Tenofovir Disoproxil Fumarate (Tenofovir DF) Versus Emtricitabine/Tenofovir DF in Subjects Resistant to Lamivudine

A Phase 3b, Randomized, Double-Blind, Double-Dummy Study Evaluating the Antiviral Efficacy, Safety, and Tolerability of Tenofovir Disoproxil Fumarate (DF) Monotherapy Versus Emtricitabine Plus Tenofovir DF Fixed-Dose Combination Therapy in Subjects With Chronic Hepatitis B Who Are Resistant to Lamivudine

The aim of therapy for the treatment of chronic hepatitis B virus (HBV) is to maintain suppression of viral replication to prevent the emergence of complications, which requires long-term therapy. Durable suppression of viral replication is achieved in the treatment of chronic viral diseases by preventing of the emergence of drug-resistant mutations. The clinical guidelines for the management of lamivudine resistant patients are variable. Some recommend switching to another agent without cross-resistance, while others recommend adding on another agent without cross-resistance. Limited clinical data exists to demonstrate whether tenofovir disoproxil fumarate (tenofovir DF; TDF) is an effective monotherapy for lamivudine resistant patients or if it should be used as part of a combination therapy regimen.

This study is designed to evaluate the effectiveness, safety, and tolerability of tenofovir DF monotherapy versus emtricitabine (FTC)/tenofovir DF combination therapy in participants with chronic HBV with lamivudine resistance (presence of the rtM204I/V mutation with or without the rtL180M mutation) over a 240-week period. Participants in this study must be receiving lamivudine treatment at the time of enrollment.

Inclusion Criteria

• Chronic HBV infection, defined as positive serum HBsAg for at least 6 months
• 18 through 75 years of age, inclusive
• HBV DNA ≥ 10^3 IU/mL
• Receiving treatment with lamivudine with confirmation of HBV reverse transcriptase mutation(s) known to confer resistance to lamivudine (rtM204I/V with or without rtL180M) by central laboratory assessment prior to randomization; adefovir dipivoxil treatment of ≤ 48 weeks at the time of screening (inclusive of combination adefovir dipivoxil + lamivudine at entry) was allowed
• Willing and able to provide written informed consent
• Negative serum pregnancy test (for females of childbearing potential only)
• Calculated creatinine clearance ≥ 50 mL/min
• Hemoglobin ≥ 10 g/dL
• Neutrophils ≥ 1000 /mm^3
• No prior oral HBV therapy with approved nucleotide and/or nucleoside therapy or other investigational agents for HBV infection other than lamivudine or adefovir dipivoxil

Exclusion Criteria

• Pregnant women, women who are breast feeding or who believe they may wish to become pregnant during the course of the study
• Males and females of reproductive potential who are not willing to use an effective method of contraception during the study
• Alanine aminotransferase (ALT) ≥ 10 × the upper limit of the normal range (ULN)
• Decompensated liver disease
• Interferon or pegylated interferon therapy within 6 months of the screening visit
• Alpha fetoprotein > 50 ng/mL
• Evidence of hepatocellular carcinoma
• Coinfection with hepatitis C virus, HIV, or hepatitis D virus
• Significant renal, cardiovascular, pulmonary, or neurological disease
• Received solid organ or bone marrow transplantation
• Receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion
• Proximal tubulopathy
• Known hypersensitivity to the study drugs, the metabolites or formulation excipients