Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B - Expert Opinion

[Guest guest]

An Expert Opinion on: Peginterferon alfa-2a alone, lamivudine alone, and the

two in combination in patients with HBeAg-negative chronic hepatitis B N

Engl J Med. 2004;351:1206-1217.

Treatment of HBeAg-negative chronic hepatitis B: is peginterferon

monotherapy the treatment of choice?

S.F. Lok, MD

Professor of Internal Medicine

University of Michigan

Ann Arbor, MI

Posting Date: October 14, 2004

HBeAg-negative chronic hepatitis is characterized by a relapsing course.[1]

Response to treatment of HBeAg-negative chronic hepatitis is usually defined

as sustained suppression of serum HBV DNA and normalization of alanine

aminotransferase levels. However, there is no consensus on how low HBV DNA

should be suppressed. Clinical trials have found that relapse can occur even

among patients who had undetectable HBV DNA by PCR assays when treatment is

withdrawn. Such findings indicate that treatment should aim at maximum viral

suppression.

The results of the study reported by Marcellin and colleagues used 2

different HBV DNA levels for reporting response: < 20,000 copies/mL and <

400 copies/mL (below the detection limit of the PCR assay used).[2] Since

the primary aim of the trial is sustained response, a more stringent

criterion for virologic response is preferred. This 3-arm trial showed that

the 2 groups that received lamivudine (alone or in combination with

peginterferon) had more rapid decrease in serum HBV DNA level than the group

that received peginterferon monotherapy. At the end of a 48-week course of

treatment, a higher proportion of patients in these 2 groups had

undetectable serum HBV DNA by PCR assay. However, 24 weeks after cessation

of treatment, the proportion of patients with undetectable serum HBV DNA by

PCR was similar in the 2 groups that received peginterferon and higher than

the group that received lamivudine only.

Based on the data reported, it is reasonable to conclude that a 48-week

course of peginterferon is superior to lamivudine in inducing sustained

virologic and biochemical responses in patients with HBeAg-negative chronic

hepatitis, and that the combination of peginterferon and lamivudine confers

no additional benefit. However, given the relapsing nature of HBeAg-negative

chronic hepatitis, longer duration of post-treatment follow-up (2-5 years)

is needed to confirm these results.

Several factors may have contributed to the favorable outcome for the

peginterferon groups. First, this trial included patients who had prior

lamivudine therapy. Although all the patients had been off treatment, it is

possible that some of the patients had preexistent lamivudine-resistant HBV,

which would have a bigger impact in the lamivudine-only group.

Lamivudine-resistant mutations were detected in 18% patients receiving

lamivudine only but in only 1% of patients in the combination group.

Antiviral agents with a lower risk of drug resistance, such as adefovir

dipivoxil, may have narrowed the differences in sustained response rates.

Second, there has been much discussion regarding the appropriate timing of

interferon and lamivudine combinations. Studies to date have shown that

lamivudine confers little or no added benefit whether lamivudine is begun

prior to or simultaneous with interferon.[3]

Finally, the issues of cost-effectiveness and long-term clinical benefit

were not addressed in this study. The cost of a 48-week course of

peginterferon is higher than that of a 2-year course of adefovir dipivoxil

and a 4-year course of lamivudine. While there are definite advantages of

achieving sustained response with a finite course of therapy, the

cost-effectiveness of a 48-week course of peginterferon versus a 2-3 year

course of an orally administered nucleoside/nucleotide analogue in achieving

long-term clinical benefit has not been determined. Such studies are

important because the proportions of patients with histologic response at

week 72 in the 3 groups were comparable.

References

1. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic

hepatitis B. Hepatology. 2001;34:617-624.

2. Marcellin P, Lau GKK, Bonino F, et al. Peginterferon alfa-2a alone,

lamivudine alone, and the two in combination in patients with HBeAg-negative

chronic hepatitis B. N Engl J Med. 2004;351:1206-1217.

3. Schalm SW, Heathcote J, Cianciara J, et al. Lamivudine and alpha

interferon combination treatment of patients with chronic hepatitis B

infection: a randomized trial. Gut. 2000;46:562-568.

http://clinicaloptions.com/hep/jopt/articles/article.asp?a=Marcellin-NEJM-2004-0\

9 & page=commentary

[Guest guest]

An Expert Opinion on: Peginterferon alfa-2a alone, lamivudine alone, and the

two in combination in patients with HBeAg-negative chronic hepatitis B N

Engl J Med. 2004;351:1206-1217.

Treatment of HBeAg-negative chronic hepatitis B: is peginterferon

monotherapy the treatment of choice?

S.F. Lok, MD

Professor of Internal Medicine

University of Michigan

Ann Arbor, MI

Posting Date: October 14, 2004

HBeAg-negative chronic hepatitis is characterized by a relapsing course.[1]

Response to treatment of HBeAg-negative chronic hepatitis is usually defined

as sustained suppression of serum HBV DNA and normalization of alanine

aminotransferase levels. However, there is no consensus on how low HBV DNA

should be suppressed. Clinical trials have found that relapse can occur even

among patients who had undetectable HBV DNA by PCR assays when treatment is

withdrawn. Such findings indicate that treatment should aim at maximum viral

suppression.

The results of the study reported by Marcellin and colleagues used 2

different HBV DNA levels for reporting response: < 20,000 copies/mL and <

400 copies/mL (below the detection limit of the PCR assay used).[2] Since

the primary aim of the trial is sustained response, a more stringent

criterion for virologic response is preferred. This 3-arm trial showed that

the 2 groups that received lamivudine (alone or in combination with

peginterferon) had more rapid decrease in serum HBV DNA level than the group

that received peginterferon monotherapy. At the end of a 48-week course of

treatment, a higher proportion of patients in these 2 groups had

undetectable serum HBV DNA by PCR assay. However, 24 weeks after cessation

of treatment, the proportion of patients with undetectable serum HBV DNA by

PCR was similar in the 2 groups that received peginterferon and higher than

the group that received lamivudine only.

Based on the data reported, it is reasonable to conclude that a 48-week

course of peginterferon is superior to lamivudine in inducing sustained

virologic and biochemical responses in patients with HBeAg-negative chronic

hepatitis, and that the combination of peginterferon and lamivudine confers

no additional benefit. However, given the relapsing nature of HBeAg-negative

chronic hepatitis, longer duration of post-treatment follow-up (2-5 years)

is needed to confirm these results.

Several factors may have contributed to the favorable outcome for the

peginterferon groups. First, this trial included patients who had prior

lamivudine therapy. Although all the patients had been off treatment, it is

possible that some of the patients had preexistent lamivudine-resistant HBV,

which would have a bigger impact in the lamivudine-only group.

Lamivudine-resistant mutations were detected in 18% patients receiving

lamivudine only but in only 1% of patients in the combination group.

Antiviral agents with a lower risk of drug resistance, such as adefovir

dipivoxil, may have narrowed the differences in sustained response rates.

Second, there has been much discussion regarding the appropriate timing of

interferon and lamivudine combinations. Studies to date have shown that

lamivudine confers little or no added benefit whether lamivudine is begun

prior to or simultaneous with interferon.[3]

Finally, the issues of cost-effectiveness and long-term clinical benefit

were not addressed in this study. The cost of a 48-week course of

peginterferon is higher than that of a 2-year course of adefovir dipivoxil

and a 4-year course of lamivudine. While there are definite advantages of

achieving sustained response with a finite course of therapy, the

cost-effectiveness of a 48-week course of peginterferon versus a 2-3 year

course of an orally administered nucleoside/nucleotide analogue in achieving

long-term clinical benefit has not been determined. Such studies are

important because the proportions of patients with histologic response at

week 72 in the 3 groups were comparable.

References

1. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic

hepatitis B. Hepatology. 2001;34:617-624.

2. Marcellin P, Lau GKK, Bonino F, et al. Peginterferon alfa-2a alone,

lamivudine alone, and the two in combination in patients with HBeAg-negative

chronic hepatitis B. N Engl J Med. 2004;351:1206-1217.

3. Schalm SW, Heathcote J, Cianciara J, et al. Lamivudine and alpha

interferon combination treatment of patients with chronic hepatitis B

infection: a randomized trial. Gut. 2000;46:562-568.

http://clinicaloptions.com/hep/jopt/articles/article.asp?a=Marcellin-NEJM-2004-0\

9 & page=commentary

[Guest guest]

An Expert Opinion on: Peginterferon alfa-2a alone, lamivudine alone, and the

two in combination in patients with HBeAg-negative chronic hepatitis B N

Engl J Med. 2004;351:1206-1217.

Treatment of HBeAg-negative chronic hepatitis B: is peginterferon

monotherapy the treatment of choice?

S.F. Lok, MD

Professor of Internal Medicine

University of Michigan

Ann Arbor, MI

Posting Date: October 14, 2004

HBeAg-negative chronic hepatitis is characterized by a relapsing course.[1]

Response to treatment of HBeAg-negative chronic hepatitis is usually defined

as sustained suppression of serum HBV DNA and normalization of alanine

aminotransferase levels. However, there is no consensus on how low HBV DNA

should be suppressed. Clinical trials have found that relapse can occur even

among patients who had undetectable HBV DNA by PCR assays when treatment is

withdrawn. Such findings indicate that treatment should aim at maximum viral

suppression.

The results of the study reported by Marcellin and colleagues used 2

different HBV DNA levels for reporting response: < 20,000 copies/mL and <

400 copies/mL (below the detection limit of the PCR assay used).[2] Since

the primary aim of the trial is sustained response, a more stringent

criterion for virologic response is preferred. This 3-arm trial showed that

the 2 groups that received lamivudine (alone or in combination with

peginterferon) had more rapid decrease in serum HBV DNA level than the group

that received peginterferon monotherapy. At the end of a 48-week course of

treatment, a higher proportion of patients in these 2 groups had

undetectable serum HBV DNA by PCR assay. However, 24 weeks after cessation

of treatment, the proportion of patients with undetectable serum HBV DNA by

PCR was similar in the 2 groups that received peginterferon and higher than

the group that received lamivudine only.

Based on the data reported, it is reasonable to conclude that a 48-week

course of peginterferon is superior to lamivudine in inducing sustained

virologic and biochemical responses in patients with HBeAg-negative chronic

hepatitis, and that the combination of peginterferon and lamivudine confers

no additional benefit. However, given the relapsing nature of HBeAg-negative

chronic hepatitis, longer duration of post-treatment follow-up (2-5 years)

is needed to confirm these results.

Several factors may have contributed to the favorable outcome for the

peginterferon groups. First, this trial included patients who had prior

lamivudine therapy. Although all the patients had been off treatment, it is

possible that some of the patients had preexistent lamivudine-resistant HBV,

which would have a bigger impact in the lamivudine-only group.

Lamivudine-resistant mutations were detected in 18% patients receiving

lamivudine only but in only 1% of patients in the combination group.

Antiviral agents with a lower risk of drug resistance, such as adefovir

dipivoxil, may have narrowed the differences in sustained response rates.

Second, there has been much discussion regarding the appropriate timing of

interferon and lamivudine combinations. Studies to date have shown that

lamivudine confers little or no added benefit whether lamivudine is begun

prior to or simultaneous with interferon.[3]

Finally, the issues of cost-effectiveness and long-term clinical benefit

were not addressed in this study. The cost of a 48-week course of

peginterferon is higher than that of a 2-year course of adefovir dipivoxil

and a 4-year course of lamivudine. While there are definite advantages of

achieving sustained response with a finite course of therapy, the

cost-effectiveness of a 48-week course of peginterferon versus a 2-3 year

course of an orally administered nucleoside/nucleotide analogue in achieving

long-term clinical benefit has not been determined. Such studies are

important because the proportions of patients with histologic response at

week 72 in the 3 groups were comparable.

References

1. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic

hepatitis B. Hepatology. 2001;34:617-624.

2. Marcellin P, Lau GKK, Bonino F, et al. Peginterferon alfa-2a alone,

lamivudine alone, and the two in combination in patients with HBeAg-negative

chronic hepatitis B. N Engl J Med. 2004;351:1206-1217.

3. Schalm SW, Heathcote J, Cianciara J, et al. Lamivudine and alpha

interferon combination treatment of patients with chronic hepatitis B

infection: a randomized trial. Gut. 2000;46:562-568.

http://clinicaloptions.com/hep/jopt/articles/article.asp?a=Marcellin-NEJM-2004-0\

9 & page=commentary

[Guest guest]

An Expert Opinion on: Peginterferon alfa-2a alone, lamivudine alone, and the

two in combination in patients with HBeAg-negative chronic hepatitis B N

Engl J Med. 2004;351:1206-1217.

Treatment of HBeAg-negative chronic hepatitis B: is peginterferon

monotherapy the treatment of choice?

S.F. Lok, MD

Professor of Internal Medicine

University of Michigan

Ann Arbor, MI

Posting Date: October 14, 2004

HBeAg-negative chronic hepatitis is characterized by a relapsing course.[1]

Response to treatment of HBeAg-negative chronic hepatitis is usually defined

as sustained suppression of serum HBV DNA and normalization of alanine

aminotransferase levels. However, there is no consensus on how low HBV DNA

should be suppressed. Clinical trials have found that relapse can occur even

among patients who had undetectable HBV DNA by PCR assays when treatment is

withdrawn. Such findings indicate that treatment should aim at maximum viral

suppression.

The results of the study reported by Marcellin and colleagues used 2

different HBV DNA levels for reporting response: < 20,000 copies/mL and <

400 copies/mL (below the detection limit of the PCR assay used).[2] Since

the primary aim of the trial is sustained response, a more stringent

criterion for virologic response is preferred. This 3-arm trial showed that

the 2 groups that received lamivudine (alone or in combination with

peginterferon) had more rapid decrease in serum HBV DNA level than the group

that received peginterferon monotherapy. At the end of a 48-week course of

treatment, a higher proportion of patients in these 2 groups had

undetectable serum HBV DNA by PCR assay. However, 24 weeks after cessation

of treatment, the proportion of patients with undetectable serum HBV DNA by

PCR was similar in the 2 groups that received peginterferon and higher than

the group that received lamivudine only.

Based on the data reported, it is reasonable to conclude that a 48-week

course of peginterferon is superior to lamivudine in inducing sustained

virologic and biochemical responses in patients with HBeAg-negative chronic

hepatitis, and that the combination of peginterferon and lamivudine confers

no additional benefit. However, given the relapsing nature of HBeAg-negative

chronic hepatitis, longer duration of post-treatment follow-up (2-5 years)

is needed to confirm these results.

Several factors may have contributed to the favorable outcome for the

peginterferon groups. First, this trial included patients who had prior

lamivudine therapy. Although all the patients had been off treatment, it is

possible that some of the patients had preexistent lamivudine-resistant HBV,

which would have a bigger impact in the lamivudine-only group.

Lamivudine-resistant mutations were detected in 18% patients receiving

lamivudine only but in only 1% of patients in the combination group.

Antiviral agents with a lower risk of drug resistance, such as adefovir

dipivoxil, may have narrowed the differences in sustained response rates.

Second, there has been much discussion regarding the appropriate timing of

interferon and lamivudine combinations. Studies to date have shown that

lamivudine confers little or no added benefit whether lamivudine is begun

prior to or simultaneous with interferon.[3]

Finally, the issues of cost-effectiveness and long-term clinical benefit

were not addressed in this study. The cost of a 48-week course of

peginterferon is higher than that of a 2-year course of adefovir dipivoxil

and a 4-year course of lamivudine. While there are definite advantages of

achieving sustained response with a finite course of therapy, the

cost-effectiveness of a 48-week course of peginterferon versus a 2-3 year

course of an orally administered nucleoside/nucleotide analogue in achieving

long-term clinical benefit has not been determined. Such studies are

important because the proportions of patients with histologic response at

week 72 in the 3 groups were comparable.

References

1. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic

hepatitis B. Hepatology. 2001;34:617-624.

2. Marcellin P, Lau GKK, Bonino F, et al. Peginterferon alfa-2a alone,

lamivudine alone, and the two in combination in patients with HBeAg-negative

chronic hepatitis B. N Engl J Med. 2004;351:1206-1217.

3. Schalm SW, Heathcote J, Cianciara J, et al. Lamivudine and alpha

interferon combination treatment of patients with chronic hepatitis B

infection: a randomized trial. Gut. 2000;46:562-568.

http://clinicaloptions.com/hep/jopt/articles/article.asp?a=Marcellin-NEJM-2004-0\

9 & page=commentary