The Family Physician Magzine Articles

NATURAL HISTORY OF CHRONIC HEPATITS B 

Hepatitis B

HBV

•         An old disease which continues to fascinate both the scientists and clinicians.

•         With the discovery of newer diagnostic tools e.g. highly sensitive PCR assays etc newer insights into disease behavior has been made possible

Chronic hepatits B infection is a dynamic state of complex interactions involving the:

                              virus

                              hepatocyte

                  host’s immune response

                  various external factors

•              Determine the severity and outcome of the disease

Shifts in the Geographic Distribution of Chronic HBV Infection

Overview of CHB Infection
in the Asia-Pacific Region

~75% of patients with CHB reside in the Asia-Pacific region, where most infections are acquired perinatally
or in early childhood^1,2

~90% HBeAg-positive mothers transmit HBV to their offspring³

Early exposure increases lifetime risk of developing serious sequelae: cirrhosis, decompensation, HCC^1–3

HBV-related liver disease is a major cause of death in the Asia-Pacific region^1-3

An estimated 600,000 persons die each year due to the acute or chronic consequences of hepatitis B³

CHB management represents a substantial socioeconomic burden to patients and national healthcare systems¹

Age of acquisition of infection determines the natural history

Perinatal and childhood infection

Adult infection

Natural History of Chronic HBV Infection

Hepatitis B Disease Progression

Natural Course of Chronic HBV

4 Phases of Chronic HBV Infection

Stages of Chronic Hepatitis B

•         Immune Tolerant Phase.

•         Immune Clearance Phase.

•         Chronic Inactive Carrier Phase.

•         Immune Reactivation Phase.

IMMUNE TOLERANT PHASE

•         Characterised by no immune response

•         Very high levels of HBV DNA

•         HBe-antigen positive

•         Normal or near normal ALT

•         Minimal or no necroinflammatory activity

•         Highly Contagious.

Natural Course of CHB

IMMUNE CLEARANCE PHASE

•         Hepatits activity,Flares, decompensation.

•         ALT may go over five times normal.

•         Gradual decline of viral load.

•         Gradual decline in necroinflammatory activity.

•         Hb-e antigen clearance with appearance of Hb-e antibody-seroconversion

Natural Course of CHB

CHRONIC INACTIVE CARRIER

•         ALT normal or near normal.

•         Low to undetectable DNA.

•         No to very little inflammatory activity in liver.

•         70%-85% remain in this stage.

•         HBsAg spontaneous clearance 1.5%/yr.

•         Cumulative 8% at 10yrs;25% at 20yrs and 45% at 40yr.

REACTIVATION PHASE

•         1.5%  of inactive carriers annually relapse.

•         Variant of immune clearance.

•         HBV variants in precore or core promotor region.

•         HBe negative and anti-HBe positive.

•         HBV DNA rises to between 2000-20 million ui/l. Necroinflammatory activity restarts.

•         Generally have more advanced disease.

Case 1: Patient History

•         40-yr-old male

•         ALT 28 IU/L

•         HBsAg positive, HBeAg positive

•         Serum HBV DNA 60,000,000 IU/mL

•         Negative viral serologies for hepatitis A and C and HIV

•         Abdominal ultrasound without any significant abnormalities

•         Previous medical history noncontributory

•         No family history of liver disease

•         No tobacco use;)

Clinical Profiles of Chronic
HBV Infection

	Immune Tolerant	HBeAg+ CHB	Inactive HBsAg Carrier	HBeAg- CHB (Precore Mutant)
HBsAg	+	+	+	+
HBeAg	+	+	–	–
Anti-HBe	–	–	+	+
ALT	Normal	á	Normal	á
HBV DNA	> 20,000 IU/mL (> 105 copies/mL)	> 20,000 IU/mL (> 105 copies/mL)	< 2000 IU/mL (< 104copies/mL)	> 2000 IU/mL (> 104 copies/mL)
Histology	Normal/mild	Active	Normal	Active

AASLD Guideline Recommendations for HBV Screening

•         US-born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity

•         Persons with chronically elevated aminotransferases

•         Persons needing immunosuppressive therapy

•         Men who have sex with men

•         Persons with multiple sexual partners or history of sexually transmitted disease

•         Inmates of correctional facilities

•         Persons who have ever used injection drugs

•         Dialysis patients

•         HIV- or HCV-infected individuals

•         Pregnant women

•         Family members, household members, and sexual contacts of HBV-infected

Initial Evaluation of Chronic HBV–Infected Patients

•         History and physical examination

•         Family history of liver disease, HCC

•         Laboratory tests to assess liver disease: CBC with platelets, hepatic panel, and prothrombin time

•         Tests for HBV replication: HBeAg/anti-HBe, HBV DNA

•         Tests to rule out viral coinfections: anti-HCV, anti-HDV (in persons from countries where HDV infection is common and in those with history of injection drug use), and anti-HIV in those at risk

•         Tests to screen for HCC: AFP and ultrasound as appropriate

•         Consider liver biopsy to grade and stage liver disease: for patients who meet criteria for chronic hepatitis

Risk Factors for Progression to Cirrhosis or HCC in HBsAg-Positive Individuals

•         Host

–        Older age (> 40 yrs)

–        Male sex

–        Asian/African ancestry

–        HCC family history

•         Clinical

–        Cirrhosis

–        HCV coinfection

•         Viral

–        HBeAg positive

–        Higher HBV DNA

–        Genotype B, C

–        Precore mutation

–        Basal core promoter mutation

•         Other

–        Smoking, alcohol

–        Obesity, diabetes

Interpretation of Serologic Results

HBsAg	Total Anti-HBc	IgM Anti-HBc	Anti-HBs	Interpretation
Negative	Negative	--	Negative	Susceptible; offer vaccination
Negative	Positive	--	Positive	Immune due to natural infection
Negative	Negative	--	Positive	Immune due to hepatitis B vaccination
Positive	Positive	Negative	Negative	Chronic HBV infection
Positive	Positive	Positive	Negative	Acute HBV infection
Negative	Positive	--	Negative	Unclear; could be any one of the following: 1. Resolved infection (most common) 2. False-positive anti-HBc; susceptible 3. “Low-level” chronic infection 4. Resolving acute infection

Is the HBV Infection Chronic

Chronic infection

–        HBsAg measured 6 months apart

–        Absence of IgM anti-HBc

–        HBV DNA

–        HBeAg

–        Raised, fluctuating, abnormal ALT

Chronic Hepatitis B Disease Types

•         HBeAg positive

–        Also known as “wild type”

–        Antibody to HBeAg negative

–        HBV DNA > 20,000 IU/mL (> 10⁵ copies/mL)

•         HBeAg negative

–        Also known as “precore mutant”

–        Antibody to HBeAg positive

–        HBV DNA > 2000 IU/mL (> 10⁴ copies/mL)

Serological profile of patients with pre-core mutant CHB

•         HBsAg +ve

•         HBeAg -ve

•         Anti HBe +ve

•         HBV DNA +ve

•         Elevated serum ALT +/-

What Is an Elevated ALT Level?

•         Reference ranges for ALT vary between 2 most widely used commercial laboratories

–        Men: 4-60 IU/L; women: 6-40 IU/L

–        Men: 0-55 IU/L; women: 0-40 IU/L

•         Both AASLD and US treatment algorithms recommend lower ULN levels for ALT when making treatment-initiation decisions

–        30 IU/L for men

–        19 IU/L for women

Remember

•         Natural history of HBV passes through various phases which are determined by interaction between the virus and the host immune system.

•         These phases have an extremely important bearing on the development of the treatment algorithms.

•         Still some questions remain unanswered.

UNANSWERED QUESTIONS

•         What factors determine about the longevity of each stage in a particular person?

•         What triggering mechanisms exist which are responsible for the switching to the next stage?

HBV Screening Algorithm

What Information Is Needed to Determine HBV Treatment Candidacy?

•         HBeAg

•         ALT

•         HBV DNA

•         Liver histology

•         Family history?

Treatment Criteria for Chronic Hepatitis B

•         Recommended HBV DNA and ALT levels outlined in the following table

Liver Society Guidelines*	HBeAg Positive		HBeAg Negative
	HBV DNA, IU/mL	ALT	HBV DNA, IU/mL	ALT
EASL 2009[1]	> 2000	> ULN†	> 2000	> ULN†
APASL 2008[2]	≥ 20,000	> 2 x ULN†	≥ 2000	> 2 x ULN†
AASLD 2009[3]	> 20,000	> 2 x ULN‡ or (+) biopsy	≥ 20,000**	≥ 2 x ULN‡ or (+) biopsy

HBV Treatment Landscape in 2013

The First Branch Point in Choosing
With What to Treat

When to Consider PegIFN

•         Favorable predictors of response^[1,2]

–        Low HBV DNA*

–        High ALT*

–        Genotype A or B > C or D^[3-5]

•         Specific patient demographics^[1,2]

–        Generally young people

•         Young women wanting pregnancy in near future

–        Absence of comorbidities

•         Patient preference^[1,2]

•         Concomitant HCV infection

*Also predictive of response to nucleos(t)ide analogues

Limitations of Response to
Finite-Duration PegIFN Therapy

•         HBeAg seroconversion in HBeAg-positive patients treated with pegIFN for 1 yr

–        25% to 35% after 3-5 yrs posttreatment follow-up

•         HBV DNA ≤ 400 copies/mL in HBeAg-negative patients treated with pegIFN for 1 yr

–        13% to 18% after 3-5 yrs posttreatment follow-up

The Second Branch Point in Choosing
With What to Treat

Tolerability and Safety:
Nucleos(t)ide Analogues vs Peginterferon.

Nucleos(t)ide Analogues

•         Safe at all stages of disease, including decompensated cirrhosis

•         Safe in immunocompromised populations

–        Selected drugs probably safe in pregnancy

•         Reported toxicities are rare

Peginterferon

•         Contraindications

–        Decompensated cirrhosis

–        Pregnancy

–        Chemotherapy prophylaxis

–        Acute HBV infection

•         Not recommended

–        Cirrhosis

•         Adverse effects common

HBV Treatment Roadmap
an Example

Undetectable* HBV DNA in HBV Patients after 1 Year of Treatment

HBeAg Loss and Seroconversion in   HBeAg+ Patients After 1 Year of Treatment

HBsAg level at Week 24 is associated with 1 year Post-treatment response

51% of patients with HBsAg <1500 IU/mL at week 24 achieved HBeAg seroconversion 1 year post-treatment

Undetectable HBV DNA over Time in HBeAg-Negative Patients

Efficacy of Entecavir vs Tenofovir in the Setting of Resistance

MONITORING OF TREATMENT OF CHB

•         INF

•         NUC

Monitoring of Patients Receiving
(Peg)IFN Therapy

Time Point	Monitoring
During treatment
Every 4 wks	§   Blood counts §   Liver panel
Every 12 wks	§   TSH §   HBV DNA levels
Every 24 wks	§   HBeAg/anti-HBe (if initially HBeAg positive)
Posttreatment
Every 12 wks during first 24 wks	§   Blood counts §   Liver panel §   TSH §   HBV DNA §   HBeAg/anti-HBe (if initially HBeAg positive)

Monitoring of Patients Receiving Nucleos(t)ide Analogue Therapy

Time Point	Monitoring
Every 12 wks	§  Liver panel §  Serum creatinine (if receiving TDF or ADV)
Every 12-24 wks	§  HBV DNA levels
Every 24 wks	§  HBeAg/anti-HBe (if initially HBeAg positive)
Every 6-12 mos	§  HBsAg in HBeAg-negative patients with persistently undetectable HBV DNA

Prevention and Monitoring of Resistance

Prevention

Avoid unnecessary treatment

Initiate potent antiviral that has low rate of drug resistance or use combination therapy

Switch to alternative therapy in patients with primary nonresponse

Monitoring

Test for serum HBV DNA (PCR) every 3-6 mos during tx

Check for medication compliance in patients with virologic breakthrough

Confirm antiviral resistance with genotypic testing

Management of Antiviral-Resistant HBV

Treatment	Strategy
Lamivudine resistance	§   Add adefovir or tenofovir §   Stop lamivudine and switch to tenofovir/emtricitabine*
Adefovir resistance	§   Add lamivudine† §   Stop adefovir and switch to tenofovir/emtricitabine* §   Switch to or add entecavir*†
Entecavir resistance	§   Switch to tenofovir or tenofovir/emtricitabine*
Telbivudine resistance‡	§   Add adefovir or tenofovir §   Stop telbivudine and switch to tenofovir/emtricitabine
Tenofovir resistance§	§   May add entecavir, telbivudine, lamivudine, or emtricitabine

CONTROVERSIES IN HBV

•         Pregnancy and HBV

CONTROVERSIES IN HBV

•         HIV AND HBV COINFECTION

Management of Patients With HIV Coinfection

•         HBV/HIV-coinfected patients who require HBV therapy should be treated^[1]

–        Liver biopsy should be considered in patients with fluctuating or mildly elevated ALT (1-2 x normal)

Not on or Anticipating Antiretroviral Therapy*	Planning Antiretroviral Therapy	Already Receiving Antiretroviral Therapy
§  Treat with antiviral therapy that is not active vs HIV, such as pegIFN or ADV 10 mg §  Although LdT does not target HIV, it should not be used in this circumstance	§  Treat with therapies that are effective against both viruses: TDF + (FTC or LAM) preferred (plus ≥ 1 other anti-HIV agent)	§  If regimen does not include drug active against HBV, may add pegIFN or ADV §  If LAM resistance, add TDF

CONTROVERSIES IN HBV

•         IMMUNOSUPPRESSANT AND HBV

Management of HBV During Chemotherapy or Immunosuppression.

•         Reactivation of HBV replication common during immunosuppression/chemotherapy (20% to 50%)

•         Prophylactic antiviral therapy recommended in HBV carriers at onset of cancer chemotherapy or immunosuppressive therapy

–        If baseline HBV DNA < 2000 IU/mL, continue treatment for
6 mos after

–        If baseline HBV DNA > 2000 IU/mL, continue treatment until they reach treatment endpoints for hepatitis B

•         Tenofovir or entecavir preferred if treatment for > 12 mos

Learning Points

Ø  Selection of patients with HBV related cirrhosis

Ø  Goals of treatment

Ø  Treatment options

Ø  How to treat?

Ø  How long to treat?

HBV related Cirrhosis

Ø  Compensated Cirrhosis with bridging Fibrosis

Ø  Decompensated Cirrhosis

–        HBeAg positive disease patients

–        HBeAg negative disease patients

Treatment Goals- Compensated Cirrhosis

Primary end points

ü  Prevention of decompensation

ü  Prevention of development of HCC

ü  Improvement of histological score

ü  Suppression of HBV DNA

Secondary end points

ü  Seroconversion of HBeAg

ALT normalization

Treatment Goals- Decompensated Cirrhosis

Primary end Point:

•         Stabilization of liver function/reversal of decompensation

•         Delay of the need of Liver transplantation

•         Reduction of the risk of HBV recurrence following LT

•         Prevention of HCC

•         Suppression of HBV DNA

•         Improved survival

Secondary end Point:

•         Seroconversion of HBeAg

•         ALT normalization

Treatment options for HBV in Cirrhosis

•         Interferon

Does not help

Problem of dose related cytopenias and bacterial infections

•         Oral anti viral agents

Drugs of choice

Management of Patients With Compensated Cirrhosis

Preferred therapies

•         ETV or TDF

–        NAs should be used; IFN can be associated with hepatitis flare

Treatment duration

•         Long-term treatment

–        Can discontinue in HBeAg-positive patients with confirmed HBeAg seroconversion and ≥ 6 mos consolidation therapy

–        Can discontinue in HBeAg-negative patients with confirmed HBsAg clearance

•         Treatment discontinuation requires close monitoring for flare or relapse

Treatment Monitoring

•         Compensated cirrhosis

–        Monthly renal profile

–         Liver Function Tests

–        3-6 monthly HBV DNA quantitaion

–        Annual HBeAg status

–        Annual Liver biopsy

–        Alpha feto protein and HCC surveillance

Management of Patients With Decompensated Cirrhosis

Preferred therapies

§  (LAM or LdT) + (ADV or TDF); TDF or ETV monotherapy*

–     Treatment should be coordinated with transplantation center

–     IFNs should not be used in decompensated cirrhosis

Treatment duration

§  Lifelong treatment recommended

Treatment Monitoring

•         Decompensated cirrhosis

–        Monthly renal profile

–        Quarterly Liver Function Tests

–        3-6 monthly HBV DNA quantitaion

–        Alpha fetoprotein estimation and HCC surveillance, 6-12 months

Prevention of HBV

Awareness

Awareness

Awareness

Vaccination

•         3 DOSES,IM

•         0,1,6 MONTHS

•         95 PERCENT PROTECTION