Update on the Treatment of Hepatitis B

[Guest guest]

Selection from: Hepatitis B: Advances in Screening, Diagnosis, and Clinical

Management

Update on the Treatment of Hepatitis B CME

S. Reau, MD

Disclosures

Introduction

Hepatitis B virus (HBV) infection is a common illness with nearly 400 million

chronic carriers worldwide and about 50 million new infections occurring

annually.[1-3] Disease consequences are widely recognized. Each year,

approximately 1 million deaths result from complications of chronic infection.

Hepatitis B is a common indication for liver transplantation and is the leading

cause of hepatocellular carcinoma (HCC). Cancer risk is highest in cirrhotic

patients with active viral replication.[4]

Despite its prevalence, many practitioners are becoming less comfortable with

the treatment of HBV infection, partly as a result of the increasing

complexities in clinical management. This intricacy has escalated recently with

the availability of several additional drugs for the treatment of hepatitis B

and the growing awareness of drug resistance.

Several recent publications highlight the advantages of the evolving

armamentarium of anti-HBV compounds as well as the application of management

strategies in avoiding untoward events.

Can Lamivudine Be Used Effectively in Patients With Hepatitis B Despite the High

Risk of Drug Resistance?

Yuen MF, Fong DYT, Wong DK, Yuen JCH, Fung J, Lai CL. Hepatitis B virus DNA

levels at week 4 of lamivudine treatment predict the 5-year ideal response.

Hepatology. 2007;46:1695-1703.

Summary: In this study, 74 hepatitis B e antigen (HBeAg)-positive chronic

hepatitis B patients received daily lamivudine with at least 5 years of

follow-up. Serum HBV DNA was measured by branched DNA assay (lower limit of

detection, 2000 copies/mL [400 IU/mL]) 13 times: at baseline, weeks 2, 4, 8, 12,

16, 24, and 32 and then at year 1, 2, 3, 4 and 5. Lamivudine resistance was

evaluated at baseline, weeks 4, 16, and 24, and then yearly. Ideal treatment

response (IR) at year 5 was defined as HBV DNA below the limit of detection,

with HBeAg seroconversion, normalization of serum alanine aminotransferase

(ALT), and the lack of YMDD mutations. At 5 years, 20 patients (27%) had HBV DNA

levels below detection; 46 (62.2%) had lamivudine resistance, and 17 patients

achieved an IR. The presence of precore or core promoter mutations and elevated

serum ALT were statistically more common in patients who achieved an IR.

Baseline HBV DNA level was not predictive of IR. Viral load at week 4 was able

to accurately predict IR, with 100% of patients with HBV DNA < 4.0 log10

copies/mL achieving an IR, although the 16-week viral load was the most accurate

time point throughout the first year. Patients with HBV DNA ™ 4.0 log10

copies/mL at week 4 had an 83.8% chance of treatment failure. This increased to

an 87.7% chance of treatment failure if the HBV DNA was ™ 3.6 log10 copies/mL or

greater at week 16. No drug resistance was detected at either of these time

points.

Comment: The introduction of the nucleoside analog lamivudine revolutionized

hepatitis B therapy. The use of this agent was found to decrease the risk of

disease progression and liver cancer in patients with HBV infection.[5,6]

However, over time it was recognized that the development of drug-resistant

mutations was greater than 70% after 5 years of therapy,[7] and that mutations

negated the beneficial effects of treatment.[5] Because hepatitis B therapy is

frequently prolonged, current treatment guidelines do not recommend lamivudine

as a first-line agent for treatment in nucleo(t)side-naive chronic active

hepatitis B.[8] Despite this, lamivudine remains a commonly prescribed

medication for the treatment of HBV infection. Its low cost and long clinical

record guarantee that it will remain in the real-life treatment algorithm

despite published treatment guidelines and availability of several superior

compounds. As emphasized by this article, even lamivudine can be used

effectively with close monitoring. Although any viral reduction is encouraging,

in this study, the absolute reduction in HBV DNA to undetectable as measured by

the assay employed was the most accurate predictor of response. These findings

suggest that lamivudine may be an effective long-term anti-HBV therapy if the

virus is adequately suppressed after 4 weeks. These data also suggest that

therapeutic modification can be safely made up to 16 weeks into the treatment

course, as the risk for drug mutations at this time point is minimal. Each

anti-HBV agent is unique; thus, this 4-week rule should not be used to guide

therapeutic response for agents other than lamivudine.

Abstract:

http://www.medscape.com/medline/abstract/18027877

What Is the Long-term Efficacy and Safety of Entecavir in HBeAg-positive

Patients Treated for Up to 96 Weeks?

Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to 96 weeks in

patients with HBeAg-positive chronic hepatitis B. Gastroenterology.

2007;133:1437-1444.

Summary: This study involved 709 HBeAg-positive nucleoside-naive patients with

chronic hepatitis B who received either 0.5 mg entecavir (n=354) or 100 mg

lamivudine (n=355) once daily for 52 weeks. At this juncture, patients either

continued blinded treatment, stopped if adequate response was achieved

( " responders, " defined as HBV DNA < 0.7 MEq/mL [~700,000 copies/mL] and loss of

HBeAg), or stopped if there was inadequate treatment response ( " nonresponders, "

defined as HBV DNA ™ 0.7 MEq/mL). Patients who achieved virologic response (HBV

DNA < 0.7 MEq/mL) but did not lose HBeAg continued therapy up to 96 weeks. Among

the 243 entecavir-treated patients and 164 lamivudine-treated patients

continuing into year 2, 75% and 52%, respectively, received 96 weeks of

treatment. Patients in year 2 dropped out if they met the protocol-defined

endpoints of " responders " or " nonresponders. " HBV DNA was quantified by

polymerase chain reaction assay, with a lower limit of detection of 300

copies/mL. At week 48, 64% of entecavir-treated and 40% of lamivudine-treated

patients had undetectable HBV DNA; this percentage increased to 74% for

entecavir-treated patients by the end of dosing during the second year (vs 37%

for lamivudine-treated patients). In both groups, most patients normalized serum

ALT, and HBeAg loss and seroconversion were comparable. Both agents were found

to be very well tolerated and safe. Thirteen entecavir-treated patients had

virologic breakthrough during the 2 years. No patients demonstrated

entecavir-resistance mutations; however, 1 had lamivudine resistance

substitutions. Among all those patients with measurable HBV DNA, 3 additional

patients were found who had lamivudine resistance at baseline and 1 had emerging

lamivudine and entecavir substitutions at week 84.

Comment: Several studies have demonstrated improved hepatic histology as well as

decreased risk of disease progression with effective virologic

suppression.[5,6,9] Thus, current goals for hepatitis B therapy are evolving to

include complete suppression of HBV replication. Although some patients may

achieve this endpoint with a finite course of therapy, for several subsets of

chronically infected hepatitis B patients, prolonged duration of medications

will be necessary to maintain long-term virologic suppression. Adequate viral

response with minimal risk of drug resistance is integral to effective control,

especially as drug resistance mutations may confer resistance to the entire

class of medications. This study establishes entecavir as an excellent long-term

drug choice for the nucleoside-naive HBeAg-positive patient. Response rates

(HBeAg loss and HBV DNA suppression) for entecavir continue to improve with

extended treatment and minimal risk for drug resistance.

Abstract:

http://www.medscape.com/medline/abstract/17983800

How Well Does Combination Nucleoside and Nucleotide Therapy Work Once Lamivudine

Resistance Has Occurred?

Lampertico P, Vigano M, Manenti E, Iavarone M, Sablon E, Colombo M. Low

resistance to adefovir combined with lamivudine: a 3-year study of 145

lamivudine-resistant hepatitis B patients. Gastroenterology. 2007;133:1445-1451.

Summary: One hundred forty-five chronic hepatitis B patients with documented

lamivudine resistance had adefovir added to their treatment regimen and were

monitored for a median of 42 months. Overall, 80% of patients became HBV DNA

negative by year 3; 20% remained viremic despite combination therapy. No patient

experienced virologic breakthrough (defined as> 1 log10 increase in serum HBV

DNA over on-treatment nadir). Adefovir-associated mutations include rt181T/V and

rtN236T. Six patients (4%) had detectable pretreatment adefovir resistance

mutations, 5 of whom ultimately cleared DNA. Three patients developed an rtA181T

mutation, 2 of whom cleared virus. No patient developed the signature adefovir

mutations rtA181V or rtN236T. Lamivudine resistance was persistently found in

94% of patients who were viremic during combination adefovir-lamivudine therapy.

Patients with persistent viremia were more likely to have HBeAg, genotype nonD,

and> 8 log10 copies/mL HBV DNA at baseline. No patient progressed to cirrhosis.

No cirrhotic patient without HCC developed clinical decompensation. However, 12%

of patients with pre-existing cirrhosis did acquire HCC.

Comment: Routine management of HBV infection is already challenging. Thus, the

added dimension of drug resistance is far from straightforward. It has been

recognized that serial monotherapy allows rapid emergence of additional

resistance mutations and is thus not recommended.[8,10,11] This is the first

study to report long-term data on the safety and efficacy of combination

adefovir-lamivudine therapy in patients with lamivudine resistance. The

significant viral suppression and low risk of emergence of signature drug

resistance mutations are both encouraging and reassuring for this strategy.

However, a small subset of patients continued to have incomplete viral

suppression. Experience with adefovir monotherapy in HBeAg-negative

treatment-naive hepatitis B patients demonstrates delayed emergence of drug

resistance. It is likely that this patient subset will also be at long-term risk

for drug resistance if viremia persists and there is no change in clinical

management. Finally, despite viral suppression, cirrhotic patients remained at

risk to develop HCC, emphasizing the continued importance of cancer screening in

this population.

Abstract:

http://www.medscape.com/medline/abstract/17983801

Conclusion

Hepatitis B therapy continues to evolve with both the availability of new agents

and improved insight into natural history. These studies reinforce that all

agents for HBV infection are potentially effective therapy, but patient and

viral response must be monitored closely. Long-term data support excellent

efficacy, safety, and low risk for drug resistance for entecavir in

HBeAg-positive nucleoside-naive patients and for combination adefovir-lamivudine

therapy in lamivudine-resistant patients.

This activity is supported by an independent educational grant from Gilead.

http://www.medscape.com/viewarticle/570498?src=mp

_________________________________________________________________

Connect and share in new ways with Windows Live.

http://www.windowslive.com/share.html?ocid=TXT_TAGHM_Wave2_sharelife_012008

[Guest guest]

Selection from: Hepatitis B: Advances in Screening, Diagnosis, and Clinical

Management

Update on the Treatment of Hepatitis B CME

S. Reau, MD

Disclosures

Introduction

Hepatitis B virus (HBV) infection is a common illness with nearly 400 million

chronic carriers worldwide and about 50 million new infections occurring

annually.[1-3] Disease consequences are widely recognized. Each year,

approximately 1 million deaths result from complications of chronic infection.

Hepatitis B is a common indication for liver transplantation and is the leading

cause of hepatocellular carcinoma (HCC). Cancer risk is highest in cirrhotic

patients with active viral replication.[4]

Despite its prevalence, many practitioners are becoming less comfortable with

the treatment of HBV infection, partly as a result of the increasing

complexities in clinical management. This intricacy has escalated recently with

the availability of several additional drugs for the treatment of hepatitis B

and the growing awareness of drug resistance.

Several recent publications highlight the advantages of the evolving

armamentarium of anti-HBV compounds as well as the application of management

strategies in avoiding untoward events.

Can Lamivudine Be Used Effectively in Patients With Hepatitis B Despite the High

Risk of Drug Resistance?

Yuen MF, Fong DYT, Wong DK, Yuen JCH, Fung J, Lai CL. Hepatitis B virus DNA

levels at week 4 of lamivudine treatment predict the 5-year ideal response.

Hepatology. 2007;46:1695-1703.

Summary: In this study, 74 hepatitis B e antigen (HBeAg)-positive chronic

hepatitis B patients received daily lamivudine with at least 5 years of

follow-up. Serum HBV DNA was measured by branched DNA assay (lower limit of

detection, 2000 copies/mL [400 IU/mL]) 13 times: at baseline, weeks 2, 4, 8, 12,

16, 24, and 32 and then at year 1, 2, 3, 4 and 5. Lamivudine resistance was

evaluated at baseline, weeks 4, 16, and 24, and then yearly. Ideal treatment

response (IR) at year 5 was defined as HBV DNA below the limit of detection,

with HBeAg seroconversion, normalization of serum alanine aminotransferase

(ALT), and the lack of YMDD mutations. At 5 years, 20 patients (27%) had HBV DNA

levels below detection; 46 (62.2%) had lamivudine resistance, and 17 patients

achieved an IR. The presence of precore or core promoter mutations and elevated

serum ALT were statistically more common in patients who achieved an IR.

Baseline HBV DNA level was not predictive of IR. Viral load at week 4 was able

to accurately predict IR, with 100% of patients with HBV DNA < 4.0 log10

copies/mL achieving an IR, although the 16-week viral load was the most accurate

time point throughout the first year. Patients with HBV DNA ™ 4.0 log10

copies/mL at week 4 had an 83.8% chance of treatment failure. This increased to

an 87.7% chance of treatment failure if the HBV DNA was ™ 3.6 log10 copies/mL or

greater at week 16. No drug resistance was detected at either of these time

points.

Comment: The introduction of the nucleoside analog lamivudine revolutionized

hepatitis B therapy. The use of this agent was found to decrease the risk of

disease progression and liver cancer in patients with HBV infection.[5,6]

However, over time it was recognized that the development of drug-resistant

mutations was greater than 70% after 5 years of therapy,[7] and that mutations

negated the beneficial effects of treatment.[5] Because hepatitis B therapy is

frequently prolonged, current treatment guidelines do not recommend lamivudine

as a first-line agent for treatment in nucleo(t)side-naive chronic active

hepatitis B.[8] Despite this, lamivudine remains a commonly prescribed

medication for the treatment of HBV infection. Its low cost and long clinical

record guarantee that it will remain in the real-life treatment algorithm

despite published treatment guidelines and availability of several superior

compounds. As emphasized by this article, even lamivudine can be used

effectively with close monitoring. Although any viral reduction is encouraging,

in this study, the absolute reduction in HBV DNA to undetectable as measured by

the assay employed was the most accurate predictor of response. These findings

suggest that lamivudine may be an effective long-term anti-HBV therapy if the

virus is adequately suppressed after 4 weeks. These data also suggest that

therapeutic modification can be safely made up to 16 weeks into the treatment

course, as the risk for drug mutations at this time point is minimal. Each

anti-HBV agent is unique; thus, this 4-week rule should not be used to guide

therapeutic response for agents other than lamivudine.

Abstract:

http://www.medscape.com/medline/abstract/18027877

What Is the Long-term Efficacy and Safety of Entecavir in HBeAg-positive

Patients Treated for Up to 96 Weeks?

Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to 96 weeks in

patients with HBeAg-positive chronic hepatitis B. Gastroenterology.

2007;133:1437-1444.

Summary: This study involved 709 HBeAg-positive nucleoside-naive patients with

chronic hepatitis B who received either 0.5 mg entecavir (n=354) or 100 mg

lamivudine (n=355) once daily for 52 weeks. At this juncture, patients either

continued blinded treatment, stopped if adequate response was achieved

( " responders, " defined as HBV DNA < 0.7 MEq/mL [~700,000 copies/mL] and loss of

HBeAg), or stopped if there was inadequate treatment response ( " nonresponders, "

defined as HBV DNA ™ 0.7 MEq/mL). Patients who achieved virologic response (HBV

DNA < 0.7 MEq/mL) but did not lose HBeAg continued therapy up to 96 weeks. Among

the 243 entecavir-treated patients and 164 lamivudine-treated patients

continuing into year 2, 75% and 52%, respectively, received 96 weeks of

treatment. Patients in year 2 dropped out if they met the protocol-defined

endpoints of " responders " or " nonresponders. " HBV DNA was quantified by

polymerase chain reaction assay, with a lower limit of detection of 300

copies/mL. At week 48, 64% of entecavir-treated and 40% of lamivudine-treated

patients had undetectable HBV DNA; this percentage increased to 74% for

entecavir-treated patients by the end of dosing during the second year (vs 37%

for lamivudine-treated patients). In both groups, most patients normalized serum

ALT, and HBeAg loss and seroconversion were comparable. Both agents were found

to be very well tolerated and safe. Thirteen entecavir-treated patients had

virologic breakthrough during the 2 years. No patients demonstrated

entecavir-resistance mutations; however, 1 had lamivudine resistance

substitutions. Among all those patients with measurable HBV DNA, 3 additional

patients were found who had lamivudine resistance at baseline and 1 had emerging

lamivudine and entecavir substitutions at week 84.

Comment: Several studies have demonstrated improved hepatic histology as well as

decreased risk of disease progression with effective virologic

suppression.[5,6,9] Thus, current goals for hepatitis B therapy are evolving to

include complete suppression of HBV replication. Although some patients may

achieve this endpoint with a finite course of therapy, for several subsets of

chronically infected hepatitis B patients, prolonged duration of medications

will be necessary to maintain long-term virologic suppression. Adequate viral

response with minimal risk of drug resistance is integral to effective control,

especially as drug resistance mutations may confer resistance to the entire

class of medications. This study establishes entecavir as an excellent long-term

drug choice for the nucleoside-naive HBeAg-positive patient. Response rates

(HBeAg loss and HBV DNA suppression) for entecavir continue to improve with

extended treatment and minimal risk for drug resistance.

Abstract:

http://www.medscape.com/medline/abstract/17983800

How Well Does Combination Nucleoside and Nucleotide Therapy Work Once Lamivudine

Resistance Has Occurred?

Lampertico P, Vigano M, Manenti E, Iavarone M, Sablon E, Colombo M. Low

resistance to adefovir combined with lamivudine: a 3-year study of 145

lamivudine-resistant hepatitis B patients. Gastroenterology. 2007;133:1445-1451.

Summary: One hundred forty-five chronic hepatitis B patients with documented

lamivudine resistance had adefovir added to their treatment regimen and were

monitored for a median of 42 months. Overall, 80% of patients became HBV DNA

negative by year 3; 20% remained viremic despite combination therapy. No patient

experienced virologic breakthrough (defined as> 1 log10 increase in serum HBV

DNA over on-treatment nadir). Adefovir-associated mutations include rt181T/V and

rtN236T. Six patients (4%) had detectable pretreatment adefovir resistance

mutations, 5 of whom ultimately cleared DNA. Three patients developed an rtA181T

mutation, 2 of whom cleared virus. No patient developed the signature adefovir

mutations rtA181V or rtN236T. Lamivudine resistance was persistently found in

94% of patients who were viremic during combination adefovir-lamivudine therapy.

Patients with persistent viremia were more likely to have HBeAg, genotype nonD,

and> 8 log10 copies/mL HBV DNA at baseline. No patient progressed to cirrhosis.

No cirrhotic patient without HCC developed clinical decompensation. However, 12%

of patients with pre-existing cirrhosis did acquire HCC.

Comment: Routine management of HBV infection is already challenging. Thus, the

added dimension of drug resistance is far from straightforward. It has been

recognized that serial monotherapy allows rapid emergence of additional

resistance mutations and is thus not recommended.[8,10,11] This is the first

study to report long-term data on the safety and efficacy of combination

adefovir-lamivudine therapy in patients with lamivudine resistance. The

significant viral suppression and low risk of emergence of signature drug

resistance mutations are both encouraging and reassuring for this strategy.

However, a small subset of patients continued to have incomplete viral

suppression. Experience with adefovir monotherapy in HBeAg-negative

treatment-naive hepatitis B patients demonstrates delayed emergence of drug

resistance. It is likely that this patient subset will also be at long-term risk

for drug resistance if viremia persists and there is no change in clinical

management. Finally, despite viral suppression, cirrhotic patients remained at

risk to develop HCC, emphasizing the continued importance of cancer screening in

this population.

Abstract:

http://www.medscape.com/medline/abstract/17983801

Conclusion

Hepatitis B therapy continues to evolve with both the availability of new agents

and improved insight into natural history. These studies reinforce that all

agents for HBV infection are potentially effective therapy, but patient and

viral response must be monitored closely. Long-term data support excellent

efficacy, safety, and low risk for drug resistance for entecavir in

HBeAg-positive nucleoside-naive patients and for combination adefovir-lamivudine

therapy in lamivudine-resistant patients.

This activity is supported by an independent educational grant from Gilead.

http://www.medscape.com/viewarticle/570498?src=mp

_________________________________________________________________

Connect and share in new ways with Windows Live.

http://www.windowslive.com/share.html?ocid=TXT_TAGHM_Wave2_sharelife_012008