In patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferon alfa-2b plus ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone.

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To gain a clearer understanding of the rate of progression to cirrhosis and its determinants in chronic hepatitis C virus (HCV) infection, a systematic review of published epidemiologic studies that incorporated assessment for cirrhosis has been undertaken. Inclusion criteria were more than 20 cases of chronic HCV infection, and information on either age of subjects or duration of infection. Of 145 studies examined, 57 fulfilled the inclusion criteria. Least-squares linear regression was employed to estimate rates of progression to cirrhosis, and to examine for factors associated with more rapid disease progression in 4 broad study categories: 1) liver clinic series (number of studies ‫؍‬ 33); 2) posttransfusion cohorts (n ‫؍‬ 5); 3) blood donor series (n ‫؍‬ 10); and 4) community-based cohorts (n ‫؍‬ 9). Estimates of progression to cirrhosis after 20 years of chronic HCV infection were 22% (95% CI, 18%-26%) for liver clinic series, 24% (11%-37%) for posttransfusion cohorts, 4% (1%-7%) for blood donor series, and 7% (4%-10%) for community-based cohorts. Factors that were associated with more rapid disease progression included older age at HCV infection, male gender, and heavy alcohol intake. Even after accounting for these factors, progression estimates were much higher for cross-sectional liver clinic series. Selection biases probably explain the higher estimates of disease progression in this group of studies. Community-based cohort studies are likely to provide a more representative basis for estimating disease progression at a population level. These suggest that for persons who acquire HCV infection in young adulthood, less than 10% are estimated to develop cirrhosis within 20 years. (HEPATOLOGY 2001;34:809-816.)The majority of persons with hepatitis C virus (HCV) infection progress to chronic infection, which can lead to liver fibrosis and the subsequent occurrence of cirrhosis, liver failure, and hepatocellular carcinoma. 1 However, it is unclear what proportion of persons will develop HCV-related hepatic complications and who is most at risk of progression. The likelihood of progression can influence choice about therapy for the individual, and is a fundamental factor in predicting disease burden at a population level.Because chronic HCV infection is largely asymptomatic and runs a protracted and highly variable course, it has been difficult to reliably measure disease progression in epidemiologic studies. 2 Early studies in blood-transfusion recipients and liver clinic patients seemed to indicate that cirrhosis would develop in 20% to 50% within 20 years of acquiring HCV infection. 3,4 Then, several more recent studies suggested progression rates that were much lower, of the order of 2% to 10%. 5-9 Some interpreted these discrepancies as being caused by different distributions of factors associated with more rapid disease progression, such as age at HCV infection, gender, and source of HCV infection, between the study populations. The higher estimates, however, continue to be used to project disease bur...

A dynamic equilibrium between viral production and clearance characterizes untreated chronic hepatitis C viral infection. After initiating antiviral treatment, a typical multiphasic decay of viremia can be observed and analyzed using mathematical models. To elucidate the antiviral mechanism of ribavirin when used in combination with (pegylated) interferon alfa, we investigated kinetic parameters in patients with chronic hepatitis C treated with either peginterferon ␣-2a with or without ribavirin and standard interferon ␣-2b plus ribavirin for 48 weeks. Serum HCV RNA was measured frequently before, during, and at the end-of-treatment and the follow-up period. By using an appropriate model for viral dynamics, kinetic parameters were derived from nonlinear, least square fitting of serum HCV RNA quantifications. The first phase of viral decay (day 1) and the second phase of viral decay (days 2 to 21) were similar for all treatment groups. After about 7 to 28 days, a third phase of viral decay was seen in several patients, and this phase of decay was significantly faster in patients treated with peginterferon ␣-2a plus ribavirin compared with those treated with peginterferon ␣-2a alone. The decay of this third phase was associated with the virologic end-of-treatment response and sustained virologic response. In conclusion, the third-phase decay of initial viral kinetics, which may represent a treatment-enhanced degradation of infected cells, was more pronounced in patients treated with peginterferon ␣-2a plus ribavirin. This finding suggests that combination treatment leads to a better restoration of the patient's immune response. C hronic infection with hepatitis C virus (HCV) is characterized by a dynamic equilibrium between virus production and clearance. 1,2 A characteristic biphasic or multiphasic initial decline of serum HCV RNA is observed when this equilibrium is disturbed by interferon alfa and can be analyzed mathematically. 1-3 Viral kinetic models estimated a very short half-life of free hepatitis C virions in vivo (Ͻ5 hours) and suggested that a rapid first phase (day 1) of viral decline relates to the decay of free viral particles, whereas the much slower second phase (days 2 to 14) of viral decline reflects the clearance of productively infected cells. Moreover, a typical biphasic decay could be explained if interferon has a single therapeutic effect of partially blocking viral production. 1-3 Kinetic analyses were central to our current understanding of antiviral therapy and have influenced approaches toward treatment of patients with chronic hepatitis C. 4 New results indicate that a third phase of viral decay can be present and may be due to suppression of the immune response during chronic HCV infection and a restoration of the cellular immune response that occurs when the serum viral load declines below an individual threshold. 5 Wide fluctuations in the plasma concentration of interferon are seen because of its short elimination half-life (4 to 10 hours) and render mathematical modeling of HCV ki...

The factors influencing lymphocyte trafficking to the liver lobule during chronic hepaititis C virus (HCV) infection are currently not well defined. Interferon-gamma-inducible protein 10 (IP-10), a chemokine that recruits activated T lymphocytes, has recently been shown by in situ hybridization to be expressed in the liver during chronic HCV infection. This study sought to define the cellular source of IP-10 in the liver by immunohistochemistry, to examine the expression of its receptor, CXCR3, on T lymphocytes isolated from blood and liver tissue, and to correlate IP-10 expression with the histological markers of inflammation and fibrosis. IP-10 was expressed by hepatocytes but not by other cell types within the liver, and the most intense immunoreactivity was evident in the areas of lobular inflammation. The IP-10 receptor was expressed on a significantly higher proportion of T lymphocytes in the liver compared with blood. CD8 T lymphocytes, which predominate in the liver lobule, were almost uniformly CXCR3-positive. The expression of IP-10 mRNA correlated with lobular necroinflammatory activity but not with inflammation or fibrosis in the portal tracts. These findings suggest that IP-10 may be induced by HCV within hepatocytes and may be important in the pathogenesis of chronic HCV infection, as recruitment of inflammatory cells into the lobule is an important predictor of disease progression.