Research ArticleLong-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: Finite treatment duration unlikely
Introduction
Recent developments in the antiviral treatment of chronic hepatitis B virus (HBV) infection have emphasized the need for biomarkers that are predictive of treatment outcomes and can be used to tailor therapy to the individual patient. In chronic HBV carriers, hepatitis B surface antigen (HBsAg) is produced as a result of translation of messenger RNAs generated from transcriptionally active cccDNA or integrated HBV DNA sequences in the host genome. HBsAg is present in the envelope of infectious HBV virions and in non-infectious spheres and tubules. The latter exceed infectious virions when replication is active; they remain produced in large amounts when replication is controlled, either spontaneously (inactive carriers) or by antiviral therapy [1], [2], [3], [4].
A number of recent studies have demonstrated the clinical utility of HBsAg quantification in monitoring HBV therapy [1], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]. Indeed, early on-treatment serum HBsAg levels predict the sustained post-treatment response to therapy and the eventual subsequent HBsAg clearance in patients with both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative chronic hepatitis B treated with a finite duration of pegylated interferon (IFN)-α [1], [5], [6], [7], [8], [9]. HBsAg clearance, followed or not by HBs seroconversion (appearance of anti-HBs antibodies) characterizes a sustained remission of HBV infection.
Standardized quantitative HBsAg level assays are available. Three commercial assays, the HBsAg assay on Architect® device (Abbott Diagnostics, Chicago, Illinois), the HBsAg II Quant assay on Elecsys® or Cobas® e devices (Roche Diagnostics GmbH, Mannheim, Germany), and the Liaison®XL HBsAg Quant assay on Liaison®XL device (DiaSorin, Saluggia, Italy) are approved in the European Union; they are available for research use only in the United States. These tests are inexpensive and easy-to-use, and high throughput is possible with automated platforms [15], [16]. Thus, HBsAg quantification can be easily used to monitor antiviral therapy in patients with chronic HBV infection.
Treatment of chronic hepatitis B with nucleoside or nucleotide analogues is aimed at reducing virus production by inhibiting the reverse transcriptase function of the HBV DNA polymerase, the enzyme responsible for viral replication. Nucleoside/nucleotide analogues do not exert a direct effect on HBsAg transcription and translation. Recent liver society guidelines recommended the use of entecavir or tenofovir as first-line therapy in patients with chronic hepatitis B and an indication for nucleoside/nucleotide analogues, because both drugs potently inhibit the HBV reverse transcriptase and have a high barrier to resistance. Entecavir and tenofovir have been shown to efficiently maintain suppression of HBV DNA levels for prolonged periods of time in the vast majority of treated patients [17], [18], [19]. As a result, most patients who started therapy with other drugs currently receive entecavir and/or tenofovir as part of their treatment regimen in areas where these drugs are available and reimbursed.
Information regarding HBsAg kinetics during treatment with nucleoside/nucleotide analogues is limited [5], [10], [11], [12], [13], [14], [18], [20], [21], [22], [23], [24], [25]. These studies indicate nucleoside/nucleotide analogue therapy results in lesser overall declines in serum HBsAg levels and HBsAg clearance appears to be less frequent than in patients receiving pegylated IFN-α-based therapy. However, this could be biased by the fact that pegylated IFN-α is generally used in subsets of patients with a greater likelihood to clear HBsAg, e.g., patients with low HBV DNA and high alanine aminotransferase levels.
The aim of the present study was to assess whether finite nucleoside/nucleotide analogue treatment duration could be envisaged during the patient’s lifetime. For this, we assessed the long-term kinetics of serum HBsAg levels in patients with chronic hepatitis B treated with various successive schedules of nucleoside/nucleotide analogues and who maintained undetectable HBV DNA in the long term, and evaluated the clinical interest of HBsAg level quantification to tailor treatment duration.
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Patients
The study was a longitudinal analysis of HBsAg levels in prospectively collected serum samples from 30 patients with histologically proven chronic hepatitis B, treated with different nucleoside/nucleotide analogue schedules, according to drug approvals and outcomes on therapy, between December 1996 and December 2010, in the Department of Hepatology and Gastroenterology of our institution. All patients were positive for HBsAg and negative for anti-HBs antibodies at the beginning of the study.
Characteristics of the study patients
Table 1 shows the individual demographic, virological and histological data of the patients. Twenty-four men and 6 women were enrolled in the long-term longitudinal study of HBsAg levels. The mean age of the patients was 55.6 ± 10.1 years (range: 30.6–88.1); 16 of them were Caucasian, 6 were Asian, and 8 were African. Eighteen patients (60.0%) were HBeAg-negative. Among the 12 patients who were HBeAg-positive before starting therapy, 6 were still HBeAg-positive at the beginning of follow-up in
Discussion
Quantification of HBsAg levels is emerging as a contributive tool in monitoring HBV infection and antiviral therapy outcomes, in complement to HBV DNA levels [4], [9], [11], [30]. In the present study, we characterized very long-term HBsAg level kinetics during prolonged oral treatment with nucleoside/nucleotide analogues in HBV mono-infected patients with HBeAg-positive and –negative chronic hepatitis B, and derived a prediction, based on mathematical modeling, of the theoretical duration of
Conflict of interest
S.C., C.H. and J.M.P. have received research grants from Roche and Gilead and have served as advisors for Roche, Gilead and Bristol-Myers Squibb.
Acknowledgments
The authors are grateful to Syria Laperche and Mélanie Mercier who kindly provided the reference sequences for HBV genotype determination.
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