Update in Management of

Chronic Hepatitis B Prepared By

Almetwally Zakaria Abdelbaset

Prof. and Head of Department of Hepatology and Gastroenterology

Faculty of Medicine , Benha University, Egypt

Approximately one third of the world’s

population has serological evidence of

past or present infection with HBV and

350–400 million people are chronic HBV

surface antigen (HBsAg) carriers

The spectrum of disease and natural

history of chronic HBV infection are

diverse and variable, ranging from an

inactive carrier state to progressive

chronic hepatitis B (CHB), which may

evolve to cirrhosis and hepatocellular

carcinoma (HCC).

HBV-related end stage liver disease or HCC

are responsible for over 0.5–1 million deaths

per year and currently represent 5–10% of

cases of liver transplantation

Host and viral factors, as well as coinfection

with other viruses, in particular hepatitis C virus

(HCV), hepatitis D virus (HDV), or HIV together

with other co-morbidities including alcohol

abuse and obesity, can affect the natural course

of HBV infection as well as efficacy of antiviral

strategies

CHB may present either as HBeAg-positive or

HBeAg-negative CHB.

The prevalence of the HBeAg-negative form of

the disease has been increasing over the last

decade as a result of aging of the HBV-infected

population and predominance of specific HBV

genotypes and represents the majority of cases

in many areas.

Morbidity and mortality in CHB are linked to

persistence of viral replication and evolution to

cirrhosis and/or HCC.

Longitudinal studies of untreated patients

indicate that, after diagnosis, the 5-year

cumulative incidence of developing cirrhosis

ranges from 8% to 20%.

The 5-year cumulative incidence of

hepatic decompensation is approximately

20% for untreated patients with

compensated cirrhosis

Untreated patients with decompensated

cirrhosis have a poor prognosis with a 14–

35% probability of survival at 5 years

The worldwide incidence of HCC has

increased, mostly due to persistent HBV

and/or HCV infections; presently it

constitutes the fifth most common cancer,

representing around 5% of all cancers.

The annual incidence of HBV-related HCC in

patients with CHB is high, ranging from 2%

to 5% when cirrhosis is established.

The annual incidence of HBV-

related HCC in patients with CHB

is high, ranging from 2% to 5%

when cirrhosis is established

Treatment of Chronic Hepatitis B

What is the evidence that treatment improves

outcome?

Who should be treated?

When should treatment be initiated?

How long should antiviral treatment be given?

How do we deal with antiviral resistance?

Antiviral treatment has been

shown to be effective in suppressing

hepatitis B virus replication,

decreasing inflammation and

fibrosis in the liver, and preventing

progression of liver disease

• However, current medications do not

eradicate hepatitis B virus; therefore, a

key question is which patients need to

start treatment and which patients can

be monitored.

However, current medications do

not eradicate hepatitis B virus; so

a key question is which patients

need to start treatment and

which patients can be monitored.

Drugs available for the treatment of CHB include

IFN, PEG-IFN and six NAs.

NAs for HBV therapy can be classified into:

Nucleosides (lamivudine, telbivudine,

emtricitabine, entecavir)

Nucleotides (adefovir and tenofovir).

PEG-IFN-2b and emtricitabine are not licensed for

HBV treatment in most European countries

Lamivudine, adefovir, entecavir, telbivudine and tenofovir

have been approved in Europe for HBV treatment, and the

combination of tenofovir and emtricitabine in one tablet has

been licensed for the treatment of human HIV infection.

The efficacy of these drugs has been assessed in randomized

controlled trials at 1 year (2 years with telbivudine).

Longer-term results are now available from extension of the

randomized trials sometimes in patient subgroups and

several cohort studies.

Which Drugs to Choose •First line drugs

–Peg-Interferon: Expensive, no resistance

–Entecavir: Very potent, less resistance , expensive

–Tenofovir: very potent, less expensive, resistance?

•Second line drugs

–Lamivudine: Potent, high resistance rate, cheapest

–Telbivudine: Potent, expensive, resistance common

–Emtricitabine: Potent, expensive, resistance common

–Adefovir: Less potent, Fails in 30%, expensive

How to Follow Patients ?

•ALT, AST, HBV DNA every 3-6 months

•If HBV DNA level increases 1 log or

above 2,000 units, test for resistance

Duration of Treatment

•HBeAg-positive:

–Until at least 6 months after loss of HBeAg and

appearance of anti-HBe

•HBeAg-negative (anti-HBe positive)

–Interferon: 1 year

–Nucleoside analogues: Indefinitely

Currently, there are two different strategies

for both eAg-positive and eAg-negative CHB

patients:

Treatment of finite duration with PEG-IFN or

a NA

Long-term treatment with NAs

An attempt for finite NA treatment should use the

most potent agents with the highest barrier to

resistance to rapidly reduce levels of viremia to

undetectable levels and avoid breakthroughs due to

HBV resistance

Long-term treatment with NA(s)

This strategy is necessary for patients who are not

expected or fail to achieve a sustained off-treatment

virological response and require extended therapy,

i.e. for HBeAg-positive patients who do not develop

anti-HBe seroconversion and HBeAg-negative

patients.

This strategy is also recommended in patients with cirrhosis irrespective of HBeAg status or anti-HBe seroconversion on treatment

This strategy is also

recommended in patients with

cirrhosis irrespective of HBeAg

status or anti-HBe

seroconversion on treatment

The most potent drugs with the optimal

resistance profile, i.e. tenofovir or entecavir,

should be used as first-line monotherapies

Treatment with either tenofovir or entecavir

monotherapy for ⩾3 years achieves

maintained virological remission in the vast

majority of patients

Tenofovir is preferred in:

patients who received lamivudine previously

young women who plan to start a family in next

few years

patients who want more flexibility with regard to

the time of day at which they take their medicine

Entecavir is preferred in:

older patients

patients with medical conditions that increase risk

of renal failure

Pegylated Interferon

Effect of Genotype

A large multicenter study of 52

weeks of pegylated interferon

alfa-2b, alone or in combination

with LAM, according to

genotype:

HBeAg-positive patients with

genotype A responded

significantly more frequently

than those with genotypes B, C,

or D in descending order.

Percent HBeAg response irrespective

of treatment assignment (pegylated

interferon/placebo vs pegylated

interferon/LAM).

Pegylated Interfon

Poor response in Egyptian patients with

predominant Genotype D.

HbeAg positive patients with high liver enzymes

could be offered a chance of treatment with peg

Inf alfa for 24 weeks.

Seroconversion to HBeAb →continue for 48 wks

No seroconversion →stop ttt and shift to oral

antiviral therapy according to previous guidelines

The main theoretical advantages of (PEG-)IFN

are the absence of resistance and the potential

for immune-mediated control of HBV infection

with an opportunity to obtain a sustained

virological response off-treatment and a chance

of HBsAg loss in patients who achieve and

maintain undetectable HBV DNA.

Frequent side effects and subcutaneous injection

are the main disadvantages of (PEG-)IFN

treatment

Frequent side effects and subcutaneous injection

are the main disadvantages of (PEG-)IFN treatment

PEG-IFN is contraindicated in patients with

decompensated HBV-related cirrhosis or autoimmune

disease, in patients with uncontrolled severe

depression or psychosis, and in female patients during

pregnancy

Liver biopsy(Indications)

HBV DNA > 2000 IU/ML with persistently normal enzymes .

HBV DNA < 2000 IU/ML with persistently elevated enzymes .

Patients < 2000 IU/ML with normal enzymes who show clinical

evidence of liver disease or have a family history of HCC

Treatment is recommended for those with >A1

and / or >F1 on the Metavir score

Liver biopsy : METAVIR scoring system

F1 F2 F3 F4

From Z. Goodman

Special Groups Compensated Cirrhosis:

Naive Cirrhotic patients with any detectable level of HBV

DNA should receive Entecavir 0.5 mg or Tenofovir

300mg.

Decompensated Cirrhosis:

Entecavir 1 mg may be appropriate. The dose of all NA,s

needs to be adjusted in patients with low creatinine

clearance (< 50ml/min)

Dialysis and Renal patients

All renal patients should be screened for HBV

Seronegative patients should be vaccinated.

Entecavir is preferred for treatment.

All drugs should be dose adjusted according

to creatinine clearance.

Pregnancy

For mothers:

- All pregnant females should be screened for HBsAg

- Newly diagnosed pregnant women in the last trimester showing an

HBV DNA level > 100.000 IU/ML are candidates for Lamivudine 100

mg or Tenofovir 300 mg starting last trimester and for 3 months

after delivery to decrease chance of new-born infection . Re-

evaluate the condition after 3 months of delivery and consider

treatment according to the previous guidelines

Pregnancy

For newborns:

HB Ig and HBV vaccine first (birth) dose for the

baby in the first 6-12 hours after delivery.

Birth dose vaccination is recommended for all

newborns.

Females who become pregnant while on treatment

– On Lamivudine monotherapy: Continue on treatment

– On Other lines of treatment : shift to class B drug

(Tenofovir 300 mg O.D.)

HBV/HDV Coinfection

Peg –INF is the only effective drug against HDV.

Efficacy of Peg –INF is assessed during treatment after 3-6 months by measuring HDV RNA levels.

Optimal duration of therapy is not well defined but therapy for at least 72 wks .

NAs have no impact on HDV replication and related disease.

Refer the patient to a specialized HBV center.

Immunosupressed Patients

Patients with high HBV DNA level should receive NA with high viral potency according to guidelines.

HBsAg neg patients with positive anti- HBc antibodies should be tested for HBV DNA. Patients with detectable viremia should be treated as HBsAg positive cases.

Follow up of cases with undetectable viremia every 1-2 months during treatment by liver enzymes and HBV DNA.

HBV/HCV Co infection

-Treat predominant virus according to PCR level.

-Patients fulfilling the inclusion criteria for HBV

treatment and have co-infection with active HCV

(HCV RNA +ve by quantitative PCR)

Monitoring for HBV is performed every 3-6

months.

Reassessment of the condition after termination

of the course and starting oral HBV treatment if

needed.

.

Peg IFN + Ribavirin

Follow up

Follow up visits (every 2-3 months)for receiving

medications & follow up for side effects and relapsing

symptoms.

Checking liver enzymes every 3 months.

Serum creatinine is done every 3 months in those

receiving Adefovir. For Tenofovir in addition monitor

creat.clearance and serum phosphate for risk of renal

impairement and osteomalacia.

Liver function tests, complete blood count, A.F.P.,

Abdominal U/S & HBV/DNA by PCR quantitative is

done every 6 months

Conclusions • Persons with chronic HBV infection need

lifelong follow-up

• Patients with moderate or advanced fibrosis or

inflammation can benefit by treatment

• Patients undergoing chemo or

immunosuppressive therapy need HBV

serology testing

• Perform surveillance of HBV infected persons

for HCC as per AASLD guidelines

Acute HBV

Spontaneous recovery in more than 95% of cases and seroconversion to anti HBs without antiviral therapy. Supportive management and close monitoring for early identification of fulminant hepatitis or liver cell failure

Fulminant or impending liver cell failure:

Entecavir 0.5 mg during the condition and for at least 6 months after seroconversion to anti HBs or for at least 12 months after seroconversion to anti HBe without HBs Ag loss

Vaccination

-Mass vaccination is recommended.

-Vaccination is highly recommended for:

Health care workers

Close contacts of viremic patients

Chronic renal failure patients before they start renal

dialysis.

Chronic hepatitis C patients.

Immunosupressed patients.

Multitransfused individuals

Although much has been

accomplished in the therapy

of HBV infection over the

past decade, much work still

remains to be done

Antiviral treatment for

CHB is effective, and

cost effective

Early Cirrhosis Can be Completely

Reversed! •Remove the cause of cirrhosis and reversal will

take place over about 10 years

•Even 30% to 50% of persons with

decompensated cirrhosis will become

compensated (look normal clinically and by LFT)

after proper treatment