In the preceding letter Janssen and Lau questioned our conclusions regarding the long-term efficacy of nucleoside or nucleotide analogs (NAs) in patients with chronic hepatitis B. Authors argue that convincing data that can prove the durability of HBeAg seroconversion under this kind of therapy are lacking and that the presented studies “may be subject to bias.” While I agree that the published long-term follow-up data in NA-treated patients are far from being optimal and indeed may be biased, they still provide some important information.

First, the frequency of HBeAg seroconversion increases with NA treatment time. After 2 to 3 years, ranges are reached that are similar to those observed after 1 year of interferon-alpha (IFNa) or pegylated IFNa (PEG-IFNa) treatment.1–6

Second, one could make the point that from current perspectives the design of the PEG-IFNa approval studies mentioned by Janssen and Lau may be regarded as being biased in favor of the IFNa-based regimen.7 However, I think it is not too helpful to compare the potential efficacy of an NA- or (PEG)-IFNa–based regimen: The philosophy of IFNa-based regimens is to induce a stable remission (i.e., seroconversion) in a limited period of time, whereas a major endpoint of NAs is to reduce hepatitis B virus (HBV) DNA to undetectable levels by maintenance therapy, thereby stopping disease progression.8, 9 When comparing the efficacy of both drugs (PEG-IFNa and lamivudine) at the end of treatment, seroconversion rates did not differ greatly between PEG-IFNa and lamivudine (27% vs. 20%), but the level of HBV DNA suppression and frequency of alanine aminotransferase (ALT) normalization were higher in the lamivudine group.7 To add an empirical point of view: in practice, probably no one would stop lamivudine treatment in HBeAg-positive patients as long as seroconversion is not achieved.

Third, we have good reason to hope that future rates of long-term response can be increased using more potent NAs; for instance, entecavir, telbivudine, or tenofovir, which may also have a more favorable resistance profile. In a recently published telbivudine phase II study, a 31% HBeAg seroconversion rate was observed after 1 year of treatment.10

Finally, the risk of seroreversion (i.e., reappearance of HBeAg after stopping NAs in patients achieving HBeAg seroconversion) is not high. There is now ample evidence that HBeAg seroconversion remains stable in about 90% of the patients when NA treatment is extended for up to 1 year beyond seroconversion.5, 6 Indeed, Lau and colleagues found the frequency of HBeAg seroconversion to drop by only 1% in the 24-week follow-up of lamivudine-treated patients who achieved seroconversion during the 48-week treatment period (i.e., from 20% at end of treatment to 19% at end of follow-up).7

Nevertheless, there is a great need to improve therapeutic options for these patients, considering the fact that, overall, only about 30% achieve stable remission after 48 weeks of a PEG-IFN therapy that is rich in side effects. And one should be prepared to accept a more individually oriented therapeutic concept.


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  • 1
    Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology 2000; 119: 172180.
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    Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. HEPATOLOGY 2003; 33: 15271532.
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    Yao GB, Cui ZY, Wang BE, Yao JL, Zeng MD. A 3-year clinical trial of lamivudine in treatment of patients with chronic hepatitis B. Hepatobiliary Pancreat Dis Int 2004; 3: 188193
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    Marcellin P, Chang TT, Lim S, Sievert W, Tong M, Arterburn S, et al. Long-term efficacy and safety of adefovir (ADV) 10 mg in HBeAg+ chronic hepatitis B (CHB) patients: increasing serologic, virologic and biochemical response over time. HEPATOLOGY 2004; 40( Suppl 1): 655A.
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    Dienstag JL, Cianciara J, Karayalcin S, Kowdley KV, Willems B, Plisek S, et al. Durability of serologic response after lamivudine treatment of chronic hepatitis B. HEPATOLOGY 2003; 37: 748755.
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    Chang TT, Shiffman M, Tong M, Marcellin P, Liaw YF, Luengrojanakul P, et al. Durability of HBeAg seroconversion after adefovir dipivoxil treatment for chronic hepatitis B. J Hepatol 2004; 40( Suppl 1): 126A.
  • 7
    Lau GKK, Piratvisuth T, Luo KX, Marcellin P, Thongasawat S, Cooksley G, et al. Peginterferon alfa-2a, lamivudine and the combination for HBeAg positive chronic hepatitis B. N Engl J Med 2005; 352: 26822695.
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    Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 15211531.
  • 9
    Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003; 124: 105117.
  • 10
    Lai CL, Leung N, Teo EK, Tong M, Wong F, Hann HW, et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 2005; 129: 528536.

Thomas Berg M.D.*, * Medizinische Klinik mit Schwerpunkt Hepatologie und, Gastroenterologie, Charité–Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany.