Advances in Hepatitis B: An Update From EASL 2008 - 2 of 2

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Advances in Hepatitis B: An Update From EASL 2008 - 2 of 2

Update on Currently Approved Agents

Entecavir

Entecavir is a potent nucleoside analog. Data presented at this year's EASL

meeting continued to support its efficacy and high barrier to resistance in

nucleoside-naive patients. Three-year data were presented from 2 long-term

Chinese studies. In the first, 160 nucleoside-naive subjects failed to fully

respond to entecavir therapy and were continued on entecavir 1 mg* a day for 144

weeks; 89% (133/149) became HBV DNA negative (< 300 copies/mL), 20% (30/150)

lost HBeAg, and 8% (12/150) achieved HBeAg seroconversion.[27] In a second

study, 128 lamivudine-refractory patients who received 48 weeks of entecavir

therapy without adequate response were rolled over to receive 1 mg of entecavir

for 144 weeks; 55% (54/98) suppressed virus below 300 copies/mL, 7/95 lost

HBeAg, and 2/95 achieved HBeAg seroconversion.[28] Similar data were presented

for a nucleoside-naive Japanese rollover cohort in which viral suppression

continued through 3 years with a cumulative 3-year resistance rate of only

1.7%.[29] Previous studies have demonstrated that entecavir results in more

rapid reduction in HBV DNA compared with adefovir at both week 12 and week

48.[30] Week 96 results were presented during EASL 2008. Entecavir continued to

more fully suppress virus, with 79% (23/29) vs 50% (10/20) of patients being HBV

DNA undetectable at the end of 96 weeks.[31]

Telbivudine

The goal of any therapeutic modality, including the nucleot(s)ide analogs, is

durable viral suppression after drug discontinuation. HBeAg loss and

seroconversion can help identify candidates for discontinuation of therapy. In a

study presented during EASL 2008, 27% (153/570) of telbivudine (nucleoside

analog)-treated and 23% (131/580) of lamivudine-treated patients attained this

goal (HBeAg loss), with excellent durability of HBeAg seroconversion (> 85%)

after 52 weeks.[32] Although telbivudine is superior to lamivudine in achieving

both viral reduction and ALT normalization, Wong and colleagues[33] could find

no difference between these agents after 52 weeks in terms of their ability to

decrease intrahepatic HBV DNA or cccDNA.

Adefovir

Once lamivudine resistance occurs, the addition of a nucleotide analog is the

most widely accepted therapeutic strategy to suppress virus. Lampertico and

colleagues[34] reported data substantiating this approach. In their study, 10 mg

of adefovir was added on to the treatment regimen (ie, to ongoing lamivudine

treatment) in lamivudine-resistant patients. After 4 years, 83% (45/54) had

undetectable HBV DNA and no patient experienced virologic breakthrough or

acquired N236T or A181V adefovir resistance mutations; 3 patients had baseline

rtA181t mutations and 3 others acquired this mutation during treatment. However,

all patients suppressed virus, with 5/6 becoming HBV DNA undetectable; 17% of 46

patients with cirrhosis developed HCC, although none experienced clinical

decompensation.

This add-on strategy appears to also work in the setting of entecavir

resistance. In a study presented during EASL 2008, 10 lamivudine-resistant

patients who had virologic breakthrough and genotypic resistance while on

entecavir treatment were switched to lamivudine + adefovir therapy. Serum HBV

DNA decreased in all 10 patients.[35] Combination therapy remains somewhat

controversial, however. When lamivudine-refractory patients were switched to

adefovir (serial monotherapy), 10.5% of 38 developed adefovir-resistance

compared with 2.2% of 90 receiving add-on adefovir (adefovir + lamivudine;

sequential therapy). A high viral load at 48 weeks (> 6 log 10 copies/mL) was

associated with a risk for adefovir resistance.[36] Puoti and colleagues[37]

tried another approach to the add-on therapy strategy: Adefovir was offered to

every patient with HBV DNA < 2000 copies/mL after lamivudine monotherapy. Twenty

of 59 patients agreed to this combination therapy regimen, none of whom

experienced virologic breakthrough. Of the 39 who refused this therapy, 21%

experienced an increase in viremia.

Interferon-Based Therapy

Both standard interferon alfa-2b and pegylated interferon-alfa 2a are approved

for the treatment of chronic hepatitis B. Interferon-based therapy is given for

a finite duration and is intended to induce immune-mediated viral suppression.

Investigators presented long-term follow-up data from a group of HBeAg-negative

patients previously treated with pegylated interferon alone, pegylated

interferon + lamivudine, or lamivudine alone for 48 weeks.[38] Four years after

therapy, 24% (55/230) of those who received pegylated interferon ± lamivudine

maintained a viral load below 10,000 copies/mL, with 17% achieving HBV DNA

negativity. HBsAg loss (clearance) continued to increase to 11% (25/230) in

patients who received pegylated interferon (vs 2% in those who received

lamivudine monotherapy). However, among those patients who suppressed HBV DNA <

400 copies/mL at 24 weeks, 35% (19/54) experienced HBsAg loss. This finding

suggests that 24-week response predicts future HBsAg loss and confirms that

pegylated interferon remains an appropriate first-line therapy for patients with

chronic hepatitis B.[38] Xu and colleagues[39] investigated the efficacy of

pegylated interferon both in HBeAg-positive patients who were naive to therapy

and in those who had failed prior interferon-based or lamivudine treatment.

Viral suppression, HBeAg loss, and HBeAg seroconversion rates were not

statistically different among naive or pretreated patients, and HBeAg

seroconversion rates ranged between 26% and 39%.

Future Therapies

Tenofovir

The nucleotide analog tenofovir, which is expected to be the next oral antiviral

agent approved for the treatment of chronic hepatitis B, was prominently

featured at this year's EASL meeting. Although it is seeking approval for the

treatment of HBV infection, tenofovir is currently approved and in wide use for

the treatment of HIV infection. This nucleotide analog has potent activity

against HBV. Interim data from 2 long-term pivotal trials were presented during

EASL 2008, and both demonstrated additional viral suppression without evidence

of resistance. Study 102 involved HBeAg-negative patients who received 48 weeks

of either tenofovir or adefovir.[40] Ninety percent then continued tenofovir

therapy or were switched from adefovir to tenofovir with an anticipated

follow-up of a minimum of 4 years; 91% (intent to treat [iTT] analysis]) of the

tenofovir-treated patients suppressed HBV DNA below 69 IU/mL at 72 weeks.

However, only 4 patients continued to have detectable virus, as 9 were missing

data; 112 subjects initially treated with adefovir switched to tenofovir at week

48, 35 of whom had detectable virus at the time of the switch. After 24 weeks of

tenofovir, 88% (ITT) of subjects had HBV DNA < 69 IU/mL, which included 33 of

the 35 previously viremic subjects. When considering just those patients with

DNA samples obtained at 72 weeks (excluding those with missing data), 98% in

both arms had HBV DNA < 69 IU/mL. There were no tenofovir-resistant mutations or

creatinine toxicities observed.

Study 103 was of similar design but involved HBeAg-positive subjects.[41]

Eighty-eight percent of patients in this cohort extended therapy, either

continuing on tenofovir or switching to tenofovir if they were previously

receiving adefovir. At week 72, 79% (ITT) of patients receiving tenofovir

monotherapy had undetectable virus compared with 76% (ITT) of patients switched

from adefovir to tenofovir. Again, when considering only patients with DNA

samples obtained at 72 weeks, 89% of tenofovir monotherapy and 82% of " switched "

subjects had HBV DNA < 69 IU/mL. Of the entire study population, 51/216 (24%)

subjects had HBeAg seroconversion, with 7 losing HBsAg. Again, no resistance

mutations were identified. Both of these studies demonstrated the high potency

and low incidence of resistance to tenofovir, confirming that this agent will

become an important addition to the drug arsenal against HBV.

Subanalyses of these cohorts demonstrated that lamivudine-experienced (n = 70)

and lamivudine-naive (n = 377) subjects responded similarly to tenofovir (88% vs

86% achieved undetectable virus, respectively).[42] Excellent viral suppression

was achieved in patients with compensated cirrhosis (85% had HBV DNA < 69

IU/mL), with a safety profile comparable to those of noncirrhotic subjects.[43]

Baseline genotype did not influence treatment response.[44]

There is some concern that tenofovir may be less effective in patients with

previous adefovir exposure. A multicenter European study recruited 127 (121

treatment-experienced) patients to address this concern.[45] In this study, 88

patients had undetectable HBV DNA after 12 months, without virologic

breakthrough. However, patients with genotypic adefovir resistance had a

significantly slower decrease in HBV DNA, but most still became HBV DNA

undetectable during the total observation period. Those patients with prior

exposure to adefovir, but without genotypic mutations, experienced rapid viral

decline. Another approach to managing patients with suboptimal response to

adefovir is to use combination therapy with a nucleotide and nucleoside analog.

Berg and colleagues[46] randomized 105 such chronic hepatitis B patients with

incomplete virologic response to adefovir to receive either tenofovir alone or

tenofovir in combination with the nucleoside analog emtricitabine*. Both

regimens demonstrated robust virologic suppression, with 68% of the pooled

population achieving undetectable HBV DNA at 24 weeks and 81% achieving

undetectable HBV DNA at last data analysis. Both strategies were effective, as

there was no differences in viral decline between the groups. As expected,

adherence to therapy contributed to response. In patients with less than 68%

treatment adherence, only 71% lost virus, whereas with higher adherence to

prescribed therapy 87% became HBV DNA undetectable.

Cost is frequently a concern when discussing therapeutic options for hepatitis

B. A simulation model found tenofovir to be the most cost-effective first-line

treatment option in Spain, France, and Italy, when predicted disease

progression, incidence and cost of chronic hepatitis B-related complications

were weighed against HBV suppression achieved with the various therapies

including lamivudine, adefovir, entecavir, and tenofovir.[47,48]

Small Interfering RNA Technology

Although the inhibition of viral replication with pharmacologic agents is an

effective therapeutic strategy, other ways to inhibit viral replication are also

under investigation. Meng and colleagues[49] presented exciting data

demonstrating how small pieces of RNA (small interfering RNA [siRNA])* targeted

against areas of the woodchuck hepatitis virus genome, which is very similar to

human HBV, could inhibit replication for a prolonged period of time in

hepatocyte culture. siRNA-induced reduction of viral replication also enhanced

expression of hepatocyte-produced antiviral proteins, suggesting that

" machinery " leading to potential immune control is also enhanced. These

investigators also combined siRNA transfection with entecavir treatment and

showed that the siRNAs could prevent viral rebound after the nucleoside was

discontinued. Although this technology is far from approved for the treatments

of patients with hepatitis B, it offers an exciting window into the future of

viral hepatitis therapeutics.

Other Agents

Several other therapies for hepatitis B are also in development. Clevudine, an

oral nucleoside analog, is also in late stages of testing, although no data were

presented at this conference. Other immune-modulating agents are also undergoing

investigation.

Conclusion

At the conclusion of this year's EASL meeting, it is obvious that our

understanding of HBV infection is rapidly evolving. This knowledge will

subsequently drive the development of both technology and therapy. Given the

information presented during EASL 2008, improved detection and improved

strategies to avoid viral resistance will continue to be investigated over the

coming years.

*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.

_________________________________________________________________

It’s easy to add contacts from Facebook and other social sites through Windows

Live™ Messenger. Learn how.

https://www.invite2messenger.net/im/?source=TXT_EML_WLH_LearnHow

[Guest guest]

Advances in Hepatitis B: An Update From EASL 2008 - 2 of 2

Update on Currently Approved Agents

Entecavir

Entecavir is a potent nucleoside analog. Data presented at this year's EASL

meeting continued to support its efficacy and high barrier to resistance in

nucleoside-naive patients. Three-year data were presented from 2 long-term

Chinese studies. In the first, 160 nucleoside-naive subjects failed to fully

respond to entecavir therapy and were continued on entecavir 1 mg* a day for 144

weeks; 89% (133/149) became HBV DNA negative (< 300 copies/mL), 20% (30/150)

lost HBeAg, and 8% (12/150) achieved HBeAg seroconversion.[27] In a second

study, 128 lamivudine-refractory patients who received 48 weeks of entecavir

therapy without adequate response were rolled over to receive 1 mg of entecavir

for 144 weeks; 55% (54/98) suppressed virus below 300 copies/mL, 7/95 lost

HBeAg, and 2/95 achieved HBeAg seroconversion.[28] Similar data were presented

for a nucleoside-naive Japanese rollover cohort in which viral suppression

continued through 3 years with a cumulative 3-year resistance rate of only

1.7%.[29] Previous studies have demonstrated that entecavir results in more

rapid reduction in HBV DNA compared with adefovir at both week 12 and week

48.[30] Week 96 results were presented during EASL 2008. Entecavir continued to

more fully suppress virus, with 79% (23/29) vs 50% (10/20) of patients being HBV

DNA undetectable at the end of 96 weeks.[31]

Telbivudine

The goal of any therapeutic modality, including the nucleot(s)ide analogs, is

durable viral suppression after drug discontinuation. HBeAg loss and

seroconversion can help identify candidates for discontinuation of therapy. In a

study presented during EASL 2008, 27% (153/570) of telbivudine (nucleoside

analog)-treated and 23% (131/580) of lamivudine-treated patients attained this

goal (HBeAg loss), with excellent durability of HBeAg seroconversion (> 85%)

after 52 weeks.[32] Although telbivudine is superior to lamivudine in achieving

both viral reduction and ALT normalization, Wong and colleagues[33] could find

no difference between these agents after 52 weeks in terms of their ability to

decrease intrahepatic HBV DNA or cccDNA.

Adefovir

Once lamivudine resistance occurs, the addition of a nucleotide analog is the

most widely accepted therapeutic strategy to suppress virus. Lampertico and

colleagues[34] reported data substantiating this approach. In their study, 10 mg

of adefovir was added on to the treatment regimen (ie, to ongoing lamivudine

treatment) in lamivudine-resistant patients. After 4 years, 83% (45/54) had

undetectable HBV DNA and no patient experienced virologic breakthrough or

acquired N236T or A181V adefovir resistance mutations; 3 patients had baseline

rtA181t mutations and 3 others acquired this mutation during treatment. However,

all patients suppressed virus, with 5/6 becoming HBV DNA undetectable; 17% of 46

patients with cirrhosis developed HCC, although none experienced clinical

decompensation.

This add-on strategy appears to also work in the setting of entecavir

resistance. In a study presented during EASL 2008, 10 lamivudine-resistant

patients who had virologic breakthrough and genotypic resistance while on

entecavir treatment were switched to lamivudine + adefovir therapy. Serum HBV

DNA decreased in all 10 patients.[35] Combination therapy remains somewhat

controversial, however. When lamivudine-refractory patients were switched to

adefovir (serial monotherapy), 10.5% of 38 developed adefovir-resistance

compared with 2.2% of 90 receiving add-on adefovir (adefovir + lamivudine;

sequential therapy). A high viral load at 48 weeks (> 6 log 10 copies/mL) was

associated with a risk for adefovir resistance.[36] Puoti and colleagues[37]

tried another approach to the add-on therapy strategy: Adefovir was offered to

every patient with HBV DNA < 2000 copies/mL after lamivudine monotherapy. Twenty

of 59 patients agreed to this combination therapy regimen, none of whom

experienced virologic breakthrough. Of the 39 who refused this therapy, 21%

experienced an increase in viremia.

Interferon-Based Therapy

Both standard interferon alfa-2b and pegylated interferon-alfa 2a are approved

for the treatment of chronic hepatitis B. Interferon-based therapy is given for

a finite duration and is intended to induce immune-mediated viral suppression.

Investigators presented long-term follow-up data from a group of HBeAg-negative

patients previously treated with pegylated interferon alone, pegylated

interferon + lamivudine, or lamivudine alone for 48 weeks.[38] Four years after

therapy, 24% (55/230) of those who received pegylated interferon ± lamivudine

maintained a viral load below 10,000 copies/mL, with 17% achieving HBV DNA

negativity. HBsAg loss (clearance) continued to increase to 11% (25/230) in

patients who received pegylated interferon (vs 2% in those who received

lamivudine monotherapy). However, among those patients who suppressed HBV DNA <

400 copies/mL at 24 weeks, 35% (19/54) experienced HBsAg loss. This finding

suggests that 24-week response predicts future HBsAg loss and confirms that

pegylated interferon remains an appropriate first-line therapy for patients with

chronic hepatitis B.[38] Xu and colleagues[39] investigated the efficacy of

pegylated interferon both in HBeAg-positive patients who were naive to therapy

and in those who had failed prior interferon-based or lamivudine treatment.

Viral suppression, HBeAg loss, and HBeAg seroconversion rates were not

statistically different among naive or pretreated patients, and HBeAg

seroconversion rates ranged between 26% and 39%.

Future Therapies

Tenofovir

The nucleotide analog tenofovir, which is expected to be the next oral antiviral

agent approved for the treatment of chronic hepatitis B, was prominently

featured at this year's EASL meeting. Although it is seeking approval for the

treatment of HBV infection, tenofovir is currently approved and in wide use for

the treatment of HIV infection. This nucleotide analog has potent activity

against HBV. Interim data from 2 long-term pivotal trials were presented during

EASL 2008, and both demonstrated additional viral suppression without evidence

of resistance. Study 102 involved HBeAg-negative patients who received 48 weeks

of either tenofovir or adefovir.[40] Ninety percent then continued tenofovir

therapy or were switched from adefovir to tenofovir with an anticipated

follow-up of a minimum of 4 years; 91% (intent to treat [iTT] analysis]) of the

tenofovir-treated patients suppressed HBV DNA below 69 IU/mL at 72 weeks.

However, only 4 patients continued to have detectable virus, as 9 were missing

data; 112 subjects initially treated with adefovir switched to tenofovir at week

48, 35 of whom had detectable virus at the time of the switch. After 24 weeks of

tenofovir, 88% (ITT) of subjects had HBV DNA < 69 IU/mL, which included 33 of

the 35 previously viremic subjects. When considering just those patients with

DNA samples obtained at 72 weeks (excluding those with missing data), 98% in

both arms had HBV DNA < 69 IU/mL. There were no tenofovir-resistant mutations or

creatinine toxicities observed.

Study 103 was of similar design but involved HBeAg-positive subjects.[41]

Eighty-eight percent of patients in this cohort extended therapy, either

continuing on tenofovir or switching to tenofovir if they were previously

receiving adefovir. At week 72, 79% (ITT) of patients receiving tenofovir

monotherapy had undetectable virus compared with 76% (ITT) of patients switched

from adefovir to tenofovir. Again, when considering only patients with DNA

samples obtained at 72 weeks, 89% of tenofovir monotherapy and 82% of " switched "

subjects had HBV DNA < 69 IU/mL. Of the entire study population, 51/216 (24%)

subjects had HBeAg seroconversion, with 7 losing HBsAg. Again, no resistance

mutations were identified. Both of these studies demonstrated the high potency

and low incidence of resistance to tenofovir, confirming that this agent will

become an important addition to the drug arsenal against HBV.

Subanalyses of these cohorts demonstrated that lamivudine-experienced (n = 70)

and lamivudine-naive (n = 377) subjects responded similarly to tenofovir (88% vs

86% achieved undetectable virus, respectively).[42] Excellent viral suppression

was achieved in patients with compensated cirrhosis (85% had HBV DNA < 69

IU/mL), with a safety profile comparable to those of noncirrhotic subjects.[43]

Baseline genotype did not influence treatment response.[44]

There is some concern that tenofovir may be less effective in patients with

previous adefovir exposure. A multicenter European study recruited 127 (121

treatment-experienced) patients to address this concern.[45] In this study, 88

patients had undetectable HBV DNA after 12 months, without virologic

breakthrough. However, patients with genotypic adefovir resistance had a

significantly slower decrease in HBV DNA, but most still became HBV DNA

undetectable during the total observation period. Those patients with prior

exposure to adefovir, but without genotypic mutations, experienced rapid viral

decline. Another approach to managing patients with suboptimal response to

adefovir is to use combination therapy with a nucleotide and nucleoside analog.

Berg and colleagues[46] randomized 105 such chronic hepatitis B patients with

incomplete virologic response to adefovir to receive either tenofovir alone or

tenofovir in combination with the nucleoside analog emtricitabine*. Both

regimens demonstrated robust virologic suppression, with 68% of the pooled

population achieving undetectable HBV DNA at 24 weeks and 81% achieving

undetectable HBV DNA at last data analysis. Both strategies were effective, as

there was no differences in viral decline between the groups. As expected,

adherence to therapy contributed to response. In patients with less than 68%

treatment adherence, only 71% lost virus, whereas with higher adherence to

prescribed therapy 87% became HBV DNA undetectable.

Cost is frequently a concern when discussing therapeutic options for hepatitis

B. A simulation model found tenofovir to be the most cost-effective first-line

treatment option in Spain, France, and Italy, when predicted disease

progression, incidence and cost of chronic hepatitis B-related complications

were weighed against HBV suppression achieved with the various therapies

including lamivudine, adefovir, entecavir, and tenofovir.[47,48]

Small Interfering RNA Technology

Although the inhibition of viral replication with pharmacologic agents is an

effective therapeutic strategy, other ways to inhibit viral replication are also

under investigation. Meng and colleagues[49] presented exciting data

demonstrating how small pieces of RNA (small interfering RNA [siRNA])* targeted

against areas of the woodchuck hepatitis virus genome, which is very similar to

human HBV, could inhibit replication for a prolonged period of time in

hepatocyte culture. siRNA-induced reduction of viral replication also enhanced

expression of hepatocyte-produced antiviral proteins, suggesting that

" machinery " leading to potential immune control is also enhanced. These

investigators also combined siRNA transfection with entecavir treatment and

showed that the siRNAs could prevent viral rebound after the nucleoside was

discontinued. Although this technology is far from approved for the treatments

of patients with hepatitis B, it offers an exciting window into the future of

viral hepatitis therapeutics.

Other Agents

Several other therapies for hepatitis B are also in development. Clevudine, an

oral nucleoside analog, is also in late stages of testing, although no data were

presented at this conference. Other immune-modulating agents are also undergoing

investigation.

Conclusion

At the conclusion of this year's EASL meeting, it is obvious that our

understanding of HBV infection is rapidly evolving. This knowledge will

subsequently drive the development of both technology and therapy. Given the

information presented during EASL 2008, improved detection and improved

strategies to avoid viral resistance will continue to be investigated over the

coming years.

*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.

_________________________________________________________________

It’s easy to add contacts from Facebook and other social sites through Windows

Live™ Messenger. Learn how.

https://www.invite2messenger.net/im/?source=TXT_EML_WLH_LearnHow

[Guest guest]

Advances in Hepatitis B: An Update From EASL 2008 - 2 of 2

Update on Currently Approved Agents

Entecavir

Entecavir is a potent nucleoside analog. Data presented at this year's EASL

meeting continued to support its efficacy and high barrier to resistance in

nucleoside-naive patients. Three-year data were presented from 2 long-term

Chinese studies. In the first, 160 nucleoside-naive subjects failed to fully

respond to entecavir therapy and were continued on entecavir 1 mg* a day for 144

weeks; 89% (133/149) became HBV DNA negative (< 300 copies/mL), 20% (30/150)

lost HBeAg, and 8% (12/150) achieved HBeAg seroconversion.[27] In a second

study, 128 lamivudine-refractory patients who received 48 weeks of entecavir

therapy without adequate response were rolled over to receive 1 mg of entecavir

for 144 weeks; 55% (54/98) suppressed virus below 300 copies/mL, 7/95 lost

HBeAg, and 2/95 achieved HBeAg seroconversion.[28] Similar data were presented

for a nucleoside-naive Japanese rollover cohort in which viral suppression

continued through 3 years with a cumulative 3-year resistance rate of only

1.7%.[29] Previous studies have demonstrated that entecavir results in more

rapid reduction in HBV DNA compared with adefovir at both week 12 and week

48.[30] Week 96 results were presented during EASL 2008. Entecavir continued to

more fully suppress virus, with 79% (23/29) vs 50% (10/20) of patients being HBV

DNA undetectable at the end of 96 weeks.[31]

Telbivudine

The goal of any therapeutic modality, including the nucleot(s)ide analogs, is

durable viral suppression after drug discontinuation. HBeAg loss and

seroconversion can help identify candidates for discontinuation of therapy. In a

study presented during EASL 2008, 27% (153/570) of telbivudine (nucleoside

analog)-treated and 23% (131/580) of lamivudine-treated patients attained this

goal (HBeAg loss), with excellent durability of HBeAg seroconversion (> 85%)

after 52 weeks.[32] Although telbivudine is superior to lamivudine in achieving

both viral reduction and ALT normalization, Wong and colleagues[33] could find

no difference between these agents after 52 weeks in terms of their ability to

decrease intrahepatic HBV DNA or cccDNA.

Adefovir

Once lamivudine resistance occurs, the addition of a nucleotide analog is the

most widely accepted therapeutic strategy to suppress virus. Lampertico and

colleagues[34] reported data substantiating this approach. In their study, 10 mg

of adefovir was added on to the treatment regimen (ie, to ongoing lamivudine

treatment) in lamivudine-resistant patients. After 4 years, 83% (45/54) had

undetectable HBV DNA and no patient experienced virologic breakthrough or

acquired N236T or A181V adefovir resistance mutations; 3 patients had baseline

rtA181t mutations and 3 others acquired this mutation during treatment. However,

all patients suppressed virus, with 5/6 becoming HBV DNA undetectable; 17% of 46

patients with cirrhosis developed HCC, although none experienced clinical

decompensation.

This add-on strategy appears to also work in the setting of entecavir

resistance. In a study presented during EASL 2008, 10 lamivudine-resistant

patients who had virologic breakthrough and genotypic resistance while on

entecavir treatment were switched to lamivudine + adefovir therapy. Serum HBV

DNA decreased in all 10 patients.[35] Combination therapy remains somewhat

controversial, however. When lamivudine-refractory patients were switched to

adefovir (serial monotherapy), 10.5% of 38 developed adefovir-resistance

compared with 2.2% of 90 receiving add-on adefovir (adefovir + lamivudine;

sequential therapy). A high viral load at 48 weeks (> 6 log 10 copies/mL) was

associated with a risk for adefovir resistance.[36] Puoti and colleagues[37]

tried another approach to the add-on therapy strategy: Adefovir was offered to

every patient with HBV DNA < 2000 copies/mL after lamivudine monotherapy. Twenty

of 59 patients agreed to this combination therapy regimen, none of whom

experienced virologic breakthrough. Of the 39 who refused this therapy, 21%

experienced an increase in viremia.

Interferon-Based Therapy

Both standard interferon alfa-2b and pegylated interferon-alfa 2a are approved

for the treatment of chronic hepatitis B. Interferon-based therapy is given for

a finite duration and is intended to induce immune-mediated viral suppression.

Investigators presented long-term follow-up data from a group of HBeAg-negative

patients previously treated with pegylated interferon alone, pegylated

interferon + lamivudine, or lamivudine alone for 48 weeks.[38] Four years after

therapy, 24% (55/230) of those who received pegylated interferon ± lamivudine

maintained a viral load below 10,000 copies/mL, with 17% achieving HBV DNA

negativity. HBsAg loss (clearance) continued to increase to 11% (25/230) in

patients who received pegylated interferon (vs 2% in those who received

lamivudine monotherapy). However, among those patients who suppressed HBV DNA <

400 copies/mL at 24 weeks, 35% (19/54) experienced HBsAg loss. This finding

suggests that 24-week response predicts future HBsAg loss and confirms that

pegylated interferon remains an appropriate first-line therapy for patients with

chronic hepatitis B.[38] Xu and colleagues[39] investigated the efficacy of

pegylated interferon both in HBeAg-positive patients who were naive to therapy

and in those who had failed prior interferon-based or lamivudine treatment.

Viral suppression, HBeAg loss, and HBeAg seroconversion rates were not

statistically different among naive or pretreated patients, and HBeAg

seroconversion rates ranged between 26% and 39%.

Future Therapies

Tenofovir

The nucleotide analog tenofovir, which is expected to be the next oral antiviral

agent approved for the treatment of chronic hepatitis B, was prominently

featured at this year's EASL meeting. Although it is seeking approval for the

treatment of HBV infection, tenofovir is currently approved and in wide use for

the treatment of HIV infection. This nucleotide analog has potent activity

against HBV. Interim data from 2 long-term pivotal trials were presented during

EASL 2008, and both demonstrated additional viral suppression without evidence

of resistance. Study 102 involved HBeAg-negative patients who received 48 weeks

of either tenofovir or adefovir.[40] Ninety percent then continued tenofovir

therapy or were switched from adefovir to tenofovir with an anticipated

follow-up of a minimum of 4 years; 91% (intent to treat [iTT] analysis]) of the

tenofovir-treated patients suppressed HBV DNA below 69 IU/mL at 72 weeks.

However, only 4 patients continued to have detectable virus, as 9 were missing

data; 112 subjects initially treated with adefovir switched to tenofovir at week

48, 35 of whom had detectable virus at the time of the switch. After 24 weeks of

tenofovir, 88% (ITT) of subjects had HBV DNA < 69 IU/mL, which included 33 of

the 35 previously viremic subjects. When considering just those patients with

DNA samples obtained at 72 weeks (excluding those with missing data), 98% in

both arms had HBV DNA < 69 IU/mL. There were no tenofovir-resistant mutations or

creatinine toxicities observed.

Study 103 was of similar design but involved HBeAg-positive subjects.[41]

Eighty-eight percent of patients in this cohort extended therapy, either

continuing on tenofovir or switching to tenofovir if they were previously

receiving adefovir. At week 72, 79% (ITT) of patients receiving tenofovir

monotherapy had undetectable virus compared with 76% (ITT) of patients switched

from adefovir to tenofovir. Again, when considering only patients with DNA

samples obtained at 72 weeks, 89% of tenofovir monotherapy and 82% of " switched "

subjects had HBV DNA < 69 IU/mL. Of the entire study population, 51/216 (24%)

subjects had HBeAg seroconversion, with 7 losing HBsAg. Again, no resistance

mutations were identified. Both of these studies demonstrated the high potency

and low incidence of resistance to tenofovir, confirming that this agent will

become an important addition to the drug arsenal against HBV.

Subanalyses of these cohorts demonstrated that lamivudine-experienced (n = 70)

and lamivudine-naive (n = 377) subjects responded similarly to tenofovir (88% vs

86% achieved undetectable virus, respectively).[42] Excellent viral suppression

was achieved in patients with compensated cirrhosis (85% had HBV DNA < 69

IU/mL), with a safety profile comparable to those of noncirrhotic subjects.[43]

Baseline genotype did not influence treatment response.[44]

There is some concern that tenofovir may be less effective in patients with

previous adefovir exposure. A multicenter European study recruited 127 (121

treatment-experienced) patients to address this concern.[45] In this study, 88

patients had undetectable HBV DNA after 12 months, without virologic

breakthrough. However, patients with genotypic adefovir resistance had a

significantly slower decrease in HBV DNA, but most still became HBV DNA

undetectable during the total observation period. Those patients with prior

exposure to adefovir, but without genotypic mutations, experienced rapid viral

decline. Another approach to managing patients with suboptimal response to

adefovir is to use combination therapy with a nucleotide and nucleoside analog.

Berg and colleagues[46] randomized 105 such chronic hepatitis B patients with

incomplete virologic response to adefovir to receive either tenofovir alone or

tenofovir in combination with the nucleoside analog emtricitabine*. Both

regimens demonstrated robust virologic suppression, with 68% of the pooled

population achieving undetectable HBV DNA at 24 weeks and 81% achieving

undetectable HBV DNA at last data analysis. Both strategies were effective, as

there was no differences in viral decline between the groups. As expected,

adherence to therapy contributed to response. In patients with less than 68%

treatment adherence, only 71% lost virus, whereas with higher adherence to

prescribed therapy 87% became HBV DNA undetectable.

Cost is frequently a concern when discussing therapeutic options for hepatitis

B. A simulation model found tenofovir to be the most cost-effective first-line

treatment option in Spain, France, and Italy, when predicted disease

progression, incidence and cost of chronic hepatitis B-related complications

were weighed against HBV suppression achieved with the various therapies

including lamivudine, adefovir, entecavir, and tenofovir.[47,48]

Small Interfering RNA Technology

Although the inhibition of viral replication with pharmacologic agents is an

effective therapeutic strategy, other ways to inhibit viral replication are also

under investigation. Meng and colleagues[49] presented exciting data

demonstrating how small pieces of RNA (small interfering RNA [siRNA])* targeted

against areas of the woodchuck hepatitis virus genome, which is very similar to

human HBV, could inhibit replication for a prolonged period of time in

hepatocyte culture. siRNA-induced reduction of viral replication also enhanced

expression of hepatocyte-produced antiviral proteins, suggesting that

" machinery " leading to potential immune control is also enhanced. These

investigators also combined siRNA transfection with entecavir treatment and

showed that the siRNAs could prevent viral rebound after the nucleoside was

discontinued. Although this technology is far from approved for the treatments

of patients with hepatitis B, it offers an exciting window into the future of

viral hepatitis therapeutics.

Other Agents

Several other therapies for hepatitis B are also in development. Clevudine, an

oral nucleoside analog, is also in late stages of testing, although no data were

presented at this conference. Other immune-modulating agents are also undergoing

investigation.

Conclusion

At the conclusion of this year's EASL meeting, it is obvious that our

understanding of HBV infection is rapidly evolving. This knowledge will

subsequently drive the development of both technology and therapy. Given the

information presented during EASL 2008, improved detection and improved

strategies to avoid viral resistance will continue to be investigated over the

coming years.

*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.

_________________________________________________________________

It’s easy to add contacts from Facebook and other social sites through Windows

Live™ Messenger. Learn how.

https://www.invite2messenger.net/im/?source=TXT_EML_WLH_LearnHow

[Guest guest]

Advances in Hepatitis B: An Update From EASL 2008 - 2 of 2

Update on Currently Approved Agents

Entecavir

Entecavir is a potent nucleoside analog. Data presented at this year's EASL

meeting continued to support its efficacy and high barrier to resistance in

nucleoside-naive patients. Three-year data were presented from 2 long-term

Chinese studies. In the first, 160 nucleoside-naive subjects failed to fully

respond to entecavir therapy and were continued on entecavir 1 mg* a day for 144

weeks; 89% (133/149) became HBV DNA negative (< 300 copies/mL), 20% (30/150)

lost HBeAg, and 8% (12/150) achieved HBeAg seroconversion.[27] In a second

study, 128 lamivudine-refractory patients who received 48 weeks of entecavir

therapy without adequate response were rolled over to receive 1 mg of entecavir

for 144 weeks; 55% (54/98) suppressed virus below 300 copies/mL, 7/95 lost

HBeAg, and 2/95 achieved HBeAg seroconversion.[28] Similar data were presented

for a nucleoside-naive Japanese rollover cohort in which viral suppression

continued through 3 years with a cumulative 3-year resistance rate of only

1.7%.[29] Previous studies have demonstrated that entecavir results in more

rapid reduction in HBV DNA compared with adefovir at both week 12 and week

48.[30] Week 96 results were presented during EASL 2008. Entecavir continued to

more fully suppress virus, with 79% (23/29) vs 50% (10/20) of patients being HBV

DNA undetectable at the end of 96 weeks.[31]

Telbivudine

The goal of any therapeutic modality, including the nucleot(s)ide analogs, is

durable viral suppression after drug discontinuation. HBeAg loss and

seroconversion can help identify candidates for discontinuation of therapy. In a

study presented during EASL 2008, 27% (153/570) of telbivudine (nucleoside

analog)-treated and 23% (131/580) of lamivudine-treated patients attained this

goal (HBeAg loss), with excellent durability of HBeAg seroconversion (> 85%)

after 52 weeks.[32] Although telbivudine is superior to lamivudine in achieving

both viral reduction and ALT normalization, Wong and colleagues[33] could find

no difference between these agents after 52 weeks in terms of their ability to

decrease intrahepatic HBV DNA or cccDNA.

Adefovir

Once lamivudine resistance occurs, the addition of a nucleotide analog is the

most widely accepted therapeutic strategy to suppress virus. Lampertico and

colleagues[34] reported data substantiating this approach. In their study, 10 mg

of adefovir was added on to the treatment regimen (ie, to ongoing lamivudine

treatment) in lamivudine-resistant patients. After 4 years, 83% (45/54) had

undetectable HBV DNA and no patient experienced virologic breakthrough or

acquired N236T or A181V adefovir resistance mutations; 3 patients had baseline

rtA181t mutations and 3 others acquired this mutation during treatment. However,

all patients suppressed virus, with 5/6 becoming HBV DNA undetectable; 17% of 46

patients with cirrhosis developed HCC, although none experienced clinical

decompensation.

This add-on strategy appears to also work in the setting of entecavir

resistance. In a study presented during EASL 2008, 10 lamivudine-resistant

patients who had virologic breakthrough and genotypic resistance while on

entecavir treatment were switched to lamivudine + adefovir therapy. Serum HBV

DNA decreased in all 10 patients.[35] Combination therapy remains somewhat

controversial, however. When lamivudine-refractory patients were switched to

adefovir (serial monotherapy), 10.5% of 38 developed adefovir-resistance

compared with 2.2% of 90 receiving add-on adefovir (adefovir + lamivudine;

sequential therapy). A high viral load at 48 weeks (> 6 log 10 copies/mL) was

associated with a risk for adefovir resistance.[36] Puoti and colleagues[37]

tried another approach to the add-on therapy strategy: Adefovir was offered to

every patient with HBV DNA < 2000 copies/mL after lamivudine monotherapy. Twenty

of 59 patients agreed to this combination therapy regimen, none of whom

experienced virologic breakthrough. Of the 39 who refused this therapy, 21%

experienced an increase in viremia.

Interferon-Based Therapy

Both standard interferon alfa-2b and pegylated interferon-alfa 2a are approved

for the treatment of chronic hepatitis B. Interferon-based therapy is given for

a finite duration and is intended to induce immune-mediated viral suppression.

Investigators presented long-term follow-up data from a group of HBeAg-negative

patients previously treated with pegylated interferon alone, pegylated

interferon + lamivudine, or lamivudine alone for 48 weeks.[38] Four years after

therapy, 24% (55/230) of those who received pegylated interferon ± lamivudine

maintained a viral load below 10,000 copies/mL, with 17% achieving HBV DNA

negativity. HBsAg loss (clearance) continued to increase to 11% (25/230) in

patients who received pegylated interferon (vs 2% in those who received

lamivudine monotherapy). However, among those patients who suppressed HBV DNA <

400 copies/mL at 24 weeks, 35% (19/54) experienced HBsAg loss. This finding

suggests that 24-week response predicts future HBsAg loss and confirms that

pegylated interferon remains an appropriate first-line therapy for patients with

chronic hepatitis B.[38] Xu and colleagues[39] investigated the efficacy of

pegylated interferon both in HBeAg-positive patients who were naive to therapy

and in those who had failed prior interferon-based or lamivudine treatment.

Viral suppression, HBeAg loss, and HBeAg seroconversion rates were not

statistically different among naive or pretreated patients, and HBeAg

seroconversion rates ranged between 26% and 39%.

Future Therapies

Tenofovir

The nucleotide analog tenofovir, which is expected to be the next oral antiviral

agent approved for the treatment of chronic hepatitis B, was prominently

featured at this year's EASL meeting. Although it is seeking approval for the

treatment of HBV infection, tenofovir is currently approved and in wide use for

the treatment of HIV infection. This nucleotide analog has potent activity

against HBV. Interim data from 2 long-term pivotal trials were presented during

EASL 2008, and both demonstrated additional viral suppression without evidence

of resistance. Study 102 involved HBeAg-negative patients who received 48 weeks

of either tenofovir or adefovir.[40] Ninety percent then continued tenofovir

therapy or were switched from adefovir to tenofovir with an anticipated

follow-up of a minimum of 4 years; 91% (intent to treat [iTT] analysis]) of the

tenofovir-treated patients suppressed HBV DNA below 69 IU/mL at 72 weeks.

However, only 4 patients continued to have detectable virus, as 9 were missing

data; 112 subjects initially treated with adefovir switched to tenofovir at week

48, 35 of whom had detectable virus at the time of the switch. After 24 weeks of

tenofovir, 88% (ITT) of subjects had HBV DNA < 69 IU/mL, which included 33 of

the 35 previously viremic subjects. When considering just those patients with

DNA samples obtained at 72 weeks (excluding those with missing data), 98% in

both arms had HBV DNA < 69 IU/mL. There were no tenofovir-resistant mutations or

creatinine toxicities observed.

Study 103 was of similar design but involved HBeAg-positive subjects.[41]

Eighty-eight percent of patients in this cohort extended therapy, either

continuing on tenofovir or switching to tenofovir if they were previously

receiving adefovir. At week 72, 79% (ITT) of patients receiving tenofovir

monotherapy had undetectable virus compared with 76% (ITT) of patients switched

from adefovir to tenofovir. Again, when considering only patients with DNA

samples obtained at 72 weeks, 89% of tenofovir monotherapy and 82% of " switched "

subjects had HBV DNA < 69 IU/mL. Of the entire study population, 51/216 (24%)

subjects had HBeAg seroconversion, with 7 losing HBsAg. Again, no resistance

mutations were identified. Both of these studies demonstrated the high potency

and low incidence of resistance to tenofovir, confirming that this agent will

become an important addition to the drug arsenal against HBV.

Subanalyses of these cohorts demonstrated that lamivudine-experienced (n = 70)

and lamivudine-naive (n = 377) subjects responded similarly to tenofovir (88% vs

86% achieved undetectable virus, respectively).[42] Excellent viral suppression

was achieved in patients with compensated cirrhosis (85% had HBV DNA < 69

IU/mL), with a safety profile comparable to those of noncirrhotic subjects.[43]

Baseline genotype did not influence treatment response.[44]

There is some concern that tenofovir may be less effective in patients with

previous adefovir exposure. A multicenter European study recruited 127 (121

treatment-experienced) patients to address this concern.[45] In this study, 88

patients had undetectable HBV DNA after 12 months, without virologic

breakthrough. However, patients with genotypic adefovir resistance had a

significantly slower decrease in HBV DNA, but most still became HBV DNA

undetectable during the total observation period. Those patients with prior

exposure to adefovir, but without genotypic mutations, experienced rapid viral

decline. Another approach to managing patients with suboptimal response to

adefovir is to use combination therapy with a nucleotide and nucleoside analog.

Berg and colleagues[46] randomized 105 such chronic hepatitis B patients with

incomplete virologic response to adefovir to receive either tenofovir alone or

tenofovir in combination with the nucleoside analog emtricitabine*. Both

regimens demonstrated robust virologic suppression, with 68% of the pooled

population achieving undetectable HBV DNA at 24 weeks and 81% achieving

undetectable HBV DNA at last data analysis. Both strategies were effective, as

there was no differences in viral decline between the groups. As expected,

adherence to therapy contributed to response. In patients with less than 68%

treatment adherence, only 71% lost virus, whereas with higher adherence to

prescribed therapy 87% became HBV DNA undetectable.

Cost is frequently a concern when discussing therapeutic options for hepatitis

B. A simulation model found tenofovir to be the most cost-effective first-line

treatment option in Spain, France, and Italy, when predicted disease

progression, incidence and cost of chronic hepatitis B-related complications

were weighed against HBV suppression achieved with the various therapies

including lamivudine, adefovir, entecavir, and tenofovir.[47,48]

Small Interfering RNA Technology

Although the inhibition of viral replication with pharmacologic agents is an

effective therapeutic strategy, other ways to inhibit viral replication are also

under investigation. Meng and colleagues[49] presented exciting data

demonstrating how small pieces of RNA (small interfering RNA [siRNA])* targeted

against areas of the woodchuck hepatitis virus genome, which is very similar to

human HBV, could inhibit replication for a prolonged period of time in

hepatocyte culture. siRNA-induced reduction of viral replication also enhanced

expression of hepatocyte-produced antiviral proteins, suggesting that

" machinery " leading to potential immune control is also enhanced. These

investigators also combined siRNA transfection with entecavir treatment and

showed that the siRNAs could prevent viral rebound after the nucleoside was

discontinued. Although this technology is far from approved for the treatments

of patients with hepatitis B, it offers an exciting window into the future of

viral hepatitis therapeutics.

Other Agents

Several other therapies for hepatitis B are also in development. Clevudine, an

oral nucleoside analog, is also in late stages of testing, although no data were

presented at this conference. Other immune-modulating agents are also undergoing

investigation.

Conclusion

At the conclusion of this year's EASL meeting, it is obvious that our

understanding of HBV infection is rapidly evolving. This knowledge will

subsequently drive the development of both technology and therapy. Given the

information presented during EASL 2008, improved detection and improved

strategies to avoid viral resistance will continue to be investigated over the

coming years.

*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.

_________________________________________________________________

It’s easy to add contacts from Facebook and other social sites through Windows

Live™ Messenger. Learn how.

https://www.invite2messenger.net/im/?source=TXT_EML_WLH_LearnHow