Epivir-HBV significantly delayed liver complications due to chronic hepatitis

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New study shows continuous use of GlaxoSmithKline's Epivir-HBV significantly delayed liver complications due to chronic hepatitis B Research Presented at AASLD Finds Long-Term Lamivudine Treatment Slows Disease Progression Boston, MA, October 28, 2003 - GlaxoSmithKline today announced the results of a new study that showed long-term treatment with Epivir-HBV (lamivudine) delayed clinical progression in chronic hepatitis B patients with advanced fibrosis or cirrhosis by significantly reducing the rate of liver complications including the development of liver cancer. The results of this 651 patient, double-blind, placebo-controlled clinical trial in the Asia Pacific region were presented today at the 54th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, MA.

An independent data and safety monitoring board (DSMB) responsible for monitoring study progress at pre-defined intervals recommended early termination of the study after approximately three years due to a significant decrease in the number of disease progression endpoints in patients receiving lamivudine when compared with patients receiving placebo.

This multinational study evaluated the effects of lamivudine (Epivir-HBV) on time-to-disease progression in advanced chronic hepatitis B. Professor Y.F. Liaw of Chang Gung Memorial Hospital and University, Taipei, Taiwan, was the principal investigator of the study and presented the results.

"Cirrhosis due to chronic hepatitis B is a common cause of liver failure, liver cancer, and a major cause of mortality in the Asia-Pacific region. One in 10 Asian Americans are also infected with hepatitis B," said Dr. Liaw. "It is well established that lamivudine markedly suppresses viral replication and confers histological improvement and improved liver function in patients with chronic hepatitis B. However, until this large controlled study, the impact of this treatment on clinical disease progression in patients with advanced disease had been unclear."

Epivir-HBV is approved in the US for the treatment of chronic hepatitis B associated with viral replication and active liver inflammation. The recommended oral dose of Epivir-HBV for treatment of chronic hepatitis B in adults is 100 mg once daily. The safety and effectiveness of treatment beyond one year and long-term treatment benefits have not been established. The optimal duration of treatment is not known. Epivir- HBV is not a cure for hepatitis B and has not been shown to reduce the risk of transmission of HBV to others.

Methodology Patients with histologically confirmed, compensated HBV related cirrhosis or advanced fibrosis were randomly assigned to either lamivudine or placebo, for up to five years. There were twice as many patients in the lamivudine group as in the placebo group.

The study was designed to allow patients to withdraw from the study to receive alternative treatment if they had evidence of disease progression endpoints which included a ³2 points increase in Child-Pugh score (a grading scale designed to measure the extent of liver disease), the development of hepatocellular carcinoma (HCC), or the development of other defined clinical events associated with liver failure. The DSMB monitored study progress at interim analyses using prospectively defined stopping criteria. Following the second interim analysis, the DSMB recommended that the study be prematurely stopped and everyone be offered lamivudine (open label) because the patients receiving lamividine showed significantly less disease progression than those on placebo.

In total, 651 patients were randomized at 41 sites in nine Asia-Pacific countries. Eighty-five percent (85%) were male, 98 % were Asian, and the mean age was 44.3 years. Median treatment exposure was 32.4 (range 0.0-42.1) months.

Results

Only 8% of lamivudine-treated patients reached disease progression endpoints compared with 18 % of patients receiving placebo.

Among the individual disease endpoints, 3% of the lamivudine group saw an increase in the Child-Pugh score, compared with 9% of those patients on placebo.

HCC occurred in 4% of lamivudine treated patients and in 7% of placebo recipients

Treatment with lamivudine was generally well tolerated. Overall, adverse events were reported among 77 % of patients who received lamivudine and 83 % of those who received placebo. The three most frequent adverse events in the study were ear, nose and throat infections (22% on lamividine and 20% on placebo), abdominal discomfort and pain (18% and 20%, respectively) and malaise and fatigue (15% and 20% respectively). Events meeting the criteria that defined them as serious adverse events occurred in 12% of patients assigned to lamivudine and 18 % in the placebo group. Elevations in serum ALT (an enzyme that is elevated if there is inflammation in the liver) occurred about twice as often the frequency among patients receiving placebo as among those receiving lamivudine.

"These results are clinically very important and could signal hope for many patients," stated Dr. Liaw. "They show that lamivudine is not only an effective treatment for chronic hepatitis B, but that it can also delay development of serious life-threatening complications associated with disease progression. These results underscore the importance of lamivudine in delaying the progression of this serious disease."

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases have been reported with the use of nucleoside analogues alone or in combination, including lamividine and other retrovirals.

Human immunodeficiency virus (HIV) counseling and testing should be offered to all patients before beginning EPIVIR-HBV and periodically during treatment, because Epivir-HBV Tablets and Oral Solution contain a lower dose of the same active ingredient (lamividine) as Epivir Tablets and Oral Solution used to treat HIV infection. If treatment with Epivir-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely because of subtherapeutic dose and inappropriate monotherapy.

Patients taking Epivir-HBV should be monitored by a physician. Deterioration of liver disease has been reported in some patients when treatment with Epivir-HBV was discontinued. Emergence of resistance hepatitis B virus and worsening of disease can occur during treatment.

To read the complete Prescribing Information for Epivir HBV, please visit our Web site at www.gsk.com or contact GlaxoSmithKline at (888) 825-5249.

Facts About Hepatitis B The virus is transmitted through direct contact with blood and other bodily fluids. The hepatitis B virus (HBV) targets the liver and can eventually lead to cirrhosis of the liver (also known as scarring), liver failure, liver cancer and death. While uncommon in the general United States population (only 0.3% of the general population has chronic HBV and liver cancer does not rank among the ten most common cancers), the statistics for the Asian/Pacific Islander (API) community are vastly different. One in ten APIs in the US are infected with hepatitis B, one in four of whom, if left untreated and unmonitored, will die from liver cancer, failure, and/or cirrhosis of the liver, according to the Centers for Disease Control (CDC) and Asian Am Pac Isl J Health, 2001;9:141-152.

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Updated October 28, 2003 ?2001-2004 GlaxoSmithKline - All Rights Reserved