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The incidence of liver disease progression among subjects with histologically advanced but compensated, chronic hepatitis C is incomplete.
The Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial was a randomized study of 3.5 years of maintenance peginterferon treatment on liver disease progression among patients who had not cleared virus on peginterferon and ribavirin therapy. Patients were followed subsequently off therapy. Because maintenance peginterferon treatment did not alter liver disease progression, we analyzed treated and control patients together. Among 1,050 subjects (60% advanced fibrosis, 40% cirrhosis), we determined the rate of progression to cirrhosis over 4 years and of clinical outcomes over 8 years.
Among patients with fibrosis, the incidence of cirrhosis was 9.9% per year. 679 clinical outcomes occurred among 329 subjects. Initial clinical outcomes occurred more frequently among subjects with cirrhosis (7.5%/year) than with fibrosis (3.3%/year) (P <0.0001). Child-Turcotte-Pugh (CTP) ≥7 was the most common first outcome, followed by hepatocellular carcinoma. Following occurrence of a score CTP ≥7, the rate of subsequent events increased to 12.9%/year, including a death rate of 10%/year. Age and sex did not influence outcome rates. Baseline platelet count was a strong predictor of all clinical outcomes. During the 8 years of follow-up, death or liver transplantation occurred among 12.2% of patients with advanced fibrosis and 31.5% of those with cirrhosis.
Among patients with advanced hepatitis C who failed peginterferon and ribavirin, the rate of liver-related outcomes, including death and liver transplantation, is high, especially once CTP reaches at least 7.
Most published data on the rate of progression of chronic hepatitis C, except after transfusion-associated “non-A, non-B hepatitis,”1 have been derived from single center studies, which were often small and lacked protocol-driven systematic data collection.1–10 Based on such reports, the annual incidence of progression to hepatic decompensation in compensated cirrhosis has been estimated to be approximately 6% (range 4–8%).
In the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial,11, 12 we enrolled 1,050 patients with histologically advanced chronic hepatitis C who had failed to achieve a sustained virological response (SVR) with peginterferon-ribavirin therapy; subjects were assigned randomly to receive low-dose peginterferon alfa-2a (90 μg/week) or no further treatment for 3.5 years.11 Because the treated and untreated-control groups experienced similar rates of clinical progression,12 the combined HALT-C Trial cohort provided a unique opportunity to determine rates of clinical progression in a large, prospectively followed population with histologically advanced, compensated chronic hepatitis C. Extension of the study beyond the 3.5-year randomized-treatment phase for up to 8 years provided the opportunity to characterize prospectively the course of advanced chronic hepatitis C more comprehensively than has been possible heretofore. In this paper, we describe the frequency and temporal development of the major clinical outcomes of hepatic decompensation. We also describe the sequential emergence of laboratory changes associated with hepatic dysfunction and their relationship to clinical outcomes.
The design of the HALT-C Trial (ClinicalTrials.gov number NCT00006164) and results of this randomized trial of peginterferon maintenance therapy were described previously.11, 12 To be eligible for the trial, adult patients with chronic hepatitis C had to have failed to achieve a sustained virologic response after a course of at least 12 weeks of interferon-based therapy and have advanced bridging fibrosis (Ishak fibrosis stage 3–4) or cirrhosis (stage 5–6) on a baseline liver biopsy within 12 months prior to enrollment. Potential subjects were excluded for a platelet count <50,000/mm3, absolute neutrophil count <1,000/mm3, hematocrit <33%, alpha-fetoprotein >200 ng/mL, Child-Turcotte-Pugh (CTP) score ≥7, or a history of decompensated liver disease or hepatocellular carcinoma (HCC). Patients with other causes of liver disease, uncontrolled co-morbid medical (including malignancies, autoimmune disorders, and immunocompromised states) or psychiatric illnesses, or contraindications to interferon were excluded, as were pregnant or breast-feeding women.
Potential participants in the HALT-C Trial were treated in a lead-in phase with pegylated interferon alfa-2a (180 μg subcutaneously weekly) and ribavirin (1,000–1,200 mg daily);13 those who failed to clear HCV RNA by Week 20, categorized as nonresponders,11, 12 were randomized to 3.5 years of 90 μg/week of pegylated interferon alfa-2a or to an untreated control group. Subjects with undetectable HCV RNA at treatment Week 20 were categorized as responders and received combination treatment for 48 weeks. Responders with detectable HCV RNA after Week 20 (breakthrough or relapsers) were also eligible for randomization. In addition, patients failing to achieve a sustained virologic response (SVR) following pegylated interferon and ribavirin administered outside the HALT-C Trial were also eligible for randomization. Of 1,730 screened subjects, 1,050 were randomized.12 Study subjects were seen in one of 10 clinical centers at 3-month intervals through month 48 and every 6 months thereafter until October, 2009.
Protocol-defined clinical outcomes included a CTP score of ≥7 on two consecutive study visits 3 months apart (6 months apart in the post-randomization phase); variceal hemorrhage, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, definite HCC, or death either related or unrelated to liver disease. For this analysis we also included liver transplantation and presumed HCC as clinical outcomes. In addition to individual clinical outcomes, we defined three groups of clinical outcome. “Any clinical outcome” was the definition used in the original HALT-C Trial protocol and included death from any cause, presumed or definite HCC, variceal hemorrhage, ascites, spontaneous bacterial peritonitis or hepatic encephalopathy. “Decompensated liver disease” was defined as variceal hemorrhage, ascites, spontaneous bacterial peritonitis or hepatic encephalopathy. “HCC/Decompensation” was defined as presumed or definite HCC, as defined previously,14 or decompensated liver disease. Protocol biopsies were performed at approximately 2 and 4 years after enrollment
The stage of histologic fibrosis was interpreted according to the Ishak score by consensus face-to-face vote of the 10 study-site pathologists and a coordinating pathologist. For subjects in the fibrosis stratum, progression to cirrhosis (Ishak fibrosis stage 5 or 6) was determined. A rotating group of HALT-C Trial investigators, masked as to identity of subject, study site, and randomization group, reviewed every clinical outcome to determine whether it met predefined criteria. In addition, after completion of the study, a “mortality committee” reviewed every death prior to December 31, 2008, again with masking of subject, site, and randomization group, and classified the death as liver-related or unrelated, based on predefined criteria.15 For deaths that occurred between January 1, 2009 and October 31, 2009, the clinical site principal investigator determined whether or not the death was liver-related. If the cause was unknown, the death was counted as non-liver-related. Three hundred and twenty-nine patients (31%) had an outcome, 197 were followed for ≥7 years without an outcome, and 298 were followed for <7 years without an outcome but were seen in the last 6 months of the trial, which represented 79% of the study cohort. Analysis of liver transplant and liver related death was also included in the current analysis.
Because laboratory data were collected at uniform intervals, we evaluated the rate of progression of laboratory markers of liver-disease progression. Prior to analyzing laboratory data, we selected the laboratory thresholds in the CTP score (albumin ≤3.5 g/dL, total serum bilirubin ≥2.0 mg/dL, international normalized ratio [INR] ≥1.7), as well as creatinine ≥1.2 mg/dL, and platelet count <100,000/mm3. We also used MELD score16 of ≥15.
Statistical analyses were performed at the Data Coordinating Center (New England Research Institutes, Watertown, MA) with SAS (release 9.1) software. Time to outcomes was measured as the number of months or years from randomization to the date of the initial clinical outcome. For analyses with the initial events after CTP score ≥7, we computed time from the date of the CTP elevation to the date of the initial clinical outcome event after the CTP elevation. For comparison of time to clinical and laboratory outcomes between the fibrosis and cirrhosis strata, we performed Kaplan-Meier life-table analyses and applied the log-rank test. Cox proportional hazards models were used to estimate the relative risks of clinical outcomes. Because outcomes occurred at relatively linear rates, they are reported as annualized rates. Outcomes were counted if they occurred within 8.0 years of randomization and before October 20, 2009. Other than death, clinical outcomes that occurred after liver transplantation were not counted. Annualized rates of cirrhosis development were extrapolated from the two and four year biopsy results.
The HALT-C Trial was approved by institutional review boards at each participating site; all patients provided written informed consent before participating in the trial.
In the HALT-C Trial,12 1,050 study patients—622 (60%) with noncirrhotic fibrosis (Ishak stages 3–4) and 428 (40%) with cirrhosis (Ishak stages 5–6)—were randomized to maintenance treatment or to an untreated control group for 3.5 years and followed after the randomized phase of the trial for up to an additional 5 years. The median duration of participation in the trial (time from randomization to first outcome or last time known to be outcome-free) was 6.0 (range 0–8.7) years. Baseline characteristics of study subjects included mean age 51 years, 71% male, 8.2% African-American, estimated mean duration of HCV infection 28 years, and mean body-mass index (BMI) 30 kg/m2. At baseline, levels of serum alanine aminotransferase were elevated in 83% (mean 2.1 × the upper limit of normal), and mean serum HCV RNA was 6.4 log10 IU/mL. Baseline mean serum total bilirubin (0.8 mg/dL), albumin (3.9 g/dL), and prothrombin time (international normalized ratio, 1.04) were normal.12 Mean platelet count was 165,000/mm3; 44.4% of patients had a platelet count <150,000/mm3.
In the fibrosis stratum, 235 clinical outcomes occurred in 122 patients with an 8-year cumulative incidence of first outcome of 28.8% and annualized rate of 3.6% (Figure 1). In the cirrhosis stratum, 444 clinical outcomes occurred in 207 patients with an 8-year cumulative rate of 60.6% and annualized rate of 7.6% (difference between strata, log-rank test, P <0.0001). Among cirrhotics, the time to first clinical outcome (non liver-related deaths excluded) occurred at a constant rate throughout the 8-year study period. Among the fibrosis group, first outcomes occurred infrequently during the first year but, thereafter, also occurred at a constant, albeit lower, rate. Overall, the rate of initial outcomes was similar among patients assigned to peginterferon (5.2% per year) as the control group (5.3% per year, P = 0.88); however, the annual rate of initial outcomes was higher in the peginterferon group than in the control group among patients in the fibrosis stratum (4.4% versus 2.9%, P = 0.04) and slightly lower in the peginterferon group than in the control group in the cirrhosis stratum (6.6% versus 8.4%, P = 0.08). In further analysis of time to first decompensation event (ignoring CTP ≥7), the rate of 1.9% per year among patients assigned to treatment was similar to the rate of 2.5% per year among the control group (P = 0.16). Because liver-related outcomes were not markedly influenced by maintenance peginterferon therapy, we combined the peginterferon group and the control group for this analysis. Furthermore, because outcomes occurred at a nearly linear rate over the 8 years of study, we estimated the annual incidence of individual clinical outcomes.
Among the clinical events that constituted outcomes in this analysis, the most frequent first outcome was CTP ≥7; followed by HCC (including presumed HCC), death (including those unrelated to liver disease), and ascites (Table 1). During the period of observation, CTP ≥7, death (including those unrelated to liver disease), ascites, and HCC were the most common outcomes experienced by patients.
Among patients with baseline fibrosis, 109 progressed to cirrhosis at month 24 and a further 69 had cirrhosis at month 48 (annualized rate of progression to cirrhosis 9.9%) (Table 2). The observed 8-year and calculated annualized incidences of each clinical outcome were 3 to 4-fold more frequent in the cirrhosis stratum than in the fibrosis stratum (Table 2). Once CTP rose to ≥7, patients with bridging fibrosis at baseline did not differ from those with cirrhosis at baseline in the rate of subsequent outcomes. Of 137 study patients with CTP ≥7 as the first clinical outcome, 93 (69%) had a subsequent clinical outcome after a median time of 11 months; liver-related death or liver transplantation was the most frequent event after a CTP ≥7, followed by clinical decompensation and ascites (Table 2). Demographic features did not influence outcome rates; the annualized incidence of outcomes, including progression to cirrhosis, did not differ between men and women or between patients younger versus older than 50 years (P >0.05) (Table 3). There were too few non-whites or Hispanics to perform meaningful analyses of individual outcomes by ethnic group.
A total of 138 deaths were observed during the study (i.e., through October 20, 2009), 82 (59%) of which were liver-related. After the first 1–2 years of observation, we observed a linear increase in all-cause death and liver-related death for the entire HALT-C Trial population (Figure 2a). The cumulative incidence of all deaths and of liver-related deaths or transplantation was higher among cirrhotic patients compared to noncirrhotic patients (Figure 2b). Following the development of a CTP score ≥7 (Figure 2c) or a decompensation event (Figure 2d), nearly all deaths were liver-related.
At baseline, the prevalence of hypoalbuminemia, thrombocytopenia, and hyperbilirubinemia was higher among patients with cirrhosis than those without cirrhosis (Figure 3a and 3b). The cumulative 8-year incidence of abnormal levels was higher in the cirrhosis stratum than the fibrosis stratum for all laboratory markers, except elevated creatinine, which was comparable in both strata (Figure 3a and 3b). During the observation period, reductions in albumin and in platelet count occurred earlier and more frequently than abnormalities in the other laboratory markers measured.
Low platelet count was shown previously to be the best predictor of overall outcomes in the randomized phase of the HALT-C Trial (through 3.5 years), irrespective of stage of fibrosis.17 With further observation, we found that the baseline platelet count was associated closely with the annual rate of initial clinical decompensation. The annualized incidence of each clinical outcome increased over decreasing ranges of platelet counts from ≥200,000/mm3 to <100,000/mm3 (Table 4). For example, patients with a platelet count <100,000/mm3 were 11-fold more likely to experience a decompensation event and 14-fold more likely to die a liver-related death or undergo liver transplantation, compared to subjects with a baseline platelet count ≥200,000/mm3.
Rates of outcomes were also evaluated according to baseline BMI, ALT activity, and serum HCV RNA. The annualized rate of cirrhosis was 8.9% for non-obese versus 11.3% for obese subjects (P = 0.07); 8.2% for ALT <90 IU/L versus 12.2% for ALT ≥90 IU/L (P = 0.001); and 11.1% for HCV RNA <6.5 log10 IU/mL versus 9.0% for HCV RNA ≥6.5 log10 IU/mL (P = 0.046). Rate of any clinical outcome was not associated with baseline obesity or with ALT activity (P ≥0.30) but was associated with lower HCV RNA level (P <0.0001). The association of outcomes with HCV RNA level was not adjusted for stage of fibrosis, which was strongly and inversely associated with HCV RNA level (P <0.0001).
Understanding the natural history of advanced hepatitis C has been challenging. Limitations in study design or execution of most, if not all, prior studies could have led to inaccurate results. No prior study had the rigor of the histological evaluation of the HALT-C Trial, in which three liver biopsies were performed and each biopsy was assessed by a team of 11 expert liver histopathologists who were masked to all patient information.11, 12 Additionally, few if any prior studies had uniform monitoring of patients at regular intervals and predefined case definitions, whereas patients in the HALT-C Trial were evaluated every 3 to 6 months throughout the study, and all outcomes were reviewed independently by experienced hepatologists. Furthermore, all patients in the HALT-C Trial had failed to clear hepatitis C virus (HCV) during peginterferon and ribavirin therapy, whereas, in several other studies, progression was evaluated in patient cohorts, only subsets of whom were treated, and in whom selection for therapy was not based on uniform criteria.
For the HALT-C Trial, our hypothesis was that 3.5 years of maintenance, low-dose [90 μg/week] peginterferon therapy would retard the progression of chronic hepatitis C in patients with advanced fibrosis; unfortunately, maintenance therapy was found to be ineffective. Because clinical outcome rates were either indistinguishable between treated and control patients or were inconsistently different (higher mortality among treated patients with noncirrhotic fibrosis and lower incidence of HCC among treated patients with cirrhosis), we pooled the two groups for an analysis of the rate of progression of chronic hepatitis C. We followed the combined cohort of >1,000 patients with clinically compensated advanced fibrosis or cirrhosis, both during the randomized (maintenance versus control) phase and the postrandomization phase for up to 8 (median 5.6) years. Thus, this is the single largest, prospective study of clinical and laboratory progression among patients with chronic hepatitis C and advanced fibrosis; one of the longest followed cohorts; and the only sizable study of an American cohort, most previous reports having focused on European and Japanese populations.2, 6–9, 18
Presented in this paper are the incident rates of clinically meaningful outcomes for patients at three stages of advanced liver disease: advanced noncirrhotic fibrosis, compensated cirrhosis, and decompensated cirrhosis (CTP ≥7). The observed annual rates of all-cause mortality and liver transplantation were 2.2% in patients with noncirrhotic fibrosis and 5.3% in those with cirrhosis, similar to rates reported in European and Japanese studies. As anticipated, the rate of clinical outcomes (especially CTP score elevation and variceal hemorrhage) was higher among patients with cirrhosis at baseline than those with noncirrhotic fibrosis. Among patients with noncirrhotic fibrosis, the annual incidence of initial clinical outcomes ranged from 0.25% per year for variceal hemorrhage to 1.4% per year for CTP elevation; of note, these outcomes of end-stage liver disease (including HCC and liver-related death) occurred in the absence of documented cirrhosis at entry into the HALT-C Trial, although we cannot exclude the possibility that some patients may have been understaged at entry or progressed to cirrhosis by the time they developed an outcome. For patients with histological cirrhosis at entry into the HALT-C Trial, the annual incidence of clinical outcomes ranged from 0.9% per year for variceal hemorrhage to 5.0% per year for CTP elevation. Among individual clinical outcomes, the most frequent initial decompensation event was an increase in CTP score to ≥7. Once the CTP became elevated, the incidence of second clinical events was indistinguishable between subjects in the fibrosis and cirrhosis strata. Thereafter, morbidity and mortality rates increased substantially, confirming the value of a rise in CTP score as an ominous prognostic sign.
Findings among HALT-C Trial patients with noncirrhotic fibrosis and cirrhosis can be compared to estimates drawn from other studies. Based on the readings from three liver biopsies over approximately 4 years, HALT-C Trial patients with bridging fibrosis had an annual incidence of cirrhosis of 9.9% per year, a rate that differed little with gender or age and that was comparable to an estimated annual incidence of 11.5% derived from a meta-analysis conducted in 2007.19 Our directly observed, empirical results differ from those in a recent modeling projection in which an approximate fourfold difference in progression to cirrhosis was assumed between younger women and older men.20 A potential explanation for the lack of an effect of gender and age on disease progression in our study may be that once advanced liver disease has developed, age and gender may no longer influence disease progression. In a recent systematic overview of outcomes among patients with HCV-related compensated cirrhosis, information was summarized from 13 cohort studies, 8 from Western Europe, 4 from Japan, and 1 from the United States.21 The 5.3% per year rate of death or transplantation in cirrhotics from the current study is well within the reported range of 2.7%–6.7%, and the 2.4% per year rate of HCC is at the lower end of the reported range of 1.8%–7.1%. For HCC, the highest reported rates came from Japan.
In addition to studying the occurrence of clinical events, we monitored the development of laboratory abnormalities that are associated with deteriorating liver function. Hypoalbuminemia and thrombocytopenia were common at study entry, but their occurrence rates and those of other laboratory abnormalities were relatively linear over the 8 years of observation. The MELD score, based on serum bilirubin, creatinine and INR/prothrombin time, determines priority for liver transplantation in the United States, with a minimum score of 15 for a patient to be considered for transplantation. Among patients with fibrosis, the rate of development of a MELD score ≥15 was low; the 8-year cumulative incidence was ~8%. Among cirrhotic patients, the 8-year cumulative incidence was higher, ~21%. These calculations do not include the MELD score upgrade for patients with HCC, who constituted nearly half of the patients in the HALT-C Trial cohort who underwent transplantation. We demonstrated previously that thrombocytopenia was a strong predictor of progressive liver disease,17 which was confirmed in this analysis with longer follow-up. Outcome rates varied many fold with progressively lower platelet counts (Table 4). Given the high rate of clinical events among patients with thrombocytopenia, it is particularly concerning that thrombocytopenia developed among approximately 40% of patients with fibrosis and 80% of patients with cirrhosis during the 8 years of observation (Figure 3). Such information could be especially useful in predicting prognosis in the absence of liver biopsy.
The major strength of this report is that it represents the largest prospective study of the progression of chronic hepatitis C and one of the only such studies conducted in the United States. Although derived from a large, multicenter study, these results would not necessarily apply to all patients with advanced hepatitis C. Study patients had to meet the stringent inclusion and exclusion criteria for the clinical trial. They could not have other causes for liver diseases, they were not injection drug users or excessive alcohol consumers at the time of enrollment, they demonstrated a the motivation and ability to tolerate long-term peginterferon therapy, and they had failed to clear HCV on standard doses of peginterferon and ribavirin. While patients in the HALT-C Trial might represent a nonrepresentative sample of current patients with HCV infection and histologically advanced liver disease, they are fairly representative of the types of patients clinicians will encounter increasingly. With the wide availability and application of antiviral therapy, many patients with advanced fibrosis who will be monitored clinically are those who have already failed a course of antiviral therapy and who do not have good treatment options for prevention of liver-disease progression. In an era of antiviral therapy, studies of the true, intervention-free natural history of chronic hepatitis C can no longer be done, and our data, reflective of a more relevant patient demographic, will provide clinical guidance most applicable to the emerging patient population.
The other strengths of this report are the rigor of data collection and the breadth of the predefined outcomes. All patients met clearly defined enrollment criteria, including a biopsy that demonstrated histologically advanced liver disease and that excluded other causes of severe disease. We are not aware of reports of other patient populations in which the progression of disease was documented for the three groups of patients included in the current study: those with precirrhotic fibrosis, compensated cirrhosis, and early decompensated liver disease. Serial liver biopsies were obtained from the large majority of patients and read centrally by expert histopathologists. Patients attended protocol-driven, regularly scheduled appointments, during which the presence and absence of each clinical outcome was determined. Finally, all clinical outcomes were confirmed by an independent panel of study hepatologists.
In conclusion, we have documented the rate of development of histologically defined cirrhosis in patients with chronic hepatitis C and advanced fibrosis as well as the incidence of clinically meaningful outcomes among patients with noncirrhotic fibrosis, cirrhosis, and early decompensated liver disease. Moreover, we demonstrated the rates at which laboratory abnormalities developed as well as the relationship of platelet count to outcome rate. Such data should be helpful in guiding physicians who follow patients with histologically advanced chronic hepatitis C, preparing them for what outcomes to anticipate and at what annual incidence.
This study was supported by the National Institute of Diabetes & Digestive & Kidney Diseases (contract numbers are listed 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 Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed below). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc. (now Genentech), through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health.
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) Barbara F. Banner, MD, Maureen Cormier, RN, Donna Giansiracusa, RN
University of Connecticut Health Center, Farmington, CT: (Grant M01RR-06192) Gloria Borders, RN, Michelle Kelley, RN, ANP
Saint Louis University School of Medicine, St Louis, MO: (Contract N01-DK-9-2324) 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 UL1 RR025758-01, Harvard Clinical and Translational Science Center) Raymond T. Chung, MD, Andrea E. Reid, MD, Atul K. Bhan, MD, Wallis A. Molchen, David P. Lundmark
University of Colorado Denver, School of Medicine, Aurora, CO: (Contract N01-DK-9-2327, Grant M01RR-00051, Grant 1 UL1 RR 025780-01) Thomas Trouillot, MD, Marcelo Kugelmas, MD, S. Russell Nash, MD, Jennifer DeSanto, RN, Carol McKinley, RN
University of California - Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827) 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, Grant M01RR-00633, Grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational Science Initiative) 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) 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) Robert J. Fontana, 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, Grant M01RR-00065) Mitchell L. Shiffman, 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 of Health, 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: Patricia R. Robuck, PhD, Jay H. Hoofnagle, MD
University of Washington, Seattle, WA: (Contract N01-DK-9-2318) David R. Gretch, MD, PhD, Minjun Chung Apodaca, BS, ASCP, Rohit Shankar, BC, ASCP, Natalia Antonov, M. Ed.
New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328) Kristin K. Snow, MSc, ScD, Margaret C. Bell, MS, MPH, Teresa M. Curto, MSW, MPH,
Inova Fairfax Hospital, Falls Church, VA: Zachary D. Goodman, MD, PhD, Fanny Monge, Michelle Parks
Data and Safety Monitoring Board Members: (Chair) Gary L. Davis, MD, Guadalupe Garcia-Tsao, MD, Michael Kutner, PhD, Stanley M. Lemon, MD, Robert P. Perrillo, MD
*The HALT-C Trial was registered with clinicaltrials.gov (#NCT00006164).
This work was presented in part by one of us (HLB) [Dienstag et al, Abstract #237, Digestive Diseases Week, May 2, 2010, New Orleans, LA]and published in abstract form [Gastroenterology 2010;138(Suppl 1):S-780-S-781].
Financial relationships of the authors with Hoffmann-La Roche, Inc. (now Genentech), are as follows: T. R. Morgan receives research support; A. M. Di Bisceglie is a consultant and receives research support; G. Szabo receives research support; R. K. Sterling is a consultant and receives research support; G. T. Everson is a consultant and receives research support; K. L. Lindsay was a consultant and received research support from Hoffmann-La Roche, Inc. (now Genentech), during this study and is now an employee of Tibotec, Inc. (a subsidiary of Johnson and Johnson), Titusville, NJ; W. M. Lee receives research support; and A. S. Lok is a consultant.
Authors with no financial relationships related to this project are: J. L. Dienstag, M. G. Ghany, H. L. Bonkovsky, H.-Y. Kim, L. B. Seeff, E. C. Wright, C. Morishima, A. M. Stoddard, and J .E. Everhart.