34-Year-Old Asian Man With Hepatitis B and Worsening LFT's on Antiviral Therapy

[Guest guest]

A 34-Year-Old Asian Man With Hepatitis B and Worsening Liver Function Tests

on Antiviral Therapy

http://www.medscape.com/editorial/cmetogo/5599Release Date: June 22, 2006;

Valid for credit through June 22, 2007

Authors: Sonja K. Olsen, MD; S. Brown, Jr, MD, MPH

Author Information and Disclosures

Credits Available

Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

Nurses - 0.3 ANCC continuing nurse education contact hours (0.3 contact

hours are in the area of pharmacology)

Supported by an independent educational grant from Gilead.

Introduction

Hepatitis B affects approximately 350 million people worldwide and an

estimated 1.25 million individuals in the United States.[1] There are an

estimated 100,000 people in the United States who become infected with

hepatitis B virus (HBV) each year despite universal vaccination practices

for children and widespread vaccination programs for adults thought to be at

high risk for infection.[2] Although most persons infected with the virus do

not develop significant hepatic disease, 15% to 40% will develop serious

complications.[3] These complications include cirrhosis, hepatocellular

carcinoma (HCC), and hepatic decompensation. Hepatitis B can be acquired

sexually, perinatally, or parenterally. The most common mode of transmission

depends on geography. In areas of low prevalence, such as the United States

and Canada, the most common mode of transmission is sexual contact followed

by intravenous-drug use. It is estimated that more than 50% of HBV in the

United States is acquired sexually.[4] In areas of high prevalence, such as

Southeast Asia and China, HBV is most commonly acquired perinatally.

The goals of therapy in HBV infection are not uniform. Because virologic

cure is usually not possible, and the ability to achieve durable viral

suppression varies, treatment decisions usually hinge on the patient's

serologic profile, the degree of liver injury, and the state of viral

replication. Suppression of viral replication and prevention of the

development of fibrosis and HCC are the primary goals for any patient.

Elimination of HBV from the serum, with seroconversion from hepatitis B

surface antigen positivity to hepatitis B surface antibody positivity, is

the rarely achieved but ultimate goal of therapy and may reflect actual

cure.

There are currently 5 medications approved by the US Food and Drug

Administration for the treatment of hepatitis B: interferon alfa-2b,

pegylated interferon alfa-2a, lamivudine, adefovir, and entecavir. The

arsenal of therapeutic options, diverse patient population, and lack of

clear guidelines make the treatment of hepatitis B a daunting task. The

National Institutes of Health (NIH) recently convened a panel of experts to

establish new guidelines for the treatment of hepatitis B. At the current

time, the official recommendations are not available, but the overall

consensus is that the number of patients who would benefit from therapy is

increasing, while the concern for viral resistance is growing, underscoring

the importance of implementing the optimal treatment regimen from the onset

of therapy.

Case Presentation

The patient is a 34-year-old Asian man who presents to clinic for further

evaluation of his " hepatitis. " He was born in Hong Kong and moved to the

United States in his teens. Approximately 2 years ago, his primary care

physician told him that his liver function tests (LFTs) were abnormal.

Further testing at that time found evidence of HBV infection, but he does

not have any additional information about his disease. He was started on

lamivudine therapy at a dose of 100 mg daily about 18 months ago, but has

been told that his LFTs are abnormal again. He has been compliant with his

medications. He is seeking another opinion. The patient reports no use of

over-the-counter medications; he denies any use of herbal medicines or other

new medicines in the past 6 months. Results of physical exam are

unremarkable. His aspartate aminotransferase level is 130 U/L (previously

reported in the 40-50 U/L range); alanine aminotransferase (ALT) level is

256 U/L (previously reported in the 40 U/L range).

What Is the Most Likely Explanation for This Patient's Elevated LFTs?

Although there are several possible etiologies for this patient's elevated

aminotransferases (acute viral hepatitis, medication effect, seroconversion

to anti-HBe antibody, etc.), the most likely explanation is that this

patient has developed resistance to lamivudine. Lamivudine resistance is a

significant clinical problem, with an estimated incidence of 14% to 20% at 1

year and 69% at 5 years.[5,6] It is typically detected in the setting of

elevated aminotransferases in a patient who has had stable LFTs while on

lamivudine therapy. Furthermore, the use of lamivudine in hepatitis B e

antigen (HBeAg)-negative patients is associated with more rapid development

of resistance -- 60% at 4 years.[7] Thus, it is imperative to follow LFTs

and HBV DNA levels in all patients who are on lamivudine monotherapy. In

fact, due to the high rates of resistance, some clinicians no longer

recommend lamivudine monotherapy as initial treatment for HBV infection

except in special cases. More frequently, other agents are used first-line

or lamivudine is used in conjunction with other antiviral agents because

resistance is so common.

Lamivudine resistance occurs via a change in the polymerase gene. The most

common alteration of the polymerase is the YMDD mutation. This mutation

involves a substitution of valine or leucine for methionine in the YMDD

motif in the HBV DNA polymerase. High pretherapy serum HBV DNA and ALT

levels, longer duration of therapy, and incomplete suppression of viral

replication are the main risk factors in accelerating the development of

lamivudine resistance.[8] Resistance can be diagnosed clinically by the

return of HBV DNA levels (1-log increase from the nadir level on 2 or more

determinations) in a patient on therapy who experienced an initial decline

in HBV DNA with the start of antiviral therapy. HBV DNA levels tend to

increase prior to the increase in serum ALT.

Therapeutic Intervention

Given that lamivudine resistance is the most likely explanation for the

patient's elevated LFTs, the addition of adefovir to lamivudine is likely

the best therapeutic option at this time. There is a significant body of

literature supporting the use of adefovir in this setting. Adefovir

dipivoxil is an oral nucleotide analog with activity against both wild-type

and lamivudine-resistant HBV. It has been studied in a wide variety of

patient populations, including HBeAg-positive and negative patients,

patients post transplant, and in the lamivudine-resistant population.[9-12]

Many experts advocate an overlap period or indefinite combination therapy

with lamivudine and a second antiviral agent. The rationale behind the

continued use of lamivudine is to prevent replication of wild-type virus in

the short term, which is thought to remain sensitive to lamivudine, and

suppression of HBV with resistance to adefovir in the long term. Although

adefovir resistance is rare, recent data suggest that the continuation of

lamivudine during long-term adefovir therapy helps prevent the development

of adefovir resistance.[13]

Entecavir, a guanosine analogue that inhibits DNA replication, is approved

for the treatment of hepatitis B at doses of 0.5 to 1.0 mg/day orally. The

long-term efficacy of entecavir in patients with lamivudine resistance

remains to be established. It is approved for use in lamivudine-resistant

patients at a dose of 1.0 mg/day. This dose is appropriate in the setting of

the lamivudine-refractory patient, and entecavir has been shown to be

effective in the treatment of lamivudine-resistant hepatitis B.[14] Although

resistance to entecavir is rare in naive patients, it has been reported in

abstract form to approach 10% after 2 years in patients with lamivudine

resistance.[15] This is higher than the 0% to 3% resistance rate seen with

adefovir in lamivudine-resistant patients.[16] Therefore, on the basis of

the data currently available, most experts do not recommend entecavir as the

first choice for treatment of lamivudine resistance. These recommendations

may change, however, as experience with entecavir increases.

Interferon has not been specifically studied in the setting of lamivudine

resistance and cannot, therefore, be considered first-line therapy for

lamivudine-resistant patients. Interferon has been studied in both

HBeAg-negative and -positive patients, and is thought to be particularly

useful in HBeAg-positive patients, those with high ALT, low-level HBV DNA (<

200 pg/mL), high histologic activity, more severe necroinflammation on

biopsy, and possibly in patients with HBV genotypes A and B vs C.[17,18]

Therefore, in the absence of histologic, genotypic, and serologic data, this

therapeutic option would not represent an appropriate next step.

Thus, of the agents currently approved for the treatment of HBV infection,

adefovir has been studied the most extensively in the setting of lamivudine

resistance and has been shown to be effective in both suppressing viral

replication and improving parameters of liver function, including the

Child-Pugh score.[11] Additionally, because adefovir has a good resistance

profile, it represents a good therapeutic option in lamivudine-resistant

patients. Last, adefovir has been shown to be effective and safe in studies

with follow-up of up to 96 months.[10] In summary, the use of adefovir in

the context of lamivudine resistance currently has the most data support,

but additional investigations are warranted to further elucidate the roles

of entecavir and pegylated interferon in addition to combination therapy.

Patient Follow-up and Concluding Remarks

The patient should have both LFTs and HBV DNA levels checked on a schedule

of approximately every 6 weeks to ensure that the current regimen of

lamivudine and adefovir therapy remains effective. This is in addition to

biannual alpha-fetoprotein measurement and ultrasound imaging to screen for

HCC.[19]

The NIH will soon be publishing new guidelines on the treatment of chronic

hepatitis B infection. These guidelines were, in part, motivated by the

development of drug resistance. Additional studies are warranted to

determine which HBV population is likely to benefit from a particular

treatment regimen.

_________________________________________________________________

On the road to retirement? Check out MSN Life Events for advice on how to

get there! http://lifeevents.msn.com/category.aspx?cid=Retirement

[Guest guest]

A 34-Year-Old Asian Man With Hepatitis B and Worsening Liver Function Tests

on Antiviral Therapy

http://www.medscape.com/editorial/cmetogo/5599Release Date: June 22, 2006;

Valid for credit through June 22, 2007

Authors: Sonja K. Olsen, MD; S. Brown, Jr, MD, MPH

Author Information and Disclosures

Credits Available

Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

Nurses - 0.3 ANCC continuing nurse education contact hours (0.3 contact

hours are in the area of pharmacology)

Supported by an independent educational grant from Gilead.

Introduction

Hepatitis B affects approximately 350 million people worldwide and an

estimated 1.25 million individuals in the United States.[1] There are an

estimated 100,000 people in the United States who become infected with

hepatitis B virus (HBV) each year despite universal vaccination practices

for children and widespread vaccination programs for adults thought to be at

high risk for infection.[2] Although most persons infected with the virus do

not develop significant hepatic disease, 15% to 40% will develop serious

complications.[3] These complications include cirrhosis, hepatocellular

carcinoma (HCC), and hepatic decompensation. Hepatitis B can be acquired

sexually, perinatally, or parenterally. The most common mode of transmission

depends on geography. In areas of low prevalence, such as the United States

and Canada, the most common mode of transmission is sexual contact followed

by intravenous-drug use. It is estimated that more than 50% of HBV in the

United States is acquired sexually.[4] In areas of high prevalence, such as

Southeast Asia and China, HBV is most commonly acquired perinatally.

The goals of therapy in HBV infection are not uniform. Because virologic

cure is usually not possible, and the ability to achieve durable viral

suppression varies, treatment decisions usually hinge on the patient's

serologic profile, the degree of liver injury, and the state of viral

replication. Suppression of viral replication and prevention of the

development of fibrosis and HCC are the primary goals for any patient.

Elimination of HBV from the serum, with seroconversion from hepatitis B

surface antigen positivity to hepatitis B surface antibody positivity, is

the rarely achieved but ultimate goal of therapy and may reflect actual

cure.

There are currently 5 medications approved by the US Food and Drug

Administration for the treatment of hepatitis B: interferon alfa-2b,

pegylated interferon alfa-2a, lamivudine, adefovir, and entecavir. The

arsenal of therapeutic options, diverse patient population, and lack of

clear guidelines make the treatment of hepatitis B a daunting task. The

National Institutes of Health (NIH) recently convened a panel of experts to

establish new guidelines for the treatment of hepatitis B. At the current

time, the official recommendations are not available, but the overall

consensus is that the number of patients who would benefit from therapy is

increasing, while the concern for viral resistance is growing, underscoring

the importance of implementing the optimal treatment regimen from the onset

of therapy.

Case Presentation

The patient is a 34-year-old Asian man who presents to clinic for further

evaluation of his " hepatitis. " He was born in Hong Kong and moved to the

United States in his teens. Approximately 2 years ago, his primary care

physician told him that his liver function tests (LFTs) were abnormal.

Further testing at that time found evidence of HBV infection, but he does

not have any additional information about his disease. He was started on

lamivudine therapy at a dose of 100 mg daily about 18 months ago, but has

been told that his LFTs are abnormal again. He has been compliant with his

medications. He is seeking another opinion. The patient reports no use of

over-the-counter medications; he denies any use of herbal medicines or other

new medicines in the past 6 months. Results of physical exam are

unremarkable. His aspartate aminotransferase level is 130 U/L (previously

reported in the 40-50 U/L range); alanine aminotransferase (ALT) level is

256 U/L (previously reported in the 40 U/L range).

What Is the Most Likely Explanation for This Patient's Elevated LFTs?

Although there are several possible etiologies for this patient's elevated

aminotransferases (acute viral hepatitis, medication effect, seroconversion

to anti-HBe antibody, etc.), the most likely explanation is that this

patient has developed resistance to lamivudine. Lamivudine resistance is a

significant clinical problem, with an estimated incidence of 14% to 20% at 1

year and 69% at 5 years.[5,6] It is typically detected in the setting of

elevated aminotransferases in a patient who has had stable LFTs while on

lamivudine therapy. Furthermore, the use of lamivudine in hepatitis B e

antigen (HBeAg)-negative patients is associated with more rapid development

of resistance -- 60% at 4 years.[7] Thus, it is imperative to follow LFTs

and HBV DNA levels in all patients who are on lamivudine monotherapy. In

fact, due to the high rates of resistance, some clinicians no longer

recommend lamivudine monotherapy as initial treatment for HBV infection

except in special cases. More frequently, other agents are used first-line

or lamivudine is used in conjunction with other antiviral agents because

resistance is so common.

Lamivudine resistance occurs via a change in the polymerase gene. The most

common alteration of the polymerase is the YMDD mutation. This mutation

involves a substitution of valine or leucine for methionine in the YMDD

motif in the HBV DNA polymerase. High pretherapy serum HBV DNA and ALT

levels, longer duration of therapy, and incomplete suppression of viral

replication are the main risk factors in accelerating the development of

lamivudine resistance.[8] Resistance can be diagnosed clinically by the

return of HBV DNA levels (1-log increase from the nadir level on 2 or more

determinations) in a patient on therapy who experienced an initial decline

in HBV DNA with the start of antiviral therapy. HBV DNA levels tend to

increase prior to the increase in serum ALT.

Therapeutic Intervention

Given that lamivudine resistance is the most likely explanation for the

patient's elevated LFTs, the addition of adefovir to lamivudine is likely

the best therapeutic option at this time. There is a significant body of

literature supporting the use of adefovir in this setting. Adefovir

dipivoxil is an oral nucleotide analog with activity against both wild-type

and lamivudine-resistant HBV. It has been studied in a wide variety of

patient populations, including HBeAg-positive and negative patients,

patients post transplant, and in the lamivudine-resistant population.[9-12]

Many experts advocate an overlap period or indefinite combination therapy

with lamivudine and a second antiviral agent. The rationale behind the

continued use of lamivudine is to prevent replication of wild-type virus in

the short term, which is thought to remain sensitive to lamivudine, and

suppression of HBV with resistance to adefovir in the long term. Although

adefovir resistance is rare, recent data suggest that the continuation of

lamivudine during long-term adefovir therapy helps prevent the development

of adefovir resistance.[13]

Entecavir, a guanosine analogue that inhibits DNA replication, is approved

for the treatment of hepatitis B at doses of 0.5 to 1.0 mg/day orally. The

long-term efficacy of entecavir in patients with lamivudine resistance

remains to be established. It is approved for use in lamivudine-resistant

patients at a dose of 1.0 mg/day. This dose is appropriate in the setting of

the lamivudine-refractory patient, and entecavir has been shown to be

effective in the treatment of lamivudine-resistant hepatitis B.[14] Although

resistance to entecavir is rare in naive patients, it has been reported in

abstract form to approach 10% after 2 years in patients with lamivudine

resistance.[15] This is higher than the 0% to 3% resistance rate seen with

adefovir in lamivudine-resistant patients.[16] Therefore, on the basis of

the data currently available, most experts do not recommend entecavir as the

first choice for treatment of lamivudine resistance. These recommendations

may change, however, as experience with entecavir increases.

Interferon has not been specifically studied in the setting of lamivudine

resistance and cannot, therefore, be considered first-line therapy for

lamivudine-resistant patients. Interferon has been studied in both

HBeAg-negative and -positive patients, and is thought to be particularly

useful in HBeAg-positive patients, those with high ALT, low-level HBV DNA (<

200 pg/mL), high histologic activity, more severe necroinflammation on

biopsy, and possibly in patients with HBV genotypes A and B vs C.[17,18]

Therefore, in the absence of histologic, genotypic, and serologic data, this

therapeutic option would not represent an appropriate next step.

Thus, of the agents currently approved for the treatment of HBV infection,

adefovir has been studied the most extensively in the setting of lamivudine

resistance and has been shown to be effective in both suppressing viral

replication and improving parameters of liver function, including the

Child-Pugh score.[11] Additionally, because adefovir has a good resistance

profile, it represents a good therapeutic option in lamivudine-resistant

patients. Last, adefovir has been shown to be effective and safe in studies

with follow-up of up to 96 months.[10] In summary, the use of adefovir in

the context of lamivudine resistance currently has the most data support,

but additional investigations are warranted to further elucidate the roles

of entecavir and pegylated interferon in addition to combination therapy.

Patient Follow-up and Concluding Remarks

The patient should have both LFTs and HBV DNA levels checked on a schedule

of approximately every 6 weeks to ensure that the current regimen of

lamivudine and adefovir therapy remains effective. This is in addition to

biannual alpha-fetoprotein measurement and ultrasound imaging to screen for

HCC.[19]

The NIH will soon be publishing new guidelines on the treatment of chronic

hepatitis B infection. These guidelines were, in part, motivated by the

development of drug resistance. Additional studies are warranted to

determine which HBV population is likely to benefit from a particular

treatment regimen.

_________________________________________________________________

On the road to retirement? Check out MSN Life Events for advice on how to

get there! http://lifeevents.msn.com/category.aspx?cid=Retirement