Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: A two-year study

doi:10.1016/j.jhep.2005.02.017

Journal of Hepatology

Volume 43, Issue 1, July 2005, Pages 60-66

This manuscript is dedicated to Dr Steven Sacks for his significant contributions to this trial and the treatment of hepatitis B

https://doi.org/10.1016/j.jhep.2005.02.017 Get rights and content

Background/Aims

The aim of this study was to evaluate long term safety and antiviral activity of different doses of emtricitabine given once daily to patients chronically infected with hepatitis B.

Methods

Eligible patients were randomized in a double-blind, parallel study to evaluate 25, 100 or 200 mg once daily doses of emtricitabine for 48 weeks. Patients were then followed for an additional 48 weeks on open-label 200 mg emtricitabine. Serum HBV DNA, ALT, and hepatitis B serology were measured at regular intervals over the 2 years. Resistance surveillance was performed after 1 and 2 years on viremic samples, i.e. >4700 copies/mL.

Results

Emtricitabine was well tolerated and produced a dose proportional antiviral response. After 2 years, 53% of the patients had serum HBV DNA ≤4700 copies/mL, 33% seroconverted to anti-HBe and 85% had normal ALT. Eighteen percent of the patients who had received 200 mg emtricitabine for 2 years developed resistance mutations.

Conclusions

Emtricitabine was well tolerated and demonstrated a potent antiviral response for up to 2 years in patients with chronic hepatitis B infection. Based on these data, 200 mg emtricitabine once daily was chosen as the optimal dose for future hepatitis B studies.

Introduction

Infection with hepatitis B virus (HBV) is a major health problem with about 400 million people chronically infected in the world. It is estimated that 1–2 million persons will die every year from HBV-related liver diseases (e.g. primary from hepatocellular carcinoma or cirrhosis of the liver) making chronic HBV one of the top 10 causes of death worldwide [1], [2], [3], [4], [5]. With the use of antiviral therapy, delay in disease progression is achieved by suppression of viral replication. Currently available treatments for chronic HBV infection are responsible for significant improvement in patient outcomes; however they can be frequently associated with side-effects, suboptimal response and selection of antiviral resistant strains leading to clinical failure [6], [7], [8], [9], [10], [11], [12], [13].

Emtricitabine (5-Fluoro-1-[(2R,5S)-2-(hydroxymethyl)-[1,3]oxathiolan-5-yl]cytosine, FTC) is a pyrimidine analogue, which has been shown to be a potent and selective inhibitor of Human Immunodeficiency Virus (HIV-1) and HBV. Specifically, emtricitabine inhibits HBV DNA polymerase and HIV-1 reverse transcriptase (RT) both in vivo and in vitro [14], [15], [16], [17].

Emtricitabine is anabolized to its triphosphate form which is the active moiety that inhibits the polymerase. The anti-HBV activity of emtricitabine has been demonstrated in the woodchuck hepatitis model as well as in a short term (56 days) dose ranging study in man [18], [19]. In the initial human trial, emtricitabine was well-tolerated and showed significant antiviral activity at all doses tested.

To confirm the dose of emtricitabine for HBV infection, three doses of emtricitabine (25 mg QD, 100 mg QD and 200 mg QD) were compared in this prospective randomized double-blind clinical trial for 1 year. Patients were then treated with open-label 200 mg emtricitabine for an additional year at the end of the randomized phase.

Section snippets

Patients

The study was conducted at six sites in North America and one site in Hong Kong. All sites obtained protocol approval from their institutional review board or ethics committees, and an informed consent was obtained for each patient prior to enrollment into the study. Eligible patients included HBeAg negative or positive men and women 18–70 years of age, chronically infected with HBV (HBsAg positive for more than 6 months), with detectable serum HBV DNA levels (>3.0 MEq/mL by Chiron HBV

Baseline characteristics

The three dose groups were similar with regard to demographics and baseline characteristics (Table 1). Patients participating in this study who were nucleoside experienced were patients who had participated in Study FTCB-101 (2 months of emtricitabine monotherapy) [18].

Patient disposition

Patient disposition is outlined in Table 2. Of the 98 patients enrolled in the study, 92 patients completed 48 weeks of randomized double-blind treatment. Four patients discontinued study prior to week 48 (three due to adverse

Discussion

Emtricitabine was well-tolerated and produced a potent antiviral effect at all three doses studied. Virologic results were consistent with the findings from the early 56 day dose ranging study where pharmacodynamic modeling showed that 94% of the maximal activity was reached with the 200 mg once-daily dose [18]. A dose response relationship was observed in the present study for virologic and genotypic endpoints, but no difference was observed for serologic (seroconversion to anti-HBe) or

Acknowledgements

Michael W. Fried is supported in part by Grant RR00046.

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^☆: The authors who have taken part in this study have declared a relationship with the manufacturers of the drugs involved.

View full text

Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: A two-year study☆

Background/Aims

Methods

Results

Conclusions

Introduction

Section snippets

Patients

Baseline characteristics

Patient disposition

Discussion

Acknowledgements

Gastroenterology

Lancet

Hepatology

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Hepatitis B virus infection

N Engl J Med

Management of chronic hepatitis B

J Hepatol

Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial

Gut

Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis

Ann Intern Med

Lamivudine as initial treatment for chronic hepatitis B in the United States

N Engl J Med

Quantitation of hepatitis B viremia and emergence of YMDD variants in patients with chronic hepatitis B treated with lamivudine

J Infect Dis

A one-year trial of lamivudine for chronic hepatitis B

N Engl J Med

Extended lamivudine retreatment for chronic hepatitis B: maintenance of viral suppression after discontinuation of therapy

Hepatology