Alpha interferon therapy of chronic hepatitis C is typically accompanied by a biphasic decrease in hepatitis C virus (HCV) RNA levels: an initial rapid decline during the first 24 to 48 hours, and a second more gradual decline during the following weeks. The rate of second-phase decline correlates with ultimate response to interferon treatment. Thus, assessment of early virological response (EVR) may predict outcome. Data from 2 large clinical trials of peginterferon and ribavirin were combined and analyzed to determine the optimal definition of an EVR which, if not achieved, was associated with a low likelihood of a sustained virological response (SVR). A fall in HCV RNA level to undetectable or by at least 2 loglo units after 12 weeks was found to be the optimal definition of an EVR. Among 965 patients, 778 (80%) achieved an EVR by week 12, including all except 1 patient with genotypes 2 or 3. Among 187 patients without an EVR, only 3 (1.6%) had an SVR. These findings suggest that patients with genotype 1 who do not achieve an EVR should stop treatment after 12 weeks. Use of an early stopping rule reduces treatment costs by at least 16% and avoids the inconvenience and side effects of treatment in the 19% of patients without an EVR who have little chance of a lasting virological response. (HEPATOLOGY 2002; 36:s 145-Sl5 1 .) he level of hepatitis C virus (HCV) RNA in the blood of patients with chronic hepatitis C T reflects a balance between virus production and clearance. Kinetic studies and mathematical modeling estimate that there is a constant high rate of production of virions in chronic hepatitis C, ranging from 10'' to 10l2 per day. In addition, the half-life of HCV is short, averaging only a few hours.2 This balance of production and clearance is altered with initiation of antiviral therapy. Treatment with alpha interferon results in a decline in HCV RNA levels that can be resolved mathematically into 2 phases. After a latent period of 8 to 10 hours following the injection of interferon, there is an initial rapid decline in HCV RNA levels, the magnitude of which correlates with dose of interferon and viral genotype. The first phase decline is Abbreviations: HCK hepatitis C virus; SVR, sustained virological response;