HepatitisBHelp.com is an informative resource for healthcare professionals. It provides information about EPIVIR-HBV, a nucleoside analogue that terminates DNA replication of hepatitis B virus (HBV). EPIVIR-HBV is indicated for the treatment of compensated chronic hepatitis B (CHB) associated with evidence of viral replication and active liver inflammation in adults and children 2 to 17 years of age. This indication is based on 1-year histologic and serologic responses in adult patients, as well as more limited data from a study in pediatric patients. It is the only oral treatment available for children with chronic hepatitis B. This site includes information about the efficacy, safety profile, and dosing recommendations of EPIVIR-HBV.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals.

Human immunodeficiency virus (HIV) counseling and testing should be offered to all patients before beginning EPIVIR-HBV and periodically during treatment, because EPIVIR-HBV Tablets and Oral solution contain a lower dose of the same active ingredient (lamivudine) as EPIVIR^® Tablets and Oral Solution used to treat HIV infection. If treatment with EPIVIR-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely because of subtherapeutic dose and inappropriate monotherapy.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

In 3 Placebo-Controlled Trials in Adult Patients With Compensated Chronic Hepatitis B (CHB), EPIVIR-HBV Significantly Reduces Viral Load

EPIVIR-HBV provided sustained HBV DNA reduction* in significantly more patients than placebo for 52 weeks of therapy (44% to 57% for EPIVIR-HBV versus 3% to 17% for placebo).11

The majority of patients treated with EPIVIR-HBV showed a decrease in HBV DNA to below the assay limit early in the course of therapy. Reappearance of assay detectable HBV DNA during treatment with EPIVIR-HBV was observed in approximately one-third of patients after initial HBV DNA response.

* Defined as at least 2 consecutive nondetectable HBV DNA values (at least 7 days apart) and maintained through end of the evaluation period with no 2 consecutive detectable HBV DNA results; and the last-visit HBV DNA value was required to be nondetectable.11

† Patients with baseline HBV DNA below the assay detection limit (solution hybridization assay) have been excluded. Missing data have been included as a failure.

‡ Not all studies collected data at all time points.

• In 4 controlled trials, YMDD-variant HBV were detected by a research assay in 16% to 32% of adult patients after 52 weeks of therapy with EPIVIR-HBV. In the pediatric trial, 1-year occurrence was 19%.
• YMDD variants are associated with diminished treatment response at 52 weeks relative to patients treated with EPIVIR-HBV without evidence of YMDD variants.
• The long-term clinical significance of YMDD-variant HBV is not known.

EPIVIR-HBV Normalizes ALT Levels in Adult Patients With Compensated CHB

EPIVIR-HBV normalized ALT* in significantly more patients than placebo for 52 weeks of therapy (41% to 72% for EPIVIR-HBV versus 7% to 24% for placebo).11

*Defined as ALT measurements ≤1.0 x the upper limit of the normal range (ULN) for at least 2 consecutive visits (at least 7 days apart), with no 2 subsequent consecutive ALT measurements (at least 7 days apart) >1.0 x ULN, through end of the evaluation period; additionally, the last ALT value was required to be <1.0 x ULN. 11

†Not all studies collected data at all time points.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti–hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti–hepatitis B therapy.

EPIVIR-HBV Significantly Reduces Liver Inflammation and Necrosis

In adult patients with compensated CHB, treatment with EPIVIR-HBV significantly reduced hepatic necro-inflammatory activity in up to 56% of patients versus up to 26% of placebo-treated patients.

*Defined as a ≥2-point reduction in the Knodell Histologic Activity Index
(HAI)18 at week 52 compared with pretreatment HAI. Patients with missing data at baseline were excluded.

The relationship between treatment response and long-term outcomes, such as hepatocellular carcinoma or decompensated cirrhosis, is not known. Safety and effectiveness of treatment beyond 1 year have not been established, and the optimal duration of treatment is not known.

In Adults With Compensated CHB, EPIVIR-HBV Increases HBeAg Seroconversion

Defined as a 3-component endpoint

• HBV DNA below assay limit*
• HBeAg loss
• HBeAb gain

Improved liver histology is not contingent on HBeAg seroconversion.15,16

*Solution hybridization assay.

The durability of HBeAg seroconversion occurring during treatment is not known.

Patients should be advised that treatment with EPIVIR-HBV has not been shown to reduce the risk of transmission of HBV to others.

In Children 2 to 17 Years of Age With Compensated CHB, EPIVIR-HBV Significantly Improves Virologic Response11,17*

Virologic response is defined as:

• Loss of HBeAg
• HBV DNA below assay limit

EPIVIR-HBV was significantly more effective than placebo in inducing virologic response in children after 1 year of therapy.

*In this placebo-controlled trial, adolescents (13 to 17 years of age) showed less treatment effect than younger children.17

In Children 2 to 17 Years of Age With Compensated CHB, EPIVIR-HBV Normalizes ALT Levels11,17*

†Defined as at least 2 consecutive ALT≤ULN and maintained to week 52 (from > ULN at baseline).

Normalization of serum ALT was achieved and maintained to week 52 more frequently in patients treated with EPIVIR-HBV compared with placebo.

*In this placebo-controlled trial, adolescents (13 to 17 years of age) showed less treatment effect than younger children.17

Important Safety Information

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals.
• Human immunodeficiency virus (HIV) counseling and testing should be offered to all patients before beginning EPIVIR-HBV and periodically during treatment, because EPIVIR-HBV Tablets and Oral Solution contain a lower dose of the same active ingredient (lamivudine) as EPIVIR® Tablets and Oral Solution used to treat HIV infection. If treatment with EPIVIR-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely because of subtherapeutic dose and inappropriate monotherapy.
• Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
• Pancreatitis has been reported, particularly in HIV-infected pediatric patients with prior nucleoside exposure.
• The safety profile of EPIVIR-HBV in children was similar to that seen in adults. In addition, respiratory symptoms (cough, bronchitis, and viral respiratory infections) were reported in both lamivudine and placebo recipients.
• Safety and efficacy of EPIVIR-HBV have been established only in patients with compensated chronic hepatitis B. Safety and efficacy in other populations have not been established.

Adverse Events (≥5% Frequency) in 3 Controlled Clinical Trials in Adults*

Patient Monitoring

Patients should be monitored regularly during treatment by a physician experienced in the management of chronic hepatitis B.

Return of persistently elevated ALT, increasing levels of HBV DNA over time, progression of clinical signs or symptoms of hepatic disease and/or worsening of hepatic necroinflammatory findings may reflect loss of response and should be considered when determining the advisability of continuing therapy with EPIVIR-HBV.

Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Optimal duration of treatment is not known.

Medication Cost Can Be an Important Concern for Patients on Therapy for a Chronic Disease

Price Comparison of Selected Treatments for Chronic Hepatitis B*

PRODUCT		HOW SUPPLIED		DOSAGE FOR ADULTS		PRICE/DOSE AWP†		PRICE/COURSE OF THERAPY
EPIVIR-HBV® (lamivudine) Tablets	60 100-mg tablets/bottle	1 tablet q.d.	$9.51	$3,471.15 (52 weeks) The optimal duration of treatment is unknown.
HEPSERA®‡ (adefovir dipivoxil) Tablets§	30 10-mg tablets/bottle	1 tablet q.d.≥	$23.89	$8,720.45 (52 weeks) The optimal duration of treatment is unknown.
BARACLUDETM|| (entecavir) Tablets¶	30 1-mg tablets/bottle 30 .5-mg tablets/bottle	1 tablet q.d.≤	$26.68	$8,964.48 (48 weeks) The optimal duration of treatment is unknown.
Pegasys®** (peginterferon alfa-2a)††	1-mL single dose vial	1 injection / week**	$468.68	$23,846.40 (48 weeks)
TyzekaTM(telbivudine) Tablets#	30-600mg tablets/bottle	1 tablet q.d.***	$20.29	$7,405.85 (52 weeks) The optimal duration of treatment is unknown.

*This price comparison is not intended to represent the comparative efficacy and safety of the listed products. Average wholesale price (AWP) is a price calculated and reported by Facts and Comparisons, First DataBank, Inc. and other third-party data vendors. AWP does not represent a price at which GlaxoSmithKline sells this product and does not necessarily reflect actual prices paid in the marketplace. The prices shown reflect only the cost of drug products and do not capture other costs that may be associated with a course of therapy.
†Average wholesale price (AWP) from Wolters Kluwer Health, Inc. Prices as of April 2007.
‡Hepsera is a registered trademark of Gilead Sciences Inc.
§Hepsera Tablets are indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
||Baraclude is a registered trademark of Bristol-Myers Squibb Company.
¶Baraclude is indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
**Pegasys is a registered trademark of Roche Laboratories Inc.
††Pegasys is indicated for the treatment of adult patients with HBeAg positive and HBeAg negative chronic hepatitis B who have compensated live disease and evidence or viral replication and liver inflammation.
#Tyzeka™ is registered trademark of Idenix Pharmaceuticals Inc. Tyzeka is indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
≥Hepsera [package insert]. Foster City, Calif: Gilead Sciences, Inc; 2006.
≤Baraclude [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
**Pegasys [package insert]. Nutley, NJ: Roche Laboratories Inc; 2005.
***Tyzeka [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2006.

Important Safety Information

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals.

Human immunodeficiency virus (HIV) counseling and testing should be offered to all patients before beginning EPIVIR-HBV and periodically during treatment, because EPIVIR-HBV Tablets contain a lower dose of the same active ingredient (lamivudine) as EPIVIR® Tablets and Oral Solution used to treat HIV infection. If treatment with EPIVIR-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely because of subtherapeutic dose and inappropriate monotherapy.

If a decision is made to administer lamivudine in dually infected patients, the higher dosage indicated for HIV therapy should be used as part of an appropriate combination regimen and the prescribing information for EPIVIR as well as EPIVIR-HBV should be consulted.

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

In controlled clinical trials, the most common adverse events with EPIVIR-HBV (and placebo) were ear, nose, and throat infections 25% (21%); malaise and fatigue 24% (28%); and headache 21% (21%).

EPIVIR-HBV is available as tablets and oral solution

• Convenient once-daily oral dosing with or without food
• Available in 100-mg tablets and 5-mg/mL oral solution
• The recommended dosage of EPIVIR-HBV in adults is 100 mg/day. The recommended dosage in children 2 to 17 years of age is 3 mg/kg, up to a maximum of 100 mg once a day
• Dosage adjustment is recommended for patients with impaired renal function

Prescribe EPIVIR-HBV for Chronic Hepatitis B Because:

• Significant reduction of viral load
• Normalized ALT levels and reduced liver inflammation
• Once-daily dosing
• Increased HBeAg seroconversion
• The only oral agent approved for use in children as young as 2 years of age with chronic hepatitis B
• Cost savings over other oral treatments

EPIVIR-HBV is indicated for the treatment of compensated chronic hepatitis B associated with evidence of viral replication and active liver inflammation in adults and children ages 2 to 17 years. This indication is based on 1-year histologic and serologic responses in adult patients, as well as more limited data from a study in pediatric patients.

The relationship between treatment response and long-term outcomes, such as hepatocellular carcinoma or decompensated cirrhosis, is not known. Safety and effectiveness of treatment beyond 1 year have not been established, and the optimal duration of treatment is not known.

EPIVIR-HBV is not appropriate for patients dually infected with HBV and HIV.

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