It is estimated that approximately 300 million people worldwide are infected with hepatitis B virus. In Asia, most persons are infected perinatally and are usually asymptomatic, but remain chronically infected. In the United States and other Western countries, most people acquire hepatitis B through sexual transmission or intravenous drug use. These persons usually become acutely ill; however, only about 10 percent become chronically infected. In this subset of patients, the only effective treatment to date has been interferon. Some recent studies have suggested that lamivudine, an oral nucleoside analog used to treat patients infected with the human immunodeficiency virus (HIV), is also effective in the treatment of hepatitis B. Dienstag and colleagues performed a randomized, placebo-controlled trial of lamivudine in patients with chronic hepatitis B infection.
Patients with a history of chronic hepatitis B infection were eligible for the study. Entry criteria included an age of at least 18 years, serology positive for hepatitis B surface antigen (HBsAg) for at least six months, hepatitis B e antigen (HBeAg) for at least one month and an elevation of the alanine aminotransferase (ALT) level that was 1.3 to 10 times the upper limit of normal for at least three months. Additional criteria were evidence of chronic hepatitis B infection on liver biopsy and a detectable level of serum HBV DNA. Excluded were patients previously treated with interferon or lamivudine, a history of significant hepatic dysfunction including a bilirubin level higher than 2.5 mg per dL (43 [micro]mol per L), an albumin level less than 3.5 g per dL (35 g per L) or a prothrombin time 3 seconds more than normal. Also excluded were patients with concurrent hepatitis C or HIV infection, and patients who were pregnant or breast-feeding.
Patients were randomized to receive 100 mg of lamivudine daily or a matching placebo for 52 weeks. Clinical and laboratory assessments were performed at weeks two and four, then every four weeks thereafter. A repeat liver biopsy was performed at week 52. Monthly surveillance was continued for an additional 16 weeks after therapy was stopped. The primary study end point was an improvement of at least two points on the histology scores of the liver biopsies. An established scoring system assessed four histologic components with a total score from zero (normal) to 22 (most severe). Secondary end points were loss of HBeAg, HBV DNA, the appearance of hepatitis B e antibody (HBeAb) and sustained normalization of ALT levels.
A total of 143 patients enrolled, and ultimately 137 were included in the intention-to-treat analysis of the data. The median age of the patients was 39 years, and more than 80 percent were males. The only difference between the two groups was the HBV DNA level at baseline, and this was higher in the lamivudine group. In the lamivudine group, 52 percent of the patients had at least a two-point reduction in the liver histology score compared with 23 percent in the placebo group. The median reduction was three in the lamivudine patients and zero in the placebo patients. Histologic worsening occurred in 11 percent of the treatment group and 24 percent of the placebo group.
During follow-up, the levels of HBV DNA were undetectable in 98 percent of the treated patients compared with 33 percent of the placebo group. The cumulative sustained response in HBV DNA at week 52 was 44 percent in the treatment group and 16 percent in the placebo group. By 52 weeks, 32 percent of treated patients and 11 percent of placebo patients were HBeAg-negative. Serum ALT levels normalized in 41 percent of the lamivudine patients and in just 7 percent of the placebo group. These trends continued to be observed during the 16-week post-treatment period. No adverse events or deaths occurred in either of the groups, and all patients remained clinically well.
The authors conclude from this study that lamivudine is an effective treatment for chronic hepatitis B infection. Serologic and histologic markers documented its efficacy. The encouraging aspects of this limited study include the tolerability of oral therapy and the response sustained at least 16 weeks after treatment is stopped.
Jeffrey T. Kirchner, D.O.
Dienstag JL. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med October 21, 1999;341:1256-63.
Editor's Note: The data are encouraging in regard to the treatment of persons with hepatitis B infection. There is a wealth of information about lamivudine because of its extensive use in the treatment of HIV infection, and the drug has an excellent safety and tolerability profile. What remains to be determined with future studies is the optimal dosage and duration of treatment with lamivudine and whether the response is prolonged. In essence, is the drug a cure for chronic hepatitis B infection?--J.T.K.
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