This large European study allows, for the first time, an approximation of the incidence of clinical events during long term follow up of sustained virological responders in Europe. The most important finding is that clinical events are rare in this population, indicating that sustained virological responders have an excellent prognosis.
The largest European study to date describing clinical outcome in sustained responders to interferon treatment did not report any events among 74 patients followed up for 2.7 years.15
Two other European studies, involving seven and 56 sustained responders, also showed no clinical events during 4.6 and 5.2 years of follow up, respectively.8,16
Bruno et al
described 32 sustained responders of whom one cirrhotic patient developed HCC.17
Although another HCC has been reported recently in a Western sustained responder,18
these cases seem to be rare and limited to patients with cirrhosis. In the present study, no HCCs occurred during long term follow up. According to several large studies, the yearly incidence of HCC among Japanese sustained virological responders still varies between 0.02% and 0.5% per year19–26
; the difference in the incidence of HCC between East and West apparently persists in conditions without detectable viral replication.
The lowest rates in Japan were reported by Yoshida et al
, with one HCC among 817 sustained responders during 5.4 years of follow up.26
The highest incidence of HCC reported among sustained responders in Japan was by Kasahara et al
who reported five HCCs among 313 sustained virological responders followed up for three years.22
Fifteen cirrhotic patients were included in this study. Only two patients with decompensated cirrhosis were reported. Among untreated cirrhotics, occurrence of clinical events of 38% (28% decompensation and 10% HCC) would be expected, according to Fattovich and colleagues.27
These results suggest, but do not prove, a change in the natural course of chronic hepatitis C. Further studies, including more cirrhotics, will be necessary to investigate the effect of treatment on the natural course of chronic hepatitis C.
In this study, sustained virological response was associated with a decrease in fibrosis score. Similar findings have been reported for sustained responders to pegylated interferon.28,29
Previous studies have shown that regression of fibrosis can also occur in biochemical responders and non-responders to interferon. In common with our study, sustained virological responders show the highest rate of regression.30
Because of the large proportion of sustained virological responders that showed regression of fibrosis and the low incidence of clinical events in these patients, in our view, non-cirrhotic patients with a sustained virological response can be regarded as cured.
A limitation of our study is that all patients had been treated with interferon monotherapy whereas the current standard therapy for chronic hepatitis C is pegylated interferon with ribavirin. This current standard however dates from 2002 and long term follow up data of peginterferon and ribavirin were not available at the time of this study.31
In general, combination therapy leads to higher sustained virological response rates32,33
and also the late relapse rate seems to decrease. In this study with data on interferon monotherapy, the late relapse rate was 4.7% (95% CI 2.0–7.4); Camma et al
reported 8.7% in a meta-analysis of 14 trials with interferon monotherapy.34
After four years of follow up of treatment with interferon and ribavirin, late virological relapse rates of 3% (95% CI 1.4–4.6) and 1% (95% CI 0–2.0) have been reported for patients treated for 24 weeks and 48 weeks, respectively.18
After treatment with pegylated interferon with or without ribavirin, a late relapse rate of 0.8% was reported after four years of follow up.35
The possibility of reinfection could not be ruled out in our cohort as data on risk behaviour and concordance of genotypes were not available. However, introduction of more sensitive PCR methods may also have contributed to a decrease in late virological relapse over time. It is possible that with an insensitive assay, patients with low viraemia are regarded as sustained virological responders.
As the late relapse rate seems to decrease with newer treatment regimens, long term clinical outcomes may be similar or even better than results obtained with interferon monotherapy. Therefore, in our opinion, the favourable clinical outcome of sustained virological responders is likely to hold true in the era of pegylated interferon and ribavirin.
In conclusion, the long term clinical outcome of patients with a sustained response to interferon is favourable. Five year survival of European sustained virological responders was similar to the general population, matched for age and sex, and no HCCs were detected during long term follow up.