Study Comparing Tenofovir Disoproxil Fumarate (TDF), Emtricitabine (FTC)/TDF, and Entecavir (ETV) in the Treatment of Chronic HBV in Subjects With Decompensated Liver Disease.

A Phase 2, Double-Blind, Multi-center, Randomized Study Comparing Tenofovir Disoproxil Fumarate, Emtricitabine Plus Tenofovir Disoproxil Fumarate, and Entecavir in the Treatment of Chronic Hepatitis B Subjects With Decompensated Liver Disease and in the Prevention of Hepatitis B Recurrence Post-Transplantation

This study was designed to evaluate and compare the safety and tolerability of tenofovir disoproxil fumarate (TDF), emtricitabine (FTC)/TDF, and entecavir (ETV) in the treatment of hepatitis B patients with decompensated liver disease. Safety was assessed by evaluating adverse events (AEs) and laboratory abnormalities. Efficacy was assessed by evaluating reductions in Child-Pugh-Turcotte (CPT) and Model for End Stage Liver Disease (MELD) scores, reductions in hepatitis B virus (HBV) deoxyribonucleic acid (DNA), changes in liver enzymes, development of drug-resistant mutations, and generation of antibody to virus.

A maximum randomized treatment duration of 168 weeks was planned. Since subjects with decompensated liver disease were enrolled into this study, it was necessary to provide early intervention strategies if profound viral suppression was not expeditiously achieved. For this reason, subjects with a decrease in plasma HBV DNA from baseline of < 2 log_10 copies/mL and plasma HBV DNA > 10,000 copies/mL (or plasma HBV DNA > 1,000 copies/mL for subjects who entered the study with HBV DNA < 10,000 copies/mL) at Week 8 had the option to start open-label FTC/TDF and continue in the study. Subjects with a virologic breakthrough or who had plasma HBV DNA levels remaining > 400 copies/mL (confirmed) at or after 24 weeks of treatment could have been unblinded at the investigator's discretion for selection of alternative anti-HBV therapy that may have included open-label FTC/TDF. If study drug was permanently discontinued, immediate initiation of another anti-HBV regimen was strongly recommended.

Inclusion Criteria:

A participant was required to meet all of the following inclusion criteria to be eligible for participation in the study:

• Chronic Hepatitis B infection

• 18 through 69 years of age, inclusive

• HBV DNA ≥ 1000 copies/mL

• Decompensated liver disease with all of the following:

  • CPT score of 7-12 (inclusive) OR history of CPT score ≥ 7 and any CPT at screen ≤ 12
  • Serum alanine aminotransferase (ALT) < 10 x the upper limit of the normal range (ULN)
  • Hemoglobin ≥ 7.5 g/dL
  • Total white blood cell (WBC) count ≥ 1,500/mm^3
  • Platelet count ≥ 30,000/mm^3

• Alpha-fetoprotein ≤ 20 ng/mL and ultrasound or other imaging with no evidence of hepatocellular carcinoma (HCC), or alpha-fetoprotein of 21-50 ng/mL and computed tomography (CT)/magnetic resonance imaging (MRI) scan with no evidence of HCC, within 6 months of screening

• Calculated creatinine clearance ≥ 50 mL/min

• Negative human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis D virus (HDV) serologies

• Less than 24 months of total prior adefovir dipivoxil exposure

• Willing and able to provide written informed consent

Exclusion Criteria:

A participant who met any of the following exclusion criteria could not be enrolled in the study:

• Pregnant women, women who were breastfeeding or who believed they may have wished to become pregnant during the course of the study
• Males and females of reproductive potential who were unwilling to use an effective method of contraception during the study
• Prior use of TDF or ETV
• History of variceal bleeding, hepatorenal syndrome, Grade 3 or 4 hepatic encephalopathy, or spontaneous bacterial peritonitis within 60 days of screening
• Grade 2 hepatic encephalopathy at screening
• History of solid organ or bone marrow transplant
• Current use of hepatotoxic drugs, nephrotoxic drugs, or drugs that interfere with renal tubular secretion
• Current therapy with immunomodulators (eg, corticosteroids, interleukin-2, etc.) or investigational drugs
• Diagnosis of proximal tubulopathy
• Use of investigational agent within 30 days prior to screening
• Known hypersensitivity to TDF, FTC, ETV, or formulation excipients of any of the study drug products