1 | World Health Organization Western Pacific Region Advanced modules for HBV Advanced modules for HBV
1 |World Health Organization
Western Pacific Region
Advanced modules for HBVAdvanced 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.
6 |World Health Organization
Western Pacific Region
Who is at risk for chronic HBV infection ?Who is at risk for chronic HBV infection ?
WHO guideline 2015
7 |World Health Organization
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
8 |World Health Organization
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
9 |World Health Organization
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)
10 |World Health Organization
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
11 |World Health Organization
Western Pacific Region
Serological pattern of chronic HBV infectionSerological pattern of chronic HBV infection
GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P22
12 |World Health Organization
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
13 |World Health Organization
Western Pacific Region
HBV Module 2Hepatitis B transmission and
prevention
HBV Module 2Hepatitis B transmission and
prevention
14 |World Health Organization
Western Pacific Region
Transmission routes of HBVTransmission 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
15 |World Health Organization
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)
16 |World Health Organization
Western Pacific Region
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)
17 |World Health Organization
Western Pacific Region
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.
18 |World Health Organization
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
19 |World Health Organization
Western Pacific Region
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
20 |World Health Organization
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
21 |World Health Organization
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%
22 |World Health Organization
Western Pacific Region
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
23 |World Health Organization
Western Pacific Region
Global health sector strategy on hepatitisGlobal 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
24 |World Health Organization
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
25 |World Health Organization
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
27 |World Health Organization
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.
28 |World Health Organization
Western Pacific Region
HBV Module 3Natural history of Hepatitis B
HBV Module 3Natural history of Hepatitis B
29 |World Health Organization
Western Pacific Region
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
30 |World Health Organization
Western Pacific Region
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)
31 |World Health Organization
Western Pacific Region
Serological pattern of acute HBV infectionSerological pattern of acute HBV infection
GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P22
32 |World Health Organization
Western Pacific Region
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)
33 |World Health Organization
Western Pacific Region
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)
34 |World Health Organization
Western Pacific Region
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
35 |World Health Organization
Western Pacific Region
Serological pattern of chronic HBV infectionSerological pattern of chronic HBV infection
GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P22
36 |World Health Organization
Western Pacific Region
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
37 |World Health Organization
Western Pacific Region
HBV Module 4Assessment of liver fibrosis
HBV Module 4Assessment of liver fibrosis
38 |World Health Organization
Western Pacific Region
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)
39 |World Health Organization
Western Pacific Region
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)
40 |World Health Organization
Western Pacific Region
Transient elastography (Fibroscan)Transient elastography (Fibroscan)
41 |World Health Organization
Western Pacific Region
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
42 |World Health Organization
Western Pacific Region
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
43 |World Health Organization
Western Pacific Region
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
44 |World Health Organization
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
45 |World Health Organization
Western Pacific Region
HBV Module 5Treatment for Chronic Hepatitis B
HBV Module 5Treatment for Chronic Hepatitis B
46 |World Health Organization
Western Pacific Region
47 |World Health Organization
Western Pacific Region
Other international treatment Guidelines 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
48 |World Health Organization
Western Pacific Region
WHO guidelinesWHO guidelinesAssessment for treatment
Monitoring
Stopping treatment
49 |World Health Organization
Western Pacific Region
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)
50 |World Health Organization
Western Pacific Region
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
51 |World Health Organization
Western Pacific Region
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)
52 |World Health Organization
Western Pacific Region
Sustained ALT normalization
Sustained undetectable HBV DNA
HBeAg seroconversion
HBsAg seroconversion
HBsAg seroconversion and development of HBsAb = “functional
cure” .. uncommon
Resulting in …
Effects of antiviral therapyEffects of antiviral therapy
1. Lim YS, et al. Gastroenterology. 2014;147:152-161.2. Chang TT, et al. Hepatology. 2010;51:422-430. 3. Zoutendijk R, et al. Gut. 2013;62:760-765. 4. Marcellin P, et al. Lancet. 2013;381:468-475. 5. Papatheodoridis GV, et al. J Hepatol. 2015;62:363-370. 6. Papatheodoridis GV, et al. Hepatol. 2016;63:1481-1492.
53 |World Health Organization
Western Pacific Region
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
Effects of antiviral therapyEffects of antiviral therapy
Fibrosis
Reversal after antiviral
54 |World Health Organization
Western Pacific Region
Cure as a Goal of TherapyCure as a Goal of Therapy
Cure not so simple . . . reasons lie in the virology
Actual cureTrue cure = all traces of HBV gone from the liver (like HCV)VERY difficult due to presence of HBV cccDNA
Functional cureUse 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)
55 |World Health Organization
Western Pacific Region
Why Is Cure Rare With Nucleos(t)ide Therapy?Why Is Cure Rare With Nucleos(t)ide Therapy?
Grimm D, et al. Hepatol Int. 2011;5:644-653.
O-
5’Cap (A)n 3’
Translocation
dAdAdGnew (-) strand DNA synthesis
pgRNA
DNA synthesis
Encapsidationof pg RNA
HBeAg
Polymeraseprotein
Core protein
Envelope proteins
S, M, L
Golgi complex
ReleaseHBsAg
HBeAg
HBV virion
HBV RNAtranscripts
PregenomicRNA
cccDNADNArepair
Transport to cellnucleus
Attachment andpenetration
Uncoating
Oral anti-HBV therapy
56 |World Health Organization
Western Pacific Region
REVEAL: HBV DNA Level andRisk of Cirrhosis
REVEAL: HBV DNA Level andRisk of Cirrhosis
Iloeje UH, et al. Gastroenterology. 2006;130:678-686.
Follow-up (Yrs)
0.4
0.3
0.2
0.1
00 1 2 3 4 5 6 7 8 9 10 11 12 13
Baseline HBV DNA Level (copies/mL)≥ 1 million 100,000-999,99910,000-99,999300-9999< 300
Cum
ulat
ive
Inci
denc
e of
Liv
er C
irrho
sis
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)
57 |World Health Organization
Western Pacific Region
REVEAL: HBV DNA Level and Risk of HCCREVEAL: HBV DNA Level and Risk of HCC• Prospective study in same REVEAL cohort (N = 3653)
• Increased HCC incidence with increasing DNA levels (P < .001)• HCC can occur in the absence of cirrhosis
Chen CJ, et al. JAMA. 2006;295:65-73.
Follow-up (Yrs)
Cum
ulat
ive
Inci
denc
e of
HC
C (%
)
6
4
2
00 1 2 3 4 5 6 7 8 9 10 11 12 13
Baseline HBV DNA (copies/mL)≥ 1 million 100,000-999,99910,000-99,999300-9999< 300
12
10
8
58 |World Health Organization
Western Pacific Region
Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.
HBV Treatment Reduces Risk of Disease Progression Including DecompensationHBV Treatment Reduces Risk of Disease Progression Including Decompensation
*Hepatic decompensation, HCC, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease.
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*
P = .001
25
20
15
10
5
030181260 36
n = 198
n = 173
n = 417 n = 385
n = 122
24
Lamivudine
Placebo
MosPts
With
Dis
ease
Pro
gres
sion
(%)
59 |World Health Organization
Western Pacific Region
HCC Incidence in Pts with Chronic HBV Infection and Cirrhosis
HCC Incidence in Pts with Chronic HBV Infection and Cirrhosis
1. Wong GL, et al. Hepatology. 2013;5:1537-1547.2. Wu CY, et al. Gastroenterology. 2014;147:143-151.3. Hosaka T, et al. Hepatology. 2013;58:98-107.
2.8
482 69
5.3
3.9
4.9
3016 2847
1.4
7.8
79 85
aHR: 0.72(95% CI: 0.64-0.81)
aHR: 0.55(95% CI: 0.31-0.99) Nucleos(t)ide
analoguesControl
0
2
4
6
8
n =
Hong Kong[1] Taiwan[2] Japan[3]
Ann
ual I
ncid
ence
of H
CC
60 |World Health Organization
Western Pacific Region
HBV Treatment Reduces Risk of Liver Transplant
HBV Treatment Reduces Risk of Liver Transplant
Jang JW, et al. Hepatology. 2015;61:1809-1820.
Prospective cohort study in pts with HBV and first-onset complications of decompensated cirrhosis (N = 707)
Treated,* responder (n = 245)Treated,* nonresponder (n = 178)Untreated (n = 284)
Bonferroni-adjusted P < .0003LT-F
ree
Surv
ival
(%)
Mos0 8412 24 36 48 60 72
100
80
60
40
20
0
*Treated predominantly with lamivudine (n = 203) or entecavir (n = 198).
Antiviral therapy improved transplant-free survival over 5 yrs (P = .0098 vs untreated)
61 |World Health Organization
Western Pacific Region
Marcellin P, et al. Lancet. 2013;381:468-475.
Long‐term TDF in Pts With HBV: Regression of Fibrosis, CirrhosisLong‐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)
62 |World Health Organization
Western Pacific Region
Reduction in HCC Mortality Through National Viral Hepatitis Therapy Program
Reduction in HCC Mortality Through National Viral Hepatitis Therapy Program
Chiang CJ, et al. Hepatology. 2015;61:1154-1162.
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
30-39 40-49 50-59 60-69
0.98
0.8
0.6
0.4
0.2
0
Sex-
Adj
uste
d H
CC
M
orta
lity
Rat
e R
atio
0.93*
0.79†
1.00.88*
0.66†
0.92*
0.76† 0.77†
2004-20072008-2011
Age Group (Yrs)*P < .01 vs 2000-2003.†P < .005 vs 2000-2003.
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Western Pacific Region
5‐Year Follow‐Up Study: CHB patients on Tenofovir DF
5‐Year Follow‐Up Study: CHB patients on Tenofovir DF
• 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.
0
20
40
60
80
100
Patie
nts
(%)
88%92%
Normalization
ALT
5-Year Outcomes
83%
AST2%
HBV DNASuppression
NewCirrhosis
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 |World Health Organization
Western Pacific Region
Long‐term TDF in Pts With HBV: Reversal of Inflammation
Long‐term TDF in Pts With HBV: Reversal of Inflammation
Parameter Outcome at 7 Yrs[1]
Normalized ALT, % (n/N) ITT* On-treatment
57.1 (323/566)80.0 (328/410)
HBV DNA < 29 IU/mL,% (n/N) ITT On-treatment
70.1 (418/596)99.3 (430/433)
HBeAg loss,† % (n/N) 54.5 (84/154)
HBe seroconversion,†% (n/N) 39.6 (61/154)
HBsAg loss,† K-M % (95% CI) 11.8 (8.1, 16.9)
HBs seroconversion,†K-M % (95% CI) 9.7 (6.4, 14.6)
Open-label study of TDF in pts with chronic HBV infection (N = 585)
Necroinflammation improved over 5 yrs(n = 348 matched biopsies)[2]
†HBeAg-positive population. 1. Buti, M et al. Dig Dis ci. 2015;60:1457.2. Marcellin P, et al. Lancet. 2013;381:468-475. 2.
Pts
(%)
P < .001P < .001
80%
Knodell Necroinflammatory Score
8%
100
80
60
40
20
0Baseline Yr 1 Yr 5
10-14 7-9 4-6 0-3
65 |World Health Organization
Western Pacific Region
Cho JY, et al. Gut. 2014;63:1943-1950.
Is HBV Suppression the Same as Inactive Disease?
Is HBV Suppression the Same as Inactive Disease?
Complete responders
Inactive CHB
P < .001
Cum
ulat
ive
Inci
denc
e of
HC
C (%
)
Mos
60
50
40
30
20
10
00 12 24 36 48 60 72
Pts at Risk, nNUC CRInactive CHB
11321014
848918
564724
497594
380469
128304
1980
Retrospective cohort study of treatment-naive pts with HBV starting oral nucleos(t)ide analogues (n = 1378) vs HBeAg-negative pts with inactive CHB (n = 1014) Group receiving
nucleos(t)ide analogues divided by continuous viral suppression (complete vsincomplete responder)
Spontaneous control better than treatment
66 |World Health Organization
Western Pacific Region
Who Should Be Treated?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
67 |World Health Organization
Western Pacific Region
All Patients with cirrhosis should be treatedAll 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
68 |World Health Organization
Western Pacific Region
Who should be treatedWho 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
69 |World Health Organization
Western Pacific Region
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
70 |World Health Organization
Western Pacific Region
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
71 |World Health Organization
Western Pacific Region
Who not to treat nowWho not to treat now
Young patients
Persistently normal ALT
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
72 |World Health Organization
Western Pacific Region
Phases of CHB infectionPhases of CHB infection
Initiate treatment Initiate treatment
73 |World Health Organization
Western Pacific Region
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)
74 |World Health Organization
Western Pacific Region
How to Treat HBV‐infected PeopleHow 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
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015)
75 |World Health Organization
Western Pacific Region
Advances in HBV treatmentAdvances in HBV treatment
1957Discoveryinterferon
1991Interferon alfa-2blicensed
1999Lamivudine (3TC)licensed
1991 Discovery lamivudine (3TC)
1990Discovery PMEA
2003Adefovir dipivoxil (PMEA prodrug)licensed
1998 Discoveryentecavir
2006Entecavirlicensed
2007Telbivudinelicensed
2001 Discoverytelbivudine 2005
Peginterferon alfa-2aPeginterferon alfa-2b*
licensed
2008 Tenofovir disoproxil fumaratelicensed
* Specific countries onlyted from: ClinicalCareOptions.com
2017Tenofovir alafenamidelicensed
76 |World Health Organization
Western Pacific Region
Antiviral agents for HBVAntiviral agents for HBV
Antiviral 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
77 |World Health Organization
Western Pacific Region
The replication cycle of HBV and sites of action of NAs
The replication cycle of HBV and sites of action of NAs
78 |World Health Organization
Western Pacific Region
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
79 |World Health Organization
Western Pacific Region
WHO Recommended First‐line HBV Treatment: Essential Medicines List
WHO Recommended First‐line HBV Treatment: Essential Medicines List
6.4.4.1.1 Nucleoside/Nucleotide reverse transcriptase inhibitors
Remarks
entecavir Oral liquid: 0.05 mg/ mL Tablet: 0.5 mg or 1 mg
- 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)
tenofovirdisoproxilfumarate (TDF)
Tablet: 300 mg (tenofovir disoproxilfumarate – 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
WHO Model List of Essential Medicines 20th List (March 2017) (Amended August 2017): adults, children
80 |World Health Organization
Western Pacific Region
Choosing Among Nucleos(t)ide AnaloguesChoosing Among Nucleos(t)ide Analogues
If no comorbidities (for most pts)
When to prioritize ETV over TAF– If less expensive (generic available)– Dosing guidelines for CrCl < 15 mL/min
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
1. Terrault NA, et al. Hepatology. 2016;63:261-283. 2. EASL. J Hepatol. 2017;67:370-398.
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 m2
Albuminuria > 30 mg or moderate proteinuria Low phosphate (< 2.5 mg/dL) Hemodialysis
Monotherapy with ETV, TDF, or TAF[1,2]
81 |World Health Organization
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Group Drug and doseChildren 2‐12 years of age and weighing ≥10 Kg
Entecavir once daily as oral solution* (mL) if available
Body weight (Kg) Dose (mL)* once daily10‐11 3>11 to 14 4>14 to 17 5>17 to 20 6>20 to 23 7>23 to 26 8>26 to30
9
>30 10
Entecavir dosing in children Entecavir dosing in children
*Solution containing 0.05 mg/mL (or 0.5 mg in 10 mL)
82 |World Health Organization
Western Pacific Region
Tenofovir: adverse effects in the trialsTenofovir: 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
83 |World Health Organization
Western Pacific Region
Tenofovir Disoproxil Fumarate: Dose in renal impairment
Tenofovir Disoproxil Fumarate: Dose in renal impairment
84 |World Health Organization
Western Pacific Region
All pts receiving TDF should undergo periodic monitoring of renal function, including phosphate levels[1]
Chronic HBV Infection: Management of Pts With Renal Impairment
Chronic HBV Infection: Management of Pts With Renal Impairment
1. EASL. J Hepatol. 2017;67:370-398. 2. Entecavir [package insert]. 2017. 3. Tenofovir disoproxil fumarate [package insert]. 2017. 4. Tenofovir alafenamide [package insert]. 2017.
Entecavir[2] TenofovirDisoproxil Fumarate[3]
TenofovirAlafenamide[4]
Reduce dose ifCrCl < 50 mL/min
Reduce dose ifCrCl < 50 mL/min
No dose reduction ifCrCl ≥ 15 mL/min
No dose recommendation atCrCl < 10 mL/min without
dialysis
Not recommended atCrCl < 15 mL/min
85 |World Health Organization
Western Pacific Region
Tenofovir Alafenemide (TAF) vs TDF: Mechanism of Action
Tenofovir Alafenemide (TAF) vs TDF: Mechanism of Action
Arribas JR, et al. CROI 2017. Abstract 453. Duarte-Rojo A. Therap Adv Gastroenterol. 2010;3:107-119. Murakami E, et al. Antimicrob Agents Chemother. 2015;59:3563-3569. Tenofovir disoproxil fumarate [package insert]. 2017. Tenofovir alafenamide [package insert]. 2017.
TAF: no dose adjustment needed in pts with CrCl > 15 mL/min
90% lower plasma
TFV than with TDF
GI tract
TDF300 mg
TAF25 mg
Plasma
TFVHepatocyte
Renal tubular
cell
Renal tubular
cell
TFV HBV
TAF: novel prodrug of TDF
86 |World Health Organization
Western Pacific Region
TAF vs TDF in Pts with HBV Infection: EfficacyTAF vs TDF in Pts with HBV Infection: Efficacy
1. Seto WK, et al. AASLD 2016. Abstract 67. 2. Chan HL, et al. EASL 2016. Abstract GS12. 3. Buti M, et al. EASL 2016. Abstract GS06.
*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.
HBeAg-Positive Pts[2]
(N = 873)HBeAg-Negative Pts[3]
(N = 425)Outcome, % TAF TDF P Value TAF TDF P ValueHBV DNA < 29 IU/mL at Wk 72[1] 71.6 71.9 .78 92.6 92.1 .84
ALT normalization at Wk 48 Central laboratory criteria* AASLD laboratory criteria†
7245
6736
.18.014
8350
7532
.076<.001
HBeAg Loss at Wk 48 Seroconversion at Wk 48
1410
128
.47
.32
HBsAg Loss at Wk 48 Seroconversion at Wk 48
<1<1
<10
.52
.22
Multicenter phase III studies in pts with chronic HBV infection (N = 1298), including pts with compensated cirrhosis
87 |World Health Organization
Western Pacific Region
TAF vs TDF in Pts With HBV Infection: SafetyTAF vs TDF in Pts With HBV Infection: Safety
1. Seto WK, et al. AASLD 2016. Abstract 67. 2. Agarwal K, et al. AASLD 2016. Abstract 1844. 3. Izumi N, et al. AASLD 2016. Abstract 1904.
Outcome TAF TDF P Value
Mean change in BMD at Wk 72, %[1]
Hip Spine
-0.16-0.57
-1.86-2.37
< .001< .001
Median change in serum creatinine at Wk 48, mg/dL[2] 0.01 0.02 .012Median change in eGFR at Wk 48, mL/min[2] -1.2 -5.4 < .001
Mean change in FibroTest score at Wk 48[3]
HBeAg-positive pts HBeAg-negative pts
-0.07-0.05
-0.04-0.03
.007
.028
Multicenter phase III studies in pts with chronic HBV infection (N = 1298), including pts with compensated cirrhosis
88 |World Health Organization
Western Pacific Region
Chronic HBV Infection: Management of Pts With NA Resistance
Chronic HBV Infection: Management of Pts With NA Resistance
*Includes either TDF or TAF in EASL guidelines; AASLD guidelines not yet updated since approval of TAF.
1. Terrault NA, et al. Hepatology. 2016;63:261-283. 2. EASL. J Hepatol. 2017;67:370-398.
Resistance Switch Strategy Add StrategyAdefovir 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]
89 |World Health Organization
Western Pacific Region
Simplified guidelines on selection of patients for Treatment of patients with Chronic hepatitis BSimplified guidelines on selection of patients for Treatment of patients with Chronic hepatitis B
90 |World Health Organization
Western Pacific Region
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
91 |World Health Organization
Western Pacific Region
Drug doseDrug dose
Adults Entecavir 0.5 mg/day oralTenofovir 300 mg/day oral
Children need dose modification
92 |World Health Organization
Western Pacific Region
Drugs need dose adjustment in renal diseaseDrugs need dose adjustment in renal disease
93 |World Health Organization
Western Pacific Region
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
94 |World Health Organization
Western Pacific Region
HBV Module 6Monitoring for Chronic Hepatitis B
HBV Module 6Monitoring for Chronic Hepatitis B
95 |World Health Organization
Western Pacific Region
Need for monitoringNeed for monitoring
All need monitoring (irrespective of need for treatment)
HBsAg +ve
Defertreatment
Notreatment
Starttreatment
96 |World Health Organization
Western Pacific Region
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
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P64
Monitoring patients with CHBMonitoring patients with CHB
97 |World Health Organization
Western Pacific Region
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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Western Pacific Region
How to monitor?How to monitor?
99 |World Health Organization
Western Pacific Region
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
100 |World Health Organization
Western Pacific Region
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…
101 |World Health Organization
Western Pacific Region
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
102 |World Health Organization
Western Pacific Region
TIME
HBeAgdecline
HBV DNAsuppression
HBeAg to Anti-HBeseroconversion
Loss ofHBsAg
Anti-HBs+ Cure
Improved histology and survival
= HBsAg seroconversion
Therapeutic endpoints over timeTherapeutic endpoints over time
103 |World Health Organization
Western Pacific Region
Why hepatitis B is not curable: A Key Difference Between HCV & HBV
Nuclear cccDNA
Why hepatitis B is not curable: A Key Difference Between HCV & HBV
Nuclear cccDNA
104 |World Health Organization
Western Pacific Region
Minimise other hepatic insultsMinimise 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
Manage stress
105 |World Health Organization
Western Pacific Region
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
106 |World Health Organization
Western Pacific Region
HBV Module 7Special population for Chronic Hepatitis B
HBV Module 7Special population for Chronic Hepatitis B
107 |World Health Organization
Western Pacific Region
Who are specific populationsWho 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
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P98GUIDELINES FOR THE CARE AND TREATMENT OF PERSONS DIAGNOSED WITH CHRONIC HEPATITIS C VIRUS INFECTION P37, P51
108 |World Health Organization
Western Pacific Region
HBV and HCV coinfectionHBV 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
potential risk of HBV reactivation during DAA treatment. GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION (WHO 2015) P103GUIDELINES FOR THE CARE AND TREATMENT OF PERSONS DIAGNOSED WITH CHRONIC HEPATITIS C VIRUS INFECTION P38
109 |World Health Organization
Western Pacific Region
HBV and HDV coinfectionHBV 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.
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P23, 102
110 |World Health Organization
Western Pacific Region
HBV and HIV coinfectionHBV 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)
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P22
111 |World Health Organization
Western Pacific Region
HBV and HIV coinfectionHBV 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)
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P22
112 |World Health Organization
Western Pacific Region
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
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P99
113 |World Health Organization
Western Pacific Region
HBV and tuberculosis (TB) coinfectionHBV and tuberculosis (TB) coinfection
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P103
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.
114 |World Health Organization
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HBV infection in pregnant womenHBV 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.
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P106
115 |World Health Organization
Western Pacific Region
Children and adolescents with HBV infectionChildren 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.
GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF PERSONS WITH CHRONIC HEPATITIS B INFECTION P105
116 |World Health Organization
Western Pacific Region
HBVPractical session
case‐based learning
HBVPractical session
case‐based learning
117 |World Health Organization
Western Pacific Region
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
118 |World Health Organization
Western Pacific Region
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
119 |World Health Organization
Western Pacific Region
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
120 |World Health Organization
Western Pacific Region
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
121 |World Health Organization
Western Pacific Region
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
122 |World Health Organization
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
123 |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
124 |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
125 |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
126 |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
127 |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
128 |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
129 |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?
130 |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
131 |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?
132 |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?
133 |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?
134 |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?
135 |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?
136 |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
137 |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
138 |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?
139 |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
140 |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?
141 |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?
142 |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?
143 |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?
144 |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
145 |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)
146 |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?
147 |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
148 |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
149 |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?
150 |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?
151 |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?
152 |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?
153 |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
154 |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