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      Interferon Therapy for Chronic Hepatitis C in Hemodialysis Patients: Increased Serum Levels of Interferon

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          Background/Aims: The efficacy and side effects of interferon (IFN) therapy have not been well clarified in hemodialysis patients with chronic hepatitis C. Methods: In 6 of 9 hemodialysis patients with chronic hepatitis C, 3 million units (MU) or 6 MU of recombinant IFN-α2b or natural IFN-α were administered intramuscularly daily for the first 2 weeks, followed by three times a week for 22 weeks. In the remaining 3 patients, 3 MU of IFN-α2b were given three times a week for 24 weeks. Serum concentrations of IFN-α2b were measured sequentially after the injection of interferon. Responders were defined as the patients with normal serum aminotransferase and negative serum HCV RNA 6 months after the cessation of IFN therapy. Results: Three of the 6 patients who were administered IFN daily in the first 2 weeks were responders, while the other 3 withdrew from the therapy due to serious adverse events such as depression, loss of consciousness and persistence of high-grade fever. Serious adverse events were not observed in the 3 patients without daily administration. Half-lives of IFN-α2b in hemodialysis patients were significantly longer than those in nonuremic patients (10.0 vs. 6.0 h, p < 0.05). Moreover, the areas under the serum concentration curve of the hemodialysis patients were significantly larger than those of nonuremic patients (756 ± 223 vs. 324 ± 223 IU·h/ml, p < 0.05), despite the fact that the dose of IFN-α administered to hemodialysis patients was half that administered to nonuremic patients. Conclusions: In hemodialysis patients with chronic hepatitis C, pharmacokinetic parameters of IFN may be different from those in nonuremic patients, and daily or high-dose administration of IFN may lead to serious adverse events in those patients.

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          Risk factors for hepatocellular carcinoma among patients with chronic liver disease.

          To detect potentially curable cases of hepatocellular carcinoma, outpatients with chronic hepatitis or compensated liver cirrhosis who were seen at the Center for Adult Diseases (Osaka, Japan) were examined periodically by means of ultrasonography and measurement of serum alpha-fetoprotein. Risk factors for hepatocellular carcinoma were identified with a Cox proportional-hazards model. A total of 917 patients, 40 to 69 years old, were registered from May 1987 to March 1991. By the end of September 1991, liver cancer had developed in 54. The three-year cumulative risk of liver cancer was 12.5 percent for 240 patients with liver cirrhosis at enrollment and 3.8 percent for 677 patients with chronic hepatitis. Cox regression analysis showed that the risk of liver cancer was increased almost sevenfold in patients with hepatitis B surface antigen (rate ratio, 6.92; 95 percent confidence interval, 2.92 to 16.39) and fourfold in patients with hepatitis C antibody (rate ratio, 4.09; 95 percent confidence interval, 1.30 to 12.85). A high alpha-fetoprotein value at enrollment was also a risk marker for liver cancer. Patients with hepatitis C virus infection have a greatly increased risk of liver cancer. Further studies are required to clarify the roles of other risk factors, including drinking and smoking habits.
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            Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection.

            A region associated with sensitivity to interferon has been identified in the nonstructural protein 5A (NS5A) of hepatitis C virus (HCV) genotype 1b. The region spans amino acid residues 2209 to 2248 (NS5A2209-2248) of HCV-J, a strain of HCV-1b whose complete genomic sequence has been identified. We examined whether the NS5A2209-2248 sequence present before therapy could be used as a predictor of the response to interferon therapy in patients with chronic HCV-1b infection. We retrospectively analyzed 84 patients with chronic HCV-1b infection who had received interferon alfa (total dose, 516 million to 880 million units) for six months. Pretreatment serum samples were analyzed. The amino acid sequence of NS5A2209-2248 was determined by direct sequencing of the HCV genome amplified by the polymerase chain reaction (PCR) and was compared with the established sequence for HCV-J. A complete response, as evidenced by the absence of HCV RNA in serum on nested reverse-transcription PCR for six months after therapy, did not occur in any of the 30 patients whose NS5A2209-2248 sequences were identical to that of HCV-J (wild type). Five of 38 patients (13 percent) with 1 to 3 changes in NS5A2209-2248 (intermediate type) had complete responses, as did all 16 patients with 4 to 11 amino acid substitutions (mutant type), indicating that the mutant type was significantly associated with a complete response (P < 0.001). Although baseline serum HCV RNA levels, as measured by a branched-chain DNA assay, were lower in patients with the mutant type of NS5A2209-2248 than in those with the other types (P < 0.001), multivariate analyses revealed that the number of amino acid substitutions in NS5A2209-2248 was the only variable associated with an independent effect on the outcome of interferon therapy (odds ratio, 5.3; 95 percent confidence interval, 1.6 to 18; P = 0.007). In patients with chronic HCV-1b infection, there is a substantial correlation between responses to interferon and mutations in the NS5A gene.

              Author and article information

              S. Karger AG
              September 1998
              04 September 1998
              : 80
              : 1
              : 51-56
              a Department of Internal Medicine, Musashino Red-Cross Hospital, Musashino-shi, b Department of Internal Medicine, Tsuchiura Kyodo Hospital, Tsuchiura-shi, and c Second Department of Internal Medicine and d Division of Health Science, Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
              45125 Nephron 1998;80:51–56
              © 1998 S. Karger AG, Basel

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              Tables: 5, References: 31, Pages: 6
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