basic modules for hbv · 2018. 12. 12. · natural history of chronic hepatitis b chronic hepatitis...

1 |World Health Organization

Western Pacific Region

Basic modules for HBVBasic modules for HBV



HBV Module 1Hepatitis B serological markers

and virology

HBV Module 1Hepatitis B serological markers

and virology


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.



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



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)



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



Serological pattern of chronic HBV infectionSerological pattern of chronic HBV infection

GUIDELINES ON HEPATITIS B AND C TESTING (WHO 2017) P22



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%)




HBV Module 2Hepatitis B transmission and

prevention

HBV Module 2Hepatitis B transmission and

prevention



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



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)



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.



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



HBV Module 3Natural history of Hepatitis B

HBV Module 3Natural history of Hepatitis B



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



Serological pattern of acute HBV infectionSerological pattern of acute HBV infection




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)



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



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)



Serological pattern of chronic HBV infectionSerological pattern of chronic HBV infection




HBV Module 4Assessment of liver fibrosis

HBV Module 4Assessment of liver fibrosis



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)



Transient elastography (Fibroscan)Transient elastography (Fibroscan)



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



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



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



HBV Module 5Treatment for Chronic Hepatitis B

HBV Module 5Treatment for Chronic Hepatitis B



WHO guidelinesWHO guidelines

Assessment for treatment

Monitoring

Stopping treatment



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




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



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



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



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



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




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



WHO recommendation: choice of drugWHO recommendation: choice of drug


In all adults, adolescents and children aged 12 years or older in whom antiviral therapy is indicated, the nucleos(t)ide analogues which have a high barrier to drug resistance (tenofovir or entecavir) are recommended.

Entecavir is recommended in children



Drug doseDrug dose Adults Entecavir 0.5 mg/day oral

Tenofovir 300 mg/day oral

Children need dose modification



HBV Module 6Monitoring for Chronic Hepatitis B

HBV Module 6Monitoring for Chronic Hepatitis B



Need for monitoringNeed for monitoring

All need monitoring (irrespective of need for treatment)

HBsAg +ve

Defertreatment

Notreatment

Starttreatment



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



How to monitor?How to monitor?



How to monitor?How to monitor? At least annually: ALT

HBsAg, 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



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…

basic modules for hbv · 2018. 12. 12. · natural history of chronic hepatitis b chronic hepatitis...

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