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REVIEW ARTICLE Table of Contents   
Year : 2005  |  Volume : 11  |  Issue : 1  |  Page : 1-19
Diagnosis and treatment of viral liver fibrosis


Groupe Hospitalier Pitie-Salpetriere, Paris, France

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Date of Submission22-Sep-2004
Date of Acceptance19-Oct-2004
 

   Abstract 

This review summarized the diagnostic value of fibrosis biomarkers and the efficacy of anti-viral treatments on fibrosis progression. Non­invasive biomarkers can facilitate the screening and management of chronic hepatitis C and B. Screening for significant fibrosis is-mandatory as very effective anti-viral treatments are available, permitting to stop or to reduce the fibrosis progression. The reduction of fibrosis progression will decrease the mortality due to complications of cirrhosis. 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

Keywords: Fibrotest, Actitest, FibroSURE, fibrosis biomarker, activity biomarker, liver biopsy limits, HCV, HBV, Alcoholic liver disease, fatty liver.

How to cite this article:
Poynard T, Imbert-Bismut F, Munteanu M, Ratziu V. Diagnosis and treatment of viral liver fibrosis. Saudi J Gastroenterol 2005;11:1-19

How to cite this URL:
Poynard T, Imbert-Bismut F, Munteanu M, Ratziu V. Diagnosis and treatment of viral liver fibrosis. Saudi J Gastroenterol [serial online] 2005 [cited 2019 Jul 15];11:1-19. Available from: http://www.saudijgastro.com/text.asp?2005/11/1/1/33332


The consensus conferences statements, recommended liver biopsy in the management of almost all patients with chronic hepatitis C and B, but also underline the necessity of developing reliable non-invasive tests [1],[2] . One of the major clinical problems is how to best evaluate and manage the increasing numbers of patients infected with the hepatitis C (HCV) and B viruses (HBV) [1],[2],[3]

Liver biopsy is still recommended in most patients [4],[5] . However, numerous studies strongly suggest that due to the limitations [6],[7],[8] and risks of biopsy [9] , as well as the improvement of the diagnostic accuracy of biochemical markers [10],[11] liver biopsy should no longer be considered mandatory.

These tests can facilitate the screening and management of chronic hepatitis C and B. Screening in these fibrotic diseases is mandatory as very effective anti-viral treatments are available, permitting to stop or to reduce the fibrosis progression. The reduction of fibrosis progression will decrease the mortality due to complications of cirrhosis.

The aim of this review is to summarize the diagnostic value of fibrosis biomarkers and the efficacy of anti-viral treatments on fibrosis progression [1],[2]


   Diagnostic value of fibrosis biomarkers Top


No available single test has demonstrated a continuous and linear correlation with fibrosis stage and fibrosis grades [12] . Serum ALT was the most commonly investigated marker, with too low sensitivity ranging from 61% to 71%. The diagnostic value was lower than combination of markers in all direct comparisons [12],[13]

Among the extracellular matrix tests, hyaluronic acid correlated best with fibrosis stage overall, but has been demonstrated mostly for extensive fibrosis [12],[14] . The AUROCs for extensive fibrosis range from 0.65 to 0.86. Markers of extracellular matrix production, such as procollagen type III peptide, and degradation, such as tissue inhibitor of metalloproteinase-1-4, were less predictive than hyaluronic acid [12] . Among the non-invasive alternatives to liver biopsy [12] , several studies have demonstrated the predictive value of two combinations of simple serum biochemical markers in patients infected with HCV: FibroTest (FT; Biopredictive, Paris, France) for the assessment of fibrosis; and ActiTest (AT; Biopredictive, Paris, France) for the assessment of necroinflammatory activity [10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[22],[23],[24],[25],[26],[27],[28],[29],[30] Similar results have not been obtained with other diagnostic tests [12],[13],[14],[15],[16],[17],[18],[19] Since September 2002 these tests (FT-AT) have been used in several countries as an alternative to liver biopsy. In a systematic review, it was concluded that these panels of tests might have the greatest value in predicting fibrosis or cirrhosis [12] . It was also stated that biochemical and serologic tests were best in predicting absent, minimal, and advanced fibrosis/cirrhosis, but were poor in predicting intermediate levels of fibrosis [12] . Recent studies have now demonstrated that the diagnostic values of FT-AT for consecutive stages of fibrosis and grades of activity were the same for both moderate and extreme stages and grades [10],[11],[26],[27] It has been also demonstrated that biomarkers such as those described here may provide a more accurate (quantitative and reproducible) picture of fibrogenic and necrotic events occurring within the liver than low quality liver biopsy. A prospective study observed that 18% of discordances were attributable to biopsy failure (mostly due to small length) and 2% to FT-AT failure [11] ). Several independent groups have validated the diagnostic values of FT-AT [28],[29],[30]

FT-AT is a noninvasive blood test that combines the quantitative results of six serum biochemical markers (alpha2­macroglobulin, haptoglobin, gamma glutamyl transpeptidase (GGT), total bilirubin, apolipoprotein Al and alanine amino transferase (ALT)) with the patient's age and gender in a patented artificial intelligence algorithm (USPTO 6,631,330) to generate a measure of fibrosis stage and necroinflammatory grade in the liver. [11] FT-AT is a continuous linear biochemical assessment of fibrosis stage and necroinflammatory activity grade. It provides a numerical quantitative estimate of liver fibrosis ranging from 0.00 to 1.00, corresponding to the well-established METAVIR scoring system of stages FO to F4 and of grades AO to A3 [31],[32] [Figure - 1]. The analyses should preferably be made on fresh serum but can be done with plasma, if necessary (blood sample on lithium heparinate). The measurements of the six parameters are made preferably on fresh seru~ra (or plasma) or that which has been stored between +2°C and +8°C for a maximum of four days in an unlit area (for the protection of bilirubin). For deferred measurements, the serum should be quickly frozen to -80°C. After thawing, it should be centrifuged for 10 minutes at 15,000g [24] . It has been prospectively demonstrated that the FT-AT can be performed on fasting or non-fasting serum samples [25] . In comparison with liver biopsy, FT-AT is cost effective, as the cost of the test varies from 90 to 350 Euros according to countries versus 1000-2000 Euros for a liver biopsy [23],[26],[27] [Table - 1]. A summary of the FT-AT diagnostic values according to cutoffs is given in [Table - 2]. In chronic liver diseases, the liver biopsy is far from a true gold standard and a high percentage of so called false negative and false positive could be due in fact to errors of biopsy. A prospective study observed that 18% of discordances were attributable to biopsy failure (mostly due to small length) and 2% to FT-AT failure [11] . Between September 1, 2002, and May 31, 2004, a total of 32,527 tests have been carried out on the secured Internet site. They concerned 54.6% male, 16% older than 65 years. The most frequent abnormal value observed during post­marketing follow-up was haptoglobin lower than 0.12 g/L in 1589 patients 4.89%). Among these patients there was 272 cases with high-risk profile of false positive (0.84%) for which the other components were not concordant in favor of significant fibrosis. Patients with extremely low haptoglobin, especially when the rest of the exams were hardly modified, could have had hemolysis. High-risk profile of false positive due to possible Gilbert Syndrome was observed in 409 (1.26%) cases.

The most frequent cause of abnormally elevated values for bilirubin was Gilbert disease, and for alpha2 macro~lobulin and haptoglobin, it was acute sepsis [11] .

FT-AT has been extensively studied in patients with chronic hepatitis C [Table - 2] and also in hepatitis B [33] , alcoholic liver disease [34], non-alcoholic fatty liver disease [35] and as markers of portal hypertension Q [36],[37]. Diagnostic values for fibrosis stages were similar. No studies have been so far published in patients with cholestatic liver diseases, auto-immune hepatitis or hemochromatosis.

One panel of biomarkers combining alpha2-macro globulin, hyaluronic acid and tissue inhibitor of metalloproteinases-1 (TIMP-1) is also on the US market (Fibrospect I and II TM, Prometheus, USA), with only few abstracts and so far without any full publication. This panel is designed only for fibrosis diagnosis without diagnostic value for necroinflammatory activity. No study has been presented in community-based population, and the risks of false negative and false positive has not been identified, as well as separate studies in different chronic liver diseases. Recently a study using profiles of serum protein N­glycans found that a profile has a similar AUROC than FT for the diagnosis of compensated cirrhosis. When combined with FT this marker had 100% specificity and 75% sensitivity for the diagnosis of compensated cirrhosis, which was not significantly different from the 92% specificity and 67% sensitivity of FT alone [28] These results validated the FT diagnostic value in chronic hepatitis C and also in alcoholic liver diseases, which represented 50% of cases.


   Efficacy of anti-HCV treatments on fibrosis progression Top


Major breakthroughs have been achieved in recent years in diagnosis and treatment of chronic hepatitis C. Unfortunately, even in developed countries, mortality due to hepatitis C is increasing ue to a lack of detection and treatment [1] . The present best strategy to prevent severe complications of Recently-approved treatments of chronic hepatitis C permit to obtain 60% of sustained virological response [1] . In these patients there is a clear benefit on the fibrosis progression with reversal of fibrosis stages at follow-up biopsy and even reversal of recently diagnosed cirrhosis [38] .

The main goal of maintenance therapy is to reduce fibrosis progression and complications in the 40% of patients without sustained virological response. The knowledge of factors associated with fibrosis progression could permit to optimize screening and treatment strategies [39],[40],[41],[42],[43],[44],[45]

Factors associated with fibrosis progression

Several factors are associated with fibrosis progression in chronic liver diseases. The highest fibrosis progression rate is observed in patients co-infected with HIV and HCV with occurrence of cirrhosis and hepatocellular carcinoma 15 to 20 years before patients infected by HCV alone [39],[40],[41],[42],[43],[44],[45] Factors associated and not associated with fibrosis are summarized in [Table - 3]. The median time from infection to cirrhosis is 30 years, with a high inter-individual variability, which is now better understood. Several factors have been clearly shown to be associated with fibrosis progression rate: duration of infection, age, male gender, alcohol consumption, HIV coinfection and low CD4 count. Metabolic conditions such as overweight and diabetes are emerging as independent cofactors of fibrogenesis [39],[40],[41],[42],[43],[44],[45],[46]

Impact of treatment on fibrosis progression

Several studies have demonstrated the impact on fibrosis progression (and on necroinflammatory grades) of different regimens (interferon, pegylated-interferon (IFN), or ribavirin, alone or in combination) in patients with chronic hepatitis C, with or without sustained virological response [38],[47],[48],[49],[50],[51],[52],[53].[54],[55],[56],[57],[58],[59],[60]

In non-responders after the optimized combination of ribavirin and pegylated interferon the best strategy is unknown. These patients should be included in randomized trials. The concept of maintenance (suppressive therapy) has been eveloped with standard interferon monotherapy showing a decrease in fibrosis progression rates [Figure - 2], and an improvement in necrosis and inflammation [Figure - 3] in non-responders. Maintenance therapy with interferon should probably be repeated as after cessation of interferon fibrosis progression restarted [Figure - 4].

If this is not possible one option is to treat the patients with extensive fibrosis by PEG interferon alone in order to decrease the progression rate to cirrhosis, while waiting for a new generation of drugs. Small dose of PEG-IFN, i.e. 0.5 ug, is interesting in this indication because of its good tolerance and the once a week injection [25] Estimated key numbers of fibrosis natural history from literature and our database: The median time from infection (FO) to cirrhosis (F4) is 30 years. The mortality at 10 years for cirrhosis is 50%. The transition probability per year from non-complicated cirrhosis to each of the complications is around 3%.

Main factors associated with fibrosis the cause of liver fibrosis. progression are age and gender, whatever.

Patients who could benefit the most of maintenance therapy are patients with rapid fibrosis progression rates. If the date of infection is known or if the patients have been biopsied twice it is possible to estimate the fibrosis progression rate per year [38],[39],[40],[42],[43],[48],[49],[50],[51],.[52] . Patients with extensive fibrosis (Stages F2, F3 or F4) as well as patients with high fibrosis progression rate (more than 0.20 METAVIR fibrosis stage progression per year) are good candidates for maintenance therapy. Estimate of fibrosis by non-invasive biochemical markers should improve even more these strategies [10],[14] Because of the sampling error of the biopsy, the intra observer variability, and the benefit-risk of biopsy, studies with paired biopsies with hundred of patients are two small, particularly in non-treated patients [39],[41],[42],[43] According to a Markov age-dependent modelling, a ten­year increment in duration of infection increased the risk of progression by 32% for IFN-treated patients and by 51% for untreated patients. The course of a series of 1000 IFN-treated and 1000 untreated patients was simulated over five years according to the initial stage of fibrosis and age and duration of infection at diagnosis. IFN treatment decreased the risk of progression to F3+F4 by a factor of 4.8, for subjects aged 40 years, infected for 10 years, and in F0+F1 at diagnosis. As age and duration of infection increased, the risk of fibrosis increased and the impact of IFN treatment decreased [48] . We pooled individual data from 3010 naive patients with pre-treatment and post-treatment biopsies from 4 randomised trials [38] . Ten different regimens combining standard interferon, PEG interferon, and ribavirin were compared. The impact of each regimen was estimated by the percentage of patients with at least 1 grade improvement in the necrosis and inflammation (METAVIR score), the percentage of patients with at least 1 stage worsening in fibrosis METAVIR score, and by the fibrosis progression rate per year. Necrosis and inflammation improvement ranged from 39% (interferon 24 weeks) to 73% (PEG 1.5 µg/kg + ribavirin >10.6mg/kg/day; P < 0.001). Fibrosis worsening ranges from 23% (interferon 24 weeks) to 8% (PEG 1.5 pg/kg + ribavirin >10.6mg/kg/day; P < 0.001). [Figure - 5]. All regimens significantly reduced the fibrosis progression rates in comparison to rates before treatment. The reversal of cirrhosis was observed in 75 patients (49%) of 153 patients with baseline cirrhosis.

Six factors were independently associated with the absence of significant fibrosis after treatment: baseline fibrosis stage (odds ration (OR) = 0.12; P < 0.0001), sustained viral response (OR = 0.36; P < 0.0001), age < 40 years (OR = 0.51; P < 0.001), body mass index < 27 kg/m 2 (OR = 0.65; P < 0.001), no or minimal baseline activity (OR = 0.70; P = 0.02), and viral load < 3.5 millions copies per millilitre (OR = 0.79; P = 0.03). Treatment with ribavirin alone in virologic non-responders to initial interferon and ribavirin decrease histological activity versus control group. In this small randomized study there no significant changes were observed in liver fibrosis [60]

Efficacy of anti-HBV treatments on fibrosis progression

Chronic hepatitis B virus (HBV) infection affects 350 million individuals globally. Approximately 15-40% may develop serious complications, including end-stage liver disease and hepatocellular carcinoma. Patients with significant hepatic inflammation and fibrosis are at the highest risk of these complications [2]

Factors associated with fibrosis progression

There is little information concerning the annual rate of development of cirrhosis in chronic HBV carriers as well as risk factors associated with the fibrosis progression rate. Factors associated and not associated with cirrhosis or hepatocellular carcinoma are summarised in [Table 6] [2] . Sophisticated viral characteristics, such as HBV genotype or precore mutations, were marginally associated with bridging fibrosis compared with gender and age. Most of the significance associations observed in univariate analysis were no longer seen when adjusted for age and sex. It is therefore mandatory that studies assessing the prognostic value of molecular characteristics take into account age and gender.

Impact of treatment on fibrosis progression

Three regimens are available for treating chronic hepatitis B: alfa-interferon (pegylated or not), lamivudine and adefovir [2],[61] . Despite some differences in virologic endpoints observed after stopping treatment [62],[63] or related to occurrence of mutants, [64] , these regimens have similar impact on the histological features at short term [2],[61] .

In 1989, a first study has already demonstrated that non-pegylated interferon improved necrosis and inflammation at liver biopsy performed 6 months or more after completion of treatment [65]

.Several prospective studies of lamivudine have been undertaken using liver biopsy to determine the progression of fibrosis and activity in patients treated mostly at one year [64],[66],[67],[68],[69],[70] . Only two studies, including one study on 63 patients, [70] have investigated treatment longer than one year, assessing the histological consequences of HBV mutants resistant to lamivudine by repeated estimates of histological features during three years of treatment [64],[70] Lamivudine has been shown to provide sustained benefit over periods up to four years. The efficacy of lamivudine in the treatment of hepatitis B is, however, compromised by the development of viral resistance [2] . This is due to the selection of HBV mutants containing mutations in the YMDD motif of the hepatitis B polymerase. These viral strains are present as minor species in the pre-treatment viral quasi-species and thus become the dominant species due to selection pressure during drug treatment. However, these polymerase mutants have reduced viability due to impaired catalytic activity and are replaced by the wild-type virus if lamivudine treatment is stopped. The histological consequences of YMDD mutations are not well established on the long term, but do not seem significant at three years follow-up [64],[70]

Adefovir 10mg daily given for 48 weeks is associated with significantly better histologic improvement, higher rate of HBeAg seroconversion, a three logarithmic reduction of HBV DNA levels and a higher chance of normalization of ALT when compared with patients receiving placebo [71] . Same efficacy on HBV DNA and ALT has been observed in another randomised trial of adefovir 10mg daily given for 48 weeks in patients with Hepatitis B e Antigen e-negative chronic hepatitis B [72] . In these two trials there was a very significant histological improvement of adefovir 10mg versus placebo [Figure - 7].

Pegylated interferon will replace non­pegylated interferon, because of a better efficacy and because a single injection per week is more convenient for patients. In a recent trial similar improvement rates at 72 weeks were observed in fibrosis 15% (21/143) in patients treated 48 weeks with pegylated-interferon 2a alone, 18% (22/125) in patients treated with lamivudine and pegylated-interferon and lamivudine combination 13% (18/143); for activity the improvement rates were 55%(79/14')),46 (57/125) and 46% (66/143) respectively [63] . As many physicians treat patients with longer duration of lamivudine or adefovir, the choice of the first line regimen is still controversial. Next trials should compare the histological impact of long term nucleoside regimen versus pegylated-interferon, using biochemical markers.

Efficacy of interferon on fibrosis progression in patients with Delta Hepatitis

Treatment of chronic hepatitis delta is notoriously difficult mainly because of a weak antiviral effect of interferon, the only available drug for this disease, and a high rate of relapse after the end of treatment [73]

Unlike HBV and HCV, where biochemical and virological responses can be achieved after 3 to 4 months of treatment, in chronic HDV response can be delayed by up to 10 months, thus requiring prolonged therapy before a patient can be considered anon responder [73],[74]

A recent study by Farci et al. which is a follow-up of a randomized trial published a decade [75],[76] ,reinforces the demonstration that sustained clearance of HDVRNA is possible and that this is accompanied by significant long term benefit not only in terms of survival and liver function but also histologically, since spectacular fibrosis reversal even at the cirrhotic stage was documented in responders. Treatment of chronic HDV infection should therefore ideally rely on high doses of interferon (9 MUI tiw) for long periods of time-at least one year and even longer in biochemical responders, if well tolerated and as long as IgM anti-HDV are still positive. Data on pegylated interferon are eagerly awaited.

Conclusions

Approved treatments of chronic viral hepatitis (HCV, HBV and HDV) are very effective in reducing the liver injury, even in patients without a definitive virologic response. Non-invasive biochemical markers of liver fibrosis should facilitate the routine management of patients and the future clinical trials.

In clinical trials, the use of biomarkers has also many advantages. The main advantage is the simplicity of the estimation procedure. We have recently estimated the kinetic of histologic responses in patients treated 48 weeks by lamivudine [77] . Another advantage of biomarkers is the reduced variability related to time differences. There is much more time variability for biopsy estimates than for biomarkers estimates. In many studies that described 2 or 3 years of treatment. the exact interval between the baseline biopsy and the end of follow-up biopsy, interval was often actually 24 weeks longer than the duration of treatment, and therefore included time without treatment [10],[64],[70] This time variability is probably more significant for necroinflammatory activity than for fibrosis, as the variation in stages is generally more rapid than the variation in grades.

 
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Correspondence Address:
Thierry Poynard
Groupe Hospitalier Pitie-Salpetriere, 47-83 Boulevard de I'Hospital, 75651 Paris Codex 13
France
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-3767.33332

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