We appreciate the interest and comments of Drs. ter Borg and Janssen. In our study, the proportion of patients who achieved HBeAg seroconversion at the end of combination treatment with pegylated interferon and lamivudine (60%) was indeed substantially higher than that reported in 2 other multicenter studies (25% to 27%) (1, 2). We agree that this result is surprising, since pegylated interferon was given for 32 weeks in our study compared with a longer treatment duration (48 to 52 weeks) in the other 2 studies. We started pegylated interferon-2b 8 weeks before the commencement of lamivudine treatment, in contrast to the other studies, which administered the drugs simultaneously. We hypothesize that our staggered administration of an immunomodulator followed by lamivudine might have allowed maximal host immune stimulation by pegylated interferon because reduction of viral load by coadministration of an antiviral agent would have been avoided. This hypothesis, however, requires confirmation by future viral kinetics studies using different regimens of combination therapy. We suspect that the inclusion of a significant proportion of patients with previous interferon or lamivudine treatment failure in the 2 multicenter studies might have affected the overall treatment response (1, 2). Hepatitis B virus genotype may not be important in our study because it was not found to influence the sustained virologic response in our patients up to 3 years after treatment (3).

We concur with Drs. ter Borg and Janssen that the rate of lamivudine resistance was high in our report. We did extensive interviews and medical record searches to exclude previous use of lamivudine when we recruited patients. Because lamivudine was registered in Hong Kong in 1999, the year we started our study, a hidden but significant previous exposure to lamivudine seemed extremely unlikely. The rate of lamivudine resistance among patients treated with lamivudine monotherapy in our study (40%) was comparable to that reported by Lau and colleagues (34%) (2). The higher rate of lamivudine resistance as compared with previous early reports may be related to the higher sensitivity of the laboratory tool we use today. We are not certain why our patients receiving combination treatment have a higher incidence of lamivudine-resistant mutations (21%) than in the other 2 studies (11%). The relatively small number of patients in our study may have biased the results. Whether patient ethnicity or viral genotype plays a role will require further investigation.