The durability of HBeAg seroconversion after lamivudine therapy was reported to be 80–90% in the first studies performed in Western countries.12,15,16,19
Recently, Song et al
observed a relapse of viral activity in half of responding patients after withdrawal of lamivudine monotherapy in an Asian cohort study.17
Ethnicity and duration of therapy prior to seroconversion have been suggested to be predictive factors for post-treatment relapse. In this study, comparing long term post-treatment data in 130 responders after lamivudine, IFN, and IFN-lamivudine combination therapy, lamivudine induced HBeAg seroconversion was significantly less durable than HBeAg seroconversion following IFN containing therapies, independent of race. However, the pretreatment factors high serum HBV DNA and low serum ALT were associated with a higher relapse rate; duration of therapy less than 48 weeks may also be a factor although this was not significant in our study.
The US studies comprised a low number of patients with HBeAg seroconversion, 11 and five, respectively, with a follow up of 4–12 months. The studies reported by Schiff et al
in two abstracts only included patients who remained HBeAg negative three months after the end of therapy, thereby excluding early relapsers.16
We have tried to increase the accuracy of the estimate of the durability of HBeAg seroconversion by including a large number of responders in the study, by prolonging the duration of follow up to three years, and by thorough statistical analysis. We corrected for differences in baseline characteristics by using multivariate analysis. The finding that our results were valid for each centre separately should markedly increase the confidence in the results.
However, factors that were not part of the multivariate analysis may still be of relevance. It is possible that patients undergoing relapse are more likely to return to their physician than patients with a sustained response. We collected data from more than 90% of responders of the centres that participated, minimising the likelihood of selection bias. Furthermore, this potential pitfall would affect all three therapies and should therefore not influence the relative risk.
The HBeAg relapse rate following IFN therapy in this study population (32% in three years) may appear high. However, when corrected for mean HBV DNA levels and stratified for ALT category, the post-treatment relapse rate following IFN (fig 2) was in accordance with the literature.1,2,5–10
Serum HBV DNA and ALT have been identified as predictors of response to antiviral therapy in chronic HBV infection.1,23
More recently, the degree of ALT elevation was found to be the most powerful predictor for HBeAg seroconversion.13,24
In this study, pretreatment HBV DNA levels were the major predictor for sustained response. In contrast with Song and colleagues,17
we also found a significant predictive value of pretreatment ALT levels for the durability of HBeAg seroconversion (higher baseline ALT—lower chance of relapse).
Differences in relapse following lamivudine and IFN therapy suggest a lack of an efficient immune control following HBeAg seroconversion in lamivudine treated patients. Resolution of acute hepatitis B is associated with a strong humoral and cellular immune response which is often maintained for years by persistence of minute amounts of HBV in liver or serum.25–27
In contrast with acute HBV infections, chronic HBV is generally associated with a weak and ineffective antiviral T cell response.26,28
Spontaneous exacerbations and antiviral therapy with IFN can elucidate a significant T helper cell response preceding HBeAgseroconversion.29–31
Although Boni et al
reported a restored HBV specific T cell response following the strong decline in HBV DNA levels in lamivudine treated patients, HBcAg specific T cell response remained undetectable during lamivudine therapy in another study.31,32
The differences in relapse after lamivudine and IFN therapies in our study suggest induction of immune control as an essential element for long term durability of HBeAg seroconversion.