Advances in Hepatitis B: An Update From EASL 2008 - 1 of 2

[Guest guest]

http://www.medscape.com/viewarticle/575102

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

Management -- Volume 2

Advances in Hepatitis B: An Update From EASL 2008 CME

S. Reau, MD

Disclosures

Introduction

An estimated 400 million people worldwide and 1.25 million US residents are

chronically infected with hepatitis B virus (HBV); globally, 50 million new

infections occur annually.[1-3] Yet despite its prevalence, the evaluation and

management of HBV infection is a source of frustration for many clinicians. This

is likely escalated by the recent surge in both therapeutic options for

hepatitis B as well as the development of several new diagnostic studies

(Figure).

The need for technologic growth is paramount when considering the substantial

health burden caused by chronic disease. HBV infection is a well-recognized

cause of significant liver morbidity and mortality. This infection places 15% to

40% of those chronically infected at risk to develop serious sequelae, including

cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC).[4] This

results in approximately 500,000-700,000 deaths annually from complications of

chronic hepatitis B.[5-7] Of a half million annual cases of HCC, 60% are linked

to HBV.[5-7] The risk for complications is most significant in those individuals

with high levels of viral replication,[8,9] and the risk for HCC is highest in

cirrhotic patients with active viral replication.[10]

Hepatitis B treatment should prevent serious sequelae, and this would be best

achieved through disease eradication prior to the development of fibrosis or

increased oncogenic potential. Unfortunately, because of extrahepatic

reservoirs, integration of HBV DNA into the host genome, and protected

intracellular covalently closed circular DNA (cccDNA), hepatitis B cannot be

cured.[11] The next best alternative is sustained suppression of HBV

replication. Currently, 6 therapeutic agents are approved to treat HBV in the

United States: interferon alfa-2b, pegylated interferon alfa-2a, and the oral

nucleot(s)ide analogs lamivudine, adefovir dipivoxil, entecavir, and

telbivudine. Several other agents, including tenofovir*, are in late stages of

development, with tenofovir's approval expected this year. (The European

Commission has recently granted marketing authorization for tenofovir for the

treatment of chronic hepatitis B in adults in the European Union.) As these

treatments do not eradicate hepatitis B, their clinical benefit is in the

ability to sustain suppression of the virus. All therapies have limitations and

differ in terms of their efficacy, side effects, resistance profile, and cost,

as well as length of administration and durability after discontinuation.

Current research centers not only on new drug development but also on better

diagnostics, clarification of the natural history of hepatitis B, and on

improving our understanding of the currently available agents. This report

highlights some of the key research in these areas as presented at the 43rd

annual meeting of the European Association for the Study of the Liver (EASL),

which convened in Milan, Italy, April 23-27, 2008.

Initiation of Therapy

Whom to treat and what to use are two of the greatest challenges in the

management of hepatitis B. Patients at highest risk of developing complications

must be accurately identified for therapy. Whether to initiate therapy involves

a risk-benefit analysis: Disease progression is weighed against both the cost

and efficacy of treatment. This includes considering not only the actual

monetary expense but also the clinical risk for side effects as well as the risk

for viral mutations that could potentially influence future therapeutic

decisions. Current guidelines use hepatitis B e antigen (HBeAg) status, alanine

aminotransferase (ALT) elevation, level of viral replication, and histology to

identify patient subsets appropriate for therapy.[2]

The Importance of Viral Load

Although the above indicated parameters are important, growing evidence from the

REVEAL (Risk Evaluation of Viral Load Elevation and Associated Liver

Disease/Cancer-HBV Study) database highlights the predominant importance of

viral load. Previously published data from the REVEAL study demonstrated a

strong association between HCC risk and baseline HBV DNA levels.[12] Further

analysis of a subset of 3584 HBeAg-positive patients without baseline cirrhosis

showed that HCC risk increased with increasing ALT and HBV DNA levels.[13]

However, increasing serum HBV DNA was a more significant predictor of HCC, and

persistently high HBV load was associated with the highest HCC risk. These

findings emphasize that long-term monitoring is imperative in the management of

chronic HBV infection and that this monitoring must include measurement of HBV

viral load.[13] Viral load was also shown to predict the risk for HBV

reactivation in inactive hepatitis B surface antigen (HBsAg) carriers.[14] The

inactive carrier state is defined as persistent HBsAg, with the presence of

hepatitis B e antibody (HBeAb) and normal ALT and aspartate aminotransferase

(AST) levels, normal histology, and HBV DNA levels < 2000 IU/mL.[2] On

multivariate analysis, HBV DNA was the only significant predictor of risk for

reactivation, with those patients with HBV DNA levels between 200 and 2000 IU/mL

having the highest risk, compared with those with HBV DNA < 200 IU/mL.[14]

The Presence of Fibrosis

Histology can strongly influence the decision about whether to initiate therapy.

Significant inflammation or fibrosis may portend an increased risk for

complications.[2] Biopsy is advocated for any person who does not meet clear-cut

guidelines for treatment. However, liver biopsy has an associated risk and can

not be easily used serially to follow a patient over time. Several studies

presented during EASL 2008 evaluated noninvasive modalities to predict high-risk

histology.

Both noninvasive serum markers[15] and transient elastography (Fibroscan;

EchoSens; Paris, France), a noninvasive tool that measures liver stiffness,

accurately predict advanced hepatic fibrosis.[16,17] In addition to known

limitations such as the presence of obesity, a severe hepatitis flare may mimic

fibrosis as assessed by transient elastography. Repeat evaluations showed that

liver stiffness abnormalities may normalize after resolution of the acute

flare.[18]

Evaluation Prior to Therapy

Selection of drug resistance mutations is a major problem in the treatment of

chronic hepatitis B. The combination of a very high virion replication rate

(1011 virions per day), along with the fact that the HBV reverse transcriptase

(encoded by the HBV polymerase gene) lacks the proofreading function, leads to

an estimated 1010 point mutations produced per day.[19] Thus, multiple single

and double mutations preexist in patients. When present only in small numbers,

these mutations are very difficult to demonstrate. In addition, most mutations

are less fit than the wild-type virus and may never result in clinical

manifestations. With nucleot(s)ide analog therapy, some mutations may have a

selective advantage; because of the ability to replicate in the presence of the

nucleot(s)ide analog, they may become the dominant virus.

Kim and colleagues[20] tested 6 treatment-naive patients with chronic hepatitis

B. After cloning the PCR product of the reverse transcriptase region of the HBV

polymerase gene (where drug resistance mutations develop), they found that all 6

patients had significant variability in the HBV polymerase gene (viral

quasispecies) including preexisting antiviral-resistant mutations. Although the

study authors suggested that pretreatment detection of these mutants may be

important, given the high but inaccurate replication rate, their presence is not

unexpected. Only with further investigation can it be determined which mutants,

and to what degree, they may be clinically relevant.

Once drug resistance develops, it is most effective to modify therapy prior to

clinical breakthrough.[21] Thus, early recognition of resistance mutations is

important. Improvements in diagnostic assays are imperative, as current

commercial assays require mutations to reach a critical mass before they can be

identified. The development of the ARMS rt-PCR (amplification refractory

mutation system real-time polymerase chain reaction) allowed for the accurate

identification of very low-level mutant populations, with a biological cut-off

of 0.07% (7:10,000).[22] Thus, future technology will certainly help in the

early, accurate identification of variants, before they become clinically

significant.

The Evolution of the Treatment Paradigm

In the past decade, HBV therapy has evolved from limited interferon treatment to

lifelong viral suppression with nucleot(s)ide analogs in some patients. The

driving force for this change was the growing recognition of the untoward

effects of viral replication and data supporting a decreased risk for disease

progression with viral suppression. The introduction of the oral nucleoside

analog lamivudine revolutionized hepatitis B therapy. Its long-term use was

found to decrease disease complications.[23] Enthusiasm waned as drug-resistant

mutations developed in more than 70% of patients after 5 years of lamivudine

therapy[24] and diminished the beneficial effects of the treatment.[23]

The realization that lamivudine resistance conferred resistance to other

nucleosides and lowered the barrier to develop resistance to adefovir increased

these growing concerns.[24-26] These limitations continue to direct efforts in

new drug development and offer a template against which to weigh a medication's

relative worth.

_________________________________________________________________

Enjoy 5 GB of free, password-protected online storage.

http://www.windowslive.com/skydrive/overview.html?ocid=TXT_TAGLM_WL_Refresh_skyd\

rive_062008

[Guest guest]

http://www.medscape.com/viewarticle/575102

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

Management -- Volume 2

Advances in Hepatitis B: An Update From EASL 2008 CME

S. Reau, MD

Disclosures

Introduction

An estimated 400 million people worldwide and 1.25 million US residents are

chronically infected with hepatitis B virus (HBV); globally, 50 million new

infections occur annually.[1-3] Yet despite its prevalence, the evaluation and

management of HBV infection is a source of frustration for many clinicians. This

is likely escalated by the recent surge in both therapeutic options for

hepatitis B as well as the development of several new diagnostic studies

(Figure).

The need for technologic growth is paramount when considering the substantial

health burden caused by chronic disease. HBV infection is a well-recognized

cause of significant liver morbidity and mortality. This infection places 15% to

40% of those chronically infected at risk to develop serious sequelae, including

cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC).[4] This

results in approximately 500,000-700,000 deaths annually from complications of

chronic hepatitis B.[5-7] Of a half million annual cases of HCC, 60% are linked

to HBV.[5-7] The risk for complications is most significant in those individuals

with high levels of viral replication,[8,9] and the risk for HCC is highest in

cirrhotic patients with active viral replication.[10]

Hepatitis B treatment should prevent serious sequelae, and this would be best

achieved through disease eradication prior to the development of fibrosis or

increased oncogenic potential. Unfortunately, because of extrahepatic

reservoirs, integration of HBV DNA into the host genome, and protected

intracellular covalently closed circular DNA (cccDNA), hepatitis B cannot be

cured.[11] The next best alternative is sustained suppression of HBV

replication. Currently, 6 therapeutic agents are approved to treat HBV in the

United States: interferon alfa-2b, pegylated interferon alfa-2a, and the oral

nucleot(s)ide analogs lamivudine, adefovir dipivoxil, entecavir, and

telbivudine. Several other agents, including tenofovir*, are in late stages of

development, with tenofovir's approval expected this year. (The European

Commission has recently granted marketing authorization for tenofovir for the

treatment of chronic hepatitis B in adults in the European Union.) As these

treatments do not eradicate hepatitis B, their clinical benefit is in the

ability to sustain suppression of the virus. All therapies have limitations and

differ in terms of their efficacy, side effects, resistance profile, and cost,

as well as length of administration and durability after discontinuation.

Current research centers not only on new drug development but also on better

diagnostics, clarification of the natural history of hepatitis B, and on

improving our understanding of the currently available agents. This report

highlights some of the key research in these areas as presented at the 43rd

annual meeting of the European Association for the Study of the Liver (EASL),

which convened in Milan, Italy, April 23-27, 2008.

Initiation of Therapy

Whom to treat and what to use are two of the greatest challenges in the

management of hepatitis B. Patients at highest risk of developing complications

must be accurately identified for therapy. Whether to initiate therapy involves

a risk-benefit analysis: Disease progression is weighed against both the cost

and efficacy of treatment. This includes considering not only the actual

monetary expense but also the clinical risk for side effects as well as the risk

for viral mutations that could potentially influence future therapeutic

decisions. Current guidelines use hepatitis B e antigen (HBeAg) status, alanine

aminotransferase (ALT) elevation, level of viral replication, and histology to

identify patient subsets appropriate for therapy.[2]

The Importance of Viral Load

Although the above indicated parameters are important, growing evidence from the

REVEAL (Risk Evaluation of Viral Load Elevation and Associated Liver

Disease/Cancer-HBV Study) database highlights the predominant importance of

viral load. Previously published data from the REVEAL study demonstrated a

strong association between HCC risk and baseline HBV DNA levels.[12] Further

analysis of a subset of 3584 HBeAg-positive patients without baseline cirrhosis

showed that HCC risk increased with increasing ALT and HBV DNA levels.[13]

However, increasing serum HBV DNA was a more significant predictor of HCC, and

persistently high HBV load was associated with the highest HCC risk. These

findings emphasize that long-term monitoring is imperative in the management of

chronic HBV infection and that this monitoring must include measurement of HBV

viral load.[13] Viral load was also shown to predict the risk for HBV

reactivation in inactive hepatitis B surface antigen (HBsAg) carriers.[14] The

inactive carrier state is defined as persistent HBsAg, with the presence of

hepatitis B e antibody (HBeAb) and normal ALT and aspartate aminotransferase

(AST) levels, normal histology, and HBV DNA levels < 2000 IU/mL.[2] On

multivariate analysis, HBV DNA was the only significant predictor of risk for

reactivation, with those patients with HBV DNA levels between 200 and 2000 IU/mL

having the highest risk, compared with those with HBV DNA < 200 IU/mL.[14]

The Presence of Fibrosis

Histology can strongly influence the decision about whether to initiate therapy.

Significant inflammation or fibrosis may portend an increased risk for

complications.[2] Biopsy is advocated for any person who does not meet clear-cut

guidelines for treatment. However, liver biopsy has an associated risk and can

not be easily used serially to follow a patient over time. Several studies

presented during EASL 2008 evaluated noninvasive modalities to predict high-risk

histology.

Both noninvasive serum markers[15] and transient elastography (Fibroscan;

EchoSens; Paris, France), a noninvasive tool that measures liver stiffness,

accurately predict advanced hepatic fibrosis.[16,17] In addition to known

limitations such as the presence of obesity, a severe hepatitis flare may mimic

fibrosis as assessed by transient elastography. Repeat evaluations showed that

liver stiffness abnormalities may normalize after resolution of the acute

flare.[18]

Evaluation Prior to Therapy

Selection of drug resistance mutations is a major problem in the treatment of

chronic hepatitis B. The combination of a very high virion replication rate

(1011 virions per day), along with the fact that the HBV reverse transcriptase

(encoded by the HBV polymerase gene) lacks the proofreading function, leads to

an estimated 1010 point mutations produced per day.[19] Thus, multiple single

and double mutations preexist in patients. When present only in small numbers,

these mutations are very difficult to demonstrate. In addition, most mutations

are less fit than the wild-type virus and may never result in clinical

manifestations. With nucleot(s)ide analog therapy, some mutations may have a

selective advantage; because of the ability to replicate in the presence of the

nucleot(s)ide analog, they may become the dominant virus.

Kim and colleagues[20] tested 6 treatment-naive patients with chronic hepatitis

B. After cloning the PCR product of the reverse transcriptase region of the HBV

polymerase gene (where drug resistance mutations develop), they found that all 6

patients had significant variability in the HBV polymerase gene (viral

quasispecies) including preexisting antiviral-resistant mutations. Although the

study authors suggested that pretreatment detection of these mutants may be

important, given the high but inaccurate replication rate, their presence is not

unexpected. Only with further investigation can it be determined which mutants,

and to what degree, they may be clinically relevant.

Once drug resistance develops, it is most effective to modify therapy prior to

clinical breakthrough.[21] Thus, early recognition of resistance mutations is

important. Improvements in diagnostic assays are imperative, as current

commercial assays require mutations to reach a critical mass before they can be

identified. The development of the ARMS rt-PCR (amplification refractory

mutation system real-time polymerase chain reaction) allowed for the accurate

identification of very low-level mutant populations, with a biological cut-off

of 0.07% (7:10,000).[22] Thus, future technology will certainly help in the

early, accurate identification of variants, before they become clinically

significant.

The Evolution of the Treatment Paradigm

In the past decade, HBV therapy has evolved from limited interferon treatment to

lifelong viral suppression with nucleot(s)ide analogs in some patients. The

driving force for this change was the growing recognition of the untoward

effects of viral replication and data supporting a decreased risk for disease

progression with viral suppression. The introduction of the oral nucleoside

analog lamivudine revolutionized hepatitis B therapy. Its long-term use was

found to decrease disease complications.[23] Enthusiasm waned as drug-resistant

mutations developed in more than 70% of patients after 5 years of lamivudine

therapy[24] and diminished the beneficial effects of the treatment.[23]

The realization that lamivudine resistance conferred resistance to other

nucleosides and lowered the barrier to develop resistance to adefovir increased

these growing concerns.[24-26] These limitations continue to direct efforts in

new drug development and offer a template against which to weigh a medication's

relative worth.

_________________________________________________________________

Enjoy 5 GB of free, password-protected online storage.

http://www.windowslive.com/skydrive/overview.html?ocid=TXT_TAGLM_WL_Refresh_skyd\

rive_062008

[Guest guest]

http://www.medscape.com/viewarticle/575102

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

Management -- Volume 2

Advances in Hepatitis B: An Update From EASL 2008 CME

S. Reau, MD

Disclosures

Introduction

An estimated 400 million people worldwide and 1.25 million US residents are

chronically infected with hepatitis B virus (HBV); globally, 50 million new

infections occur annually.[1-3] Yet despite its prevalence, the evaluation and

management of HBV infection is a source of frustration for many clinicians. This

is likely escalated by the recent surge in both therapeutic options for

hepatitis B as well as the development of several new diagnostic studies

(Figure).

The need for technologic growth is paramount when considering the substantial

health burden caused by chronic disease. HBV infection is a well-recognized

cause of significant liver morbidity and mortality. This infection places 15% to

40% of those chronically infected at risk to develop serious sequelae, including

cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC).[4] This

results in approximately 500,000-700,000 deaths annually from complications of

chronic hepatitis B.[5-7] Of a half million annual cases of HCC, 60% are linked

to HBV.[5-7] The risk for complications is most significant in those individuals

with high levels of viral replication,[8,9] and the risk for HCC is highest in

cirrhotic patients with active viral replication.[10]

Hepatitis B treatment should prevent serious sequelae, and this would be best

achieved through disease eradication prior to the development of fibrosis or

increased oncogenic potential. Unfortunately, because of extrahepatic

reservoirs, integration of HBV DNA into the host genome, and protected

intracellular covalently closed circular DNA (cccDNA), hepatitis B cannot be

cured.[11] The next best alternative is sustained suppression of HBV

replication. Currently, 6 therapeutic agents are approved to treat HBV in the

United States: interferon alfa-2b, pegylated interferon alfa-2a, and the oral

nucleot(s)ide analogs lamivudine, adefovir dipivoxil, entecavir, and

telbivudine. Several other agents, including tenofovir*, are in late stages of

development, with tenofovir's approval expected this year. (The European

Commission has recently granted marketing authorization for tenofovir for the

treatment of chronic hepatitis B in adults in the European Union.) As these

treatments do not eradicate hepatitis B, their clinical benefit is in the

ability to sustain suppression of the virus. All therapies have limitations and

differ in terms of their efficacy, side effects, resistance profile, and cost,

as well as length of administration and durability after discontinuation.

Current research centers not only on new drug development but also on better

diagnostics, clarification of the natural history of hepatitis B, and on

improving our understanding of the currently available agents. This report

highlights some of the key research in these areas as presented at the 43rd

annual meeting of the European Association for the Study of the Liver (EASL),

which convened in Milan, Italy, April 23-27, 2008.

Initiation of Therapy

Whom to treat and what to use are two of the greatest challenges in the

management of hepatitis B. Patients at highest risk of developing complications

must be accurately identified for therapy. Whether to initiate therapy involves

a risk-benefit analysis: Disease progression is weighed against both the cost

and efficacy of treatment. This includes considering not only the actual

monetary expense but also the clinical risk for side effects as well as the risk

for viral mutations that could potentially influence future therapeutic

decisions. Current guidelines use hepatitis B e antigen (HBeAg) status, alanine

aminotransferase (ALT) elevation, level of viral replication, and histology to

identify patient subsets appropriate for therapy.[2]

The Importance of Viral Load

Although the above indicated parameters are important, growing evidence from the

REVEAL (Risk Evaluation of Viral Load Elevation and Associated Liver

Disease/Cancer-HBV Study) database highlights the predominant importance of

viral load. Previously published data from the REVEAL study demonstrated a

strong association between HCC risk and baseline HBV DNA levels.[12] Further

analysis of a subset of 3584 HBeAg-positive patients without baseline cirrhosis

showed that HCC risk increased with increasing ALT and HBV DNA levels.[13]

However, increasing serum HBV DNA was a more significant predictor of HCC, and

persistently high HBV load was associated with the highest HCC risk. These

findings emphasize that long-term monitoring is imperative in the management of

chronic HBV infection and that this monitoring must include measurement of HBV

viral load.[13] Viral load was also shown to predict the risk for HBV

reactivation in inactive hepatitis B surface antigen (HBsAg) carriers.[14] The

inactive carrier state is defined as persistent HBsAg, with the presence of

hepatitis B e antibody (HBeAb) and normal ALT and aspartate aminotransferase

(AST) levels, normal histology, and HBV DNA levels < 2000 IU/mL.[2] On

multivariate analysis, HBV DNA was the only significant predictor of risk for

reactivation, with those patients with HBV DNA levels between 200 and 2000 IU/mL

having the highest risk, compared with those with HBV DNA < 200 IU/mL.[14]

The Presence of Fibrosis

Histology can strongly influence the decision about whether to initiate therapy.

Significant inflammation or fibrosis may portend an increased risk for

complications.[2] Biopsy is advocated for any person who does not meet clear-cut

guidelines for treatment. However, liver biopsy has an associated risk and can

not be easily used serially to follow a patient over time. Several studies

presented during EASL 2008 evaluated noninvasive modalities to predict high-risk

histology.

Both noninvasive serum markers[15] and transient elastography (Fibroscan;

EchoSens; Paris, France), a noninvasive tool that measures liver stiffness,

accurately predict advanced hepatic fibrosis.[16,17] In addition to known

limitations such as the presence of obesity, a severe hepatitis flare may mimic

fibrosis as assessed by transient elastography. Repeat evaluations showed that

liver stiffness abnormalities may normalize after resolution of the acute

flare.[18]

Evaluation Prior to Therapy

Selection of drug resistance mutations is a major problem in the treatment of

chronic hepatitis B. The combination of a very high virion replication rate

(1011 virions per day), along with the fact that the HBV reverse transcriptase

(encoded by the HBV polymerase gene) lacks the proofreading function, leads to

an estimated 1010 point mutations produced per day.[19] Thus, multiple single

and double mutations preexist in patients. When present only in small numbers,

these mutations are very difficult to demonstrate. In addition, most mutations

are less fit than the wild-type virus and may never result in clinical

manifestations. With nucleot(s)ide analog therapy, some mutations may have a

selective advantage; because of the ability to replicate in the presence of the

nucleot(s)ide analog, they may become the dominant virus.

Kim and colleagues[20] tested 6 treatment-naive patients with chronic hepatitis

B. After cloning the PCR product of the reverse transcriptase region of the HBV

polymerase gene (where drug resistance mutations develop), they found that all 6

patients had significant variability in the HBV polymerase gene (viral

quasispecies) including preexisting antiviral-resistant mutations. Although the

study authors suggested that pretreatment detection of these mutants may be

important, given the high but inaccurate replication rate, their presence is not

unexpected. Only with further investigation can it be determined which mutants,

and to what degree, they may be clinically relevant.

Once drug resistance develops, it is most effective to modify therapy prior to

clinical breakthrough.[21] Thus, early recognition of resistance mutations is

important. Improvements in diagnostic assays are imperative, as current

commercial assays require mutations to reach a critical mass before they can be

identified. The development of the ARMS rt-PCR (amplification refractory

mutation system real-time polymerase chain reaction) allowed for the accurate

identification of very low-level mutant populations, with a biological cut-off

of 0.07% (7:10,000).[22] Thus, future technology will certainly help in the

early, accurate identification of variants, before they become clinically

significant.

The Evolution of the Treatment Paradigm

In the past decade, HBV therapy has evolved from limited interferon treatment to

lifelong viral suppression with nucleot(s)ide analogs in some patients. The

driving force for this change was the growing recognition of the untoward

effects of viral replication and data supporting a decreased risk for disease

progression with viral suppression. The introduction of the oral nucleoside

analog lamivudine revolutionized hepatitis B therapy. Its long-term use was

found to decrease disease complications.[23] Enthusiasm waned as drug-resistant

mutations developed in more than 70% of patients after 5 years of lamivudine

therapy[24] and diminished the beneficial effects of the treatment.[23]

The realization that lamivudine resistance conferred resistance to other

nucleosides and lowered the barrier to develop resistance to adefovir increased

these growing concerns.[24-26] These limitations continue to direct efforts in

new drug development and offer a template against which to weigh a medication's

relative worth.

_________________________________________________________________

Enjoy 5 GB of free, password-protected online storage.

http://www.windowslive.com/skydrive/overview.html?ocid=TXT_TAGLM_WL_Refresh_skyd\

rive_062008

[Guest guest]

http://www.medscape.com/viewarticle/575102

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

Management -- Volume 2

Advances in Hepatitis B: An Update From EASL 2008 CME

S. Reau, MD

Disclosures

Introduction

An estimated 400 million people worldwide and 1.25 million US residents are

chronically infected with hepatitis B virus (HBV); globally, 50 million new

infections occur annually.[1-3] Yet despite its prevalence, the evaluation and

management of HBV infection is a source of frustration for many clinicians. This

is likely escalated by the recent surge in both therapeutic options for

hepatitis B as well as the development of several new diagnostic studies

(Figure).

The need for technologic growth is paramount when considering the substantial

health burden caused by chronic disease. HBV infection is a well-recognized

cause of significant liver morbidity and mortality. This infection places 15% to

40% of those chronically infected at risk to develop serious sequelae, including

cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC).[4] This

results in approximately 500,000-700,000 deaths annually from complications of

chronic hepatitis B.[5-7] Of a half million annual cases of HCC, 60% are linked

to HBV.[5-7] The risk for complications is most significant in those individuals

with high levels of viral replication,[8,9] and the risk for HCC is highest in

cirrhotic patients with active viral replication.[10]

Hepatitis B treatment should prevent serious sequelae, and this would be best

achieved through disease eradication prior to the development of fibrosis or

increased oncogenic potential. Unfortunately, because of extrahepatic

reservoirs, integration of HBV DNA into the host genome, and protected

intracellular covalently closed circular DNA (cccDNA), hepatitis B cannot be

cured.[11] The next best alternative is sustained suppression of HBV

replication. Currently, 6 therapeutic agents are approved to treat HBV in the

United States: interferon alfa-2b, pegylated interferon alfa-2a, and the oral

nucleot(s)ide analogs lamivudine, adefovir dipivoxil, entecavir, and

telbivudine. Several other agents, including tenofovir*, are in late stages of

development, with tenofovir's approval expected this year. (The European

Commission has recently granted marketing authorization for tenofovir for the

treatment of chronic hepatitis B in adults in the European Union.) As these

treatments do not eradicate hepatitis B, their clinical benefit is in the

ability to sustain suppression of the virus. All therapies have limitations and

differ in terms of their efficacy, side effects, resistance profile, and cost,

as well as length of administration and durability after discontinuation.

Current research centers not only on new drug development but also on better

diagnostics, clarification of the natural history of hepatitis B, and on

improving our understanding of the currently available agents. This report

highlights some of the key research in these areas as presented at the 43rd

annual meeting of the European Association for the Study of the Liver (EASL),

which convened in Milan, Italy, April 23-27, 2008.

Initiation of Therapy

Whom to treat and what to use are two of the greatest challenges in the

management of hepatitis B. Patients at highest risk of developing complications

must be accurately identified for therapy. Whether to initiate therapy involves

a risk-benefit analysis: Disease progression is weighed against both the cost

and efficacy of treatment. This includes considering not only the actual

monetary expense but also the clinical risk for side effects as well as the risk

for viral mutations that could potentially influence future therapeutic

decisions. Current guidelines use hepatitis B e antigen (HBeAg) status, alanine

aminotransferase (ALT) elevation, level of viral replication, and histology to

identify patient subsets appropriate for therapy.[2]

The Importance of Viral Load

Although the above indicated parameters are important, growing evidence from the

REVEAL (Risk Evaluation of Viral Load Elevation and Associated Liver

Disease/Cancer-HBV Study) database highlights the predominant importance of

viral load. Previously published data from the REVEAL study demonstrated a

strong association between HCC risk and baseline HBV DNA levels.[12] Further

analysis of a subset of 3584 HBeAg-positive patients without baseline cirrhosis

showed that HCC risk increased with increasing ALT and HBV DNA levels.[13]

However, increasing serum HBV DNA was a more significant predictor of HCC, and

persistently high HBV load was associated with the highest HCC risk. These

findings emphasize that long-term monitoring is imperative in the management of

chronic HBV infection and that this monitoring must include measurement of HBV

viral load.[13] Viral load was also shown to predict the risk for HBV

reactivation in inactive hepatitis B surface antigen (HBsAg) carriers.[14] The

inactive carrier state is defined as persistent HBsAg, with the presence of

hepatitis B e antibody (HBeAb) and normal ALT and aspartate aminotransferase

(AST) levels, normal histology, and HBV DNA levels < 2000 IU/mL.[2] On

multivariate analysis, HBV DNA was the only significant predictor of risk for

reactivation, with those patients with HBV DNA levels between 200 and 2000 IU/mL

having the highest risk, compared with those with HBV DNA < 200 IU/mL.[14]

The Presence of Fibrosis

Histology can strongly influence the decision about whether to initiate therapy.

Significant inflammation or fibrosis may portend an increased risk for

complications.[2] Biopsy is advocated for any person who does not meet clear-cut

guidelines for treatment. However, liver biopsy has an associated risk and can

not be easily used serially to follow a patient over time. Several studies

presented during EASL 2008 evaluated noninvasive modalities to predict high-risk

histology.

Both noninvasive serum markers[15] and transient elastography (Fibroscan;

EchoSens; Paris, France), a noninvasive tool that measures liver stiffness,

accurately predict advanced hepatic fibrosis.[16,17] In addition to known

limitations such as the presence of obesity, a severe hepatitis flare may mimic

fibrosis as assessed by transient elastography. Repeat evaluations showed that

liver stiffness abnormalities may normalize after resolution of the acute

flare.[18]

Evaluation Prior to Therapy

Selection of drug resistance mutations is a major problem in the treatment of

chronic hepatitis B. The combination of a very high virion replication rate

(1011 virions per day), along with the fact that the HBV reverse transcriptase

(encoded by the HBV polymerase gene) lacks the proofreading function, leads to

an estimated 1010 point mutations produced per day.[19] Thus, multiple single

and double mutations preexist in patients. When present only in small numbers,

these mutations are very difficult to demonstrate. In addition, most mutations

are less fit than the wild-type virus and may never result in clinical

manifestations. With nucleot(s)ide analog therapy, some mutations may have a

selective advantage; because of the ability to replicate in the presence of the

nucleot(s)ide analog, they may become the dominant virus.

Kim and colleagues[20] tested 6 treatment-naive patients with chronic hepatitis

B. After cloning the PCR product of the reverse transcriptase region of the HBV

polymerase gene (where drug resistance mutations develop), they found that all 6

patients had significant variability in the HBV polymerase gene (viral

quasispecies) including preexisting antiviral-resistant mutations. Although the

study authors suggested that pretreatment detection of these mutants may be

important, given the high but inaccurate replication rate, their presence is not

unexpected. Only with further investigation can it be determined which mutants,

and to what degree, they may be clinically relevant.

Once drug resistance develops, it is most effective to modify therapy prior to

clinical breakthrough.[21] Thus, early recognition of resistance mutations is

important. Improvements in diagnostic assays are imperative, as current

commercial assays require mutations to reach a critical mass before they can be

identified. The development of the ARMS rt-PCR (amplification refractory

mutation system real-time polymerase chain reaction) allowed for the accurate

identification of very low-level mutant populations, with a biological cut-off

of 0.07% (7:10,000).[22] Thus, future technology will certainly help in the

early, accurate identification of variants, before they become clinically

significant.

The Evolution of the Treatment Paradigm

In the past decade, HBV therapy has evolved from limited interferon treatment to

lifelong viral suppression with nucleot(s)ide analogs in some patients. The

driving force for this change was the growing recognition of the untoward

effects of viral replication and data supporting a decreased risk for disease

progression with viral suppression. The introduction of the oral nucleoside

analog lamivudine revolutionized hepatitis B therapy. Its long-term use was

found to decrease disease complications.[23] Enthusiasm waned as drug-resistant

mutations developed in more than 70% of patients after 5 years of lamivudine

therapy[24] and diminished the beneficial effects of the treatment.[23]

The realization that lamivudine resistance conferred resistance to other

nucleosides and lowered the barrier to develop resistance to adefovir increased

these growing concerns.[24-26] These limitations continue to direct efforts in

new drug development and offer a template against which to weigh a medication's

relative worth.

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