This Study Reports Cancer Can Develop in Small Number of Sustained Virologic Responders to HCV Therapy

Long-term follow-up of sustained responders to interferon therapy, in patients with chronic hepatitis C:
(This study reports cancer develops in a small percentage of sustained virologic responders, but it appears from abstract that it can be managed in many if not most cases.......)
     Toyoda H., Kumada T., Tokuda A., Horiguchi Y., Nakano H., Honda T., Nakano S., Hayashi K., Katano Y., Nakano I., Hayakawa T., Nishimura D., Kato K., Imada K., Imoto M., Fukuda Y. J. Viral Hepat (2000) 7(6): 414-19

Interferon (IFN) therapy has been proven to induce the normalization of serum alanine aminotransferase (ALT) levels and to eradicate the hepatitis C virus (HCV) in some patients with chronic hepatitis C, and these patients are usually defined as 'sustained responders'. However, there have been some reports of hepatocellular carcinoma (HCC) in these patients, and the development of HCC remains life-threatening in patients who clear HCV. We analyzed the long-term prognoses of patients with chronic hepatitis C in whom HCV was eradicated with IFN. We investigated 392 sustained responders to IFN therapy, from 1277 patients with chronic HCV infection who received IFN treatment at one of our institutions between April 1989 and March 1999.

We analyzed the medical records and looked for the development of HCC. About 30% of the sustained responders had been lost to follow-up 3 years after the end of IFN therapy, and the follow-up rate of sustained responders was significantly lower than that of non-sustained responders (P < 0.0001). HCC were found in eight patients: in seven patients HCC developed within 5 years after completion of IFN therapy; but in one patient, a single HCC less than 3 cm in diameter was detected between 7 and 8 years after completion of IFN.

Of the five patients who had regular medical follow-up, the HCC was solitary, and the patients survived without any evidence of recurrence. Of the three patients who had not been followed-up, two died from HCC and HCC recurred in the third. These results suggest that HCC can develop in sustained responders and that sustained responders should be followed-up closely after completion of IFN so that HCC may be detected at an early stage. The optimal duration of the follow-up period of the sustained responders remains unclear. Additional prospective studies are required in order to establish an appropriate follow-up protocol for sustained responders to IFN.

The full text of the article reported HCV RNA was not detectable in the serum of these patients developing HCC. All patients who had been followed-up regularly are alive without any evidence of recurrence. Of the three patients who were not followed-up, two died and HCC recurred in the third. The point is that after being SVR if you continue to be closely followed it appears you can catch the HCC (cancer) early enough to be treated. A literature search by the authors found a few people developing HCC after SVR, but just a few. In the case reports and follow-up studies of patients who had received IFN, HCC developed in the majority within 5 years after the completion of therapy; HCC did not occur more than 5 years after the completion of therapy in any of these studies except for one patient in whom HCC was detected 6 years after completion of therapy. Some HCCs have beenreported to grow very slowly and therefore the HCCs in some sustained responders may be caused by microscopic HCC tumours present before the start of IFN therapy.

In a recent report by Okanoue et al., no suppressive effect of IFN on the development of HCC was observed in patients with an advanced stage of liver histology before IFN therapy, even when the patients were sustained responders. From the pathological evaluation before IFN therapy in the case reports, however, three patients had mild fibrosis while the other two had severe fibrosis, which is associated with a higher risk of HCC than mild or moderate fibrosis. In our patients, the extent of liver fibrosis before IFN treat- ment was F1 or F2 in five of the eight patients. Thus, even sustained responders who do not have advanced liver fibrosis before IFN can develop HCC.

In conclusion, HCC can develop after termination of IFN therapy, even in patients who have achieved continuous normalization of their serum ALT levels and eradication of serum HCV. Sustained responders will probably be considered `cured' and may miss follow-up. This may result in failure to detect small HCCs, allowing the HCC to grow to a large size. Our data suggest that sustained responders shouldbe followed-up closely after completion of IFN therapy, even patients without advanced liver fibrosis before therapy. The optimal duration of the follow-up period for sustained responders is unclear. Further prospective studies, includingcost-effectiveness studies, will help to establish a standard protocol for following-up sustained responders to IFN. Such a protocol should facilitate early detection of HCC in this population.