Four Years of Treatment With Lamivudine
Aim: To evaluate the clinical and virological impact of the prolonged use of lamivudine in 94 patients with HBe antigen-negative chronic hepatitis B.
Methods: Initial virological and biochemical responses were obtained in 84 (89%) and in 83 (88%) patients respectively.
Results: The virological response peaked within the first 12 months, but diminished to 39% at 48 months because of drug resistance. Overall a virological breakthrough developed in 44 patients (52.4%). After virological breakthrough, the actuarial probability of maintaining biochemical remission diminished to 15% at 24 months and 0% at 29 months. There was no response in 10.6%. Polymerase gene mutations were observed in 82.5% of virological breakthroughs but also in 75% of the non-responders. Overall 7.4% of patients developed a hepatocellular carcinoma.
Conclusion: Almost 90% of patients responded initially to lamivudine but the emergence of drug resistance progressively reduced the rate of virological remission to 39% at the fourth year of therapy. YMDD mutants explained the 75% of lamivudine resistances and were also selected very early in non-responders. Although the biochemical response is invariably lost within 29 months of the YMDD mutant's duration, the clinical outcome was benign despite severe postvirological breakthrough hepatitic flares in about 12% of cases.
Most information on the efficacy of lamivudine (Lam) in the treatment of chronic hepatitis B (CHB) has been derived from studies on patients with disease sustained by wild-type hepatitis B virus (HBV). In this setting therapeutic remissions are marked by durable seroconversion from HBe antigen (HBeAg) to antibodies to HBeAg (anti-HBe) and by the normalization of liver enzymes and clearance of serum HBV DNA.
However, over 90% of contemporary patients with CHB in the Mediterranean area lack HBeAg and many have instead anti-HBe in serum. The disease is sustained by mutants of HBV that contain nucleotide substitutions in the core/precore regions of the viral genome; it often runs a discontinuous but relentless course, punctuated by intermittent flares of viraemia and cytolysis.
Only one major therapeutic trial and many small series open-label studies have been performed to establish the efficacy of Lam in HBeAg-negative CHB (e-CHB). In this setting, the efficacy of therapy is difficult to assess, as the only parameters of response are the normalization of aminotransferase and the disappearance of serum HBV DNA; in addition the intermittent nature of the disease makes it difficult to distinguish spontaneous from therapy-induced remissions.
Not surprisingly, the indications to use of Lam in e-CHB are poorly defined. Although the indication has emerged to give the drug over the long-term in order to control reactivation of viraemia and associated necroinflammation, the efficacy, safety and ultimate clinical impact of long-term therapy with Lam in unselected populations of e-CHB is as yet unknown.
In this study, we report our experience with the prolonged routine use (up to 4 years) of Lam in 94 Italian patients affected by e-CHB.
Aim: To evaluate the clinical and virological impact of the prolonged use of lamivudine in 94 patients with HBe antigen-negative chronic hepatitis B.
Methods: Initial virological and biochemical responses were obtained in 84 (89%) and in 83 (88%) patients respectively.
Results: The virological response peaked within the first 12 months, but diminished to 39% at 48 months because of drug resistance. Overall a virological breakthrough developed in 44 patients (52.4%). After virological breakthrough, the actuarial probability of maintaining biochemical remission diminished to 15% at 24 months and 0% at 29 months. There was no response in 10.6%. Polymerase gene mutations were observed in 82.5% of virological breakthroughs but also in 75% of the non-responders. Overall 7.4% of patients developed a hepatocellular carcinoma.
Conclusion: Almost 90% of patients responded initially to lamivudine but the emergence of drug resistance progressively reduced the rate of virological remission to 39% at the fourth year of therapy. YMDD mutants explained the 75% of lamivudine resistances and were also selected very early in non-responders. Although the biochemical response is invariably lost within 29 months of the YMDD mutant's duration, the clinical outcome was benign despite severe postvirological breakthrough hepatitic flares in about 12% of cases.
Most information on the efficacy of lamivudine (Lam) in the treatment of chronic hepatitis B (CHB) has been derived from studies on patients with disease sustained by wild-type hepatitis B virus (HBV). In this setting therapeutic remissions are marked by durable seroconversion from HBe antigen (HBeAg) to antibodies to HBeAg (anti-HBe) and by the normalization of liver enzymes and clearance of serum HBV DNA.
However, over 90% of contemporary patients with CHB in the Mediterranean area lack HBeAg and many have instead anti-HBe in serum. The disease is sustained by mutants of HBV that contain nucleotide substitutions in the core/precore regions of the viral genome; it often runs a discontinuous but relentless course, punctuated by intermittent flares of viraemia and cytolysis.
Only one major therapeutic trial and many small series open-label studies have been performed to establish the efficacy of Lam in HBeAg-negative CHB (e-CHB). In this setting, the efficacy of therapy is difficult to assess, as the only parameters of response are the normalization of aminotransferase and the disappearance of serum HBV DNA; in addition the intermittent nature of the disease makes it difficult to distinguish spontaneous from therapy-induced remissions.
Not surprisingly, the indications to use of Lam in e-CHB are poorly defined. Although the indication has emerged to give the drug over the long-term in order to control reactivation of viraemia and associated necroinflammation, the efficacy, safety and ultimate clinical impact of long-term therapy with Lam in unselected populations of e-CHB is as yet unknown.
In this study, we report our experience with the prolonged routine use (up to 4 years) of Lam in 94 Italian patients affected by e-CHB.
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