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.