBV HCVSerological markers
Anti‐HBs/anti‐HBc antibodiesHBe antigen, Anti‐HBe,
HBV DNA
HCV RNA
Severity Aminotransferase (AST/ALT)Bilirubin, albumin, alkaline phosphatase (ALP)
Staging Liver biopsyNon‐invasive tests
‐APRI, FIB‐4, FibroTest, Transietn elastography
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Why should we treat HBV infectionWhy 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
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)
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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
Clinical management of HBV infectionClinical management of HBV infection
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Which patients should we treat for HBVWhich patients should we treat for HBV
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P36‐37
Optimal timing of treatment for HBV is still debated.
HBV HCV• 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
• All patients
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Populaiton
HBsAg‐
Non cirrhotic patients aged <30
Normal(<19 F, <30 M)
<2,000
Treatment Deferred
HBsAg+
Non cirrhotic patients aged >30
Fluctuating
2,000‐20,000
Treatment Deferred
Cirrhotic patients or APRI >2
Persistently elevated
>20,000
Treatment Deferred
Treatment Deferred
Treatment Deferred
Treatment Recommended
Treatment Recommended
CIRRHOSIS
No Treatment Required
Summary of WHO Recommendation Summary of WHO Recommendation ALT HBV DNAHBsAg
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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
Clinical management of HBV infectionClinical management of HBV infection
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How to treat HBV infectionHow 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
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)
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Antiviral agents for HBVAntiviral agents for HBVAntiviral agent Potency against
HBV Resistance barrier Antivity against HIV Cost
Interferons Moderate Not applicable Moderate High
Tenofovir High High HighLow (high in HongKong 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
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P21
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WHO recommendation: choice of drugWHO recommendation: choice of drug
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)
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
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Drug doseDrug dose Adults Entecavir 0.5 mg/day oral
Tenofovir 300 mg/day oral
Children need dose modification
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Drugs need dose adjustment in renal diseaseDrugs need dose adjustment in renal disease
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Duration of treatmentDuration 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
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HBV Module 6Monitoring for Chronic Hepatitis B
HBV Module 6Monitoring for Chronic Hepatitis B
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Need for monitoringNeed for monitoring
All need monitoring (irrespective of need for treatment)
HBsAg +ve
Defertreatment
Notreatment
Starttreatment
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Who should we monitor and whyWho 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
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P64
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How to monitor?How to monitor?
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How to monitor?How to monitor?
At least annually: ALTHBsAg, HBeAg, HBV DNA levelAPRIAdherence to treatmentDrug adverse events (renal function)
More frequent In those who do not clearly meet criteria for treatment Following treatment discontinuation
Surveillance for hepatocellular cancer
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How to monitor HBV infected patientsHow to monitor HBV infected patients: every 12 mos
Disease progression/ treatment response
: every 12 monthsMonitoring for
treatment toxicities
: every 6 monthsDetection of liver cancer(cirrhosis / family history)
Adherence Renal function Ultrasound
ALT, HBV DNA, HBeAg Risk factors for renal dysfunction α‐fetoprotein
Non‐invasive test
Baseline 6month 12month 18month 24month…
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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
Clinical management of HCV infectionClinical management of HCV infection
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When to stop treatment of HBVWhen 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)
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P64
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HBVPractical session
case‐based learning
HBVPractical session
case‐based learning
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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 1Case study 1
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What test do you order?
• HBV DNA 2.8 x108 IU/mL, HIV rapid diagnostic test negative
• Hb 11.8 g/dL, Neutrophil 2.5 x109/L, PLT 98 x109/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?
What monitoring do you require?
Case study 1Case study 1
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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
• 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)
Case study 1Case study 1
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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 2Case study 2
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What test do you order?
• HBV DNA 1.7 x108 IU/mL
• Hb 9.8 g/dL, Neutrophil 2.8 x109/L, PLT 188 x109/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 2Case study 2
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Western Pacific Region
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 2Case study 2
76 |World Health Organization
Western Pacific Region
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 3Case study 3
77 |World Health Organization
Western Pacific Region
What test do you order?
• HBV DNA 1.2 x108 IU/mL
• Neutrophil 3.0 x109/L, PLT 218 x109/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
What is the stage of liver disease?
Is treatment recommended?
What monitoring do you require?
Case study 3Case study 3
78 |World Health Organization
Western Pacific Region
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
What monitoring do you require?
• Monitor for efficacy and toxicity (baseline and every 12 month)
Case study 3Case study 3
79 |World Health Organization
Western Pacific Region
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 x109/L, PLT 282 x109/L
• AST 112 U/L (ULN 30), ALT 120 U/L, HBsAg positive
Clinical Question
What test do you order?
Case study 4Case study 4
80 |World Health Organization
Western Pacific Region
What test do you order?
• HBV DNA 3.5 x108 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?
What monitoring do you require?
Case study 4Case study 4
81 |World Health Organization
Western Pacific Region
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
• Assist for treatment: alcohol sobriety, drug abstinence
What monitoring do you require?
• Monitor for efficacy and toxicity (baseline and every 12 month)
Case study 4Case study 4
82 |World Health Organization
Western Pacific Region
Case study 5Case 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?
83 |World Health Organization
Western Pacific Region
Investigations ValuesHemoglobin (g/dL) 11.8Platelets (x 109/L) 98Total bilirubin (mg/dL) 1.2Albumin (g/dL) 3.4ALT (IU/L)AST (IU/L)
66 (<40 IU/L)98 (<40 IU/L)
Prothrombin time (INR) 1.6HBV DNA (IU/L) 1,120USG abdomen Coarse echo‐texture of liver
Portal vein diameter = 14 mmSplenomegaly, no ascites
Case study 5: Test resultsCase study 5: Test results
84 |World Health Organization
Western Pacific Region
Case study 5: Issues in managementCase 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?
85 |World Health Organization
Western Pacific Region
Case study 5: QuestionsCase study 5: Questions
What is the stage of liver disease?
Is treatment recommended?
What is the treatment?
What is the monitoring required?
86 |World Health Organization
Western Pacific Region
Case study 5: QuestionsCase 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?
87 |World Health Organization
Western Pacific Region
Case study 5: QuestionsCase 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?
88 |World Health Organization
Western Pacific Region
Case study 5: QuestionsCase 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?
89 |World Health Organization
Western Pacific Region
Case study 5: QuestionsCase 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?– Monitor for efficacy, decompensation and liver cancer Lifelong
90 |World Health Organization
Western Pacific Region
Case study 5: Take home messagesCase 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 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
91 |World Health Organization
Western Pacific Region
Case study 6Case 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?
92 |World Health Organization
Western Pacific Region
Investigations ValuesHemoglobin (g/dL) 12.8Platelets (x 109/L) 218Total bilirubin (mg/dL) 0.8Albumin (g/dL) 4.0ALT (IU/L)AST (IU/L)
34 (<40 IU/L)28 (<40 IU/L)
Prothrombin time (INR) 1.1HBV DNA (copies/ml) 8000USG abdomen Normal liver size and echotexture
Portal vein diameter = 10 mmNormal spleen; no ascites
Case study 6: Test resultsCase study 6: Test results
93 |World Health Organization
Western Pacific Region
Case study 6: QuestionsCase study 6: Questions
What is the stage of liver disease?
–
Is treatment recommended?
What is the treatment?
What is the monitoring required?
94 |World Health Organization
Western Pacific Region
Case study 6: QuestionsCase 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?
95 |World Health Organization
Western Pacific Region
Case study 6: QuestionsCase 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?
96 |World Health Organization
Western Pacific Region
Case study 6: QuestionsCase 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?
97 |World Health Organization
Western Pacific Region
Case study 6: QuestionsCase 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?– Monitor for disease activity and liver cancer
98 |World Health Organization
Western Pacific Region
Case study 6: Take home messagesCase 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)
99 |World Health Organization
Western Pacific Region
Case study 7Case 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?
100 |World Health Organization
Western Pacific Region
Investigations ValuesHemoglobin (g/dL) 10.8Platelets (x 109/L) 255Total bilirubin (mg/dL) 1.2Albumin (g/dL) 3.8ALT (IU/L)AST (IU/L)
76 (<40 IU/L)56 (<40 IU/L)
Prothrombin time (INR) 1.2HBV DNA (IU/ml) 123,000USG abdomen Normal liver size and echotexture
Portal vein diameter = 10 mmNormal spleen; no ascites
Case study 7: Test resultsCase study 7: Test results
101 |World Health Organization
Western Pacific Region
Investigations ValuesHemoglobin 10.8 g/dLPlatelets 255 x 109/L
Total bilirubin 1.2 mg/dLAlbumin 3.8 g/dLALTAST
76 IU/L (<30 IU/L)56
Prothrombin time INR 1.2HBV DNA quantitative 123,000 IU/mLUSG abdomen • Normal size liver
• Portal vein diameter 10 mm• No splenomegaly or ascites
What test would you order?
Case study 7Case study 7
102 |World Health Organization
Western Pacific Region
Case study 7: QuestionsCase study 7: Questions
What is the stage of liver disease?
–
Is treatment recommended?
What is the treatment?
What is the monitoring required?
103 |World Health Organization
Western Pacific Region
Case study 7: QuestionsCase 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?
104 |World Health Organization
Western Pacific Region
Case study 7: QuestionsCase 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?
105 |World Health Organization
Western Pacific Region
Case study 7: QuestionsCase 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?– Tenofovir, 300 mg, once daily, oral
What is the monitoring required?
106 |World Health Organization
Western Pacific Region
Case study 7: QuestionsCase 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?– Tenofovir, 300 mg, once daily, oral
What is the monitoring required?– Monitor for response, drug toxicity and liver cancer
107 |World Health Organization
Western Pacific Region
Take home messages: Case study 7Take 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