The major objective of treatment of recurrent chronic hepatitis C after OLT is to prevent progression to cirrhosis and thereby prevent loss of the graft. The combination of IFN-α and ribavirin is effective and achieves a sustained virological response in 25% of patients.12
However, it has become important to assess the long term effects to determine whether the treatment has indeed modified the natural history of HCV infection after OLT.
We have described the virological and histological course of 14 liver transplanted patients who were selected because they were serum HCV RNA negative at the end of antiviral therapy. Ninety three per cent of the included patients had persistently normal ALT levels and negative HCV RNA in the prolonged follow up period after treatment. In these patients, absence of HCV RNA in serum and in the graft, together with normalisation of serum ALT levels and marked histological improvement after treatment, very likely indicated eradication of the chronic HCV infection and subsequent interruption of the disease progression, with a low risk of further relapse or development of cirrhosis on the graft. In non-immunocompromised patients with chronic hepatitis, previous studies16,17
have shown similar results but until now no similar data were reported in the liver transplanted population. To confirm these results, further studies recruiting more patients are needed.
This study used both ALT normalisation and negative HCV RNA as end points. Indeed, the natural course of patients with sustained ALT normalisation and positive HCV RNA is not clear; sometimes late relapse may occur. Furthermore, chronic HCV viraemia with persistently normal ALT activity may show chronic hepatitis in graft biopsy specimens. Using these criteria, we did not observe biochemical or virological relapse in 93% of patients three years after cessation of the combination therapy (3/13 patients with a sustained complete response have been followed up for more than four years as of this writing). Although the sustained disappearance of detectable serum HCV RNA may not be sufficient to rule out a persistent low level viral infection, normal serum ALT levels in 13/14 patients who were negative for HCV RNA and were followed for three years suggests sustained inhibition of viral replication. Thus normal serum ALT levels in the absence of detectable serum HCV RNA during the six month post-treatment follow up period seem to be reliable indicators of sustained response.
Although four patients had severe chronic hepatitis C without cirrhosis before antiviral therapy, no new cases of cirrhosis appeared during follow up; this suggests that combination therapy following ribavirin monotherapy for one year has long term benefit in transplanted patients with HCV chronic hepatitis. In our study, one patient with graft cirrhosis had a sustained virological response, confirming that the long term response is possible even in patients with cirrhosis. Furthermore, no decompensation and no hepatocellular carcinoma occurred in this patient. However, in our study, the number of patients with cirrhosis was too small to draw any conclusions about the impact of antiviral therapy on the risk of graft failure and hepatocellular carcinoma.
After three years of follow up after withdrawal of antiviral therapy, 5/14 patients (36%) had normal or near normal histological findings. Histological improvement was present at the end of treatment and the HAI score remained stable thereafter (fig 1). This improvement was due to lowered inflammatory scores as fibrosis scores were essentially unchanged, as shown on fig 2. However, severe liver inflammation without signs of chronic rejection persisted for up to three years in one patient, despite normal serum ALT values and negative results on testing for serum and liver HCV RNA. Two explanations for this result can be postulated. Firstly, the constant presence of inflammatory infiltrates may be due to persistence of some degree of graft cellular immune response to HCV which probably takes many years to disappear. Secondly, the technique may not be sufficiently sensitive to detect low level viral infection and the explanation that a continuing low level HCV RNA replication persists in the graft cannot be entirely excluded. Another hypothesis for this case with inflammation on biopsy, several years after being negative for HCV-RNA, is that it is unrelated to HCV and may be due to other mechanisms such as a drug induced problem, de novo autoimmune hepatitis, or less likely an atypical rejection.
The absence of detectable graft HCV-RNA in 13/14 patients is consistent with the view that HCV infection may be cleared with antiviral therapy even in immunocompromised patients. These results suggest that persistence of graft HCV RNA at the end of antiviral therapy was the most important factor for relapse. This is similar to results reported in non-transplanted patients.18,19
The presence of a low level of HCV RNA in the liver, not detected on PCR, cannot be ruled out because the technique used in this study was not sufficiently sensitive. In our study however, no relapse occurred among the 13 patients without graft HCV RNA at the end of treatment and during follow up.
In the only one case of late relapse observed in this study, serum HCV RNA was negative at the end of treatment. This was not a false positive result of PCR because serum was also tested using PCR (Amplicor), with the same result. This case may suggest that the treatment does not completely suppress viral replication and very low replication rates remain in the compartment of replication competent cells (mainly hepatocytes). Another interesting finding in this case was detection of serum and graft HCV RNA despite the absence of hepatitis over 15 months. This observation of late relapse raises the question of the cytopathogenicity of HCV for hepatocytes and suggests that mechanisms other than direct cytotoxicity may be implicated in HCV induced graft damage.
In conclusion, this is the first study in the transplantation setting to show that persistent suppression of HCV replication can be obtained after early treatment and patients may be cured of the disease. Absence of detectable graft HCV RNA at the end of treatment in patients with recurrent chronic hepatitis C seems to be a reliable indicator of long term biochemical and virological response. Furthermore, disappearance of detectable viraemia leads to significant histological improvement.