Elsevier

Journal of Hepatology

Volume 56, Issue 6, June 2012, Pages 1254-1258
Journal of Hepatology

Research Article
HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5 years

https://doi.org/10.1016/j.jhep.2012.01.022Get rights and content

Background & Aims

In long-term responder patients, it is unclear whether lamivudine (LAM) monotherapy should be continued or switched to a high-genetic-barrier analogue. This study aims at assessing LAM efficacy over a 5-year period and the residual risk of drug resistance. The rate of HBsAg clearance and LAM long-term safety profile were also evaluated.

Methods

One hundred and ninety-one patients with chronic HBeAg-negative hepatitis B successfully treated with LAM monotherapy for at least 5 years were included. Biochemical and virological tests were assessed every 3 months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients.

Results

One hundred and ninety-one patients (148 males, median age 53 years, 72 with compensated cirrhosis) responding to 60-month LAM monotherapy continued to receive LAM monotherapy beyond the initial 5 years and were followed for an additional 36-month median period (range 1–108). Virological response was maintained in 128/191 patients (67%) and HBsAg clearance was observed in 15/128 (11.7%) after a 32-month median period (range 1–65). The 63 remaining patients (33%) showed virological breakthrough after a 15-month median treatment (range 1–78). RT region analysis was performed in 38/63 breakthrough patients and LAM resistant mutations were found in 37/38. No significant side effects were observed.

Conclusions

In long-term responder patients, continuation of LAM monotherapy resulted in persistent viral suppression in most cases with undetectable HBV DNA by real-time PCR; moreover, 11.7% of these patients cleared HBsAg. Selection of LAM resistance, however, can still occur even after successful long-term therapy, thus emphasising the importance of a careful virological monitoring.

Introduction

Lamivudine (2.3-dideoxy-3-thiacytidine) was the first nucleoside analogue approved for treatment of chronic hepatitis B [1], [2]. Clinical trials have shown that administration of LAM resulted in a decrease in both serum HBV DNA and alanine aminotransferase (ALT) levels and an improved liver necroinflammation and fibrosis, thus reducing disease progression and development of hepatocellular carcinoma [3], [4], [5]. The absence of clinical side effects also assured a good compliance. However, a high rate of LAM resistance (LAM-R) was reported; LAM-R progressively increased during treatment at rates of 14–32% annually, exceeding 70% after 5 years [6], [7], [8]. LAM-R development is responsible for the treatment failure and may confer crossresistance to all L-nucleosides, and might determine a reduced efficacy of other nucleos(t)ide analogue (NA) groups, thus limiting successive treatment options [9]. Therefore, LAM is not recommended by current guidelines for first-line monotherapy and has been substituted by the most potent NAs (entecavir or tenofovir) with a higher resistance barrier [10], [11]. Nevertheless, a certain percentage of patients (25–30%) continue to maintain viral suppression after 5 years of continuous LAM monotherapy and it has yet to be established if, in these patients, LAM should be continued or switched to a drug with a better resistance profile.

In this study, we assessed the efficacy of further extending the administration of monotherapy in a cohort of chronic hepatitis B patients successfully treated with LAM for more than 5 years, including the rate of HBsAg clearance and the residual risk of drug resistance. Moreover, the long-term safety profile of LAM was evaluated.

Section snippets

Patients

From March 1997 to September 2005, 636 NA-naïve consecutive patients with HBeAg negative chronic hepatitis B were treated with LAM monotherapy (100 mg/day orally) in eight Italian centres (Bari, Foggia, Napoli, S. Giovanni Rotondo, Torino, Milano, Palermo, Pisa). During the first five years of treatment, 445/636 patients (70%) developed LAM-R, while 191 patients, who maintained a virological response for at least 5 years (long-term responders), continued to receive LAM monotherapy and were

Results

After 5 years of LAM monotherapy, 191 HBeAg-negative chronic hepatitis B patients continued to have undetectable HBV DNA (assay sensitivity limit was 380 IU/ml for 51 patients and 40 IU/ml for 140 patients) and were included in the study. Median age was 53 years (range 24–76), 148 were males, histological or clinical diagnosis of cirrhosis was present in 72/191 patients (37.7%) (all were Child A). All patients were negative for HDV, HCV, HIV co-infections and continued to receive LAM monotherapy

Discussion

Data on prolonged LAM monotherapy in HBeAg-negative patients with chronic hepatitis B or cirrhosis are scarce and it has yet to be established if LAM should be continued or switched to a drug with a higher genetic barrier in these patients.

To our knowledge, this is the first study evaluating both the efficacy of continuing LAM monotherapy and the residual risk of drug resistance in a large patients’ cohort with HBeAg-negative chronic hepatitis B successfully treated with LAM for at least 5 

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Acknowledgements

The authors are grateful to Ms. Paulene Butts for her assistance in the preparation of the manuscript.

References (20)

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