Introduction to chronic Hepatitis B Infection in Malaysia, epidemiology and common treatment. Phases of chronic Hepatitis B Infection, clinical presentation and complications.

1. Chronic Hepatitis B
Joyann Hee Yan Han
BMS 14091168

2. Introduction
• Hepatitis B affects 240 million people worldwide
– Intermediate to high prevalence in the Asia Pacific region - ¾ of chronic HBV-positive people
worldwide
• Chronic hepatitis B virus infection is when the patient is HBsAg seropositive for more than 6
months
– Chronic infection may develop in nearly half of children infected with HBV before the age of 6 years
and in <5% of individuals infected as adults
• Human hepatitis B virus belongs to the family of Hepadnaviridae of small, enveloped,
primarily hepatotropic DNA viruses
– The virus replicates in the host and assembles exclusively in the hepatocytes and virions are released
non-cytopathically through the cellular secretory pathway
Chronic hepatitis B is defined as chronic necro-inflammatory liver disease due to persistent hepatitis B virus infection

3. Current Situation in Malaysia
• In Malaysia, an estimated 1 million people are chronically infected with HBV.
• Before the nationwide universal hepatitis B vaccination of all newborn infants
since 1989, Malaysia was an intermediate endemicity country, with surface
antigen of HBV (HBsAg) prevalence of 5 to 7%.
• In Malaysia, universal hepatitis B vaccination of all newborn infants has been
implemented since 1989. The nationwide coverage for universal vaccination of
HBV is about 96.29% (2014).
• This vaccination program resulted in decline of HBsAg positivity from 2.5% among
those born in 1985 (before the implementation of universal infant vaccination) to
0.4% among those born in 1996.
• In a survey of almost 900 patients with chronic HBV carried out by the Malaysian
Liver Foundation, 50% of the hepatitis B carriers were HBV deoxyribonucleic acid
positive, and of these, 30 to 40% have evidence of liver disease and require
treatment.

4. Hepatitis B virus prevalence in Malaysia

5. Signs and Symptoms
• The majority of acute viral hepatitis infections are
asymptomatic or they can cause an anicteric
illness that may not be diagnosed as hepatitis
• Symptomatic hepatitis B will depend on the mode
and time of transmission
– Vertical transmission from mother to child is almost
always asymptomatic; other routes of transmission
are more likely to produce symptomatic disease (30%
of cases transmitted by IV drug use are icteric)

6. 1) Preicteric Phase
Nonspecific systemic symptoms (eg myalgia, nausea, vomiting, fatigue, malaise with discomfort
in the right upper quadrant of the abdomen)
• Altered sense of smell or taste, coryza, photophobia, headache, cough, diarrhea, dark urine
and serum sickness-like syndrome
• Hepatomegaly, splenomegaly and lymphadenopathy may be seen on physical exam
2) Icteric Phase
Jaundice, usually noted after onset of fever or upon lysis of fever
3) Fulminant Hepatitis
Development of symptoms of hepatic encephalopathy (eg confusion, drowsiness within 8 weeks
of symptoms or within 2 weeks of onset of jaundice)
• Hypoglycemia, prolonged prothrombin time (PT)

7. History
Important points in the clinical history of patients with suspected viral hepatitis
• Contacts with jaundiced patients
• IV drug use
• History of blood transfusion
• Surgery or hospitalizations
• Family history of chronic liver disease
• Occupation
• Food and water sources
• Alcohol use
• Laboratory Tests

8. Serological Tests
• Usually characterized by the presence of hepatitis B surface antigen (HBsAg) which suggests infectivity
– Anti-HBs is produced following a resolved infection and is the only hepatitis B virus (HBV) antibody marker present after
immunization
– Persistence of HBsAg for at least 6 months indicate chronic infection
• Anti-HBc (anti-core antibody) is the 1st antibody to appear in the serum and is a marker of natural
immunity
– Its presence indicates an immune response against HBV within liver cells and is a specific marker of acute hepatitis B infection
– Presence of anti-HBc IgM is diagnostic for acute HBV infection but may occur during a flare of chronic hepatitis B
• Hepatitis B e antigen (HBeAg) is a marker of active viral replication
– This may be negative at the time that the patient is evaluated for acute hepatitis B since viral replication may have already
ceased
• HBV DNA tests for HBV replication and aids in the evaluation of treatment efficacy with antiviral agents
• New biomarkers of HBV infection are:
Viral covalently closed circular DNA (cccDNA) - shown to persist in the liver of infected patients even after long-term nucleotide
analogue therapy and even after HBsAg loss and seroconversion; used in clinical trials evaluating treatment concepts to cure HBV
infection
– Hepatitis B core-related antigen (HBcrAG) - helpful in defining the phase of chronic HBV infection especially in the HBe-negative
patients as well as predicting the long-term HCC risk
– Circulating HBV RNA

10. • Other lab tests that are recommended in patients suspected to have viral
hepatitis:
• Liver function tests (LFTs)
– Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
– Serum bilirubin, alkaline phosphatase (ALP)
• Prothrombin time (PT), international normalized ratio (INR), renal function
tests
• Noninvasive tests such as the aminotransferase/platelet ratio index (APRI)
or fibrosis-4 (FIB-4) may be used to assess the degree of hepatic fibrosis
– Transient elastography may be an option for patients with contraindications
to liver biopsy

11. Evaluation
If patient meets criteria for chronic hepatitis B:
Liver biopsy must be done:
• to grade stage of liver disease as chronic hepatitis
B may evolve to cirrhosis and hepatocellular
cancer
• Liver biopsy is essential in determining disease
activity in cases of inconclusive biochemical and
HBV markers

13. Phases of Chronic Hepatitis B
1) HBeAg-positive Chronic HBV Infection (Immune-tolerant)
• Presence of serum HBeAg
• Very high levels of HBV DNA
• ALT persistently within the normal range (<19 U/L for females and <30 U/L in males) or minimally elevated
• Minimal or no liver necroinflammation or fibrosis
• Frequently occurred and prolonged in patients infected perinatally and is associated with preserved HBV specific T
cell function at least until young adulthood
• Patients at this stage are highly contagious because of the high levels of HBV DNA
2) HBeAg-positive Chronic Hepatitis B (Immune-clearance HBeAg-positive)
• Presence of serum HBeAg
• High levels of HBV DNA
• Elevated ALT
• Moderate to severe liver necroinflammation and accelerated progression of fibrosis
• Usually occurs in patients infected during adulthood
• Patients may have HBeAg seroconversion and HBV DNA suppression that progress to HBeAg-negative infection
phase while others may fail to control HBV and progress to the HBeAg-negative chronic hepatitis B phase for many
years

14. 3) HBeAg-negative Chronic HBV Infection (Inactive Carrier/Immune Control)
• Absence of serum HBeAg
• Undetectable or low (<2,000 IU/mL) HBV DNA levels
• Normal ALT
• Minimal liver necroinflammation and variable fibrosis as a result of previous hepatic injury during the HBeAg-
positive immune-active phase
• Low risk of progressing to cirrhosis or HCC but progression to chronic hepatitis B may occur
4) HBeAg-negative Chronic Hepatitis B (HBeAg-negative Immune Reactivation/Escape)
• Absence of serum HBeAg usually with detectable anti-HBe
• Persistent or fluctuating moderate to high levels of serum HBV DNA
• Fluctuating or persistently elevated ALT
• There is liver necroinflammation and fibrosis
• Associated with low rates of spontaneous disease remission
5) HBsAg-negative (Occult HBV Infection)
• Serum negative HBsAg and positive antibodies to HBcAg with or without detectable antibodies to HBsAg
• Normal ALT
• Usually, but not always, undetectable serum HBV DNA
• Liver has frequently detectable HBV DNA (cccDNA)
• Several studies have shown that almost all patients with occult HBV infection have normal liver biochemistry and
minimal or no liver necroinflammation and fibrosis
• However, it may still be associated with the development of liver cirrhosis and HCC

17. General management
1) Serologic screening of chronic Hepatitis B virus infection amongst patient’s family members
2) Prevention of transmission of Hepatitis B virus to others :
- Ensure that their sexual partners are vaccinated
- No sharing of toothbrushes and razors
- Cover open wounds
- No donation of body parts
- Clean blood spills with bleach/detergents
Note: Hepatitis B virus transmission is not transmissible through:
• Sharing of utensils, food or kissing as part of social greetings
• Participating in all activities including contact sports
• Social interaction with others (e.g. in schools, day care centres)
3) Prevention of super-infection - Unless contraindicated, hepatitis A vaccination should be given to
prevent superimposed acute hepatitis A in patients with chronic hepatitis B virus infection.

18. Specific management
Management of patients with chronic hepatitis B should be tailored according to the patients’ clinical state of
liver disease (compensated versus decompensated liver disease) as well as their virologic and biochemical (i.e.
the liver function test, in particular the serum transaminase levels) status.
1) For patients with HBsAg positive > 6 months and well– compensated liver disease, in association with:
(A) HBeAg–positive hepatitis B virus infection

19. (B) HBeAg–negative hepatitis B virus infection:
2) For patients with decompensated hepatitis B virus–related cirrhosis:
Refer to gastroenterologist or hepatologist for management.

20. Direct acting antiviral + (self-injected) pegylated interferon alpha +/- ribavirin (cirrhosis)

23. Monitoring
• Monitor patient to ensure that fulminant liver failure does
not develop
• Monitor liver function tests (LFT) every 1-4 weeks until
normal; ALT every 3-6 months if patient did not meet
criteria for treatment
• Further monitoring of HBV DNA every 3-6 months in non-
responders is recommended to recognize delayed response
and to plan retreatment if required
• Monitor for hepatocellular carcinoma in high-risk patients
every 6-12 months using ultrasound and alpha-fetoprotein

26. Screening for Hepatitis B
• Depending on local health services, the following groups should be tested for chronic HBV
infection:
– Persons born in hyperendemic areas, men who have sex with men (MSM), IV drug users, dialysis
patients, HIV-positive individuals, pregnant women and family members, household members and
sexual contacts of HBV-infected persons, blood or organ donors, healthcare workers, patients
needing chemotherapy
• Individuals who are seronegative should be vaccinated against HBV
• If Anti-HBc positive only, patient may have had a past resolved HBV infection or a false-positive test and that
vaccination may be given if patient is from an endemic area
• HBsAg-positive patients should be evaluated to assess progression of liver disease and need for antiviral
therapy
• Anti-HBs-positive patients have developed natural immunity and do not need to be vaccinated
• Patients with chronic hepatitis B should also be tested for co-infection with hepatitis C virus
(HCV), hepatitis D virus (HDV) and human immunodeficiency virus (HIV), if they are at risk
for these infections

27. The Ministry of Health in Malaysia has identified viral hepatitis as one of the priority diseases. To
achieve GHSS-VH (Global Health Sector Strategy on Viral Hepatitis) by 2030, the Health Ministry
and other non-governmental organizations, such as My Commitment to Cure (MyC2C) are
working together to develop a strategic road map to reach the target in Malaysia by 2030.

28. PREVENTION AND POST-EXPOSURE PROPHYLAXIS OF HEPATITIS B
Patient Group for Whom Prevention or Post-exposure Prophylaxis
is Recommended
Recommended Prevention or Post-exposure Prophylaxis Regimen
Prevention
• Unvaccinated children, adolescents and adults
• Premature infants with immediate risk of HBV infection
• Unvaccinated persons who attend STD clinics, including
pregnant women
• Persons with any of the following sexual risk factors: History of
STD and HIV, multiple sex partners, sex with an injection drug
user, MSM, victims of sexual assault
• Illegal IV drug users
• Household members, sex partners and drug-sharing partners of
a person with chronic HBV infection
• Persons on hemodialysis, are receiving clotting factor
concentrates, who have occupational exposure to blood, or are
needing immunosuppressive therapy
• Healthcare personnel in treatment facilities
• Inmates of correctional facilities
• Patients with diabetes mellitus, chronic liver disease
• Travelers to places with endemic HBV infection
Hepatitis B Vaccine
Post-exposure Prophylaxis
Unvaccinated or nonimmune sex partners of persons with acute
hepatitis B
Administer Immunoglobulin and begin hepatitis B vaccination
series (if not contraindicated) within 14 days after the most
recent sexual contact

29. • Cirrhosis
• Decompensation (chronic
liver failure) – ascites,
variceal bleeding, hepatic
encephalopathy
• Hepatocellular carcinoma
• Others: Membranous
glomerulonephritis,
Polyarteritis nodusa
(vasculitis)
Complications & Prognosis

30. References
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