AASLD 2006 - Clinical Advances in Hepatitis B

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http://www.medscape.com/viewarticle/548122

The Liver Meeting: 57th Annual Meeting of the American Association for the

Study of Liver Diseases | AASLD 2006: Viral Hepatitis

AASLD 2006 - Clinical Advances in Hepatitis B and Hepatitis C CME

Disclosures

Tram T. Tran, MD

Hepatitis B

New therapies for the treatment of hepatitis B have emerged over the past

several years, demonstrating excellent therapeutic results in viral

suppression and leading to improvement in liver injury from chronic

hepatitis B infection. There are 6 therapies currently approved by the US

Food and Drug Administration (FDA) for the treatment of hepatitis B in

adults: interferon alfa-2b; lamivudine; adefovir dipivoxil; entecavir;

pegylated interferon alfa-2a; and the oral antiviral agent telbivudine,

which received approval just last month. Research presented at this year's

meeting of the American Association for the Study of Liver Diseases (AASLD)

focused on these therapeutic options as well as on new strategies in

applying these agents, including the utility of early viral suppression as a

determinant of response to therapy.

Lamivudine

Lamivudine is a potent nucleoside analog and was the first oral therapy

approved for the treatment of hepatitis B. Unfortunately, high rates of

viral resistance, manifesting as the YMDD mutation, emerged after even short

periods of lamivudine therapy (24% resistance at 1 year, increasing up to

70% by 4 years of therapy).[1] However, despite this high rate of viral

resistance, due to its relatively low cost and ready availability,

lamivudine remains widely used worldwide.

Yuen and colleagues[2] examined the long-term impact of rapid early viral

suppression at week 12 of lamivudine therapy on seroconversion rates, viral

resistance, and alanine aminotransferase (ALT) normalization in 74 patients

with chronic hepatitis B. As defined by the study, using hepatitis B virus

[HBV] DNA of 4 logs as a cut-off level for good response, if patients

achieved viral suppression to < 4 logs, they were able to attain higher

rates of seroconversion (90% vs 20%), ALT normalization (100% vs 51%), and

lower resistance (63% vs 0%) compared with patients with HBV DNA > 4 logs,

after 5 years of therapy. The sensitivity and specificity of using this

cut-off level for determination of good response was 50% and 100%,

respectively, in this small study.

Rapid and profound suppression of viral replication may be a good predictor

of long-term outcomes and resistance, but larger studies are needed to

determine true negative and positive predictive values and the most

clinically relevant time points.

Adefovir

Adefovir is a nucleotide analog with effective antiviral activity against

the lamivudine-resistant YMDD viral strain. Previously, once resistance had

developed to lamivudine, therapy was initiated with adefovir and lamivudine

was often discontinued after some period of overlap. However, recent data

have suggested that the addition of adefovir to lamivudine, instead of the

switch from lamivudine to adefovir monotherapy, may be more effective in

preventing the development of adefovir resistance.[3] Marzano and

colleagues[4] studied the impact of add-on vs switch therapy with adefovir

on HBV viral suppression in a group of 52 patients with clinical or

genotypic lamivudine resistance. Patients were randomly assigned to adefovir

alone or lamivudine plus adefovir (ie, adefovir combined with ongoing

lamivudine). The investigators reported that overall viral response to

adefovir monotherapy vs combined adefovir + lamivudine therapy was similar

in patients with lower viral levels, confirming previous findings.[5]

However, patients with high viral loads (HBV DNA > 5 log copies/mL) were

less likely to achieve viral suppression with a shift to adefovir

monotherapy, and were at higher risk for the development of adefovir

resistance. Thus, combination therapy, either as a rescue strategy after

development of resistance or as therapy in the naive patient, may be

beneficial for the prevention of resistance; additional, larger studies are

warranted.

The current treatment paradigm for patients with hepatitis B e antigen

(HBeAg)-negative chronic hepatitis B is continued, indefinite viral

suppression because of the high relapse rates once suppressive antiviral

therapy is discontinued. Hadziyannis and colleagues[6] assessed relapse in

HBeAg-negative patients who had been on long-term adefovir therapy. The

study involved patients on adefovir therapy for 4-5 years who had achieved

and maintained biochemical remission (ALT normalization), had viral

suppression (HBV DNA < 1000 copies/mL), and had no detectable adefovir

resistance mutations; antiviral therapy was discontinued and subjects were

monitored for relapse. Results showed that although all patients had some

evidence of viral rebound (¡Ü 50,000 copies/mL), 67% were able to maintain

normalized serum ALT. Patients with biochemical relapse were successfully

re-treated with resumption of therapy. Thus, on the basis of these study

findings, discontinuation of antiviral therapy in the difficult-to-manage

HBeAg-negative chronic hepatitis B patient population may be feasible,

although all patients experience virologic relapse and the possibility of

biochemical flare.

Entecavir

Entecavir was approved for the treatment of hepatitis B in 2005, and data

continue to be reported on the long-term outcomes of patients. The phase 3

randomized study comparing entecavir with lamivudine in the treatment of

nucleoside-naive HBeAg-positive patients was continued for a total of 96

weeks. Thereafter, patients who had achieved virologic suppression (HBV DNA

< 0.7 Meq/mL), but had not yet lost HBeAg or seroconverted, were allowed to

enter into the follow-up roll-over study for continued monitoring.[7] A

total of 122 patients were enrolled into this follow-up study, and endpoints

included HBeAg loss or seroconversion, normalization of serum ALT, and viral

suppression to HBV DNA < 300 copies/mL. Of note, these patients were given a

higher dose of entecavir than that used in the original study (1.0 mg

entecavir vs 0.5 mg) due to the roll-over study design. Results showed that

by week 144, 90% of patients who continued entecavir treatment achieved

complete viral suppression, 80% normalized ALT, and an additional 33% lost

HBeAg; 16% had seroconversion in the third year on therapy (cumulative

seroconversion rate was not reported). Safety profile was similar to that

reported in previous studies, with no major changes to the entecavir safety

profile. Thus, continued entecavir treatment to 3 years in the

nucleoside-naive HBeAg-positive patient appears to result in high rates of

viral suppression and normalization of serum ALT, along with improved

chances of HBeAg seroconversion.

Long-term treatment with any antiviral therapy leads to concerns regarding

the potential development of viral resistance mutations, the loss of

efficacy, and histologic and biochemical rebound. As mentioned previously,

lamivudine resistance, with the development of the YMDD mutation, has been

well established at high rates approaching 70% at 4 years[1]; adefovir

resistance is now reported at 29% with 5 years of therapy.[8] Colonno and

colleagues[9] reported the 3-year resistance data for patients treated with

entecavir during this year's AASLD meeting. All patients with detectable HBV

DNA (> 300 copies/mL) and any patient experiencing a viral rebound of > 1

log during entecavir therapy were analyzed for genotypic mutations

conferring entecavir resistance. The authors reported entecavir resistance

to be less than 1% in each of the 3 years on therapy for nucleoside-naive

patients receiving treatment. Cumulatively, genotypic mutations to entecavir

occurred in 6%, 14%, and 29% of patients with baseline lamivudine resistance

prior to entecavir therapy for years 1, 2, and 3 of entecavir treatment.

Thus, entecavir appears to have an excellent 3-year resistance profile in

nucleoside-naive patients, with resistance rates of < 1% per year on

therapy. Patients with previous lamivudine resistance are at higher risk of

developing entecavir resistance.

Telbivudine

Telbivudine is the most recent FDA-approved therapy for the treatment of

chronic HBV infection, and is a nucleoside analogue that inhibits the HBV

polymerase. The 2-year results from the phase 3 trial comparing telbivudine

with lamivudine in chronic hepatitis B (GLOBE) were presented by Lai and

colleagues[10] during AASLD 2006. Patients (n = 1367) were randomized to

telbivudine 600 mg orally once daily or lamivudine 100 mg once daily, with

the usual inclusion criteria (ALT > 1.3-10 X upper limit of normal; HBV DNA

> 6 log10 copies/mL; compensated liver disease). Results showed superior

efficacy for telbivudine vs lamivudine by week 104 in HBeAg-negative chronic

hepatitis B patients with regard to HBV DNA suppression (HBV DNA

undetectable: 82% vs 57%). In the HBeAg-positive cohort, telbivudine was

also more effective than lamivudine with respect to HBV DNA suppression to

undetectable levels and normalization of serum ALT; seroconversion was

achieved in 30% of patients by week 104 in the telbivudine group (vs 25% in

the lamivudine group; NS). Resistance occurred in patients receiving both

therapies, with rates of 8.1% (HBeAg-negative) and 21% (HBeAg-positive)

observed in the telbivudine arms. It is interesting to note that analysis of

patients who achieved rapid viral suppression at week 24 was predictive of

lower resistance rates for telbivudine (2% for the HBeAg-negative cohort; 4%

for the HBeAg-positive cohort).

Bzowej and colleagues[11] presented findings from a study assessing the

efficacy of telbivudine vs adefovir in 135 patients with HBeAg-positive

chronic hepatitis B. Patients were randomized initially to treatment with

telbivudine or adefovir for 24 weeks, and then a secondary randomization at

24 weeks took place in those patients receiving adefovir, to either continue

adefovir therapy or switch to telbivudine. Telbivudine demonstrated

significantly greater efficacy in viral suppression in the first 24 weeks

compared with adefovir (38% vs 12% undetectable HBV DNA); this trend

continued into the 52-week data, with better virologic response rates seen

in those patients either on (or switched to) telbivudine compared with those

who remained on adefovir.

Thus, telbivudine demonstrates better efficacy than lamivudine for most

clinical endpoints of treatment. Virologic breakthrough due to resistance

was statistically lower in the telbivudine-treated patients than in those

treated with of lamivudine, and some prediction of resistance may be

possible on the basis of early viral response at week 24. In addition,

telbivudine appears to have better viral suppression than adefovir at 24 and

52 weeks, although rates of HBeAg seroconversion and ALT normalization were

not significantly different.

Pegylated Interferon

Pegylated interferon is indicated for the treatment of chronic hepatitis B,

but due to issues of cost and associated side effects, is not as widely used

as the oral antiviral therapies. However, a finite duration of treatment and

the lack of concern for viral resistance still make interferon-based therapy

a viable option for some patients.

Marcellin and colleagues[12] reported follow-up data from a large trial of

HBeAg-negative chronic hepatitis B patients previously treated with

pegylated interferon with or without lamivudine vs lamivudine alone for a

total of 48 weeks. Data from the initial 48 weeks of therapy have been

previously reported, and revealed that no additional benefit was associated

with combined pegylated interferon plus lamivudine compared with pegylated

interferon alone.[13] The current study[12] evaluated the durability of

response to pegylated interferon with or without lamivudine for up to 2

years post treatment. They found that in the pegylated interferon

monotherapy group, at 24 months post treatment, 28% of patients were able to

maintain HBV DNA levels < 10,000 copies/mL and 32% were able to maintain

normal ALT levels. Data also confirmed that the addition of lamivudine to

pegylated interferon did not provide any benefit with regard to virologic or

biochemical sustained response.

Patients with HBeAg-negative chronic hepatitis B represent a more

difficult-to-treat population due to the high relapse rates post therapy.

Immunomodulation with interferon for 1 year appears to have some positive

benefit in 28% of patients, even 24 months after therapy.

_________________________________________________________________

Get live scores and news about your team: Add the Live.com Football Page

www.live.com/?addtemplate=football & icid=T001MSN30A0701

[Guest guest]

http://www.medscape.com/viewarticle/548122

The Liver Meeting: 57th Annual Meeting of the American Association for the

Study of Liver Diseases | AASLD 2006: Viral Hepatitis

AASLD 2006 - Clinical Advances in Hepatitis B and Hepatitis C CME

Disclosures

Tram T. Tran, MD

Hepatitis B

New therapies for the treatment of hepatitis B have emerged over the past

several years, demonstrating excellent therapeutic results in viral

suppression and leading to improvement in liver injury from chronic

hepatitis B infection. There are 6 therapies currently approved by the US

Food and Drug Administration (FDA) for the treatment of hepatitis B in

adults: interferon alfa-2b; lamivudine; adefovir dipivoxil; entecavir;

pegylated interferon alfa-2a; and the oral antiviral agent telbivudine,

which received approval just last month. Research presented at this year's

meeting of the American Association for the Study of Liver Diseases (AASLD)

focused on these therapeutic options as well as on new strategies in

applying these agents, including the utility of early viral suppression as a

determinant of response to therapy.

Lamivudine

Lamivudine is a potent nucleoside analog and was the first oral therapy

approved for the treatment of hepatitis B. Unfortunately, high rates of

viral resistance, manifesting as the YMDD mutation, emerged after even short

periods of lamivudine therapy (24% resistance at 1 year, increasing up to

70% by 4 years of therapy).[1] However, despite this high rate of viral

resistance, due to its relatively low cost and ready availability,

lamivudine remains widely used worldwide.

Yuen and colleagues[2] examined the long-term impact of rapid early viral

suppression at week 12 of lamivudine therapy on seroconversion rates, viral

resistance, and alanine aminotransferase (ALT) normalization in 74 patients

with chronic hepatitis B. As defined by the study, using hepatitis B virus

[HBV] DNA of 4 logs as a cut-off level for good response, if patients

achieved viral suppression to < 4 logs, they were able to attain higher

rates of seroconversion (90% vs 20%), ALT normalization (100% vs 51%), and

lower resistance (63% vs 0%) compared with patients with HBV DNA > 4 logs,

after 5 years of therapy. The sensitivity and specificity of using this

cut-off level for determination of good response was 50% and 100%,

respectively, in this small study.

Rapid and profound suppression of viral replication may be a good predictor

of long-term outcomes and resistance, but larger studies are needed to

determine true negative and positive predictive values and the most

clinically relevant time points.

Adefovir

Adefovir is a nucleotide analog with effective antiviral activity against

the lamivudine-resistant YMDD viral strain. Previously, once resistance had

developed to lamivudine, therapy was initiated with adefovir and lamivudine

was often discontinued after some period of overlap. However, recent data

have suggested that the addition of adefovir to lamivudine, instead of the

switch from lamivudine to adefovir monotherapy, may be more effective in

preventing the development of adefovir resistance.[3] Marzano and

colleagues[4] studied the impact of add-on vs switch therapy with adefovir

on HBV viral suppression in a group of 52 patients with clinical or

genotypic lamivudine resistance. Patients were randomly assigned to adefovir

alone or lamivudine plus adefovir (ie, adefovir combined with ongoing

lamivudine). The investigators reported that overall viral response to

adefovir monotherapy vs combined adefovir + lamivudine therapy was similar

in patients with lower viral levels, confirming previous findings.[5]

However, patients with high viral loads (HBV DNA > 5 log copies/mL) were

less likely to achieve viral suppression with a shift to adefovir

monotherapy, and were at higher risk for the development of adefovir

resistance. Thus, combination therapy, either as a rescue strategy after

development of resistance or as therapy in the naive patient, may be

beneficial for the prevention of resistance; additional, larger studies are

warranted.

The current treatment paradigm for patients with hepatitis B e antigen

(HBeAg)-negative chronic hepatitis B is continued, indefinite viral

suppression because of the high relapse rates once suppressive antiviral

therapy is discontinued. Hadziyannis and colleagues[6] assessed relapse in

HBeAg-negative patients who had been on long-term adefovir therapy. The

study involved patients on adefovir therapy for 4-5 years who had achieved

and maintained biochemical remission (ALT normalization), had viral

suppression (HBV DNA < 1000 copies/mL), and had no detectable adefovir

resistance mutations; antiviral therapy was discontinued and subjects were

monitored for relapse. Results showed that although all patients had some

evidence of viral rebound (¡Ü 50,000 copies/mL), 67% were able to maintain

normalized serum ALT. Patients with biochemical relapse were successfully

re-treated with resumption of therapy. Thus, on the basis of these study

findings, discontinuation of antiviral therapy in the difficult-to-manage

HBeAg-negative chronic hepatitis B patient population may be feasible,

although all patients experience virologic relapse and the possibility of

biochemical flare.

Entecavir

Entecavir was approved for the treatment of hepatitis B in 2005, and data

continue to be reported on the long-term outcomes of patients. The phase 3

randomized study comparing entecavir with lamivudine in the treatment of

nucleoside-naive HBeAg-positive patients was continued for a total of 96

weeks. Thereafter, patients who had achieved virologic suppression (HBV DNA

< 0.7 Meq/mL), but had not yet lost HBeAg or seroconverted, were allowed to

enter into the follow-up roll-over study for continued monitoring.[7] A

total of 122 patients were enrolled into this follow-up study, and endpoints

included HBeAg loss or seroconversion, normalization of serum ALT, and viral

suppression to HBV DNA < 300 copies/mL. Of note, these patients were given a

higher dose of entecavir than that used in the original study (1.0 mg

entecavir vs 0.5 mg) due to the roll-over study design. Results showed that

by week 144, 90% of patients who continued entecavir treatment achieved

complete viral suppression, 80% normalized ALT, and an additional 33% lost

HBeAg; 16% had seroconversion in the third year on therapy (cumulative

seroconversion rate was not reported). Safety profile was similar to that

reported in previous studies, with no major changes to the entecavir safety

profile. Thus, continued entecavir treatment to 3 years in the

nucleoside-naive HBeAg-positive patient appears to result in high rates of

viral suppression and normalization of serum ALT, along with improved

chances of HBeAg seroconversion.

Long-term treatment with any antiviral therapy leads to concerns regarding

the potential development of viral resistance mutations, the loss of

efficacy, and histologic and biochemical rebound. As mentioned previously,

lamivudine resistance, with the development of the YMDD mutation, has been

well established at high rates approaching 70% at 4 years[1]; adefovir

resistance is now reported at 29% with 5 years of therapy.[8] Colonno and

colleagues[9] reported the 3-year resistance data for patients treated with

entecavir during this year's AASLD meeting. All patients with detectable HBV

DNA (> 300 copies/mL) and any patient experiencing a viral rebound of > 1

log during entecavir therapy were analyzed for genotypic mutations

conferring entecavir resistance. The authors reported entecavir resistance

to be less than 1% in each of the 3 years on therapy for nucleoside-naive

patients receiving treatment. Cumulatively, genotypic mutations to entecavir

occurred in 6%, 14%, and 29% of patients with baseline lamivudine resistance

prior to entecavir therapy for years 1, 2, and 3 of entecavir treatment.

Thus, entecavir appears to have an excellent 3-year resistance profile in

nucleoside-naive patients, with resistance rates of < 1% per year on

therapy. Patients with previous lamivudine resistance are at higher risk of

developing entecavir resistance.

Telbivudine

Telbivudine is the most recent FDA-approved therapy for the treatment of

chronic HBV infection, and is a nucleoside analogue that inhibits the HBV

polymerase. The 2-year results from the phase 3 trial comparing telbivudine

with lamivudine in chronic hepatitis B (GLOBE) were presented by Lai and

colleagues[10] during AASLD 2006. Patients (n = 1367) were randomized to

telbivudine 600 mg orally once daily or lamivudine 100 mg once daily, with

the usual inclusion criteria (ALT > 1.3-10 X upper limit of normal; HBV DNA

> 6 log10 copies/mL; compensated liver disease). Results showed superior

efficacy for telbivudine vs lamivudine by week 104 in HBeAg-negative chronic

hepatitis B patients with regard to HBV DNA suppression (HBV DNA

undetectable: 82% vs 57%). In the HBeAg-positive cohort, telbivudine was

also more effective than lamivudine with respect to HBV DNA suppression to

undetectable levels and normalization of serum ALT; seroconversion was

achieved in 30% of patients by week 104 in the telbivudine group (vs 25% in

the lamivudine group; NS). Resistance occurred in patients receiving both

therapies, with rates of 8.1% (HBeAg-negative) and 21% (HBeAg-positive)

observed in the telbivudine arms. It is interesting to note that analysis of

patients who achieved rapid viral suppression at week 24 was predictive of

lower resistance rates for telbivudine (2% for the HBeAg-negative cohort; 4%

for the HBeAg-positive cohort).

Bzowej and colleagues[11] presented findings from a study assessing the

efficacy of telbivudine vs adefovir in 135 patients with HBeAg-positive

chronic hepatitis B. Patients were randomized initially to treatment with

telbivudine or adefovir for 24 weeks, and then a secondary randomization at

24 weeks took place in those patients receiving adefovir, to either continue

adefovir therapy or switch to telbivudine. Telbivudine demonstrated

significantly greater efficacy in viral suppression in the first 24 weeks

compared with adefovir (38% vs 12% undetectable HBV DNA); this trend

continued into the 52-week data, with better virologic response rates seen

in those patients either on (or switched to) telbivudine compared with those

who remained on adefovir.

Thus, telbivudine demonstrates better efficacy than lamivudine for most

clinical endpoints of treatment. Virologic breakthrough due to resistance

was statistically lower in the telbivudine-treated patients than in those

treated with of lamivudine, and some prediction of resistance may be

possible on the basis of early viral response at week 24. In addition,

telbivudine appears to have better viral suppression than adefovir at 24 and

52 weeks, although rates of HBeAg seroconversion and ALT normalization were

not significantly different.

Pegylated Interferon

Pegylated interferon is indicated for the treatment of chronic hepatitis B,

but due to issues of cost and associated side effects, is not as widely used

as the oral antiviral therapies. However, a finite duration of treatment and

the lack of concern for viral resistance still make interferon-based therapy

a viable option for some patients.

Marcellin and colleagues[12] reported follow-up data from a large trial of

HBeAg-negative chronic hepatitis B patients previously treated with

pegylated interferon with or without lamivudine vs lamivudine alone for a

total of 48 weeks. Data from the initial 48 weeks of therapy have been

previously reported, and revealed that no additional benefit was associated

with combined pegylated interferon plus lamivudine compared with pegylated

interferon alone.[13] The current study[12] evaluated the durability of

response to pegylated interferon with or without lamivudine for up to 2

years post treatment. They found that in the pegylated interferon

monotherapy group, at 24 months post treatment, 28% of patients were able to

maintain HBV DNA levels < 10,000 copies/mL and 32% were able to maintain

normal ALT levels. Data also confirmed that the addition of lamivudine to

pegylated interferon did not provide any benefit with regard to virologic or

biochemical sustained response.

Patients with HBeAg-negative chronic hepatitis B represent a more

difficult-to-treat population due to the high relapse rates post therapy.

Immunomodulation with interferon for 1 year appears to have some positive

benefit in 28% of patients, even 24 months after therapy.

_________________________________________________________________

Get live scores and news about your team: Add the Live.com Football Page

www.live.com/?addtemplate=football & icid=T001MSN30A0701