Hepatitis C virus (HCV) is an RNA virus that replicates in both the liver and lymphoid cells. Interferon-alpha (IFN-alpha) is a useful treatment of chronic hepatitis C (CHC) although resistance to this drug occurs frequently. The mechanisms underlying resistance to IFN remain unknown. In this work, we have measured the levels of glutathione in plasma and peripheral lymphoid cells from 15 healthy controls and 24 CHC patients, 10 of whom were without treatment and 14 showed high serum alanine aminotransferase (ALT) values despite therapy with lymphoblastoid IFN for more than 4 months. In all patients, glutathione levels in plasma and in mononuclear cells were depressed in comparison to controls. In IFN-unresponsive patients, the addition of 600 mg tid of oral N-acetyl cysteine (NAC), a glutathione precursor, resulted in a steady decrease of ALT values in all patients, with complete normalization in 41% of cases after 5-6 months of combined therapy. Administration of NAC alone for 1 month was without effect in the 10 patients that were not receiving IFN. Supplementation of IFN with NAC induced a near normalization of intralymphocytic glutathione, but plasma levels were only moderately increased. HCV replication was markedly inhibited in lymphocytes and viremia was cleared in one of the 8 patients tested. In conclusion, NAC enhances the response to IFN in CHC. Controlled studies are needed to ascertain whether antioxidant therapy might act in synergy with IFN in chronic viral hepatitis.
We investigated the presence of positive (genomic) and negative (replicative intermediate) hepatitis C virus RNA strands in liver, peripheral mononuclear cells and serum from patients with chronic hepatitis C using a selective and semiquantitative polymerase chain reaction procedure. Negative and positive hepatitis C virus RNA strands were present in liver, serum and lymphoid cells in all untreated patients and in all those who did not respond to interferon therapy. In the latter group of patients, the titers of RNA strands in the liver and peripheral mononuclear cells at the end of the treatment were similar to those encountered in untreated patients, but the serum titers were about 100 times lower than pretreatment values. In patients who responded to interferon with normalization of serum aminotransferase levels (n = 10), the rate of detection and the titer of the two viral strands in liver, serum and mononuclear cells were markedly decreased at the end of the therapy. In the six responders who did not relapse after interferon withdrawal, both hepatitis C virus RNA strands were absent from the liver, serum and lymphoid cells. By contrast, the positive RNA strand was present in liver cells, mononuclear cells or both at the end of therapy in all patients who experienced posttherapy relapse. In conclusion, our results indicate that interferon can clear hepatitis C virus from hepatic and extrahepatic sites only in responder patients. Disappearance of genomic hepatitis C virus RNA from the liver and from mononuclear cells may predict complete response without posttherapy relapse.
We investigated the presence of positive (genomic) and negative (replicative intermediate) hepatitis C virus RNA strands in liver, peripheral mononuclear cells and serum from patients with chronic hepatitis C using a selective and semiquantitative polymerase chain reaction procedure. Negative and positive hepatitis C virus RNA strands were present in liver, serum and lymphoid cells in all untreated patients and in all those who did not respond to interferon therapy. In the latter group of patients, the titers of RNA strands in the liver and peripheral mononuclear cells at the end of the treatment were similar to those encountered in untreated patients, but the serum titers were about 100 times lower than pretreatment values. In patients who responded to interferon with normalization of serum aminotransferase levels (n = 10), the rate of detection and the titer of the two viral strands in liver, serum and mononuclear cells were markedly decreased at the end of the therapy. In the six responders who did not relapse after interferon withdrawal, both hepatitis C virus RNA strands were absent from the liver, serum and lymphoid cells. By contrast, the positive RNA strand was present in liver cells, mononuclear cells or both at the end of therapy in all patients who experienced posttherapy relapse. In conclusion, our results indicate that interferon can clear hepatitis C virus from hepatic and extrahepatic sites only in responder patients. Disappearance of genomic hepatitis C virus RNA from the liver and from mononuclear cells may predict complete response without posttherapy relapse.
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