Approach to the Hepatitis B Patient With Lamivudine Resistance

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Ask the Experts about Liver Disease

From Medscape Gastroenterology

Approach to the Hepatitis B Patient With Lamivudine Resistance

Question

A patient with chronic hepatitis B has developed resistance to lamivudine.

Is it reasonable to continue lamivudine in combination with a second

antiviral medication for a short period of time before stopping the

lamivudine? What are alternative options for the management of antiviral

drug resistance emerging during treatment of chronic hepatitis B with

lamivudine?

Response from Emmet B. Keeffe, MD, MACP

Professor of Medicine, Stanford University School of Medicine, Stanford,

California; Chief of Hepatology, Co-Director of Liver Transplant Program,

Stanford University Medical Center, Stanford, California

Management options for patients who develop hepatitis B virus (HBV)

antiviral drug resistance during treatment with lamivudine are summarized in

the Table , which was developed on the basis of the updated US treatment

algorithm.[1] The oral antiviral agents adefovir and entecavir are both

acceptable alternatives that are licensed by the US Food and Drug

Administration (FDA) for the treatment of patients with lamivudine

resistance. However, adefovir may be preferred over entecavir on the basis

of emerging data showing a cumulative 32% rate of entecavir resistance after

3 years of therapy in patients with preexisting lamivudine resistance.[1,2]

Whether adefovir is given as monotherapy or in combination with continued

lamivudine may depend on the status of the patient's liver disease. Data

from a recent study in compensated patients revealed mild increases in

alanine aminotransferase (ALT) levels in some patients when switching from

lamivudine to adefovir, but no patient experienced clinically significant

ALT elevations.[3] These observations suggest that switching patients from

lamivudine to adefovir, with or without an overlap period of combination

lamivudine and adefovir, may be a safe strategy in many patients.

However, because the consequences of returning wild-type HBV infection are

potentially more hazardous in patients with advanced liver disease and

switching to adefovir is associated with a 15% to 19% rate of adefovir

resistance after 2 years in lamivudine-resistant patients,[4,5] the addition

of adefovir to continued lamivudine therapy is preferred in patients with

cirrhosis. Pending the availability of future data from studies currently

under way, the addition of adefovir to lamivudine may be preferred to

switching to adefovir monotherapy in all patients with lamivudine

resistance, in order to avoid the increased rate of developing adefovir

genotypic resistance in lamivudine-resistant patients (15% to 19%) when

compared with naive patients treated with adefovir (0% at Year 1, 2% at Year

2, 11% at Year 3, 18% at Year 4, and 29% at Year 5).[6] Entecavir is

associated with a 5-log10 reduction in serum HBV DNA levels in

lamivudine-refractory patients, but this potency needs to be weighed against

the development of genotypic resistance and virologic breakthrough, which

occur in 6% and 1% of patients, respectively, at Year 1, and increase by

Year 3 to 32% and 25%, respectively.[2] Potential future therapy for

managing lamivudine resistance may involve adding tenofovir or switching to

the combination of emtricitabine and tenofovir, which preliminary data

suggest are effective regimens (not currently FDA approved), or switching to

the combination of telbivudine plus tenofovir, which theoretically should be

effective but has not been studied.[1]

Posted 12/12/2006

--------------------------------------------------------------------------------

Table. Potential Management Options for Patients With Hepatitis B Antiviral

Drug Resistance to Lamivudine*[1]

References

Keeffe EB, Dieterich DT, Han SB, et al. A treatment algorithm for the

management of chronic hepatitis B virus infection in the United States: an

update. Clin Gastroenterol Hepatol. 2006;4:936-962. Abstract

Colonno RJ, Rose RE, Pokornowski K, et al. Assessment at three years shows

high barrier to resistance is maintained in entecavir-treated nucleoside

naïve patients while resistance emergence increases over time in lamivudine

refractory patients [abstract]. Hepatology. 2006;44(Suppl 1):229A-230A.

s M, Hann HW, P, et al. Adefovir dipivoxil alone or in

combination with lamivudine in patients with lamivudine resistance and

chronic hepatitis B. Gastroenterology. 2004;126:91-101. Abstract

Lee YS, Suh DJ, Lim YS, et al. Emergence of rtA181V/T and rtN236T mutations

after 48 weeks of adefovir dipivoxil therapy in patients with

lamivudine-resistant chronic hepatitis B [abstract]. Hepatology.

2005;42(Suppl 1):578A.

Lok AS, Fung SK, Han SH, et al. Virological response and resistance to

adefovir (ADV) therapy in liver transplant (OLT) patients [abstract].

Hepatology. 2005;42(Suppl 1):232A.

Hadziyannis S, Tassopoulos N, Chang TT, et al. Long-term adefovir dipivoxil

treatment induces regression of liver fibrosis in patients with

HBeAg-negative chronic hepatitis B: Results after 5 years of therapy

[abstract]. Hepatology. 2005;42(Suppl 1):754A.

Disclosure: Emmet B. Keeffe, MD, MACP, has disclosed that he has received

grants for clinical research from Roche, and has received grants for

educational activities from Bristol-Myers Squibb, Gilead, GlaxoKline,

and Roche. Dr. Keeffe has also disclosed that he has served as an advisor or

consultant to Bristol-Myers Squibb, Gilead, GlaxoKline, Roche, and

Valeant.

http://www.medscape.com/viewarticle/548391

_________________________________________________________________

The MSN Entertainment Guide to Golden Globes is here. Get all the scoop.

http://tv.msn.com/tv/globes2007/

[Guest guest]

Ask the Experts about Liver Disease

From Medscape Gastroenterology

Approach to the Hepatitis B Patient With Lamivudine Resistance

Question

A patient with chronic hepatitis B has developed resistance to lamivudine.

Is it reasonable to continue lamivudine in combination with a second

antiviral medication for a short period of time before stopping the

lamivudine? What are alternative options for the management of antiviral

drug resistance emerging during treatment of chronic hepatitis B with

lamivudine?

Response from Emmet B. Keeffe, MD, MACP

Professor of Medicine, Stanford University School of Medicine, Stanford,

California; Chief of Hepatology, Co-Director of Liver Transplant Program,

Stanford University Medical Center, Stanford, California

Management options for patients who develop hepatitis B virus (HBV)

antiviral drug resistance during treatment with lamivudine are summarized in

the Table , which was developed on the basis of the updated US treatment

algorithm.[1] The oral antiviral agents adefovir and entecavir are both

acceptable alternatives that are licensed by the US Food and Drug

Administration (FDA) for the treatment of patients with lamivudine

resistance. However, adefovir may be preferred over entecavir on the basis

of emerging data showing a cumulative 32% rate of entecavir resistance after

3 years of therapy in patients with preexisting lamivudine resistance.[1,2]

Whether adefovir is given as monotherapy or in combination with continued

lamivudine may depend on the status of the patient's liver disease. Data

from a recent study in compensated patients revealed mild increases in

alanine aminotransferase (ALT) levels in some patients when switching from

lamivudine to adefovir, but no patient experienced clinically significant

ALT elevations.[3] These observations suggest that switching patients from

lamivudine to adefovir, with or without an overlap period of combination

lamivudine and adefovir, may be a safe strategy in many patients.

However, because the consequences of returning wild-type HBV infection are

potentially more hazardous in patients with advanced liver disease and

switching to adefovir is associated with a 15% to 19% rate of adefovir

resistance after 2 years in lamivudine-resistant patients,[4,5] the addition

of adefovir to continued lamivudine therapy is preferred in patients with

cirrhosis. Pending the availability of future data from studies currently

under way, the addition of adefovir to lamivudine may be preferred to

switching to adefovir monotherapy in all patients with lamivudine

resistance, in order to avoid the increased rate of developing adefovir

genotypic resistance in lamivudine-resistant patients (15% to 19%) when

compared with naive patients treated with adefovir (0% at Year 1, 2% at Year

2, 11% at Year 3, 18% at Year 4, and 29% at Year 5).[6] Entecavir is

associated with a 5-log10 reduction in serum HBV DNA levels in

lamivudine-refractory patients, but this potency needs to be weighed against

the development of genotypic resistance and virologic breakthrough, which

occur in 6% and 1% of patients, respectively, at Year 1, and increase by

Year 3 to 32% and 25%, respectively.[2] Potential future therapy for

managing lamivudine resistance may involve adding tenofovir or switching to

the combination of emtricitabine and tenofovir, which preliminary data

suggest are effective regimens (not currently FDA approved), or switching to

the combination of telbivudine plus tenofovir, which theoretically should be

effective but has not been studied.[1]

Posted 12/12/2006

--------------------------------------------------------------------------------

Table. Potential Management Options for Patients With Hepatitis B Antiviral

Drug Resistance to Lamivudine*[1]

References

Keeffe EB, Dieterich DT, Han SB, et al. A treatment algorithm for the

management of chronic hepatitis B virus infection in the United States: an

update. Clin Gastroenterol Hepatol. 2006;4:936-962. Abstract

Colonno RJ, Rose RE, Pokornowski K, et al. Assessment at three years shows

high barrier to resistance is maintained in entecavir-treated nucleoside

naïve patients while resistance emergence increases over time in lamivudine

refractory patients [abstract]. Hepatology. 2006;44(Suppl 1):229A-230A.

s M, Hann HW, P, et al. Adefovir dipivoxil alone or in

combination with lamivudine in patients with lamivudine resistance and

chronic hepatitis B. Gastroenterology. 2004;126:91-101. Abstract

Lee YS, Suh DJ, Lim YS, et al. Emergence of rtA181V/T and rtN236T mutations

after 48 weeks of adefovir dipivoxil therapy in patients with

lamivudine-resistant chronic hepatitis B [abstract]. Hepatology.

2005;42(Suppl 1):578A.

Lok AS, Fung SK, Han SH, et al. Virological response and resistance to

adefovir (ADV) therapy in liver transplant (OLT) patients [abstract].

Hepatology. 2005;42(Suppl 1):232A.

Hadziyannis S, Tassopoulos N, Chang TT, et al. Long-term adefovir dipivoxil

treatment induces regression of liver fibrosis in patients with

HBeAg-negative chronic hepatitis B: Results after 5 years of therapy

[abstract]. Hepatology. 2005;42(Suppl 1):754A.

Disclosure: Emmet B. Keeffe, MD, MACP, has disclosed that he has received

grants for clinical research from Roche, and has received grants for

educational activities from Bristol-Myers Squibb, Gilead, GlaxoKline,

and Roche. Dr. Keeffe has also disclosed that he has served as an advisor or

consultant to Bristol-Myers Squibb, Gilead, GlaxoKline, Roche, and

Valeant.

http://www.medscape.com/viewarticle/548391

_________________________________________________________________

The MSN Entertainment Guide to Golden Globes is here. Get all the scoop.

http://tv.msn.com/tv/globes2007/