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Chapter 3.1
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DISCUSSION
The aim of this study was to determine the long-term clinical outcome of chronic hepatitis
C patients who did not respond to interferon monotherapy and to evaluate the effect
of glycyrrhizin treatment on the incidence of HCC in this group of patients.
During follow-up 107 patients developed HCC. This is well in accordance with data
published by Yoshida et al., who presented the rates of development of HCC by age, sex
and fi brosis stage in their population of non-sustained responders. Applying these rates
to our dataset would lead to an expected number of 117 HCCs (95% CI 99-139) during
6.1 years of follow-up. 10 In our cohort the overall yearly incidence of HCC was 1.6%. Previous
large cohort studies found a yearly incidence of 0.3 to 2.7% per year in Japanese
non sustained responders to interferon treatment. 10-12 In the literature, lower rates of
HCC development are described in patients who relapsed after an initial response and
in patients with persistently low ALT levels. 13 Similarly, in our cohort, patients with lower
baseline ALT levels had a smaller probability of developing HCC.
As chronic hepatitis C only progresses slowly, it is hard to evaluate the effi cacy of
treatment on clinical outcomes like mortality and development of HCC in randomized
controlled trials. Therefore, “best” information should be derived from cohort studies.
However, cohort studies are only reliable if the drop-out rate is low compared to the
events. In retrospective cohort studies the risk of introducing bias is even larger. Incomplete
capture of early clinical events, confounding bias and compliance bias have been
described as possible confounders in retrospective studies. 14 In large randomized trials
this problem is usually avoided, as unmeasured confounders are likely to be equally
divided over the groups by randomization.
We executed this retrospective cohort analysis with great care to avoid these biases.
Incomplete capture of clinical events could not play a role in our analysis as the development
of HCC was monitored during the whole follow-up period. Secondly, confounding
bias may have played a role as raised ALT-levels increased both the chance of receiving
glycyrrhizin treatment as the risk of developing HCC. Sophisticated statistical analyses
were used to correct for this confounder. 9,15,16
Finally, compliance bias may have played a role in this study, as patients who are willing
to attend the hospital several times a week for intravenous injections of glycyrrhizin are
possibly also more likely to adhere to other protective types of behavior. However, the
fact that the follow-up of patients who did not receive glycyrrhizin was similar to those
who did, suggests that they were equally compliant in their hospital visits.
A previous study on the effect of glycyrrhizin on clinical outcome did show a signifi cant
protective effect on development of HCC. 17 In our study we refi ned the methodology
by using an intention-to-treat approach. All patients who received glycyrrhizin were