Long-Term Outcomes in HCV with SVR: cure, regression of fibrosis

Fatty Liver Accelerates Fibrosis: diabetes, mitochondrial dyfunction, obesity associated

Impact of competing risks on observed rate of hepatitis C progression

Natural history of initially mild chronic hepatitis C

Serum Immunoglobulins Predict the Extent of Hepatic Fibrosis in HCV Patients

Common Heterozygous Hemochromatosis Gene Mutations Are Risk Factors for Inflammation and Fibrosis in Chronic Hepatitis C

Intercept Pharmaceuticals Announces Publication of Study Demonstrating Its Lead Compound Can Reverse Liver Fibrosis

Hepatic Fibrosis Influences Early Virological Response Rates in Chronic Hepatitis C

Viscum Album and Solanum Lycopersicum Inhibit Fibrosis in Chronic Hepatitis C
 

Fatty Liver Accelerates Fibrosis: diabetes, mitochondrial dyfunction, obesity associated
Natural history of nonalcoholic steatohepatitis: A longitudinal study of repeat liver biopsies"
 
Hepatology
Volume 40, Issue 4, October 2004
 
Eduardo Fassio 1 *, Estela Álvarez 2, Nora Domínguez 1, Graciela Landeira 1, Cristina Longo 1
 
1Hepatology Unit, Gastroenterology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires, Argentina
2Pathology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires, Argentina
 
"...Our study shows that 31.8% of 22 patients with NASH had a progression of liver fibrosis over a median follow-up of 4.3 years. These findings confirmed the progressive potential of NASH. However, most of the patients (68.2%) had no fibrosis progression...
 
... A two-hit hypothesis has been proposed to explain the mechanisms of liver damage in NASH... The first hit has been associated with insulin resistance... in only a proportion of patients with insulin resistance and NASH will an advanced liver disease develop, and other factors, or hits (like oxidative stress, mitochondrial dysfunction, and abnormal cytokine production), should be present to produce severe cellular injury or fibrosis...
 
... Among 12 variables studied at baseline, we found that the prevalence of obesity and BMI were the only variables [associated with fibrosis]... Presence of diabetes has been shown to be an independent predictor of severe fibrosis in a retrospective study that analyzed a large number of patients. Among our patients, four of seven (57%) from group P and 4 of 15 (27%) from group NP had diabetes...
 
... Some very recent, noncontrolled studies have shown that insulin-sensitizing agents (rosiglitazone and pioglitazone) can lead to improvement in histological features in NASH patients after 48 weeks of treatment. If these results were confirmed in larger, controlled studies, this kind of therapy would be accepted as being able to modify the natural evolution of NASH and would be recommended promptly for clinical practice..."
 
ABSTRACT/SUMMARY
 
Nonalcoholic steatohepatitis may cause severe fibrosis, cirrhosis, and hepatocellular carcinoma, but supporting evidence is based on indirect data. Few publications have examined the results of repeat liver biopsies to evaluate progression of fibrosis.
 
The aims of this study were to assess rate of fibrosis progression in untreated patients with nonalcoholic steatohepatitis and to identify associated variables.
 
Among 106 patients, a second liver biopsy was proposed to those who had undergone their first liver biopsy at least 3 years before. None of them had been given pharmacological therapy. Liver biopsy samples were evaluated blindly. Variables were compared between patients with (group P) and without (group NP) fibrosis progression, using a Wilcoxon rank-sum test for numerical variables and a difference of two binomial proportions for categorical ones.
 
Twenty-two patients (median age, 45 years; age range, 20-69 years; 13 women; diabetes in 8 patients, obesity in 10 patients) underwent a second liver biopsy 4.3 years (range, 3.0-14.3 years) after the first.
 
Fibrosis progression was found in 7 patients in group P (31.8%), no progression was found in 15 patients in group NP. There were no differences between both groups regarding age, gender, diabetes, hyperlipidemia, ALT levels, AST-to-ALT ratio levels, albumin levels, prothrombin activity, steatosis, or inflammation.
 
Obesity was significantly more prevalent in group P (86%) than in group NP (27%; P = .01). Basal body mass index was higher in group P (median, 33.2; range, 29.1-38.2) than in group NP (median, 29.0; range, 24.0-38.1; P = .024). Time between biopsies was not different between groups.
 
In conclusion, progression of liver fibrosis was found in a third of nonalcoholic steatohepatitis patients 4.3 years after the first liver biopsy, and obesity and body mass index were the only associated factors with such progression.
 
Article Text
 
Nonalcoholic fatty liver disease is probably the main cause of chronic liver disease in the West. The histological spectrum of nonalcoholic fatty liver disease includes simple steatosis (type 1), steatosis plus lobular inflammation (type 2), steatosis plus ballooning degeneration (type 3), and steatosis plus ballooning degeneration plus Mallory bodies or fibrosis (type 4). This classification is clinically important. Whereas simple steatosis seems to be a benign and nonprogressive condition, nonalcoholic steatohepatitis (NASH) that includes the types 3 and 4 of nonalcoholic fatty liver disease is recognized as a potentially progressive disease that may cause cirrhosis and liver-related death.
 
However, our knowledge of the natural history of NASH is still very limited and is largely based on indirect evidence. Cross-sectional series have shown that 30% to 40% of patients have advanced liver fibrosis at the time of presentation, whereas 10% to 15% of them may have established cirrhosis. Three studies have found that patients with cryptogenic cirrhosis have a greater rate of diabetes, obesity, or both than those with cirrhosis resulting from other causes, suggesting that cryptogenic cirrhosis may represent burned out NASH. In patients who underwent liver transplantation for cryptogenic cirrhosis, steatosis, and NASH have been shown in the graft during follow-up. Finally, the appearance of hepatocellular carcinoma has been reported in NASH patients, and in two large series of patients with hepatocellular carcinoma evaluated retrospectively, it has been found that cryptogenic cirrhosis (with the clinical phenotype of NASH) was the underlying liver disease in 7% to 13% of the cohort.
 
Therefore, indirect data suggest that NASH may cause the entire spectrum of complications of chronic liver disease: progressive fibrosis, cirrhosis, end-stage liver disease, and hepatocellular carcinoma. However, longitudinal studies showing what percentage of patients with NASH will have a progressive course are lacking. To our knowledge, the published results of repeat liver biopsies come from only 56 patients without cirrhosis but with NASH (included in six different studies). The second biopsies were performed 1.2 to 15.7 years after the first and showed fibrosis progression in 39.3% of patients. The first four studies were clinical series examining NASH in which only a minority of patients underwent a repeat biopsy, whereas the last two studies were specially designed to evaluate histological changes. Furthermore, none of the previous studies addressed whether basal variables could differentiate patients with and without progression. These previous results are very interesting, but the number of patients studied is still very limited, and further prospective studies should be conducted to expand the knowledge of the natural history of NASH.
 
Thus, the aims of this prospective, longitudinal study were to assess the progression rate of liver fibrosis in nontreated NASH patients and to identify clinical, biochemical, and histological variables associated with fibrosis progression.
 
AUTHOR DISCUSSION
 
Our study shows that 31.8% of 22 patients with NASH had a progression of liver fibrosis over a median follow-up of 4.3 years. These findings confirmed the progressive potential of NASH. However, most of the patients (68.2%) had no fibrosis progression. The different evolution can not be explained by a smaller time span between biopsies in the NP group. These patients underwent their second liver biopsy at a median time of 4.3 years after the first (range, 3.2-7.9 years), not significantly different from those in the P group.
 
It is important to emphasize that both the pathogenesis and the natural history of nonalcoholic fatty liver disease and NASH are still incompletely understood, but they may be closely related. It has been postulated that most of the patients with nonalcoholic fatty liver disease have a fatty liver alone, a smaller proportion has steatohepatitis, and a percentage has advanced fibrosis. A two-hit hypothesis has been proposed to explain the mechanisms of liver damage in NASH. The first hit has been associated with insulin resistance, which has been demonstrated in almost all NASH patients studied and would cause the accumulation of excess fat in the hepatocytes. However, in only a proportion of patients with insulin resistance and NASH will an advanced liver disease develop, and other factors, or hits (like oxidative stress, mitochondrial dysfunction, and abnormal cytokine production), should be present to produce severe cellular injury or fibrosis.
 
Considering that only approximately one third of NASH patients will have increasing liver fibrosis in the midterm, it would be useful to know the factors associated with that evolution, and our study sought to identify clinical, biochemical, and histological variables able to predict progression. Among 12 variables studied at baseline, we found that the prevalence of obesity and BMI were the only variables that were significantly different between the groups (with 86% and 27% of patients being obese in the groups P and NP, respectively). Interestingly, the changes in BMI during the follow-up were not different between the groups. In fact, the gradients (final vs. basal values) of BMI were very close to 0 in both groups. Thus, among NASH patients, those with obesity would be very prone to fibrosis progression. Furthermore, in this subgroup of patients, the dietary recommendations seem to be insufficient to prevent progression, and they should be included in trials of experimental pharmacological therapy (or immediately treated when a drug is accepted as being efficacious). Presence of diabetes has been shown to be an independent predictor of severe fibrosis in a retrospective study that analyzed a large number of patients. Among our patients, four of seven (57%) from group P and 4 of 15 (27%) from group NP had diabetes. The P value (.2267) was far from being significant, but we can not exclude a type II error because of the small sample size of patients having both NASH and diabetes.
 
All the patients were referred to the Nutrition Department and encouraged to follow a low-calorie and low-fat diet. However, it is known that it is difficult for these patients to adhere to dietary therapy in the long term. During the follow-up, 27% of patients (6 of 22) achieved a 5% or more reduction in their body weight, and that percentage was not different between groups P and NP. Thus, we believe that it is unlikely that the dietary treatment could have played an important role in modifying the evolution of our patients' courses, but we can not exclude a mild beneficial effect. Among the four patients showing a decrease in the final fibrosis score, only one had had that kind of weight reduction.
 
Comparing our results with those of 59 patients without cirrhosis but with NASH and repeat liver biopsies previously published in the literature, we found in our study a lower rate of fibrosis progression (32%) during a longer follow-up (median, 4.3 years; mean, 5.3 years) than those observed in the first four studies that were clinical series and included 30 patients. It is difficult to determine the reasons for that difference, because the demographical or analytical data are not fully available in the papers. However, among 24 patients whose clinical data are known, 22 (91.7%) were obese (the only predictor of progression, according to our results), and this could be the main explanation for a faster progression. The last two studies, like ours, were designed to analyze changes in histological findings, and Harrison et al. reported results impressively similar: 7 of their 22 patients showed fibrosis progression in a mean time of 5.7 years between biopsies. The clinical data of their patients also were similar to ours, but the obesity prevalence was slightly higher (77%).
 
Other findings of our study worth noting are as follows. First, the inflammatory activity in the basal liver biopsy was not different between patients with or without fibrosis progression, in contrast to what was expected. However, it should be noted that the grade of inflammation was mild in most of the patients (19 of 22). Second, changes in grade of steatosis run an independent course from those in fibrosis, being found in the final liver biopsy a decrease in steatosis and an increase in fibrosis, either in the entire population or in group P patients. This observation is consistent with the suggestion that NASH patients may lose the fatty infiltration when they reach the stage of cirrhosis, which becomes a cryptogenic cirrhosis. Third, the evolution of ALT values was not different between both groups and, especially in group P, a normalization of ALT values was observed in six of seven patients. It is important to emphasize that a normalization of ALT levels does not guarantee fibrosis stabilization or improvement, because many pilot studies evaluating pharmacological treatments in NASH have claimed different drugs to be efficacious based only on the decreasing ALT values.
 
The rate of progression of liver fibrosis has not been studied previously in NASH. Considering the entire population, the rate of liver fibrosis progression was estimated in 0.059 units of fibrosis per year. In a recent study, in patients with chronic hepatitis C, Ghany et al. found progression of liver fibrosis in 39% over a mean interval of 44 months (range, 2-211 mo) between both biopsies. The rate of liver fibrosis progression was estimated in 0.12 fibrosis units per year. Thus, our figure of fibrosis progression in NASH patients is approximately half of that found in hepatitis C patients. However, in patients from group P, the rate of progression was estimated to be 0.280 units of fibrosis per year.
 
Some very recent, noncontrolled studies have shown that insulin-sensitizing agents (rosiglitazone and pioglitazone) can lead to improvement in histological features in NASH patients after 48 weeks of treatment. If these results were confirmed in larger, controlled studies, this kind of therapy would be accepted as being able to modify the natural evolution of NASH and would be recommended promptly for clinical practice. In that eventuality, studies like ours, aimed at understanding natural history, no longer would be carried out because they would be considered unethical, and the knowledge of the natural history of NASH would remain rather limited.
 
In summary, the results of this longitudinal study have shown progression of liver fibrosis in approximately one third of patients with NASH in a median follow-up of 4.3 years, the presence of obesity being the only factor associated with the progression. Patients with NASH who are obese should be included in controlled trials of experimental pharmacological therapy or should be treated promptly when some agreement exists regarding the efficacy of any drug in retarding the progression of fibrosis.
 
Patients and Methods
 
From October 1986 through December 2002, 106 patients were diagnosed with NASH in the Liver Unit at the Professor Alejandro Posadas Hospital. The diagnosis of NASH was based on the following four criteria. Persistently abnormal alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, or both was the first criterion. A daily alcohol intake of less than 40 g in men and less than 20 g in women, as confirmed by patient anamnesis and interview of close family members, was the second criterion. These cutoff levels of ethanol intake were chosen because they were the usual ones when we designed the study. Surrogate biochemical markers of alcohol consumption were not used. Appropriate exclusion of other causes of chronic liver disease, such as hepatitis B and C, autoimmune hepatitis, drug-induced hepatitis, primary biliary cirrhosis, hemochromatosis, Wilson disease, was the third criterion. The fourth criterion was characteristic features in the liver biopsy, including macrovesicular steatosis (>10% of hepatocytes) and lobular inflammation plus ballooning degeneration, Mallory hyaline fibrosis, sinusoidal fibrosis, or a combination thereof. Patients demonstrating only steatosis and lobular inflammation in their biopsy results were not considered to have NASH. Either ballooning degeneration or sinusoidal fibrosis had to be present to confirm the diagnosis of NASH. This population included 55 males and 51 females with a median age of 45 years (range, 17-78 years).
 
Patients were considered to have diabetes mellitus either if they were receiving insulin or oral hypoglycemic treatment or if a fasting plasma glucose test result was 126 mg/dL or more, according to the American Diabetes Association definition. Hyperlipidemia was diagnosed when fasting levels of cholesterol were more than 200 mg/dL, fasting levels of triglycerides were more than 200 mg/dL in two occasions, or both. Obesity was defined as a body mass index (BMI) of more than 30, both in men and women. BMI was calculated using the following formula: kg(weight)/m2(height). Waist circumference or waist-to-hip ratio measurements were not obtained in these patients.
 
All the patients were referred to the Nutrition Department for the treatment of their metabolic disorders (hyperlipidemia, obesity, glucose intolerance, or diabetes), but no experimental pharmacological treatment for NASH (e.g. ursodeoxycholic acid, vitamin E, glitazones) was given to any patient. No patient was taking drugs associated with secondary NASH, such as corticosteroids, perhexiline, tamoxifen, and amiodarone.
 
All the patients were scheduled to undergo a repeat liver biopsy at least 3 years after the previous biopsy. Patients lost to follow-up were contacted by phone calls or conventional mailing. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethics and research committees of our hospital. Informed consent was obtained from each enrolled patient.
 
Liver biopsy samples were obtained by the percutaneous route using the Menghini method. One or two passes were performed to assure samples at least 25 mm in length. Formalin-fixed, paraffin-embedded liver sections were stained routinely with hematoxylin and eosin, silver reticulin, Masson trichrome, Perls' Prussian blue, and diastase-resistant periodic acid-Schiff.
 
After determining patient inclusion, all the liver biopsy specimens (basal and final samples) were reexamined in a blind and nonpaired manner by an experienced pathologist (E.A.) who was unaware of the clinical and biochemical data of the patients or the order of the biopsies. Studies on the liver specimens included a semiquantitative assessment of the grades of steatosis (mild or grade 1, >10% but <33% of hepatocytes affected; moderate or grade 2, 33%-66% of hepatocytes affected; severe or grade 3, >66% of hepatocytes affected); of inflammatory activity (according to Brunt classification); and of fibrosis (according to Brunt classification and to Ishak classification). Brunt classification of fibrosis assessment includes five stages: stage 0, no fibrosis; stage 1, zone 3 perisinusoidal or pericellular fibrosis, focally or extensively present; stage 2, zone 3 perisinusoidal or pericellular fibrosis with focal or extensive periportal fibrosis; stage 3, zone 3 perisinusoidal or pericellular fibrosis and portal fibrosis with focal or extensive bridging fibrosis; stage 4, cirrhosis. Ishak classification ranges from zero to six stages: stage 0, no fibrosis; stage 1, fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, fibrous expansion of most portal areas with occasional portal to portal bridging; stage 4, fibrous expansion of portal areas with marked bridging (portal to portal) as well as portal to central; stage 5, marked bridging with occasional nodules (incomplete cirrhosis); stage 6, cirrhosis, probable or definite.
 
Progression of liver fibrosis was defined as an increase 1 grade or more in the final stage with respect to the basal biopsy, in any of the two classifications. Although Brunt classification was designed especially for NASH patients, we decided to analyze changes in fibrosis according to Ishak classification as well, because of its greater flexibility in evaluating septal fibrosis (score 3 for occasional bridging, score 4 for marked bridging), incomplete cirrhosis (score 5), and definite cirrhosis (score 6).
 
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Long-Term Outcomes in HCV with SVR: cure, regression of fibrosis
	Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy: study finds - 29% of SVRs show regression of fibrosis; HCV is curable & long-term outcome of sustained viral responders is good; Five year survival of European sustained virological responders was similar to the general population, matched for age & sex and no HCCs were detected during long term follow up.   Gut October 2004;53:1504-1508   B J Veldt1, G Saracco2, N Boyer3, C Cammà4, A Bellobuono5, U Hopf6, I Castillo7, O Weiland8, F Nevens9, B E Hansen10 and S W Schalm1   1 Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, the Netherlands 2 Department of Gastroenterology, Ospedale Molinette, Torino, Italy 3 Hôpital Beaujon, Clichy, France 4 Cattedra e Unità Operativa di Gastroenterologia, University of Palermo, and IBIM, Consiglio Nazionale delle Richerche, Palermo, Italy 5 Ospedale Generale di zona "San Giuseppe", Milan, Italy 6 Charité, Campus Virchow-Klinikum Universitätsmedizin, Berlin, Germany 7 Fundacion Estudio Hepatitis Virales, Madrid, Spain 8 Karolinska Institute, Huddinge Hospital, Huddinge, Sweden 9 University Hospital Leuven, Belgium 10 Department of Gastroenterology and Hepatology, and Department of Epidemiology and Biostatistics, Erasmus Medical Centre, Rotterdam, the Netherlands   SVR Shows Regression of Fibrosis:   "...One hundred and twenty five patients (110 sustained virological responders and 15 biochemical responders) underwent liver biopsy both before and after treatment. Mean time between these two biopsies was 1.6 years. Thirty two sustained virological responders (29%) and none of the biochemical responders showed regression of fibrosis. Progression of fibrosis was seen in six sustained virological responders (5%) and in three biochemical responders (20%)..."   "Cure"   "...In this study, sustained virological response was associated with a decrease in fibrosis score. Similar findings have been reported for sustained responders to pegylated interferon. Previous studies have shown that regression of fibrosis can also occur in biochemical responders and non-responders to interferon. In common with our study, sustained virological responders show the highest rate of regression. Because of the large proportion of sustained virological responders that showed regression of fibrosis and the low incidence of clinical events in these patients, in our view, non-cirrhotic patients with a sustained virological response can be regarded as cured..."   "...A limitation of our study is that all patients had been treated with interferon monotherapy whereas the current standard therapy for chronic hepatitis C is pegylated interferon with ribavirin. This current standard however dates from 2002 and long term follow up data of peginterferon and ribavirin were not available at the time of this study. In general, combination therapy leads to higher sustained virological response rates and also the late relapse rate seems to decrease...As the late relapse rate seems to decrease with newer treatment regimens (Peginterferon), long term clinical outcomes may be similar or even better than results obtained with interferon monotherapy. Therefore, in our opinion, the favourable clinical outcome of sustained virological responders is likely to hold true in the era of pegylated interferon and ribavirin..."   ABSTRACT/SUMMARY   The key end point for treatment efficacy in chronic hepatitis C is absence of detectable virus at six months after treatment. However, the incidence of clinical events during long term follow up of patients with sustained virological response is still poorly documented and may differ between the Eastern and Western world.   The aim of this study is to assess clinical end points during long term follow up of European patients with a sustained virological response to interferon monotherapy.   The study methodology was a meta-analysis of individual patient data from eight European protocolled follow up studies of interferon treatment for chronic hepatitis C.   Results:   A total of 286 sustained virological responders and 50 biochemical responders (detectable virus but normal alanine aminotransferase levels) were followed up for 59 months. Fifteen sustained virological responders (5.2%) had cirrhosis before treatment and 112 (39%) had genotype 1. The late virological relapse rate after five years of follow up was 4.7% (95% confidence interval (CI) 2.0--7.4) among sustained virological responders; all late relapses occurred within four years after treatment.   Among sustained virological responders, the rate of decompensation after five years of follow up was 1.0% (95% CI 0.0--2.3) and none developed hepatocellular carcinoma (HCC).   Survival was comparable with the general population, matched for age and sex, the standard mortality ratio being 1.4 (95% CI 0.3--2.5). Clinical outcome of patients with cirrhosis was similar to other sustained virological responders. For biochemical responders, the rates of development of decompensation and HCC during long term follow up were 9.1% (95% CI 0.5--17.7) and 7.1% (95% CI 0--15.0), respectively.   The authors concluded that five year survival of European sustained virological responders was similar to the overall population, matched for age and sex. No HCCs were detected during long term follow up.   INTRODUCTION   Chronic infection with the hepatitis C virus (HCV) can lead to decompensated liver cirrhosis and hepatocellular carcinoma (HCC). However, treatment of hepatitis C is based on surrogate end points, and evaluation of treatment for clinical end points has only slowly been forthcoming due to the slow course of the disease and the small number of clinical events in patients treated for hepatitis C.   Protocolled studies use sustained virological response as the key outcome measure for hepatitis C treatment. This sustained virological response is defined as no detectable HCV-RNA in serum at six months after treatment. The aim of this study was to determine the long term clinical outcome of sustained virological responders who had been treated in protocolled studies.   RESULTS   Study population   Data were obtained for 343 patients treated for chronic hepatitis C. A total of 286 patients had a sustained virological response and 50 had a biochemical response. Seven patients did not fit the entry criterion of HCV-RNA data availability at the end of treatment and after six months of follow up and were excluded from further analysis.   Characteristics of sustained virological responders and biochemical responders are shown in table 1. Patients had been treated with recombinant interferon a2a, a2b, or natural interferon monotherapy. Patients were treated for an average duration of 39 weeks (range 11--96). Patients with genotype 1 were treated longer (mean duration 41 weeks v. 38 weeks in other genotypes; p<0.01) and received a higher total dose of interferon (581 mega units (MU) v 525 MU in other genotypes; p<0.01, Mann-Whitney U test).   Table 1.       SVR Biochem resp p-value No 286 50   Age 41 45 0.04 Male 59% 52% 0.35 Months Follow up 59 59 0.99 Total IFN dose(MU) 550 469 0.05 geno 1 39% 42% 0.71 cirrhosis 5.2% 22% 0.00   Sustained Virological Responders   Of 286 sustained responders, 15 patients had cirrhosis before the start of treatment, as determined by liver biopsy.   Two patients presented with decompensated cirrhosis after 30 and 60 months of follow up (fig 1). These patients were hepatitis B surface antigen negative and HCV-RNA negative, and no other risk factors for liver disease were reported. The latter patient died of decompensated cirrhosis. Five other patients died of non-liver related causes. One patient died of lung cancer and two patients died of trauma; another patient died of cardiovascular complications and one patient died of a haemolytic uraemic syndrome.   The standard mortality ratio of sustained responders was 1.4 (95% confidence interval (CI) 0.3--2.5), and there was no statistically significant difference in mortality between sustained virological responders and the general population, matched for age and sex.
	Biochemical responders   Fifty patients had normal transaminase levels at the end of follow up and six months after treatment while HCV-RNA was still detectable. Of these biochemical responders, three patients died during long term follow up, all of liver related causes. The occurrence of decompensation and HCC among biochemical responders was 9.1% (95% CI 0.5--17.7) and 7.1% (95% CI 0--15.0), respectively. Biochemical responders were older and had a higher prevalence of cirrhosis. Although there was a trend to a higher standard mortality ratio (corrected for age and sex) in biochemical responders after five years of follow up, the difference did not reach statistical significance.   Liver histology   One hundred and twenty five patients (110 sustained virological responders and 15 biochemical responders) underwent liver biopsy both before and after treatment. Mean time between these two biopsies was 1.6 years (SD 0.8). Thirty two sustained virological responders (29%) and none of the biochemical responders showed regression of fibrosis. Progression of fibrosis was seen in six sustained virological responders (5%) and in three biochemical responders (20%). Baseline characteristics of sustained virological responders and biochemical responders who underwent two biopsies were different, with sustained virological responders being younger (mean 39 (SD 13) v 47 (14) years), having a lower mean pretreatment fibrosis stage (1.75 (1.1) v 2.5 (1.4)), and having a shorter time between the two biopsies (1.5 (0.6) v 2.3 (1.5) years). Therefore, we performed a multiple regression analysis to determine independent risk factors for progression of fibrosis. Fibrosis progression was associated with older age, lower pretreatment fibrosis score, and biochemical response rather than sustained virological response.   Late relapsers   Twelve sustained responders had a late virological relapse. In six patients (50%), late virological relapse was accompanied by an elevation in transaminase levels. Multivariate Cox regression analysis did not show any pretreatment factors to be associated with an increased risk for late virological relapse. None of the late relapsers developed decompensation or HCC during follow up. No late virological relapses were seen after four years of follow up, the maximal delay between the last negative polymerase chain reaction (PCR) and the first positive PCR result being 12 months.
	AUTHOR DISCUSSION   This large European study allows, for the first time, an approximation of the incidence of clinical events during long term follow up of sustained virological responders in Europe. The most important finding is that clinical events are rare in this population, indicating that sustained virological responders have an excellent prognosis.   The largest European study to date describing clinical outcome in sustained responders to interferon treatment did not report any events among 74 patients followed up for 2.7 years. Two other European studies, involving seven and 56 sustained responders, also showed no clinical events during 4.6 and 5.2 years of follow up, respectively. Bruno et al described 32 sustained responders of whom one cirrhotic patient developed HCC.17 Although another HCC has been reported recently in a Western sustained responder, these cases seem to be rare and limited to patients with cirrhosis. In the present study, no HCCs occurred during long term follow up. According to several large studies, the yearly incidence of HCC among Japanese sustained virological responders still varies between 0.02% and 0.5% per year; the difference in the incidence of HCC between East and West apparently persists in conditions without detectable viral replication.   The lowest rates in Japan were reported by Yoshida et al, with one HCC among 817 sustained responders during 5.4 years of follow up.26 The highest incidence of HCC reported among sustained responders in Japan was by Kasahara et al who reported five HCCs among 313 sustained virological responders followed up for three years.   Fifteen cirrhotic patients were included in this study. Only two patients with decompensated cirrhosis were reported. Among untreated cirrhotics, occurrence of clinical events of 38% (28% decompensation and 10% HCC) would be expected, according to Fattovich and colleagues. These results suggest, but do not prove, a change in the natural course of chronic hepatitis C. Further studies, including more cirrhotics, will be necessary to investigate the effect of treatment on the natural course of chronic hepatitis C.   In this study, sustained virological response was associated with a decrease in fibrosis score. Similar findings have been reported for sustained responders to pegylated interferon. Previous studies have shown that regression of fibrosis can also occur in biochemical responders and non-responders to interferon. In common with our study, sustained virological responders show the highest rate of regression. Because of the large proportion of sustained virological responders that showed regression of fibrosis and the low incidence of clinical events in these patients, in our view, non-cirrhotic patients with a sustained virological response can be regarded as cured.   A limitation of our study is that all patients had been treated with interferon monotherapy whereas the current standard therapy for chronic hepatitis C is pegylated interferon with ribavirin. This current standard however dates from 2002 and long term follow up data of peginterferon and ribavirin were not available at the time of this study. In general, combination therapy leads to higher sustained virological response rates32,33 and also the late relapse rate seems to decrease. In this study with data on interferon monotherapy, the late relapse rate was 4.7% (95% CI 2.0--7.4); Camma et al reported 8.7% in a meta-analysis of 14 trials with interferon monotherapy. After four years of follow up of treatment with interferon and ribavirin, late virological relapse rates of 3% (95% CI 1.4--4.6) and 1% (95% CI 0--2.0) have been reported for patients treated for 24 weeks and 48 weeks, respectively. After treatment with pegylated interferon with or without ribavirin, a late relapse rate of 0.8% was reported after four years of follow up. The possibility of reinfection could not be ruled out in our cohort as data on risk behaviour and concordance of genotypes were not available. However, introduction of more sensitive PCR methods may also have contributed to a decrease in late virological relapse over time. It is possible that with an insensitive assay, patients with low viraemia are regarded as sustained virological responders.   As the late relapse rate seems to decrease with newer treatment regimens, long term clinical outcomes may be similar or even better than results obtained with interferon monotherapy. Therefore, in our opinion, the favourable clinical outcome of sustained virological responders is likely to hold true in the era of pegylated interferon and ribavirin.   In conclusion, the long term clinical outcome of patients with a sustained response to interferon is favourable. Five year survival of European sustained virological responders was similar to the general population, matched for age and sex, and no HCCs were detected during long term follow up.   STUDY METHODS   Study design   All European centres that had published long term data on patients treated for chronic hepatitis C before 1997 were invited to participate in the protocol and to include patients with response to treatment.   Additional entry criteria were study follow up longer than one year and availability of HCV-RNA data. Nine centres met these criteria. Patients from eight European hepatology units were included in the study.   Patient selection   Data from 343 consecutive chronic hepatitis C patients with response to interferon monotherapy were obtained. All patients had participated in protocolled studies (clear cohort or randomised controlled trial). Data were collected on separate case record forms, one per patient, by the local investigator. The case record forms were sent to the coordination centre in Rotterdam where data were entered into a central database. Before the data were entered, they were checked and, in case of doubt, contact was made with the local investigator.   Data recorded   Information was obtained on demographics (date of birth, sex) and on details of treatment (initial dose, duration of treatment, and total dose of interferon). Virological data (genotype, viraemia) and biochemical data (platelet count, bilirubin, albumin, and transaminase levels) were measured in certified laboratories of participating hospitals and added to the case record form by the local investigator. Centrally, results were corrected for local normal values. Results of pre- and post-treatment liver biopsies were recorded using the HAI score for activity and the Knodell score for fibrosis. All centres used polymerase chain reaction (PCR) methods with a detection limit of 100 copies/ml, except for one centre where PCR with a detection limit of 1000 copies/ml was used before 1998. No late virological relapses were reported from this centre after introduction of a test with a sensitivity of 100 copies/ml.   Follow up data were recorded every six months and included alanine aminotransferase (ALT) levels, HCV-RNA, and the occurrence of clinical events (decompensation, HCC, death).   Patients were considered to have decompensation if they showed any of the following symptoms: ascites, bleeding varices, jaundice, or hepatic encephalopathy. Patients were classified as having developed cirrhosis on the basis of ultrasound (nodular contour, diminished hepatopetal flow, collaterals), serology (platelets <80000, albumin <35 g/l, clotting factors<50%), or liver biopsy. Patients were considered to have HCC if the {alpha} fetoprotein level was >400 and ultrasound confirmed a focal lesion, or if biopsy proved so. Death was classified as liver related or liver unrelated.   Sustained virological response was defined as no detectable HCV-RNA at the end of treatment and after six months of follow up. Patients with normal ALT levels at these time points, but with detectable HCV-RNA at the end of treatment or six months thereafter, were referred to as biochemical responders. Sustained virological responders were considered to have a late virological relapse if HCV-RNA was detectable on any occasion after six months of follow up, confirmed by either a second PCR or elevation of ALT levels above the upper limit of normal.   Statistical analysis   To evaluate factors of influence on late virological relapse, univariate and multivariate Cox regression analyses were performed. The Kaplan-Meier method was used to evaluate the five year late relapse rate and to determine the rate of occurrence of clinical events during five years of follow up. The number of expected deaths and the expected survival probability were calculated based on sex and age ranked mortality among the Dutch general population, which is similar to most European countries. The standard mortality ratio was calculated by dividing the observed number of deaths by the expected number of deaths.   We used multiple regression analysis to identify risk factors for fibrosis progression.   Statistical analyses were performed using SPSS for Windows (SPSS Inc, Chicago, Illinois, USA). All analyses were performed by the Meta-Analysis of Individual Data group in Rotterdam (BEH, SWS, BJV), which is experienced in the conduct of such studies.
http://www.natap.org/

Impact of competing risks on observed rate of hepatitis C progression

Researchers in America report on the effect that competing risks have on the observed rate of fibrosis progression of chronic hepatitis C (CHC), in the most recent issue of Gastroenterology

Previous studies about the natural history of chronic hepatitis C (CHC) have shown that age at the time of infection is correlated with the rate at which hepatic fibrosis progresses. However, the presence of a competing risk, namely higher mortality from natural causes, may contribute to this observation. Terry Therneau and colleagues at the Mayo Clinic and Foundation in Minnesota carried out a simulation experiment to measure the magnitude of the effect of competing risks on the observed rate of fibrosis progression of CHC. The researchers created a computer-based probabilistic model in which fibrosis of CHC progressed from stage 0 to 4 (cirrhosis) in 20-year-old and 50-year-old male and female cohorts. The rate of fibrosis progression was randomly assigned to each simulated individual from a distribution common to all age- and sex-specific cohorts. The cohorts also experienced mortality from natural causes according to the 2000 census data. The group found that the observed median time to reach cirrhosis for the 50-year-old cohorts was 20.4 ± 0.2 years compared with 29.7 ± 0.2 for the 20-year-old cohorts. The median time to reach cirrhosis in men was 24.2 ± 0.6 years compared with 25.9 ± 0.6 in women (P = 0.01). Overall, the researchers found that the observed rate of progression was slowest among young women. Similarly, accelerating mortality from natural causes, simulating the impact of comorbid conditions that shorten survival, reduced the observed time to reach cirrhosis. Dr Therneau concluded, "Even if the underlying rate of fibrosis progression in CHC was held constant, the time to reach cirrhosis will be observed to be substantially shorter in subjects with a higher competing mortality."

Gastroenterology2004;127(3) 21 September 2004

Serum Immunoglobulins Predict the Extent of Hepatic Fibrosis in HCV Patients

Recently, the authors of the current study documented that immunoglobulins stimulate the proliferative activity of rat hepatic stellate cells in vitro. The aim of the present study was to determine whether there is any association between serum immunoglobulin levels and hepatic fibrosis in patients with chronic hepatitis C virus (HCV) infection.

Charts from 116 patients with biochemical, serologic, virologic and histologic evidence of chronic hepatitis C infection and serum immunoglobulin levels (IgA, IgG, IgM and total) were reviewed.

The mean (+/-SD) age of the study population was 46 +/- 11 years and 67 (58%) were male. There were significant correlations between serum IgA (r = 0.39, P = 0.00001), IgG (r = 0.49, P = 0.000002) and total (r = 0.51, P = 0.000003) immunoglobulin levels and the stage of hepatic fibrosis.

When serum immunoglobulin levels were included into logistic regression analysis with variables known to be associated with advanced disease (male gender, age >40 years at onset of infection, duration of infection beyond 20 years and concurrent alcohol abuse) only IgA, IgG and total immunoglobulin levels (P < 0.05, <0.05 and <0.005, respectively) emerged as independent predictors of hepatic fibrosis.

The authors conclude, "Our data indicate a strong association between serum immunoglobulin levels (IgA, IgG and total) and hepatic fibrosis in patients with HCV infection. This finding supports the need to further investigate whether immunoglobulins independently promote disease progression in patients with chronic HCV infection."

Department of Medicine, Section of Hepatology, University of Manitoba, Winnipeg, Canada.

08/11/04

Reference
K Watt and others. Serum immunoglobulins predict the extent of hepatic fibrosis in patients with chronic hepatitis C virus infection. Journal of Viral Hepatitis 11(3): 251-256. May 2004

http://www.hivandhepatitis.com/hep_c/news/2004/081104_a.html

Common Heterozygous Hemochromatosis Gene Mutations Are Risk Factors for Inflammation and Fibrosis in Chronic Hepatitis C

Chronic hepatitis C is frequently associated with increased hepatic iron stores. It remains controversial whether heterozygous mutations of hemochromatosis genes affect fibrosis progression. Therefore the aim of the current study was to assess associations between HFE mutations and hepatic inflammation and stage of fibrosis in German hepatitis C patients.

Liver biopsies from 166 patients were scored for inflammatory activity (A0-4) and hepatic fibrosis (F0-4). Gene mutations were determined by LightCycler, restriction fragment length polymorphism analysis, or direct sequencing.

Results

The frequencies of common HFE mutations C282Y and H63D are 4.2% and 21.3%, whereas the recently described S65C substitution and the Y250X mutation in the transferrin receptor 2 gene are very rare.

In regression analysis, heterozygous carriers of C282Y or H63D mutations display significantly (P<0.05) higher inflammatory activities and more advanced fibrosis than patients without mutations.

For C282Y heterozygous patients, the odds ratios for marked inflammatory activity (A2-4) and advanced liver fibrosis or cirrhosis (F2-4) are 4.9 and 4.6, respectively, compared with patients carrying homozygous wild-type alleles.

C282Y mutations are associated with significantly (P<0.05) increased serum iron and aminotransferase levels, whereas H63D heterozygotes display higher transferrin saturation, serum iron, and ferritin concentrations compared to wild-type (P<0.01).

Conclusions

In conclusion, the authors write, "Common heterozygous hemochromatosis mutations are associated with higher grades of inflammation and more severe hepatic fibrosis. Our findings support a role of HFE mutations as primary risk factors for fibrogenesis and disease progression in chronic hepatitis C."

Department of Medicine III, University Hospital Aachen, Aachen University (RWTH), Aachen, Germany.

08/11/04

Reference
A Geier and others. Common heterozygous hemochromatosis gene mutations are risk factors for inflammation and fibrosis in chronic hepatitis C. Liver International 24(4): 285-294. August 2004.
http://www.hivandhepatitis.com/hep_c/news/2004/081104_c.html

Intercept Pharmaceuticals Announces Publication of Study Demonstrating Its Lead Compound Can Reverse Liver Fibrosis

          - Proof-of-Principle Study Published in Gastroenterology -

    NEW YORK, Aug. 12 /PRNewswire/ -- Intercept Pharmaceuticals, Inc., an
emerging specialty pharmaceutical company focused on developing small molecule
drugs for the treatment of chronic liver and metabolic diseases, today
announced publication in Gastroenterology of a major set of studies led by its
scientific co-founder, Stefano Fiorucci, M.D., demonstrating that Intercept's
lead FXR agonist, INT-747, can stop development of, and perhaps even reverse,
liver fibrosis in animal models.
    Liver fibrosis is the process of chronic scarring that leads eventually to
cirrhosis and liver failure.  It affects individuals with alcoholic liver
disease, chronic viral infections like hepatitis B and C, and obesity
associated non-alcoholic fatty liver disease (NAFLD), making it a major cause
of disability and death for tens of millions of people worldwide.  There
currently are no approved treatments for liver fibrosis, leaving liver
transplant as the only option available for those few patients with end-stage
disease able to receive a donor organ.
    "Publication of this landmark study which confirms the therapeutic
rationale underlying our lead compound for liver fibrosis is an important
milestone for our company," said Mark Pruzanski, M.D., President and CEO of
Intercept Pharmaceuticals.  "Until recently, liver fibrosis and cirrhosis have
not been considered treatable, yet Dr. Fiorucci and his team have now
demonstrated in validated animal models that liver fibrosis may be slowed and
perhaps even reversed by Intercept's lead compound.  Based on these
encouraging results, we plan to advance INT-747 into human clinical trials in
early 2005."
    Prior work by Intercept's founders and other researchers elucidated the
role of FXR, a member of the nuclear hormone receptor family, in the
regulation of bile flow and rate of bile synthesis from dietary cholesterol.
These studies suggested that FXR agonists may have utility in the treatment of
a variety of cholestatic liver diseases which impair enterohepatic bile flow,
resulting in progressive damage to the liver. More recently, as reported in
the Gastroenterology paper, Intercept has uncovered the potential of FXR
agonists to directly repress the degenerative processes underlying liver
fibrosis.
    "On behalf of the many researchers, clinicians and patients who have been
frustrated by our inability to treat liver fibrosis, I am encouraged to report
the positive results of our initial work with INT-747," said Stefano Fiorucci,
M.D., Professor of Gastroenterology at the University of Perugia in Italy and
a well known liver disease researcher and clinician. "Agents like INT-747 for
the first time give us the possibility of treating this often fatal condition
to preserve adequate liver function and perhaps even restore lost function.  I
look forward to working with the Intercept team to rapidly advance INT-747 and
associated compounds towards human clinical testing."
    Intercept's lead compound, a potent, orally bioavailable FXR agonist
formerly known as 6ECDCA, was discovered in 2001 through a collaboration
between GlaxoSmithKline and University of Perugia scientists.  Worldwide
intellectual property rights to the compound and to a number of other FXR
agonists, antagonists and modulators have been assigned to Intercept.  FXR is
known to be expressed in the liver, intestine and kidney, and Intercept
intends to continue to lead research efforts to fully elucidate the
therapeutic potential of this target.

    About Intercept Pharmaceuticals
    New York City-based Intercept Pharmaceuticals, Inc. is an emerging
specialty pharmaceutical company focused on developing small molecule drugs
for the treatment of chronic liver and metabolic diseases. The company is
currently advancing its lead drug candidate, INT-747(6ECDCA), for the
treatment of a group of life threatening fibrotic and cholestatic liver
diseases for which there are virtually no effective marketed drugs. The
company intends to lead in the advancement of drug candidates acting on FXR in
multiple indications through clinical proof-of-concept.  As a ligand-regulated
nuclear hormone receptor, FXR is a member of a target class that has
consistently yielded successful marketed pharmaceuticals in a variety of
indications.

     Contacts:                            Media:
     Intercept Pharmaceuticals            GendeLLindheim BioCom Partners
     Mark Pruzanski, M.D.                 Barbara Lindheim
     (917) 744-4043                       (212) 918-4650
     mark@interceptpharma.com

Hepatic Fibrosis Influences Early Virological Response Rates in Chronic Hepatitis C
 

Early virological response (EVR), during HCV therapy is defined as undetectable HCV RNA or at least a 2-log decrease in HCV RNA at week 12. Failure to achieve this has been shown to accurately predict non-response.

The aim of the current study was to determine the influence of hepatic fibrosis on EVR rates.

138 genotype 1 CHC patients who had received either combination peginterferon alfa-2b (Peg-Intron) 1.5mcg/kg weekly or standard interferon alfa (3MU TIW) and ribavirin (1000-1200 mg/d) were retrospectively identified from the databases of 2 hospitals.

Serum HCV RNA was measured at baseline, week 12, and at 24 weeks after completion of therapy using a quantitative PCR assay with a lower limit of detection of 100 copies/ml (NGI, Los Angeles, CA).

Pre-treatment liver biopsies were scored for fibrosis by the METAVIR system.

Results

Of 138 patients, 95 (69%) were male, 81 (59%) were Caucasian, 47 (34%) were African American. 61 (44%) had Metavir stage F0-F1 and 77 (56%) had Metavir stage F2-F4.

Overall 67/138 (49%) patients achieved EVR and 33/138 (24%) achieved SVR.

Patients most likely to achieve an EVR were those with fibrosis stage F0-F1 compared with F2-F4 (62% vs 38%; p=0.006), male patients with lower grades of fibrosis (66% vs 40%; p=0.02) and Caucasian patients with fibrosis scores 0-1 (74% vs 42%; p=0.004).

Only 15/47 (32%) of African American patients achieved EVR and 9/47(19%) achieved SVR.

There was no difference in EVR between African American high and low-grade fibrosis groups.

In the low-grade fibrosis group, Caucasians were more likely to achieve EVR than African Americans (74% vs 32%; p=0.012).

The authors conclude, “In difficult to treat HCV genotype 1 infection, the negative predictive value of EVR still holds true irrespective of fibrosis score. Male and Caucasian patients with lower grades of fibrosis were more likely to achieve EVR compared to patients with higher grades of fibrosis. This study also confirms previously observed poor rates of response in African Americans.”

06/07/04

Reference
A T Dev and others. Hepatic Fibrosis Influences Early Virological Response Rates in Chronic Hepatitis C (CHC). Abstract 1159 (poster). Digestive Disease Week. May 15-20, 2004. New Orleans, LA.

http://www.hivandhepatitis.com/2004icr/ddw2004/docs/0607/060904_b.html

Viscum Album and Solanum Lycopersicum Inhibit Fibrosis in Chronic Hepatitis C
 

Untreated HCV leads to liver cirrhosis and hepatocellular carcinoma in 20-30% of cases after 25 years of infection. No successful treatment is known following failure or contraindications to standard therapy (pegylated interferon and ribavirin).

German researchers investigated the effect on fibrosis in a pilot study using a complementary concept with mistletoe and herbal extracts of Solanum lycopersicum, Fragaria vesca/Vitis vinifera (Hepatodoron).

8 patients with HCV (genotype 1) were treated with Viscum album (Abnobaviscum aceris or Helixor M) 3 x weekly 1 Amp. sc., Solanum lyc. D4-D6 2-6 Tbl. and Hepatodoron 2-6 Tbl. daily.

A liver biopsy was conducted before and 6-10 months after treatment and the HAI score was calculated.

Results

In 8 patients (5 female, 3 male; mean age 43, mean duration of HCV 20.5 years) the HAI score before treatment was 7.75; after 18 - 23 months (12 months of treatment and 6-11 months follow-up) the score was 5.25 (p=0.05).

The fibrosis stage decreased from 2.5 to 1.375 (p=0.05). In 5 patients, fibrosis decreased by 1-3 score points, 1 patient increased by 1 scored point and 2 were stable.

Discussion

Viscum album and the herbal extract were able to inhibit and reduce fibrosis in liver biopsies scored by HAI, according to the authors. They conclude, “This therapy concept might be beneficial to non-responders and patients not compliant with standard HCV therapy. Further studies are necessary to confirm this preliminary data.”

05/24/04

Reference
Friedemann Schad and others. Viscum Album L and Solanum Lycopersicum Inhibit Fibrosis in Chronic Hepatitis C (HCV): A Pilot Study. Abstract 1154 (poster). Digestive Disease Week. May 15-20, 2004. New Orleans, LA.

Treatment with Peginterferon Alfa-2b (PEG-Intron) Plus Ribavirin Is Cost-effective for Hepatitis C Patients with F1 Fibrosis
 

Although not all patients with histologically mild chronic hepatitis C progress, prior studies suggest that antiviral treatment should be cost-effective, but those studies were based on mild inflammation and involved interferon alone or with ribavirin.

The objective of this study was to determine the cost-effectiveness of peginterferon alfa-2b (PEG-Intron) + ribavirin for histologically mild F1 fibrosis.

Using data from Manns (Lancet 2001), researchers compared no antiviral therapy to peginterferon alfa-2b + >10.6 mg/kg ribavirin. Lifelong clinical and economic outcomes were based on Cox proportional hazard models estimating the likelihood of developing Metavir fibrosis stages F1-F4 over time (using 2313 liver biopsies), and on recent UNOS, SEER and NIH data (Wong, AASLD 2003).

Drug costs applied the 12-week stopping rule. Cost-effectiveness results are presented as incremental cost per discounted (3%) quality-adjusted life year gained.

Cost-effectiveness ratios below $50,000 per discounted quality-adjusted life year gained were considered to be cost-effective.

Results

Observed sustained viral response rates for peginterferon alfa-2b + ribavirin treatment of F1 were 63% overall, 52% for genotype 1 and 91% for genotype 2/3.

Antiviral treatment reduced the 20-year incidence of cirrhosis from 20% to 7.6% overall, to 9.7% for genotype 1 and to 1.8% for genotype 2/3.

Antiviral treatment extended life expectancy by 2.3 years overall, 1.9 years for genotype 1 and 3.4 years for genotype 2/3.

Quality-adjusted life expectancy benefits of treatment were 4.7 years overall, 3.9 years for genotype 1 and 6.8 years for genotype 2/3.

Antiviral treatment reduced the future cost of hepatitis C complications by $27,500 overall, $22,900 for genotype 1 and $40,100 for genotype 2/3.

Compared to no antiviral treatment, cost-effectiveness ratios for treatment were $5100 per discounted quality-adjusted life year gained overall, $9000 per discounted quality-adjusted life year gained for genotype 1 and $400 per discounted quality-adjusted life year gained for genotype 2/3.

The authors conclude, “Weight-based peginterferon alfa-2b + ribavirin should be cost-effective for patients with F1 fibrosis.”

05/21/04

Reference
J B Wong and others. Cost-Effectiveness of Peginterferon á-2b plus Ribavirin Treatment of Chronic Hepatitis C with F1 Fibrosis. Abstract 1215 (poster). Digestive Disease Week 2004. May 15-20, 2004. New Orleans, LA.

www.hivandhepatitis.com

Update on Cirrhosis -- The Role of Fibrosis Markers

New Orleans, Wednesday, May 19, 2004 -- Important new data presented at this year's Digestive Disease Week (DDW) meeting emphasized and reviewed the current state of noninvasive (serum) markers as surrogates for measuring fibrosis by liver biopsy. This report highlights some of the more key information from these proceedings and places it in relevant and appropriate context for the clinician.

Background and Context

The natural history of cirrhosis is such that chronic liver injury (and usually inflammation) leads first to fibrosis, and, if present over long periods of time, to cirrhosis. It would thus be ideal to be able to assess where in the disease progression each patient may be found. Currently, the primary method to assess the degree of fibrosis is liver biopsy. However, liver biopsy is known to be associated with morbidity and even mortality. Furthermore, physicians and patients alike often have a preference to avoid liver biopsy. Thus, there is considerable interest in the development of noninvasive markers of liver fibrosis (and liver function, for that matter).

During this year's DDW meeting, considerable interest was displayed in the area of fibrosis assessment. Reflective of this focus, a symposium entitled "Prognostic Markers of Liver Disease" was convened, as sponsored by the Liver and Biliary section, and a number of study abstracts were presented.

Serum Markers to Assess Fibrosis

A number of serum markers are currently available that can be used to assess liver fibrosis. The rationale for these tests is that they offer the advantage of measures of liver function or use mathematical formulas that take into account liver function, often in combination with markers that are fibrosis-specific. Examples of these types of tests are the APRI (a novel index, AST [aspartate aminotransferase]-to-platelet ratio index)^[1] and the Fibrotest.^[2] It is emphasized that in general, these tests are effective at excluding advanced fibrosis (cirrhosis) and minimal or no fibrosis. However, they typically do not accurately differentiate intermediate grades of fibrosis (ie, Metavir grades F1-F3), and thus indeterminate values become problematic in clinical practice. The more fibrosis-specific tests include definitive serum markers such as YKL-40, hyaluronic acid, collagens, fibronectins, and combinations of serum markers. Included in the "combination" category is the FibroSpect II, a unique noninvasive diagnostic panel to assist in the detection of liver fibrosis. This panel uses a combination of components in the fibrogenic cascade, such as hyaluronic acid, TIMP-1 (tissue inhibitor of metalloproteinase), and alpha-2-macroglobulin.

Patel and colleagues^[3] presented the results of a study assessing the utility of this serum panel in a cohort of 244 patients with hepatitis C-related liver disease. They found that this test had a 71% to 87% positive predictive value for differentiating mild fibrosis (Metavir F0-F1) from more severe (Metavir F2-F4) disease. Again, these findings are consistent with the general tenet that these tests are able to differentiate advanced liver disease from minimal disease, but highlight the concept that they lack the ability to discriminate among intermediate degrees of fibrosis.

The Future of Prognostic Markers

Scott L. Friedman^[4] emphasized the evolution of proteomics in this field, suggesting that fingerprints of the protein composition in the blood may be able to accurately reflect the fibrogenic activity of the liver. Recent work in this area has suggested the feasibility of this approach. This point was considerably strengthened by Hui and coworkers^[5] who assessed the utility of a novel non-electrophoresis-based proteomic technology, SELDI-TOF MS (surface-enhanced laser desorption/ionization time-of-flight mass spectrometry), in predicting different degrees of liver fibrosis in chronic hepatitis B. They used SELDI-TOF MS to perform protein profiling, followed by implementation of artificial neural networks to generate models for prediction of fibrosis. The results were striking in that they were able to identify 30 proteomic profiles that were significantly associated with fibrosis in patients with hepatitis B. When these investigators divided subjects into those with moderate/severe fibrosis (Ishak stage 3-4) and those with cirrhosis (Ishak stage 5-6), they were able to demonstrate that the method had a sensitivity and specificity of greater than 90% for prediction of either moderate/severe fibrosis or cirrhosis. These data suggest that this methodology may be extremely useful in the future for more precise assessment of fibrosis risk.

Concluding Remarks

At present, methods to accurately assess fibrosis noninvasively are in evolution, and although controversy about their usefulness exists, it is anticipated that as the methods become more refined, such noninvasive measurement of fibrosis will be readily feasible

http://www.medscape.com/viewarticle/478434

Internet Conference Report
 Digestive Disease Week (DDW 2004)
  May 15 - 20, 2004, New Orleans, Louisiana

Fibrosis Progression Is Dependent upon Hepatic Inflammation in Chronic Hepatitis C

Many patients (pts) with chronic HCV develop progressive fibrosis while others remain stable for 5-10 yrs or longer. Liver biopsy (LBX) is utilized to stage fibrosis. However, the role of hepatic inflammation (INFL) and the effect of this on fibrosis remains undefined.

Pts with chronic HCV who were either non-responders (NR) to prior IFN/RBV or who deferred treatment (tx) were enrolled in a prospective study to monitor fibrosis progression.

All pts underwent baseline LBX (prior to IFN tx, if administered), were followed prospectively and had repeat LBX after a mean of 6 years (>5 yrs after stopping IFN). LBX were scored according to Knodell HAI without knowledge of clinical or previous histologic data. HCV RNA was determined by Amplicor and genotype by InnoLippa.

Results

To date, 142 pts have undergone paired LBX. Mean age at first LBX was 43 yrs, 61% were male, 63% Caucasian and 89% genotype 1. 85% received IFN/RBV after the initial LBX.

At baseline 22% had no fibrosis (NF), 37% portal fibrosis (PF), 30% bridging (BF) and 11% cirrhosis (CX). Mean INFL score increased significantly (p=0.02) with increasing fibrosis. This was solely the result of an increase in piecemeal necrosis (PMN) and was associated with increased ALT (108 vs 125 IU/ml; p=0.02).

No relationship existed between fibrosis stage and either age, sex, race, genotype or serum HCV RNA.

On repeat LBX, fibrosis progression was observed in 56/142 pts: 70% in those with NF, 74% PF and 21% with BF. Pts with progression had a significant increase in INFL and PMN scores compared to those with no progression; this was unrelated to ALT, age, sex, race, GT, and HCV RNA.

Progression was significantly (p<0.001) slower in pts with BF than NF or PF. After a mean follow-up of 6 yrs, no difference in fibrosis progression was observed between NR and those who deferred therapy (57 vs 42%).

Conclusions

Fibrosis progression in NR with chronic HCV is directly related to INFL, specifically PMN, but not serum HCV RNA or demographic factors. This is unaffected by a single course of IFN in those with non-response.

These data suggest that NR with mild INFL are at low risk for fibrosis progression and unlikely to benefit from maintenance IFN therapy regardless of histologic stage.

Pts with significant INFL are at higher risk to progress and may benefit from agents which reduce INFL.

These data underscore the importance of LBX in the management of chronic HCV.

05/26/04

Reference
J M Myung and others. Fibrosis Progression Is Dependent upon Hepatic Inflammation in Patients with Chronic HCV. Abstract 2018 (poster). Digestive Disease Week. May 15-20, 2004. New Orleans, LA.

www.hivandhepatitis.com

Internet Conference Report
 Digestive Disease Week (DDW 2004)
  May 15 - 20, 2004, New Orleans, Louisiana

Factors Associated with HCV Stage 3/4 Fibrosis