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Improvement in Liver Histology Demonstrated in Phase III Emtricitabine Trial
Study FTCB-301 is a 48-week, double-blind, placebo-controlled clinical trial conducted at 34 sites in seven countries in North America, Europe and Asia. The trial was designed to compare the efficacy and safety of emtricitabine 200 mg once daily versus placebo in 248 patients with chronic hepatitis B who had not previously received therapy with a nucleoside analogue. Patients were randomized (2:1) to receive emtricitabine 200 mg once daily or placebo for 48 weeks. Prior to study entry, all patients were hepatitis B surface ("s") antigen positive for at least six months. Both hepatitis B "e" antigen negative and hepatitis B "e" antigen positive patients were enrolled in the study. At study entry, patients were required to have elevated levels of the liver enzyme alanine aminotransferase (ALT) and detectable serum levels of HBV DNA.
After 48 weeks, 62 percent of patients treated with emtricitabine 200 mg once daily exhibited significant improvements in liver histology, compared with 25 percent of patients receiving placebo (p Study FTCB-301 also examined changes after 48 weeks in HBV DNA (Digene Hybrid Capture II Assay), ALT levels, genotype mutations and serology. At baseline, emtricitabine and placebo patients had, respectively, median HBV DNA levels of 7.67 log10 copies/mL and 7.42 log10 copies/mL and median ALT of 81 IU/L and 92 IU/L. Treatment with emtricitabine resulted in a median reduction in HBV DNA from baseline of 3.00 log10 copies/mL compared with a median reduction in the placebo group of 0.44 log10 copies/mL (p Through 48 weeks, the discontinuation rate was similar between the treatment and placebo arms, with five percent of patients receiving emtricitabine and seven percent receiving placebo discontinuing from study. The most common adverse events were influenza, upper respiratory infection, headache, fatigue, abdominal pain, post-procedural pain (associated with liver biopsy) and cough. Additionally, there were no significant differences in the incidence of adverse events and grade 3 and 4 laboratory abnormalities between either arm of the study, with the exception of elevated ALT levels, which occurred more frequently in the placebo group.
Emtricitabine is a nucleoside analogue reverse transcriptase inhibitor. It works by blocking reverse transcriptase, an enzyme involved in the replication of HBV in the body. In addition to studies in patients with chronic hepatitis B, emtricitabine has been studied in patients with HIV. Approved in 2003, emtricitabine is marketed as Emtriva™ for use in combination with other antiretrovirals for the treatment of HIV infection in the United States and Europe.
In HIV clinical studies, more than 2000 HIV-infected adults have been treated with Emtriva for periods of 10 days to 200 weeks in Phase I, II and III clinical trials. Assessment of adverse events (without regard to relationship to study drug) is based on pooled data from two Phase III studies in which 571 treatment-naïve and 440 treatment-experienced patients received Emtriva (n=580) or a comparator drug (n=431) for 48 weeks. The most common adverse events that occurred in patients receiving Emtriva were headache, diarrhea, nausea and rash, which were generally of mild to moderate severity. Approximately one percent of patients discontinued participation in the clinical studies due to these events. All adverse events were reported with similar frequency in Emtriva and control treatment groups with the exception of skin discoloration, which was reported with higher frequency in the Emtriva treated group. Skin discoloration, manifested by hyperpigmentation (excess pigmentation) on the palms and/or soles, was generally mild and asymptomatic. The mechanism and clinical significance of this adverse event are unknown. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals.
Chronic Hepatitis B
Hepatitis B is a serious disease that attacks the liver and can cause chronic (lifelong) infection, cirrhosis of the liver, liver cancer and death in up to a third of patients. Worldwide, there are approximately 400 million people with chronic hepatitis B, of which approximately one million people will die this year from complications from the disease, making chronic hepatitis B one of the 10 most common causes of death. Gilead currently markets Hepsera® (adefovir dipivoxil 10 mg) for the treatment of chronic HBV infection in both the United States and Europe. In April 2002, Gilead signed a licensing agreement with GlaxoSmithKline (GSK), granting GSK rights to commercialize Hepsera in Asia, Latin America and other territories.
Source: Gilead Sciences, Inc.