	Predicting progression to cirrhosis in chronic hepatitis C virus infection
	A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase
	Biochemical Markers Accurately Predict Significant Fibrosis
	Fibrosis and Disease Progression in Hepatitis C
	The Natural History of Fibrosis in Chronic Hepatitis C: Older Age at Infection Onset and Increasing Duration of infection are Primary Determinants of Fibrosis Progression

Journal of Viral Hepatitis
Volume 10 Issue 4 Page 285 - July 2003
doi:10.1046/j.1365-2893.2003.00436.x

Predicting progression to cirrhosis in chronic hepatitis C virus infection

A. J. Freeman, M. G. Law, J. M. Kaldor and G. J. Dore

Summary. A systematic evaluation of published studies was undertaken to identify factors associated with accelerated fibrosis progression in patients with chronic hepatitis C virus (HCV) infection. An ecologic analysis was used to estimate relative risk (RR) of cirrhosis across four study methodologies: liver clinic series, post-transfusion cohorts, community-based studies and blood donor series. In each study category, the following factors were independently associated with disease progression: male sex (RR = 1.08); heavy alcohol consumption (RR = 1.61); elevated serum ALT levels (RR = 1.23) and histology demonstrating high-grade necro-inflammatory activity. After adjusting for these cofactors, older age at HCV infection and acquisition of HCV through blood transfusion were not implicated in influencing disease outcome. Although not able to be examined in this study,co-infection with HIV, and to a lesser extent HBV, is also likely to result in worse outcomes for patients with chronic HCV infection. Virological factors such as HCV genotype, viral load and quasispecies diversity are less likely to be important. A Weibull distribution was used to model disease progression at a population level. The influence of cofactors on individual prognosis was examined and an algorithm to predict the risk of subsequently developing cirrhosis is presented.

The majority of cases of primary hepatitis C virus (HCV) infection result in persistent viraemia []. Progression to cirrhosis marks the onset of risk for complications such as liver failure and hepatocellular carcinoma []. However, while liver disease progression appears more indolent than previously reported, it is highly variable []. Identifying factors that influence outcome is important in order to counsel individuals regarding prognosis and facilitate decisions related to clinical management. A number of factors have been proposed as promoting HCV-related liver fibrosis. These include: host ethnicity, gender, obesity, alcohol consumption, smoking, age at infection, mode of HCV acquisition, serum transaminase levels, histological grade of inflammation, co-infection with hepatitis B virus (HBV) or HIV, HCV genotype, viral load and quasispecies diversity [].

We recently completed a systematic review of HCV natural history studies in which study methodology was shown to greatly influence disease progression estimates. For example, cirrhosis prevalence after 20 years infection was estimated at 24% in cross-sectional liver clinic series, but only 7% in community-based studies []. We have therefore examined studies included in this review to identify factors that influence liver disease progression, and to assess consistency of cofactors across study settings.

Methods

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Published studies of people with chronic HCV infection who had undergone assessment for stage of chronic liver disease were identified as described previously []. The studies were divided into four groups: cross-sectional series of people referred to specialist liver clinics, longitudinal studies of people with post-transfusion non-A non-B hepatitis subsequently diagnosed with chronic HCV infection, community-based studies and cross-sectional series of people diagnosed at blood donor screening. The prevalence of cirrhosis in the population studied, and data related to factors proposed as influencing progression to cirrhosis, was extracted. The factors examined included: patient ethnicity, sex distribution, alcohol consumption, age at infection, mode of HCV acquisition, serum transaminase levels, histological grade of inflammation, HBV status, HIV co-infection, HCV genotype and viral load.

An ecologic analysis was used to estimate relative risk of cirrhosis for factors identified as influencing fibrosis progression. For each study, mean duration of HCV infection was abstracted when available. In those studies not reporting mean duration of HCV infection, it was estimated as described previously []. For each study, cirrhosis prevalence was standardized to a duration of chronic HCV infection of 20 years based on a linear fibrosis progression rate. For example, a study with an estimated mean duration of HCV infection of 10 years and 5% cirrhosis prevalence would have an estimated 20 year cirrhosis prevalence of 10%. The impact of continuous variables on progression to cirrhosis was graphically assessed by plotting cirrhosis prevalence after 20 years against the study mean for each factor. For categorical data, the proportion of subjects positive for the factor in question was plotted against cirrhosis prevalence after 20 years. Age at infection was analysed as a continuous and as a categorical variable (< 30 and =" src="http://www.blackwell-synergy.com/na102/home/ACS/journals/entities/2265.gif" align=bottom border=0> 30 years). Only studies that provided information regarding the factor in question were included. To allow estimation of relative risk of cirrhosis using linear regression, a transformation was performed: y = ln { ln [1 cirrhosis(20)]}. Then, for each study category with a sufficient number of eligible studies, least squares linear regression lines were fitted: y = _{study category} + x _factor. Confidence intervals were based on the standard error of the slope of the regression line. Where regression line slope was not significantly different between study categories, it was assumed that the modifying effect of the factor in question was the same regardless of the population examined. A mean linear regression line slope, weighted according to the number of studies in each category, was generated. For factors identified as influencing disease progression, mean regression line slope was significantly different from zero and it was used to estimate the relative risk of cirrhosis: RR_factor = exp( _factor). Stepwise multiple linear regression was performed to adjust forcolinearity between the factors studied.

With regard to histological inflammation, the inflammatory component of the histological activity index (HAI [], maximum score 12 excluding confluent necrosis) was extracted where available. Alternative grading scores (Scheuer [], inflammatory component, maximum score 8; Metavir [], maximum score 3) were proportionally adjusted to a score out of 12. Where grade of liver disease was not scored, patients with chronic persistent hepatitis (CPH) were allocated a score of 3; patients with mild, moderate and severe chronic active hepatitis (CAH) were allocated a score of 6, 9 and 12 respectively; and an estimated mean HAI was calculated. In six studies that reported mean HAI and described grade of liver disease in terms of Scheuer score or CPH and CAH, the calculated HAI was not significantly different and the two values correlated (Spearman r = 0.94, P = 0.02) []. Analyses were performed including and excluding studies in which HAI had to be calculated. HAI was analysed as a continuous and as a categorical variable.

Cirrhosis prevalence beyond 20 years chronic HCV infection is uncertain. A Weibull distribution was chosen to estimate progression to cirrhosis among subjects with chronic HCV infection: cirrhosis (T) = 1 exp ( exp ( + ) T ). The equation was solved for and using estimates of cirrhosis prevalence after 20 and 40 years chronic HCV infection of 6.5% (3.5-9.5%) [] and 20% (10-40%) [] respectively. To predict progression to cirrhosis based on risk factor profile, data was normalized to the community-based studies as these would appear to be the most representative of disease progression among the majority of people with chronic HCV infection in industrialized countries.

Data was analysed using Stata 7.0 (Stata Corporation, TX, USA). A P value less than 0.05 was considered significant. Data is presented with 95% confidence intervals.

Results

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Fifty-seven studies that examined stage of liver disease in people with chronic HCV infection were included in the analysis. Most studies provided demographic information, mode of HCV acquisition and data regarding the proportion of cases with an elevated alanine aminotransferase (ALT) (). However, many did not provide information on other factors such as alcohol consumption, HCV genotype and viral load. People with HIV and HBV were either excluded or made up only a small proportion, therefore, this analysis was unable to examine the impact of coinfection with either HIV or HBV on HCV-related liver disease progression. Data was also not available to examine obesity, smoking and quasispecies diversity.

Univariate analysis demonstrated that the following factors influenced progression to cirrhosis: gender, alcohol consumption, serum ALT levels, HAI and age at infection (). Despite different rates of progression to cirrhosis [], regression line slopes were not significantly different across the study categories for these cofactors. Mode of HCV acquisition was not implicated as influencing prognosis. Multivariate analysis demonstrated that male sex was associated with heavy alcohol consumption and elevated ALT was associated with higher HAI. However, after adjusting for these associations, gender, alcohol consumption, serum ALT levels and HAI were demonstrated to independently influence progression to cirrhosis (). After adjusting for these factors more clearly associated with fibrosis progression, age at HCV infection was no longer significantly associated with cirrhosis.

A Weibull distribution was generated to estimate cirrhosis prevalence and model the influence of cofactors on disease progression (). An algorithm () was used to predict progression to cirrhosis based on risk factor profile (). For example, a woman with an elevated ALT and an HAI of five would have an estimated risk of cirrhosis of 7% (4-10%) after 20 years infection if she was not a heavy drinker. Her risk would increase to 11% (6-15%) in the setting of heavy alcohol consumption. Risk of cirrhosis at 30 years ranged from 10% for women with no cofactors associated with disease progression, to 25% for men with elevated ALT levels, a high HAI score and heavy alcohol intake.

Discussion

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This report examines factors associated with progression to cirrhosis in people with chronic HCV infection. Following an extensive review of HCV natural history studies across four broad study categories, and including multivariate analysis of factors associated with disease progression, four were identified as independently influencing prognosis: gender, alcohol consumption, serum ALT level and histological grade of inflammation.

Heavy alcohol use has consistently been associated with more rapid progression to cirrhosis in patients with chronic HCV infection []. A cross-sectional study of 6664 referred patients demonstrated that cirrhosis was more frequent in those who reported heavy drinking (34.9%vs 18.2%) []. A further study estimated the independent relative risk associated with high alcohol intake to be 1.9 (1.0-3.9) []; a figure similar to the pooled estimate reported here. The impact of low or moderate alcohol intake is less clear [].

With regard to gender, other studies have also demonstrated that men have a worse prognosis than women []. Low rates of cirrhosis in young women infected with contaminated anti-D support this association []. Alternatively, considering the association between male gender and heavy alcohol consumption in the analysis reported here, an apparent gender effect may relate to residual confounding because of under-reporting of alcohol use by men.

Despite the observation that the presence of an elevated ALT was associated with a higher HAI score, biochemical and histological evidence of hepatic inflammation were independently associated with more rapid progression to cirrhosis. Both cross-sectional [] and longitudinal [] studies have demonstrated that more active hepatic inflammation is associated with more rapid fibrosis progression. Therefore, in addition to stage of liver disease [], grade of hepatic inflammation influences prognosis. For people with mild hepatic fibrosis, the degree of hepatic inflammation may therefore be an important consideration in decisions relating to antiviral therapeutic intervention. People who have progressed to moderate or greater stages of hepatic fibrosis are generally recommended to commence antiviral therapy [].

Serum transaminase levels fluctuate significantly in patients with chronic HCV infection and poorly predict the extent of liver damage []. However, cross-sectional [] and recent longitudinal [] studies have demonstrated slower disease progression rates for chronic HCV-infected patients with persistently normal ALT levels compared to patients with elevated ALT levels []. Our review supports an independent association between elevated serum transaminase levels and increased risk of progression to cirrhosis.

A number of studies have demonstrated that subjects infected at an older age develop cirrhosis over a shorter period []. In one study, among patients 50 years or older at the time of infection, the average time to development of cirrhosis was 9.8 years compared with 23.6 years for younger patients []. Children with chronic HCV infection have been shown to have disproportionably low rates of fibrosis progression []. However, in the analysis reported here, after adjusting for factors more clearly associated with disease progression, age at infection did not predict the development of cirrhosis. A possible explanation is that higher grade hepatic inflammation is more often established in people infected at an older age, thus providing the stimulus for more rapid development of hepatic fibrosis.

The analysis reported here was unable to examine the impact of coinfection with either HBV or HIV on HCV-related liver disease progression. It has been suggested that HBV infection increases fibrosis in patients with chronic HCV infection []. However, one large study considered HBV infection and demonstrated that while co-infection may increase the risk of cirrhosis, the effect was likely to be small (HBVs Ag-positive, 24.6% cirrhotic; HBVs Ag-negative, 21.2% cirrhotic) []. Similarly, while some studies have demonstrated that concurrent HBV and HCV, infection significantly increases the incidence of hepatocellular carcinoma in patients with cirrhosis [], other evidence suggests that this may not be the case [].

In contrast to HBV, co-infection with HIV is highly likely to result in significantly more rapid disease progression []. In one study, mean interval from HCV acquisition to cirrhosis was 23.2 years for HIV-negative patients (n = 431), and 6.9 years for HIV-positive patients (n = 116) []. HIV infection has been estimated to carry a relative risk of 2.2 (1.1-4.5) for the development of cirrhosis in patients with chronic HCV infection []. The corresponding relative risk in haemophiliacs with HIV is estimated to be 3.7 (1.3-11.1) []. Worse outcomes among HIV-infected patients with chronic HCV infection are associated with immunosuppression as reflected by lower CD4-lymphocyte counts and increased HCV viral load [].

It is unclear whether viral factors, such as virulence of the infecting viral genotype, viral load and quasispecies diversity, impact on the development of HCV-related cirrhosis. Infection with HCV genotype 1, particularly subtype 1b, has been reported to increase the rate of progression to HCV-related cirrhosis []. Rather than a direct effect attributable to HCV genotype, it may be that genotype prevalence is changing, other genotypes are becoming more common and patients with genotype 1b have simply been infected for longer []. Studies that have considered other factors related to disease progression have typically failed to find any association between HCV genotype and cirrhosis [].

Progression to cirrhosis has also been associated with higher serum viral load in some studies []. In the analysis reported here, few studies provided viral load data, therefore the absence of an identifiable impact on disease progression must be interpreted with caution. However, recent evidence suggests that viral load does not influence disease progression in chronic HCV infection []. Similarly, data from a limited number of studies does not support a role for quasispecies diversity in influencing progression to cirrhosis [].

Ethnicity may influence the prevalence of cirrhosis in an HCV-infected population. This was not clarified in the analysis reported here as data regarding the ethnic distribution of the population studied was rarely available. Country of origin was extracted and no significant differences were seen. It has been reported that severe adverse effects are more common in Japan []. Certainly the rate of hepatocellular carcinoma among HCV-infected Japanese is high []. However, whether this is because of racial differences in the host response to the HCV, the environment or viral factors is uncertain.

Despite the limitations of ecologic analyses [], the relative risk of fibrosis progression related to significant cofactors in our analysis can be used to estimate risk of cirrhosis from time of infection. As the vast majority of people with chronic HCV infection present with established liver disease, further models are needed to predict both current stage of disease and predict future risk of disease progression.

A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase

	At the end of this report is study of interferon plus ribavirin in HCV+ patients with normal ALT presented at DDW 2002 by Ira Jacobson, MD. Journal of Hepatology 38 (2003) 511-517 Chee-Kin Hui, Tigist Belaye, Kevin Montegrande, Teresa Lyn Wright * Department of Medicine, GI Research (111B), Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA An estimated 20-30% of patients with chronic hepatitis C (HCV) infection have persistently normal alanine transaminase (PNALT). Studies have suggested that these patients have only mild hepatitis and that they may either not progress to cirrhosis at all or progress at a much slower rate than those with elevated serum alanine transaminase (ALT) levels. However, studies performed in those with PNALT have highlighted several characteristics of these so called ÔasymptomaticÕ HCV carriers. For example, the presence of serum HCV RNA is almost invariably associated with some degree of liver damage despite PNALT levels, challenging the very concept of ÔhealthyÕ HCV RNA carriers. In fact, Puoti, et al. found that 26% of their subject with PNALT had moderate to severe hepatitis whereas only 6% of those with raised ALT had moderate to severe hepatitis. This study coupled with othersÕ, have led to controversies concerning the histological findings in patients with PNALT as liver cirrhosis occurred in 5-20% of these patients suggesting that the clinical course of PNALT is not necessarily benign. One clinical issue is whether fibrosis progresses in patients with PNALT at the same rate as does the fibrosis in patients with elevated ALT. Mathurin, et al. conducted a cross-sectional study to address this question but his study was based on a rate of fibrosis progression calculated from the presumed duration of infection rather than a direct histological comparison between patients with PNALT and those with raised ALT. A second study by Martinot-Peignoux, et al. compared PNALT patients with detectable HCV RNA to those with undetectable HCV RNA, and found more mild liver disease in the latter group, but did not include a compar-ison group of patients with elevated serum ALT. Since it is now known that fibrosis progression in HCV is non-linear, cross-sectional studies to determine fibrosis progression may not be accurate. We have therefore, conducted a study to compare directly the progression of fibrosis in patients with PNALT to those with elevated ALT, to compare the development of severe fibrosis in patients with PNALT and elevated ALT and to compare the long-term outcome of patients with PNALT and elevated ALT. Abstract. Detectable serum hepatitis C virus (HCV) RNA in HCV patients with persistently normal alanine transaminase (PNALT) has been found to be associated with significant liver damage. The primary outcome of this study was to compare the histological progression of fibrosis in patients with PNALT and elevated alanine transaminase (ALT). Forty patients with PNALT (Group 1) and 41 patients with elevated ALT (Group 2) were recruited into this study. Only patients with fibrosis of F0 to F2 were recruited into this study. The median time to second liver biopsies was 6.3 (range 2.0-11.1) years. Nine patients (22.5%) in Group 1 and 17 patients (41.5%) from Group 2 had progression of fibrosis. There was a trend towards a significantly higher cumulative probability of fibrosis progression in Group 2 (P =0.06). In patients with an initial F0 to F1 fibrosis, there was a significant difference in cumulative probability of fibrosis progression between Groups 1 and 2 (22.6% (7/31) vs. 43.3% (13/31), respectively, P =0.02). Anti-HCV patients with PNALT with an initial fibrosis of F0 or F1 were less likely to develop progression of fibrosis than those with elevated ALT, although patients with PNALT may have histologically and clinically progressive disease. The authors suggest it may be worthwhile to consider liver biopsy in patients with PNALT in order to stage accurately the stage of fibrosis as those with F2 fibrosis show a tendency for fibrosis progression as those with elevated ALT. Progression of fibrosis in F0 and F1 There were 61 patients in the study with F0 or F1 fibrosis on initial liver biopsies, 31 patients from Group 1 and 30 patients from Group 2. A significant difference could be detected in the time to second biopsy and in the serum HCV RNA level between Groups 1 and 2 (P=0:04 and P <0:0001, respectively). Progression of fibrosis occurred in seven patients (22.6%) in Group 1 and 13 patients (43.3%) in Group 2. There was a significant cumulative probability of fibrosis progression in Group 2 compared with Group 1 (P=0:02). Six patients developed severe fibrosis on repeat biopsies. These six patients (20.0%) were all from Group 2. No patients in Group 1 with an initial fibrosis F0 and F1 developed severe fibrosis. There was a significant cumulative probability of severe fibrosis in Group 2 (P=0:0002). Progression of fibrosis in patients with F2 fibrosis There were 20 patients with fibrosis F2 on initial liver biopsies, nine patients (22.5%) from Group 1 and 11 patients (26.8%) from Group 2. There were no significant differences in the genotype, body mass index (BMI) and HCV RNA between the two groups. In those with a fibrosis of F2 on initial biopsies, six patients (30.0%) had progression in fibrosis. Two patients (22.2%) were from Group 1 while four patients (40.0%) were from Group 2. There was no significant difference in the cumulative probability of fibrosis progression between the two groups (P=0:82). Severe fibrosis was detected in six patients (7.4%), two patients (22.2%) from Group 1 and four patients (40.0%) from Group 2. There was also no significant difference in the cumulative probability of severe fibrosis between Groups 1 and 2 (P=0:82). Alcohol and fibrosis There were 20 patients (24.7%) with excess alcohol consumption (defined as more than 50 g per day). In these 20 patients, seven patients (35.0%) developed fibrosis progression while two patients (10.0%) developed severe fibrosis. Excess alcohol consumption was not significantly related to the cumulative probability of fibrosis progression (P=0:43) nor was it significantly related to the cumulative probability of severe fibrosis (P=0:20). Clinical complications Patients in Groups 1 and 2 were followed up for a median of 8.8 (range 3.0-11.5) and 5.5 (range 2.2-10.7) years, respectively (P=0:81). Eleven patients (27.5%) in Group 1 developed elevated ALT on serial follow-up. At the time of analysis, six patients developed clinical evidence of cirrhosis. Two patients (5%) were from Group 1 while four patients (9.8%) were from Group 2 (P=0:56, log rank). The complications developed by patients in Group 1 were ascites, while in Group 2, two patients had ascites, one had bleeding esophageal varices and the other had hepatocellular carcinoma detected on CT of the liver. Discussion by authors An understanding of the natural history or progression of fibrosis of HCV is important for making decisions regarding therapy or screening. As predictive markers for fibrosis are unavailable at this time, the only way or means to determine fibrosis is by performing liver biopsies. Poynard, et al. found that HCV is a progressive fibrotic disease and is not merely an inflammatory hepatitis. In studies on liver fibrosis in patients with PNALT by Mathurin et al. and Persico et al., they have found that those with PNALT have mild chronic hepatitis and that the stage of disease activity does not increase over a period of 5 years and progression to cirrhosis is slow. However, severe liver disease with either cirrhosis or severe fibrosis does occurs in patients with PNALT, at a range of 8.7-20%. To the best of our knowledge, direct comparison between patients with PNALT to those with elevated ALT has not been performed. Therefore in order to compare directly these two groups of patients, we have studied patients with fibrosis F0-F2 in order to compare histologically the fibrosis progression and the development of severe fibrosis in these two groups of patients. At second liver biopsy, we have shown that there was a significant difference in the fibrosis between the two groups. Fibrosis progression was higher in Group 2 than in Group 1. Furthermore, patients in Group 2 developed a higher occur-rence of severe fibrosis. When we performed a subgroup analysis, a significant difference was detected in the cumulative probability of fibrosis progression and the development of severe fibrosis between when patients with an initial fibrosis of F0 or F1 in Group 1 were compared with those in Group 2. This significant difference in fibrosis progression and in development of severe fibrosis occurred in Group 2 despite the fact that the time to second liver biopsy was significantly longer in Group 1 when compared with Group 2. This means that patients with PNALT with F0 and F1 fibrosis progress at a slower rate than patients with elevated ALT with the same stage of fibrosis. We do not believe that the difference in the progression of fibrosis or severe fibrosis could be related to the higher HCV RNA in Group 2 as HCV RNA levels have not been shown to be associated with severe fibrosis or progression in fibrosis in large cross-sectional studies. Furthermore, although monthly fluctuations of HCV RNA has been shown to be lower in patients with normal ALT, as compared with those with elevated ALT, liver histology has not been shown to have any significant correlation with the replication activity of the virus. Studies of sufficient sample size and duration would need to be performed to evaluate the predictive value of initial HCV RNA in fibrosis progression. To date, no such studies have been performed. On the other hand, there was no significant difference in the cumulative probability of fibrosis progression and the cumulative probability of severe fibrosis between Groups 1 and 2 when we compared patients with an initial F2 fibrosis. But, the number of patients with initial F2 fibrosis in both groups were too small to draw any definite conclusion. There is a consensus that heavy alcohol consumption is associated with fibrosis progression. We, however, found no significant association between alcohol consumption and fibrosis progression or with severe fibrosis. This is probably because 75.3% of our patients had F0 or F1 fibrosis which has been previously shown by Poynard et al. To be unrelated to alcohol consumption in terms of fibrosis progression. Even though no significant difference was detected between fibrosis progression and severe alcohol consumption, there were more patients with severe alcohol consumption who developed fibrosis progression when compared with those without severe alcohol consumption. So severe alcohol consumption may have a role in the progression of fibrosis but it alone cannot explain the variability in fibrosis progression observed as only one patient with severe alcohol consumption developed severe fibrosis. The results of this study must be interpreted with care considering the limitations of this study. Firstly, the patients should have been followed up every 3 months in order to determine whether they truly had PNALT or transient prolonged biochemical remission, but this recommendation was only published in 2001. Secondly, since we do not have any data on the patients ALT levels before they were referred to our center, we have no way of determining whether they had PNALT historically or were in transient although prolonged biochemical remission at the time of presentation. Thirdly, since the patients were identified retrospectively through our database, we cannot or are unable to determine the reason why patients in Group 2 were not treated for chronic hepatitis C. Fourthly, being based in a specialty clinic population, the patients in this study were probably not representative of community-based cohorts and selected patients should not be used to predict the HCV-related disease progression at a community level. Finally, the lack of a significant difference does not imply equivalence because of the undetermined power of statistical tests. In conclusion, this is the first study to demonstrate histologically that fibrosis progression in PNALT patients with fibrosis of F0 or F1 were significantly lower than patients with elevated ALT with fibrosis F0 or F1, but histological and clinical progressive disease do occur in this group. In contrast to the most recent NIH recommendation, it may be worthwhile to consider liver biopsy in patients with PNALT in order to stage accurately the stage of fibrosis as those with F2 fibrosis show a tendency for fibrosis progression as those with elevated ALT. Excerpts from Editorial by Claudio Puoti Department of Gastroenterology and Internal Medicine, ÔE. De SantisÕ Hospital, Via Achille Grandi 43, 00045 Genzano, Rome, Italy As to liver histology, the prevalence of HCV carriers with normal liver (the true ÔhealthyÕ HCV carriers) seems to be very low (from 0 to 20%) [9,14,17,23]. The majority of patients have some degree of liver damage on liver biopsy. Liver disease is usually minimal/mild and fibrosis is generally absent or minimal, although the association of normal ALT with cirrhosis or with HCC has been reported. In all studies, liver histology was, on average, significantly less severe in subjects with PNAL than with abnormal ALT. A recent European Collaborative Study reported that an important proportion of carriers with PNAL had some histological signs of fibrosis, sometimes severe, and in rare cases cirrhosis was found. The natural course of HCV infection in patients with normal ALT levels is actually not well understood, as only few studies exist. In the study of Martinot-Peignoux et al. no significant differences in both activity and fibro-sis score were seen at second biopsy performed after a mean follow-up of 3.5 years. Persico et al. showed that liver histology after 5 years of follow-up was not changed with respect to that observed at the entry to study. Two studies found that the estimated rate of fibrosis progression was significantly lower in carriers with PNAL than in subjects with abnormal ALT. Spontaneous HCV RNA clearance has been described in 15% of subjects with PNAL after 3-7 years of follow-up. Finally, in a large study from Japan, HCC developed in one-third of people with abnormal ALT, in 4% of those with intermittently abnormal ALT and none of the subjects with PNAL. These data seem to show that HCV carriers with normal ALT have mild and stable disease, with a favourable prognosis. In the current issue of the Journal, Hui et al. provide new evidence that the outcome of HCV carriers with PNAL is really benign and on average not progressive. Severe fibrosis at second biopsy was detected in 5% of patients with PNAL and 24% of those with abnormal ALT values. Interestingly, no patients with PNAL and an initial fibrosis of F0 to F1 developed severe fibrosis. It is note-worthy that the duration of the histological follow-up in the study of Hui is one of the largest thus far published. The reasons for this seemingly benign course of disease are not well understood. It has been suggested an association with a specific genetic background or a weaker immune response to HCV-infected liver cells, with some degree of immune-tolerance. However, is the natural history of HCV carriers with PNAL always so benign? Cividini et al. reported a significant progression of fibrosis >2 points in score) in 17% of the patients with well-defined ALT normality, and the development in one case of HCC in well-compensated cirrhosis after 5 years of follow-up, despite persistent ALT normality. Sudden worsening of disease with ALT increase and histological deterioration has been described after up to 15 years of follow-up. Huy et al. themselves, although confirming that fibrosis progresses at a slower rate among subjects with PNAL, found at the same time overall fibrosis progression in 22% of the patients with normal ALT. Further, it is very impressive the finding that 5% of the patients with normal ALT in this study developed clinical evidence of cirrhosis during the follow-up. Should patients with CHC and normal ALT undergo anti-viral treatment? It might be taken into account that IFN treatment is associated with consistent side effects and reduced quality of life and is not inexpensive, while the risk of progression of the disease in this setting is extremely low. Thus, the cost effectiveness of the treatment in carriers with PNAL is yet to be proven. The 1997 NIH Consensus Conference and the EASL Consensus Conference stated that IFN treatment should not be recommended in these subjects. At the time of that Consensus Conferences only few trials of IFN monotherapy were available. The overall sustained virological response (SVR) in subjects with PNAL was very low (less than 20%) although not different than that observed in patients with abnormal ALT. Further, many patients showed ALT flares during treatment. Given these findings, it was concluded that IFN treatment in subjects with PNAL was not beneficial and may actually worsen the underlying disease. In the last few years, treatment of CHC has progressed from IFN monotherapy to IFN plus ribavirin combination therapy, and more recently to PEG-IFN plus ribavirin. Using IFN plus ribavirin therapy for 24 or 48 weeks in patients with persistently normal or with minimally raised ALT levels (less than 1.3-1.5 ULN), SVR rates of 25-50% have been reported. The response rates were higher in patients with genotype non-1 and in those treated for 48 weeks. More recently, the introduction of the new combination therapy of PEG-IFN plus ribavirin allowed response rates higher than 50%, with a favourable risk-benefit ratio also in patients with benign or slow progressive disease. Although no data in patients with PNAL are yet available, international studies with the new combination Given the efficacy of the new treatments, which soon became the standard of care for CHC, the 2002 NIH Consensus Development Conference suggested that the issue of whether or not to treat subjects with PNAL should be re-evaluated, and that the issue at hand should be whether or not patients with mild disease should be treated. ALT levels may have less importance in deciding who should be treated. Many other factors might influence the decision to treat, such as the age of the patient, HCV genotype, liver histology, patientsÕ motivation, symptoms, extra-hepatic manifestations, and co-morbid illness. In conclusion, the majority of HCV carriers with normal ALT have mild degree of inflammation and fibrosis and non progressive disease. Nevertheless, some of them might progress towards more severe liver disease. These patients should be followed up at regular intervals in order to identify ALT flares or disease progression. Preliminary data show that antiviral combination treatment gives SVR similar to that obtained in patients with abnormal aminotransferase levels. However, given the scarcity of data, the potential risks of such treatment and the histological mildness and slow progression of the disease in these patients, until the results of studies with PEG-IFN plus ribavirin are available and the cost-effectiveness of these new options have been investigated, HCV carriers with normal ALT should not receive antiviral treatment outside clinical trials. Many questions remain still unanswered: is the natural history of the HCV infection different in subjects with PNAL and in patients with minimally raised ALT? Is CHC the same entity in subjects with persistently normal ALT and in patients with sporadic ALT flare-ups? Finally: what should we treat, the test (ALT) or the disease (liver damage)? The solution of these conundrums will come from well-sized, long-term prospective studies. "Interferon alfa-2b plus Ribavirin for HCV-infected Patients with Normal ALT" presented by Ira Jaccobson, MD, at the DDW conference in May 2002 in San Francisco. ..response rates were comparable to patients with normal ALT. The trend towards superiority of IFN 5 MU leaves open question on optimal dosing. Combination therapy is safe- de novo ALT elevations are seldom problematic.. For background Ira Jacobson (Cornell Hospital, NYC) reported that persistently normal ALT is common with HCV. Histology (liver disease) is often mild and progression slow in the HCV mono-infected patient. In the HCV/HIV coinfected patient a number of studies show that HCV disease progression can be accelerated by HIV. In the mono-infected patient <5% to 20% have significant hepatic fibrosis. Interferon therapy has been associated with leading to elevated ALT 40% of the time in patients with normal ALT. At the 1997 NIH Consensus Conference treatment of patients with normal ALT was considered investigational. The next NIH Consensus Conference takes place this June 2002. The aim of this study is to assess the efficacy and safety of 2 different doses of alfa-2b interferon combined with ribavirin in HCV+ patients with normal ALT. To qualify for this study, patients had to have a biopsy consistent with chronic hepatitis; normal ALT on 2 or more occasions at least 3 months apart; compensated liver disease. Patients were randomized to receive one of two regimens: group 1- IFN alf-2b 3Million Units 3 times per week + ribavirin 1000-1200 mg/day; or, group 2- interferon alfa-2b 5 MU 3 times per week + ribavirin 1000-1200 mg/day. Treatment was for 48 weeks, and if patients were HCV-RNA positive at week 24 they could stop therapy. There was a follow--up period of 24 weeks following therapy cessation to assess the 72 week SVR. There were 28 patients in each group, 41% male; 69% genotype 1 in 3 MU group and 81% genotype 1 in 5 MU group. 24% genotype 2/3 in 3 MU group vs 11% in 5 MU group. Mean ALT was 35 in group 1 and 31 in group 2. Fibrosis stage 0-1: 18% in each group. Fibrosis stage 2-4 11% in group 1, 9% in group 2. 16 patients had stage 0. 20 patients had stage 1. 13 patients had stage 2. 6 patients had stage 3. 1 patient had stage 4. So, 7/28 (25%) patients with apparently normal ALT had stage 3/4. RESULTS The overall response rate was 32% for all patients , but 28% for the 3 MU group and 40% in the 5 MU group. Genotype 1 patients receiving 5 MU had 40% SVR vs 10% for patients receiving 3 MU. For genotype 2/3 patients over 80% receiving 3 MU had SVR and 70% receiving 5 MU had SVR. 3 patients relapsed after ending 48 weeks treatment. 4 patients had viral breakthrough on therapy. 32% of patients with stage 0,1 (n=36) had SVR and 30% with stage 2, 3, 4 had SVR. 40% of patients with <2 million HCV-RNA had SVR and 20% with >2 million had SVR.

	Adverse Events 5 patients experienced ALT elevations. All were reportedly transient, one with transient 2.2 bilirubin. They were not more than 2x upper limit of normal. There were 2 serious adverse events: 1 suicidal ideation; confusion, anxiety. 9/56 patients (16%) discontinued due to an adverse event. Dose modifications were similar in both groups. There were no unexpected adverse events. Jacobson concluded there was a trend towards a better response with IFN 5 MU in patients with genotype 1. ALT elevations were infrequent, mild, and transient. Response in stage 2-4 was similar to stage 0-1. ALT was reduced during treatment and in SR. AE, and serious AE was similar as in other studies. Response rates were comparable to patients with normal ALT. The trend towards superiority of IFN 5 MU leaves open question on optimal dosing. Combination therapy is safe- de novo ALT elevations are seldom problematic. Treatment should be individualized based on patient characteristics, including history. Therapy should not be ruled out based on ALT alone. This trial was conducted before pegylated IFN was available, so studies using peg IFN in patients with normal ALT are in progress.

Biochemical Markers Accurately Predict Significant Fibrosis

By Brian Boyle, MD

Liver biopsy remains the gold standard for assessing hepatitis C virus (HCV)-related liver injury, including inflammation and fibrosis. Liver biopsy is an invasive procedure, however, and even in the best hands is associated with a low rate of complications including bleeding and infection.

In a study published in AIDS, investigators attempted to determine whether an algorithm could be constructed that estimated the degree of liver injury incurred by the patient using non-invasive markers. The study was a cross-sectional, cohort study in a French tertiary-care hospital that enrolled 130 HIV/HCV-co-infected patients with a liver biopsy and serum available for the laboratories.

The investigators found that a non-invasive index of biochemical markers accurately predicted fibrosis in HIV/HCV-co-infected individuals. The use of a five-marker index (including bilirubin, GGT, haptoglobin, apolipoprotein A1, and a2-macroglobulin).was able to distinguish, with a relatively high degree of accuracy, between clinically important outcomes.

Using certain statistically-derived cut-offs, the five-marker index had a positive predictive value for septal fibrosis of 86% and a negative predictive value of 93%. If biopsy was restricted to patients with scores in an intermediate range (i.e., those with suboptimal predictive values), the use of the five-marker index could potentially reduce the indication the need for liver biopsy by 55%, with 89% accuracy.

The authors conclude, "An index including five biochemical markers accurately predicts significant fibrosis in patients with HIV/HCV co-infection, and may substantially reduce the necessity for liver biopsy." If these data are confirmed in larger trials, it may be possible to avoid liver biopsy in a number of HIV/HCV co-infected certain patients.

04/02/03

Reference
R Myers and others. Serum biochemical markers accurately predict liver fibrosis in HIV and hepatitis C virus co-infected patients. AIDS 2003;17:721-725.

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Fibrosis and Disease Progression in Hepatitis C

www.hivandhepatitis.com

The progression of fibrosis in chronic hepatitis C determines the ultimate prognosis and thus the need and urgency of therapy. Fibrogenesis is a complex dynamic process, which is mediated by necro-inflammation and activation of stellate cells.

Chronic infection with hepatitis C virus (HCV) typically induces injury and inflammation of the liver, which appear to be responsible for the associated fibrogenesis. Fibrogenesis is a dynamic process characterized by the synthesis of constituents of the extracellular matrix, which is a complex mixture of glycoproteins (collagen, elastin, fibronectin, laminin) and proteoglycans organized in a tridimensional network.

Fibrogenesis is a non-specific mechanism, which lasts as long as injury persists in the liver and is believed to help limit the extension of the inflammatory reaction. Fibrosis, therefore, is a physiologic mechanism, which is at first beneficial, but which can become pathological if the viral infection and chronic hepatocellular injury persist.

Fibrosis is characterized by the deposition of collagen and other extracellular matrix proteins and their organization in complex polymers, which are insoluble and induce loss of the liver architecture. In all forms of chronic hepatitis, including chronic hepatitis C, active fibrosis begins around the portal areas (periportal or zone 1 fibrosis) and gradually extends out into the lobules towards the central veins (zone 3) with septa formation and then bridging fibrosis.

Liver Biopsy

The liver biopsy remains the gold standard to assess fibrosis. Scoring systems allow a semi-quantitative assessment and are useful for cross-sectional and cohort studies and in treatment trials. Several systems for scoring liver fibrosis have been proposed, each based on visual assessment of collagen staining of liver biopsy samples. The more frequently used systems are the histology activity index (HAI: Knodell score),the Ishak modification of the HAI score, and the Metavir score.

The scoring systems for hepatic fibrosis have been extremely helpful in natural history studies and clinical trials of therapy of hepatitis C. However, all of these systems have important limitations.

Hepatic fibrosis may not be homogenous throughout the liver, and the liver specimen obtained by the needle biopsy may not accurately reflect the overall average degree of fibrosis. The reliability of the assessment of fibrosis stage increases with the size of the liver sample. The sample size is critical, a minimum length of 10 mm being essential.

Regardless of biopsy length, however, fibrosis may be underestimated and cirrhosis missed in some patients. In addition, scoring systems are artificial and based on visual assessment.

Fibrosis may not progress linearly in the same manner as the scoring systems: thus, progression from stage 1 to stage 2 may be far more important and require a longer period than progression from stage 3 to stage 4 (or vice versa). Thus, nonparametric analysis is needed in assessing differences in fibrosis scores in clinical studies.

The rate at which fibrosis progresses varies markedly between patients. The major factors known to be associated with fibrosis progression are older age at infection, male gender, and excessive alcohol consumption.

Age

Age at onset of infection has consistently been found to be a major factor influencing the rate of progression of fibrosis in hepatitis C. Thus, studies of posttransfusion hepatitis in which most patients are over the age of 40 at the time of onset of infection have indicated that at least 20% of patients develop cirrhosis during the first 15 to 20 years of HCV infection.

Gender

Most studies of hepatic fibrosis have reported that male sex is significantly associated with progression of fibrosis. The mechanisms by which sex affects fibrosis progression are unknown.

In contrast, in studies of young women infected as a result of exposure to HCV-contamined Rh immune globulin, less than 5% develop cirrhosis within the first 15 to 20 years of infection.

Alcohol

In almost all studies, a high consumption of alcohol (more than 50 g/d) has been found to be associated with higher fibrosis stage. The effects of a lower level of alcohol consumption, between 10 and 40 g/d, have not been clearly defined.

In univariate analysis, patients who drank moderate amounts of alcohol (<50 g daily) had a slightly higher estimated rate of fibrosis progression (0.143) than non-drinkers (0.125), but the difference was not statistically significant and was confounded by other features, such as gender, body weight, and age.

Alcohol, which by itself can cause liver disease and fibrosis, may worsen fibrosis in hepatitis C at amounts that are not injurious in non-infected persons, but the amount of alcohol beyond which the progression of fibrosis is increased in hepatitis C is unknown. Because of the negative influence of high alcohol consumption, abstinence or minimal consumption are usually recommended in patients with chronic hepatitis C.

Besides its direct effects on fibrogenesis, excess alcohol intake may have other adverse effects on the course of hepatitis C. Thus, alcohol may affect immune responses to HCV and may cause increases in HCV RNA levels in serum and liver, an effect that has been reported by some investigators, but not all.

Immune Status and HCV-HIV Coinfection

Immune status probably has a major affect on the natural history of hepatitis C and the development of cirrhosis. Several studies have shown that hepatitis C is more likely to progress to cirrhosis, and that the rate of fibrosis progression is greater in HIV-coinfected patients.

In a study from Spain, the mean estimated time to development of cirrhosis was 7 years in HIV-positive and 23 years in HIV-negative injection drug users with hepatitis C. In a study from France, the HAI score was significantly higher among 80 HIV-positive patients compared with 80 HIV-negative injection drug users (matched for age, gender, and duration of disease). During a mean follow-up of 52 ± 30 months, the incidence of cirrhosis was significantly higher among HIV-positive than -negative patients.

Viral factors

In retrospective and cross-sectional studies, virological factors, such as serum HCV RNA levels and HCV genotype, have not been associated with the rate of progression of fibrosis in chronic hepatitis C.

Other factors, which have been suggested to be important, include genetic, racial/ethnic, and metabolic. The role of heterozygote mutations of HFE gene is controversial. The influence of overweight has been emphasized recently; it is believed that steatosis related to overweight is responsible for the more rapid progression of fibrosis. In addition, diabetes has been shown to be associated with fibrosis.

There are no tests that reliably predict the rate of progression of fibrosis in an individual patient. High serum alanine aminotransferase (ALT) levels are associated with a higher risk of fibrosis progression, and worsening of fibrosis is uncommon in patients with persistently normal serum aminotransferase levels.

The liver biopsy remains the best method to assess fibrosis and is valuable in determining prognosis and aiding in the decision for or against therapy. In untreated patients, regular ALT measurements are useful, and repeat liver biopsy is the only reliable means of assessing the progression of fibrosis and is commonly recommended every 3 to 5 years in untreated patients. A second liver biopsy can distinguish patients with rapidly progressive fibrosis, but may also merely indicate that the initial biopsy underestimated the degree of fibrosis. Overall, the risk of progression of fibrosis of more than 1 point in a 3- to 5-year period is low. In patients with factors associated with a higher risk of progression, such as age above 50 years, excessive alcohol consumption, or high serum ALT levels, liver biopsy may be recommended more frequently (every 2 to 3 years); in contrast, in the younger patient with no other risk factor, the liver biopsies may be performed less frequently (every 5 to 10 years).

10/17/03

Reference
P Marcellin and others. Fibrosis and disease progression in hepatitis C Hepatology 36(5): S47-S56. November 2003, part 2.

The Natural History of Fibrosis in Chronic Hepatitis C: Older Age at Infection Onset and Increasing Duration of infection are Primary Determinants of Fibrosis Progression

The natural history of hepatitis C (HCV) remains controversial with little data beyond the first 2 decades and conflicting estimates based on study design and population characteristics, such as age and gender.

Using 2313 liver biopsies from untreated patients including some with biopsies 20 to 40 years post infection, researchers translated a Cox proportional hazards model into a fibrosis-based Markov model.

The objective of this study was to compare cohort simulation projections to published outcomes and to predict future outcomes.

Cox proportional hazards models estimated the likelihood of developing Metavir fibrosis stages F1, F2, F3 or F4 over time. For all models, covariates included age, gender, alcohol consumption (>50 gm/day), injection drug use, and Metavir inflammation A2 or A3.

These Cox models and recent UNOS, SEER and NIH data were used to modify a previously published computer cohort simulation (Wong, JAMA 1998). Summary patient characteristics from the retrospective-prospective Kenny-Walsh (NEJM 1999) and Thomas (JAMA 2000) studies were then applied to the fibrosis-based Markov model to estimate the observed outcomes and to project future outcomes.

Study Results

For the Kenny-Walsh study (n=376), the mean age of the Irish women when they received HCV-contaminated anti-D immune globulin was 28 years.

After a mean of 17 years, liver biopsy revealed F0 in 49%, F1 in 34%, F2 in 10%, F3 in 5% and F4 in 2%. Markov model projections were 50% F0, 36% F1, 10% F2, 2% F3 and 1.6% F4. After 27 years of follow-up, the model predicted 20% F2, 4% F3 and 7% F4; and after 37 years of follow-up, 27% F2, 8% F3 and 20% F4.

To examine the impact of selected cohort factors, the 17-year incidence of cirrhosis (base-case estimate 1.6%) was 3% if all of the women had instead acquired HCV through injection drug use and 6% if they drank >50 gm alcohol per day. If the women had been older, the 17-year cirrhosis incidence rose to 5% for 38 year-olds and 14% for 48 year-olds.

Thus, age and duration of infection are the primary determinants of fibrosis progression.

Despite the slow fibrosis progression, the projected life expectancy for this cohort was 41.8 years and 37.3 quality-adjusted life years compared to an expected 51.7 years for 28 year-old women.

The projected lifetime medical care costs were $52,000 without antiviral treatment [emphasis added].

For the Thomas study (n=1667), the median age at first injection drug use was 20 years. With follow-up exceeding 15 years in over 75% of patients, cirrhosis was found in 2.4%. The Markov model predicted a 2.5% incidence of cirrhosis after 15 years. Future cirrhosis predictions were 11% after 25 years and 30% after 35 years.

Again, to examine the impact of selected cohort factors, the 15-year incidence of cirrhosis (base-case estimate 2.4%) was 1.3% if all of the patients had instead acquired HCV through transfusion and 7% if they drank >50 gm alcohol per day.

If the patients had been older, the 15-year cirrhosis incidence rose to 8% for 30 year-olds, 21% for 40 year-olds, and 46% for 50-year olds. Thus, age and duration of infection are the primary determinants of fibrosis progression.

The projected life expectancy for this cohort was 30.4 years and 26.2 quality-adjusted life years compared to an expected 56.3 years for 20 year-olds.

The projected lifetime medical care costs were $66,359 without antiviral treatment [emphasis added].

Conclusions

Our fibrosis-based Markov model predictions matched observed community cohort HCV outcomes well.

The model suggests rapid fibrosis progression beyond 20 years and very rapid progression beyond 30 years.

Despite the slow early progression, hepatitis C may still significantly reduce life expectancy and quality of life and induce substantial medical care costs because of the normally long life expectancy in these community cohorts and this delayed rapid progression.

Although men, injection drug use, alcohol use and active hepatic inflammation all raise the likelihood of progression, increasing duration of infection and older age at infection onset are the primary determinants of fibrosis progression.

12/01/03

Reference
JB Wong and others. NATURAL HISTORY OF FIBROSIS IN CHRONIC HEPATITIS C. Abstract 56 (oral). Hepatology 38:4 (Suppl). October 2003. (54^th Annual Meeting of the American Association for the Study of Liver Diseases. October 24-28, 2003. Boston, MA.)