Chronic hepatitis C virus (HCV) infection poses a major worldwide health care problem as a leading cause of chronic liver disease and cirrhosis. The burden of disease in the United States and in Europe is substantial, and HCV infection is now the most common underlying diagnosis in patients listed for liver transplantation. The liver disease is usually insidious in onset and most of the morbidity and mortality occur as a direct consequence of the development of liver fibrosis and cirrhosis and later complications. In the majority of patients, a striking feature of this disease is the relatively slow rate of progression of the liver fibrosis, with significant problems usually developing after an interval of 15–20 years or longer. Fortunately, the last decade has witnessed major improvements in our ability to treat this disease, with progressive improvements in the rates of viral clearance accompanied by normalization of transaminases and improvements in necro-inflammatory scores on liver histology. For some time, a key question has been whether treatments that lead to viral clearance can influence the rate of progression of liver fibrosis and perhaps in some cases lead to regression of this complex pathologic process. The article in this issue of GASTROENTEROLOGY by Poynard et al. 1 analyzes the results of 4 previous major clinical trials2–5 involving 3010 patients that were randomized to various treatment regimes with either interferon or pegylated interferon, with or without the addition of ribavirin (a total of 10 different regimens are analyzed), and that had both pre-and post-treatment liver biopsies. This report extends a previous similar study of 1509 chronic HCV patients6 but concentrates more on the effects of antiviral treatment on patients with established cirrhosis. The observations in the new study by Poynard et al. are very important and provide clear evidence for major beneficial effects of antiviral therapy on liver fibrosis; put simply, the more effective the treatment regime in terms of clearance of HCV, the more likely there is to be a decrease in severity of liver fibrosis. The most striking result was the finding that of a total of 153 patients with cirrhosis, reversal was observed in 75 (49%).

Do I hear you say “But that’s impossible, cirrhosis isn’t reversible!” If so, this paper and a summary of other studies in the field may help to change your mind. There is now a substantial body of evidence in both human liver disease and in animal models to indicate that liver fibrosis and cirrhosis are dynamic processes that can both progress and regress over time, depending in part on whether or not the underlying cause is persistent. But first, are we sure that the observations of Poynard et al. are correct, or could there have been any confounding factors? These could theoretically include the sampling error of liver biopsy, variable pathological interpretation of the same liver biopsy (intraobserver variation), or overenthusiastic interpretation of minor changes in liver fibrosis scores. All of these problems were considered and addressed in the study. Sampling error is a perennial problem, but is less likely to be