In patients with chronic hepatitis C who relapse after treatment with interferon, therapy with interferon and oral ribavirin results in higher rates of sustained virologic, biochemical, and histologic response than treatment with interferon alone.

No abstract

Among numerous established human hepatoma cell lines, none has been shown susceptible to hepatitis B virus (HBV) infection. We describe here a cell line, called HepaRG, which exhibits hepatocytelike morphology, expresses specific hepatocyte functions, and supports HBV infection as well as primary cultures of normal human hepatocytes. Differentiation and infectability are maintained only when these cells are cultured in the presence of corticoids and dimethyl sulfoxide. The specificity of this HBV infection model was ascertained by both the neutralization capacity of HBV-envelope protein-specific antibodies and the competition with an envelope-derived peptide. HepaRG cells therefore represent a tool for deciphering the mechanism of HBV entry. Moreover, their close resemblance to normal human hepatocytes makes them suitable for many applications including drug metabolism studies.H epatitis B, one of the major infectious diseases worldwide, is caused by a small enveloped DNA virus, the hepatitis B virus (HBV). HBV exhibits a very narrow host range and shows a strong tropism for liver parenchymal cells. It has therefore been assumed that susceptibility to HBV infection is restricted to differentiated cells. Accordingly, it was found that only human hepatocyte primary cultures were susceptible to HBV infection (1-4). However, the use of this model is hampered by the limited availability and the inherent variability of human liver material. Even though several human hepatoma-derived cell lines support HBV replication after HBV DNA transfection (5-9), none of them are susceptible to HBV infection.We describe here a hepatoma-derived cell line that expresses a representative panel of liver-specific genes and is susceptible to HBV infection. This goal was achieved by combining an original selection procedure applied early after the cell line establishment in culture and the use of appropriate culture conditions, allowing the commitment of these cells to an optimal differentiation status. MethodsIsolation of the Cell Line and Culture Conditions. Cells were isolated from a liver tumor of a female patient suffering from hepatocarcinoma and hepatitis C infection. All experimental procedures were conducted in conformity with French laws and regulations and were approved by the National Ethics Committee. The samples were minced into small pieces, washed with Hepes buffer (pH 7.7; 140 mM NaCl͞2.68 mM KCl͞0.2 mM Na 2 HPO 4 ͞10 mM Hepes), and digested with 0.025% collagenase D (Boehringer Mannheim) diluted in the same buffer supplemented with 0.075% CaCl 2 under gentle stirring at 37°C. The cell suspension was washed twice in Hepes buffer and resuspended in a William's E medium supplemented with 10% FCS, 100 units͞ml penicillin, 100 g͞ml streptomycin, 5 g͞ml insulin, and 5 ϫ 10 Ϫ7 M hydrocortisone hemisuccinate. Cell suspension was distributed in several dishes without any coating feeder layer. After several weeks, cell growth was sufficient to fulfill the culture dishes. Cells appeared well differentiated, with a hepatocyte-like ...

FOR THE HEPATITIS INTERVENTIONAL THERAPY GROUP 10This international, randomized, active-controlled, parallel-group, double-blind dose-finding study compared peginterferon alfa-2b (PegIntron ™ ) to interferon alfa-2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1,219 subjects to receive either the standard three-times-weekly (TIW) interferon alfa-2b dose (3 MIU) or the once-weekly (QW) peginterferon alfa-2b (0.5, 1.0, or 1.5 g/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 peginterferon alfa-2b doses significantly (P < .042) improved virologic response rates (loss of detectable serum HCV RNA) after treatment and after follow-up, as compared with interferon alfa-2b. Unlike the end-of-treatment virologic response, the sustained virologic response rate was not doserelated above 1.0 g/kg peginterferon alfa-2b because of a higher relapse rate among patients treated with 1.5 g/kg peginterferon alfa-2b, particularly among patients infected with genotype 1. All 3 peginterferon alfa-2b doses decreased liver inflammation to a greater extent than did interferon alfa-2b, particularly in subjects with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, peginterferon alfa-2b maintained (0.5 g/kg) or surpassed (1.0, 1.5 g/kg) the clinical efficacy of interferon alfa-2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 g/kg peginterferon alfa-2b in patients infected with genotype 1 and high viral levels warrants further evaluation. (HEPATOLOGY 2001;34:395-403.)The current international standard of care treatment for chronic hepatitis C, interferon alfa-2b in combination with ribavirin, has proven highly effective, achieving sustained viral eradication in approximately 40% of patients. 1,2 Interferon alfa-2b is administered as a fixed dose 3 times per week, but this schedule is burdensome to patients and may be associated with virologic breakthrough infections. 3,4 To maintain constant pressure on the virus and reduce the frequency of drug administration, a pegylated formulation of interferon alfa-2b has been developed. The advantages of protein pegylation are well established, having been described for many clinically applicable proteins. [5][6][7][8] Covalently attached polyethylene glycol (peg) delays protein clearance and reduces immunogenicity. 8 The resulting longer plasma half-life increases exposure to the drug and therefore may improve efficacy and allow for less frequent dosing. Less frequent dosing, in turn, may improve patient compliance and quality of life.Peginterferon alfa-2b (PegIntron ™ ), a protein-conjugate containing a single straight-chain peg with a molecular weight of 12,000 daltons and interferon alfa-2b in a 1:1 ratio, maintains its antiviral activity but has an approximately 10-fold longer plasma half-life than interferon alfa-2b in humans (29-34 hours vs. 3.6 ho...