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Observation of treatment responses to interferon-[alpha] by quantitative analyses of hepatitis C virus RNA Wu, He


Non-A, non-B (NANB) hepatitis accounts for 90% of cases of transfusion associated hepatitis and 20-40% of sporadic cases. Most of them become chronic and develop severe consequences such as cirrhosis and primary hepatocellular carcimona. Recently, hepatitis C virus (HCV), an RNA virus, was identified as the major etiological agent of NANB hepatitis. Interferon-a (IFNa) has been shown to be beneficial in treatment of patients with chronic hepatitis C by decreasing alanine arnino-transferase (ALT) levels and improving liver histology, since IFNa has a wide spectrum of antiviral activities. Unfortunately there is little information about the state of HCV replication during or after IFNa treatment. It is not clear whether therapy eradicates the presence of the virus or merely suppresses viral replication. Therefore, the relationship between response to IFNa treatment and suppression of viral activity during therapy requires further study. We hypothesized that: 1) IFNa could inhibit the replication of HCV in the patient with chronic hepatitis C. 2) HCV-RNA would decrease or disappear in both serum and liver cells in the responding patients. 3) the changes of HCV-RNA in both serum and liver cell could be measured by the quantitative RT-PCR detection. The overall objective of this study was to evaluate therapeutic efficacy of IFNa for the treatment of chronic hepatitis C. The following specific aims were: 1) to reveal the state of HCV replication, as quantitatively measured by serum and liver HCV-RNA, in patients with chronic hepatitis C before and after treatment with odFN. 2) to compare quantitative analysis results of HCV-RNA with serum AST levels as a marker of hepatic necroinflammatory changes. 3) to determine whether apparently favourable changes in disease activity are correlated with suppression of viral replication. A quantitative reverse transcription polymerase chain reaction (RT-PCR) assay was established for the detection of HCV-RNA. Sensitivity of the RT-PCR assay was quantitatively analyzed by a piece of recombinant HCV-RNA which was in vitro transcribed from a transcription vector HCV-cDNA. Specificity of the RT PCR assay was verified by Southern Blot and DNA typing methods. Serum HCV-RNA was quantitatively detected by the established RT-PCR assay on 12 patients with chronic hepatitis C and treated with interferon-a. Liver HCV-RNA was also measured in 4 of 12 patients. The therapeutic efficacy of interferon was assessed by the correlation between clinical responses and quantitative results for HCV-RNA. The results showed that 7 of 12 (58%) patients had a beneficial response to IFNx treatment at 3-6 months of therapy as reflected by a decreased titer of HCV RNA. Four of 7 (57%) initial responders relapsed 3 months later. Three (25%) patients’ sera became negative for HCV-RNA after more than 12 months in treatment. Serum HCV-RNA titers had parallel changes with liver function in 7 (58%) patients. There was a positive correlation between patients with lower serum HCV-RNA titers prior to initiation of treatment and better therapeutic responses. Although similar trials need to be carried out on large sample size of patients, the following conclusions could be drawn from preliminary results: interferon-cx has a beneficial effect on more than half the patients with chronic hepatitis C by inhibiting viral replication and improving the liver function within the first 6 months of treatment; long term IFNa treatment (6-12 months or more) may increase the probability of eradicating HCV; the results of quantitative analysis on HCV-RNA may be used as a valuable mean to predict and monitor the therapeutic response of IFNc. Topics that further studies should focus on are to monitor the therapeutic response by using other means such as measurement of 2’,5’-oligoadenylate synthetase activity, to reveal the possible reason for poor response such as genotype variation and anti-IFN antibody, to try other approaches to IFN administration, and to develop other antiviral agents.

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