Key Learning Objectives
At the end of the session, the participants will be able to describe:
- a definition of fibrosis stages
- a definition of liver fibrosis progression estimates
- advantages and disadvantages of the different estimates
- factors associated with liver fibrosis progression
- the impact of a treatment on fibrosis progression in patients with or without sustained virologic response
Current understanding of HCV infection has been advanced by the concept of liver fibrosis progression. HCV can be lethal when it leads to cirrhosis, the last stage of liver fibrosis. Therefore, an accurate estimate of fibrosis progression represents an important surrogate endpoint for evaluation of the vulnerability of any given patient for these potential complications and for assessment of any treatment’s impact on natural history. A major interest of this estimate is that approved treatments in chronic hepatitis C, interferon and recently the combination (IFN-R) of interferon alfa-2b (IFN) and ribavirin (R) have not only anti-viral, but also anti-fibrotic and immunomodulatory effects. Thus, these treatments have the potential to affect the fibrosis progression in patients regardless of the virologic response.
Limitations of any estimate of fibrosis include:
- the difficulty in obtaining paired liver biopsies
- the necessity for large numbers of patients to achieve statistical power
- the heterogeneity of fibrosis assessments
Even in randomized trials, less than 50% of patients undergo a second liver biopsy after the end of the treatment. Because the time elapsed between biopsies is relatively short (usually between 12 to 24 months), the number of events (transition from one stage to another) is rare. Therefore, the comparisons between fibrosis progression rates requires a large sample size to observe significant differences.
Assessment of Fibrosis Progression
The assessment of fibrosis progression according to time can be assessed by three methods permitting one to calculate an observed, an estimated and a simulated rate.
The observed (direct) fibrosis progression rate was defined as the ratio between the difference in fibrosis stage expressed in METAVIR units between two biopsies and the interval between the two biopsies in years. For example, for a patient with fibrosis stage 2 at the first biopsy and stage 3 at the second biopsy performed two years later, the fibrosis progression rate was 0.500 fibrosis units per year. The advantage of this assessment is that the duration is exactly known. The limitation is that the duration between biopsies is rather short (mean 20 months) in comparison to the mean time of transition between fibrosis stages (7 years) and that there is a risk of sampling and interpretation errors for both biopsies.
Adapted from Poynard, et al. Lancet 1997;349:825
The estimated (indirect) fibrosis progression per year is defined as the ratio between the fibrosis stage in METAVIR units and the estimated duration of infection in years. In this model it is assumed that the patient has no liver fibrosis on the day of infection (stage F0) and that the fibrosis progression is constant. For example, for a patient with fibrosis stage 2 and an eight-year duration of infection, the fibrosis progression rate was 0.250 fibrosis unit per year. The advantage of this assessment is the longer duration (mean 16 years) and that there is no variability at infection if the assumption of F0 is correct. The limitations are that the duration of infection can be unknown and when known it remains an estimate, (i.e., it is assumed that the first transfusion or the first IV drug injection was the true date of infection). It is also possible that some patients have already a fibrosis (i.e., due to alcohol) the day of infection.
Adapted from Poynard, et al. Lancet 1997;349:825
The simulated rate is obtained by calculating the expected fibrosis progression rate according to a regression function. For example, in a previous data base of 1157 patients never treated and with known duration of infection, the expected fibrosis progression rate per year, by logistic regression, was = 0.058 – (0.0035 x duration of infection in years) + (0.0037 x age at infection in years) + (0.021 x sex (0 if female, 1 if male) + (0.028 x alcohol consumption (0 if less than 50 g per day, 1 if 50 g or more). This simulated rate is used to construct a second control group with the baseline characteristics of treated patients. The main limitation is that only 30% of the variance is explained.
Adapted from Sobesky et al. Gastroenterology 1999;116:378-86
Several examples of the usefulness and limitations of the fibrosis progression modeling will be given including:
Natural history of liver fibrosis progression in a:
- general population infected by HCV
- population of HCV infected patients with persistent normal ALT
- population of patients co-infected with HCV and HIV
Impact of treatment on the liver fibrosis progression in:
- patients treated by interferon alone
- patients treated by interferon-ribavirin combination
- Projecting future healthcare burden from hepatitis C and improving the pharmaco-economic models
Thierry Poynard, MD, PhD
- The METAVIR cooperative group. Inter- and intra-observer variation in the assessment of liver biopsy of chronic hepatitis C. Hepatology 1994;20;1:15-20.
- Poynard T, Bedossa P, Opolon P, for the OBSVIRC, METAVIR and CLINIVIR and DOSVIRC groups. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825-32.
- Sobesky R, Mathurin P, Charlotte F, Moussalli J, Olivi M, Vidaud M, et al for the MULTIVIRC group. Modeling the impact of alfa interferon treatment on liver fibrosis progression in chronic hepatitis C: a dynamic view. Gastroenterology 1999;116:378-86.
- Poynard T, McHutchison J, Davis G, Esteban-Mur R, Goodman Z, Bedossa P, Albrecht J, and the FIBROVIRC Project Group. Impact of interferon alfa-2b and ribavirin on the liver fibrosis progression in patients with chronic hepatitis C. Hepatology 1998;28:497A.
- Deuffic S, Poynard T, Buffat L, Valleron A-J. Trends in primary liver cancer [letter]. Lancet 1998;351:214-5.
- Benhamou Y, Di Martino V, Bocher M, Charlotte F, Azria F, Perrin M, et al for the MULTIVIRC group. Liver fibrosis progression in patients coinfected with HIV and HCV. Hepatology 1998;2:564A.
- Mathurin P, Moussalli J, Cadranel JF, et al. Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity. Hepatology 1998;27:868-72.