Factors That Determine the Development and Progression of Gastroesophageal Varices in Patients With Chronic Hepatitis C

Factors that Determine the Development and Progression ofGastroesophageal Varices in Patients with Chronic Hepatitis C

Robert J. Fontana, M.D.1, Arun J. Sanyal, M.D.2, Marc G. Ghany, M.D.3, William M. Lee, M.D.4, Andrea E. Reid, M.D.5, Deepa Naishadham, M.A., M.S.6, Gregory T. Everson, M.D.7, Jeffrey

© 2009 The American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.Address all correspondence to: Robert J. Fontana, MD Associate Professor of Medicine 3912 Taubman Center Ann Arbor, MI48109-0362 Tel: 734-936-4780 Fax: 734-936-7392 [email protected] to Manuscript 1, 2, 3, 4, 5 Study concept and design; acquisition of data; analysis and interpretation of data; drafting ofthe manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; studysupervision; 6 Analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectualcontent; statistical analysis; 7, 8, 9, 10, 11, 12 Acquisition of data; analysis and interpretation of data; critical revision of the manuscriptfor important intellectual contentAuthor Emails Robert J. Fontana [email protected] J. Sanyal [email protected] G. Ghany [email protected] M. Lee [email protected] E. Reid [email protected] Naishadham [email protected] T. Everson [email protected] A. Kahn [email protected] M. Di Bisceglie [email protected] Szabo [email protected] R. Morgan [email protected] E. Everhart [email protected] of InterestSection A. The following are disclosures that pertain to the industrial sponsors who have partnered with the NIDDK to support this study,which are also listed in the text of the manuscript.Financial relationships of the authors with Hoffmann-La Roche, Inc., are as follows:R.J. Fontana is on the speaker’s bureau; W.M. Lee receives research support; G. T. Everson is a consultant, on the speaker’s bureau, andreceives research support; A.M. Di Bisceglie is a consultant and receives research support; G. Szabo receives research support; and T.R.Morgan is consultant, on the speaker’s bureau, and receives research support.Section B. In addition, many of the HALT-C Trial investigators have other associations with industry relating to the area of hepatitis C,and, to achieve the highest level of disclosure, we list these for you as well.R.J. Fontana: Bristol-Meyers Squibb – Speaker’s bureau and consultant. Abbott Pharmaceuticals – Consultant. Bayer/Siemens –Consultant.A.J. Sanyal has served on ad hoc Advisory Boards of Bayer, Salix, Gilead, Astellas, Sanofi, Exhalenz in the last year. He has participatedin clinical trials by Bayer, Sanofi, Gilead, Exhalenz, Salix and Roche.W.M. Lee receives research support from Aegerion, Globeimmune, Orasure, Schering-Plough, Siemens Diagnostics and VertexPharmaceuticals.G. T. Everson receives research support from Schering-Plough, Pharmasset, GlobeImmune, Source, Novartis/Human Genome Sciences,and GlaxoSmithKline; and is a consultant and receives research support from Vertex Pharmaceuticals.A.M. Di Bisceglie is a consultant and receives research support from Vertex Pharmaceuticals, Idenix Pharmaceuticals, Gilead Sciences,Anadys, GlobeImmune and Pharmasset; has served as a consultant to Schering-Plough, Novartis, Bristol-Myers-Squibb and Abbott.G. Szabo receives research support from Idenix Pharmaceuticals, Vertex Pharmaceuticals, GlaxoSmithKline, Bristol-Myers-Squibb,IDERA, Novartis, and Schering Plough Corporation.T.R. Morgan is a consultant, serves on an advisory board, and receives research support from Vertex Pharmaceuticals; and receivesresearch support from Merck, Schering Plough Corporation, and WAKO Diagnostics.This is publication #48 from the HALT-C Trial Group.*The HALT-C Trial was registered with clinicaltrials.gov (#NCT00006164).Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customerswe are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resultingproof before it is published in its final citable form. Please note that during the production process errors may be discovered which couldaffect the content, and all legal disclaimers that apply to the journal pertain.

NIH Public AccessAuthor ManuscriptGastroenterology. Author manuscript; available in PMC 2011 June 1.

Published in final edited form as:Gastroenterology. 2010 June ; 138(7): 2321–2331.e2. doi:10.1053/j.gastro.2010.02.058.

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http://clinicaltrials.gov

A. Kahn, M.D.8, Adrian M. Di Bisceglie, M.D.9, Gyongyi Szabo, M.D.10, Timothy R. Morgan,M.D.11, James E. Everhart, M.D.12, and the HALT-C Trial Group1Division of Gastroenterology, Department of Internal Medicine, University of Michigan MedicalSchool, Ann Arbor, MI.2Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond,VA.3Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases,National Institutes of Health, Department of Health and Human Services, Bethesda, MD.4Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas,TX.5Gastrointestinal Unit (Medical Services), Massachusetts General Hospital, Boston, MA.6New England Research Institutes, Watertown, MA.7Section of Hepatology, Division of Gastroenterology and Hepatology, University of ColoradoDenver, School of Medicine, Aurora, CO.8Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of SouthernCalifornia, Los Angeles, CA.9Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis,MO.10Hepatology and Liver Center, Division of Gastroenterology, Department of Medicine, Universityof Massachusetts Medical School, Worcester, MA.11Division of Gastroenterology, University of California - Irvine, Irvine, CA and GastroenterologyService, VA Long Beach Healthcare System, Long Beach, CA.12Division of Digestive Diseases and Nutrition, National Institutes of Diabetes and Digestive andKidney Diseases, National Institutes of Health, Department of Health and Human Services,Bethesda, MD.

AbstractBackground & Aims—We aimed to identify the incidence and predictors of de novogastroesophageal variceal formation and progression in a large cohort of patients with chronichepatitis C (CHC) and advanced fibrosis.

Methods—All participants in the HALT-C Trial were offered an endoscopy before treatment andagain after 4 years. Patients with varices at baseline also had a endoscopy at 2 years. Baselinelaboratory and clinical parameters were analyzed as predictors of de novo variceal formation andvariceal progression.

Results—De novo varices developed in 157 of the 598 (26.2%) patients. Most of the new variceswere small (76.4%) and only 1% of patients developed variceal hemorrhage. The likelihood ofdeveloping varices was associated with subject race (Hispanic > Caucasian > African American, p=0.0005), lower baseline levels of albumin (P=0.051), and higher levels of hyaluronic acid (P< 0.001)with an area under the receiver operating characteristic (AUROC) curve=0.70. Among 210 patientswith existing gastroesophageal varices, 74 (35.2%) had variceal progression or bleeding duringfollow-up. Patients with a higher baseline ratios of serum aspartate /alanine aminotransferase(P=0.028) and lower platelet counts (P=0.0002) were at greatest risk of variceal progression (AUROC= 0.72). Prolonged, low-dose peginterferon α2a therapy and β-blockers did not influence the risk ofdeveloping new or enlarging varices.

Fontana et al. Page 2

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Conclusion—Development of varices in patients with CHC is associated with patient race/ethnicityand laboratory markers of disease severity. Prolonged low dose peginterferon α2a therapy and β-blockers do not reduce the risk of variceal development nor progression.

Keywordscirrhosis; portal hypertension; esophagogastroduodenoscopy; hyaluronic acid

IntroductionThe presence of varices in the esophagus or stomach (i.e. gastroesophageal varices) in patientswith chronic liver disease has important prognostic and therapeutic implications. For example,patients with moderate to large varices should receive prophylactic beta-blockers or undergoband ligation to reduce the risk of variceal hemorrhage (1). In addition, patients with varicesshould avoid aspirin, non-steroidal anti-inflammatory drugs, and other anticoagulants to reducethe risk of gastrointestinal bleeding. Although upper endoscopy is the “gold standard” fordiagnosing varices, the cost, risk, and inconvenience associated with this invasive procedurehave led many to seek alternative means to predict the presence and severity of varices (2,3).Development of reliable and simple non-invasive tests that accurately predict the presence ofvarices could greatly improve the clinical care of the increasing number of patients with chronicliver disease. In addition, accurate laboratory or clinical predictors of variceal progressioncould help guide surveillance and interventional strategies in patients with known varices.

The severity of cirrhosis as determined by the Child-Turcotte-Pugh (CTP) score hasconsistently been associated with the likelihood of having gastroesophageal varices. Forexample, subjects with decompensated cirrhosis are significantly more likely to have varicesor develop variceal bleeding during follow-up compared to subjects with compensated cirrhosis(4,5). However, many of these studies involved a limited number of patients with variablefollow-up and included a large proportion of patients with alcoholic liver disease (5). In theUnited States and most western countries, chronic hepatitis C (CHC) infection has emerged asa leading cause of liver failure, hepatocellular carcinoma (HCC) and liver transplantation (6).Improved understanding of the factors that influence disease progression including thedevelopment of gastroesophageal varices are urgently needed.

The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is aprospective, multi-center study designed to determine if maintenance peginterferon can reducethe rate of disease progression in patients with CHC and advanced but compensated fibrosis(7). The overall rate of liver decompensation as well as histological fibrosis progression wassimilar in the peginterferon treated and untreated control patients (7). However, the largenumber of well-characterized patients provided a unique opportunity to prospectively studyvarious aspects of liver disease progression including the development of gastroesophagealvarices. In a prior report, esophageal varices were detected in 16% of the HALT-C Trial patientswith bridging fibrosis and 39% of those with compensated cirrhosis at study entry (8).Correlates of baseline varices included male gender, non-African American race, andlaboratory markers of disease severity. The aims of the current study are to identify theincidence of de novo gastroesophageal varix formation in HALT-C Trial patients withoutbaseline varices as well as the incidence of variceal progression in patients with establishedvarices during a median follow-up of 4 years. In addition, baseline laboratory and clinical datawere analyzed to develop models that accurately and reliably predict the presence andprogression of gastroesophageal varices.



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MethodsThe design of the HALT-C Trial has been previously described (7). Briefly, patients with priornon-response to standard interferon and advanced hepatic fibrosis on biopsy (i.e. Ishak fibrosisscore > 3) with no history of hepatic decompensation or HCC were treated with pegylatedinterferon and ribavirin during the “lead-in” phase. Patients with persistently detectable HCVRNA at week 20, were randomized to maintenance peginterferon-α2a 90 ug/ week (Pegasys;Roche Laboratories, Nutley NJ) or no treatment for the next 3.5 years. Week 20 virologicalresponders in the lead-in continued combination therapy for 48 weeks. However, patients withdetectable HCV RNA during treatment (breakthrough) or after stopping treatment (relapse)were also eligible for randomization. In addition, “express” patients who had received at least24 weeks of peginterferon and ribavirin were eligible for enrollment in the randomized phase.This study was approved by the Institutional Review Board at each site and all subjects providedwritten informed consent for endoscopy.

Endoscopic evaluation and endpointsA written endoscopy protocol was developed that included standardized criteria for identifyingand grading esophageal varices, gastric varices and portal hypertensive gastropathy. All of thephysician investigators completed a tutorial prior to the study initiation. Furthermore,endoscopic findings were immediately recorded on a templated form on the date of theendoscopy and the data were queried and verified against source documents at annual audits.All subjects underwent a pretreatment baseline endoscopy prior to randomization and subjectswith baseline gastroesophageal varices had a repeat endoscopy at 18 months followingrandomization which is deemed study year 2. In addition, all randomized patients who had notdied or undergone liver transplantation underwent a follow-up endoscopy at year 3.5 followingrandomization which is deemed study year 4. The presence and grade of esophageal variceswere evaluated with the esophagus insufflated as follows (9):

F1= small varices with mild impingement on the lumen (< 25%)

F2 = medium varices, intermediate in size between F1 and F3

F3= large varices with considerable impingement on the lumen (> 50%).

Gastric varices were recorded according to the Sarin classification (10)

De Novo varices were defined as newly identified esophageal or gastric varices or thedevelopment of variceal hemorrhage during follow-up in the patients without varices atbaseline. Variceal progression was defined as an increase in esophageal varix size of at least1 grade at the year 2 or year 4 endoscopy, development of variceal bleeding any time in therandomized phase, or development of new gastric varices. Regression of varices was definedas a decrease in esophageal varix size by 1 grade or more at the year 4 endoscopy.

Laboratory and clinical assessmentLifetime alcohol consumption was estimated using a modification of the Skinner survey atenrollment (7). Routine baseline laboratory values (i.e. serum aminotransferases, albumin,bilirubin, platelet count) were obtained at the local laboratories. HOMA-IR was calculated asHOMA= [(insulin* glucose)/22.5]*0.5551. Serum HCV RNA testing was done at baseline andduring the randomized phase using the quantitative COBAS Amplicor HCV Monitor Test(Roche Molecular Diagnostics, Branchburg, NJ) with a lower limit of detection of 600 IU/mlat a central laboratory. Serum iron, total iron binding capacity, total bile acids and hyaluronicacid levels were determined at a reference laboratory (WAKO Diagnostics, Richmond VA).Liver biopsies were evaluated by a panel of expert liver pathologists and scored for the degreeof hepatic fibrosis and inflammation defined by the Ishak scoring system and the degree of



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hepatic steatosis was estimated as grade 0 to 4 (11). Splenomegaly was defined by a spleenlength > 13 cm on sonography.

All patients were seen every 3 months during the randomized phase for laboratory and clinicalassessment. In addition, annual liver ultrasounds were obtained to screen for HCC and serumalpha fetoprotein levels were obtained every 6 months as well. Clinical endpoints for the studyincluded an increase in CTP score to > 7 on two separate occasions 3 months apart, varicealbleeding, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, HCC, or death.For the subgroup of patients with bridging fibrosis at baseline, a two point increase in the IshakFibrosis score was considered histological progression.

Statistical methodsStatistical analyses were performed at the data coordinating center with the use of SASsoftware, 9.2 (SAS Institute, Cary, NC). Log transformation of non-normally distributedvariables was undertaken when indicated. Multivariate logistic regression methods were usedto explore factors associated with new varices development, variceal progression, and varicealregression. For multivariate models, individual factors that were associated with the outcomeon bivariate analysis with a p < 0.20 were initially included. Then only variables that weresignificant with p < 0.05 were retained in the final multivariate model. The area under thereceiver operating curve (AUROC) was calculated from a plot of sensitivity versus 1-specificity and can range from 0.5 (no predictive ability) to 1 (perfect discrimination).

ResultsPatient population

A pretreatment screening endoscopy was available in 1,016 of the 1,050 (96.8%) patientsrandomized in the HALT-C Trial. Gastroesophageal varices were absent in 744 (73.2%)patients while 272 (26.8%) had either baseline esophageal varices (261) or gastric varices alone(11) (Figure 1). The 34 patients who did not undergo a pretreatment screening endoscopy didnot differ from the patients included in this analysis except for having significantly lower BMI,baseline serum AST/ ALT and being younger (p< 0.05 for each).

In the 744 subjects without baseline gastroesophageal varices, 146 patients did not undergo afollow-up endoscopy by year 4 due to liver disease progression (n=40), study withdrawal(n=66), or patient refusal (n= 40). The 146 excluded patients had similar baseline demographicfeatures to the 598 patients included in this analysis. However, the excluded patients also hada greater lifetime history of alcohol consumption (p=0.0002), were more likely to be smokers(p=0.0024), and had laboratory markers of more severe liver disease at entry (i.e. higher AST/ALT, p= 0.038, lower albumin p= 0.0093) (data not shown). In addition, the excluded patientswere more likely to develop a clinical outcome during follow-up in the HALT-C Trial (27%vs 8%, p < 0.0001). Clinical characteristics of the 598 patients without pretreatmentgastroesophageal varices include a mean age of 50.1 years, 72% were Caucasian, and 32% hadhistological cirrhosis (Table 1).

Sixty-two of the 272 subjects with pretreatment gastroesophageal varices failed to undergo afollow-up endoscopy due to liver disease progression (n= 32), study withdrawal (n=26), orpatient refusal (n= 4). The 62 excluded patients had similar demographic features to the 210patients included in this analysis but also had greater likelihood of smoking (p=0.015), higherserum alkaline phosphatase levels (p=0.025) and lower serum albumin levels (p=0.0013) (datanot shown). In addition, the excluded patients were more likely to develop a primary clinicaloutcome during follow-up (52% vs 27%, p=0.0003). The mean age of the 210 patients includedin this analysis was 50.8 years, 78% were male, 81% were Caucasian, 64% had cirrhosis, and



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only 9.5 % (20) had gastroesophageal varices while the remainder (190) had esophageal varicesalone (Table 2). Adherence to the endoscopy schedule was excellent with 203 (97%) of thepatients undergoing a surveillance endoscopy at year 2 and 192 (91%) undergoing asurveillance endoscopy at study year 4.

Development of de novo gastroesophageal varicesDuring a median follow-up of 48 months (range: 1.7 to 74 months), 157 of the 598 HALT-Cpatients (26.2%) without baseline varices developed gastroesophageal varices and only 8(5.1%) developed new gastric varices alone. New varices were detected at year 2 in 3 patientsand at year 4 in 150 patients while 4 additional patients presented with variceal hemorrhage.The size of the de novo esophageal varices at diagnosis was grade 1 in 120 patients (76.4%),grade 2 in 21 patients (13.4%), and grade 3 in 4 patients (2.5%). Subjects who developed newvarices were significantly more likely to be Hispanic, less likely to be African-American, havea higher BMI, and have a lower serum albumin level (Table 1). In addition, subjects with newvarices had significantly higher baseline serum AST/ ALT, total bilirubin, INR, alkalinephosphatase, hyaluronic acid (HA), and total bile acid levels compared to patients without newvarices (Table 1). The pretreatment liver biopsies of patients with new onset varices were alsomore likely to demonstrate cirrhosis, Mallory-Denk bodies, and more severe hepatic steatosis.During follow-up, patients with de novo varices were also significantly more likely to developa clinical outcome (Odds ratio 5.46: p< 0.0001). Conversely, the rate of de novo varices wassignificantly higher in the 50 (8%) patients with clinical progression compared to the 127 (92%)patients without a clinical outcome (62% vs 23%, p< 0.0001)

Multivariate modeling of baseline clinical and laboratory predictors identified subject race andpretreatment serum albumin and log HA levels as significantly associated with developingvarices. Specifically, the odds ratio for Hispanics versus Caucasians was 4.20 (95% CI: 1.92,9.20) and for African Americans versus Caucasians was 0.77 (95% CI: 0.47, 1.28). Similarly,for every one gm/dl unit decrease in albumin, the odds ratio was 0.55 (95% CI: 0.30,1.00) andfor every one unit increase in serum HA levels, the odds ratio was 3.84 (95% CI: 2.36, 6.26).The AUROC of the multivariate model for identifying patients at risk of developing variceswas 0.721 (95% CI: 0.65, 0.79). The addition of the pretreatment Ishak fibrosis, Mallory-Denkbodies, and steatosis scores to the model did not substantially change the model performancenor the inclusion of serial HA levels (Data not shown). Finally, the frequency of beta-blockeruse (44% vs 34%, p= 0.07) during the randomized phase was not significantly different in thosewith and without denovo varices.

The risk of developing varices in patients of varying ethnicity and baseline hyaluronic acidlevels was estimated from the logistic regression model (Figure 2). It was assumed that allpatients would have a baseline serum albumin level that was similar to the median value of theHALT-C Trial patients of 3.9 g/dl. In subjects with a baseline hyaluronic acid level of < 50ng/ml (i.e. log < 1.7), the risk of developing varices ranged from 13% in African Americansto 22% in Caucasians and 44% in Hispanics. Similarly, the risk of developing varices in patientswith a baseline hyaluronic acid level of > 126 ng/ml (i.e. log > 2.1) varied from 36% to 51%and 75% amongst the African American, Caucasian, and Hispanic subgroups, respectively.

Progression of baseline varicesDuring a median follow-up of 48 months, 74 (35.2%) subjects experienced variceal progressionwhich included 46 detected at year 2, 23 detected at year 4, and 5 presenting with varicealbleeding. On univariate analysis, subjects with variceal progression had significantly higherbaseline serum AST/ ALT, total bilirubin, and hyaluronic acid levels and significantly lowerserum albumin and platelet levels compared to non-progressors (Table 2). In addition, thepatients with variceal progression were more likely to have splenomegaly on their pretreatment



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liver ultrasound. Administration of beta-blockers during the randomized phase was morecommon in those with compared to those without variceal progression (78% vs 50%, p=0.0003). Patients with variceal progression were also more likely to experience a clinicaloutcome compared to those without variceal progression (Table 2). Conversely, the rate ofvariceal progression was also significantly higher in the 56 (27%) patients with clinicalprogression compared to the 154 (73%) patients without a clinical outcome (64% vs 25%, p<0.0001). The overall risk of bleeding among those with baseline varices was ~ 7% over 4 yearsas compared to 0.7% in those without baseline varices (p < 0.001).

On multivariate analysis, baseline serum AST/ALT and platelet counts were the onlyparameters independently associated with variceal progression. Specifically, for every one unitincrease in the serum AST/ ALT ratio, the odds ratio was 3.39 (95% CI: 1.17, 9.84) and forevery decrease in baseline platelet counts of 50,000/ml the odds ratio for variceal progressionwas 0.53 (95% CI: 0.38, 0.75). The addition of baseline histological parameters includinghepatic steatosis did not improve model performance (data not shown). For every decrease inthe platelet count by 50,000/ ml, the likelihood of variceal progression during follow-upincreased by 88%. The impact of baseline platelet counts and varying serum AST/ ALT levelson the risk of variceal progression can be seen in supplemental figure 1. In subjects with abaseline serum AST/ ALT level < 0.8, the impact of baseline platelet count varies from 8%risk in subjects with platelets > 150,000/ml to 37% in subjects with platelet counts < 100,000/ml. In contrast, in subjects with a baseline serum AST/ ALT > 1.5, indicative of more severeliver disease, the baseline platelet count can vary the risk of variceal progression from 23% to66%.

Impact of pegylated Interferon on development and progression of varicesThe HALT-C Trial was designed to determine if maintenance peginterferon would reduce therate of clinical and histological disease progression. If effective, it was anticipated that varicealdevelopment and progression would also be less frequent in the peginterferon treated patients.However, peginterferon therapy was not a predictor of new varices formation compared to notherapy (27% vs 26%, p=0.81) (Figure 3A). Similarly, the frequency of variceal progressionwas similar in the treated and untreated patients during the randomized phase (30% vs 40%,p=0.157) and the overall likelihood of changes in variceal status were not different (p=0.353)(Figure 3B).

Finally, the role of medication adherence amongst the peginterferon treated patients wasexplored in relationship to variceal outcomes by defining adherent patients as those who wereable to take > 80% of the prescribed dose of peginterferon for at least 80% of the time. In thisanalysis, 62% of the peginterferon treated patients without varices were adherent butmedication adherence was not associated with the risk of developing de novo varices (25% vs30%, P=0.30). Similarly, 47% of the peginterferon treated patients with baseline varices wereadherent but again medication adherence was not associated with the risk of varicealprogression (26% vs 35%, p= 0.33).

DiscussionPrior studies had suggested that interferon therapy in patients with CHC that did not clear virusmay lead to histological improvement (12,13). As a result, several large randomized controlledtrials of peginterferon therapy were initiated with the hope that the anti-inflammatory and anti-fibrotic effect of treatment in persistently viremic patients would slow the rate of diseaseprogression. However, the HALT-C Trial and other studies have failed to demonstrate anysignificant benefit regarding clinical and histological disease progression with maintenanceinterferon therapy (7,14-16). Previous studies have also demonstrated that administration of



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interferon to cirrhotic patients with CHC can lead to a reduction in portal pressure (17,18).Although reductions in portal pressure were consistently greatest in patients with an initial orsustained virological response, some non-responders with improved liver histology alsoexperienced improved portal pressures. Therefore, we hypothesized that antiviral therapywould be associated with a reduction in the rate of development of de novo varices as well asa reduced rate of variceal progression compared to no treatment.

Overall, 26.2% of the HALT-C Trial patients without baseline varices developed de novovarices during a median follow-up of 4 years. As expected, patients that developed variceswere also significantly more likely to experience a clinical outcome or histological progressioncompared to patients without de novo varices (Table 1). The majority of these new esophagealvarices were small (76%) and only 1% of patients developed variceal hemorrhage. Theannualized rate of new varices formation of 6.5% per year is slightly lower compared to thatreported in a randomized controlled trial of beta-blockers (8.9% per year) as well as in a naturalhistory study of variceal development (10% per year) (5,19). Of note, all of the patients in thelatter studies had cirrhosis and underwent annual endoscopy whereas only ~ 33% of the HALT-C patients at risk for varices had cirrhosis and an endoscopy was repeated at 4 years (Table 1).Also, the HALT-C Trial patients who did not undergo a follow-up endoscopy had clinicalprofiles that suggested they were at greater risk of developing varices. Thus, our observed ratesof variceal formation may be underestimates. Interestingly, African American patients in theHALT-C Trial were at a reduced risk of developing de novo varices compared to Caucasianswhile Hispanics were at the highest risk (Figure 2). These data are consistent with our prioranalysis demonstrating that African Americans are also less likely to have varices on screeningendoscopy after controlling for disease severity and liver histology (8). The reduced risk ofdeveloping varices amongst African Americans may be related to their tendency to have lesssevere necroinflammation or hepatic steatosis compared to Caucasians with HCV at initialpresentation and during follow-up (20,21). The increased risk of Hispanic patients to developvarices should be interpreted with caution due to the small number of Hispanics enrolled (i.e.only 6% of HALT-C patients but 13.3% of general US population). Nonetheless, the increasedprevalence of metabolic syndrome, hepatic steatosis, and advanced fibrosis reported in cross-sectional studies of Hispanic compared to Caucasian patients with CHC may, in part, explainour findings (22). In support of this, the frequency of significant hepatic steatosis (i.e ≥ 2) was32.5% in the African Americans, 42.5% in Caucasians, and 54.8% in Hispanic HALT-Cpatients (p = 0.002). When we controlled for subject BMI and liver histology, Hispanicethnicity remained an independent risk factor for developing varices. Additional longitudinalstudies of larger numbers of Hispanic and African-American HCV patients are eagerly awaitedto follow-up on these findings.

Baseline serum albumin and hyaluronic acid levels were also significantly associated with anincreased risk of developing varices which is consistent with prior studies demonstrating thatthese analytes correlate with the extent of hepatic fibrosis and disease severity in patients withCHC (23). Increases in serum hyaluronic acid levels are believed to be due to reducedendothelial clearance of HA from hepatic sinusoids as well as from increased hepatic stellatecell production with advancing fibrosis. A number of laboratory parameters associated withthe likelihood of developing varices in prior studies (e.g. platelet counts, total bilirubin levels,serum AST/ ALT) were also associated with the likelihood of developing varices in our patientpopulation (Table 1) (24). However, their lack of independent contribution to our model likelyreflects their collinearity with serum albumin and hyaluronic acid levels. Similarly, histologicalmarkers of disease severity were also associated with the risk of developing varices onunivariate analysis but were not on multivariate modeling presumably for the same reasons.

Administration of low dose peginterferonα2a did not reduce the risk of developing new varices(Figure 4A). Although only low doses of peginterferonα2a were used, the likelihood of



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https://www.researchgate.net/publication/278335953_Beta-blockers_to_prevent_gastroesophageal_varices_in_cirrhosis_-_Reply?el=1_x_8&enrichId=rgreq-fde9be516f26daf50112bf699537afc4-XXX&enrichSource=Y292ZXJQYWdlOzQxODI0NTcxO0FTOjE1MTMxNzAwNzgzNTEzOEAxNDEzMDg4MTk0ODQ0

developing varices was also not influenced by medication adherence amongst the treatedpatients. Therefore, our results demonstrate that maintenance peginterferon does not reducethe risk of developing varices. These results are consistent with the overall HALT-C Trialresults wherein the rate of liver disease progression by clinical and histological assessment wasnot reduced in treated compared to untreated patients despite improvements in serumaminotransferase and HCV RNA levels (7). Our study results differ from preliminary reportsof other studies of low-dose peginterferonα2b compared to no treatment or colchicine whereina reduced risk of variceal development and bleeding have been noted (16,25). The differingresults may, in part, relate to the differing entry criteria of the studies. For example, 100% ofthe patients in the EPIC3 trial and 83% of the Colchicine versus PegIntron Long-Term (CoPilot)study patients had histological cirrhosis while only 40% of the HALT-C patients had cirrhosis.In addition, Co-Pilot allowed patients with a CTP score of < 8 while HALT-C limitedenrollment to patients with a CTP < 7. In addition, the lower reported rate of de novo varices/variceal progression with peginterferonα2b in CoPilot may relate to the absence of retreatmentwith full dose peginterferon and ribavirin prior to randomization. This could result in theCoPilot patients receiving peginterferonα2b having a greater chance of virological suppressionand reduced necrointlammation compared to those treated with peginterferonα2a in HALT-C.However, both of the trials involving peginterferonα2b also failed to demonstrate a reductionin the overall rate of disease progression and clinical outcomes compared to the control arm(15,16).

A second aim of our study was to determine the rate of variceal progression amongst patientswith CHC. Overall, 35.2% of the 210 patients with baseline gastroesophageal varicesexperienced variceal progression and these patients were also significantly more likely todevelop a clinical outcome or histological progression compared to the patients withoutvariceal progression (Table 2). The annualized rate of 8.8% per year is similar to that reportedin other studies of patients with small varices followed over time (19). On multivariate analysis,baseline serum AST/ ALT and platelet counts were independently associated with varicealprogression. Since the serum AST/ ALT ratio is associated with more advanced hepatic fibrosisin patients with CHC, it is not surprising that this parameter was also associated with varicealprogression. In fact, baseline serum AST/ ALT levels are a component of a model developedin the HALT-C cohort to distinguish patients with bridging fibrosis from those with cirrhosisas well as to identify patients at increased risk of clinical outcomes during follow-up (26,27)In addition, subjects with variceal progression were more likely to have cirrhosis (Table 2)although the addition of liver histology parameters did not substantially improve the model’sperformance.

Use of these simple and widely available laboratory parameters may be of value to practitioners.For example, the likelihood of developing variceal progression can be categorized as low,medium and high using various platelet levels for a patient with a given serum AST/ ALT level(Supplemental Figure 1). However, contrary to expectations, maintenance peginterferontherapy was not associated with a reduced likelihood of variceal progression (Figure 3B). Inaddition, adherence to peginterferon was not associated with a reduced risk of varicealprogression amongst the treated patients although the trend was in the expected direction (26%vs 35%, p= 0.33). The lack of an association between subject ethnicity and variceal progressionmay relate to the limited number of patients with baseline varices in this analysis.

The serial endoscopic data also demonstrated that 17% of patients with baseline varices had areduction in the size of their varices by at least 1 grade and remarkably 3% had a reduction invariceal size by more than 2 stages (See supplemental material). It is possible that the regressionin varices may relate to inter-observer variability in the grading of varix size which is knownto vary by 10 to 15% (28). Alternatively, the reproducibility of assessing esophageal varicesin a given patient due to technical factors of insufflating the esophagus may have also played



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a role. However, on univariate analysis patients with lower INR levels and higher plateletcounts, indicative of less severe liver disease, were more likely to experience regression.Nonetheless, the use of maintenance peginterferon was not associated with variceal regression(Figure 3B). In addition, baseline use of beta-blockers and statins were also not associated withvariceal regression.

Strengths of our study include the large number of well-characterized patients with CHC thatwere prospectively assessed using a standardized endoscopy protocol while being carefullymonitored in a multi-center clinical trial. Furthermore, overall patient retention in the HALT-C Trial was excellent at 85% (7). In addition, the majority of patients with a pretreatmentscreening endoscopy did undergo a follow-up study as planned (80% of those without varicesand 90% of those with varices). However, the subjects without baseline varices who did notget a follow-up endoscopy had more severe liver disease at entry and were significantly morelikely to develop a clinical outcome during follow-up leading to a potential underestimationof the rate of varices formation. Similarly, amongst the 272 patients with baseline varices, theexcluded subjects that did not undergo a follow-up endoscopy tended to have more severe liverdisease at entry and were also more likely to develop a clinical outcome. Additional limitationsregarding our study design was the lack of central review of endoscopic findings which mayhave led to substantial inter-individual variability in grading varices as has been shown in priorstudies (28). To address these concerns, formal training on the grading of varices wasundertaken at the initiation of the study and a standardized scoring form was used in all patientsat all sites by a limited number of experienced investigators (8). Finally, direct portal pressuremeasurements were not obtained at baseline nor during follow-up. Although thesemeasurements are closely associated with the risk of developing new or worsening varices, theincremental risk, cost, and inconvenience of this invasive method precluded us fromincorporating it into this trial (1,5).

In summary, 26.2% of HALT-C Trial participants developed new gastroesophageal varicesand 35.2% of those with baseline varices experienced variceal progression during a medianfollow-up of 4 years. The risk of developing varices was significantly influenced by patientethnicity and laboratory markers of disease severity at entry but not influenced by the use ofmaintenance peginterferon. Assessment of baseline serum albumin and hyaluronic acid levelscan help stratify patients with CHC into low, medium, and high risk of developing varices(Figure 2). Use of these models may improve patient and physician adherence withrecommendations for endoscopic screening and assist in targeting the highest risk patients forthe most frequent follow-up. Similarly, determination of serum AST/ ALT and platelet countsin patients with CHC and known varices may help identify those that may benefit from beta-blocker prophylaxis or pre-emptive band ligation as well as more frequent endoscopicsurveillance.

Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.

AcknowledgmentsThis study was supported by the National Institute of Diabetes & Digestive & Kidney Diseases (contract numbers arelisted below). Additional support was provided by the National Institute of Allergy and Infectious Diseases (NIAID),the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General ClinicalResearch Center and Clinical and Translational Science Center grants from the National Center for ResearchResources, National Institutes of Health (grant numbers are listed below). The content is solely the responsibility ofthe authors and does not necessarily represent the official views of the National Center for Research Resources or theNational Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc.,through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health.



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In addition to the authors of this manuscript, the following individuals were instrumental in the planning, conduct and/or care of patients enrolled in this study at each of the participating institutions as follows:

University of Massachusetts Medical Center, Worcester, MA: (Contract N01-DK-9-2326) Gyongyi Szabo, MD,Barbara F. Banner, MD, Maureen Cormier, RN, Donna Giansiracusa, RN

University of Connecticut Health Center, Farmington, CT: (Grant M01RR-06192) Herbert L. Bonkovsky, MD,Gloria Borders, RN, Michelle Kelley, RN, ANP

Saint Louis University School of Medicine, St Louis, MO: (Contract N01-DK-9-2324) Adrian M. Di Bisceglie,MD, Bruce Bacon, MD, Brent Neuschwander-Tetri, MD, Elizabeth M. Brunt, MD, Debra King, RN

Massachusetts General Hospital, Boston, MA: (Contract N01-DK-9-2319, Grant M01RR-01066; Grant 1 UL1RR025758-01, Harvard Clinical and Translational Science Center) Jules L. Dienstag, MD, Raymond T. Chung,MD, Atul K. Bhan, MD, Wallis A. Molchen, Cara C. Gooch

University of Colorado School of Medicine, Denver, CO: (Contract N01-DK-9-2327, Grant M01RR-00051,Grant 1 UL1 RR 025780-01) Gregory T. Everson, MD, S. Russell Nash, MD, Jennifer DeSanto, RN, CarolMcKinley, RN

University of California - Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827) Timothy R.Morgan, MD, John C. Hoefs, MD, John R. Craig, MD, M. Mazen Jamal, MD, MPH, Muhammad Sheikh, MD,Choon Park, RN

University of Texas Southwestern Medical Center, Dallas, TX: (Contract N01-DK-9-2321, GrantM01RR-00633, Grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational ScienceInitiative) Thomas E. Rogers, MD, Peter F. Malet, MD, Janel Shelton, Nicole Crowder, LVN, Rivka Elbein,RN, BSN, Nancy Liston, MPH

University of Southern California, Los Angeles, CA: (Contract N01-DK-9-2325, Grant M01RR-00043) KarenL. Lindsay, MD, MMM, Sugantha Govindarajan, MD, Carol B. Jones, RN, Susan L. Milstein, RN

University of Michigan Medical Center, Ann Arbor, MI: (Contract N01-DK-9-2323, Grant M01RR-00042,Grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research) Anna S. Lok, MD, Joel K. Greenson,MD, Pamela A. Richtmyer, LPN, CCRC, R. Tess Bonham, BS

Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, GrantM01RR-00065) Mitchell L. Shiffman, MD, Richard K. Sterling, MD, Melissa J. Contos, MD, A. Scott Mills,MD, Charlotte Hofmann, RN, Paula Smith, RN

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes ofHealth, Bethesda, MD: T. Jake Liang, MD, David Kleiner, MD, PhD, Yoon Park, RN, Elenita Rivera, RN,Vanessa Haynes-Williams, RN

National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition,Bethesda, MD: James E. Everhart, MD, Leonard B. Seeff, MD, Patricia R. Robuck, PhD, Jay H. Hoofnagle,MD, Elizabeth C. Wright, PhD

University of Washington, Seattle, WA: (Contract N01-DK-9-2318) Chihiro Morishima, MD, David R. Gretch,MD, PhD, Minjun Chung Apodaca, BS, ASCP

New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328) Kristin K. Snow, MSc, ScD,Anne M. Stoddard, ScD, Teresa M. Curto, MSW, MPH

Armed Forces Institute of Pathology, Washington, DC: Zachary D. Goodman, MD, PhD

Data and Safety Monitoring Board Members: (Chair) Gary L. Davis, MD, Guadalupe Garcia-Tsao, MD, MichaelKutner, PhD, Stanley M. Lemon, MD, Robert P. Perrillo, MD

Abbreviations

BMI Body mass index

CHC Chronic hepatitis C

CTP Child-Turcotte-Pugh

HA Hyaluronic acid

HALT-C Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial

HCC Hepatocellular cancer



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HCV Hepatitis C virus

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https://www.researchgate.net/publication/5534693_Changing_trends_in_Hepatitis_C-related_mortality_in_the_United_States_1995-2004?el=1_x_8&enrichId=rgreq-fde9be516f26daf50112bf699537afc4-XXX&enrichSource=Y292ZXJQYWdlOzQxODI0NTcxO0FTOjE1MTMxNzAwNzgzNTEzOEAxNDEzMDg4MTk0ODQ0

https://www.researchgate.net/publication/6113827_Prevention_and_Management_of_Gastroesophageal_Varices_and_Variceal_Hemorrhage_in_Cirrhosis?el=1_x_8&enrichId=rgreq-fde9be516f26daf50112bf699537afc4-XXX&enrichSource=Y292ZXJQYWdlOzQxODI0NTcxO0FTOjE1MTMxNzAwNzgzNTEzOEAxNDEzMDg4MTk0ODQ0

https://www.researchgate.net/publication/6113827_Prevention_and_Management_of_Gastroesophageal_Varices_and_Variceal_Hemorrhage_in_Cirrhosis?el=1_x_8&enrichId=rgreq-fde9be516f26daf50112bf699537afc4-XXX&enrichSource=Y292ZXJQYWdlOzQxODI0NTcxO0FTOjE1MTMxNzAwNzgzNTEzOEAxNDEzMDg4MTk0ODQ0

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https://www.researchgate.net/publication/246701137_A_multivariate_model_predicts_presence_and_size_of_varices_A_validation_study?el=1_x_8&enrichId=rgreq-fde9be516f26daf50112bf699537afc4-XXX&enrichSource=Y292ZXJQYWdlOzQxODI0NTcxO0FTOjE1MTMxNzAwNzgzNTEzOEAxNDEzMDg4MTk0ODQ0

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https://www.researchgate.net/publication/7337757_Ethnic_differences_in_the_presentation_of_chronic_hepatitis_C?el=1_x_8&enrichId=rgreq-fde9be516f26daf50112bf699537afc4-XXX&enrichSource=Y292ZXJQYWdlOzQxODI0NTcxO0FTOjE1MTMxNzAwNzgzNTEzOEAxNDEzMDg4MTk0ODQ0

https://www.researchgate.net/publication/7337757_Ethnic_differences_in_the_presentation_of_chronic_hepatitis_C?el=1_x_8&enrichId=rgreq-fde9be516f26daf50112bf699537afc4-XXX&enrichSource=Y292ZXJQYWdlOzQxODI0NTcxO0FTOjE1MTMxNzAwNzgzNTEzOEAxNDEzMDg4MTk0ODQ0

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https://www.researchgate.net/publication/23174285_Non-invasive_and_minimally_invasive_diagnosis_of_oesophageal_varices?el=1_x_8&enrichId=rgreq-fde9be516f26daf50112bf699537afc4-XXX&enrichSource=Y292ZXJQYWdlOzQxODI0NTcxO0FTOjE1MTMxNzAwNzgzNTEzOEAxNDEzMDg4MTk0ODQ0

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https://www.researchgate.net/publication/246739202_259_The_Effects_of_Long_Term_PEG-Interferon_Therapy_On_the_Development_of_Esophageal_Varices_and_Variceal_Bleeding_Jn_Patients_with_Hepatitis_C_and_Advanced_Fibrosis_Final_Results_from_the_Copilot_Tri?el=1_x_8&enrichId=rgreq-fde9be516f26daf50112bf699537afc4-XXX&enrichSource=Y292ZXJQYWdlOzQxODI0NTcxO0FTOjE1MTMxNzAwNzgzNTEzOEAxNDEzMDg4MTk0ODQ0




Figure 1.Description of the HALT-C Trial cohort. Amongst the 744 patients without baseline varices,441 continued to have no detectable varices during follow-up while 157 developed newgastroesophageal varices. Amongst the 272 patients with baseline gastroesophageal varices,136 patients had stable or improved varices while 74 subjects had worsening varices.



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Figure 2.Logistic regression model to predict the likelihood of developing new varices in HALT-C Trialpatients. The predicted probability of developing new varices over 4 years according to baselinehyaluronic acid level and subject ethnicity using an imputed serum albumin level of 3.9 g/dlin the model. (log HA < 1.7 is < 50 ng/ml, log HA 1.7 to < 2.1 is 50 to < 126 ng/ml, and logHA ≥ 2.1 is > 126 ng/ml).



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Figure 3.Gastroesophageal varices in peginterferon treated and untreated patients. 3A). Amongst the598 patients without baseline varices, 302 were randomized to receive peginterferon and 296to receive no further treatment. By year 4, the proportion of patients with new varices in thetreated and untreated groups was similar (27% vs 26%, p= 0.81). In addition, the distributionof the types of varices that were detected was similar (p=0.06) 3B). Amongst the 210 patientswith baseline gastroesophageal varices, 99 received peginterferon and 111 received no furtherantiviral treatment. By year 4, the proportion of patients with worsening, stable, and improvedvarices was similar (p=0.35).



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Tabl

e 1

Cha

ract

eris

tics o

f the

598

HA

LT-C

Tria

l pat

ient

s with

out g

astro

esop

hage

al v

aric

es a

t pre

treat

men

t scr

eeni

ng e

ndos

copy

Cha

ract

eris

ticA

ll pa

tient

sN

=598

De

Nov

ova

rice

sn=

157

Non

-pr

ogre

ssor

sn=

441

p-va

lue

*O

R (9

5%C

I)

Dem

ogra

phic

s

Age

(yrs

)50

.1 (7

.1)

50.9

(7.2

)49

.8 (7

.1)

0.10

1.02

(1.0

0,1.

05)

% M

ale

69%

68%

69%

0.77

0.94

(0.6

4,1.

40)

Rac

e0.

0003

%

His

pani

c6%

13%

4%3.

72(1

.89,

7.31

)

%

Bla

ck22

%19

%23

%0.

86(0

.54,

1.37

)

%

Cau

casi

an72

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mor

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% D

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111.

40(0

.92,

2.12

)

B

MI (

kg/m

2 )29

.8 (5

.3)

30.6

(5.5

)29

.5 (5

.2)

0.03

301.

04(1

.00,

1.07

)

%

Tru

ncal

obe

sity

51%

56%

49%

0.15

241.

31(0

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1.90

)

%

Cur

rent

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er28

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%0.

250.

78(0

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1.19

)

Tota

l life

time

drin

ks15

358

(239

40)

1279

3(1

8289

)16

273

(256

14)

0.12

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00)

% B

asel

ine

NSA

ID/C

ox-

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tor

5%4%

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430.

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7%7%

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840.

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)


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Cha

ract

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ticA

ll pa

tient

sN

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% S

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0.44

1.70

(0.4

0,7.

19)

HC

V p

aram

eter

s

Prio

r HA

LT-C

stat

us0.

37

%

Non

-res

pond

er63

%67

%62

%1.

09(0

.68,

1.74

)

%

Bre

akth

ru/ r

elap

ser

17%

13%

18%

0.75

(0.4

0,1.

40)

%

Exp

ress

20%

20%

20%

1 R

ef

Log

HC

V R

NA

(IU

/ml)

6.5

(0.5

)6.

37 (0

.5)

6.54

(0.5

)0.

0004

0.52

(0.3

7,0.

75)

% H

CV

gen

otyp

e 1

94%

90%

95%

0.02

530.

45(0

.23,

0.91

)

Lab

orat

ory

para

met

ers

Hem

oglo

bin

(g/d

l)15

.0 (1

.4)

14.9

(1.6

)15

.1 (1

.4)

0.25

0.93

(0.8

2, 1

.05)

Seru

m A

ST/A

LT0.

85 (0

.3)

0.91

(0.3

)0.

83 (0

.3)

0.00

272.

55(1

.38,

4.7

0)

Alk

pho

s rat

io (U

LN)

0.82

(0.4

)0.

91 (0

.4)

0.79

(0.4

)0.

0011

2.12

(1.3

5, 3

.33)

Tota

l bili

rubi

n (m

g/dl

)0.

73 (0

.4)

0.81

(0.4

)0.

7 (0

.4)

0.00

142.

29(1

.38,

3.8

2)

INR

0.00

05

%

>1.

031

%42

%27

%1.

96(1

.34-

2.87

)

%

≤ 1

.069

%58

%73

%1

Ref

Alb

umin

(g/d

l)3.

93 (0

.4)

3.83

(0.4

)3.

96 (0

.3)

<.00

010.

33(0

.20,

0.5

7)


NIH


NIH


NIH



Cha

ract

eris

ticA

ll pa

tient

sN

=598

De

Nov

ova

rice

sn=

157

Non

-pr

ogre

ssor

sn=

441

p-va

lue

*O

R (9

5%C

I)

Plat

elet

s (10

3 /ml)

177

(61.

5)15

9 (6

7.9)

183

(57.

8)<.

0001

0.50

(0.3

6, 0

.70)

Tota

l Bile

aci

ds (u

mol

/l)14

.1 (1

6.5)

20.5

(24)

11.7

(12)

<.00

011.

03(1

.02,

1.0

4)

HO

MA

-IR

14.1

(17.

7)15

.2 (1

7.3)

13.7

(17.

9)0.

421.

00(0

.99,

1.0

2)

Log

HA

(ng/

ml)

1.89

(0.5

)2.

12 (0

.5)

1.81

(0.4

)<.

0001

4.69

(2.9

8, 7

.37)

% S

plen

omeg

aly

onul

traso

und

28%

38%

25%

0.00

181.

87(1

.26,

2.7

6)

Bas

elin

e H

isto

logy

% C

irrho

sis (

Isha

k 5/

6)32

%42

%29

%0.

0025

1.79

(1.2

3, 2

.62)

Mea

n H

AI B

asel

ine

7.4

(2.1

)7.

5 (2

)7.

4 (2

.1)

0.49

1.03

(0.9

4, 1

.13)

% H

epat

ic st

eato

sis ≥

242

%54

%37

%0.

0005

1.93

(1.3

3, 2

.78)

% M

allo

ry B

odie

s14

%21

%12

%0.

0064

1.95

(1.2

1, 3

.15)

% Z

one

3 fib

rosi

s0.

15

064

%67

%63

%0.

64(0

.30,

1.36

)

130

%25

%32

%0.

47(0

.21,

1.06

)

26%

38%

5%1

Ref

Ran

dom

ized

pha

se

% P

egin

terf

eron

arm

50%

50%

49%

0.81

1.05

(0.7

3,1.

51)


NIH


NIH


NIH



Cha

ract

eris

ticA

ll pa

tient

sN

=598

De

Nov

ova

rice

sn=

157

Non

-pr

ogre

ssor

sn=

441

p-va

lue

*O

R (9

5%C

I)

% C

linic

al o

utco

me

8%20

%4%

<0.0

001

5.46

(2.9

9,10

.01)

% T

wo-

poin

t inc

reas

e in

Isha

k fib

rosi

s sco

re26

%53

%18

%<0

.000

15.

20(3

.11,

8.68

)

Dat

a re

porte

d as

mea

n +

std

dev

or %

* com

parin

g de

nov

o vs

non

-pro

gres

sors


NIH


NIH


NIH



Tabl

e 2

Cha

ract

eris

tics o

f the

210

HA

LT-C

Tria

l pat

ient

s with

gas

troes

opha

geal

var

ices

at p

retre

atm

ent s

cree

ning

end

osco

py

Cha

ract

eris

ticA

ll pa

tient

sN

=210

Var

icea

lpr

ogre

ssor

sn=

74

Non

-pr

ogre

ssor

sn=

136

p-va

lue

*O

R (9

5% C

I)

Dem

ogra

phic

s

Age

(yrs

)50

.8 (7

.0)

51.5

(7.6

)50

.5 (6

.7)

0.35

1.02

(0.9

8, 1

.06)

% M

ale

78%

77%

79%

0.78

0.91

(0.4

6, 1

.79)

Rac

e0.

188

%

His

pani

c10

%15

%8%

1.88

(0.7

7, 4

.60)

%

Bla

ck9%

5%10

%0.

54(0

.17,

1.7

1)

%

Cau

casi

an81

%80

%82

%1

Ref

Co-

mor

bidi

ties

% D

iabe

tes m

ellit

us26

%28

%25

%0.

601.

19(0

.63,

2.2

5)

B

MI (

kg/m

2 )29

.8 (4

.5)

29.5

(4.4

)30

(4.6

)0.

440.

94(0

.80,

1.1

0)

%

Tru

ncal

obe

sity

50%

47%

52%

0.52

0.83

(0.4

7, 1

.47)

%

Cur

rent

smok

er26

%30

%24

%0.

331.

38(0

.73,

2.6

0)

To

tal l

ifetim

e dr

inks

2011

3 (3

6096

)25

283

(525

92)

1730

0 (2

2336

)0.

155

1.00

(1.0

0, 1

.00)

% B

asel

ine

NSA

ID/

Cox

-2 In

hibi

tor

4%3%

4%0.

540.

60(0

.12,

3.0

6)

% B

-Blo

cker

at

base

line

15%

19%

13%

0.28

1.53

(0.7

1, 3

.29)

% S

tatin

s at b

asel

ine

1%0%

1.5%

0.54

NA


NIH


NIH


NIH



Cha

ract

eris

ticA

ll pa

tient

sN

=210

Var

icea

lpr

ogre

ssor

sn=

74

Non

-pr

ogre

ssor

sn=

136

p-va

lue

*O

R (9

5% C

I)

HC

V p

aram

eter

s

Prio

r HA

LT-C

stat

us0.

28

%

Non

-res

pond

er63

%69

%60

%1.

29(0

.67,

2.5

1)

%

Bre

akth

ru/re

laps

e11

%7%

13%

0.57

(0.1

8, 1

.79)

%

Exp

ress

26%

24%

27%

1 R

ef

Log

HC

V R

NA

(IU

/ml)

% H

CV

gen

otyp

e 1

93%

97%

90%

0.08

63.

78(0

.83,

17.

24)

Lab

orat

ory

para

met

ers

Hem

oglo

bin

(g/d

l)15

.1 (1

.4)

14.8

(1.4

)15

.2 (1

.4)

0.06

80.

83(0

.67,

1.0

1)

Seru

m A

ST/A

LT0.

94 (0

.3)

1.03

(0.3

)0.

89 (0

.3)

0.00

145.

19(1

.87,

14.2

7)

Alk

pho

s rat

io (U

LN)

0.87

(0.4

)0.

92 (0

.4)

0.84

(0.4

)0.

189

1.65

(0.7

8, 3

.50)

Tota

l bili

rubi

n (m

g/dl

)0.

97 (0

.5)

1.10

(0.5

)0.

90 (0

.5)

0.00

652.

25(1

.26,

4.0

4)

INR

0.08

11

%

> 1

.060

%68

%55

%1.

69(0

.94,

3.0

6)

%

≤ 1

.040

%32

%45

%

Alb

umin

(g/d

l)3.

8 (0

.5)

3.7

(0.4

)3.

8 (0

.5)

0.04

870.

52(0

.27,

1.0

0)

Plat

elet

s (10

3 /ml)

132.

5 (6

0.7)

107.

8 (4

4.1)

146.

0 (6

4.3)

<0.0

001

0.24

(0.1

2, 0

.47)


NIH


NIH


NIH



Cha

ract

eris

ticA

ll pa

tient

sN

=210

Var

icea

lpr

ogre

ssor

sn=

74

Non

-pr

ogre

ssor

sn=

136

p-va

lue

*O

R (9

5% C

I)

Tota

l Bile

aci

ds(u

mol

/L)

22.4

(22)

26.7

(23.

7)20

.2 (2

0.8)

0.05

241.

01(1

.00,

1.0

3)

HO

MA

-IR

20.6

(29.

8)25

.8 (3

3.6)

17.6

(27.

2)0.

116

1.01

(1.0

0, 1

.02)

Log

HA

(ng/

ml)

2.18

(0.5

)2.

37 (0

.4)

2.09

(0.5

)<0

.000

12.

12(1

.47,

3.0

7)

% S

plen

omeg

aly

onul

traso

und

49%

62%

42%

0.00

622.

28(1

.26,

4.1

2)

Bas

elin

e E

ndos

copy

% G

astri

c va

rices

10%

29%

3%<0

.000

113

.2(4

.17,

41.

74)

Esop

hage

al v

arix

size

0.30

%

Gra

de 1

76%

70%

79%

1.03

(0.2

5, 4

.14)

%

Gra

de 2

19%

25%

16%

1.80

(0.4

1, 8

.03)

%

Gra

de 3

5%5%

5%1

Ref

Bas

elin

e H

isto

logy

% C

irrho

sis (

Isha

k5/

6)64

%78

%56

%0.

0015

2.86

(1.5

0, 5

.48)

Mea

n H

AI B

asel

ine

7.90

(2)

8.07

(2.1

)7.

82 (2

)0.

391.

06(0

.92,

1.2

3)

% H

epat

ic st

eato

sis ≥

240

%31

%46

%0.

0420

0.54

(0.3

0, 0

.98)

% M

allo

ry B

odie

s16

%14

%18

%0.

440.

73(0

.33,

1.6

2)

% Z

one

3 fib

rosi

s0.

40

065

%68

%64

%2.

43(0

.66,

8.9

8)


NIH


NIH


NIH



Cha

ract

eris

ticA

ll pa

tient

sN

=210

Var

icea

lpr

ogre

ssor

sn=

74

Non

-pr

ogre

ssor

sn=

136

p-va

lue

*O

R (9

5% C

I)

127

%28

%26

%2.

50(0

.63,

9.8

8)

28%

4%10

%1

Ref

Ran

dom

ized

pha

se

% P

egin

terf

eron

arm

47%

41%

51%

0.15

840.

66(0

.37,

1.1

7)

% C

linic

al o

utco

me

27%

49%

15%

<0.

0001

5.50

(2.8

5, 1

0.61

)

% T

wo-

poin

t inc

reas

ein

Isha

k fib

rosi

s sco

re40

%69

%32

%0.

0119

4.64

(1.4

0, 1

5.39

)

Dat

a re

porte

d as

mea

n +

std

dev

or %

* com

parin

g de

nov

o vs

non

-pro

gres

sors


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