Impact of interferon-alpha treatment on liver fibrosis in patients with chronic hepatitis B: an overview of published trials.

BACKGROUND: The impact of interferon treatment in patients with hepatitis B virus (HBV) infection on fibrosis progression in comparison with its natural history has yet to be assessed in any large-scale randomized studies. The present report is a review of the evidence-based data published so far. METHODS: Studies were included if they had at least two repeated estimates of liver fibrosis per patient treated with interferon-alpha (whether pegylated or not). Meta-analysis was performed using a random-effects model. RESULTS: Altogether, 13 studies were included in the review, involving a total of 707 HBV patients treated with interferon-alpha-2a or -2b for 12-83 months. Only one study included pegylated interferon as monotherapy. A total of 787 untreated patients were also followed. Only one study used a non-invasive biomarker. There was a significant reduction in the fibrosis progression rate, with a risk reduction of 0.49 (95% CI: -0.64--0.34; chi(2)=119; degrees of freedom [DF]=6; P<0.0001), and significant heterogeneity (Cochran Q=81; P<0.0001). This significant impact was similar for both randomized (reduction of risk: -0.45; 95% CI: -0.64--0.26; P<0.0001) and not-randomized (controlled) studies (reduction of risk: -0.53; 95% CI: -0.79--0.28; P<0.0001). CONCLUSION: According to these findings, the benefit of interferon treatment on fibrosis progression is clinically significant in patients with advanced fibrosis by the reduction of fibrosis progression to cirrhosis. Pegylated interferon now needs to be compared, in terms of benefit-risk factors, with the new generation of HBV treatments (such as entecavir and tenofovir), using non-invasive biomarkers.

[Alcohol, steatohepatitis, insulin resistance and hepatitis C]. / Alcool, stéatohépatite métabolique, insulinorésistance et hépatite C.

Patients with chronic hepatitis C have frequently other morbidities, either because they are frequent in the general population (metabolic syndrome) and/or because the route of contamination (chronic alcohol consumption succeeding to drug abuse). These co-morbidities have a harmfull impact on fibrosis progression during the natural history of HCV infection and reduce the efficacy of antiviral treatments. Thus, it is crucial to diagnose early and treat these different diseases which may be combined. They are the metabolic syndrome and/or chronic alcohol consumption resulting in insuline resistance, infection by the human immune deficiency virus or by the hepatitis B virus as well as chronic tobacco use or excessive consumption of cannabis. An optimal is based on a multidisciplinary approach to reduce fibrosis progression and improve the efficiency of antiviral therapies. However, the hepatologist has to come back to a global care, which is mandatory at the individual level as well as for the public health.

Methodological aspects of the interpretation of non-invasive biomarkers of liver fibrosis: a 2008 update.

This review summarizes the methodological aspects of the interpretation of non-invasive biomarkers in liver fibrosis. A scoring system has been updated to better compare the quality of fibrosis biomarkers. Several methodological issues are related to the classical methodology using biopsy, as this is considered the gold standard. However, from evidence-based data, it appears that the methodology needs to change to prevent flawed conclusions among key opinion leaders as well as in obsolete guidelines. As waiting for the perfect biomarker for the diagnosis of advanced fibrosis to come along is probably a waste of time, in the meantime, methods can be improved. The main proposals for improving the methodology are, to take into account the spectrum bias, to assess accuracy between adjacent stages, to compare biomarkers in the same patient, to assess the cause of failure among discordant cases and to use specific statistical methods adapted for imperfect gold standards.

Chronic liver dysfunction in heart transplant recipients, with special reference to viral B, C, and non-A, non-B, non-C hepatitis. A retrospective study in 80 patients with follow-up of 60 months.

In order to assess the prevalence, causes, and severity of chronic liver dysfunction (LD) in heart transplant patients, 80 transplanted patients followed for 60 months (median; range, 1.5-98 months) were reviewed. Sustained liver dysfunction was found in 50 patients, occurring during the first year after heart transplantation in 42 (84%) of them. Most patients were asymptomatic (80%). Causes for the liver dysfunction included non-A, non-B hepatitis in 16 cases (32%), viral B hepatitis in 13 (26%), delta hepatitis in one (2%), drug-induced hepatitis in six (12%), and cardiac failure in seven (14%). Anti-HCV antibodies were found in 56.2% of patients with non-A, non-B hepatitis and in 22% of patients with HBV hepatitis. It was found neither in patients with drug-induced hepatitis cardiac failure nor in patients with normal liver tests. This study outlines a high prevalence of LD (62.5%) in heart transplant patients, the high frequency of viral-related chronic LD (usually of moderate severity), and high incidence of HCV and HBV hepatitis.

Effect of interferon therapy on the natural history of hepatitis C virus-related cirrhosis and hepatocellular carcinoma.

In patients with chronic hepatitis C who have a sustained virologic response to IFN therapy, there is a dramatic effect on the natural history of the disease, with ALT levels becoming normal, histologic activity improving or disappearing, and the progression of fibrosis slowing. A sustained virologic response 6 months after the end of treatment is predictive of a sustained remission 4 years later. From these results, a long-term survival benefit is expected from IFN treatment in patients with an intermediate or rapid rate of fibrosis. For patients with chronic hepatitis C who do not experience a sustained eradication of virus, there is evidence that IFN treatment significantly reduces the viral load and serum ALT level, improves histologic activity, and blocks fibrosis progression, in comparison with the natural history of this disease. Therefore, patients who still have a detectable level of HCV RNA should no longer be considered nonresponders to IFN therapy. Although the number of randomized trials is [figure: see text] small, cumulative data suggest that IFN therapy can reduce the incidence of and the mortality from hepatocellular carcinoma in patients with cirrhosis.

Acute hepatitis during hypersensitivity syndrome due to midecamycin.

We report here the first case of symptomatic acute hepatic injury due to midecamycin in a 58-year-old man. The clinical picture was compatible with a hypersensitivity syndrome with cutaneous, renal and hepatic involvement. Liver eosinophil polynuclear infiltrate, hypereosinophilia and acute interstitial nephritis were consistent with the hypothesis of an immunoallergic mechanism.

[Neuro-lupus associated with Zollinger-Ellison syndrome with hepatic metastases: an incidental association?]. / Neuro-lupus associé à un syndrome de Zollinger-Ellison avec métastases hépatiques: une association fortuite?

A 29-year old woman presented with neuro-lupus and hepatic metastases of gastrinoma. We suggest that this hitherto undescribed association might not be fortuitous.

[Do general practitioners want to manage chronic hepatitis C and take part in hepatitis C health networks? A national survey]. / Les médecins généralistes souhaitent-ils prendre en charge l'hépatite chronique virale C et participer aux réseaux ville-hôpital?

OBJECTIVES: To assess information that general practitioners had on hepatitis C and on the hepatitis C network in hospitals and private practice. METHODOLOGY: A national telephone survey of 604 general practitioners was conducted between March 18 and 23, 1998. RESULTS: Screening and management of hepatitis C was important for 89% and 97% of general practitioners. Screening was performed in relation to the relative risk (IV drug users 89%, blood transfusion before 1991 88%). General practitioners wanted more information on treatment (54%), patient counselling (42%) and the potential risks of the disease (42%). Of 604 general practitioners, 6% were involved in a hepatitis C network, while 21% were involved in another network (drug users 9%, AIDS 8%). Of the 94% general practitioners who were not part of the network, 33% were willing to join a hepatitis C network. Only 56% were aware of a hepatitis C network (press article 30%, mailing 17% or local meeting 12%). The difficulties for the involvement of general practitioners were: lack of time, topics not adapted to daily practice and geographic constraints (74%), too few patients in their practice (52%), no need (38%), the idea itself of a network and lack of information (28%). CONCLUSION: General practitioners screen patients at risk of hepatitis C. They want to be better informed about treatment, patient counselling, and the potential risks of hepatitis C. They are less involved in hepatitis C networks than in other networks (drug, AIDS). However, one third of general practitioners would like to be involved in a hepatitis C network. These results could be useful for implementing post-graduate courses and general practitioner training.

A prospective assessment of an 'a la carte' regimen of PEG-interferon alpha2b and ribavirin combination in patients with chronic hepatitis C using biochemical markers.

In therapy with standard interferon and ribavirin, five independent risk factors (RF) were predictive of relapse. The aim was to prospectively validate an a la carte regimen of pegylated interferon (PEG-IFN) alpha2b 1.5 microg/kg and ribavirin 11 mg/kg [PEG-IFN-ribavirin (PEG-IFN-R)], taking into account these five risk factors in order to determine whether to continue an additional 24 weeks of treatment in polymerase chain reaction (PCR) negative patients after 24 weeks. Treatment was stopped after 24 weeks in PCR positive patients. The same regimen was continued in PCR negative patients for an additional 24 weeks if patients had two or more RF. FibroTest and ActiTest assessed the impact of treatment on the histological features from baseline to end of follow-up. A total of 96 patients were included; 84 (87.5%) had at least two RF and 12 (12.5%) had no or one RF. A total of 70 patients were sustained virologic response (SVR; 73%), 19 were nonresponders (20%) and seven were relapsers (7%). The SVR in genotypes 2 or 3 was 85% (34/40) vs 64% in other genotypes (36/56; P = 0.02). There was a decrease (P = 0.003) in fibrosis as estimated by FibroTest, from 0.38 +/- 0.03 (mean +/- SE) at baseline to 0.33 +/- 0.03 at the 12-week follow-up, and a decrease in activity as estimated by ActiTest, from 0.49 +/- 0.02 to 0.19 +/- 0.03 (P < 0.0001). Improvement in activity was already significant at 12 weeks, even in virologic nonresponders. This study confirms that an a la carte regimen which takes into account not only genotype but also baseline viral load, fibrosis stage, gender and age, is efficient for the PEG-IFN-R combination. It achieves a 73% SVR and a significant decrease in fibrosis and activity as estimated by biochemical markers.

Management of hepatitis C.

Chronic hepatitis C is a major health care problem throughout the world. The disease may progress to cirrhosis, with complications such as hepatocellular carcinoma. The usual primary goal of therapy is viral eradication, as patients with long-term remission are generally regarded as unlikely to develop cirrhosis or hepatocellular carcinoma. Another primary goal should be the reduction in liver fibrosis progression. Interferon-alpha (IFN-alpha) is the only drug approved for the treatment of hepatitis C in Europe and North America. Its effectiveness appears to be related to dose and duration of therapy. The best efficacy/risk ratio seems to be in favour of 3 million units (MU) IFN-alpha three times per week on a 12-month schedule. With this regimen, a sustained alanine aminotransferase (ALT) response is achieved in nearly 35% of patients. Ribavirin has emerged as potentially the second most effective drug. While it appears unsatisfactory when given alone, it seems much more effective in combination with IFN. Combining them seems to exert a synergistic effect between the two drugs and sustained remission might be achieved in nearly 50% of patients with combination therapy. Controversy persists concerning the long-term benefit of therapy in transient responders and non-responders. It is possible that IFN therapy, in comparison to natural history, might reduce liver fibrosis progression and prevent hepatocellular carcinoma, even in non-responders, and have greater efficacy if used in long-term treatment. Whatever the treatment schedule, prolonged viral eradication may not be achieved in all patients and new drugs should be sought to improve the results of therapy.

Biochemical markers of liver fibrosis in patients infected by hepatitis C virus: longitudinal validation in a randomized trial.

A liver fibrosis index was recently prospectively validated in a cross-sectional study where patients infected by hepatitis C virus (HCV) had only one biopsy and no longitudinal follow-up. The aim of this study was to retrospectively assess the diagnostic value of this index in patients included in a randomized trial of interferon (IFN) using repeated measurements, two biopsies and hyaluronic acid as a comparative reference. One-hundred and sixty-five patients who had had two interpretable liver biopsies and at least one stored serum sample before IFN treatment were selected. Seventy-eight patients received 3 MU of IFN-alpha thrice weekly for 24 weeks and 87 followed a reinforced regimen for 48 weeks. A fibrosis index combining five biochemical markers (alpha2-macroglobulin, haptoglobin, apolipoprotein A1, gamma-glutamyl transpeptidase (GGT) and total bilirubin adjusted for gender and age) as well as hyaluronic acid was assessed on 461 samples available at baseline, at the end of treatment and at the end of follow-up (72 weeks). There was a significant decrease of the fibrosis index score among the 17 sustained virologic responders, from 0.33 +/- 0.06 (mean +/- SE) at baseline to 0.18 +/- 0.06 at 72 weeks in comparison with 92 nonresponders (from 0.41 +/- 0.03 at baseline to 0.44 +/- 0.03 at 72 weeks; P < 0.001) and in comparison with 56 relapsers (from 0.36 +/- 0.03 at baseline to 0.32 +/- 0.03 at 72 weeks; P=0.05). No significant differences were observed for hyaluronic acid.Hence, this fibrosis index could be used as a surrogate marker of the antifibrotic effect of treatments in patients with chronic hepatitis C.

Effects of cirrhosis, interferon and azathioprine on adverse events in patients with chronic hepatitis C treated with ribavirin.

To determine adverse events of ribavirin in the treatment of chronic hepatitis C, 41 patients (18 with cirrhosis), treated with ribavirin at an initial dose of 600-1200mg day(-1), were analysed retrospectively (six patients were treated twice because adverse effects during the first treatment necessitated cessation of ribavirin). Indications for ribavirin included a contraindication (n = 15) an intolerance (n = 11) or a non-response (n = 15) to interferon (IFN). Ribavirin was combined with IFN 3 million units (MU) three times weekly for 15 patients and with azathioprine for six patients (five of whom were transplant patients). No cirrhotics and only one patient treated with ribavirin + IFN received azathioprine. The mean duration of treatment was 5 months (range 1-18 months). Sixteen of 47 treatments (34%) with ribavirin were stopped: four because of vomiting (8.5%), two for psychiatric disorder, one for dry cough, one for an unrelated cause, and eight (at 1-2 months) because of a fall in the level of haemoglobin (Hb) of 4.6 g dl(-1) (range 2.7-5.9 g dl[-1]); however, according to the rules of international protocol, we would have expected only four treatments (two in patients receiving azathioprine) with Hb < 8.5 g dl(-1) to be stopped. The decrease in Hb level occurred more slowly in patients treated with IFN plus ribavirin than in patients treated with ribavirin alone and was of lower clinical significance in patients with cirrhosis than in patients without cirrhosis. After exclusion of patients receiving azathioprine, there was no significant difference in the fall of Hb level between cirrhotic and non-cirrhotic patients and between patients treated with IFN plus ribavirin and patients treated with ribavirin alone. Interestingly, the platelet count of patients treated with IFN plus ribavirin fell less than in patients treated with IFN alone. The most important and expected adverse event associated with ribavirin was haemolysis. Anaemia < 8.5 g dl(-1), requiring cessation of ribavirin therapy, was present in 9% of patients and was worsened by azathioprine. Abdominal discomfort and dry cough were other, potentially important, clinical adverse events found in our study.

Modeling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C: a dynamic view. The Multivirc Group.

BACKGROUND & AIMS: Impact of hepatitis C treatment has never taken into account the dynamics of fibrosis progression. This study assessed the impact of interferon on liver fibrosis progression in patients with chronic hepatitis C according to 3-month aminotransferase activity response. METHODS: We recruited 287 patients, 185 treated and 102 control, with paired biopsy specimens. Before follow-up, the fibrosis progression rate per year was estimated as the ratio between fibrosis stage in METAVIR units (1 U, 1 stage; 4 U, cirrhosis) and the duration of infection. During follow-up, fibrosis progression was assessed by the observed difference between stages divided by duration between biopsies. RESULTS: The median fibrosis progression rate in treated patients decreased compared with the rate before treatment from 0.103 F METAVIR U/yr (95% confidence interval [CI], 0.087-0.120) to 0.000 (95% CI, 0.000-0.000; P

Is antiviral treatment (IFN alpha and/or ribavirin) justified in cirrhosis related to hepatitis C virus? Société Royale Belge de Gastro-entérologie.

AIM: To assess the benefit risk ratio of interferon and ribavirin in the treatment of patients with post hepatitis C cirrhosis we summarize the spontaneous over mortality of this disease, and made an overview of the randomized trials and of other controlled studies. RESULTS: In comparison to controls, patients with post hepatitis C cirrhosis have a 17 fold increase risk of dying from a liver disease that a control population, and a 6 fold increase from primary liver cancer. In France the hepatitis C epidemic which start in the sixties explains now the observed dramatic increase in mortality by primary liver cancer, both in men and women. Meta-analysis of randomized trials and controlled retrospective studies showed that interferon treatment is associated with a significant increase in ALT response at the end of the treatment, with a decrease in hepatocellular incidence as well as a decrease in mortality in comparison with controls. Very few data are published concerning ribavirin alone or in combination with interferon in patients with cirrhosis. Preliminary data suggest that this combination during 48 weeks permit to obtain in patients with compensated cirrhosis 20% of sustained virological response. The safety was acceptable but patients with low initial blood cells count must be carefully followed. In conclusion this overview clearly demonstrates a benefit-risk ratio in favor of treatment in patients with post hepatitis C cirrhosis by interferon.