Four years of treatment with lamivudine: clinical and virological evaluations in HBe antigen‐negative chronic hepatitis B

Abstract

SUMMARYAim: 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.

Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: A systematic review

“…Most patients were males (79.7%) and the majority was Caucasians (50.6%) or Asians (48.0%). HCC screening at baseline was reported to be performed in 15 studies including 2807 patients [18,19,21,22,[24][25][26][27]29,32,[34][35][36][37][38] and HCC surveillance during therapy (mostly by alpha-fetoprotein and/or abdominal ultrasound) at least every 6 months in 11 of these studies including 1553 patients [19,21,22,[25][26][27]32,[35][36][37][38], while HCC screening and/or surveillance were not described or performed in the remaining studies (Table 2). It should be noted that the proportion of cirrhotic patients was significantly higher in studies with than without reported strategies for HCC surveillance (650/1553 or 41.9% vs 630/2328 or 27.1%, p < 0.001).…”

“…The mean or median age of the patients was between 30 and 40 years in three studies [18,23,32], between 40 and 50 years in 10 studies [21,22,24,25,29,31,34,[36][37][38] and in the non-cirrhotic patients of one additional study [20], and P50 years in 7 studies [19,[26][27][28]30,33,35] and in the cirrhotic patients of one study [20]. Most patients were males (79.7%) and the majority was Caucasians (50.6%) or Asians (48.0%).…”

“…Sixteen studies included nucleos(t)ide naive chronic hepatitis B patients with lamivudine monotherapy used initially in 14 [18][19][20][21][22][24][25][26][27][28]32,[34][35][36], emtricitabine in one [23] and adefovir in the remaining study [29]. Five studies included patients with lamivudine resistance treated with adefovir monotherapy or adefovir and lamivudine combination therapy [30,31,33,37,38].…”

“…Studies were considered to be of high quality for this review if they fulfilled three of the following five criteria: (a) provided definitions for HCC diagnosis, (b) described HCC screening at baseline, (c) described HCC surveillance during therapy, (d) provided HCC data separately in patients with and without cirrhosis, and (e) provided HCC data in relation to virological response. According to these criteria, 14 studies were characterized to be of high [19][20][21][22][24][25][26][27]29,32,[35][36][37][38] and 7 to be of low quality [18,23,28,30,31,33,34]. Ten studies were considered as large [18,20,22,26,29,32,33,[36][37][38] and 11 as small [19,21,[23][24][25]27,28,30,31,34,35] if the total number of patients was more than 100 or less than 100, respectively.…”

Mutations outside the YMDD motif in the P protein can also cause DHBV resistant to Lamivudine

“…Polymerase gene mutations were observed in 82.5% of virological breakthroughs but also in 75% of the nonresponders [32] . So the mutations outside the YMDD motif in the P protein can independently cause DHBV resistant to Lamivudine is not very strange.…”