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WW'�0���0���~INTERLEUKIN-28B POLYMORPHISM AND RISK OF DECOMPENSATION IN PATIENTS WITH HCV-INDUCED COMPENSATED CIRRHOSIS: A LONG-TERM COHORTFrank DutkoMaria Luisa RussoMaria Luisa Russo5@��_@@*|j�b�@�Iz�e�����՜.��+,��D��՜.��+,��\���M 	��0��Caolan80	2�gd��i��t	���&\�LCd � b	#^.���:�,"�INTERLEUKIN-28B POLYMORPHISM AND CLINICAL OUTCOMES IN PATIENTS WITH HCV-INDUCED COMPENSATED CIRRHOSIS: A LONG-TERM COHORT STUDY.
Running title: IL-28b and CLINICAL OUTCOMES in hcv cirrhosis.

Savino Bruno1, Alex J. Thompson2,3, Rosina Critelli4, Andrea Crosignani5, Sonia Rossi1, Stefania De Lisi1, Elisabetta Cariani6, Paola Zermiani5, Valentina Vaira7, Vincenzo Boccaccio1, Patrick Maisonneuve8 and Erica Villa4

1Department of Internal Medicine, A.O. Fatebenefratelli e Oftalmico, Milan, Italy; 2Department of Gastroenterology and Department of Medicine, St Vincent s Hospital, The University of Melbourne, VIC, Australia; 3Duke Clinical Research Institute and Department of Gastroenterology, Duke University, Durham, NC, USA; 4Department of Gastroenterology, University of Modena and Reggio Emilia, Modena, Italy; 5Department of Internal Medicine, A.O. San Paolo, University of Milan, Italy; 6Clinical Pathology-Toxicology, Ospedale Civile S. Agostino-Estense, Modena, Italy; 7Division of Pathology, Fondazione IRCCS Ca  Granda, Ospedale Maggiore Policlinico, Milan, Italy, 8Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
Corresponding Author:
S. Bruno
Director of Internal Medicine, Liver and Endoscopy Units
Department of Internal Medicine
 A.O. Fatebenefratelli e Oftalmico
Corso di Porta Nuova, 23 20121 Milano, Italy
tel +39 0263632421
fax +39 0263632714
mobile +39 3338485866
mail savino.bruno@fbf.milano.it


ABSTRACT

Background: Interleukin (IL)-28B polymorphism is associated both with spontaneous clearance of hepatitis C virus (HCV) and response to antiviral therapy in chronic hepatitis. However, few data are available about its predictive value on SVR in patients with established cirrhosis. Furthermore, whether IL-28B genotype influences liver disease progression remains unclear.
Methods: We determined IL-28B genotype (rs1297860) by PCR on DNA extracted from frozen blood or paraffin-embedded liver tissue in a large cohort of consecutive patients with compensated HCV-related cirrhosis enrolled between 1989 and 1992. During follow-up, surveillance was carried out at six- month intervals, while IFN-based therapy was administered on clinical ground.
The Fisher s exact test was used to assess the association between IL-28B genotype and SVR achievement.The follow-up of patients who achieved SVR was then censored at the time of antiviral treatment initiation and  Kaplan-Meier curves and Cox regression analysis were used to assess the association between IL-28B genotype and clinical events.
Results: IL-28B genotype was determined in 264 patients (52% males, mean age 57�8 years, 67% infected by HCV genotype 1, G1). The proportion of CC, CT and TT genotype was 36%, 50% and 14%, respectively. During a median follow-up of 14.8 years, 149 (56%) of patients received therapy. Overall, SVR was achieved in 31 (21%) patients, 40% in those with CC genotype (22% in G1 and 61% in G2, respectively) compared to 10% and 13% among patients with CT and TT genotypes (p<0.0001). Univariate and multivariate analysis found no association between IL-28B (CC vs non-CC genotype) and clinical events.
Conclusion: Determination of IL-28B is fundamental for allocating patients with compensated cirrhosis to IFN-based therapy especially those infected by non-1 HCV genotype. However, IL-28B genotype is not a predictor of outcome in non-responders.

Keywords: compensated cirrhosis; IL-28B polymorphism; IFN-based therapy





INTRODUCTION

Chronic hepatitis C virus (HCV) infection currently represents the main cause of liver-related morbidity and mortality in developed countries (1). Although only a minority of patients with chronic hepatitis C (CHC) will develop progressive liver fibrosis leading to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC), HCV is still the most common indication for liver transplantation in Western countries.
Several factors are recognized to influence disease progression (2), however, it remains difficult to predict the natural disease s history and the ability to identify patients at risk for rapid fibrosis progression remains an unmet clinical need. In the last years, growing evidence suggested that genetic factors might influence the outcome of CHC and several single nucleotide polymorphisms have been identified as promising candidates to play a role in small cohorts of patients (3-4).
Genetic variation in the region of the interleukin (IL)-28B gene in chromosome 19 (eg. rs12979860, rs8099917) has been found being strongly associated with spontaneous (4,5) HCV clearance irrespective to viral genotype, while its treatment-induced effect on the achievement of sustained virologic response (SVR) has been well established despite it was mainly investigated in genotype 1 patients (6); reliable data of IL 28B in predicting SVR by IFN-based therapy in patients infected by non-1 easy-to-treat genotypes and/or with cirrhosis, by contrast, are few (7).
There has been much interest, as well, to determine whether IL-28B genotype might be associated with disease progression in patients with CHC irrespective to the achievement of SVR. Conflicting data have emerged. The favorable IL-28B genotype (eg. CC for rs12979860) was recently linked to more rapid fibrosis progression by Bochud et al. (8), although the association was only observed among non-genotype 1 HCV patients. In contrast, other cross-sectional studies have observed an association between unfavorable IL-28B genotypes (eg. CT, TT for rs129769860) and advanced fibrosis and HCC (5,9). Finally, a recent long-term study did not show any relationship between IL-28B genotype and fibrosis progression in a large cohort of patients with CHC and known date of infection (10). Therefore, the relationship between IL28B genotype and disease progression in CHC patients remains controversial and, no study has yet evaluated its impact on the clinical outcome of in patients with established cirrhosis. In this study we, therefore, aimed i) to assess the predictive value of IL-28B polymorphism on SVR in cirrhotic patients and ii) to evaluate the association between IL-28B polymorphism and clinical outcomes in a large cohort of patients with compensated HCV cirrhosis prospectively followed for up to 20 years 

Methods

Patients
Between January 1989 and December 1992, all consecutive cirrhotic (F4 METAVIR) (11) patients who presented at three referral centers in Milan Area of Northern Italy and tested positive for serum anti-HCV were enrolled in a prospective study aimed at evaluating the long-term outcome of patients with HCV-induced cirrhosis. The cohort has been described in detail previously (12). For the purpose of the present study we considered only patients with compensated cirrhosis. The diagnosis of cirrhosis was based on liver biopsy or on clinical criteria (13). Moreover, when AST to platelet ratio index (APRI) became available, all patients with no histology and/or without esophageal varices were scored using 1.5 as cut-off value to define cirrhosis (14).
Upper endoscopy was offered to all patients at the time of inclusion in the study and prophylactic treatment with beta-blockers was started if medium size esophageal varices (EV) were found.
Patients aged >70 years, patients with HCC, and patients with co-infections or co-morbidities (HBV, HIV, alcoholic, autoimmune, metabolic liver disease) were excluded. Model for end stage liver disease (MELD) score (15) was classified according to current criteria. A history of significant alcohol consumption was defined as >60g/day for women, and >80g/day for men, for at least 5 years duration, as previously described (12). All study participants provided written informed consent and approved the storage of their frozen DNA specimens for research purposes. The study was approved by local ethics committees and performed in accordance with provisions of the Declaration of Helsinki and Good Clinical Practice guidelines.

Follow-up and definition of clinical outcomes
Patients underwent a regular semi-annual surveillance based on clinical, laboratory and abdominal ultrasound evaluation. Examination of the upper gastrointestinal tract was planned at 1 to 3-year intervals. For the purpose of this study, we evaluated decompensation, HCC development, liver and non liver-related mortality (all cause mortality) as outcomes. Decompensation was defined as development of ascites, bleeding from varices rupture and occurrence of overt hepatic encephalopathy. Up to 2001, diagnoses of HCC were based on histological assessment obtained by fine-needle liver biopsy (16) whenever a focal liver lesion was detected by ultrasound. After 2001, diagnoses were made according to the Barcelona Conference criteria (17). Liver-related mortality was defined as death caused by either end-stage liver disease (ESLD) or HCC progression or liver transplantation. Patients lost to follow-up were individually contacted and invited to have a clinical visit, blood testing and an ultrasound examination. For those who were no longer traceable, vital status information was obtained from local vital record offices.
HCV testing
Anti-HCV was assessed by first and second-generation enzyme-linked immune-adsorbent assay. HCV RNA testing was performed using PCR and patients who tested HCV-RNA negative by PCR were excluded, as previously described (12). HCV genotype was determined on frozen sera by nested-reverse transcription- PCR of HCV core sequences using type-specific primers (18) and, when possible, later confirmed on fresh sera by INNOLiPA, (HCVII, Innogenetics, Ghent, Belgium).
Treatment of HCV Infection
After enrollment, antiviral therapy was offered to patients without contraindications. The majority of patients received interferon (IFN) mono-therapy at the dose of 3 MIU three times a week, regardless of HCV genotype, for at least 6 months as recommended at that time. When available, combination therapy with IFN or pegylated IFN (Peg-IFN) and ribavirin was administered according to international guidelines. SVR was defined as undetectable serum HCV-RNA (lower limit of detection=50 UI/ml) six months after stopping therapy.
IL28 genotyping
IL-28B genotype (rs12979860) was retrospectively evaluated in all patients who had at least one stored clinical specimen suitable for DNA extraction (whole blood, frozen serum, formalin-fixed paraffin embedded tissue (FFPE) using a homemade real-time PCR-based approach (19).

Statistical analysis

The Fisher s exact test and the Mantel-Haenszel chi-square test for the trend were used to assess differences in the distribution of respectively categorical and ordinal variables between groups of patients at baseline, while continuous variables were compared using the Student T test. Survival was calculated from the date of enrollment to the date of last follow-up visit, liver transplantation or death. Follow-up of patients who achieved SVR by antiviral therapy during the course of study period was then censored at the time of the initiation of treatment in order to avoid confounding between SVR and IL-28B in predicting the outcome. Kaplan-Meier curves were drawn to illustrate the outcome of patients according to IL-28B genotype. The log-rank test was used to compare outcome between groups. Multivariate Cox proportional hazards regression model was used to assess the prognostic value of IL-28B genotype on outcome including development of decompensation, HCC, hepatic mortality and all causes mortality. Models were adjusted for established prognostic factors including age (continuous), gender, HCV genotype (1 versus non-1), presence of varices, albumin (g/dl, continuous), and MELD score (continuous) at baseline. Models included dummy variables to represent missing values for some co-variables (presence of varices, HCV genotype, MELD score, albumin). All p-values were two-sided. All analyses were performed with the SAS software (version 8.2, Cary NC).

Results

Among the 465 patients enrolled in the original cohort (12), 65 were decompensated at baseline and were excluded from the current analysis. One hundred and thirty six (34.0%) of the 400 compensated patients were further excluded because biological samples were no longer available. The characteristics of patients with/without biological samples are shown in supplementary table 1.
Cirrhosis was defined by liver biopsy in 183 patients (69.3%) while 10 patients (3.8%) had EV at study entry. In the remaining 71 (26.8%) patients the diagnosis was based on clinical/ultrasonographic criteria and confirmed by APRI score in all except 5 patients.
Table 1 shows the demographic, virologic and clinical features at study entry of the 264 patients included in the study, according to IL-28B genotype (rs12979860). The majority (66.9%) of patients were infected with genotype 1 (166 infected with genotype 1b and 2 with genotype 1a), 52.3% were male and the mean age at enrollment was 57 years. The percentage of CC, CT and TT IL-28B genotypes was 35.6%, 50.8% and 13.6%, respectively. There was a trend for CC genotype to be less common in patients with genotype 1 vs. non-1 HCV (31.5% vs. 43.4%, P=0.07), but there were no other differences in patient characteristics at enrollment according to IL-28B genotype.

IL28 polymorphism and SVR
IFN mono-therapy was administered to 149 patients (56.4%, 100 infected by genotype 1 and 43 by genotype 2, in 6 viral genotype was not available); 27 (10.2%) were later retreated with IFN plus ribavirin combination therapy. Overall, 31 patients (20.8% of those treated) achieved SVR.
The achievement of SVR was significantly associated with IL-28B genotype even after adjustment for viral genotype (P=0.0001). SVR was attained in 21/53 (39.6%) patients carrying the CC genotype compared to 7/73 (9.6%) and 3/23 (13.0%) in those carrying the CT and TT genotypes, respectively (CC vs. non-CC P=0.0001) (figure 1).



Impact of IL28B polymorphism on the outcome of liver disease
During a mean follow-up of 14.8 (range 0.7-23.1) years, 95 patients developed HCC (annual rate 2.9/100-year), 100 had hepatic decompensation (3.1/100-year) and 132 died (3.6/100-year). Censoring follow-up of patients who achieved SVR at the time of initiation of anti-viral therapy, the annual rate of HCC, decompensation and death were respectively 3.1/100-year, 3.5/100-year and 4.0/100-year. Six of the patients who achieved SVR subsequently developed HCC, 1 had decompensation and 4 died from any cause.
The cause of death was related to liver disease in 101 cases and to extra-hepatic causes in 31. In total, 46 patients (17.4%) were lost at follow-up at some point, but contributed to a mean period of observation of 8.6 years. No association was observed between IL-28B polymorphism and the development of decompensation, HCC, liver related or all causes mortality) according to Kaplan-Meier analysis (figure 2).
At multivariate analysis, age (1 year increase), varices (yes vs. no), MELD score (1 point increase), albumin (1g/dl increase) and HCV Genotype (1 vs. other ones) were independently associated with multiple liver outcomes (including decompensation, HCC, hepatic mortality, or death from any cause). In contrast, no significant difference was observed between IL 28 CC compared to those with non-CC genotype (table 2).

Discussion

IL-28B polymorphism is the strongest host factor predicting for response to IFN-based therapy for CHC infected by genotype 1 HCV. However, its impact on disease progression is still poorly investigated. To our knowledge this is the study with the longest surveillance period ever carried out, so far in patients with HCV-related cirrhosis As a result, it may reliable assess the association between IL-28B polymorphism and clinical outcome in a large, well-characterized cohort. More details regarding events and risk factors independently associated with outcomes, including the effect of SVR, for this cohort have been described previously (12).
In the present study we found a significant association between favorable IL-28B polymorphism and achievement of SVR, in agreement with previous reports (20) mainly performed in patients without cirrhosis. Therefore, it is conceivable that it may still indirectly influence clinical outcomes. Nevertheless, despite the large sample size, the long-term duration of follow-up, the frequency of clinical outcomes, and, accordingly, substantial power for detecting an effect, we did not observe an association between IL-28B polymorphism and the risk of liver-related morbidity, including decompensation, HCC, need for LT, liver-related and overall mortality.
We acknowledge that this analysis misses to estimate the duration of infection and, consequently, it lacks assessing the rate of fibrosis progression prior to the diagnosis of cirrhosis. However, the study has some unique strengths: the long duration of follow-up, the relevant number of events observed prospectively and, of main importance for the reliability of the results, the low proportion of patients who achieved SVR (20%, which was normal in that era) who contributed to the analysis only for the period during which they were still viremic. This methodological approach has allowed to closely evaluate the effect of IL-28B, irrespective of its well-known association with  SVR. Thus, we may, realistically, estimate, the natural history of the disease. 
Despite Di Marco and coworkers found that severity of liver fibrosis was associated with IL-28B unfavorable genotypes in a cross-sectional study (21), other studies, carried out with similar methodology, are in agreement with our results since they have failed to observe any significant association between IL-28B genotype and liver fibrosis stage. An analysis of the IDEAL study which included a negligible number of cirrhotic patients did not detect any association between IL-28B genotype and fibrosis stage (22). Marabita et al., as well, did not found an association between IL-28B polymorphism and liver fibrosis progression in an Italian cohort with earlier stage fibrosis (10). Finally, a recent genome-wide analysis did not identify IL-28B variants to be significantly associated with progression of liver fibrosis in a cohort of individuals of European ancestry (23).
Another information provided by this study is that although the association between IL-28B polymorphism and treatment response by IFN-based therapy is a well-known phenomenon in chronic hepatitis C, in our cohort of patients we observed a very high SVR rate among IL-28B CC patients with cirrhosis, especially in individuals infected by genotype 2. Possibly, CC polymorphisms led to a SVR by its high rate of Rapid Virologic Response (RVR) (20), in agreement by two large cohort studies of cirrhotic patients where the achievement of RVR during Peg-IFN therapy was associated with SVR (24,25). The reliability of IL-28B genotype in predicting the outcome of IFN-based treatment in patients with  hard-to-cure  characteristics has strong clinical usefulness, because the cost of new IFN-free direct-acting antiviral agents (DAAs) will represent a barrier against the widespread of these molecules, worldwide. In addition, in cirrhotic patients infected by genotype 2 or 3 the rate of SVR achieved by the most promising DAA is similar to those achieved by IFN (26,27). Therefore, mainly in Eastern countries, where the IL 28B CC favorable variant is the prevalent one, individuals with such characteristics could be inexpensively treated with IFN-based therapy.
	In conclusion, in a large and well-characterized cohort of patients with HCV compensated cirrhosis, the IL-28B favorable genotype was strongly associated with achievement of SVR during IFN-based therapy, which in turn prevents liver deterioration.  However, in non-treated or non-SVR patients, IL-28B genotype was not associated with disease progression. In an era of new antiviral agents, its assessment remains important for allocating patients, including those with cirrhosis, to less expensive therapy either in countries where the favorable IL28B genotype is prevalent or in those where cost of new IFN-free molecules could not be afforded.
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