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Chapter 2.3
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DISCUSSION
Recently a model was presented that predicts sustained response (SR) of HBeAg positive
chronic hepatitis B patients to PEG-IFN therapy, using baseline characteristics. 9 In the
present study a simple statistical method was introduced for the assessment of dynamic
prediction using single or repeated measurements applying contemporary methods and
readily available programming procedures. 15 It enabled individual updates of prediction
of SR by adding on-treatment data on HBV DNA decline. Patients without a 2 log10 HBV
DNA decline within 24 weeks of treatment were identifi ed as having a lower probability
of response, and discontinuation should be considered in these patients.
The total number of patients who achieved SR, defi ned as HBeAg loss and HBV DNA
below 10.000 copies/ml was only 18/125 = 14% in our study, thus, in order to minimize
overfi tting, a simplifi ed model was reached using only duration of treatment and HBV
DNA decline as additional variables. Ideally, the model fi t should be confi rmed using
an independent and preferably larger dataset. Since such a dataset was not available,
internal cross-validation and bootstrap methods were applied to verify the fi ndings.
Absolute HBV DNA levels and HBV DNA decline were equally good predictors of (non-)
response, but a model fi tted with HBV DNA decline provided better performance.
Adding ALT levels or interaction terms did not signifi cantly improve the models. These
fi ndings confi rm the importance of frequent HBV DNA monitoring during therapy as
proposed in recent guidelines. 16
Different patterns of HBV DNA decline during PEG-IFN treatment have been described
in relation to response in the literature, but no solid stopping rule has yet been identifi
ed. In a previous study three response profi les during treatment were described; early
HBV DNA decline within the fi rst four weeks, delayed decline between weeks 4 through
32, and late decline after week 32. 17 There was an association between HBV DNA levels
and HBeAg and HBsAg loss at the end of follow-up, but a stopping rule was only suggested
for patients with genotype A. Absence of a 1 log10 decline at week 32 was a good
predictor of non-response in those patients. In another study HBV DNA kinetics during
the fi rst 4 weeks of treatment were analyzed in detail, 18 but no association between the
kinetic parameters and HBeAg loss was found. Using patients treated with nucleos(t)ide
analogous or PEG-IFN Dahari et al19 described 5 HBV DNA decline profi les: a classic
biphasic decline, a fl at-responder profi le, a rebounder profi le, a triphasic decline and a
stepwise decline. These observations confi rm that the relationship between HBV DNA
levels during PEG-IFN therapy and HBeAg loss is complex. The HBV DNA patterns as
predictor of response are stronger in this study because the combined endpoint, HBeAg
loss and HBV DNA below 10.000 copies/ml (2,000 IU/l), was chosen. As pointed out