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					    Romanian Journal of Hepatology

                                                      Romanian Journal of Hepatology 2, no 1, (2006) 9 - 21

                        Luminita Bonyhay, Irina Cucos, Mona Munteanu, Françoise Imbert-Bismut,
                                              Vlad Ratziu, Thierry Poynard
                               Université Pierre et Marie Curie et Groupe Hospitalier Pitié-Salpêtrière

    This review summarizes the diagnostic value of fibrosis biomarkers and the efficacy of antiviral treatments on
fibrosis progression. Non-invasive biomarkers can facilitate the screening and management of chronic hepatitis C and
B. Screening for significant fibrosis is mandatory since very effective antiviral treatments are available, preventing or
reducing fibrosis progression. The reduction in fibrosis progressionwill decrease mortality due to complications of
    In patients with chronic hepatitis C, pegylated-interferons combined with ribavirin are effective in reducing
fibrosis progression. In patients with chronic hepatitis B, lamivudine, adefovir and pegylated-interferon are also
effective in reducing fibrosis progression. In patients with chronic hepatitis Delta, pegylated-interferon is also
effective in reducing fibrosis progression.

  Fibrosis, FibroTest, ActiTest, FibroSURE, fibrosis biomarker, necroinflammatory activity biomarker, liver biopsy, HCV,
HBV, alcoholic liver disease, fatty liver.

    Introduction                                                                        These non-invasive tests can facilitate the
    Consensus conference statements recommend liver                                 screening and management of chronic hepatitis C and
biopsy in the management of almost all patients with                                B. Screening in these fibrotic diseases is mandatory
chronic hepatitis C and B, but also underline the                                   as very effective antiviral treatments are available,
necessity of developing reliable non-invasive tests.                                preventing or to reducing fibrosis progression. The
[(57), (35)] One of major clinical problem is how to                                reduction in fibrosis progression will decrease mortality
best evaluate and manage the increasing numbers of                                  due to the complications of cirrhosis.
patients infected with the hepatitis C (HCV) and B                                     The aim of this review is to summarize the
viruses (HBV) [(57), (35), (1)]. Liver biopsy is still                              diagnostic value of fibrosis biomarkers and the efficacy
recommended in most patients [(16), (8)]. However,                                  of antiviral treatments on fibrosis progression. [(57),
numerous studies strongly suggest that due to the                                   (35)]
limitations [(63), (13), (6)] and risks of biopsy (49), as
well as the improvement in the diagnostic accuracy of                                    Diagnostic value of fibrosis biomarkers
biochemical markers [(53), (59)], that liver biopsy                                     No available single test has demonstrated a
should no longer be considered mandatory.                                           continuous and linear correlation with fibrosis stage
                                                                                    and grades. (23) Serum ALT has been the most
Corresponding author:    Pr Vlad Ratziu                                             commonly investigated marker, but its sensitivity ranges
                         Université Pierre et Marie Curie et Groupe                 from only 61% to 71%. Its diagnostic value is lower
                         Hospitalier Pitié-Salpêtrière,
                         47-83 Boulevard de l'Hôpital,                              than the combination of markers in all direct
                         75651 Paris Cedex 13, France                               comparisons. [(23), (31)]
                         Phone : +33 1 42 16 10 02
                         Fax: +33 1 42 16 14 27                                        Among the extracellular matrix tests, hyaluronic acid
                         Email: vratziu@teaser.fr                                   correlated best with fibrosis stage overall, but has been
                                    L.Bonyhay et al ./ Romanian Journal of Hepatology 2, no 1, (2006) 9 - 21

demonstrated mostly for extensive fibrosis. [(23), (51)].                   corresponding to the well-established METAVIR 31
The area under the ROC curves (AUROCs) for                                  (1994, p.15) scoring system of stages F0 to F4 and of
extensive fibrosis range from 0.65 to 0.86.                                 grades A0 to A3. (5) (Figure 1).
    Markers of extracellular matrix production, such as                         The analyses should preferably be made on fresh
procollagen type III peptide, and degradation, such as                      serum, but can be done with plasma, if necessary,
tissue inhibitor of metalloproteinase-1-4, were less                        (blood sample on lithium heparinate). The
predictive than hyaluronic acid (23).                                       measurements of the six parameters are made
    Among the non-invasive alternatives to liver biopsy                     preferably on fresh serum or plasma, or that which has
(23), several studies have demonstrated the predictive                      been stored between +2°C and +8°C for a maximum of
value of two combinations of simple serum biochemical                       four days in an unlit area, for the protection of bilirubin.
markers in patients infected with HCV: FibroTest (FT;                       For deferred measurements, the serum should be
Biopredictive, Paris, France) for the assessment of                         quickly frozen to 80°C. After thawing, it should be
fibrosis; and ActiTest (AT; Biopredictive, Paris, France)                   centrifuged for 10 minutes at 15,000g. (32). It has been
for the assessment of necroinflammatory activity [(53),                     prospectively demonstrated that the FT-AT can be
(59), (31), (51), (42), (44), (43), (71), (37), (26), (64),                 performed on fasting or non-fasting serum samples.
(54), (56), (32), (41), (58), (60), (10), (27), (7)]. Similar               (41).
results have not been obtained with other diagnostic                            In comparison with liver biopsy, FT-AT is co        st
tests [(23), (31), (51), (42), (44), (43), (71), (37)]. Since               effective; the cost of the test ranges from 90 to 350
September 2002 these tests (FT-AT) have been used                           Euros by country versus 1000-2000 Euros for a liver
in several countries as an alternative to liver biopsy. In                  biopsy. [(56), (58), (60)] (Table 1).
a systematic review, it was concluded that these                                A summary of the FT-AT diagnostic values defined
panels of tests might have the greatest value in                            by cutoffs is given in Table 2. In chronic liver diseases,
predicting fibrosis or cirrhosis (23). It was also stated                   the liver biopsy is far from a true gold standard with a
that biochemical and serologic tests were best at                           high percentage of false negatives and false positives
predicting no or minimal fibrosis and at predicting                         actually due to technical errors in performing biopsies.
advanced fibrosis/cirrhosis and were poor at predicting
                                                                            Figure 1: Conversion between FibroTest and fibrosis stages,
intermediate levels of fibrosis (23). Recent studies
                                                                            and ActiTest and necroinflammatory activity grades
have now demonstrated that the diagnostic values of
                                                                            Panel 1A: FibroTest values according to status, from blood
FT-AT for consecutive stages of fibrosis and grades of
                                                                            donors to patients with cirrhosis
activity were the same for both moderate and extreme
                                                                            Panel 1B: ActiTest values according to status, from blood
stages and grades. [(53), (59), (58), (60)]. It also has                    donors to patients with severe necrosis
been demonstrated that biomarkers such as those                                        F0 = no fibrosis
described here may provide a more accurate                                             F1 = portal fibrosis,
(quantitative and reproducible) assessment of                                          F2 = some septa,
                                                                                       F3 = many septa,
fibrogenic and necrotic events occurring within the liver
                                                                                       F4 = cirrhosis;
than low quality liver biopsy. A prospective study                                     A0 = no activity,
demonstrated that 18% of discordances were primarily                                   A1 = minimal activity,
due to biopsy failure, mostly due to small length, and                                 A2 = moderate,
                                                                                       A3 = severe.
2% to FT-AT failure (59). Several independent groups
have validated the diagnostic values of FT-AT [(10),                        Consensus conferences recommend treatment in patients
                                                                            with either F2 stage or A2 grade.
(27), (7)].
                                                                                Notched box plots show the relationship between
    FT-AT is a noninvasive blood test that combines the                     FibroTest and the stage of fibrosis (A) and between ActiTest
quantitative results of six serum biochemical markers                       and the grade of activity (B).
[alpha2-macroglobulin, haptoglobin, gamma-glutamyl-                             The horizontal line inside each box represents the median
transpeptidase (GGT), total bilirubin, apolipoprotein A1                    and the width of each box the median ± 1.57 interquartile
and alanine amino transferase (ALT)] with the patient's                     range/vn to assess the 95% level of significance between
age and gender in a patented artificial intelligence                        group medians. Failure of the shaded boxes to overlap signifies
algorithm (USPTO 6,631,330) to generate a measure                           statistical significance (P <0.05). The horizontal lines above
                                                                            and below each box encompass the interquartile range (from
of fibrosis stage and necroinflammatory grade in the
                                                                            25th to 75th percentile), and the vertical lines from the ends of
liver. (59).
                                                                            the box encompass the adjacent values (upper: 75th percentile
     FT-AT is a continuous linear biochemical                               plus 1.5 times interquartile range, lower 25th percentile minus
assessment of fibrosis stage and necroinflammatory                          1.5 times interquartile range).
activity grade. It provides a numerical quantitative                        Panel 1C: Conversion between FibroTest and fibrosis stages
estimate of liver fibrosis ranging from 0.00 to 1.00,                       and ActiTest and activity grades.
                                                 L.Bonyhay et al ./ Romanian Journal of Hepatology 2, no 1, (2006) 9 - 21

   FibroTest: from blood donors to cirrhosis; n=1570                                     ActiTest: from blood donors to severe necrosis; n=1570

                 1.00                                                                                     1.00
     Fibro est

                 0.67                                                                                     0.67


                         Donor      F0    F1       F2    F3    F4                                         0.00
                                                                                                                     Donor     A0      A1     A2        A3
   Panel 1A: FibroTest values according to status, from                                       Panel 1B: ActiTest values according to status, from
   blood donors to patients with cirrhosis                                                    blood donors to patients with severe necrosis

                  METAVIR           Knodell               Ishak
 FibroTest        Fibrosis stage    Fibrosis stage        Fibrosis stage                                  METAVIR            Knodell          Ishak
                  estimate          estimate              estimate                       ActiTest         Fibrosis stage     Fibrosis stage   Fibrosis stage
                                                                                                          estimate           estimate         estimate
 0.75 - 1.00         F4                  F4                  F6
 0.73 - 0.74       F3 - F4             F3 - F4               F5                         0.62 - 1.00          A3                A5               A4
 0.59 - 0.72         F3                  F3                  F4                         0.61 - 0.61        A2 - A3             A4               A3
 0.49 - 0.58         F2                F1 - F3               F3                         0.53 - 0.60          A2                A3               A2
 0.32 - 0.48       F1 - F2             F1 - F3             F1 - F3                      0.37 - 0.52        A1 - A2           A1 - A3          A1 - A2
 0.28 - 0.31         F1                  F1                  F2                         0.30 - 0.36          A1                A1               A1
 0.22 - 0.27       F0 - F1             F0 - F1               F1                         0.18 - 0.29        A0 - A1           A0 - A1          A0 - A1
 0.00 - 0.21         F0                  F0                  F0                         0.00 - 0.17          A0                A0               A0

Panel 1C: Conversion between FibroTest and fibrosis stages                               Panel 1D: Conversion between ActiTest and activity
using METAVIR, Knodell and Ishak Fibrosis Scoring systems.                               grades using METAVIR, Knodell and Ishak necro-
                                                                                         inflammatory activity scoring systems
                         Figure 1: Conversion between FibroTest and fibrosis stages, and ActiTest and activity grades

                                             Liver biopsy                                          Biochemical markers

                  History                   Classical standard                                    New tests or panel of tests
                  Disease diagnosis         Fibrosis, activity, steatosis, iron                   Fibrosis, activity (transaminases, ActiTest)
                  Estimate                  Semi-quantitative                                     Quantitative and continuous
                  False negative            Regeneration nodule, small biopsy                     Acute inflammation
                  False positive             Subcapsular biopsy, small biopsy                     Hemolysis, Gilbert's disease, acute hepatitis,
                                                                                                  extra-hepatic cholestasis, acute inflammation
                  Adverse events             3 deaths /10,000                                     None
                                             3 severe / 1,000
                                             30 painful events/ 100
                  Sampling error             33% discordance in fibrosis staging                  None
                                             24% discordance in activity grading
                  Observer error             Fibrosis stage discordance (20%)                     Coefficient variation less than 10%
                                             Activity grade discordance (40%)
                  Minimal requirements      At least 25 mm size                                    Standardized assays, kits and analyzers
                                            More than 5 portal tract
                  Hospitalisation           6 to 24 hours                                          None
                  Contra-indications        Coagulation disorder,                                  None
                                            Risk of respiratory insufficiency
                  Cost                      1,032 Euros for uncomplicated biopsy                  90-300 Euros for FibroTest-ActiTest-FibroSure
                                            2,745 Euros for complicated biopsy

                              Table 1: Summary of advantages and limits of liver biopsy and biochemical markers

A prospective study observed that 18% of                                                 male and 16% were older than 65 years of age. The
discordances were attributable to biopsy failure (mostly                                 most frequent abnormal value observed during post-
due to small length) and 2% to FT-AT failure (59).                                       marketing surveillance was haptoglobin lower than
Between September 1, 2002, and May 31, 2004, a                                           0.12 g/L in 1589 patients (4.89%). Among these
total of 32,527 tests have been reported on the                                          patients, there were 272 cases with high-risk profiles
secured AT-FT Internet site. The subjects were 54.6%                                     for false positives (0.84%) for which the other
                                  L.Bonyhay et al ./ Romanian Journal of Hepatology 2, no 1, (2006) 9 - 21

components were concordant in favor of significant                        were observed in 409 (1.26%) cases. The most
fibrosis. Patients with extremely low haptoglobins,                       frequent cause of abnormally elevated values for
especially when the rest of the results were hardly                       bilirubin was Gilbert's disease, and for haptoglobin,
elevated, could have had hemolysis. High-risk profiles                    it was acute sepsis. (59)
for false positives due to possible Gilbert's disease

  Table 2: Summary of the diagnostic value of FibroTest for the staging of hepatic fibrosis and comparisons with hyaluronic
  acid, the Forns Index and the APRI Index in patients with chronic hepatitis C, from published studies.

      First author   Number Methodology              Marker             Stage            AUROC        Cut-off   Sensitivity Specificity
                     Patients                                           Prevalence       SE

      Imbert-Bismut, 189     Prospective             FibroTest         F2F3F4            0.84          0.10     0.97         0.24
      2001                   Single center                             0.38              0.03          0.30     0.79         0.65
                             First year cohort                                                         0.60     0.51         0.94
                                                                                                       0.80     0.29         0.95
      Imbert-Bismut, 134     Prospective             FibroTest         F2F3F4            0.87          0.10     1.00         0.22
      2001                   Single center                             0.45              0.03          0.30     0.87         0.59
                             Validation cohort                                                         0.60     0.70         0.95
                                                                                                       0.80     0.38         0.97
      Poynard, 2001 165      Retrospective           FibroTest         F3F4              0.74          0.10     0.96         0.24
                             Randomized trial                          Knodell           0.03          0.30     0.81         0.65
                             Multicenter                               0.32                            0.60     0.50         0.92
                                                                                                       0.80     0.13         0.98
      Poynard, 2001 165      Retrospective           Hyaluronic        F3F4              0.65          20       0.81         0.39
                             Randomized trial                          Knodell           0.03          40       0.47         0.65
                             Multicenter                               0.32                            100      0.23         0.91
      Poynard, 2003 352      Retrospective           FibroTest         F2F3F4            0.73          0.10     0.97         0.08
                             Randomized trial                          0.39              0.03          0.30     0.86         0.45
                             Multicenter                                                               0.60     0.50         0.79
                             Before treatment                                                          0.80     0.20         0.95
      Poynard, 2003 352      Retrospective           FibroTest        F2F3F4             0.77          0.10     0.98         0.15
                             Randomized trial                         0.32               0.03          0.30     0.85         0.39
                             Multicenter                                                               0.60     0.46         0.81
                             After treatment                                                           0.80     0.16         0.97
      Rossi, 2003    125     Prospective             FibroTest        F2F3F4             0.74          0.10     0.92         0.29
                             Multicenter                              0.38               0.05          0.30     0.75         0.61
                             Non-validated                                                             0.60     0.42         0.94
                             analyzers                                                                 0.80     0.22         0.96
      Myers, 2003    130     Retrospective           FibroTest        F2F3F4             0.86          0.10     0.98         0.17
                             Single center                            0.45               0.04          0.30     0.90         0.60
                             HCV-HIV Co-                                                               0.60     0.66         0.92
                             infection                                                                 0.80     0.34         0.96
      Thabut, 2003   249     Retrospective      FibroTest             F2F3F4             0.84          0.10     0.98         0.22
                             Single center                            0.38               0.02          0.30     0.84         0.65
                             From Imbert-Bismut                                                        0.60     0.58         0.93
                             publication                                                               0.80     0.29         0.95
      Thabut, 2003   249     Retrospective      Forns Index            F2F3F4            0.78          1        1.00         0.04
                             Single center                             0.38              0.03          3        1.00         0.26
                             From Imbert-Bismut                                                        6        0.55         0.86
                             2001                                                                      8        0.19         0.97
      Le Calvez,     323     Retrospective      FibroTest             F2F3F4             0.83          0.10     0.97        0.30
      2004                   Single center                            0.41               0.02          0.30     0.81        0.66
                             From Imbert-Bismut                                                        0.60     0.58        0.93
                             2001                                                                      0.80     0.33        0.95

      Le Calvez,     323     Retrospective      APRI Index            F2F3F4             0.74          0.50     0.81        0.56
      2004                   Single center                            0.41               0.03          1.00     0.54        0.84
                             From Imbert-Bismut                                                        1.50     0.36        0.91
                             2001                                                                      2.00     0.24        0.95
      Callewaert,    82      Prospective             FibroTest        F4                 0.89          0.10     1.00        0.33
      2004                                                            0.29               0.04          0.30     0.92        0.62
                                                                                                       0.60     0.79        0.81
                                                                                                       0.80     0.67        0.92
      Callewaert,    82      Prospective             Glyco Cirrho      F4                0.87          -0.2     1.00        0.12
      2004                                           Test              compensated       0.04          0.1      0.79        0.88
                                                                       0.29                            0.4      0.21        0.95
                                                                                                       0.6      0.17        1.00

                                             Table 2A: Summary of published studies
                                        L.Bonyhay et al ./ Romanian Journal of Hepatology 2, no 1, (2006) 9 - 21

       Integrated   Number     Marker        Stage          AUROC        Cut-off          Sensitivity    Specificity       Negative     Positive
       database     Patients                 Prevalence     SE           used for                                          Predictive   Predictive
                                                                         METAVIR                                           Value        Value

       With blood    1,570     FibroTest     F2F3F4         0.83           0.21           0.92           0.55              0.94         0.48
       Donors                                0.31           0.01           0.27           0.87           0.62              0.92         0.51
                                                                           0.31           0.84           0.68              0.91         0.54
                                                                           0.48           0.68           0.81              0.85         0.61
                                                                           0.58           0.56           0.87              0.82         0.67
                                                                           0.72           0.38           0.95              0.77         0.76
                                                                           0.74           0.35           0.95              0.76         0.76
                                                                           0.75           0.33           0.96              0.76         0.78
       Without blood 1,270     FibroTest     F2F3F4         0.78          0.21            0.92           0.41              0.89         0.49
       Donors                                0.38           0.01          0.27            0.87           0.48              0.86         0.51
                                                                          0.31            0.84           0.55              0.85         0.54
                                                                          0.48            0.68           0.73              0.79         0.61
                                                                          0.58            0.56           0.83              0.75         0.67
                                                                          0.72            0.38           0.95              0.70         0.76
                                                                          0.74            0.35           0.93              0.70         0.76
                                                                          0.75            0.33           0.94              0.69         0.78

     Table 2B: Integrated database, with predictive values for significant fibrosis according to METAVIR conversion cut-offs
    FT-AT has been extensively studied in patients with                           hepatitis C is to decrease fibrosis progression (Figure 2).
chronic hepatitis C (Table 2) and also in hepatitis B (45),                          Recently approved treatments for chronic hepatitis
alcoholic liver disease (46), nonalcoholic fatty liver                            C obtain 60% sustained virological response. (57) In
disease (62) and as markers of portal hypertension                                these patients there is a clear benefit on fibrosis
[(72), (73)] and recently as prognostic factors of survival.                      progression with reversal of fibrosis stages at follow-up
(78) The diagnostic values for fibrosis stages were
similar. No studies have so far been published in
patients with cholestatic liver diseases, autoimmune                                                                    Liver
                                                                                                                   Fibrotic disease
hepatitis or hemochromatosis.
    One panel of biomarkers combining alpha2-macro-
globulin, hyaluronic acid and tissue inhibitor of metallo-                                                                 F0
                                                                                                                       No fibrosis
proteinases-1 (TIMP-1) is also on the US market
(Fibrospect I and II ™, Prometheus, USA), with limited
abstracts and no full publication. This panel is designed                                                               F1
                                                                                                              Fibrosis without septa
only for fibrosis diagnosis without diagnostic value of
necroinflammatory activity. There have been no studies
presented from a community-based population, and                                                                          F2
the risks of false negative and false positive have not                                                                Few septa

been identified, and there have not been studies in
different chronic liver diseases.
    Recently a study using profiles of serum protein                                                                 Many septa
N-glycans presented a similar AUROC as that seen for
FT in compensated cirrhosis. When combined with FT,
this marker had 100% specificity and 75% sensitivity                                                                       F4
for the diagnosis of compensated cirrhosis, which was
not significantly different from the 92% specificity and
67% sensitivity of FT alone (10). The results validate
the diagnostic value of FT in chronic hepatitis C and                                 Hemorrhage                Hepatic insufficiency           Cancer
also in alcoholic liver diseases which combined
represent 50% of cases.                                                           Figure 2: The model of fibrosis progression in chronic liver
   Efficacy of anti-HCV treatments on fibrosis                                    disease
   progression                                                                    Estimated key numbers of fibrosis natural history from
    Major breakthroughs have been achieved in recent                              literature and our database: the median time from infection
years in the diagnosis and treatment of chronic                                   (F0) to cirrhosis (F4) is 30 years. The mortality at 10 years for
hepatitis C. Unfortunately, even in developed countries,                          cirrhosis is 50%. The transition probability per year from non-
mortality due to hepatitis C is increasing due to a lack                          complicated cirrhosis to each of the complications is around
of detection and treatment. (57) The present best                                 3 %. Main factors associated with fibrosis progression are
strategy to prevent severe complications of chronic                               age and gender, whatever the cause of liver fibrosis.
                                           L.Bonyhay et al ./ Romanian Journal of Hepatology 2, no 1, (2006) 9 - 21

biopsy and even reversal of recently diagnosed                                     coinfected with HIV and HCV with occurrence of
cirrhosis. (52) The main goal of maintenance therapy is                            cirrhosis and hepatocellular carcinoma 15 to 20 years
to reduce fibrosis progression and complications in the                            before patients infected with HCV alone. [(48), (50), (2),
40 % of patients without sustained virological response.                           (55), (24), (30), (28)] Factors associated and not
The knowledge of factors associated with fibrosis                                  associated with fibrosis are summarized in Table 3.
progression could permit the optimization of screening                             The median time from infection to cirrhosis is 30 years,
and treatment strategies [(48), (50), (2), (55), (24), (30),                       with a high inter-individual variability, which is now
(28)].                                                                             better understood. Several factors have been clearly
                                                                                   shown to be associated with fibrosis progression rate:
   Factors associated with fibrosis progression                                    duration of infection, age, male gender, alcohol
    Several factors are associated with fibrosis                                   consumption, HIV coinfection and low CD4 counts.
progression in chronic liver diseases. The highest                                 Metabolic conditions such as obesity and diabetes are
fibrosis progression rate is observed in patients                                  emerging as independent cofactors of fibrogenesis.
                                                                                   [(48), (50), (2), (55), (24), (30), (28), (22)].

          Associated in uni and multivariate                             Not sure                                     Not associated with
          analysis with fibrosis progression                                                                          fibrosis progression

            Fibrosis stage                                                Inflammation                                Last serum viral load
            Age at infection                                              Hemochromatosis heterozygote                Genotypes non-3
            Duration of infection                                         Cigarette consumption                       Mode of infection
            Age at biopsy                                                 Moderate alcohol consumption                Liver viral load
            Consumption of alcohol > 50g per day                          Genotype 3
            HIV coinfection                                               Schistosomiasis
            CD4 count < 200 cells/ml
            Female gender
            Body Mass Index and or Diabetes and or Steatosis

                       Table 3: Factors associated or not with fibrosis progression, in patients infected with HCV

   Impact of treatment on fibrosis progression
                                                                                   (Figure 3) and an improvement in necrosis and
    Several studies have demonstrated the impact on                                inflammation (Figure 4). Maintenance therapy with
fibrosis progression, and on necroinflammatory grades,                             interferon should probably be repeated as after
of different regimens, interferon, pegylated-interferon                            cessation of interferon fibrosis progression restarted
(IFN), or ribavirin, alone or in combination, (see table 4)                        (Figure 5). If this is not possible, one option is to treat
in patients with chronic hepatitis C, with or without                              patients who have extensive fibrosis with PEG
sustained virological response. [(52), (66), (14), (68),                           interferon alone in order to decrease the progression
(67), (3), (12), (4), (47), (76), (77), (18), (11), (38), (29)]                    rate to cirrhosis, while waiting for a new generation of
    In nonresponders, after the optimized combination                              drugs. Small doses of PEG-IFN, i.e. 0.5 ug, are
of ribavirin and pegylated interferon, the best strategy                           interesting in this indication because of its good
is unknown. These patients should be included in                                   tolerance and the once weekly injection (41). Patients
randomized trials. The concept of maintenance                                      who could benefit the most from maintenance therapy
(suppressive) therapy has been developed with                                      are patients with rapid fibrosis progression rates. If the
standard interferon monotherapy showing in non-                                    date of infection is known or if the patients have been
responders a decrease in fibrosis progression rates                                biopsied twice, it is possible to estimate the fibrosis

                              Factors                         Liver fibrosis progression          Hepatocellular carcinoma
                                                              decrease                            decrease

                              Interferon                          Yes                                  Yes
                              Interferon-Ribavirin                Yes                                  Unknown
                              PEG Interferon                      Yes                                  Unknown
                              PEG-Interferon-Ribavirin            Yes                                  Unknown

            Table 4: Treatments associated with decrease in liver fibrosis progression or decrease in hepatocellular
                     carcinoma incidence in prospective or retrospective studies in chronic hepatitis C
                                                                  L.Bonyhay et al ./ Romanian Journal of Hepatology 2, no 1, (2006) 9 - 21

                                                                                             102 Controls Matched
                                                                                               91 Non Responders (ALT 3 mo)

                                                                   F METAVIR


                                                                               1                    94 Responders (ALT 3 mo)
                                                                                   0    10        20         30                                          40
                                                                                              Duration (years)
                                          Figure 3: Suppressive (or maintenance) concept.
                                          Adapted with permission (68) Interferon reduces the fibrosis progression among viral non-responders
                                          in comparison with spontaneous progression without treatment. Interferon was given for 24-48 weeks
                                          in total, without stopping treatment if ALT was still elevated after 3 months of treatment.

                                                                                                                  Improvement of Fibrosis Stage
   Necrosis and inflammation grade

                                                  IFN 30 months   IFN 6 months                                                                                duration between biopsies <3years    >3 years

                                     14                                                                                                            0.8
                                     10                                                                                                            0.2
                                      8                                                                                                              0
                                      4                                                                                                           -0.6
                                      2                                                                                                           -0.8
                                                                                                                                                              IFN-SR           IFN-NR             Untreated
                                           M0         M6              M18              M30

   Figure 4: Histological benefit of maintenance therapy                                                         Figure 5: Suppressive (or maintenance) concept.
   with interferon. Adapted with permission (66)                                                                 Adapted with permission (67)
   Virologic nonresponders after six months of interferon                                                      Interferon improved the fibrosis stages both in viral
   were randomized to 24 more months (maintenance                                                              responders and in viral nonresponders in comparison
   therapy n=27) versus no further treatment (n=26).                                                           with untreated patients. When the duration between
   There was a significant histological improvement in                                                         biopsies was longer than three years, the
   patients receiving maintenance therapy.                                                                     improvement was greater in sustained responders. In
                                                                                                               viral non-responders, fibrosis progression restarted
                                                                                                               after three years. In untreated patients fibrosis
                                                                                                               progression was time dependent.

progression rate per year [(52), (48), (50), (55), (24),                                                  aged 40 years, infected for 10 years, and F0+F1 at
(14), (68), (67), (3), (12)]. Patients with extensive                                                     diagnosis. As the patient's age and duration of
fibrosis, Stages F2, F3 or F4, as well as patients with                                                   infection increased, the risk of fibrosis increased and
high fibrosis progression rate, more than 0.20                                                            the impact of IFN treatment decreased.
METAVIR fibrosis stage progression per year, are good                                                         We pooled individual data from 3010 naïve patients
candidates for maintenance therapy. Estimates of                                                          with pretreatment and posttreatment biopsies from four
fibrosis by non-invasive biochemical markers should                                                       randomised trials. (52) Ten different regimens
improve even more these strategies [(53), (51)].                                                          combining standard interferon, PEG interferon, and
Because of the sampling error of biopsies, intra                                                          ribavirin were compared. The impact of each regimen
observer variability, and risk-benefit of biopsies, studies                                               was estimated by the percentage of patients with at
with paired biopsies with hundred of patients are too                                                     least a one grade improvement in necrosis and
small, particularly in non-treated patients [(48), (2), (55),                                             inflammation (METAVIR score), the percentage of
(24)].                                                                                                    patients with at least a one stage worsening in fibrosis
    According to a Markov age-dependent modeling, a                                                       METAVIR score, and by the fibrosis progression rate
ten-year increment in duration of infection increases                                                     per year. Necrosis and inflammation improvement
the risk of progression by 32% for IFN treated patients                                                   ranged from 39% (interferon 24 weeks) to 73% (PEG
and by 51% for untreated patients. The course of a                                                        1.5 g/kg plus ribavirin >10.6mg/kg/day; P < 0.001).
series of 1000 IFN treated and 1000 untreated patients                                                    Fibrosis worsening ranged from 23% (interferon 24
was simulated over 5 years according to the initial                                                       weeks) to 8% (PEG 1.5 g/kg plus ribavirin >
stage of fibrosis and age and duration of infection at                                                    10.6mg/kg/day; P < 0.001). (Figure 6). All regimens
diagnosis. IFN treatment decreased the risk of                                                            significantly reduced the fibrosis progression rates in
progression to F3+F4 by a factor of 4.8, for subjects                                                     comparison to rates before treatment. The reversal of
 (14).                                                                                                    cirrhosis was observed in 75 patients (49%) of 153
                                             L.Bonyhay et al ./ Romanian Journal of Hepatology 2, no 1, (2006) 9 - 21

        Improve d          Stabilized            Worsened                                        Improve d            Stabilized              Worsened
       100%                                                                                      100%                       6 12 6
                               14 14 10 20 8                                                          22 19 17 15 18 15 12
                23 18 17 16 18                                                                                                   21
        80%                                                                                       80%                      24
                                                                                                                        24    23
                                                                                                            35 36 33 34
        60%                                                                                       60% 39 40
                               66 66 67 57
                65 66 62 62 65                                                                    40%
        40%                                                                                                                                   64 70 65 73
                                                                                                  20% 39 41 48 49 49
                      22 21 17 20 20 23 23 24                                                       0%
                12 16
         0%                                                                                                 IFN IFN PEG PEG PEG IFN- IFN- PEG PEG PEG
                IFN   IFN PEG PEG PEG IFN- IFN- PEG PEG PEG                                                 24w 48w     0.5   0.1   1.5   R    R    0.5- 1.5- 1.5-
                24w 48w   0.5   0.1   1.5   R    R    0.5-R 1.5-R 1.5-R                                                                   24w 48w   R     R    R
                                            24w 48w               opt                                                                                         opt

    Figure 6:    Impact of ten different regimens on fibrosis stage (panel A) and necroinflammatory activity grade (panel B).
                 A total of 3010 patients with paired biopsies were analysed by the same pathologist. Adapted with
                 permission (52). IFN=xx, PEG=yy, etc, etc

patients with baseline cirrhosis.                                                    of mutants, (70), these regimens have similar impact on
    Six factors were independently associated with the                               short term histologic features. [(35), (75)]
absence of significant fibrosis after treatment: baseline                                In 1989, the first study demonstrated that non-
fibrosis stage (odds ration [OR] = 0.12; P < 0.0001),                                pegylated-interferon improved necrosis and inflammation
sustained viral response (OR = 0.36; P < 0.0001), age                                at liver biopsy performed 6 months or more after
< 40 years (OR = 0.51; P < 0.001), body mass index <                                 completion of treatment (9).
27 kg/m2 (OR = 0.65; P < 0.001), no or minimal                                           Several prospective studies of lamivudine have
baseline necroinflammatory activity (OR = 0.70; P =                                  been undertaken using liver biopsy to determine the
0.02), and viral load < 3.5 millions copies per millilitre                           progression of fibrosis and activity in patients treated
(OR = 0.79; P = 0.03).                                                               mostly at one year. [(70), (34), (15), (33), (69), (17)].
    Treatment with ribavirin alone in virologic non-                                 Only two studies, including one study of 63 patients,
responders to initial interferon and ribavirin showed                                (17) have investigated treatment longer than one year,
decreased histological activity versus the control group.                            assessing the histological consequences of HBV
In this small randomized study there was no significant                              mutants resistant to lamivudine, by repeated estimates
change observed in liver fibrosis. (29)                                              of histological features during three years of treatment.
                                                                                     [(70), (17)] Lamivudine has been shown to provide
    Factors associated with fibrosis progression
                                                                                     sustained benefit over periods of up to four years. The
    There is little information concerning the annual rate
                                                                                     efficacy of lamivudine in the treatment of hepatitis B is,
of development of cirrhosis in chronic HBV carriers as
                                                                                     however, compromised by the development of viral
well as risk factors associated with the fibrosis
progression rate. Factors associated and not                                         resistance. (35). This is due to the selection of HBV
associated with cirrhosis or hepatocellular carcinoma                                mutants containing mutations in the YMDD motif of the
are summarised in Table 5. (35) Sophisticated viral                                  hepatitis B polymerase. These viral strains are present
characteristics, such as HBV genotype or precore                                     as minor species in the pretreatment viral quasispecies
mutations, were marginally associated with bridging                                  and thus become the dominant species due to
fibrosis compared with gender and age. Most of the                                   selection pressure during drug treatment. However,
significant associations observed in univariate                                      these polymerase mutants have reduced viability due
analyses were no longer seen when adjusted for age                                   to impaired catalytic activity and are replaced by the
and sex. It is therefore imperative that studies                                     wild-type virus if lamivudine treatment is stopped. The
assessing the prognostic value of molecular                                          long term histological consequences of YMDD
characteristics take into account age and gender.                                    mutations are not well established, but do not seem
                                                                                     significant at three years follow-up. [(70), (17)]
   Impact of treatment on fibrosis progression
                                                                                          Adefovir 10 mg daily given for 48 weeks is
    Three regimens are available for treating chronic                                associated with significantly better histologic
hepatitis B: alpha-interferon (pegylated or not),                                    improvement, higher rates of HBeAg seroconversion,
lamivudine and adefovir. [(35), (75)] Despite some                                   a three logarithmic reduction in HBV DNA levels and a
differences in virologic endpoints observed after                                    higher chance of normalization of ALT when compared
stopping treatment, [(65), (40)] or related to occurrence                            with patients receiving placebo. (39) Similar efficacy on
                                              L.Bonyhay et al ./ Romanian Journal of Hepatology 2, no 1, (2006) 9 - 21

               Factors                                         Progression to cirrhosis          Progression to hepatocellular carcinoma

               Age at infection                                    Yes                             Yes
               Duration of infection                               Yes                             Yes
               Male gender                                         Yes                             Yes
               Age at biopsy                                       Yes                             Yes
               Consumption of alcohol > 50g per day                Yes                             Yes
               HCV coinfection                                     Yes                             Not sure
               Delta coinfection                                   Yes                             Not sure
               CD4 count < 200 cells /ml                           Yes                             Not sure
               Fibrosis stage                                      Yes                             Yes
               Necrosis                                            Not sure                        Not sure
               Inflammation                                        Not sure                        Not sure
               Genotype                                            Not sure                        Not sure
               Pre-core mutant                                     Not sure                        Not sure
               Core-Promoter mutant                                Not sure                        Not sure
               Sero conversion anti-HBe                            Not sure                        Not sure
               HBV-DNA level                                       Not sure                        Not sure
               Aflatoxin                                           Not sure                        Yes

                           Table 5: Factors associated with progression to cirrhosis or to cancer in HBV carriers

   Figure 7: Impact of adefovir 10 mg on fibrosis stage and necroinflammat                       ory activity grade in patients with chronic hepatitis
   B: ranked assessment of fibrosis and necroinflammatory scores. (Percent                        age of patients)
    Antigen HBe positive (panel a): 168 patients and baseline biopsy treated with adefovir                          , 161 with placebo
   Antigen HBe negative (panel b): 121 patients and baseline biopsy treated with adefovir                            , 57 with placebo
    There was a significant difference (p<0.001) both for fibrosis and necroinflammatory (activity) scores

         Improved              Stabilized          Worsened                                  Improved               Stabilized           Worsened
       100%                                                                                100%                          4                         3
                                    14                       13                                                                                   17
                     26                         34
         80%                                                 15                              80%          38
                                                                                                                       47           51
         60%                        45                                                       60%
                     50                                                                                   36                         7
         40%                                                                                 40%                                                  80
                                                                                             20%                       48           42
         20%                        41          41
                     24                                                                                   25
          0%                                                                                  0%
                    Fibrosis       Fibrosis   Activity     Activity                                      Fibrosis     Fibrosis     Activity     Activity
                    Placebo       Adefovir    Placebo      Adefovir                                      Placebo     Adefovir      Placebo      Adefovir
                                    10mg                    10mg                                                       10mg                      10mg

    Panel a: HBe Ag positive chronic hepatitis B                                           Panel b: Hbe Ag negative chronic hepatitis B

HBV DNA and ALT have been observed in another                                         lamivudine, and 13% (        18/143) in patient s treated with
randomised trial of adefovir 10 mg daily given for 48                                 pegylated-interferon an       d lamivudine combinat            ion; for
weeks in patients with hepatitis B e Antigen negative                                 necroinflammatory acti       vity the improvement ra         tes were
chronic hepatitis B. (25) In these two trials there was a                             55% (79/143), 46 %              (57/125) and 46% (66             /143),
very significant histologic improvement with adefovir                                 respectively . (40) As m any physicians treat p            atients for
10 mg versus placebo (Figure 7).                                                      longer durations with la     mivudine or adefovir       , the choice
     Pegylated-interferon will replace nonpegylated-                                  of the first line regim      en is still controversia       l. Future
interferon, because of superior efficacy and because a                                trials should compar     e the histologic impa      ct of long term
single injection per week is more convenient for                                      nucleoside regimens versus pegylated-interferon,
patients. In a recent trial similar improvement rates at                              using biochemical markers.
72 weeks were observed for fibrosis 15% (21/143) in
patients treated for 48 weeks with pegylated-interferon
2a alone, 18% (22/125) in patients treated with
                                 L.Bonyhay et al ./ Romanian Journal of Hepatology 2, no 1, (2006) 9 - 21

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