This study will evaluate the long-term safety and effectiveness of lamivudine therapy and the possibility of stopping therapy in patients whose hepatitis B is chronic, that is, long lasting, and which has responded to treatment. Chronic hepatitis B, caused by a virus, is a common form of liver disease affecting about 1 million Americans and about 5 percent of the world's population. Health effects include a continuous state of being infectious and the risk of transmitting hepatitis to other people, symptoms of liver disease, and development of cirrhosis-that is, severe damage to the liver-and liver cancer. Lamivudine is a medication that blocks hepatitis B effectively but does not make it disappear completely. Scientists believe that the immune system must also be active to rid the body of the last traces of hepatitis B. Patients ages 18 and older who have chronic hepatitis B and are being treated with lamivudine may be eligible to participate in this study. They will undergo a medical history and physical examination and will be given lamivudine in 100 mg tablets to be taken as one tablet, once each day. Patients will be asked to return to the outpatient clinic every 3 months, when they will undergo a brief interview and measurement of vital signs-such as blood pressure, pulse, and body weight. During the visits, they will fill out questionnaires about any symptoms or side effects they have, and they will be seen by a doctor and have a brief medical history and examination. There will be a collection of blood for complete blood counts, liver enzymes, and hepatitis B virus. Extra blood tests may be done to analyze patients' immune reactions to hepatitis B. Patients will also receive refills of their lamivudine tablets. They will continue to be treated with lamivudine as long as it seems to control the hepatitis infection and liver disease. At intervals of about 1 year, patients will have ultrasound examinations, lasting about 1 hour, of the liver and abdomen. Then at intervals of about 5 years, patients will undergo liver biopsies, which require a hospital stay of 2 to 3 days. A liver biopsy is done by passing a needle through the skin into the liver to obtain a piece of liver about 2 inches long and 1/16-inch in diameter. A small amount of bleeding probably occurs with most liver biopsies. Internal bleeding is a risk, which may require that the patient stay in the hospital a few days longer, for rest, observation and pain medicine. The biopsy provides information that proves whether lamivudine is controlling the liver disease and preventing it from worsening or progressing to cirrhosis. Side effects of lamivudine include fatigue, muscle aches, fever and chills, sore throat, nausea, stomach pain or cramps, and diarrhea. Serious side effects are rare, occurring in less than 1% of people taking lamivudine. They include inflammation of the pancreas, nerve damage, and buildup of lactic acid in the blood. About 25% of patients experience a temporary worsening, or flare, of hepatitis during the first few months of treatment. If flares are severe, it is important for researchers to determine whether they are caused by resistance to lamivudine or by the immune system acting against the hepatitis B virus or another liver condition. A flare of hepatitis can also occur when lamivudine is stopped, that is, a withdrawal. In such situations, testing for hepatitis B virus levels and other liver conditions is important. It may lead to other treatments or stopping lamivudine and taking another medication instead. While patients are participating in the study, they will have a careful evaluation of their hepatitis and general condition. They may have an improvement in their disease as a result of long-term lamivudine therapy.
The major aims of this study are to evaluate the long-term efficacy and safety of lamivudine therapy and the possibility of stopping therapy in a cohort of patients with chronic hepatitis B who have a maintained response to treatment. Lamivudine is a nucleoside analogue with potent activity against hepatitis B virus (HBV), which is approved for use in the United States and is used extensively throughout the world to treat HBV and HIV infection. Lamivudine is well tolerated and adverse events are rare. Its major shortcoming is the development of antiviral resistance after prolonged therapy which results in loss of effectiveness, marked by rise in viral levels and return of disease activity. Some patients, however, have a maintained response to lamivudine therapy and in these individuals treatment is continued indefinitely or until hepatitis B surface antigen (HBsAg) is lost and therapy can be permanently stopped. This protocol will allow for the long-term treatment and evaluation of these patients. Patients will be maintained on lamivudine at a dose of 100 mg daily and seen every three months for interim medical history and serum testing for aminotransferase levels and hepatitis B markers, with liver biopsies done every 5 years. Lamivudine will be stopped if HBsAg is lost. The protocol also includes an option to attempt withdrawal of therapy under controlled conditions focusing on inducing immune reactivity to HBV and clearance of HBsAg. Patients will stop lamivudine for short periods (1 week, and later for 2, 4 and 8 weeks) and be monitored during and for 12 weeks afterwards for aminotransferase levels, HBV DNA levels and CD4+ and CD8+ T cell responses to HBV antigens. Patients who demonstrate significant worsening of hepatitis will not undergo further attempts at withdrawal. The endpoint to successful therapy is defined as loss of hepatitis B surface antigen (HBsAg) and development of antibody (anti-HBs).
Study Type
INTERVENTIONAL
Purpose
TREATMENT
Enrollment
50
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
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