Treatment of the HBV-Infected Patient: When to Start, When to Stop, and When to Change Therapy-1 of

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Selection from: Hepatitis B: Advances in Screening, Diagnosis, and Clinical

Management

Treatment of the HBV-Infected Patient: When to Start, When to Stop, and When to

Change Therapy CME

Emmet B. Keeffe, MD, MACP

Disclosures

Introduction

Chronic hepatitis B virus (HBV) infection is a potentially serious disease that

can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma

(HCC). It is estimated that 350 to 400 million people worldwide are chronically

infected with HBV.[1,2] In the United States, there are an estimated 1.25

million people with HBV infection,[3] but this estimate fails to account for

persons who are incarcerated or who are immigrants from endemic regions with

high rates of HBV infection. The size of the Asian-American population has

increased significantly over the last decade, and recent surveys of Asian-,

Korean-, and Vietnamese-Americans have shown that 10% to 23% have detectable

hepatitis B surface antigen (HBsAg).[4,5] In spite of the known progressive

natural history of chronic HBV infection, chronic hepatitis B patients who meet

criteria for treatment based on standard guidelines have generally been

undertreated. However, therapeutic options to control viral replication and

disease progression fortunately continue to expand,[6-11] and these advances

will likely result in more patients undergoing treatment and deriving long-term

benefits with a reduced incidence of cirrhosis and HCC.[12]

Natural History of Chronic HBV Infection

HBV is spread parenterally via perinatal transmission or through contact with

infected blood or bodily fluids. The most common risk factors include children

born of mothers with HBV infection, high-risk sexual behavior, and injection

drug use. Individuals infected as a newborn or in early childhood are usually

asymptomatic, and chronic infection occurs in 30% to 90% of these cases. Adults

are more likely to be symptomatic, and the rate of chronic infection is much

lower, ranging from 2% to 5%. Although the diagnosis of chronic HBV infection is

formally based on the serologic detection of HBsAg on 2 separate occasions 6

months apart, this waiting period is usually not necessary in appropriate

clinical settings, such as the detection of HBsAg in an Asian-American with

other family members who have chronic hepatitis B.[7,8]

The natural history of chronic HBV infection can be divided into 4 phases:

immune tolerance, immune clearance (hepatitis B e antigen [HBeAg]-positive

chronic hepatitis , inactive HBsAg carrier state, and reactivation

(HBeAg-negative chronic hepatitis .[2] The immune tolerance phase, present in

those patients infected at birth or early childhood, is characterized by the

presence of HBeAg, high serum HBV DNA levels (at least> 20,000 IU/mL and usually

much higher), and persistently normal alanine aminotransferase (ALT) levels.

This phase is followed by an immune clearance phase of variable duration, with

serum HBV DNA levels remaining high, but with serum ALT levels that are

persistently or intermittently elevated and features of chronic hepatitis with

or without fibrosis present on liver biopsy.

Clearance of HBeAg and development of anti-HBe (HBeAg seroconversion) usually

results in transition to the inactive HBsAg carrier state, typified by serum HBV

DNA levels that are < 2000 IU/mL or undetectable, and normal ALT levels. The

majority of patients in this phase have a relatively benign course, but some may

undergo reactivation, and the risk of developing HCC, although lower, is still

present.[2,7,8]

Finally, some patients, under immune pressure either during the period of HBeAg

seroconversion or after a period of time in the inactive carrier state, develop

precore or basal core promoter mutations that abolish or downregulate production

of HBeAg, but HBV continues to replicate at high levels and cause various

degrees of liver damage. This fourth phase of chronic HBV infection is referred

to as HBeAg-negative chronic hepatitis B and is characterized by fluctuating

serum HBV DNA levels> 2000 IU/mL, persistently or intermittently elevated ALT

levels, and progressive liver damage on liver biopsy.[2,7,8]

When to Start Therapy

Treatment is indicated in patients in the immune clearance and reactivation

phases (ie, in those individuals with high serum HBV DNA levels, elevated ALT

levels, and/or necroinflammation on liver biopsy, and who are predicted to have

the highest chance of response to therapy). Liver biopsy is not performed

routinely in practice but may be helpful when candidacy for therapy is

uncertain, such as in the differential diagnosis of an inactive carrier vs

HBeAg-negative chronic hepatitis B, or to determine if significant liver disease

is present in the older patient with normal serum ALT

levels.[6-8] The revised normal ALT levels should be used when considering

criteria for treatment (ie, upper limits of normal (ULN) for men = 30 U/L, and

for women = 19 U/L).[7]

The primary goal of therapy for chronic hepatitis B is long-term suppression of

serum HBV DNA, which will likely decrease progression to cirrhosis and HCC, as

based on results of large cohort studies from Taiwan showing that baseline serum

HBV DNA levels ≥ 104 copies/mL were associated with the subsequent development

of these complications more than a decade

later.[13,14] Furthermore, in patients with advanced hepatic fibrosis or

cirrhosis, the administration of lamivudine over 3 years has been shown to

decrease the likelihood of decompensation of chronic liver disease and the

incidence of new HCC.[15]

The medications currently approved by the US Food and Drug Administration (FDA)

for the initial treatment of chronic hepatitis B include interferon alfa-2b,

peginterferon alfa-2a, and the oral nucleoside/nucleotide analogs lamivudine,

adefovir dipivoxil, entecavir, and telbivudine, with tenofovir under FDA review

for likely approval in 2008.

Each of these drugs has a number of advantages and disadvantages. Issues for

consideration in the selection of therapy include efficacy, safety, incidence of

resistance, method of administration, and cost. Peginterferon alfa-2a has the

advantages of a 1-year finite duration of therapy, higher rate of HBeAg

seroconversion at 1 year, lack of resistance, and higher likelihood of HBsAg

loss and seroconversion. Disadvantages of peginterferon therapy are parenteral

administration, frequent side effects (especially flu-like symptoms, depression

or irritability, and cytopenias), need for more intensive laboratory monitoring,

contraindication in advanced liver disease, and higher cost.[6-8] Genotyping may

be useful to help decide whether treatment with peginterferon alfa-2a is

warranted based on the highest rate of efficacy being in patients with genotype

A and lowest efficacy being in those infected with HBV genotype D.[6-8] The

nucleoside/nucleotide agents have the advantages of oral administration,

excellent tolerance, use in advanced liver disease, and high potency in lowering

serum HBV DNA levels. The primary disadvantages of these agents are the need for

long-term administration and variable rates of antiviral drug resistance.[6-8]

Oral drugs with a high genetic barrier to resistance and/or high potency (eg,

entecavir or tenofovir) are generally preferred to reduce the likelihood of

resistance.[7,8,16] The preferred options for the treatment of chronic hepatitis

B in 2008 will likely include peginterferon alfa-2a, entecavir, tenofovir, and

potentially telbivudine, providing serum HBV DNA is undetectable after 24 weeks

of therapy, which predicts the absence or very low rate of resistance at year 1

and year 2 of therapy with this agent.[16,17] Interferon alfa-2b is no longer

used given the availability and convenience of peginterferon alfa-2a, and

lamivudine is not recommended as initial therapy on the basis of an unacceptably

high rate of resistance and proven inferiority to both entecavir and telbivudine

in pivotal trials.[7,8] Tenofovir, which was recently shown to be superior to

adefovir,[18,19] will likely replace adefovir as a preferred initial therapy in

2008 following its approval by the FDA and regulatory agencies in other

countries.[16]

A treatment algorithm for chronic hepatitis B previously developed and published

by a panel of hepatologists from the United States in 2006[8] was recently

updated in December 2007 and is being prepared for publication.[16] This

algorithm extends evidence-based recommendations of published society guidelines

from the American Association for the Study of Liver Diseases (AASLD),[8] the

European Association for the Study of the Liver (EASL),[9] and the Asian Pacific

Association for the Study of the Liver (APASL).[10,11]

Among patients with HBeAg-positive chronic hepatitis B and compensated liver

disease, those with serum HBV DNA ≥ 20,000 IU/mL plus an ALT level greater

than the ULN and/or significant disease on liver biopsy are candidates for

therapy (Table 1).[7,8,16] For those patients with HBeAg-negative chronic

hepatitis B and compensated liver disease, a lower serum HBV DNA threshold of

≥ 2000 IU/mL, along with an elevated ALT level and/or significant disease on

liver biopsy, is an indication for therapy (Table 2).[7,8,16]

Table 1. Recommendations for Treatment: HBeAg-Positive Patients[7]

HBeAg Status HBV DNAa ALTb Treatment Strategy

Positive

< 20,000 Normal No treatment

Monitor every 6-12 monthsc

Consider therapy in patients with known significant histologic disease even if

low-level replication

Positive

≥ 20,000 Normal Low rate of HBeAg seroconversion for all treatments

Younger patients often immune tolerant

Consider liver biopsy examination, particularly if older than age 35-40 years;

treat if disease; in the absence of biopsy examination, observe for increase in

ALT levels

If treated, entecavir, adefovir,* or peginterferon alfa-2a are preferredd;

telbivudine possible for patients with undetectable HBV DNA at week 24 of

therapy

For individuals receiving treatment, continue 6-12 months after HBeAg →

anti-HBe and HBV DNA negative

Positive

≥ 20,000 Elevated Entecavir, adefovir,* or peginterferon alfa-2a are

preferred first-line optionsd,e; telbivudine possible for patients with

undetectable HBV DNA at week 24 of therapy

If high HBV DNA, entecavir, adefovir,* or telbivudine preferred over

peginterferon alfa-2a

For individuals receiving treatment, continue 6-12 months after HBeAg →

anti-HBe and HBV DNA negative

HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; ALT = alanine

aminotransferase; anti-HBe = antibody to hepatitis B e antigen

*Tenofovir should replace adefovir as the preferred initial therapy after

licensure in 2008.

aValues shown in IU/mL (1 IU/mL is equivalent to approximately 5.6 copies/mL).

bThe upper limit of normal for serum ALT concentrations for men and women are 30

IU/L and 19 IU/L, respectively.

cOn initial diagnosis, every 3 months for 1 year to ensure stability.

dGenotyping may be useful to help decide between treating with peginterferon

alfa-2a rather than an oral agent (ie, peginterferon has been shown to be

considerably more effective in patients with genotype A vs D).

ePeginterferon alfa-2a, entecavir, and telbivudine are preferred over lamivudine

because they have been shown to be superior in randomized clinical trials and/or

have lower rates of resistance.

Modified from Keeffe EB, Dieterich DT, Han SB, et al. A treatment algorithm for

the management of chronic hepatitis B virus infection in the United States: an

update. Clin Gastroenterol Hepatol. 2006;4:936-962.

Table 2. Recommendations for Treatment: HBeAg-Negative Patients[7]

HBeAg Status HBV DNAa ALTb Treatment Strategy

Negative

< 2000 Normal No treatment; majority inactive HBsAg carriers

Monitor every 6-12 monthsc

Consider therapy in patients with known significant histologic disease even if

low-level replication

Negative

≥ 2000 Normal Consider liver biopsy examination; treat if disease; in the

absence of biopsy examination, observe for increase in ALT levels

If treated, entecavir, adefovir,* or peginterferon alfa-2a are preferredd;

telbivudine possible for patients with undetectable HBV DNA at week 24 of

therapy

For individuals receiving treatment, the course of peginterferon is 1 year,

whereas long-term treatment is recommended for oral agents

Negative

≥ 2000 Elevated Entecavir, adefovir,* or peginterferon alfa-2a are preferred

first-line optionsd;

telbivudine possible for patients with undetectable HBV DNA at week 24 of

therapy

For individuals receiving treatment, the course of peginterferon is 1 year

Long-term treatment required for oral agents

HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B

surface antigen; ALT = alanine aminotransferase

*Tenofovir should replace adefovir as the preferred initial therapy after

licensure in 2008.

aValues shown in IU/mL (1 IU/mL is equivalent to approximately 5.6 copies/mL).

bThe upper limit of normal for serum ALT concentrations for men and women are 30

IU/L and 19 IU/L, respectively.

cOn initial diagnosis, every 3 months for 1 year to ensure stability.

dLamivudine is not considered a reasonable treatment option because of the high

risk for resistance with long-term therapy and proven inferiority to entecavir

and telbivudine in randomized clinical trials.

Modified from Keeffe EB, Dieterich DT, Han SB, et al. A treatment algorithm for

the management of chronic hepatitis B virus infection in the United States: an

update. Clin Gastroenterol Hepatol. 2006;4:936-962.

For patients with compensated cirrhosis, a serum HBV DNA threshold of ≥ 2000

IU/mL is sufficient for initiation of therapy, irrespective of HBeAg status and

regardless of whether ALT levels are elevated (Table 3).[7,8,16] For those with

chronic hepatitis B and decompensated cirrhosis, a serum HBV DNA level of ≥

200 IU/mL is sufficient to begin treatment with an oral agent as well as to

consider candidacy for liver transplantation.[7,16] Recent trends are to treat

patients with compensated or decompensated cirrhosis associated with any

detection of serum HBV DNA, irrespective of the level.[7,16] Oral agents are

preferred when treating patients with cirrhosis, and peginterferon is either

relatively or absolutely contraindicated in these patients.[7,8] There are also

increasing trends toward using combination nucleoside/nucleotide agents in

treating cirrhotic patients, as well as in treating patients with HBV and HIV

coinfection and individuals post liver transplantation performed for HBV

infection.[7,16]

Table 3. Recommendations for Treatment: HBeAg-Positive or -Negative Compensated

Cirrhotic Patients[7]

HBeAg Status HBV DNAa Cirrhosis Treatment Strategy

Positive or negative

< 2000 Compensated May choose to treat or observe

Entecavir or adefovir* preferredb

Positive or negative

≥ 2000 Compensated Entecavir or adefovir* are first-line options

Long-term treatment required, and combination therapy may be preferredc

Positive or negative

< 200 IU/mL or ≥ 200 IU/mL Decompensated Combination therapy preferredc

Long-term treatment required

Wait-list for liver transplantation

HBV = hepatitis B virus; HBeAg = hepatitis B e antigen

*Tenofovir should replace adefovir as the preferred initial therapy after

licensure in 2008.

aValues shown in IU/mL (1 IU/mL is equivalent to approximately 5.6 copies/mL).

bAlthough there are no data available for peginterferon alfa-2a, it may be an

option in patients with early, well-compensated cirrhosis.

cAdefovir or tenofovir plus lamivudine, telbivudine, or entecavir.

Modified from Keeffe EB, Dieterich DT, Han SB, et al. A treatment algorithm for

the management of chronic hepatitis B virus infection in the United States: an

update. Clin Gastroenterol Hepatol. 2006;4:936-962.

Finally, patients who require cancer chemotherapy or treatment with an

anti-tumor necrosis factor (TNF)-alpha agent and who have detectable HBsAg,

whether they are inactive carriers or have chronic hepatitis B that has not been

treated, should receive an oral antiviral agent as prophylaxis against

reactivation of HBV infection.[20] The antiviral agent should be started just

before and continued for 6 to 12 months after discontinuation of chemotherapy or

the anti-TNF agent, or should be used long-term if the patient meets standard

criteria for treatment of chronic

hepatitis B.[20]

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[Guest guest]

Selection from: Hepatitis B: Advances in Screening, Diagnosis, and Clinical

Management

Treatment of the HBV-Infected Patient: When to Start, When to Stop, and When to

Change Therapy CME

Emmet B. Keeffe, MD, MACP

Disclosures

Introduction

Chronic hepatitis B virus (HBV) infection is a potentially serious disease that

can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma

(HCC). It is estimated that 350 to 400 million people worldwide are chronically

infected with HBV.[1,2] In the United States, there are an estimated 1.25

million people with HBV infection,[3] but this estimate fails to account for

persons who are incarcerated or who are immigrants from endemic regions with

high rates of HBV infection. The size of the Asian-American population has

increased significantly over the last decade, and recent surveys of Asian-,

Korean-, and Vietnamese-Americans have shown that 10% to 23% have detectable

hepatitis B surface antigen (HBsAg).[4,5] In spite of the known progressive

natural history of chronic HBV infection, chronic hepatitis B patients who meet

criteria for treatment based on standard guidelines have generally been

undertreated. However, therapeutic options to control viral replication and

disease progression fortunately continue to expand,[6-11] and these advances

will likely result in more patients undergoing treatment and deriving long-term

benefits with a reduced incidence of cirrhosis and HCC.[12]

Natural History of Chronic HBV Infection

HBV is spread parenterally via perinatal transmission or through contact with

infected blood or bodily fluids. The most common risk factors include children

born of mothers with HBV infection, high-risk sexual behavior, and injection

drug use. Individuals infected as a newborn or in early childhood are usually

asymptomatic, and chronic infection occurs in 30% to 90% of these cases. Adults

are more likely to be symptomatic, and the rate of chronic infection is much

lower, ranging from 2% to 5%. Although the diagnosis of chronic HBV infection is

formally based on the serologic detection of HBsAg on 2 separate occasions 6

months apart, this waiting period is usually not necessary in appropriate

clinical settings, such as the detection of HBsAg in an Asian-American with

other family members who have chronic hepatitis B.[7,8]

The natural history of chronic HBV infection can be divided into 4 phases:

immune tolerance, immune clearance (hepatitis B e antigen [HBeAg]-positive

chronic hepatitis , inactive HBsAg carrier state, and reactivation

(HBeAg-negative chronic hepatitis .[2] The immune tolerance phase, present in

those patients infected at birth or early childhood, is characterized by the

presence of HBeAg, high serum HBV DNA levels (at least> 20,000 IU/mL and usually

much higher), and persistently normal alanine aminotransferase (ALT) levels.

This phase is followed by an immune clearance phase of variable duration, with

serum HBV DNA levels remaining high, but with serum ALT levels that are

persistently or intermittently elevated and features of chronic hepatitis with

or without fibrosis present on liver biopsy.

Clearance of HBeAg and development of anti-HBe (HBeAg seroconversion) usually

results in transition to the inactive HBsAg carrier state, typified by serum HBV

DNA levels that are < 2000 IU/mL or undetectable, and normal ALT levels. The

majority of patients in this phase have a relatively benign course, but some may

undergo reactivation, and the risk of developing HCC, although lower, is still

present.[2,7,8]

Finally, some patients, under immune pressure either during the period of HBeAg

seroconversion or after a period of time in the inactive carrier state, develop

precore or basal core promoter mutations that abolish or downregulate production

of HBeAg, but HBV continues to replicate at high levels and cause various

degrees of liver damage. This fourth phase of chronic HBV infection is referred

to as HBeAg-negative chronic hepatitis B and is characterized by fluctuating

serum HBV DNA levels> 2000 IU/mL, persistently or intermittently elevated ALT

levels, and progressive liver damage on liver biopsy.[2,7,8]

When to Start Therapy

Treatment is indicated in patients in the immune clearance and reactivation

phases (ie, in those individuals with high serum HBV DNA levels, elevated ALT

levels, and/or necroinflammation on liver biopsy, and who are predicted to have

the highest chance of response to therapy). Liver biopsy is not performed

routinely in practice but may be helpful when candidacy for therapy is

uncertain, such as in the differential diagnosis of an inactive carrier vs

HBeAg-negative chronic hepatitis B, or to determine if significant liver disease

is present in the older patient with normal serum ALT

levels.[6-8] The revised normal ALT levels should be used when considering

criteria for treatment (ie, upper limits of normal (ULN) for men = 30 U/L, and

for women = 19 U/L).[7]

The primary goal of therapy for chronic hepatitis B is long-term suppression of

serum HBV DNA, which will likely decrease progression to cirrhosis and HCC, as

based on results of large cohort studies from Taiwan showing that baseline serum

HBV DNA levels ≥ 104 copies/mL were associated with the subsequent development

of these complications more than a decade

later.[13,14] Furthermore, in patients with advanced hepatic fibrosis or

cirrhosis, the administration of lamivudine over 3 years has been shown to

decrease the likelihood of decompensation of chronic liver disease and the

incidence of new HCC.[15]

The medications currently approved by the US Food and Drug Administration (FDA)

for the initial treatment of chronic hepatitis B include interferon alfa-2b,

peginterferon alfa-2a, and the oral nucleoside/nucleotide analogs lamivudine,

adefovir dipivoxil, entecavir, and telbivudine, with tenofovir under FDA review

for likely approval in 2008.

Each of these drugs has a number of advantages and disadvantages. Issues for

consideration in the selection of therapy include efficacy, safety, incidence of

resistance, method of administration, and cost. Peginterferon alfa-2a has the

advantages of a 1-year finite duration of therapy, higher rate of HBeAg

seroconversion at 1 year, lack of resistance, and higher likelihood of HBsAg

loss and seroconversion. Disadvantages of peginterferon therapy are parenteral

administration, frequent side effects (especially flu-like symptoms, depression

or irritability, and cytopenias), need for more intensive laboratory monitoring,

contraindication in advanced liver disease, and higher cost.[6-8] Genotyping may

be useful to help decide whether treatment with peginterferon alfa-2a is

warranted based on the highest rate of efficacy being in patients with genotype

A and lowest efficacy being in those infected with HBV genotype D.[6-8] The

nucleoside/nucleotide agents have the advantages of oral administration,

excellent tolerance, use in advanced liver disease, and high potency in lowering

serum HBV DNA levels. The primary disadvantages of these agents are the need for

long-term administration and variable rates of antiviral drug resistance.[6-8]

Oral drugs with a high genetic barrier to resistance and/or high potency (eg,

entecavir or tenofovir) are generally preferred to reduce the likelihood of

resistance.[7,8,16] The preferred options for the treatment of chronic hepatitis

B in 2008 will likely include peginterferon alfa-2a, entecavir, tenofovir, and

potentially telbivudine, providing serum HBV DNA is undetectable after 24 weeks

of therapy, which predicts the absence or very low rate of resistance at year 1

and year 2 of therapy with this agent.[16,17] Interferon alfa-2b is no longer

used given the availability and convenience of peginterferon alfa-2a, and

lamivudine is not recommended as initial therapy on the basis of an unacceptably

high rate of resistance and proven inferiority to both entecavir and telbivudine

in pivotal trials.[7,8] Tenofovir, which was recently shown to be superior to

adefovir,[18,19] will likely replace adefovir as a preferred initial therapy in

2008 following its approval by the FDA and regulatory agencies in other

countries.[16]

A treatment algorithm for chronic hepatitis B previously developed and published

by a panel of hepatologists from the United States in 2006[8] was recently

updated in December 2007 and is being prepared for publication.[16] This

algorithm extends evidence-based recommendations of published society guidelines

from the American Association for the Study of Liver Diseases (AASLD),[8] the

European Association for the Study of the Liver (EASL),[9] and the Asian Pacific

Association for the Study of the Liver (APASL).[10,11]

Among patients with HBeAg-positive chronic hepatitis B and compensated liver

disease, those with serum HBV DNA ≥ 20,000 IU/mL plus an ALT level greater

than the ULN and/or significant disease on liver biopsy are candidates for

therapy (Table 1).[7,8,16] For those patients with HBeAg-negative chronic

hepatitis B and compensated liver disease, a lower serum HBV DNA threshold of

≥ 2000 IU/mL, along with an elevated ALT level and/or significant disease on

liver biopsy, is an indication for therapy (Table 2).[7,8,16]

Table 1. Recommendations for Treatment: HBeAg-Positive Patients[7]

HBeAg Status HBV DNAa ALTb Treatment Strategy

Positive

< 20,000 Normal No treatment

Monitor every 6-12 monthsc

Consider therapy in patients with known significant histologic disease even if

low-level replication

Positive

≥ 20,000 Normal Low rate of HBeAg seroconversion for all treatments

Younger patients often immune tolerant

Consider liver biopsy examination, particularly if older than age 35-40 years;

treat if disease; in the absence of biopsy examination, observe for increase in

ALT levels

If treated, entecavir, adefovir,* or peginterferon alfa-2a are preferredd;

telbivudine possible for patients with undetectable HBV DNA at week 24 of

therapy

For individuals receiving treatment, continue 6-12 months after HBeAg →

anti-HBe and HBV DNA negative

Positive

≥ 20,000 Elevated Entecavir, adefovir,* or peginterferon alfa-2a are

preferred first-line optionsd,e; telbivudine possible for patients with

undetectable HBV DNA at week 24 of therapy

If high HBV DNA, entecavir, adefovir,* or telbivudine preferred over

peginterferon alfa-2a

For individuals receiving treatment, continue 6-12 months after HBeAg →

anti-HBe and HBV DNA negative

HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; ALT = alanine

aminotransferase; anti-HBe = antibody to hepatitis B e antigen

*Tenofovir should replace adefovir as the preferred initial therapy after

licensure in 2008.

aValues shown in IU/mL (1 IU/mL is equivalent to approximately 5.6 copies/mL).

bThe upper limit of normal for serum ALT concentrations for men and women are 30

IU/L and 19 IU/L, respectively.

cOn initial diagnosis, every 3 months for 1 year to ensure stability.

dGenotyping may be useful to help decide between treating with peginterferon

alfa-2a rather than an oral agent (ie, peginterferon has been shown to be

considerably more effective in patients with genotype A vs D).

ePeginterferon alfa-2a, entecavir, and telbivudine are preferred over lamivudine

because they have been shown to be superior in randomized clinical trials and/or

have lower rates of resistance.

Modified from Keeffe EB, Dieterich DT, Han SB, et al. A treatment algorithm for

the management of chronic hepatitis B virus infection in the United States: an

update. Clin Gastroenterol Hepatol. 2006;4:936-962.

Table 2. Recommendations for Treatment: HBeAg-Negative Patients[7]

HBeAg Status HBV DNAa ALTb Treatment Strategy

Negative

< 2000 Normal No treatment; majority inactive HBsAg carriers

Monitor every 6-12 monthsc

Consider therapy in patients with known significant histologic disease even if

low-level replication

Negative

≥ 2000 Normal Consider liver biopsy examination; treat if disease; in the

absence of biopsy examination, observe for increase in ALT levels

If treated, entecavir, adefovir,* or peginterferon alfa-2a are preferredd;

telbivudine possible for patients with undetectable HBV DNA at week 24 of

therapy

For individuals receiving treatment, the course of peginterferon is 1 year,

whereas long-term treatment is recommended for oral agents

Negative

≥ 2000 Elevated Entecavir, adefovir,* or peginterferon alfa-2a are preferred

first-line optionsd;

telbivudine possible for patients with undetectable HBV DNA at week 24 of

therapy

For individuals receiving treatment, the course of peginterferon is 1 year

Long-term treatment required for oral agents

HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B

surface antigen; ALT = alanine aminotransferase

*Tenofovir should replace adefovir as the preferred initial therapy after

licensure in 2008.

aValues shown in IU/mL (1 IU/mL is equivalent to approximately 5.6 copies/mL).

bThe upper limit of normal for serum ALT concentrations for men and women are 30

IU/L and 19 IU/L, respectively.

cOn initial diagnosis, every 3 months for 1 year to ensure stability.

dLamivudine is not considered a reasonable treatment option because of the high

risk for resistance with long-term therapy and proven inferiority to entecavir

and telbivudine in randomized clinical trials.

Modified from Keeffe EB, Dieterich DT, Han SB, et al. A treatment algorithm for

the management of chronic hepatitis B virus infection in the United States: an

update. Clin Gastroenterol Hepatol. 2006;4:936-962.

For patients with compensated cirrhosis, a serum HBV DNA threshold of ≥ 2000

IU/mL is sufficient for initiation of therapy, irrespective of HBeAg status and

regardless of whether ALT levels are elevated (Table 3).[7,8,16] For those with

chronic hepatitis B and decompensated cirrhosis, a serum HBV DNA level of ≥

200 IU/mL is sufficient to begin treatment with an oral agent as well as to

consider candidacy for liver transplantation.[7,16] Recent trends are to treat

patients with compensated or decompensated cirrhosis associated with any

detection of serum HBV DNA, irrespective of the level.[7,16] Oral agents are

preferred when treating patients with cirrhosis, and peginterferon is either

relatively or absolutely contraindicated in these patients.[7,8] There are also

increasing trends toward using combination nucleoside/nucleotide agents in

treating cirrhotic patients, as well as in treating patients with HBV and HIV

coinfection and individuals post liver transplantation performed for HBV

infection.[7,16]

Table 3. Recommendations for Treatment: HBeAg-Positive or -Negative Compensated

Cirrhotic Patients[7]

HBeAg Status HBV DNAa Cirrhosis Treatment Strategy

Positive or negative

< 2000 Compensated May choose to treat or observe

Entecavir or adefovir* preferredb

Positive or negative

≥ 2000 Compensated Entecavir or adefovir* are first-line options

Long-term treatment required, and combination therapy may be preferredc

Positive or negative

< 200 IU/mL or ≥ 200 IU/mL Decompensated Combination therapy preferredc

Long-term treatment required

Wait-list for liver transplantation

HBV = hepatitis B virus; HBeAg = hepatitis B e antigen

*Tenofovir should replace adefovir as the preferred initial therapy after

licensure in 2008.

aValues shown in IU/mL (1 IU/mL is equivalent to approximately 5.6 copies/mL).

bAlthough there are no data available for peginterferon alfa-2a, it may be an

option in patients with early, well-compensated cirrhosis.

cAdefovir or tenofovir plus lamivudine, telbivudine, or entecavir.

Modified from Keeffe EB, Dieterich DT, Han SB, et al. A treatment algorithm for

the management of chronic hepatitis B virus infection in the United States: an

update. Clin Gastroenterol Hepatol. 2006;4:936-962.

Finally, patients who require cancer chemotherapy or treatment with an

anti-tumor necrosis factor (TNF)-alpha agent and who have detectable HBsAg,

whether they are inactive carriers or have chronic hepatitis B that has not been

treated, should receive an oral antiviral agent as prophylaxis against

reactivation of HBV infection.[20] The antiviral agent should be started just

before and continued for 6 to 12 months after discontinuation of chemotherapy or

the anti-TNF agent, or should be used long-term if the patient meets standard

criteria for treatment of chronic

hepatitis B.[20]

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