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We assessed the effects of long-term peginterferon therapy and disease progression on health-related quality of life (HRQOL), symptoms, and sexual health in patients with chronic hepatitis C (CHC) and advanced fibrosis or cirrhosis.
517 HALT-C Trial patients received peginterferon alfa-2a (90 μg/week); 532 received no additional treatment for 3.5 years. Patients were followed for outcomes of death, hepatocellular carcinoma and hepatic decompensation. Sexual health, SF-36 scores, and symptoms were serially assessed by repeated measures analyses of covariance.
Patients with cirrhosis (n=427) reported lower general well-being and more fatigue (p<0.001) than patients with fibrosis (n=622). Physical scores declined significantly over time, independent of treatment, and patients with cirrhosis reported lower scores. Vitality scores were lower in those with cirrhosis, and treated patients experienced a greater decline over time than untreated patients; HRQOL rebounded after treatment ended. Patients with a clinical outcome had significantly greater declines in all SF-36 and symptom scores. Among men, sexual health scores were significantly worse in treated patients and in those with a clinical outcome.
Clinical progression of CHC and maintenance peginterferon therapy led to worsening of symptoms, HRQOL, and, in men, sexual health in a large patient cohort followed over 4 years.
Chronic hepatitis C (CHC) is a leading cause of chronic liver disease, liver failure, and hepatocellular carcinoma (HCC) in the United States and other Western countries 1. Among the estimated 3.2 million adult Americans infected chronically with hepatitis C virus (HCV), many are unaware of their infections because they lack clinically apparent signs or symptoms 2. With disease progression, however, patients may experience various nonspecific symptoms such as fatigue, nausea, and right upper quadrant pain 3–6. In addition, many patients with CHC report reduced quality of life although the relationship to disease severity is modest and at times inconsistent 7–13. The weak correlation of liver disease severity and clinical symptoms with quality of life in patients with CHC may result, in part, from the influence of other commonly encountered medical and psychiatric comorbidities, such as diabetes mellitus and depression 14, 15.
Several longitudinal studies of interferon therapy in patients with CHC have shown improvements in health-related quality of life (HRQOL) in patients able to achieve a sustained virological response compared to nonresponders and relapsers 10, 11, 16–35. Whether these improvements resulted from a sustained loss of viral replication or from the psychological improvement following the cure of a chronic disease and an improvement in prognosis is unknown. Because of the slow rate of disease progression and the resultant need to follow a large number of patients prospectively for several years, none of these studies demonstrated an association between objective disease progression and worsening symptoms or HRQOL. Sexual dysfunction associated with CHC has also been reported 36, 37, but the relationship between sexual dysfunction and disease severity or progression has not been well defined. Furthermore, psychological concerns about harboring an infectious disease that can be transmitted to others may influence sexual health parameters in patients with CHC.
Recently, the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial demonstrated that maintenance peginterferon therapy did not reduce the rate of clinical or histological disease progression in patients with CHC and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin 38. During the trial, prospective assessment of symptoms and HRQOL was incorporated as a planned secondary outcome. We hypothesized that, because of the side-effect profile of interferon therapy, prolonged treatment with low-dose peginterferon would be difficult to tolerate and therefore associated with worsening fatigue, reduced general well being, and reductions in HRQOL. In addition, we set out to measure the impact of maintenance peginterferon therapy on sexual health. We have previously shown that 1) HALT-C participants with cirrhosis had lower HRQOL scores than participants with noncirrhotic fibrosis at entry into the study and 2) HALT-C participants who achieved a sustained virologic response (SVR) after peginterferon/ribavirin therapy had improved HRQOL and sexual health scores 22. The current analyses summarize the results of the assessment of symptoms, HRQOL, and sexual enjoyment, desire, and function before, during, and after the randomized phase of the trial, focusing on the effects of low-dose peginterferon therapy and disease progression.
The design of the HALT-C Trial and its major outcomes have been described previously 38, 39. Briefly, patients with CHC and advanced fibrosis, with or without cirrhosis, who had failed to respond to a previous course of antiviral therapy, were enrolled into the trial at 10 study centers in the United States. Enrollment criteria included age of 18 years or older; the presence of HCV RNA in serum; failure to achieve an SVR with a previous adequate course of combination antiviral therapy; advanced hepatic fibrosis on liver biopsy [Ishak stage ≥3 fibrosis 40] stratified into a noncirrhotic fibrosis group (stage 3 or 4) and a cirrhosis group (stage 5 or 6); no history of hepatic decompensation or HCC; and the absence of various exclusion criteria including uncontrolled medical or psychiatric conditions, interferon intolerance, and active use of illicit drugs or alcohol abuse 39.
After baseline evaluation, patients were retreated during a “lead-in” phase with peginterferon alfa-2a (180 μg weekly: Pegasys™: Roche Pharmaceuticals, Nutley, NJ) and ribavirin (1,000 to 1,200 mg daily: Copegus™: Roche). Patients with detectable serum HCV RNA levels at week 20 were classified as nonresponders and were randomized at week 24 into either the maintenance-therapy group (90 μg of peginterferon alfa-2a weekly without ribavirin) or the untreated control group. Patients with undetectable serum HCV RNA at week 20 continued therapy for 48 weeks 41. If HCV RNA was detected again after week 20, either during treatment (breakthrough) or after cessation of treatment (relapse), the patient was offered the opportunity to undergo randomization into the HALT-C Trial (“breakthrough or relapse” cohort). During the trial, the protocol was amended to allow patients who had failed treatment with peginterferon plus ribavirin outside of the study to undergo randomization (“express” cohort). Treatment ceased per protocol at study month 48.
Primary clinical outcomes included: death, hepatic decompensation (variceal hemorrhage, ascites, spontaneous bacterial peritonitis, or hepatic encephalopathy); HCC; a Child-Turcotte-Pugh (CTP) score 42 of ≥7 on two consecutive study visits; and, for patients with noncirrhotic fibrosis at baseline, an increase in the Ishak fibrosis score of ≥2 points according to assessment of liver-biopsy specimens obtained during the study.
During the randomized phase of the trial, patients were seen every 3 months to obtain a medical history, physical examination, and laboratory testing to monitor the effects of peginterferon therapy and to assess for clinical endpoints and adverse events. The patients underwent hepatic ultrasound every 12 months to screen for HCC, as well as liver biopsy at baseline and study months 24 and 48. After trial completion at study month 48, patients were followed at six month intervals. The study was approved by local institutional review boards and all patients provided written informed consent.
To measure HRQOL, we administered the highly reliable and validated Short Form Health Survey (SF-36) 43 at annual study visits. The SF-36 Physical and Mental Summary scales (0=worst; 100=best) (25) are standardized around a population mean score of 50. Observed differences of 3 points or greater on the measured scales are considered clinically significant 44. Three questions that addressed self-reported sexual satisfaction and enjoyment, desire and interest, and functioning and performance were added to the SF-36 (see Appendix 1). The composite Sexual Health scale was calculated as the mean of completed items in the scale (0=worst; 100=best) and was not adjusted to reflect a population mean 22.
We asked study patients to rank their clinical symptoms on a self-administered 10 cm visual analogue scale, with the score equaling the measured distance from the 0 cm left mark (see Appendix 1) 45. For these analyses, we analyzed the baseline and annual symptom scores for fatigue (none = 0 cm to worst ever = 10 cm) and general well-being (“how you feel overall”, very good = 0 cm to very bad = 10 cm).
Statistical analyses were performed at the Data Coordinating Center (New England Research Institutes, Watertown, MA) with SAS software, version 9.1 (SAS Institute, Cary, NC, USA). 1,049 of the 1,050 randomized patients with complete baseline data were analyzed. There were six response variables: two symptom scores, three SF-36 scales, and the Sexual Health scale. The response variables were assessed at study months 0 (baseline), trial months 12, 24, 36, 48, and study month 54 (6 months post-trial). Repeated measures analyses of covariance (ANCOVA) were used to investigate changes in each of the six response variables over time controlling for baseline level of the variable, stratum (cirrhosis/noncirrhotic fibrosis), randomization assignment (treatment/control), time, age, gender, and race as fixed effects. For any factors significantly associated with a response variable, we tested the interaction of that factor and time. The Conditional Model Concordance Correlation Coefficient was used for assessing the adequacy of each model 46; the coefficient can range from −1 to 1, and a value ≤0 indicates poor fit.
To evaluate the association of clinical and histologic outcomes with the response variables, we included a time varying covariate with two categories: whether or not patient met the definition of any outcome at or before the date of the visit at which the response variable was assessed. The patient’s first outcome (including death) was used for analyses. The covariate was added to each model as a predictor after controlling for stratum (cirrhosis/noncirrhotic fibrosis), randomization assignment, time, age, gender, race, and baseline level of the response variable. Patients lost to follow-up (including those who died) provided no information after the point they were lost. For analyses of histologic progression (≥2-point increase in Ishak fibrosis score), we analyzed only patients in the noncirrhotic fibrosis stratum with at least one follow-up biopsy. For the Sexual Health scale, separate analyses were done for males and females.
A flowchart of participants enrolled in the HALT-C Trial and the 1,049 with complete baseline data included in these analyses is shown in Figure 1. At entry, the mean age of the participants was 50.1 ± 7.2 years, 71% were male, and 72% were non-Hispanic whites (Table 1). One-third of participants (34%) were taking antidepressant or anxiolytic medications at baseline. Although most participants had previously used alcohol (83%) or smoked cigarettes (76%), few were still drinking (17%) or smoking (30%) at baseline. At baseline, 622 participants (59%) had noncirrhotic fibrosis (Ishak 3-4), and 427 (41%) had cirrhosis (Ishak 5-6). The mean body mass index was higher and HCV RNA levels were lower in participants with cirrhosis than in those with fibrosis, while the other clinical and demographic features were similar in the fibrosis and cirrhosis groups. No major differences were present at baseline between the treatment and control groups (data not shown).
Table 2 shows the slope coefficients derived from the final ANCOVA models for the association of each patient characteristic with the six response variables (symptoms, SF-36, and sexual health scores). None of the interaction effects of patient characteristics by time was statistically significant. Thus, each slope coefficient estimates the difference in the response variable at each value of the patient characteristic averaged over the entire time period. For categorical predictors (such as gender), the coefficient represents the difference between the average level of response variable in two groups. For continuous predictors (such as age), the coefficient represents the relationship of the average level of response variable to the average level of predictor. The Conditional Model Concordance Correlation Coefficient was consistent with adequate to good fit of each model. At Month 12, 21 participants had experienced a clinical outcome (2 in the fibrosis stratum and 19 in the cirrhosis stratum). At Month 54, 85 participants had experienced a clinical outcome (28 in the fibrosis stratum and 57 in the cirrhosis stratum).
At baseline, self-reported fatigue and general well-being scores were not significantly different in participants with fibrosis compared to those with cirrhosis (Table 1). General well-being fluctuated significantly over time (p=0.002) but on average, participants with fibrosis reported greater general well-being (0.21 units, p=0.04) than those with cirrhosis (Figure 2A). Although fatigue did not change significantly over time (p=0.93), participants with fibrosis reported less fatigue on average (−0.41 units, p=0.009) than those with cirrhosis (Figure 2B). Further, participants in whom a clinical outcome developed reported significantly lower general well-being (−0.52 units, p<0.001) and greater fatigue (0.60 units, p<0.001) compared to patients who did not develop an outcome. Assignment to the treatment or control group was not significantly associated with either fatigue or general well-being scores over time (Figure 2C).
At baseline, participants in the cirrhosis stratum had significantly lower scores on the SF-36 Physical Summary, Mental Summary, and Vitality scales compared to those in the fibrosis stratum (Table 1). Only the Physical Summary scores changed significantly over the course of the study (p=0.006). On average, participants with fibrosis reported higher Physical Summary scores than those with cirrhosis (1.04 points, p=0.02), but scores in both groups declined over time (Figure 3A). Further, the decline in Physical Summary scores was greater for persons who experienced a clinical outcome than for those who did not (−4.61 points, p<0.001). As shown in Figure 3B, participants with a clinical outcome also had a greater decline in the Mental Summary scores (−1.22 points, p=0.03) compared to patients without an outcome. Histological stratum was not significantly associated with Mental Summary scores. Participants who experienced a clinical outcome had a significantly greater decline in Vitality scores than those who did not (−3.92 points, p<0.001, Figure 3C). In addition, participants in the fibrosis stratum had higher Vitality scores than participants in the cirrhosis stratum (3.38 versus, p<0.001).
Vitality scores (Figure 3D) were significantly lower in participants assigned to the treatment group compared to control participants (−2.88 points, p=0.002); after therapy was stopped at month 48, Vitality scores rebounded back to baseline levels and to level in the control group. Also, we detected a trend towards lower Physical Summary scores in the treatment group compared to the control group (−0.84 points, p=0.06); however, treatment/control assignment was not significantly associated with Mental Summary scores (Figure 3E).
Supplemental Figure 1 provides information on the changes from baseline to 3.5 years by gender and treatment group in sexual enjoyment, desire, and function questions (Appendix 1). In general, approximately half of patients reported no change over the course of the study. Compared to control patients, a greater percentage of treated patients reported a decline over time in sexual enjoyment (Figure 2a: 35% vs 24% for males and 32% vs 25% for females); sexual desire (Figure 2b: 33% vs 23% for males and 26% vs 22% for females); and sexual function (Figure 2c: 37% vs 25% for males and 33% vs 20% for females). Likewise, treated patients were also less likely to report an improvement over time in enjoyment, desire, and function compared to control patients.
At baseline, men in the cirrhosis stratum had significantly lower scores on the composite Sexual Health scale compared to men in the fibrosis stratum, while scores were not significantly different for women (Table 1). The Sexual Health scores declined slightly but the change over time was not statistically significant (Table 2). Histological stratum was not significantly associated with Sexual Health scores in the ANCOVA model. As shown in Figure 4A, men who experienced a clinical outcome had lower scores on average than those without outcomes (−11.21 points, p<0.001). Among men (Figure 4B), lower Sexual Health scores were seen in the treatment group compared to the control group (−8.70 points, p<0.001). The majority of the decline in the treated men occurred early, with a minimal decline thereafter that paralleled the decline in the control group (p for trend=0.07). In contrast, women had little change in mean Sexual Health scores over time, and no significant difference was observed between treated and control female participants.
Among the 476 participants in the noncirrhotic fibrosis stratum with at least one follow-up liver biopsy, 152 (32%) had an increase in Ishak score of ≥2 points during the study. In multivariate analyses, progression to cirrhosis was associated with a decrease in Vitality scores (−2.21 points, p=0.04), an increase in fatigue scores (0.44 units, p=0.001), and worsening of general well-being scores (−0.31 units, p=0.003) during follow-up. In contrast, Physical and Mental Summary scores and Sexual Health scores did not change significantly in association with worsening of fibrosis.
In persons with early stages of CHC, symptoms tend to be mild, and HRQOL is relatively well preserved. However, these clinical features are often worse in patients with advanced cirrhosis assessed in cross-sectional studies. The number of patients with liver disease progression serially assessed over time has been limited. In the current analyses from a large prospective randomized controlled trial of long-term low-dose peginterferon therapy for advanced-stage CHC, HRQOL was prospectively assessed. Clinical progression of liver disease was associated with statistically and clinically significant declines in all components of HRQOL. Symptoms of fatigue were also greater and general well-being was lower in participants with cirrhosis and participants who experienced a clinical endpoint. Similarly, Physical Summary and Vitality scores were lower in participants with cirrhosis than in those with noncirrhotic fibrosis. These findings, while not unexpected, provide evidence that the selected instruments (i.e., the SF-36 and visual analogue symptom scales) can reliably correlate with important baseline clinical features of CHC as well as an objective measure of worsening of disease severity over time.
The current results also demonstrate that maintenance peginterferon therapy was associated with statistically and clinically significant decreases in Vitality and Physical Summary scores. Furthermore, men who received peginterferon reported significant declines in sexual health that did not rebound after cessation of treatment, despite minimal worsening of fatigue and well-being. Mental Summary scores, however, did not worsen significantly with peginterferon therapy. Our findings suggest that poor baseline mental health scores among participants with CHC may relate more to underlying medical and psychiatric comorbidities and less to severity of liver disease, whereas the physical domains of HRQOL assessment reflect disease severity and progression more reliably. This inference is supported by the high frequency of anxiolytic/antidepressant medication use as well as the frequent history of prior alcohol and drug use disorders in the HALT-C patient population 47. In addition, the low dose of peginterferon used (without ribavirin) and dose reductions to maintain treatment tolerability may have yielded a peginterferon dose that was too low to cause worsening in mental health scores over time.
Maintenance peginterferon therapy for nonresponder patients with advanced CHC was not only ineffective in decreasing disease progression and preventing clinical outcomes 38, but also impaired HRQOL and sexual health (the latter observed only among men). A similar decline in symptoms of fatigue and well-being that distinguished treated patients from untreated control patients was not identified. Our observation of a treatment-related reduction in HRQOL and sexual health but not of symptoms suggests that the clinical instrument used to assess symptoms was less sensitive than the SF-36 instrument used to measure HRQOL. Alternatively, the less pronounced effects of therapy on symptoms may have resulted from the fact that peginterferon doses could be reduced because of severe fatigue and other drug side effects, which could have blunted the intensity and duration of treatment-related symptoms. Similarly, symptom scores did not improve significantly after month 48, when patients still taking low-dose peginterferon stopped treatment per protocol.
Previous studies have shown that HRQOL is poor among patients with CHC compared to uninfected population controls and is substantially impaired in patients with histologically documented cirrhosis 5, 6, 8–10, 12, 13. A recent prospective study demonstrated that higher HRQOL predicted lower mortality in patients with cirrhosis awaiting liver transplantion 48. The current prospective study supports the previous studies, demonstrating that HRQOL declines when cirrhosis develops and declines further when disease complications and decompensation occur in patients with cirrhosis. Mean SF-36 scores were consistently lower in HALT-C patients than scores for age-matched general US population norms 43, 44. Thus, our findings support use of changes in HRQOL as a variable of interest in subsequent clinical trials of maintenance therapies for CHC. In previous analyses of the lead-in phase of HALT-C, HRQOL worsened significantly during full-dose peginterferon and ribavirin therapy and improved back to baseline levels when treatment was stopped. Furthermore, patients with a sustained virologic response had improvements in HRQOL to levels that exceeded their baseline 22. The results of the current analyses support the importance of changes in HRQOL as a potential surrogate marker for liver disease progression in patients with CHC followed over several years.
The shortcomings of the current analyses include the limited range of disease severity among the HALT-C cohort, in that all enrolled participants had advanced fibrosis and did not have a response to previous antiviral treatment. No participants with early or intermediate stages of disease and no treatment naïve patients were included in whom to assess whether HRQOL or symptoms worsen over time with or without peginterferon therapy. Still, in participants who had noncirrhotic fibrosis at the start of therapy and who did not progress to cirrhosis histologically, symptoms and HRQOL were stable, suggesting that these instruments are reliable markers for disease progression or its absence in late stages of CHC. Another shortcoming of the current study was the use of a sexual health assessment instrument that had not been validated in other studies or the general population. The Sexual Health scale used in this trial was calculated from three questions regarding sexual enjoyment, desire, and function. Men reported lower Sexual Health scale scores while receiving maintenance peginterferon therapy. However, the scale will need validation before it can be used widely for the sexual health. The gender differences in sexual health components noted in the current analyses are consistent with prior studies 36. However, the greater impact of treatment and disease progression on sexual health scores in men could be due to differing side-effect profiles of peginterferon or hormonal changes with liver disease progression in men compared to women. Changes usage of antihypertensive or antidepressant medications over time were not included in the analyses and could have been potential confounders.
In summary, our study findings indicate that the physical components of HRQOL and sexual health (in men) decline during low-dose, long-term peginterferon therapy. In addition, clinical progression of disease is associated with lower SF-36 Physical and Mental Summary scores and worsening of fatigue and general well-being over 54 months of follow-up. These results help validate the utility of the selected instruments in detecting clinically significant symptoms and changes in health-related quality of life over time in patients with chronic liver disease and provide support for their use as a tool for monitoring disease progression in future longitudinal studies of chronic hepatitis C.
Financial Support: H.L. Bonkovsky receives research support from Hoffmann-La Roche, Inc. R.J. Fontana is on the speaker’s bureau for Hoffmann-La Roche, Inc. R.K. Sterling is a consultant, receives research support, and is on the speaker’s bureau for Hoffmann-La Roche, Inc. A.M. Di Bisceglie is a consultant and receives research support from Hoffmann-La Roche, Inc. T.R. Morgan is a consultant, on the speaker’s bureau and receives research support Hoffmann-La Roche, Inc. Authors with no financial relationships related to this project are K. K. Snow, H.-Y. Kim, J. L. Dienstag, and M.G. Ghany.
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., through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health.
We acknowledge the contribution of Jay H. Hoofnagle, MD, for the design of the symptom and sexual health questionnaires. 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) 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, 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, 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) William M. Lee, MD, 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) Karen L. 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, 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: Jay H. Hoofnagle, MD, James E. Everhart, MD, Leonard B. Seeff, MD, Patricia R. Robuck, PhD, 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, Rohit Shankar, BC, ASCP, Natalia Antonov, M. Ed.
New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328) Anne M. Stoddard, ScD, Teresa M. Curto, MSW, MPH, Margaret C. Bell, MS, MPH, Raymond C. Rosen, PhD
Armed Forces Institute of Pathology, Washington, DC: Zachary D. Goodman, MD
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
Mean score on the following three questions if answered 1–5 (transformed to a 0 – 100 scale): How much of the time during the last four weeks, have you …
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*The HALT-C Trial was registered with clinicaltrials.gov (#NCT00006164).