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Treatment of the HBV-Infected Patient: When to Start, When to Stop, and When to

Change Therapy-2 of 2

When to Stop Therapy

Patients should be monitored at least every 3 to 6 months while receiving

therapy with the oral agents, and more frequently when treated with

peginterferon alfa-2a due to higher rates of side effects and potential

inability to tolerate therapy. Patients who are treated with peginterferon

alfa-2a receive therapy for a fixed duration of 1 year,[7,8,16] but it is

possible that a shorter duration of therapy may achieve the same outcomes.

Therapy is stopped prior to the standard treatment period of 1 year only if side

effects are intolerable, which occurs in less than 5% of patients.[7,8,16]

The endpoint of treatment for patients with HBeAg-positive chronic hepatitis B

who are treated with the oral antiviral agents is HBeAg seroconversion to

anti-HBe in association with very low or undetectable serum HBV DNA.[6-11] Based

on the experience with lamivudine showing a lower rate of relapse when therapy

is continued an additional 6 to 12 months beyond this point,[21] this practice

has also been applied to the other oral agents. Some guidelines suggest that

patients with cirrhosis should be treated long-term with oral agents, even after

HBeAg seroconversion has been achieved, to avoid the risk of relapse.[7,16]

Because patients with HBeAg-negative chronic hepatitis B invariably relapse when

therapy is stopped after 1 year, even when serum HBV DNA is undetectable,

current guidelines recommend long-term therapy.[6-11] Although some recent

studies have demonstrated that relapse rates are lower if treatment with

lamivudine or adefovir is stopped after several years of undetectable serum HBV

DNA,[22,23] current recommendations for the management of patients with

HBeAg-negative chronic hepatitis B continue to support long-term

treatment.[6-8,16] It is unknown but possible that loss of HBsAg with

seroconversion to anti-HBs is an acceptable endpoint in patients with

HBeAg-negative chronic hepatitis B. Patients who are about to embark on such a

long course of antiviral therapy for chronic hepatitis B with the goal of

reducing the potential complications of cirrhosis or HCC are often reassured by

the analogy of long-term treatment of hypercholesterolemia, hypertension, or

diabetes mellitus to prevent stroke or heart disease.

When to Change Therapy

An appropriate time to alter therapy by switching to or adding another drug is

treatment failure, either primary treatment failure or an inadequate response

while receiving treatment with oral agents.[7,8,24] The definition of primary

treatment failure is a serum HBV DNA decline of less than 1 log10 IU/mL from

baseline at week 12 of treatment, whereas an inadequate virologic response is

defined as a serum HBV DNA ™ 2000 IU/mL at week 24 of treatment.[24] The first

step in the evaluation of potential primary treatment failure is to exclude

patient nonadherence to prescribed therapy as a potential cause. With respect to

oral antiviral therapy, if the agent has indeed been taken on a

regular/prescribed basis, the patient is considered to have primary treatment

failure and should be switched to a more potent drug or possibly a combination

of drugs.[24]

An inadequate virologic response (serum HBV DNA ™ 2000 IU/mL after 24 weeks of

oral antiviral therapy) is a much more common reason for altering therapy, and a

" roadmap " outlining the management of these patients was recently published.[24]

Patients who have an inadequate response need to have their treatment changed to

an alternative regimen, with either a different drug that is more potent and not

cross-resistant or the addition of a second drug. Patients who only achieve a

partial response after 24 weeks of treatment (serum HBV DNA ™ 60 IU/mL to < 2000

IU/mL) may also need to change to a different therapeutic regimen. For some, a

second drug can be added that is not cross-resistant with the first drug.

However, if patients are being treated with a drug that has a low rate of

resistance development, such as entecavir, they can continue treatment to and

beyond 48 weeks. In this situation, patients should undergo serum HBV DNA

testing every 3 to 6 months. Some drugs, such as adefovir, have a delayed

antiviral effect. These patients should remain on therapy but be monitored every

3 months, with further assessment after 48 weeks of therapy. If their response

remains partial or becomes inadequate at this time point, as defined by the

" roadmap " concept, therapy should be changed.[24]

Chronic hepatitis B patients with an inadequate response after 24 weeks of

therapy with a drug with a risk of resistance, such as telbivudine, need to

switch to a different, more effective drug.[24] Alternatively, a second drug

without cross-resistance to the first drug can be added to the regimen. The

patient should then be monitored every 3 months up to week 48. If the serum HBV

DNA falls to undetectable levels by week 48, HBV DNA testing may occur every 6

months. However, patients with advanced disease should continue to be monitored

every 3 months, regardless of their response to treatment.[24]

Another appropriate time to alter therapy by switching or adding another drug to

the treatment regimen is when there is development of HBV antiviral drug

resistance. Treatment with adefovir is associated with a 29% rate of resistance

in HBeAg-negative patients after 5 years of therapy.[25] Entecavir is associated

with one of the lowest cumulative rates of resistance in treatment-naive

patients, < 1% after 4 years of therapy.[26] Resistance with telbivudine occurs

at intermediate rates, with 25% of HBeAg-positive patients and 11% of

HBeAg-negative patients experiencing resistance after 2 years of therapy.[27]

The pivotal telbivudine trial demonstrated that the greater the degree of viral

suppression at week 24 of therapy, the better the outcomes after 1 and 2 years

of therapy in terms of undetectable serum HBV DNA, HBeAg seroconversion, ALT

normalization, and rate of HBV antiviral drug resistance.[17,27] Finally, HBV

antiviral resistance was not noted in the tenofovir pivotal trials in

HBeAg-positive and HBeAg-negative patients treated for 1 year.[18,19] Table 4

summarizes the potential management of HBV antiviral resistance based on the US

treatment algorithm and the AASLD guidelines.[7,8,16] The general principle of

the recommendations outlined in Table 4 is to add a second drug that is not

cross-resistant with the first (eg, adding a nucleotide drug such as adefovir or

tenofovir when resistance to a nucleoside agent such as lamivudine, telbivudine,

or entecavir is detected. The opposite concept applies to the patient with

adefovir resistance (ie, add a nucleoside agent). This strategy of adding a

second drug vs sequential treatment is supported by studies showing that the

rate of subsequent adefovir resistance is considerably higher using the switch

strategy in the setting of preexisting lamivudine

resistance.[28-30]

Table 4. Potential Management of Hepatitis B Antiviral Drug Resistance[7,8]

Lamivudine resistance

Continue lamivudine and add adefovir or tenofovir*

Switch to emtricitabine/tenofovir*

Adefovir resistance

Continue adefovir and add lamivudine or telbivudine

Switch to or add entecavir (if no prior lamivudine resistance)

Switch to emtricitabine/tenofovir*

Entecavir resistance

Switch to or add adefovir or tenofovir*

Switch to emtricitabine/tenofovir*

Telbivudine resistance

Continue telbivudine and add adefovir or tenofovir*

Switch to emtricitabine/tenofovir*

*Not approved by US Food and Drug Administration

Conclusion

The treatment of chronic hepatitis B has evolved rapidly over the past 10 years

since the licensure of lamivudine as the first oral agent in 1998. The future

prospects for yet improved therapy are bright and will bring new drugs, such as

tenofovir, as well as better approaches to on-treatment management that will

reduce the likelihood of resistance and optimize outcomes.

Editor's note: Medscape would like to thank Dr. Keeffe for his many excellent

contributions to our site over the past years. Dr. Keeffe's commitment to

providing the highest quality clinical education has made him one of Medscape

Gastroenterology's most read and respected authors. In early 2008, Dr. Keeffe

will be embarking on an exciting new phase of clinical research as Vice

President and Chief Medical Officer of Romark Laboratories. The Medscape

Gastroenterology team wishes Dr. Keeffe much success in his future endeavors.

This activity is supported by an independent educational grant from Gilead.

http://www.medscape.com/viewarticle/570478

_________________________________________________________________

Connect and share in new ways with Windows Live.

http://www.windowslive.com/share.html?ocid=TXT_TAGHM_Wave2_sharelife_012008

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Treatment of the HBV-Infected Patient: When to Start, When to Stop, and When to

Change Therapy-2 of 2

When to Stop Therapy

Patients should be monitored at least every 3 to 6 months while receiving

therapy with the oral agents, and more frequently when treated with

peginterferon alfa-2a due to higher rates of side effects and potential

inability to tolerate therapy. Patients who are treated with peginterferon

alfa-2a receive therapy for a fixed duration of 1 year,[7,8,16] but it is

possible that a shorter duration of therapy may achieve the same outcomes.

Therapy is stopped prior to the standard treatment period of 1 year only if side

effects are intolerable, which occurs in less than 5% of patients.[7,8,16]

The endpoint of treatment for patients with HBeAg-positive chronic hepatitis B

who are treated with the oral antiviral agents is HBeAg seroconversion to

anti-HBe in association with very low or undetectable serum HBV DNA.[6-11] Based

on the experience with lamivudine showing a lower rate of relapse when therapy

is continued an additional 6 to 12 months beyond this point,[21] this practice

has also been applied to the other oral agents. Some guidelines suggest that

patients with cirrhosis should be treated long-term with oral agents, even after

HBeAg seroconversion has been achieved, to avoid the risk of relapse.[7,16]

Because patients with HBeAg-negative chronic hepatitis B invariably relapse when

therapy is stopped after 1 year, even when serum HBV DNA is undetectable,

current guidelines recommend long-term therapy.[6-11] Although some recent

studies have demonstrated that relapse rates are lower if treatment with

lamivudine or adefovir is stopped after several years of undetectable serum HBV

DNA,[22,23] current recommendations for the management of patients with

HBeAg-negative chronic hepatitis B continue to support long-term

treatment.[6-8,16] It is unknown but possible that loss of HBsAg with

seroconversion to anti-HBs is an acceptable endpoint in patients with

HBeAg-negative chronic hepatitis B. Patients who are about to embark on such a

long course of antiviral therapy for chronic hepatitis B with the goal of

reducing the potential complications of cirrhosis or HCC are often reassured by

the analogy of long-term treatment of hypercholesterolemia, hypertension, or

diabetes mellitus to prevent stroke or heart disease.

When to Change Therapy

An appropriate time to alter therapy by switching to or adding another drug is

treatment failure, either primary treatment failure or an inadequate response

while receiving treatment with oral agents.[7,8,24] The definition of primary

treatment failure is a serum HBV DNA decline of less than 1 log10 IU/mL from

baseline at week 12 of treatment, whereas an inadequate virologic response is

defined as a serum HBV DNA ™ 2000 IU/mL at week 24 of treatment.[24] The first

step in the evaluation of potential primary treatment failure is to exclude

patient nonadherence to prescribed therapy as a potential cause. With respect to

oral antiviral therapy, if the agent has indeed been taken on a

regular/prescribed basis, the patient is considered to have primary treatment

failure and should be switched to a more potent drug or possibly a combination

of drugs.[24]

An inadequate virologic response (serum HBV DNA ™ 2000 IU/mL after 24 weeks of

oral antiviral therapy) is a much more common reason for altering therapy, and a

" roadmap " outlining the management of these patients was recently published.[24]

Patients who have an inadequate response need to have their treatment changed to

an alternative regimen, with either a different drug that is more potent and not

cross-resistant or the addition of a second drug. Patients who only achieve a

partial response after 24 weeks of treatment (serum HBV DNA ™ 60 IU/mL to < 2000

IU/mL) may also need to change to a different therapeutic regimen. For some, a

second drug can be added that is not cross-resistant with the first drug.

However, if patients are being treated with a drug that has a low rate of

resistance development, such as entecavir, they can continue treatment to and

beyond 48 weeks. In this situation, patients should undergo serum HBV DNA

testing every 3 to 6 months. Some drugs, such as adefovir, have a delayed

antiviral effect. These patients should remain on therapy but be monitored every

3 months, with further assessment after 48 weeks of therapy. If their response

remains partial or becomes inadequate at this time point, as defined by the

" roadmap " concept, therapy should be changed.[24]

Chronic hepatitis B patients with an inadequate response after 24 weeks of

therapy with a drug with a risk of resistance, such as telbivudine, need to

switch to a different, more effective drug.[24] Alternatively, a second drug

without cross-resistance to the first drug can be added to the regimen. The

patient should then be monitored every 3 months up to week 48. If the serum HBV

DNA falls to undetectable levels by week 48, HBV DNA testing may occur every 6

months. However, patients with advanced disease should continue to be monitored

every 3 months, regardless of their response to treatment.[24]

Another appropriate time to alter therapy by switching or adding another drug to

the treatment regimen is when there is development of HBV antiviral drug

resistance. Treatment with adefovir is associated with a 29% rate of resistance

in HBeAg-negative patients after 5 years of therapy.[25] Entecavir is associated

with one of the lowest cumulative rates of resistance in treatment-naive

patients, < 1% after 4 years of therapy.[26] Resistance with telbivudine occurs

at intermediate rates, with 25% of HBeAg-positive patients and 11% of

HBeAg-negative patients experiencing resistance after 2 years of therapy.[27]

The pivotal telbivudine trial demonstrated that the greater the degree of viral

suppression at week 24 of therapy, the better the outcomes after 1 and 2 years

of therapy in terms of undetectable serum HBV DNA, HBeAg seroconversion, ALT

normalization, and rate of HBV antiviral drug resistance.[17,27] Finally, HBV

antiviral resistance was not noted in the tenofovir pivotal trials in

HBeAg-positive and HBeAg-negative patients treated for 1 year.[18,19] Table 4

summarizes the potential management of HBV antiviral resistance based on the US

treatment algorithm and the AASLD guidelines.[7,8,16] The general principle of

the recommendations outlined in Table 4 is to add a second drug that is not

cross-resistant with the first (eg, adding a nucleotide drug such as adefovir or

tenofovir when resistance to a nucleoside agent such as lamivudine, telbivudine,

or entecavir is detected. The opposite concept applies to the patient with

adefovir resistance (ie, add a nucleoside agent). This strategy of adding a

second drug vs sequential treatment is supported by studies showing that the

rate of subsequent adefovir resistance is considerably higher using the switch

strategy in the setting of preexisting lamivudine

resistance.[28-30]

Table 4. Potential Management of Hepatitis B Antiviral Drug Resistance[7,8]

Lamivudine resistance

Continue lamivudine and add adefovir or tenofovir*

Switch to emtricitabine/tenofovir*

Adefovir resistance

Continue adefovir and add lamivudine or telbivudine

Switch to or add entecavir (if no prior lamivudine resistance)

Switch to emtricitabine/tenofovir*

Entecavir resistance

Switch to or add adefovir or tenofovir*

Switch to emtricitabine/tenofovir*

Telbivudine resistance

Continue telbivudine and add adefovir or tenofovir*

Switch to emtricitabine/tenofovir*

*Not approved by US Food and Drug Administration

Conclusion

The treatment of chronic hepatitis B has evolved rapidly over the past 10 years

since the licensure of lamivudine as the first oral agent in 1998. The future

prospects for yet improved therapy are bright and will bring new drugs, such as

tenofovir, as well as better approaches to on-treatment management that will

reduce the likelihood of resistance and optimize outcomes.

Editor's note: Medscape would like to thank Dr. Keeffe for his many excellent

contributions to our site over the past years. Dr. Keeffe's commitment to

providing the highest quality clinical education has made him one of Medscape

Gastroenterology's most read and respected authors. In early 2008, Dr. Keeffe

will be embarking on an exciting new phase of clinical research as Vice

President and Chief Medical Officer of Romark Laboratories. The Medscape

Gastroenterology team wishes Dr. Keeffe much success in his future endeavors.

This activity is supported by an independent educational grant from Gilead.

http://www.medscape.com/viewarticle/570478

_________________________________________________________________

Connect and share in new ways with Windows Live.

http://www.windowslive.com/share.html?ocid=TXT_TAGHM_Wave2_sharelife_012008

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Share on other sites

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