Understanding Resistance in Hepatitis B -- Clinical Implications - 1 of 2

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http://www.medscape.com/viewarticle/575106

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

Management -- Volume 2

Understanding Resistance in Hepatitis B -- Clinical Implications CME

Chakradhar M. Reddy, MD , MD, FACP

Disclosures

Introduction

Recent estimates suggest that worldwide, 2 billion people have been infected

with hepatitis B virus (HBV), with more than 360 million individuals chronically

infected and at substantial risk for major complications (most notably,

decompensated cirrhosis and hepatocellular carcinoma).[1] The annual estimated

mortality from chronic HBV-related liver disease globally is 500,000 to 700,000

deaths each year.[2-4] Approximately 60% of the world's population lives in

areas where HBV infection is highly endemic.[5] In these regions, including

Southeast Asia, the South Pacific, and sub-Saharan Africa, up to 10% to 12% of

the population is chronically infected, with the remainder having serologic

evidence of prior HBV infection.[6] In contrast, in low-prevalence regions in

the more developed world, HBV infection is usually observed in individuals of

lower socioeconomic status, immigrants from endemic areas, those who engage in

high-risk sexual behavior, and injection drug users.[5] A recent updated

estimate suggests that there may be as many as 2 million chronically infected

individuals in the United States. This reflects the continued high prevalence

rates of HBV infection in immigrant communities despite the decline in the

number of acute infections per year from approximately 260,000 to 60,000 since

the inception of the HBV vaccine about 20 years ago.[7-9]

Treatment Goals

Antiviral therapy against HBV is recommended in patients to prevent progression

of liver disease (ie, active necroinflammation with fibrosis, cirrhosis,

decompensation of cirrhosis or hepatocellular carcinoma, and recurrence after

liver transplantation).[8,10] The endpoint of treatment for hepatitis B e

antigen (HBeAg)-positive patients is profound suppression of HBV replication;

normalization of serum alanine aminotransferase (ALT); loss of HBeAg, with or

without detection of hepatitis B e antibody (anti-HBe); and improvement in liver

histology.[8] In contrast, the endpoint of treatment for HBeAg-negative patients

has not been clearly defined -- the target has been durable suppression of HBV

DNA, but the rate of relapse after therapy is stopped is high.[8,11] In

addition, HBeAg-negative patients are typically older[12] and have a longer

duration of disease that is often more advanced.

Currently, the US Food and Drug Administration (FDA) has approved the following

medications for the treatment of chronic HBV infection: interferon alfa-2b;

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

adefovir, entecavir, and telbivudine. Tenofovir* and tenofovir in combination

with emtricitabine,* [13-15] which are approved for the treatment of HIV

infection, have also demonstrated efficacy in the treatment of chronic HBV

infection. Tenofovir is currently under FDA review for likely approval in 2008.

Resistance

Antiviral drug resistance reflects the reduced susceptibility of a virus to the

inhibitory effect of a drug.[16] In clinical trials and in clinical practice,

resistance is defined as the selection of variants bearing amino acid

substitutions conferring reduced susceptibility to a drug that results in

primary or secondary treatment failure.[10] Resistance to antiviral drug therapy

is a well-known phenomenon in the treatment of HIV,[17] and more recently, has

been recognized in the setting of anti-HBV treatment.[18] In treatment of HBV

infection, the development of viable resistant strains may lead to the

progression of liver disease and even decompensation of cirrhosis.[19-21]

Development of Resistance

Unique among DNA viruses, HBV replicates via a reverse transcription process

despite containing a DNA genome. However, the HBV reverse transcriptase is an

error-prone enzyme, as it lacks a proofreading ability. This, coupled with the

high replicative rate of HBV, leads to the occurrence of random mutations with

amino acid substitutions in the reverse transcriptase portion of the HBV

genome.[22] Some of these mutations select for drug resistance even in the

absence of antiviral therapy. They mutations are preferentially selected when

oral antiviral therapy is introduced. Figure 1 shows a schema detailing the

development of antiviral drug resistance. Genetic barriers to resistance vary

among compounds; for instance, the nucleoside analog entecavir appears to have a

particularly high barrier to resistance, [23] requiring several amino acid

substitutions to induce resistance -- that is, amino acid sequence changes due

to mutations that in turn lead to decreased antiviral activity against resistant

mutant virus. In contrast, the chance of antiviral resistance is greater if the

compound has a low genetic barrier to resistance, such as lamivudine (marked

decrease in susceptibility because of a single amino acid substitution not

affecting viral genome replication capacity).[24] These treatment-induced

mutations are distinct from spontaneous mutations occurring elsewhere in the

viral genome in the precore and core promoter regions, which down-regulate

production of HBeAg but permit active HBV replication.

Figure. Schema showing development of antiviral drug resistance.

Several factors have been implicated in the development of antiviral

resistance:[25-28]

Viral factors

Antiviral-resistant HBV variants are preferentially selected in the presence of

antiviral therapy because they replicate more effectively than wild-type virus

in the presence of the antiviral drug.

High pretreatment HBV DNA levels

Antiviral factors

Slow or inadequate viral suppression

Resistance from prior antiviral treatment inducing cross-resistance to

subsequent therapy

Host factors

Medication nonadherence

Impaired host immunity

Antiviral Resistance: Terminology

Two types of mutations induced by oral antiviral therapy for chronic hepatitis B

are now recognized: Primary drug-resistant mutations cause an amino acid

substitution that results in reduced susceptibility to a specific antiviral

agent; and secondary compensatory mutations do not affect drug sensitivity but

restore functional defects in viral polymerase activity (ie, replication

fitness) associated with primary drug resistance. The development of resistance

needs to be differentiated from primary nonresponse to medication, including

medication nonadherence. Cross-resistance is defined as a mutation that confers

resistance to more than one antiviral drug by in vitro testing[29] (Table 1).

Table 1. Definitions of Antiviral Resistance[8,32]

Virologic breakthrough Increase in serum HBV DNA by 1 log10 (10-fold) above

nadir after achieving virologic response during continued treatment

Viral rebound Increase in serum HBV DNA to 20,000 IU/mL or above pretreatment

level after achieving virologic response during continued treatment

Biochemical breakthrough Increase in ALT above upper limit of normal after

achieving normalization during continued treatment

Genotypic resistance Detection of mutations that have been shown in in vitro

studies to confer resistance to the nucleoside/nucleotide that is being

administered

Phenotypic resistance In vitro confirmation that the mutation detected decreases

susceptibility (as demonstrated by increase in inhibitory concentrations) to the

nucleoside/nucleotide analog administered

Primary treatment failure

(nonresponse)

Inability of nucleoside/nucleotide analog treatment to reduce serum HBV DNA by

1 log10 IU/mL after the first 6 months of treatment

Cross-resistance Mutation(s) that confers resistance to more than 1 antiviral

drug by in vitro testing

Nomenclature

The current nomenclature used to describe antiviral-resistant HBV mutations in

the HBV DNA polymerase gene includes " rt " (for the reverse transcriptase region

of the HBV polymerase gene), which is common to all treatment-induced mutations,

followed by the first letter of the original amino acid location in the gene,

and ending with the letter of the replaced amino acid. For example, the common

lamivudine-resistant mutations are rtM204V and rtM204I, in which methionine is

either replaced by valine or isoleucine at position 204.[30-32] Current

resistant patterns associated with available antiviral therapies are shown in

Table 2.

Table 2. Resistance Patterns in the Hepatitis B Polymerase

Gene[35,39,45,47-49,68-71]

Drugs Location on Reverse Transcriptase

L80V/I I169T V173L L180M A181T/V T184S/A/I/L A194T S202C/G/I M204V/I/S N236T

M250I/V

LAM X X X X

FTC X X X

ETV X X X X* X X

LdT X X X

ADV X X

TDF X X X

ADV = adefovir; ETV = entecavir; FTC = emtricitabine; LAM = lamivudine; LdT =

telbivudine; TDF = tenofovir.

*In the presence of primary resistance mutations (L180M + M204V).

Interferon-Based Therapy

Standard interferons and pegylated interferons exert antiviral activity by

immune-modulatory and antiproliferative effects. This class of antiviral therapy

does not seem to demonstrate viral resistance -- rather, treatment failure

(nonresponse to therapy) can be observed. Additionally, approximately 50% of

responders may relapse after cessation of therapy, and relapse can occur as long

as 5 years after cessation of therapy.[8] For these reasons, as well as because

of the side effect profile (eg, flu-like symptoms, fever, myalgia, mild bone

marrow suppression, psychiatric side effects),[8,10] interferon-based therapy

has limited efficacy, especially in decompensated cirrhosis[33] and in

post-liver transplantation patients. Interferon-based therapies are typically

given for a predefined course (eg, 1 year), whereas oral antiviral agents are

often continued for more prolonged periods, and such prolonged treatment courses

increase risk for selecting resistant strains.[31]

_________________________________________________________________

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[Guest guest]

http://www.medscape.com/viewarticle/575106

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

Management -- Volume 2

Understanding Resistance in Hepatitis B -- Clinical Implications CME

Chakradhar M. Reddy, MD , MD, FACP

Disclosures

Introduction

Recent estimates suggest that worldwide, 2 billion people have been infected

with hepatitis B virus (HBV), with more than 360 million individuals chronically

infected and at substantial risk for major complications (most notably,

decompensated cirrhosis and hepatocellular carcinoma).[1] The annual estimated

mortality from chronic HBV-related liver disease globally is 500,000 to 700,000

deaths each year.[2-4] Approximately 60% of the world's population lives in

areas where HBV infection is highly endemic.[5] In these regions, including

Southeast Asia, the South Pacific, and sub-Saharan Africa, up to 10% to 12% of

the population is chronically infected, with the remainder having serologic

evidence of prior HBV infection.[6] In contrast, in low-prevalence regions in

the more developed world, HBV infection is usually observed in individuals of

lower socioeconomic status, immigrants from endemic areas, those who engage in

high-risk sexual behavior, and injection drug users.[5] A recent updated

estimate suggests that there may be as many as 2 million chronically infected

individuals in the United States. This reflects the continued high prevalence

rates of HBV infection in immigrant communities despite the decline in the

number of acute infections per year from approximately 260,000 to 60,000 since

the inception of the HBV vaccine about 20 years ago.[7-9]

Treatment Goals

Antiviral therapy against HBV is recommended in patients to prevent progression

of liver disease (ie, active necroinflammation with fibrosis, cirrhosis,

decompensation of cirrhosis or hepatocellular carcinoma, and recurrence after

liver transplantation).[8,10] The endpoint of treatment for hepatitis B e

antigen (HBeAg)-positive patients is profound suppression of HBV replication;

normalization of serum alanine aminotransferase (ALT); loss of HBeAg, with or

without detection of hepatitis B e antibody (anti-HBe); and improvement in liver

histology.[8] In contrast, the endpoint of treatment for HBeAg-negative patients

has not been clearly defined -- the target has been durable suppression of HBV

DNA, but the rate of relapse after therapy is stopped is high.[8,11] In

addition, HBeAg-negative patients are typically older[12] and have a longer

duration of disease that is often more advanced.

Currently, the US Food and Drug Administration (FDA) has approved the following

medications for the treatment of chronic HBV infection: interferon alfa-2b;

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

adefovir, entecavir, and telbivudine. Tenofovir* and tenofovir in combination

with emtricitabine,* [13-15] which are approved for the treatment of HIV

infection, have also demonstrated efficacy in the treatment of chronic HBV

infection. Tenofovir is currently under FDA review for likely approval in 2008.

Resistance

Antiviral drug resistance reflects the reduced susceptibility of a virus to the

inhibitory effect of a drug.[16] In clinical trials and in clinical practice,

resistance is defined as the selection of variants bearing amino acid

substitutions conferring reduced susceptibility to a drug that results in

primary or secondary treatment failure.[10] Resistance to antiviral drug therapy

is a well-known phenomenon in the treatment of HIV,[17] and more recently, has

been recognized in the setting of anti-HBV treatment.[18] In treatment of HBV

infection, the development of viable resistant strains may lead to the

progression of liver disease and even decompensation of cirrhosis.[19-21]

Development of Resistance

Unique among DNA viruses, HBV replicates via a reverse transcription process

despite containing a DNA genome. However, the HBV reverse transcriptase is an

error-prone enzyme, as it lacks a proofreading ability. This, coupled with the

high replicative rate of HBV, leads to the occurrence of random mutations with

amino acid substitutions in the reverse transcriptase portion of the HBV

genome.[22] Some of these mutations select for drug resistance even in the

absence of antiviral therapy. They mutations are preferentially selected when

oral antiviral therapy is introduced. Figure 1 shows a schema detailing the

development of antiviral drug resistance. Genetic barriers to resistance vary

among compounds; for instance, the nucleoside analog entecavir appears to have a

particularly high barrier to resistance, [23] requiring several amino acid

substitutions to induce resistance -- that is, amino acid sequence changes due

to mutations that in turn lead to decreased antiviral activity against resistant

mutant virus. In contrast, the chance of antiviral resistance is greater if the

compound has a low genetic barrier to resistance, such as lamivudine (marked

decrease in susceptibility because of a single amino acid substitution not

affecting viral genome replication capacity).[24] These treatment-induced

mutations are distinct from spontaneous mutations occurring elsewhere in the

viral genome in the precore and core promoter regions, which down-regulate

production of HBeAg but permit active HBV replication.

Figure. Schema showing development of antiviral drug resistance.

Several factors have been implicated in the development of antiviral

resistance:[25-28]

Viral factors

Antiviral-resistant HBV variants are preferentially selected in the presence of

antiviral therapy because they replicate more effectively than wild-type virus

in the presence of the antiviral drug.

High pretreatment HBV DNA levels

Antiviral factors

Slow or inadequate viral suppression

Resistance from prior antiviral treatment inducing cross-resistance to

subsequent therapy

Host factors

Medication nonadherence

Impaired host immunity

Antiviral Resistance: Terminology

Two types of mutations induced by oral antiviral therapy for chronic hepatitis B

are now recognized: Primary drug-resistant mutations cause an amino acid

substitution that results in reduced susceptibility to a specific antiviral

agent; and secondary compensatory mutations do not affect drug sensitivity but

restore functional defects in viral polymerase activity (ie, replication

fitness) associated with primary drug resistance. The development of resistance

needs to be differentiated from primary nonresponse to medication, including

medication nonadherence. Cross-resistance is defined as a mutation that confers

resistance to more than one antiviral drug by in vitro testing[29] (Table 1).

Table 1. Definitions of Antiviral Resistance[8,32]

Virologic breakthrough Increase in serum HBV DNA by 1 log10 (10-fold) above

nadir after achieving virologic response during continued treatment

Viral rebound Increase in serum HBV DNA to 20,000 IU/mL or above pretreatment

level after achieving virologic response during continued treatment

Biochemical breakthrough Increase in ALT above upper limit of normal after

achieving normalization during continued treatment

Genotypic resistance Detection of mutations that have been shown in in vitro

studies to confer resistance to the nucleoside/nucleotide that is being

administered

Phenotypic resistance In vitro confirmation that the mutation detected decreases

susceptibility (as demonstrated by increase in inhibitory concentrations) to the

nucleoside/nucleotide analog administered

Primary treatment failure

(nonresponse)

Inability of nucleoside/nucleotide analog treatment to reduce serum HBV DNA by

1 log10 IU/mL after the first 6 months of treatment

Cross-resistance Mutation(s) that confers resistance to more than 1 antiviral

drug by in vitro testing

Nomenclature

The current nomenclature used to describe antiviral-resistant HBV mutations in

the HBV DNA polymerase gene includes " rt " (for the reverse transcriptase region

of the HBV polymerase gene), which is common to all treatment-induced mutations,

followed by the first letter of the original amino acid location in the gene,

and ending with the letter of the replaced amino acid. For example, the common

lamivudine-resistant mutations are rtM204V and rtM204I, in which methionine is

either replaced by valine or isoleucine at position 204.[30-32] Current

resistant patterns associated with available antiviral therapies are shown in

Table 2.

Table 2. Resistance Patterns in the Hepatitis B Polymerase

Gene[35,39,45,47-49,68-71]

Drugs Location on Reverse Transcriptase

L80V/I I169T V173L L180M A181T/V T184S/A/I/L A194T S202C/G/I M204V/I/S N236T

M250I/V

LAM X X X X

FTC X X X

ETV X X X X* X X

LdT X X X

ADV X X

TDF X X X

ADV = adefovir; ETV = entecavir; FTC = emtricitabine; LAM = lamivudine; LdT =

telbivudine; TDF = tenofovir.

*In the presence of primary resistance mutations (L180M + M204V).

Interferon-Based Therapy

Standard interferons and pegylated interferons exert antiviral activity by

immune-modulatory and antiproliferative effects. This class of antiviral therapy

does not seem to demonstrate viral resistance -- rather, treatment failure

(nonresponse to therapy) can be observed. Additionally, approximately 50% of

responders may relapse after cessation of therapy, and relapse can occur as long

as 5 years after cessation of therapy.[8] For these reasons, as well as because

of the side effect profile (eg, flu-like symptoms, fever, myalgia, mild bone

marrow suppression, psychiatric side effects),[8,10] interferon-based therapy

has limited efficacy, especially in decompensated cirrhosis[33] and in

post-liver transplantation patients. Interferon-based therapies are typically

given for a predefined course (eg, 1 year), whereas oral antiviral agents are

often continued for more prolonged periods, and such prolonged treatment courses

increase risk for selecting resistant strains.[31]

_________________________________________________________________

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[Guest guest]

http://www.medscape.com/viewarticle/575106

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

Management -- Volume 2

Understanding Resistance in Hepatitis B -- Clinical Implications CME

Chakradhar M. Reddy, MD , MD, FACP

Disclosures

Introduction

Recent estimates suggest that worldwide, 2 billion people have been infected

with hepatitis B virus (HBV), with more than 360 million individuals chronically

infected and at substantial risk for major complications (most notably,

decompensated cirrhosis and hepatocellular carcinoma).[1] The annual estimated

mortality from chronic HBV-related liver disease globally is 500,000 to 700,000

deaths each year.[2-4] Approximately 60% of the world's population lives in

areas where HBV infection is highly endemic.[5] In these regions, including

Southeast Asia, the South Pacific, and sub-Saharan Africa, up to 10% to 12% of

the population is chronically infected, with the remainder having serologic

evidence of prior HBV infection.[6] In contrast, in low-prevalence regions in

the more developed world, HBV infection is usually observed in individuals of

lower socioeconomic status, immigrants from endemic areas, those who engage in

high-risk sexual behavior, and injection drug users.[5] A recent updated

estimate suggests that there may be as many as 2 million chronically infected

individuals in the United States. This reflects the continued high prevalence

rates of HBV infection in immigrant communities despite the decline in the

number of acute infections per year from approximately 260,000 to 60,000 since

the inception of the HBV vaccine about 20 years ago.[7-9]

Treatment Goals

Antiviral therapy against HBV is recommended in patients to prevent progression

of liver disease (ie, active necroinflammation with fibrosis, cirrhosis,

decompensation of cirrhosis or hepatocellular carcinoma, and recurrence after

liver transplantation).[8,10] The endpoint of treatment for hepatitis B e

antigen (HBeAg)-positive patients is profound suppression of HBV replication;

normalization of serum alanine aminotransferase (ALT); loss of HBeAg, with or

without detection of hepatitis B e antibody (anti-HBe); and improvement in liver

histology.[8] In contrast, the endpoint of treatment for HBeAg-negative patients

has not been clearly defined -- the target has been durable suppression of HBV

DNA, but the rate of relapse after therapy is stopped is high.[8,11] In

addition, HBeAg-negative patients are typically older[12] and have a longer

duration of disease that is often more advanced.

Currently, the US Food and Drug Administration (FDA) has approved the following

medications for the treatment of chronic HBV infection: interferon alfa-2b;

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

adefovir, entecavir, and telbivudine. Tenofovir* and tenofovir in combination

with emtricitabine,* [13-15] which are approved for the treatment of HIV

infection, have also demonstrated efficacy in the treatment of chronic HBV

infection. Tenofovir is currently under FDA review for likely approval in 2008.

Resistance

Antiviral drug resistance reflects the reduced susceptibility of a virus to the

inhibitory effect of a drug.[16] In clinical trials and in clinical practice,

resistance is defined as the selection of variants bearing amino acid

substitutions conferring reduced susceptibility to a drug that results in

primary or secondary treatment failure.[10] Resistance to antiviral drug therapy

is a well-known phenomenon in the treatment of HIV,[17] and more recently, has

been recognized in the setting of anti-HBV treatment.[18] In treatment of HBV

infection, the development of viable resistant strains may lead to the

progression of liver disease and even decompensation of cirrhosis.[19-21]

Development of Resistance

Unique among DNA viruses, HBV replicates via a reverse transcription process

despite containing a DNA genome. However, the HBV reverse transcriptase is an

error-prone enzyme, as it lacks a proofreading ability. This, coupled with the

high replicative rate of HBV, leads to the occurrence of random mutations with

amino acid substitutions in the reverse transcriptase portion of the HBV

genome.[22] Some of these mutations select for drug resistance even in the

absence of antiviral therapy. They mutations are preferentially selected when

oral antiviral therapy is introduced. Figure 1 shows a schema detailing the

development of antiviral drug resistance. Genetic barriers to resistance vary

among compounds; for instance, the nucleoside analog entecavir appears to have a

particularly high barrier to resistance, [23] requiring several amino acid

substitutions to induce resistance -- that is, amino acid sequence changes due

to mutations that in turn lead to decreased antiviral activity against resistant

mutant virus. In contrast, the chance of antiviral resistance is greater if the

compound has a low genetic barrier to resistance, such as lamivudine (marked

decrease in susceptibility because of a single amino acid substitution not

affecting viral genome replication capacity).[24] These treatment-induced

mutations are distinct from spontaneous mutations occurring elsewhere in the

viral genome in the precore and core promoter regions, which down-regulate

production of HBeAg but permit active HBV replication.

Figure. Schema showing development of antiviral drug resistance.

Several factors have been implicated in the development of antiviral

resistance:[25-28]

Viral factors

Antiviral-resistant HBV variants are preferentially selected in the presence of

antiviral therapy because they replicate more effectively than wild-type virus

in the presence of the antiviral drug.

High pretreatment HBV DNA levels

Antiviral factors

Slow or inadequate viral suppression

Resistance from prior antiviral treatment inducing cross-resistance to

subsequent therapy

Host factors

Medication nonadherence

Impaired host immunity

Antiviral Resistance: Terminology

Two types of mutations induced by oral antiviral therapy for chronic hepatitis B

are now recognized: Primary drug-resistant mutations cause an amino acid

substitution that results in reduced susceptibility to a specific antiviral

agent; and secondary compensatory mutations do not affect drug sensitivity but

restore functional defects in viral polymerase activity (ie, replication

fitness) associated with primary drug resistance. The development of resistance

needs to be differentiated from primary nonresponse to medication, including

medication nonadherence. Cross-resistance is defined as a mutation that confers

resistance to more than one antiviral drug by in vitro testing[29] (Table 1).

Table 1. Definitions of Antiviral Resistance[8,32]

Virologic breakthrough Increase in serum HBV DNA by 1 log10 (10-fold) above

nadir after achieving virologic response during continued treatment

Viral rebound Increase in serum HBV DNA to 20,000 IU/mL or above pretreatment

level after achieving virologic response during continued treatment

Biochemical breakthrough Increase in ALT above upper limit of normal after

achieving normalization during continued treatment

Genotypic resistance Detection of mutations that have been shown in in vitro

studies to confer resistance to the nucleoside/nucleotide that is being

administered

Phenotypic resistance In vitro confirmation that the mutation detected decreases

susceptibility (as demonstrated by increase in inhibitory concentrations) to the

nucleoside/nucleotide analog administered

Primary treatment failure

(nonresponse)

Inability of nucleoside/nucleotide analog treatment to reduce serum HBV DNA by

1 log10 IU/mL after the first 6 months of treatment

Cross-resistance Mutation(s) that confers resistance to more than 1 antiviral

drug by in vitro testing

Nomenclature

The current nomenclature used to describe antiviral-resistant HBV mutations in

the HBV DNA polymerase gene includes " rt " (for the reverse transcriptase region

of the HBV polymerase gene), which is common to all treatment-induced mutations,

followed by the first letter of the original amino acid location in the gene,

and ending with the letter of the replaced amino acid. For example, the common

lamivudine-resistant mutations are rtM204V and rtM204I, in which methionine is

either replaced by valine or isoleucine at position 204.[30-32] Current

resistant patterns associated with available antiviral therapies are shown in

Table 2.

Table 2. Resistance Patterns in the Hepatitis B Polymerase

Gene[35,39,45,47-49,68-71]

Drugs Location on Reverse Transcriptase

L80V/I I169T V173L L180M A181T/V T184S/A/I/L A194T S202C/G/I M204V/I/S N236T

M250I/V

LAM X X X X

FTC X X X

ETV X X X X* X X

LdT X X X

ADV X X

TDF X X X

ADV = adefovir; ETV = entecavir; FTC = emtricitabine; LAM = lamivudine; LdT =

telbivudine; TDF = tenofovir.

*In the presence of primary resistance mutations (L180M + M204V).

Interferon-Based Therapy

Standard interferons and pegylated interferons exert antiviral activity by

immune-modulatory and antiproliferative effects. This class of antiviral therapy

does not seem to demonstrate viral resistance -- rather, treatment failure

(nonresponse to therapy) can be observed. Additionally, approximately 50% of

responders may relapse after cessation of therapy, and relapse can occur as long

as 5 years after cessation of therapy.[8] For these reasons, as well as because

of the side effect profile (eg, flu-like symptoms, fever, myalgia, mild bone

marrow suppression, psychiatric side effects),[8,10] interferon-based therapy

has limited efficacy, especially in decompensated cirrhosis[33] and in

post-liver transplantation patients. Interferon-based therapies are typically

given for a predefined course (eg, 1 year), whereas oral antiviral agents are

often continued for more prolonged periods, and such prolonged treatment courses

increase risk for selecting resistant strains.[31]

_________________________________________________________________

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http://www.medscape.com/viewarticle/575106

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

Management -- Volume 2

Understanding Resistance in Hepatitis B -- Clinical Implications CME

Chakradhar M. Reddy, MD , MD, FACP

Disclosures

Introduction

Recent estimates suggest that worldwide, 2 billion people have been infected

with hepatitis B virus (HBV), with more than 360 million individuals chronically

infected and at substantial risk for major complications (most notably,

decompensated cirrhosis and hepatocellular carcinoma).[1] The annual estimated

mortality from chronic HBV-related liver disease globally is 500,000 to 700,000

deaths each year.[2-4] Approximately 60% of the world's population lives in

areas where HBV infection is highly endemic.[5] In these regions, including

Southeast Asia, the South Pacific, and sub-Saharan Africa, up to 10% to 12% of

the population is chronically infected, with the remainder having serologic

evidence of prior HBV infection.[6] In contrast, in low-prevalence regions in

the more developed world, HBV infection is usually observed in individuals of

lower socioeconomic status, immigrants from endemic areas, those who engage in

high-risk sexual behavior, and injection drug users.[5] A recent updated

estimate suggests that there may be as many as 2 million chronically infected

individuals in the United States. This reflects the continued high prevalence

rates of HBV infection in immigrant communities despite the decline in the

number of acute infections per year from approximately 260,000 to 60,000 since

the inception of the HBV vaccine about 20 years ago.[7-9]

Treatment Goals

Antiviral therapy against HBV is recommended in patients to prevent progression

of liver disease (ie, active necroinflammation with fibrosis, cirrhosis,

decompensation of cirrhosis or hepatocellular carcinoma, and recurrence after

liver transplantation).[8,10] The endpoint of treatment for hepatitis B e

antigen (HBeAg)-positive patients is profound suppression of HBV replication;

normalization of serum alanine aminotransferase (ALT); loss of HBeAg, with or

without detection of hepatitis B e antibody (anti-HBe); and improvement in liver

histology.[8] In contrast, the endpoint of treatment for HBeAg-negative patients

has not been clearly defined -- the target has been durable suppression of HBV

DNA, but the rate of relapse after therapy is stopped is high.[8,11] In

addition, HBeAg-negative patients are typically older[12] and have a longer

duration of disease that is often more advanced.

Currently, the US Food and Drug Administration (FDA) has approved the following

medications for the treatment of chronic HBV infection: interferon alfa-2b;

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

adefovir, entecavir, and telbivudine. Tenofovir* and tenofovir in combination

with emtricitabine,* [13-15] which are approved for the treatment of HIV

infection, have also demonstrated efficacy in the treatment of chronic HBV

infection. Tenofovir is currently under FDA review for likely approval in 2008.

Resistance

Antiviral drug resistance reflects the reduced susceptibility of a virus to the

inhibitory effect of a drug.[16] In clinical trials and in clinical practice,

resistance is defined as the selection of variants bearing amino acid

substitutions conferring reduced susceptibility to a drug that results in

primary or secondary treatment failure.[10] Resistance to antiviral drug therapy

is a well-known phenomenon in the treatment of HIV,[17] and more recently, has

been recognized in the setting of anti-HBV treatment.[18] In treatment of HBV

infection, the development of viable resistant strains may lead to the

progression of liver disease and even decompensation of cirrhosis.[19-21]

Development of Resistance

Unique among DNA viruses, HBV replicates via a reverse transcription process

despite containing a DNA genome. However, the HBV reverse transcriptase is an

error-prone enzyme, as it lacks a proofreading ability. This, coupled with the

high replicative rate of HBV, leads to the occurrence of random mutations with

amino acid substitutions in the reverse transcriptase portion of the HBV

genome.[22] Some of these mutations select for drug resistance even in the

absence of antiviral therapy. They mutations are preferentially selected when

oral antiviral therapy is introduced. Figure 1 shows a schema detailing the

development of antiviral drug resistance. Genetic barriers to resistance vary

among compounds; for instance, the nucleoside analog entecavir appears to have a

particularly high barrier to resistance, [23] requiring several amino acid

substitutions to induce resistance -- that is, amino acid sequence changes due

to mutations that in turn lead to decreased antiviral activity against resistant

mutant virus. In contrast, the chance of antiviral resistance is greater if the

compound has a low genetic barrier to resistance, such as lamivudine (marked

decrease in susceptibility because of a single amino acid substitution not

affecting viral genome replication capacity).[24] These treatment-induced

mutations are distinct from spontaneous mutations occurring elsewhere in the

viral genome in the precore and core promoter regions, which down-regulate

production of HBeAg but permit active HBV replication.

Figure. Schema showing development of antiviral drug resistance.

Several factors have been implicated in the development of antiviral

resistance:[25-28]

Viral factors

Antiviral-resistant HBV variants are preferentially selected in the presence of

antiviral therapy because they replicate more effectively than wild-type virus

in the presence of the antiviral drug.

High pretreatment HBV DNA levels

Antiviral factors

Slow or inadequate viral suppression

Resistance from prior antiviral treatment inducing cross-resistance to

subsequent therapy

Host factors

Medication nonadherence

Impaired host immunity

Antiviral Resistance: Terminology

Two types of mutations induced by oral antiviral therapy for chronic hepatitis B

are now recognized: Primary drug-resistant mutations cause an amino acid

substitution that results in reduced susceptibility to a specific antiviral

agent; and secondary compensatory mutations do not affect drug sensitivity but

restore functional defects in viral polymerase activity (ie, replication

fitness) associated with primary drug resistance. The development of resistance

needs to be differentiated from primary nonresponse to medication, including

medication nonadherence. Cross-resistance is defined as a mutation that confers

resistance to more than one antiviral drug by in vitro testing[29] (Table 1).

Table 1. Definitions of Antiviral Resistance[8,32]

Virologic breakthrough Increase in serum HBV DNA by 1 log10 (10-fold) above

nadir after achieving virologic response during continued treatment

Viral rebound Increase in serum HBV DNA to 20,000 IU/mL or above pretreatment

level after achieving virologic response during continued treatment

Biochemical breakthrough Increase in ALT above upper limit of normal after

achieving normalization during continued treatment

Genotypic resistance Detection of mutations that have been shown in in vitro

studies to confer resistance to the nucleoside/nucleotide that is being

administered

Phenotypic resistance In vitro confirmation that the mutation detected decreases

susceptibility (as demonstrated by increase in inhibitory concentrations) to the

nucleoside/nucleotide analog administered

Primary treatment failure

(nonresponse)

Inability of nucleoside/nucleotide analog treatment to reduce serum HBV DNA by

1 log10 IU/mL after the first 6 months of treatment

Cross-resistance Mutation(s) that confers resistance to more than 1 antiviral

drug by in vitro testing

Nomenclature

The current nomenclature used to describe antiviral-resistant HBV mutations in

the HBV DNA polymerase gene includes " rt " (for the reverse transcriptase region

of the HBV polymerase gene), which is common to all treatment-induced mutations,

followed by the first letter of the original amino acid location in the gene,

and ending with the letter of the replaced amino acid. For example, the common

lamivudine-resistant mutations are rtM204V and rtM204I, in which methionine is

either replaced by valine or isoleucine at position 204.[30-32] Current

resistant patterns associated with available antiviral therapies are shown in

Table 2.

Table 2. Resistance Patterns in the Hepatitis B Polymerase

Gene[35,39,45,47-49,68-71]

Drugs Location on Reverse Transcriptase

L80V/I I169T V173L L180M A181T/V T184S/A/I/L A194T S202C/G/I M204V/I/S N236T

M250I/V

LAM X X X X

FTC X X X

ETV X X X X* X X

LdT X X X

ADV X X

TDF X X X

ADV = adefovir; ETV = entecavir; FTC = emtricitabine; LAM = lamivudine; LdT =

telbivudine; TDF = tenofovir.

*In the presence of primary resistance mutations (L180M + M204V).

Interferon-Based Therapy

Standard interferons and pegylated interferons exert antiviral activity by

immune-modulatory and antiproliferative effects. This class of antiviral therapy

does not seem to demonstrate viral resistance -- rather, treatment failure

(nonresponse to therapy) can be observed. Additionally, approximately 50% of

responders may relapse after cessation of therapy, and relapse can occur as long

as 5 years after cessation of therapy.[8] For these reasons, as well as because

of the side effect profile (eg, flu-like symptoms, fever, myalgia, mild bone

marrow suppression, psychiatric side effects),[8,10] interferon-based therapy

has limited efficacy, especially in decompensated cirrhosis[33] and in

post-liver transplantation patients. Interferon-based therapies are typically

given for a predefined course (eg, 1 year), whereas oral antiviral agents are

often continued for more prolonged periods, and such prolonged treatment courses

increase risk for selecting resistant strains.[31]

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