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Fig. 2. Three different rates of progression of fibrosis (from stage 0 to 4) by duration of infection. A rapid rate might be seen in men infected after the age of 40 years who drink more than 50 g alcohol daily. A slow rate might be seen in women infected before the age of 40 years who are non-drinkers or drink less than 50 g alcohol daily. (Reprinted with permission from Elsevier Science [The Lancet, 1997, vol 349, pp 825-832].15)

with worsening will be confounded by factors associated with sampling error.

Prospective Studies. Prospective studies of the nat- ural history of hepatitis C with timed liver biopsies in a wide array of patients who are not treated would be the ideal approach to define rates of fibrosis in this disease. However, such prospective studies are difficult to or- ganize and conduct. Because there are effective thera- pies for hepatitis C, it is not reasonable or ethical to follow patients with severe disease without therapy. Patients willing to enroll in a natural history study in which they do not receive treatment are not likely to be representative of hepatitis C overall. In addition, in most prospective studies, the time between 2 liver bi- opsies is usually relatively short (3 to 8 years) in rela- tionship to the natural duration of the disease (20 to 50 years). Nevertheless, prospective studies have been conducted, but largely on patients with mild disease or normal serum aminotransferase levels.

Rates of Progression of Fibrosis

Estimates From Cross-Sectional Studies. Cross-sec- tional studies using mathematical modelling performed on large numbers of patients with a single liver biopsy suggest that the average (median) rate of progression of fibrosis in chronic hepatitis C is 0.13 Metavir fibrosis points per year.15 Based on this rate, the average patient would develop cirrhosis within 30 years (Fig. 2). Impor- tantly, rates of progression of fibrosis were not normally distributed, and greatly different estimated rates of pro- gression were found in different patient groups. Thus, the

HEPATOLOGY, November 2002

rate of progression was higher for men than women (0.15 vs. 0.11 fibrosis units per year), in older than younger persons (0.33 if infected over the age of 50 vs. 0.09 if below the age of 20 years), and in heavy alcohol drinkers than in non-drinkers (0.17 vs. 0.12). As a consequence, the estimated average time to development of cirrhosis ranged considerably, from as short as 13 years in men infected with hepatitis C after 40 years of age who drink more than 50 g alcohol daily, to as long as 42 years in women infected under the age of 40 who are non-drink- ers. These estimates were based on the assumption that the progression of fibrosis is linear, which may not be the case. For instance, the time required to progress from stage 1 to 2 may be far longer than the time required to progress from stage 3 to 4. Moreover, fibrosis progression may occur intermittently and may accelerate with age (particularly after the age of 50). Finally, fibrosis may remain stable for decades and not progress. Indeed, in some patients fibrosis may regress spontaneously.

In a more recent study with mathematical modelling based on liver biopsies from 2,213 patients, Poynard et al.16 proposed a new model for fibrosis progression in chronic hepatitis C, in which the fibrosis progression occurs at dif- ferent rates in 4 consecutive phases of infection with acceler- ation after 50 years of age. During the first phase representing the initial 10 years of infection, there is little if any progres- sion unless infection occurs after the age of 50 or human immunodeficiency virus (HIV) infection is present. Dur- ing the second phase, lasting approximately 15 years, there is slow, but steady, progression in fibrosis. Fibrosis progression is intermediate in rate during the next 10 years of the third phase. Finally, in the last phase, there is rapid progression of fibrosis (Fig. 3). In this model, the mean delay to development of cirrhosis is approximately 40 years, unless infection occurs at an older age.

Fig. 3. Probability of developing cirrhosis (Metavir fibrosis stage 4) by duration of infection in 5 cohorts of patients based on age of onset of infection, 21 years, 21 to 30 years, 31 to 40 years, 41-50 years, or greater than 50 years of age. (Reprinted with permission from Elsevier Science, Copyright 2001.16)

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