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

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

The Oral Antivirals

The nucleoside/nucleotide agents have the advantages of oral administration,

excellent side-effect profile, can be used in advanced liver disease, and have

high potency in decreasing serum HBV DNA; primary disadvantages include the need

for long-term administration and variable rates of antiviral drug

resistance.[8,31]

Lamivudine

The nucleoside analog lamivudine is a synthetic monophosphate that is converted

intracellularly to an active triphosphate compound that is then incorporated

into the viral DNA polymerase, acting as a chain terminator for the DNA

polymerase activity.[34] The HBV polymerase gene contains 7 functional domains,

designated A through G. Lamivudine resistance results from M204V and M204I

mutations in the C domain of the HBV DNA polymerase.[35] HBV variants containing

the M204V and M204I mutations display reduced reverse-transcriptase activity and

replication capacity, but compensatory mutations in the B domain (V173L and

L180M) restore the replication fitness of the virus. Data from patients with

HBeAg-positive chronic hepatitis B receiving lamivudine therapy up to 6 years

showed that the proportion of patients with documented lamivudine-resistant

mutations increased from 23% to 65% from years 1 to 5, respectively.[19] Studies

evaluating the efficacy of 2-year lamivudine treatment in HBeAg-negative chronic

hepatitis B showed that the patterns of lamivudine resistance have varied,

ranging from 31% in one study[36] to 70% with significant fibrosis and cirrhosis

in another.[37]

Adefovir

The nucleotide analog adefovir dipivoxil exerts its anti-HBV activity by

inhibiting the priming of reverse transcription by preventing incorporation of

dATP into the viral primer and inhibiting viral-minus strand DNA elongation.[38]

Two mutations, N236T in the D domain of the HBV polymerase and A181V in the B

domain, have been described that confer a 5- to 10-fold decreased susceptibility

to adefovir.[39,40]. Recently, another mutation, I233V, has been described, but

this variant remains sensitive to adefovir.[41]In a study of 125 HBeAg-negative

patients who were treated with adefovir up to 240 weeks, mutations associated

with the HBV DNA polymerase were detected in 29%, virologic breakthrough was

observed in 20%, and biochemical breakthrough (ie, ALT increases) was detected

in 11%.[39] In a study of the long-term safety and efficacy of adefovir in

HBeAg-positive patients, the adefovir-resistance mutations A181V and/or N236T

were not detected in any of 171 patients at year 1 but developed in 20% of

subjects beginning at week 195.[42]

Entecavir

The guanosine nucleoside analog entecavir is triphosphorylated to its active

form and competitively inhibits all activities of the HBV DNA polymerase.[43]

This agent is 100-fold more potent against HBV in culture than either lamivudine

or adefovir.[43] After 5 years of entecavir monotherapy, cumulative probability

for entecavir resistance was estimated to be 1.2% in nucleoside-naive

patients.[44] When entecavir was administered to patients who were refractory to

lamivudine, entecavir resistance was estimated at up to 50% after 5 years.[44]

Entecavir resistance is associated with cross-resistance to

lamivudine-conferring mutations plus additional changes at T184 S/A/I/L,

S202G/C, and/or M250V/I.[45]

Telbivudine

Telbivudine is a synthetic thymidine nucleoside analog that is converted to its

active triphosphate form and inhibits the HBV DNA polymerase by competing with

thymidine 5'-triphosphate, the natural substrate; this competition blocks

reverse transcription, leading to DNA chain termination.[46] Data from a large

trial showed that the 2-year cumulative rate of telbivudine resistance (defined

by virologic breakthrough) in HBeAg-positive patients was 21.6% and 8.6% in

HBeAg-negative patients.[47] Telbivudine has primary mutations of M204I and

secondary mutations L80I/V and L80I/V+L180M that are sometimes seen in

conjunction with M204I.[47,48]

Emtricitabine*

Emtricitabine is a cytosine analog that is phosphorylated intracellularly to the

active form, emtricitabine 5'-triphosphate, which selectively interferes with

the reverse transcriptase activity of HIV and HBV.[43,49,50] The role of

emtricitabine as monotherapy is limited due to its structural similarity to

lamivudine and the corresponding risk for drug resistance.[51] In a 2-year study

evaluating the safety and antiviral activity of emtricitabine in 98 patients

with chronic hepatitis B, 18% developed resistance mutations. Mutations

conferring resistance against emtricitabine were similar to those that resulted

in resistance to lamivudine (M204I or M204V with or without L180M or V173L).[49]

Tenofovir

Tenofovir disoproxil fumarate* is converted to tenofovir, an acyclic nucleoside

phosphonate (nucleotide) analog of adenosine 5¡Ç -monophosphate, that, following

phosphorylation, inhibits the activity of HIV-1 reverse transcriptase by

competing with the natural substrate deoxyadenosine 5¡Ç -triphosphate and, after

incorporation into DNA, by DNA chain termination.[14,15,52] Tenofovir has been

shown in vitro to inhibit replication of wild-type HBV and retains activity

against HBV variants conferring resistance to lamivudine and adefovir. Data from

a study analyzing the efficacy of tenofovir in a subset of patients with

adefovir resistance, suggested that there is cross-resistance between adefovir

and tenofovir even though switching from adefovir to tenofovir in

adefovir-resistant patients resulted in a further decrease in serum HBV DNA.[53]

This finding contrasted with the results of another study that showed tenofovir

was effective in patients who experienced virologic breakthrough or suboptimal

response to adefovir.[54] Longer-term data are needed to assess resistance rates

in treatment-naive and adefovir-resistant patients.

Testing for Resistance

The sequence of events in the development of resistance against antiviral

therapy starts with genotypic resistance followed by phenotypic resistance with

virologic breakthrough that, in turn, precedes clinical and/or biochemical

breakthrough. Early detection of viral resistance is important for better

outcomes in liver disease, especially in the case of known resistant

mutations.[55,56]

Genotype Resistance

A line-probe assay for the simultaneous detection of hepatitis B wild-type virus

and a drug-induced mutation using direct sequencing is the most convenient

method for identifying resistance mutations. Direct sequencing (ie, direct

sequence analysis of the HBV polymerase gene) can detect variants that

constitute 10% to 20% of the virus population.[29] Hybridization techniques,

such as restriction fragment length polymorphism and reverse hybridization,

detect only known specific mutations. The advantage of hybridization methods is

that they detect identified resistant variants when they are present as minor

populations (

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

The Oral Antivirals

The nucleoside/nucleotide agents have the advantages of oral administration,

excellent side-effect profile, can be used in advanced liver disease, and have

high potency in decreasing serum HBV DNA; primary disadvantages include the need

for long-term administration and variable rates of antiviral drug

resistance.[8,31]

Lamivudine

The nucleoside analog lamivudine is a synthetic monophosphate that is converted

intracellularly to an active triphosphate compound that is then incorporated

into the viral DNA polymerase, acting as a chain terminator for the DNA

polymerase activity.[34] The HBV polymerase gene contains 7 functional domains,

designated A through G. Lamivudine resistance results from M204V and M204I

mutations in the C domain of the HBV DNA polymerase.[35] HBV variants containing

the M204V and M204I mutations display reduced reverse-transcriptase activity and

replication capacity, but compensatory mutations in the B domain (V173L and

L180M) restore the replication fitness of the virus. Data from patients with

HBeAg-positive chronic hepatitis B receiving lamivudine therapy up to 6 years

showed that the proportion of patients with documented lamivudine-resistant

mutations increased from 23% to 65% from years 1 to 5, respectively.[19] Studies

evaluating the efficacy of 2-year lamivudine treatment in HBeAg-negative chronic

hepatitis B showed that the patterns of lamivudine resistance have varied,

ranging from 31% in one study[36] to 70% with significant fibrosis and cirrhosis

in another.[37]

Adefovir

The nucleotide analog adefovir dipivoxil exerts its anti-HBV activity by

inhibiting the priming of reverse transcription by preventing incorporation of

dATP into the viral primer and inhibiting viral-minus strand DNA elongation.[38]

Two mutations, N236T in the D domain of the HBV polymerase and A181V in the B

domain, have been described that confer a 5- to 10-fold decreased susceptibility

to adefovir.[39,40]. Recently, another mutation, I233V, has been described, but

this variant remains sensitive to adefovir.[41]In a study of 125 HBeAg-negative

patients who were treated with adefovir up to 240 weeks, mutations associated

with the HBV DNA polymerase were detected in 29%, virologic breakthrough was

observed in 20%, and biochemical breakthrough (ie, ALT increases) was detected

in 11%.[39] In a study of the long-term safety and efficacy of adefovir in

HBeAg-positive patients, the adefovir-resistance mutations A181V and/or N236T

were not detected in any of 171 patients at year 1 but developed in 20% of

subjects beginning at week 195.[42]

Entecavir

The guanosine nucleoside analog entecavir is triphosphorylated to its active

form and competitively inhibits all activities of the HBV DNA polymerase.[43]

This agent is 100-fold more potent against HBV in culture than either lamivudine

or adefovir.[43] After 5 years of entecavir monotherapy, cumulative probability

for entecavir resistance was estimated to be 1.2% in nucleoside-naive

patients.[44] When entecavir was administered to patients who were refractory to

lamivudine, entecavir resistance was estimated at up to 50% after 5 years.[44]

Entecavir resistance is associated with cross-resistance to

lamivudine-conferring mutations plus additional changes at T184 S/A/I/L,

S202G/C, and/or M250V/I.[45]

Telbivudine

Telbivudine is a synthetic thymidine nucleoside analog that is converted to its

active triphosphate form and inhibits the HBV DNA polymerase by competing with

thymidine 5'-triphosphate, the natural substrate; this competition blocks

reverse transcription, leading to DNA chain termination.[46] Data from a large

trial showed that the 2-year cumulative rate of telbivudine resistance (defined

by virologic breakthrough) in HBeAg-positive patients was 21.6% and 8.6% in

HBeAg-negative patients.[47] Telbivudine has primary mutations of M204I and

secondary mutations L80I/V and L80I/V+L180M that are sometimes seen in

conjunction with M204I.[47,48]

Emtricitabine*

Emtricitabine is a cytosine analog that is phosphorylated intracellularly to the

active form, emtricitabine 5'-triphosphate, which selectively interferes with

the reverse transcriptase activity of HIV and HBV.[43,49,50] The role of

emtricitabine as monotherapy is limited due to its structural similarity to

lamivudine and the corresponding risk for drug resistance.[51] In a 2-year study

evaluating the safety and antiviral activity of emtricitabine in 98 patients

with chronic hepatitis B, 18% developed resistance mutations. Mutations

conferring resistance against emtricitabine were similar to those that resulted

in resistance to lamivudine (M204I or M204V with or without L180M or V173L).[49]

Tenofovir

Tenofovir disoproxil fumarate* is converted to tenofovir, an acyclic nucleoside

phosphonate (nucleotide) analog of adenosine 5¡Ç -monophosphate, that, following

phosphorylation, inhibits the activity of HIV-1 reverse transcriptase by

competing with the natural substrate deoxyadenosine 5¡Ç -triphosphate and, after

incorporation into DNA, by DNA chain termination.[14,15,52] Tenofovir has been

shown in vitro to inhibit replication of wild-type HBV and retains activity

against HBV variants conferring resistance to lamivudine and adefovir. Data from

a study analyzing the efficacy of tenofovir in a subset of patients with

adefovir resistance, suggested that there is cross-resistance between adefovir

and tenofovir even though switching from adefovir to tenofovir in

adefovir-resistant patients resulted in a further decrease in serum HBV DNA.[53]

This finding contrasted with the results of another study that showed tenofovir

was effective in patients who experienced virologic breakthrough or suboptimal

response to adefovir.[54] Longer-term data are needed to assess resistance rates

in treatment-naive and adefovir-resistant patients.

Testing for Resistance

The sequence of events in the development of resistance against antiviral

therapy starts with genotypic resistance followed by phenotypic resistance with

virologic breakthrough that, in turn, precedes clinical and/or biochemical

breakthrough. Early detection of viral resistance is important for better

outcomes in liver disease, especially in the case of known resistant

mutations.[55,56]

Genotype Resistance

A line-probe assay for the simultaneous detection of hepatitis B wild-type virus

and a drug-induced mutation using direct sequencing is the most convenient

method for identifying resistance mutations. Direct sequencing (ie, direct

sequence analysis of the HBV polymerase gene) can detect variants that

constitute 10% to 20% of the virus population.[29] Hybridization techniques,

such as restriction fragment length polymorphism and reverse hybridization,

detect only known specific mutations. The advantage of hybridization methods is

that they detect identified resistant variants when they are present as minor

populations (

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

The Oral Antivirals

The nucleoside/nucleotide agents have the advantages of oral administration,

excellent side-effect profile, can be used in advanced liver disease, and have

high potency in decreasing serum HBV DNA; primary disadvantages include the need

for long-term administration and variable rates of antiviral drug

resistance.[8,31]

Lamivudine

The nucleoside analog lamivudine is a synthetic monophosphate that is converted

intracellularly to an active triphosphate compound that is then incorporated

into the viral DNA polymerase, acting as a chain terminator for the DNA

polymerase activity.[34] The HBV polymerase gene contains 7 functional domains,

designated A through G. Lamivudine resistance results from M204V and M204I

mutations in the C domain of the HBV DNA polymerase.[35] HBV variants containing

the M204V and M204I mutations display reduced reverse-transcriptase activity and

replication capacity, but compensatory mutations in the B domain (V173L and

L180M) restore the replication fitness of the virus. Data from patients with

HBeAg-positive chronic hepatitis B receiving lamivudine therapy up to 6 years

showed that the proportion of patients with documented lamivudine-resistant

mutations increased from 23% to 65% from years 1 to 5, respectively.[19] Studies

evaluating the efficacy of 2-year lamivudine treatment in HBeAg-negative chronic

hepatitis B showed that the patterns of lamivudine resistance have varied,

ranging from 31% in one study[36] to 70% with significant fibrosis and cirrhosis

in another.[37]

Adefovir

The nucleotide analog adefovir dipivoxil exerts its anti-HBV activity by

inhibiting the priming of reverse transcription by preventing incorporation of

dATP into the viral primer and inhibiting viral-minus strand DNA elongation.[38]

Two mutations, N236T in the D domain of the HBV polymerase and A181V in the B

domain, have been described that confer a 5- to 10-fold decreased susceptibility

to adefovir.[39,40]. Recently, another mutation, I233V, has been described, but

this variant remains sensitive to adefovir.[41]In a study of 125 HBeAg-negative

patients who were treated with adefovir up to 240 weeks, mutations associated

with the HBV DNA polymerase were detected in 29%, virologic breakthrough was

observed in 20%, and biochemical breakthrough (ie, ALT increases) was detected

in 11%.[39] In a study of the long-term safety and efficacy of adefovir in

HBeAg-positive patients, the adefovir-resistance mutations A181V and/or N236T

were not detected in any of 171 patients at year 1 but developed in 20% of

subjects beginning at week 195.[42]

Entecavir

The guanosine nucleoside analog entecavir is triphosphorylated to its active

form and competitively inhibits all activities of the HBV DNA polymerase.[43]

This agent is 100-fold more potent against HBV in culture than either lamivudine

or adefovir.[43] After 5 years of entecavir monotherapy, cumulative probability

for entecavir resistance was estimated to be 1.2% in nucleoside-naive

patients.[44] When entecavir was administered to patients who were refractory to

lamivudine, entecavir resistance was estimated at up to 50% after 5 years.[44]

Entecavir resistance is associated with cross-resistance to

lamivudine-conferring mutations plus additional changes at T184 S/A/I/L,

S202G/C, and/or M250V/I.[45]

Telbivudine

Telbivudine is a synthetic thymidine nucleoside analog that is converted to its

active triphosphate form and inhibits the HBV DNA polymerase by competing with

thymidine 5'-triphosphate, the natural substrate; this competition blocks

reverse transcription, leading to DNA chain termination.[46] Data from a large

trial showed that the 2-year cumulative rate of telbivudine resistance (defined

by virologic breakthrough) in HBeAg-positive patients was 21.6% and 8.6% in

HBeAg-negative patients.[47] Telbivudine has primary mutations of M204I and

secondary mutations L80I/V and L80I/V+L180M that are sometimes seen in

conjunction with M204I.[47,48]

Emtricitabine*

Emtricitabine is a cytosine analog that is phosphorylated intracellularly to the

active form, emtricitabine 5'-triphosphate, which selectively interferes with

the reverse transcriptase activity of HIV and HBV.[43,49,50] The role of

emtricitabine as monotherapy is limited due to its structural similarity to

lamivudine and the corresponding risk for drug resistance.[51] In a 2-year study

evaluating the safety and antiviral activity of emtricitabine in 98 patients

with chronic hepatitis B, 18% developed resistance mutations. Mutations

conferring resistance against emtricitabine were similar to those that resulted

in resistance to lamivudine (M204I or M204V with or without L180M or V173L).[49]

Tenofovir

Tenofovir disoproxil fumarate* is converted to tenofovir, an acyclic nucleoside

phosphonate (nucleotide) analog of adenosine 5¡Ç -monophosphate, that, following

phosphorylation, inhibits the activity of HIV-1 reverse transcriptase by

competing with the natural substrate deoxyadenosine 5¡Ç -triphosphate and, after

incorporation into DNA, by DNA chain termination.[14,15,52] Tenofovir has been

shown in vitro to inhibit replication of wild-type HBV and retains activity

against HBV variants conferring resistance to lamivudine and adefovir. Data from

a study analyzing the efficacy of tenofovir in a subset of patients with

adefovir resistance, suggested that there is cross-resistance between adefovir

and tenofovir even though switching from adefovir to tenofovir in

adefovir-resistant patients resulted in a further decrease in serum HBV DNA.[53]

This finding contrasted with the results of another study that showed tenofovir

was effective in patients who experienced virologic breakthrough or suboptimal

response to adefovir.[54] Longer-term data are needed to assess resistance rates

in treatment-naive and adefovir-resistant patients.

Testing for Resistance

The sequence of events in the development of resistance against antiviral

therapy starts with genotypic resistance followed by phenotypic resistance with

virologic breakthrough that, in turn, precedes clinical and/or biochemical

breakthrough. Early detection of viral resistance is important for better

outcomes in liver disease, especially in the case of known resistant

mutations.[55,56]

Genotype Resistance

A line-probe assay for the simultaneous detection of hepatitis B wild-type virus

and a drug-induced mutation using direct sequencing is the most convenient

method for identifying resistance mutations. Direct sequencing (ie, direct

sequence analysis of the HBV polymerase gene) can detect variants that

constitute 10% to 20% of the virus population.[29] Hybridization techniques,

such as restriction fragment length polymorphism and reverse hybridization,

detect only known specific mutations. The advantage of hybridization methods is

that they detect identified resistant variants when they are present as minor

populations (

_________________________________________________________________

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

The Oral Antivirals

The nucleoside/nucleotide agents have the advantages of oral administration,

excellent side-effect profile, can be used in advanced liver disease, and have

high potency in decreasing serum HBV DNA; primary disadvantages include the need

for long-term administration and variable rates of antiviral drug

resistance.[8,31]

Lamivudine

The nucleoside analog lamivudine is a synthetic monophosphate that is converted

intracellularly to an active triphosphate compound that is then incorporated

into the viral DNA polymerase, acting as a chain terminator for the DNA

polymerase activity.[34] The HBV polymerase gene contains 7 functional domains,

designated A through G. Lamivudine resistance results from M204V and M204I

mutations in the C domain of the HBV DNA polymerase.[35] HBV variants containing

the M204V and M204I mutations display reduced reverse-transcriptase activity and

replication capacity, but compensatory mutations in the B domain (V173L and

L180M) restore the replication fitness of the virus. Data from patients with

HBeAg-positive chronic hepatitis B receiving lamivudine therapy up to 6 years

showed that the proportion of patients with documented lamivudine-resistant

mutations increased from 23% to 65% from years 1 to 5, respectively.[19] Studies

evaluating the efficacy of 2-year lamivudine treatment in HBeAg-negative chronic

hepatitis B showed that the patterns of lamivudine resistance have varied,

ranging from 31% in one study[36] to 70% with significant fibrosis and cirrhosis

in another.[37]

Adefovir

The nucleotide analog adefovir dipivoxil exerts its anti-HBV activity by

inhibiting the priming of reverse transcription by preventing incorporation of

dATP into the viral primer and inhibiting viral-minus strand DNA elongation.[38]

Two mutations, N236T in the D domain of the HBV polymerase and A181V in the B

domain, have been described that confer a 5- to 10-fold decreased susceptibility

to adefovir.[39,40]. Recently, another mutation, I233V, has been described, but

this variant remains sensitive to adefovir.[41]In a study of 125 HBeAg-negative

patients who were treated with adefovir up to 240 weeks, mutations associated

with the HBV DNA polymerase were detected in 29%, virologic breakthrough was

observed in 20%, and biochemical breakthrough (ie, ALT increases) was detected

in 11%.[39] In a study of the long-term safety and efficacy of adefovir in

HBeAg-positive patients, the adefovir-resistance mutations A181V and/or N236T

were not detected in any of 171 patients at year 1 but developed in 20% of

subjects beginning at week 195.[42]

Entecavir

The guanosine nucleoside analog entecavir is triphosphorylated to its active

form and competitively inhibits all activities of the HBV DNA polymerase.[43]

This agent is 100-fold more potent against HBV in culture than either lamivudine

or adefovir.[43] After 5 years of entecavir monotherapy, cumulative probability

for entecavir resistance was estimated to be 1.2% in nucleoside-naive

patients.[44] When entecavir was administered to patients who were refractory to

lamivudine, entecavir resistance was estimated at up to 50% after 5 years.[44]

Entecavir resistance is associated with cross-resistance to

lamivudine-conferring mutations plus additional changes at T184 S/A/I/L,

S202G/C, and/or M250V/I.[45]

Telbivudine

Telbivudine is a synthetic thymidine nucleoside analog that is converted to its

active triphosphate form and inhibits the HBV DNA polymerase by competing with

thymidine 5'-triphosphate, the natural substrate; this competition blocks

reverse transcription, leading to DNA chain termination.[46] Data from a large

trial showed that the 2-year cumulative rate of telbivudine resistance (defined

by virologic breakthrough) in HBeAg-positive patients was 21.6% and 8.6% in

HBeAg-negative patients.[47] Telbivudine has primary mutations of M204I and

secondary mutations L80I/V and L80I/V+L180M that are sometimes seen in

conjunction with M204I.[47,48]

Emtricitabine*

Emtricitabine is a cytosine analog that is phosphorylated intracellularly to the

active form, emtricitabine 5'-triphosphate, which selectively interferes with

the reverse transcriptase activity of HIV and HBV.[43,49,50] The role of

emtricitabine as monotherapy is limited due to its structural similarity to

lamivudine and the corresponding risk for drug resistance.[51] In a 2-year study

evaluating the safety and antiviral activity of emtricitabine in 98 patients

with chronic hepatitis B, 18% developed resistance mutations. Mutations

conferring resistance against emtricitabine were similar to those that resulted

in resistance to lamivudine (M204I or M204V with or without L180M or V173L).[49]

Tenofovir

Tenofovir disoproxil fumarate* is converted to tenofovir, an acyclic nucleoside

phosphonate (nucleotide) analog of adenosine 5¡Ç -monophosphate, that, following

phosphorylation, inhibits the activity of HIV-1 reverse transcriptase by

competing with the natural substrate deoxyadenosine 5¡Ç -triphosphate and, after

incorporation into DNA, by DNA chain termination.[14,15,52] Tenofovir has been

shown in vitro to inhibit replication of wild-type HBV and retains activity

against HBV variants conferring resistance to lamivudine and adefovir. Data from

a study analyzing the efficacy of tenofovir in a subset of patients with

adefovir resistance, suggested that there is cross-resistance between adefovir

and tenofovir even though switching from adefovir to tenofovir in

adefovir-resistant patients resulted in a further decrease in serum HBV DNA.[53]

This finding contrasted with the results of another study that showed tenofovir

was effective in patients who experienced virologic breakthrough or suboptimal

response to adefovir.[54] Longer-term data are needed to assess resistance rates

in treatment-naive and adefovir-resistant patients.

Testing for Resistance

The sequence of events in the development of resistance against antiviral

therapy starts with genotypic resistance followed by phenotypic resistance with

virologic breakthrough that, in turn, precedes clinical and/or biochemical

breakthrough. Early detection of viral resistance is important for better

outcomes in liver disease, especially in the case of known resistant

mutations.[55,56]

Genotype Resistance

A line-probe assay for the simultaneous detection of hepatitis B wild-type virus

and a drug-induced mutation using direct sequencing is the most convenient

method for identifying resistance mutations. Direct sequencing (ie, direct

sequence analysis of the HBV polymerase gene) can detect variants that

constitute 10% to 20% of the virus population.[29] Hybridization techniques,

such as restriction fragment length polymorphism and reverse hybridization,

detect only known specific mutations. The advantage of hybridization methods is

that they detect identified resistant variants when they are present as minor

populations (

_________________________________________________________________

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