Adherence Issues in the Treatment of Hepatitis B

[Guest guest]

http://www.medscape.com/viewarticle/583708

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

Management - Volume 4

Adherence Issues in the Treatment of Hepatitis B CME

Natasha M. Walzer L. Flamm, MD

Disclosures

Overview

Chronic hepatitis B virus (HBV) infection is a serious global health problem,

with more than 350 million people suffering from chronic infection, ~1 million

of whom will die annually of chronic liver disease.[1] The complications of

chronic hepatitis B include cirrhosis, hepatic decompensation, and

hepatocellular carcinoma (HCC). Chronic HBV infection remains the major cause of

HCC worldwide. Persistent viral replication has been shown to correlate with

disease progression and the development of HCC.[2,3] Antiviral therapy has

assumed a critical role in the treatment of patients with chronic hepatitis B.

Substantial advances have been made in the treatment of hepatitis B in the past

decade; however, the efficacy of new drugs is hampered by the emergence of viral

resistance and by poor sustained response off treatment. Treatment with

antiviral agents commits many patients to lifelong therapy and risks the

selection of HBV strains that are resistant to one or more agents. Strategies to

reduce viral resistance must be developed to maintain the effectiveness of these

novel treatments. Although data in HBV are lacking, it is clear from the HIV

literature that medication nonadherence to direct antiviral therapy can have an

adverse impact on the development of resistance and disease progression.[4,5]

Treatment of Hepatitis B

Eradication of HBV from the patient as defined by the loss of hepatitis B

surface antigen positivity is an infrequently achieved outcome. As a result,

persistent viral suppression and seroconversion from hepatitis B e antigen

(HBeAg) positivity to the corresponding anti-HBe antibody-positive state (in

patients with initial HBeAg positivity) is the primary treatment goal. Available

types of medical therapy include immune modulators and direct antiviral

medications that inhibit HBV replication by inhibiting the HBV DNA polymerase.

There are 7 drugs currently approved by the US Food and Drug Administration for

the treatment of chronic hepatitis B, including oral nucleos(t)ide analogs

(lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir

disoproxil fumarate) and immunomodulatory agents (interferon alfa-2b and

pegylated interferon alfa-2a). The oral nucleos(t)ide analogs have emerged

within the last decade and inhibit the HBV DNA polymerase through chain

termination. These treatments are highly effective, have few side effects, and

are more convenient than interferon -- however, sustained viral suppression is

not achieved in the absence of HBeAg seroconversion after withdrawal of a

48-week course of therapy.[6] As a result, a long duration of therapy in the

majority of patients is required to maintain continued viral suppression, and

this is associated with an increased risk for the development of drug

resistance.

An important distinction when considering treatment of chronic HBV infection is

the presence or absence of HBeAg at the outset. Many adults at the time of

diagnosis of chronic hepatitis B are HBeAg positive with high levels of

circulating HBV DNA, although serum alanine aminotransferase (ALT) levels and

histologic activity are variable. The majority of these patients will undergo

spontaneous seroconversion from HBeAg to anti-HBe.[7] Those who remain HBeAg

positive for at least 6 months should be evaluated for antiviral therapy to

prevent hepatic decompensation and development of HCC. The treatment goal is

seroconversion from HBeAg to anti-HBe with undetectable HBV DNA (defined as an

undetectable viral load to a sensitivity of 20 to 100 IU/mL [approximately

100-500 copies/mL]).[8] Alternatively, other patients may have HBeAg negativity

at the outset, characterized by persistent HBV DNA replication. This situation

is usually secondary to a mutation in the precore gene leading to the formation

of a stop codon that truncates production of HBeAg despite ongoing viral

replication.[9] Clinically, active hepatitis in this setting is defined by

elevated levels of HBV DNA, usually between 2000 and 20 million IU/mL, and

fluctuations in serum ALT.[10] Patients with HBeAg-negative disease are usually

older and more likely to have cirrhosis at the time of presentation.[11]

Antiviral therapy is indicated if the viral load is>/= 20,000 IU/mL, the ALT

level is elevated, or there is inflammation on liver biopsy.[12] Seroconversion

is not possible, and in these patients the only measurable treatment goal is a

virologic and/or biochemical treatment response.[12]

Antiviral Resistance

HBV is a DNA virus that contains a DNA polymerase with reverse transcriptase

activity. Reverse transcriptase has a high inherent error rate when transcribing

RNA into DNA because it lacks proofreading capacity. This high error rate allows

mutations to accumulate at an accelerated rate compared with other forms of

replication. The likelihood of the development of drug-resistant mutants

increases when this system is put under the selective pressure of potent enzyme

inhibitors.[13] Antiviral drug resistance has been reported in up to 70% of

patients after 4 years of lamivudine therapy, 29% after 5 years of adefovir

therapy, 1% after 4 years of entecavir therapy, and in 9% to 22% of patients

after 2 years of telbivudine therapy in nucleoside-naive patients.[14-16]

Resistance to tenofovir was described by one group,[17] but this was not

confirmed in another study.[18] Resistance does not occur with interferon-based

therapy because it is not a direct antiviral enzyme inhibitor.

The development of resistance is influenced by a number of factors -- most

notably, adherence, viral persistence,[19] and pharmacokinetics.[20,21] Poor

adherence to prescribed medical therapy allows for inconsistent medication

levels and persistent viral replication, increasing the likelihood of the

formation of viral quasispecies that may be resistant to the currently

prescribed medication. In HIV infection, adherence to highly active

antiretroviral therapy (HAART) is an important modifiable risk factor in the

development of drug-resistant mutants. Indeed, missing approximately 11% to 30%

of HAART doses after achieving viral suppression is associated with the greatest

risk for viral rebound with clinically significant resistance.[22] In another

report, missing 1 of 5 doses of HAART was found to lead to antiretroviral

therapy resistance.[23] The level of antiretroviral therapy adherence required

to obtain optimal long-term benefit appears to be greater than 90%.[22] Although

data on HBV infection in regard to adherence are lacking, it is likely that poor

adherence would increase the risk of developing resistant mutations in this

setting as well.

High pretreatment HBV DNA levels, slow viral suppression on treatment, and

pre-existing resistance mutations are viral factors that increase the likelihood

of drug resistance.[24-26] Strategies to reduce the formation of drug-resistant

mutations are currently being explored. Combination oral therapy regimens* using

agents with favorable cross-resistance profiles or the combination of a

nucleotide/nucleoside analog plus an immunomodulatory agent* (pegylated

interferon) have been proposed as strategies to decrease the development of

resistant mutations; however, current data have produced mixed results. For

example, although treatment with adefovir and lamivudine in combination vs

lamivudine monotherapy demonstrated superior antiviral efficacy, it did not

eliminate lamivudine resistance, nor did it enhance the rate of seroconversion

from HBeAg to anti-HBe.[27]

The development of antiviral resistance can have significant clinical

consequences. Commonly, there is a return to pretreatment viral replication

levels and disease progression in both HBeAg-positive and HBeAg-negative

patients.[28,29] The implications of antiviral resistance are clearly

demonstrated with the long-term use of lamivudine. Patients with resistance to

lamivudine showed more frequent hepatic flares, hepatic decompensation, and more

elevated Child-Pugh scores in patients with cirrhosis.[14-16,20,21,30] Similar

problems have occurred with adefovir[31]; however, overall data are lacking

because most patients are switched to a different agent once resistance is

identified. Suppression of lamivudine-resistant mutations can be achieved by

switching to adefovir or tenofovir or by adding adefovir or tenofovir to current

lamivudine therapy.[12,32]

Detection of Drug Resistance

Initial viral suppression of chronic HBV infection is achieved in most patients

with the currently available therapies. Drug resistance is usually detected as

either a biochemical or virologic breakthrough. Virologic breakthrough is

defined as a ™ 1 log10 IU/mL increase in serum HBV DNA level from nadir in 2

consecutive samples 1 month apart in patients who have previously responded and

have been adherent to antiviral medication.[33] Biochemical breakthrough is

defined as elevation in serum aminotransferase levels during treatment in a

patient who had achieved initial normalization and who has been adherent to the

prescribed medical regimen.[33]

All patients receiving nucleos(t)ide analog therapy for chronic hepatitis B

should be closely monitored for virologic response and breakthrough during

treatment and for durability of response and viral relapse after treatment has

stopped. Serum HBV DNA should be tested prior to treatment and then every 3

months thereafter during treatment. If medication adherence is verified and

resistance is suspected, tests for antiviral-resistant mutations should be

performed whenever possible to confirm genotypic resistance and to determine the

pattern of mutations. This is accomplished by a direct sequence analysis of the

HBV polymerase gene. This information is useful when determining a follow-up

treatment strategy, as cross-resistance to other antiviral agents is identified

and an appropriate treatment strategy can be defined.[12]

Ascertaining Medication Nonadherence

There is currently no " gold standard " for measuring antiviral adherence. The

various tools available include patient self-reports, clinical assessments, pill

counts, measurements of plasma drug levels, and medication event monitoring

systems. The majority of these methods, however, are not practical outside of

the context of clinical treatment trials. Prescription-refill percentages and

untimed drug concentration measurements, however, are validated ways that have

been shown to document medication nonadherence. Plasma drug concentrations,

although possibly affected by variable pharmacokinetics, have been shown to

correlate with pill counts and future prescription refill data.[34]

Unfortunately, such measurements may be costly.[34,35] Data have suggested that

self-reporting of adherence correlates with pharmacy dispensing records and can

be adopted into routine clinical care.[36] Although none of these methods has

been evaluated specifically in the HBV-infected population, most of the

principles can be generalized to include therapy for any virus with a high

mutation rate.

Strategies to Enhance Adherence

Adherence to prescribed medications is influenced by a number of factors. These

factors include the number of pills that need to be taken, the number of

administrations per day, the cost of medications, the side-effect profile of the

medications, the presence of depressive symptoms, and the presence of substance

abuse.[37] These factors should be elicited carefully in the medical history

prior to the institution of any medical therapy, but specifically in therapies

where adherence can result in antiviral resistance and an adverse clinical

outcome.

Multiple strategies have been employed in the treatment of HIV to enhance

adherence to prescribed therapy. These include case management, couple-based

counseling, pharmacist-based education, telephone support, reminder devices,

home visits by a nurse, and directly observed therapy.[38] However, these

strategies assume that patients at risk for medication nonadherence can be

appropriately identified from the outset. Unfortunately, healthcare providers

can only identify a fraction of patients with suboptimal adherence.[39,40] A

multivariate analysis in patients on HIV therapy demonstrated that a 95% or

greater adherence to prescribed therapy was independently associated with older

age and lower psychiatric morbidity.[37] Of note, the side-effect profiles of

the medications did not contribute to poor adherence. One possible strategy to

improve medication adherence is to make an increased effort to diagnose and

treat psychiatric conditions prior to and throughout antiviral therapy.

Conclusion

There have been substantial improvements in the treatment of chronic HBV

infection in the last decade with the development of direct antiviral therapy

via polymerase enzyme inhibition. These medications are highly effective and

have a favorable side-effect profile. However, the medications must be used on a

chronic basis, and chronic use is limited by drug-resistant mutations.

Prevention of the formation of drug-resistant mutations is critical to extending

the benefit of these therapies to improve long-term clinical outcomes.

Strategies to limit resistance, including methods to improve adherence to

therapy and, most important, defining the role of combination therapy in

preventing and/or treating resistant mutations, are an important focus of future

research in HBV infection.

*The US Food and Drug Administration has not approved this medication for this

use.

This activity is supported by an independent educational grant from Gilead

[Guest guest]

http://www.medscape.com/viewarticle/583708

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

Management - Volume 4

Adherence Issues in the Treatment of Hepatitis B CME

Natasha M. Walzer L. Flamm, MD

Disclosures

Overview

Chronic hepatitis B virus (HBV) infection is a serious global health problem,

with more than 350 million people suffering from chronic infection, ~1 million

of whom will die annually of chronic liver disease.[1] The complications of

chronic hepatitis B include cirrhosis, hepatic decompensation, and

hepatocellular carcinoma (HCC). Chronic HBV infection remains the major cause of

HCC worldwide. Persistent viral replication has been shown to correlate with

disease progression and the development of HCC.[2,3] Antiviral therapy has

assumed a critical role in the treatment of patients with chronic hepatitis B.

Substantial advances have been made in the treatment of hepatitis B in the past

decade; however, the efficacy of new drugs is hampered by the emergence of viral

resistance and by poor sustained response off treatment. Treatment with

antiviral agents commits many patients to lifelong therapy and risks the

selection of HBV strains that are resistant to one or more agents. Strategies to

reduce viral resistance must be developed to maintain the effectiveness of these

novel treatments. Although data in HBV are lacking, it is clear from the HIV

literature that medication nonadherence to direct antiviral therapy can have an

adverse impact on the development of resistance and disease progression.[4,5]

Treatment of Hepatitis B

Eradication of HBV from the patient as defined by the loss of hepatitis B

surface antigen positivity is an infrequently achieved outcome. As a result,

persistent viral suppression and seroconversion from hepatitis B e antigen

(HBeAg) positivity to the corresponding anti-HBe antibody-positive state (in

patients with initial HBeAg positivity) is the primary treatment goal. Available

types of medical therapy include immune modulators and direct antiviral

medications that inhibit HBV replication by inhibiting the HBV DNA polymerase.

There are 7 drugs currently approved by the US Food and Drug Administration for

the treatment of chronic hepatitis B, including oral nucleos(t)ide analogs

(lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir

disoproxil fumarate) and immunomodulatory agents (interferon alfa-2b and

pegylated interferon alfa-2a). The oral nucleos(t)ide analogs have emerged

within the last decade and inhibit the HBV DNA polymerase through chain

termination. These treatments are highly effective, have few side effects, and

are more convenient than interferon -- however, sustained viral suppression is

not achieved in the absence of HBeAg seroconversion after withdrawal of a

48-week course of therapy.[6] As a result, a long duration of therapy in the

majority of patients is required to maintain continued viral suppression, and

this is associated with an increased risk for the development of drug

resistance.

An important distinction when considering treatment of chronic HBV infection is

the presence or absence of HBeAg at the outset. Many adults at the time of

diagnosis of chronic hepatitis B are HBeAg positive with high levels of

circulating HBV DNA, although serum alanine aminotransferase (ALT) levels and

histologic activity are variable. The majority of these patients will undergo

spontaneous seroconversion from HBeAg to anti-HBe.[7] Those who remain HBeAg

positive for at least 6 months should be evaluated for antiviral therapy to

prevent hepatic decompensation and development of HCC. The treatment goal is

seroconversion from HBeAg to anti-HBe with undetectable HBV DNA (defined as an

undetectable viral load to a sensitivity of 20 to 100 IU/mL [approximately

100-500 copies/mL]).[8] Alternatively, other patients may have HBeAg negativity

at the outset, characterized by persistent HBV DNA replication. This situation

is usually secondary to a mutation in the precore gene leading to the formation

of a stop codon that truncates production of HBeAg despite ongoing viral

replication.[9] Clinically, active hepatitis in this setting is defined by

elevated levels of HBV DNA, usually between 2000 and 20 million IU/mL, and

fluctuations in serum ALT.[10] Patients with HBeAg-negative disease are usually

older and more likely to have cirrhosis at the time of presentation.[11]

Antiviral therapy is indicated if the viral load is>/= 20,000 IU/mL, the ALT

level is elevated, or there is inflammation on liver biopsy.[12] Seroconversion

is not possible, and in these patients the only measurable treatment goal is a

virologic and/or biochemical treatment response.[12]

Antiviral Resistance

HBV is a DNA virus that contains a DNA polymerase with reverse transcriptase

activity. Reverse transcriptase has a high inherent error rate when transcribing

RNA into DNA because it lacks proofreading capacity. This high error rate allows

mutations to accumulate at an accelerated rate compared with other forms of

replication. The likelihood of the development of drug-resistant mutants

increases when this system is put under the selective pressure of potent enzyme

inhibitors.[13] Antiviral drug resistance has been reported in up to 70% of

patients after 4 years of lamivudine therapy, 29% after 5 years of adefovir

therapy, 1% after 4 years of entecavir therapy, and in 9% to 22% of patients

after 2 years of telbivudine therapy in nucleoside-naive patients.[14-16]

Resistance to tenofovir was described by one group,[17] but this was not

confirmed in another study.[18] Resistance does not occur with interferon-based

therapy because it is not a direct antiviral enzyme inhibitor.

The development of resistance is influenced by a number of factors -- most

notably, adherence, viral persistence,[19] and pharmacokinetics.[20,21] Poor

adherence to prescribed medical therapy allows for inconsistent medication

levels and persistent viral replication, increasing the likelihood of the

formation of viral quasispecies that may be resistant to the currently

prescribed medication. In HIV infection, adherence to highly active

antiretroviral therapy (HAART) is an important modifiable risk factor in the

development of drug-resistant mutants. Indeed, missing approximately 11% to 30%

of HAART doses after achieving viral suppression is associated with the greatest

risk for viral rebound with clinically significant resistance.[22] In another

report, missing 1 of 5 doses of HAART was found to lead to antiretroviral

therapy resistance.[23] The level of antiretroviral therapy adherence required

to obtain optimal long-term benefit appears to be greater than 90%.[22] Although

data on HBV infection in regard to adherence are lacking, it is likely that poor

adherence would increase the risk of developing resistant mutations in this

setting as well.

High pretreatment HBV DNA levels, slow viral suppression on treatment, and

pre-existing resistance mutations are viral factors that increase the likelihood

of drug resistance.[24-26] Strategies to reduce the formation of drug-resistant

mutations are currently being explored. Combination oral therapy regimens* using

agents with favorable cross-resistance profiles or the combination of a

nucleotide/nucleoside analog plus an immunomodulatory agent* (pegylated

interferon) have been proposed as strategies to decrease the development of

resistant mutations; however, current data have produced mixed results. For

example, although treatment with adefovir and lamivudine in combination vs

lamivudine monotherapy demonstrated superior antiviral efficacy, it did not

eliminate lamivudine resistance, nor did it enhance the rate of seroconversion

from HBeAg to anti-HBe.[27]

The development of antiviral resistance can have significant clinical

consequences. Commonly, there is a return to pretreatment viral replication

levels and disease progression in both HBeAg-positive and HBeAg-negative

patients.[28,29] The implications of antiviral resistance are clearly

demonstrated with the long-term use of lamivudine. Patients with resistance to

lamivudine showed more frequent hepatic flares, hepatic decompensation, and more

elevated Child-Pugh scores in patients with cirrhosis.[14-16,20,21,30] Similar

problems have occurred with adefovir[31]; however, overall data are lacking

because most patients are switched to a different agent once resistance is

identified. Suppression of lamivudine-resistant mutations can be achieved by

switching to adefovir or tenofovir or by adding adefovir or tenofovir to current

lamivudine therapy.[12,32]

Detection of Drug Resistance

Initial viral suppression of chronic HBV infection is achieved in most patients

with the currently available therapies. Drug resistance is usually detected as

either a biochemical or virologic breakthrough. Virologic breakthrough is

defined as a ™ 1 log10 IU/mL increase in serum HBV DNA level from nadir in 2

consecutive samples 1 month apart in patients who have previously responded and

have been adherent to antiviral medication.[33] Biochemical breakthrough is

defined as elevation in serum aminotransferase levels during treatment in a

patient who had achieved initial normalization and who has been adherent to the

prescribed medical regimen.[33]

All patients receiving nucleos(t)ide analog therapy for chronic hepatitis B

should be closely monitored for virologic response and breakthrough during

treatment and for durability of response and viral relapse after treatment has

stopped. Serum HBV DNA should be tested prior to treatment and then every 3

months thereafter during treatment. If medication adherence is verified and

resistance is suspected, tests for antiviral-resistant mutations should be

performed whenever possible to confirm genotypic resistance and to determine the

pattern of mutations. This is accomplished by a direct sequence analysis of the

HBV polymerase gene. This information is useful when determining a follow-up

treatment strategy, as cross-resistance to other antiviral agents is identified

and an appropriate treatment strategy can be defined.[12]

Ascertaining Medication Nonadherence

There is currently no " gold standard " for measuring antiviral adherence. The

various tools available include patient self-reports, clinical assessments, pill

counts, measurements of plasma drug levels, and medication event monitoring

systems. The majority of these methods, however, are not practical outside of

the context of clinical treatment trials. Prescription-refill percentages and

untimed drug concentration measurements, however, are validated ways that have

been shown to document medication nonadherence. Plasma drug concentrations,

although possibly affected by variable pharmacokinetics, have been shown to

correlate with pill counts and future prescription refill data.[34]

Unfortunately, such measurements may be costly.[34,35] Data have suggested that

self-reporting of adherence correlates with pharmacy dispensing records and can

be adopted into routine clinical care.[36] Although none of these methods has

been evaluated specifically in the HBV-infected population, most of the

principles can be generalized to include therapy for any virus with a high

mutation rate.

Strategies to Enhance Adherence

Adherence to prescribed medications is influenced by a number of factors. These

factors include the number of pills that need to be taken, the number of

administrations per day, the cost of medications, the side-effect profile of the

medications, the presence of depressive symptoms, and the presence of substance

abuse.[37] These factors should be elicited carefully in the medical history

prior to the institution of any medical therapy, but specifically in therapies

where adherence can result in antiviral resistance and an adverse clinical

outcome.

Multiple strategies have been employed in the treatment of HIV to enhance

adherence to prescribed therapy. These include case management, couple-based

counseling, pharmacist-based education, telephone support, reminder devices,

home visits by a nurse, and directly observed therapy.[38] However, these

strategies assume that patients at risk for medication nonadherence can be

appropriately identified from the outset. Unfortunately, healthcare providers

can only identify a fraction of patients with suboptimal adherence.[39,40] A

multivariate analysis in patients on HIV therapy demonstrated that a 95% or

greater adherence to prescribed therapy was independently associated with older

age and lower psychiatric morbidity.[37] Of note, the side-effect profiles of

the medications did not contribute to poor adherence. One possible strategy to

improve medication adherence is to make an increased effort to diagnose and

treat psychiatric conditions prior to and throughout antiviral therapy.

Conclusion

There have been substantial improvements in the treatment of chronic HBV

infection in the last decade with the development of direct antiviral therapy

via polymerase enzyme inhibition. These medications are highly effective and

have a favorable side-effect profile. However, the medications must be used on a

chronic basis, and chronic use is limited by drug-resistant mutations.

Prevention of the formation of drug-resistant mutations is critical to extending

the benefit of these therapies to improve long-term clinical outcomes.

Strategies to limit resistance, including methods to improve adherence to

therapy and, most important, defining the role of combination therapy in

preventing and/or treating resistant mutations, are an important focus of future

research in HBV infection.

*The US Food and Drug Administration has not approved this medication for this

use.

This activity is supported by an independent educational grant from Gilead