Clinical Experience With Lamivudine
Clinical Experience With Lamivudine
Lamivudine, an oral nucleoside analogue, has demonstrated efficacy against the hepatitis B virus (HBV) in both HBeAg-positive and HBeAg-negative patients with chronic hepatitis B. Treatment with lamivudine is safe and well tolerated and induces a virological and biochemical response in most patients within a short time. Significant histological improvement was seen in clinical trials after 52 weeks of lamivudine treatment. However, durable posttreatment remission of chronic hepatitis B has not been shown to occur in a significant number of lamivudine-treated patients. To maintain the response to treatment, therefore, long-term therapy is required. Prolongation of therapy, however, is associated with the emergence of HBV resistance to lamivudine in most patients. This is accompanied by virological rebound and reversal of the initial therapeutic response, and sometimes by exacerbation of hepatitis. The need remains for effective, safe, and tolerable oral agents with durable activity against HBV.
In 1998, lamivudine became the first commercially available oral agent for the treatment of chronic hepatitis B. Lamivudine is a synthetic nucleoside analogue that undergoes intracellular phosphorylation to its active metabolite, lamivudine triphosphate. DNA chain termination results from incorporation of the monophosphate form into viral DNA. Unlike interferon, lamivudine has direct antiviral activity and is a powerful inhibitor of HBV reverse transcriptase.
The introduction of lamivudine as the first oral agent approved for the treatment of chronic hepatitis B was a landmark in the management of this disease. However, emergence of lamivudine-resistant HBV mutations -- specifically, mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the HBV polymerase gene -- was apparent in both in vitro studies and the initial clinical trials. The frequency of the YMDD mutation increases with longer duration of lamivudine therapy and contributes to a lack of durability in lamivudine's clinical efficacy. In long-term therapy, this mutation is associated with viral breakthrough, exacerbation of hepatitis, and deterioration of liver histology in patients who have previously responded to lamivudine. In certain at-risk populations, including patients with human immunodeficiency virus (HIV) coinfection and those undergoing liver transplantation, a more marked deterioration has been observed.
This article reviews the data on the efficacy and safety of lamivudine therapy for chronic hepatitis B in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. The available data concerning the significance of the YMDD mutation are reviewed.
Lamivudine, an oral nucleoside analogue, has demonstrated efficacy against the hepatitis B virus (HBV) in both HBeAg-positive and HBeAg-negative patients with chronic hepatitis B. Treatment with lamivudine is safe and well tolerated and induces a virological and biochemical response in most patients within a short time. Significant histological improvement was seen in clinical trials after 52 weeks of lamivudine treatment. However, durable posttreatment remission of chronic hepatitis B has not been shown to occur in a significant number of lamivudine-treated patients. To maintain the response to treatment, therefore, long-term therapy is required. Prolongation of therapy, however, is associated with the emergence of HBV resistance to lamivudine in most patients. This is accompanied by virological rebound and reversal of the initial therapeutic response, and sometimes by exacerbation of hepatitis. The need remains for effective, safe, and tolerable oral agents with durable activity against HBV.
In 1998, lamivudine became the first commercially available oral agent for the treatment of chronic hepatitis B. Lamivudine is a synthetic nucleoside analogue that undergoes intracellular phosphorylation to its active metabolite, lamivudine triphosphate. DNA chain termination results from incorporation of the monophosphate form into viral DNA. Unlike interferon, lamivudine has direct antiviral activity and is a powerful inhibitor of HBV reverse transcriptase.
The introduction of lamivudine as the first oral agent approved for the treatment of chronic hepatitis B was a landmark in the management of this disease. However, emergence of lamivudine-resistant HBV mutations -- specifically, mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the HBV polymerase gene -- was apparent in both in vitro studies and the initial clinical trials. The frequency of the YMDD mutation increases with longer duration of lamivudine therapy and contributes to a lack of durability in lamivudine's clinical efficacy. In long-term therapy, this mutation is associated with viral breakthrough, exacerbation of hepatitis, and deterioration of liver histology in patients who have previously responded to lamivudine. In certain at-risk populations, including patients with human immunodeficiency virus (HIV) coinfection and those undergoing liver transplantation, a more marked deterioration has been observed.
This article reviews the data on the efficacy and safety of lamivudine therapy for chronic hepatitis B in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. The available data concerning the significance of the YMDD mutation are reviewed.
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