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

Gilead Sciences280 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

280

Conditions

Hepatitis B

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96

Time frame: Week 96

Secondary Outcomes

Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240

Time frame: Weeks 48, 144, 192, and 240

Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240

Time frame: Weeks 48, 96, 144, 192, and 240

HBV DNA Level at Weeks 48, 96, 144, 192, and 240

Time frame: Weeks 48, 96, 144, 192, and 240

Percentage of Participants With Normal ALT at Weeks 48, 96, 144, 192, and 240

Normal ALT was defined as having a value less than or equal to the ULN. The ULN was 43 U/L for males and 34 U/L for females aged 18 to \< 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.

Time frame: Weeks 48, 96, 144, 192, and 240

Percentage of Participants With HBeAg Loss at Weeks 48, 96, 144, 192, and 240

The percentage of participants who were HBeAg positive at baseline and who had HBeAg Loss at the given time point was summarized. Loss of HBeAg was defined as change of detectable HBeAg from positive to negative.