• HBV DNA <400 copies/mL [ Time Frame: 48 weeks and then annually through 384 weeks ] [ Designated as safety issue: No ]
• Histological Improvement [ Time Frame: 48 weeks and 240 weeks ] [ Designated as safety issue: No ]
• Development of resistance mutations [ Time Frame: 48 weeks and then annually through 384 weeks ] [ Designated as safety issue: No ]
• Safety and Tolerability [ Time Frame: 48 weeks and then annually through 384 weeks ] [ Designated as safety issue: Yes ]
• ALT normalization [ Time Frame: 48 weeks and then annually through 384 weeks ] [ Designated as safety issue: No ]

• HBV DNA <400 copies/mL [ Time Frame: 48 weeks and 240 weeks ] [ Designated as safety issue: No ]
• Histological Improvement [ Time Frame: 48 weeks and 240 weeks ] [ Designated as safety issue: No ]
• Development of resistance mutations [ Time Frame: 48 weeks and 240 weeks ] [ Designated as safety issue: No ]
• Safety and Tolerability [ Time Frame: 48 weeks and 240 weeks ] [ Designated as safety issue: Yes ]
• ALT normalization [ Time Frame: 48 weeks and 240 weeks ] [ Designated as safety issue: No ]

This study is designed to evaluate the safety and antiviral activity of tenofovir disoproxil fumarate (DF) compared to Hepsera for 48 weeks for the treatment of HBeAg negative chronic hepatitis B. Patients will either receive tenofovir or the approved hepatitis B therapy, Hepsera for 48 weeks. After 48 weeks all patients will be switched to open label tenofovir.

The efficacy of tenofovir versus Hepsera will be evaluated for histologic improvement, reductions in serum hepatitis B virus (HBV) DNA, changes in liver enzymes, and the generation of antibody to the virus. Safety will be assessed by evaluating adverse events, laboratory abnormalities and the development of drug-resistant mutations. After 48 weeks all patients will receive tenofovir and the efficacy and safety of tenofovir will continue to be monitored for an additional 336 weeks.

• Drug: tenofovir disoproxil fumarate
• Drug: adefovir dipivoxil

• Experimental: Double blind tenofovir disoproxil fumarate 300 mg once daily for 48 weeks then switch to open label tenofovir disoproxil fumarate 300 mg once daily for an additional 336 weeks
• Active Comparator: Double blind adefovir dipivoxil 10 mg once daily for 48 weeks then switch to tenofovir disoproxil fumarate 300 mg once daily for an additional 336 weeks

Inclusion Criteria:

A patient must meet all of the following inclusion criteria to be eligible for participation in this study:

• Chronic HBV infection, defined as positive serum HBsAg for at least 6 months.
• 18 through 69 years of age, inclusive.

• Active HBeAg negative chronic HBV infection, with all of the following:

  • HBeAg negative and HBeAb positive at screening;
  • ALT levels > ULN and </= 10 x ULN;
  • serum HBV DNA > 100,000 copies/mL at screening;
  • creatinine clearance >/= 70 mL/min;
  • hemoglobin >/= 8 g/dL;
  • neutrophils >/= 1,000 /mL.
• Knodell necroinflammatory score >/= 3 and a Knodell fibrosis score < 4. However, up to 120 patients with cirrhosis, i.e., a Knodell fibrosis score equal to 4, will be eligible for enrollment.
• Negative serum β-HCG
• Nucleotide naïve, i.e., no prior nucleotide (tenofovir DF or adefovir dipivoxil) therapy for greater than 12 weeks.
• Nucleoside naïve, i.e., no prior nucleoside (any nucleoside) therapy for greater than 12 weeks. However, up to 120 patients with greater than 12 weeks prior lamivudine experience will be eligible.
• Willing and able to provide written informed consent.
• Had a liver biopsy performed within 6 months of baseline and has readable biopsy slides or agrees to have a biopsy performed prior to baseline

Exclusion Criteria:

• Pregnant women, women who are breast feeding, or women who believe they may wish to become pregnant during the course of the study
• Males and females of reproductive potential who are unwilling to use an "effective" method of contraception during the study.
• Decompensated liver disease defined as conjugated bilirubin > 1.5 x ULN, PT > 1.5 x ULN, platelets < 75,000/mL, serum albumin < 3.0 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy, variceal hemorrhage)
• Received any nucleoside, nucleotide (tenofovir DF or adefovir dipivoxil) or interferon (pegylated or not) therapy within 6 months prior to the pre treatment biopsy
• Evidence of hepatocellular carcinoma (HCC)
• Coinfection with hepatitis C virus (HCV), HIV, or hepatitis D virus (HDV)
• Significant renal, cardiovascular, pulmonary, or neurological disease
• Received solid organ or bone marrow transplantation
• Is currently receiving therapy with immunomodulators (e.g., corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion
• Has proximal tubulopathy