To stop or not to stop: The quest for long-term viral suppression

[Guest guest]

http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1746.2011.06604.x/full

To stop or not to stop: The quest for long-term viral suppression

Fung, Ching-Lung Lai, Man-Fung Yuen

Article first published online: 17 FEB 2011

DOI: 10.1111/j.1440-1746.2011.06604.x

© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell

Publishing Asia Pty Ltd

Issue

Journal of Gastroenterology and Hepatology

Volume 26, Issue 3, pages 420–422, March 2011

Article

In patients with chronic hepatitis B (CHB), hepatitis B surface antigen (HBsAg)

seroconversion is one of the ultimate goals of antiviral therapy. However, this

is only achievable in a small proportion of patients receiving treatment. Other

end-points that are commonly used include the normalization of alanine

aminotransferase (ALT), viral suppression, and hepatitis B e antigen (HBeAg)

seroconversion. However, HBeAg seroconversion is an inadequate end-point because

it does not guarantee long-term remission and inactivity of the hepatitis B

virus (HBV). Thus, although HBeAg seroconversion remains an important milestone

in the natural history of CHB infection, a significant proportion (30–50%) of

patients will either have ongoing active disease immediately after HBeAg

seroclearance or undergo reactivation following a variable period of quiescence.

The exact immunological mechanism for the continuation of disease activity after

HBeAg seroconversion is not known. However, the continuing viral replication

might be partly explained by the spontaneous mutations in the precore or core

promoter regions that reduce the production of HBeAg. It has been shown that the

precore and core promoter mutations start to develop even before HBeAg

seroconversion. In Asian HBeAg-negative patients with detectable HBV DNA,

50–60% have the precore mutations, and up to 70% have the core promoter

mutations. However, approximately 10% still have both precore and core promoter

wild-type sequences.

There are considerable differences between the current major regional treatment

guidelines as to the criteria for stopping therapy in both HBeAg-positive and

-negative patients with CHB. This highlights the fact that there is no consensus

regarding the treatment end-points. The guidelines will continue to evolve with

increasing understanding of the natural history of CHB infection.

For HBeAg-positive patients, the current European Association for the Study of

the Liver (EASL) guidelines1 state that the ideal end-point of therapy is

sustained HBsAg loss with or without seroconversion. In contrast, the American

Association for the Study of Liver Diseases (AASLD)2 and Asian Pacific

Association for the Study of the Liver (APASL)3 guidelines view “durableâ€

HBeAg seroconversion as an adequate end-point. The APASL guidelines also specify

that the HBeAg seroconversion should be accompanied by undetectable HBV DNA.

However, the question remains whether treatment-induced HBeAg seroconversion

together with virological response is truly durable. Even with pegylated

interferon therapy, in a 5-year long-term follow-up study, despite the

cumulative incidence of HBeAg seroconversion of up to 60%, only 29% of patients

had HBV DNA <20 000 IU/mL, and 13% had HBV DNA <20 IU/mL.4 With lamivudine

(LAM), an early study of 34 Korean patients who stopped LAM after HBeAg

seroconversion showed a cumulative relapse rate of 49% after 2 years.5 Another

study of 82 patients from Taiwan showed that 48% had relapsed by 12 months, with

genotype C infections being associated with higher rates of relapse.6 A study of

132 Korean patients reported a relapse rate of 66% at 12 months after stopping

LAM.7 A more recent Korean study of 178 patients who stopped LAM after achieving

HBeAg seroconversion showed a lower relapse rate of 30% at 5 years.8 In 125

Chinese patients who stopped LAM after HBeAg loss or seroconversion, the 4-year

cumulative relapse (defined as serum HBV DNA ≥ 2000 IU/mL) rates were 41% and

29%, respectively.9

Common to all these studies is the fact that older age and shorter duration of

consolidation therapy after HBeAg seroconversion are associated with higher

rates of relapse. However, it is important to note carefully the definition of

relapse in the different studies. The low 5-year relapse rate of 30% in the

previously-described study is likely due to the high cut-off level of >28 000

IU/mL used to define the reappearance of HBV DNA. When virological rebound was

defined strictly as a 1 log increase in HBV DNA, the virological rebound rate

was 82% at 4 years in a study of 22 patients who stopped LAM after HBeAg

seroconversion. Seventy-eight percent of patients had undetectable HBV DNA at

the time of last follow up in those who continued with LAM, compared to 0% in

those who stopped (P < 0.001).10 Altogether, these studies show that

off-treatment response after HBeAg seroconversion is not durable.

An argument can be made for those in the younger age group in whom antiviral

therapy might be stopped with a lower risk of relapse after an extended

consolidation treatment period. However, there is no agreement as to the

acceptable age cut-off and the length of consolidation. Soo et al. reported a

31% cumulative relapse rate after 2 years following LAM cessation in 85 CHB

patients who had received at least 24 months of consolidation.11

For HBeAg-negative patients, both the EASL and AASLD guidelines recommend that

treatment should be continued until HBsAg clearance is achieved.1,2 The APASL

guidelines, however, are less definite, and recommend that consideration should

be given to stopping treatment if HBV DNA remains undetectable on three separate

occasions, 6 months apart.3 In this issue of the Journal of Gastroenterology and

Hepatology, Liu and colleagues reported the relapse rates of 61 HBeAg-negative

CHB patients in whom LAM was stopped.12 These patients were treated for at least

24 months, and had undetectable HBV DNA (<200 IU/mL) and normal ALT levels for

at least 18 months. Relapse was defined as HBV DNA ≥2000 IU/mL. In their

cohort, 31 (51%) patients suffered relapse, with a cumulative relapse rate of

52% after 3 years. Similar to previous studies, younger age was associated with

a lower relapse rate. The authors conclude that despite the cessation criteria

recommended by the APASL guidelines, the maintenance of viral suppression was

not durable.

Another recent study using less stringent cessation criterion was associated

with a similarly high relapse rate.13 In this study, of those who achieved a

protocol-defined response (HBV DNA <1.4 × 105 IU/mL and ALT <1.25 × upper

limit of normal) with entecavir or LAM at 48 weeks, seven of 257 (3%)

entecavir-treated and 10 of 201 (5%) LAM-treated patients sustained HBV DNA <60

IU/mL at 24 weeks off treatment. In contrast, those who continued treatment into

year 2 had maintenance of virological suppression.13

Currently, HBsAg seroclearance remains an elusive goal for the majority of

patients treated with oral antiviral agents or with pegylated interferon.

Despite this, durable suppression of HBV DNA is now achievable with long-term

antiviral therapy. The importance of viral load on long-term outcome cannot be

over-emphasized, with evidence showing that the lower the HBV DNA, the lower the

risk of hepatocellular carcinoma and cirrhosis development.14–16 Early

concerns regarding the development of drug-resistant mutations with long-term

treatment have largely been mitigated by the availability of highly-potent

antiviral agents with a high genetic barrier to resistance, such as entecavir

and tenofovir. Relapse, despite continual therapy after HBeAg seroconversion, is

usually preceded by the development of resistance in the majority, and is often

seen in patients treated with LAM monotherapy.17 However, the resistance rate is

lower than that observed in HBeAg-positive patients. After treatment-induced

HBeAg seroconversion, the resistance rate was reported to be 10% after a median

treatment length of 79 months.10

Virological rebound following cessation of antiviral therapy can be associated

with negative consequences. First, inadequate monitoring can result in severe

flares of hepatitis. Second, re-challenging the HBV with the same drug after

rebound of viral load can theoretically increase the chance of drug resistance.

In regions where expensive antiviral drugs might not be readily available as

first-line treatment, long-term treatment with LAM might be the only option.

Long-term therapy is still advisable, since the risk of relapse from stopping

therapy is greater than that of resistance. The adoption of the roadmap concept,

with testing of HBV DNA at week 24, might further minimize resistance.

In summary, the study by Liu and colleagues has provided further evidence that

off-treatment virological response is not durable, even with adherence to strict

cessation criteria. For both HBeAg-positive and -negative patients, the ideal

treatment end-points in the era of potent antiviral therapy with low resistance

should be the seroclearance of HBsAg.

References<CUT>

[Guest guest]

http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1746.2011.06604.x/full

To stop or not to stop: The quest for long-term viral suppression

Fung, Ching-Lung Lai, Man-Fung Yuen

Article first published online: 17 FEB 2011

DOI: 10.1111/j.1440-1746.2011.06604.x

© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell

Publishing Asia Pty Ltd

Issue

Journal of Gastroenterology and Hepatology

Volume 26, Issue 3, pages 420–422, March 2011

Article

In patients with chronic hepatitis B (CHB), hepatitis B surface antigen (HBsAg)

seroconversion is one of the ultimate goals of antiviral therapy. However, this

is only achievable in a small proportion of patients receiving treatment. Other

end-points that are commonly used include the normalization of alanine

aminotransferase (ALT), viral suppression, and hepatitis B e antigen (HBeAg)

seroconversion. However, HBeAg seroconversion is an inadequate end-point because

it does not guarantee long-term remission and inactivity of the hepatitis B

virus (HBV). Thus, although HBeAg seroconversion remains an important milestone

in the natural history of CHB infection, a significant proportion (30–50%) of

patients will either have ongoing active disease immediately after HBeAg

seroclearance or undergo reactivation following a variable period of quiescence.

The exact immunological mechanism for the continuation of disease activity after

HBeAg seroconversion is not known. However, the continuing viral replication

might be partly explained by the spontaneous mutations in the precore or core

promoter regions that reduce the production of HBeAg. It has been shown that the

precore and core promoter mutations start to develop even before HBeAg

seroconversion. In Asian HBeAg-negative patients with detectable HBV DNA,

50–60% have the precore mutations, and up to 70% have the core promoter

mutations. However, approximately 10% still have both precore and core promoter

wild-type sequences.

There are considerable differences between the current major regional treatment

guidelines as to the criteria for stopping therapy in both HBeAg-positive and

-negative patients with CHB. This highlights the fact that there is no consensus

regarding the treatment end-points. The guidelines will continue to evolve with

increasing understanding of the natural history of CHB infection.

For HBeAg-positive patients, the current European Association for the Study of

the Liver (EASL) guidelines1 state that the ideal end-point of therapy is

sustained HBsAg loss with or without seroconversion. In contrast, the American

Association for the Study of Liver Diseases (AASLD)2 and Asian Pacific

Association for the Study of the Liver (APASL)3 guidelines view “durableâ€

HBeAg seroconversion as an adequate end-point. The APASL guidelines also specify

that the HBeAg seroconversion should be accompanied by undetectable HBV DNA.

However, the question remains whether treatment-induced HBeAg seroconversion

together with virological response is truly durable. Even with pegylated

interferon therapy, in a 5-year long-term follow-up study, despite the

cumulative incidence of HBeAg seroconversion of up to 60%, only 29% of patients

had HBV DNA <20 000 IU/mL, and 13% had HBV DNA <20 IU/mL.4 With lamivudine

(LAM), an early study of 34 Korean patients who stopped LAM after HBeAg

seroconversion showed a cumulative relapse rate of 49% after 2 years.5 Another

study of 82 patients from Taiwan showed that 48% had relapsed by 12 months, with

genotype C infections being associated with higher rates of relapse.6 A study of

132 Korean patients reported a relapse rate of 66% at 12 months after stopping

LAM.7 A more recent Korean study of 178 patients who stopped LAM after achieving

HBeAg seroconversion showed a lower relapse rate of 30% at 5 years.8 In 125

Chinese patients who stopped LAM after HBeAg loss or seroconversion, the 4-year

cumulative relapse (defined as serum HBV DNA ≥ 2000 IU/mL) rates were 41% and

29%, respectively.9

Common to all these studies is the fact that older age and shorter duration of

consolidation therapy after HBeAg seroconversion are associated with higher

rates of relapse. However, it is important to note carefully the definition of

relapse in the different studies. The low 5-year relapse rate of 30% in the

previously-described study is likely due to the high cut-off level of >28 000

IU/mL used to define the reappearance of HBV DNA. When virological rebound was

defined strictly as a 1 log increase in HBV DNA, the virological rebound rate

was 82% at 4 years in a study of 22 patients who stopped LAM after HBeAg

seroconversion. Seventy-eight percent of patients had undetectable HBV DNA at

the time of last follow up in those who continued with LAM, compared to 0% in

those who stopped (P < 0.001).10 Altogether, these studies show that

off-treatment response after HBeAg seroconversion is not durable.

An argument can be made for those in the younger age group in whom antiviral

therapy might be stopped with a lower risk of relapse after an extended

consolidation treatment period. However, there is no agreement as to the

acceptable age cut-off and the length of consolidation. Soo et al. reported a

31% cumulative relapse rate after 2 years following LAM cessation in 85 CHB

patients who had received at least 24 months of consolidation.11

For HBeAg-negative patients, both the EASL and AASLD guidelines recommend that

treatment should be continued until HBsAg clearance is achieved.1,2 The APASL

guidelines, however, are less definite, and recommend that consideration should

be given to stopping treatment if HBV DNA remains undetectable on three separate

occasions, 6 months apart.3 In this issue of the Journal of Gastroenterology and

Hepatology, Liu and colleagues reported the relapse rates of 61 HBeAg-negative

CHB patients in whom LAM was stopped.12 These patients were treated for at least

24 months, and had undetectable HBV DNA (<200 IU/mL) and normal ALT levels for

at least 18 months. Relapse was defined as HBV DNA ≥2000 IU/mL. In their

cohort, 31 (51%) patients suffered relapse, with a cumulative relapse rate of

52% after 3 years. Similar to previous studies, younger age was associated with

a lower relapse rate. The authors conclude that despite the cessation criteria

recommended by the APASL guidelines, the maintenance of viral suppression was

not durable.

Another recent study using less stringent cessation criterion was associated

with a similarly high relapse rate.13 In this study, of those who achieved a

protocol-defined response (HBV DNA <1.4 × 105 IU/mL and ALT <1.25 × upper

limit of normal) with entecavir or LAM at 48 weeks, seven of 257 (3%)

entecavir-treated and 10 of 201 (5%) LAM-treated patients sustained HBV DNA <60

IU/mL at 24 weeks off treatment. In contrast, those who continued treatment into

year 2 had maintenance of virological suppression.13

Currently, HBsAg seroclearance remains an elusive goal for the majority of

patients treated with oral antiviral agents or with pegylated interferon.

Despite this, durable suppression of HBV DNA is now achievable with long-term

antiviral therapy. The importance of viral load on long-term outcome cannot be

over-emphasized, with evidence showing that the lower the HBV DNA, the lower the

risk of hepatocellular carcinoma and cirrhosis development.14–16 Early

concerns regarding the development of drug-resistant mutations with long-term

treatment have largely been mitigated by the availability of highly-potent

antiviral agents with a high genetic barrier to resistance, such as entecavir

and tenofovir. Relapse, despite continual therapy after HBeAg seroconversion, is

usually preceded by the development of resistance in the majority, and is often

seen in patients treated with LAM monotherapy.17 However, the resistance rate is

lower than that observed in HBeAg-positive patients. After treatment-induced

HBeAg seroconversion, the resistance rate was reported to be 10% after a median

treatment length of 79 months.10

Virological rebound following cessation of antiviral therapy can be associated

with negative consequences. First, inadequate monitoring can result in severe

flares of hepatitis. Second, re-challenging the HBV with the same drug after

rebound of viral load can theoretically increase the chance of drug resistance.

In regions where expensive antiviral drugs might not be readily available as

first-line treatment, long-term treatment with LAM might be the only option.

Long-term therapy is still advisable, since the risk of relapse from stopping

therapy is greater than that of resistance. The adoption of the roadmap concept,

with testing of HBV DNA at week 24, might further minimize resistance.

In summary, the study by Liu and colleagues has provided further evidence that

off-treatment virological response is not durable, even with adherence to strict

cessation criteria. For both HBeAg-positive and -negative patients, the ideal

treatment end-points in the era of potent antiviral therapy with low resistance

should be the seroclearance of HBsAg.

References<CUT>