Makiyama et al. presented a large, retrospective multicenter study, the main purpose of which was to define relevant predictors of the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) who were treated with interferon monotherapy between 1991–2001. These patients were classified as being sustained responders (SRs) on the basis of a continuous normal alanine aminotransferase level after therapy with interferon.1 We would like to point out that their definition of “sustained responder” would be more properly termed “biochemical responder.”
In this paper both the end-of-therapy and follow-up HCV RNA assessments are lacking; there are therefore no parameters to allow us to define patients as nonresponders, cases of disease recurrence, or true SRs (with a persistent HCV RNA clearance from the serum).2
Makiyama et al. provided virologic analysis (serum HCV RNA level using reverse transcriptase-polymerase chain reaction analysis) only in those patients who developed HCC, whereas no virologic data were reported for the follow-up of the SRs who did not develop HCC. The number of patients evaluated was large and these data could have great relevance in determining the significance of absent HCV replication in hepatocarcinogenesis. To our knowledge to date, there has been no clear demonstration of any correlation between HCV RNA clearance and long-term clinical outcome in view of HCC development. Three recent studies reported discordant data; no HCC was reported to have developed during the long-term follow-up of 286 European patients who were sustained virologic responders (SVRs).3 Toyoda et al.4 reported 9 cases of HCC among 392 patients who were SVRs, whereas a global incidence rate of 11%% was demostrated by Tsuda et al. although their study cohort was small.5
Liver carcinogenesis is most likely a multistep process. To our knowledge, although much is known regarding the etiopathogenesis of HCC, its exact mechanism remains unknown. We agree with Makiyama et al. that HCV persistence seems to be irrelevant for the development of HCC, but assessment of the virologic status is a mandatory evaluation in those patients treated with interferon. The persistence or disappearance of HCV RNA, in addition to patient age and gender and histologic criteria, could help to tailor the optimal biochemical and instrumental follow-up schedule for those patients who are biochemical responders.