A comprehensive assessment of patient reported symptom burden, medical comorbidities, and functional well being in patients initiating direct acting antiviral therapy for chronic hepatitis C: Results from a large US multi-center observational study
A comprehensive assessment of patient reported symptom burden, medical comorbidities, and functional well being in patients initiating direct acting antiviral therapy for chronic hepatitis C: Results from a large US multi-center observational study
Donna M. Evon 0 1
Paul W. Stewart 1
Jipcy Amador 1
Marina Serper 1
Anna S. Lok 1 3
Richard K. Sterling 1
Souvik Sarkar 1 2
Carol E. Golin 1
Bryce B. Reeve 1
David R. Nelson 1
Nancy Reau 1
Joseph K. Lim 1
K. Rajender Reddy 1
Adrian M. Di Bisceglie 1
Michael W. Fried 0 1
0 Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America, 2 Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, United States of America, 3 Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania , United States of America
1 Editor: Chen-Hua Liu, National Taiwan University Hospital , TAIWAN
2 Division of Gastroenterology and Hepatology, Department of Medicine, University of California Davis, Davis, California, United States of America, 7 Division of General Medicine and Clinical Epidemiology, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America, 8 Department of Health Behaviors, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America, 9 Department of Population Health Sciences, Duke University , Durham , North Carolina, United States of America, 10 Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Florida, Gainesville, Florida, United States of America, 11 Department of Internal Medicine, Section of Hepatology, Rush University , Chicago , Illinois, United States of America , 12 Digestive Diseases , Department of Internal Medicine, Yale University , New Haven , Connecticut, United States of America, 13 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University , St. Louis, Missouri , United States of America
3 Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan , Ann Arbor , Michigan, United States of America, 5 Division of Gastroenterology, Hepatology & Nutrition, Department of Internal Medicine, Virginia Commonwealth University , Richmond, Virginia , United States of America
Symptom burden, medical comorbidities, and functional well-being of patients with chronic
hepatitis C virus (HCV) initiating direct acting antiviral (DAA) therapy in real-world clinical
settings are not known. We characterized these patient-reported outcomes (PROs) among
HCV-infected patients and explored associations with sociodemographic, liver disease, and
psychiatric/substance abuse variables.
Methods and findings
PROP UP is a large US multicenter observational study that enrolled 1,600 patients with
chronic HCV in 2016±2017. Data collected prior to initiating DAA therapy assessed the
Donna Evon, for more details: Donna_Evon@med. unc.edu.
Funding: This study was funded through a Patient
Centered Outcomes Research Institute (PCORI)
Award to Donna Evon (CER 1408 20660).
Additional support for this study (data
management) was partially supported by the
NIDDK-funded Center for Gastrointestinal Biology
and Disease (P30-DK34987; PI: Sandler).
Additional support for Dr. Golin's salary was
partially supported by the NIH Eunice Kennedy
Shriver National Institute of Child Health and
Human Development (K24 HD06920) and by the
University of North Carolina Center for AIDS
Research (CFAR) (P30 AI 50410). The statements
presented in this article are solely the responsibility
of the authors and do not necessarily represent the
views of PCORI, its Board of Governors or
Methodology Committee. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: Donna M. Evon has received
research funding from Gilead. Michael Fried has
received research funding from and served as a
consultant for AbbVie, BMS, Gilead, and Merck,
and TARGET PharmaSolutions. Stock in TARGET
PharmaSolutions is held in an independently
managed trust. Anna S. Lok has received research
support from AbbVie, BMS, Gilead, and Merck; and
served as an advisor for Gilead. Richard K. Sterling
has received research support from AbbVie, BMS,
Gilead, Merck, and Roche and served as a
consultant for Merck, Bayer, Salix, AbbVie, Gilead,
Jansen, ViiV, Baxter, and Pfizer. Joseph K. Lim has
received research support (paid to Yale University)
and served as a consultant for Bristol-Myers
Squibb and Gilead. Nancy Reau has received
research funding (paid to Rush) from AbbVie and
Intercept and has served as a consultant for
AbbVie, Gilead, Merck, and BMS. Souvik Sarkar
served on a Gilead and Abbvie Advisory Board.
David R. Nelson has received research grant
support from AbbVie, BMS, Gilead, Janssen, and
Merck. K. Rajender Reddy is an Ad-Hoc Advisor to
Gilead, BMS, Janssen, Merck, and Abbvie and has
received research support from Gilead, BMS,
Janssen, Merck, and AbbVie (paid to the University
of Pennsylvania). Adrian M. Di Bisceglie has
received research support from AbbVie, BMS and
Gilead and has served on advisory boards for
AbbVie, BMS and Merck. Paul Stewart has served
as a consultant to TARGET PharmaSolutions. Jipcy
Amador served as a biostatistics intern at TARGET
PharmaSolutions in 2017. Carol E. Golin and Bryce
Reeve declare that they have no conflict of interests
following PROs: number of medical comorbidities; neuropsychiatric, somatic,
gastrointestinal symptoms (PROMIS surveys); overall symptom burden (Memorial Symptom
Assessment Scale); and functional well-being (HCV-PRO). Candidate predictors included liver
disease markers and patient-reported sociodemographic, psychiatric, and alcohol/drug use
features. Predictive models were explored using a random selection of 700 participants;
models were then validated with data from the remaining 900 participants. The cohort was
55% male, 39% non-white, 48% had cirrhosis (12% with advanced cirrhosis); 52% were
disabled or unemployed; 63% were on public health insurance or uninsured; and over 40% had
markers of psychiatric illness. The median number of medical comorbidities was 4 (range:
0±15), with sleep disorders, chronic pain, diabetes, joint pain and muscle aches being
present in 20±50%. Fatigue, sleep disturbance, pain and neuropsychiatric symptoms were
present in over 60% and gastrointestinal symptoms in 40±50%. In multivariable validation
models, the strongest and most frequent predictors of worse PROs were disability,
unemployment, and use of psychiatric medications, while liver markers generally were not.
This large multi-center cohort study provides a comprehensive and contemporary
assessment of the symptom burden and comorbid medical conditions in patients with HCV treated
in real world settings. Pain, fatigue, and sleep disturbance were common and often severe.
Sociodemographic and psychiatric markers were the most robust predictors of PROs.
Future research that includes a rapidly changing population of HCV-infected individuals
needs to evaluate how DAA therapy affects PROs and elucidate which symptoms resolve
with viral eradication.
Chronic hepatitis C virus (HCV) infection affects over 3 million Americans and is a leading
cause of liver failure, cirrhosis, and liver cancer[
]. Though primarily associated with liver
disease, recent evidence suggests that HCV is a multi-faceted systemic condition that may be
linked to many extra-hepatic disorders (EHDs) including arthritic-like pain, endocrine,
metabolic, kidney, neuropsychiatric, and cardiovascular conditions [3±5]. Studies conducted
during the interferon (IFN) treatment era found associations between HCV and neuropsychiatric,
somatic and gastrointestinal (GI) symptom clusters, most commonly fatigue, sleep
disturbance, irritability, depression, and pain[6±11]. Symptoms may be attributable to liver disease
or to underlying inflammatory processes that mediate the relationship between HCV infection
and EHDs [
]. Beyond disease-related factors, psychosocial factors may also contribute to
symptom burden. Psychiatric and substance use disorders, salient risk factors for contracting
HCV, are highly prevalent among HCV patients and may be directly associated with poor
health outcomes, irrespective of HCV infection or liver disease[9, 10, 13±15]. Indeed,
neuropsychiatric symptoms are reported in up to 50% of HCV patients, independent of liver
]. Additionally, the HCV population is further disadvantaged by social
2 / 26
to disclose. This does not alter our adherence to
PLOS ONE policies on sharing data and materials.
Abbreviations: ALT, alanine aminotransferase test;
AST, aspartate aminotransferase tes; APRI, AST to
platelet ratio index; AUDIT, Alcohol Use Disorders
Identification Test; CI, Confidence interval; DAA,
Direct acting antiviral; EHDs, extrahepatic
disorders; FIB-4, Fibrosis-4 Index for Liver Fibrosis;
GI, Gastrointestinal; HCV, hepatitis C virus; HrQOL,
health-related quality of life; Hx, history; IFN,
Interferon; INR, international normalized ratio; IRB,
Institutional Review Board; LASSO, Least absolute
shrinkage and selection operator; MELD, Model for
End-Stage Liver Disease; MSAS, Memorial
Symptom Assessment Scale; PCORI, Patient
Centered Outcomes Research Institute; PRO,
patient-reported outcome; PROMIS,
Reported Outcome Measurement Information
System; PROP UP, The Patient-Reported
Outcomes Project of HCV-TARGET; RBV, Ribavirin;
SD, Standard deviation; SDoH, social determinants
of health; TMSAS, Total Memorial Symptom
Assessment Scale; Tx, treatment.
determinants of poor health (SDoH), including economic instability, low income,
unemployment and lack of health insurance[17±19]. Finally, the psychological sequelae of harboring a
transmittable disease, social stigma, and anxiety related to deteriorating liver health may also
contribute to symptom burden and poor health outcomes[20±24]. Fortunately, the impact of
these factors on health outcomes may be mitigated by public awareness that a short course of
well tolerated direct acting antiviral (DAA) therapy has over 95% efficacy in achieving
Much of the data on HCV-associated symptoms, health-related quality of life (HRQOL),
and treatment side effects, comes from the IFN treatment era [6±8, 25]. Qualitative studies
elucidated patients' experiences of symptoms and HRQOL[7, 26±28], but far fewer quantitative
studies provided any in-depth analysis of HCV symptoms, especially among patients not on
]. During the IFN era, researchers identified 22 key patient-reported outcome
(PRO) concepts from qualitative studies as important to the HCV population. The majority
of these PRO concepts received inadequate attention then and have received virtually no
attention during the current DAA era. Several recent studies of HCV-infected patients treated with
DAAs have investigated a few PRO concepts, such as HRQOL, fatigue, and work productivity
]. However, these data were derived from drug registration trials that enrolled highly
selected patients with limited participation of under-represented racial minorities and
subgroups with decompensated liver disease, EHDs, and medical, psychiatric and addiction
A comprehensive understanding of baseline symptom burden in patients with HCV is
necessary to lay the groundwork for subsequent real-world investigations of potential changes in
symptoms during DAA therapy and after virologic cure. We aimed to characterize
patientreported symptoms, medical conditions, and functional well-being in a large multi-center US
cohort who initiated DAA therapy in clinical practices in 2016-2017. Our secondary aim was
to evaluate sociodemographic/SDoH, liver-related, and other clinical features associated with
these health outcomes.
The Patient-Reported Outcomes Project of HCV-TARGET (PROP UP) study is funded by the
Patient-Centered Outcomes Research Institute (PCORI) and is a unique HCV study developed
with engagement of patients affected by HCV and patient advocates. PROP UP is a
multi-center, prospective, observational study that enrolled 1,600 patients across the U.S. to characterize
patients' experiences associated with HCV, DAA treatments, and virologic cure. The rationale
and study protocol for PROP UP has been previously published[
]. Site recruitment began in
January 2016 and ended in October 2017 at 11 U.S. medical centers (9 academic hepatology
and 2 private gastroenterology). All sites were under the jurisdiction of their local Institutional
Review Board (IRB) and obtained approval prior to study initiation (S1 Table). Inclusion
criteria were made purposely broad to capture real world clinical experiences, and mainly required
completion of baseline PROs and initiation of one of five DAA regimens. The current analysis
used cross-sectional data collected at baseline prior to patients starting DAA therapy.
Brief details of the measures are provided below, as extensive details are provided elsewhere[
Number of medical comorbidities. Participants responded to a list of 30 chronic medical
conditions regarding whether they (a) never had the condition; (b) have experienced the
3 / 26
condition in the past; or (c) have experienced the condition in the last year (current condition).
For these analyses we focused on predictors of current medical comorbidities.
Specific symptoms. The National Institutes of Health PROMIS instruments were used to
capture three symptom clusters associated with HCV in the literature: neuropsychiatric
(depression, anxiety, anger, cognitive concerns); somatic (pain interference, fatigue, sleep
disturbance); and GI (abdominal pain, nausea/vomiting, diarrhea) clusters[32±34]. Psychometric
testing of these PROMIS instruments in patients with HCV demonstrated satisfactory
reliability and validity[
]. Higher PROMIS T-scores reflect worse symptoms.
Overall symptom burden. A comprehensive list of 32 symptoms common to many
medical conditions were assessed using the Memorial Symptom Assessment Scale (MSAS)[
Participants reported the presence or absence of symptoms, and if present, its severity,
frequency and level of distress. A total symptom burden (TMSAS) score was calculated. A higher
TMSAS score reflects higher symptom burden.
Functional well-being. The HCV-PRO is a newly developed HCV-specific survey
designed to evaluate the functional well-being of patients with HCV[
]. The scale includes
16 items that measure various aspects of physical and emotional functioning, productivity,
intimacy, and perceived quality of life related to having HCV. The total score ranges from 0 to
100; higher scores indicate better functional well-being.
Sociodemographics. Participants reported age, sex, racial background, educational
attainment, annual household income, marital status, employment status, and health insurance
status were explored as potential predictors of PROs.
Liver-related clinical and laboratory markers. The following data were extracted from
participants' medical records by trained site coordinators: HCV genotype, HCV RNA level,
aspartate aminotransferase test (AST), alanine aminotransferase test (ALT), albumin, total
bilirubin, platelets, hemoglobin, creatinine, and international normalized ratio (INR). Based on
these laboratory data, we calculated various measures of advanced fibrosis/cirrhosis: (a) the
AST to platelet ratio index (APRI); (b) the Fibrosis-4 Index for Liver Fibrosis (FIB-4), and (c)
the Model for End-Stage Liver Disease (MELD), where FIB-4 >3.25 indicated advanced
fibrosis; APRI >2.0 and MELD >6 indicated cirrhosis, and MELD 12 indicated advanced
cirrhosis[41±43]. Site coordinators were also trained to review multiple sources of evidence in
patient medical records, such as biopsy results, ultrasounds, MRIs, transient elastography
scores, serum biomarker scores, and clinical notes for evidence of cirrhosis /stage 4 fibrosis.
Based on the evidence, the trained site coordinators categorized patients as cirrhotic or
noncirrhotic (Yes/No). All cross-referenced information in the dataset (e.g., labs, APRI, FIB-4,
MELD, treatment type, duration, use of ribavirin) was reviewed to validate the accuracy of the
cirrhosis categorization. When needed, sites were queried for additional information to
support cirrhosis categorization (e.g., transient elastography scores). Adjudication of cases with
inconsistent data was made by an experienced hepatologist (M.W.F.) who reviewed all
available cross-referenced information or in less than .05% of cases, final adjudication was
conducted by the site investigator who had access to the comprehensive medical record. These
laboratory biomarkers and clinical data were explored as potential predictor variables.
Mental health and substance abuse history. Participants responded to five questions
related to psychiatric history, two questions from the AUDIT[
] related to frequency and
quantity of alcohol consumption, and two questions from the Substance Abuse Mental Illness
Symptoms Screener (SAMISS) queried frequency of drug abuse in the past year, including use
of nonprescription street drugs and prescription drugs [
]. Psychiatric questions queried
(Yes/No) past and current psychiatric medication use, psychiatric diagnoses, psychiatric
treatment, and inpatient psychiatric hospitalization.
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Statistical analysis strategy
Descriptive statistics. To characterize the study cohort, graphical and tabular descriptive
statistical methods (means, standard deviations (SD), range) were used to visualize the data
and describe the empirical distributions of the four PRO constructs: (1) Number of medical
comorbidities; (2) Specific Symptom Clusters (PROMIS instruments); (3) Overall Symptom
Burden (TMSAS); and (4) Functional Well-Being (HCV-PRO), as well as participant
characteristics (sociodemographics, liver-related features, psychiatric and substance abuse history).
Bivariate associations. To help characterize relationships between each patient
characteristic and each PRO, unadjusted point and interval estimates of correlation coefficients were
tabulated along with unadjusted estimates of subgroup PRO means/medians. Pearson
correlation coefficients were used for continuous-vs-continuous pairs of variables; point-biserial
correlation coefficients were used for binary (e.g. gender, cirrhosis)-vs-continuous pairs;
Spearman correlation coefficients were used for ordinal (e.g., cirrhosis status combined with
MELD score)-vs-continuous pairs; and for continuous PRO measures and multi-level nominal
categorical variables (e.g., race, employment), we used the square root of the unadjusted R2 for
the general linear model of the PRO measure conditional on the categorical variable as a
predictor. The square root of R2 is a non-directional absolute value (r).
Multivariable models of association. In the inferential investigation of patient
characteristics that may be predictive of PROs, we implemented a cross-validation strategy. Participants
were assigned by randomization to two groups: sample 1 or sample 2. Sample 1 (n = 700) was
used for exploratory model-building analyses to generate a set of candidate predictor variables
that might be associated with each outcome. Sample 2 (n = 900) was used to test and
potentially validate the candidate models. Essentially, two identical studies were performed in which
the second was used to validate predictor models generated by the first.
Based on documented and informal information from the data collection process, missing
values of the outcome variables and the candidate predictor variables are presumed missing at
random or missing completely at random. Complete-case analyses (omitting patients with
missing data) suffers from selection bias and loss of precision. Therefore, missing values for
the predictor variables were addressed via multiple imputation. Patients having a missing
value for an outcome variable were omitted from that regression analysis. A multivariate
multiple imputation algorithm (SAS procedure MI) was used to generate 40 completed copies of
the dataset for the multivariable analyses. Each statistical regression model of interest was fitted
to all 40 datasets. The 40 sets of results were combined (SAS procedure MIANALYZE) to
produce the final results shown for each multivariable regression model.
The candidate predictor variables for model-building based in Sample 1 are found in
Table 1 and include: (1) sociodemographics; (2) liver-related clinical and laboratory markers;
and (3) mental health and substance abuse variables. Some of the laboratory markers were
transformed to log10 scale. In using Sample 1 to select candidate multivariable models for each
PRO, we first examined models accounting for sociodemographics, then we looked at the
additional contribution of liver lab and clinical variables, and finally psychiatric and substance
abuse variables were included. Model-building with Sample 1 relied on stepwise variable
selection algorithms or use LASSO (least absolute shrinkage and selection operator)
variable-selection algorithms. Having completed all exploratory analyses and model development with
Sample 1 (n = 700), we then used the data from Sample 2 (n = 900) for validation. Candidate
predictor variables in models based on Sample 2 were considered ªvalidatedº if their regression
coefficients were statistically significant at level α = 0.01.
Model-based analyses for the patient-reported `Number of Medical Comorbidities' relied
on generalized log-linear models representing a mean count of comorbid conditions as a
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PLOS ONE | https://doi.org/10.1371/journal.pone.0196908
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function of patient characteristics. Similarly, multivariable analyses for TMSAS and HCV-PRO
measures relied on generalized linear models. The PROMIS Fatigue and PROMIS Sleep
Disturbance T-scores also were studied using generalized linear models because they exhibited
symmetric discrete distributions.
In contrast, the other eight symptom-specific PROMIS T-scores exhibited semi-continuous
empirical distributions; that is, the scores follow a discrete distribution with a clumping of
values at the floor of each scale (patients who reported no symptom). Therefore, the analysis of
each of these 8 PROMIS measures relied on a generalized linear model for zero-inflated
Poisson distributions. To represent both the probability of having the symptom and the
conditional mean score as functions of patient characteristics, the zero-inflated Poisson model
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specifies two simultaneous regression equations for the modified T-score: one for the
distribution of non-zero values (patients who have the symptom) and one for the clump of values at
zero (for patients without the symptom). The dependent variable was computed as (T-score −
K) with K being the observed floor of the scale. The floor values (K) were: Depression score >
42; Anger score > 35; Anxiety score > 45; Cognitive Concerns > 25; Pain Interference > 45;
Belly Pain > 30; Diarrhea > 32; Nausea/Vomiting > 37 (these floor values were also used for
other analyses of dichotomized T-scores). In these analyses, we focused on identifying patient
characteristics associated with the non-zero values (having the symptom) to identify patients
at risk for high symptom burden.
For all the PROs, sensitivity analyses included variations on the type of model fitted,
variations on the engine used for exploratory hypothesis generation (e.g. stepwise, LASSO,
leastangle regression, model averaging) and variations on the assumptions and criteria used (e.g.
link function, α-levels for entry and exit). For the PROMIS T-scores, sensitivity analyses
included logistic regression for the dichotomized T-scores, cumulative logit model analysis
for categorized T-scores (low, medium, high), and zero-inflated negative binomial model
analysis. All statistical estimates were computed along with corresponding 95% confidence
intervals. Statistical computations were performed using SAS System software version 9.4 (SAS
Institute, Cary, NC). PROMIS T-scores were computed using R software, version 3.1.2 (2014
The R Foundation for Statistical Computing), and RStudio software, version 1.0.136 (RStudio
The study flowchart, which includes the number of patients screened, consented, and enrolled
in PROP UP, is displayed in Fig 1. Of the nearly 2,400 patients screened, 87% consented to
participate in the study. Of the 2082 consented patients, the main reasons patients were not
enrolled included incomplete baseline surveys at the time that treatment was initiated (6%);
insurance payer denials of DAA therapy (5%); patient lack of follow through with clinical
Fig 1. Study flowchart.
8 / 26
requirements to start DAA therapy (e.g., completion of paperwork, urine toxicology screens)
(3%); and verbal withdrawal from the study after consent (3%).
To explore the potential for selection bias that could affect generalizability of the study
results, we compared the 1600 enrolled patients with 757 patients who were screened or
consented, but not enrolled, on age, sex, and race. Compared to the 1600 patients enrolled, the 757
screen/enrollment failures were similar in age (55 years versus 57 years), sex (61% male versus
55%), and race (59% White versus 61%; 29% Black versus 33%).
Baseline patient characteristics are detailed in Table 1. Notably, 39% of patients self-identified
as Black/African American (n = 519) or Other Race (n = 101), which was comprised of `other'
(n = 41), bi-racial/multi-racial (n = 32), American Indian (n = 17), Asian (n = 6), `not reported'
(n = 6) and native Hawaiian/Pacific Islander (n = 5). Annual household income was low (less
or equal to $40,000) in 75% of patients. Around 45% of patients reported being recipients of
disability benefits or in the process of applying for disability benefits, 36% were working a
part-time or full-time job, and 7% were unemployed, out of work or looking for work.
Fiftyone percent of patients had public health insurance (Medicare or Medicaid), 12% were
uninsured, and 37% had private insurance or private plus Medicare.
Number of medical comorbidities and association with patient
In addition to liver-related problems, patients reported the presence of current and past
comorbid conditions, 97% of these conditions was endorsed by at least one participant. The 10
most frequently reported comorbidities are listed in Table 2. Patients endorsed a mean of four
comorbidities (range: 0±15) (S2 Table). Less than 10% (n = 154) reported no medical
comorbidities, thus the majority had at least one medical condition other than chronic HCV.
Notably, many of these comorbid conditions could represent EHDs.
As shown in Table 3, a greater number of medical conditions correlated with
sociodemographics (.20 r .40; being older, low income, public health insurance, disability), liver-related
markers (.17 r .18; MELD 12, low albumin, low hemoglobin, high creatinine), and mental
health markers (15 r .24; psychiatric medication use, diagnosis, treatment, inpatient
hospitalization). Correlations with alcohol and substance abuse were lower (0 r .09).
a Each participant only counted once in combined column.
Combined Symptomsa n (%)
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Specific symptom clusters and association with patient characteristics
Fig 2 displays histograms for the T-scores for each of the PROMIS symptoms. Eight PROMIS
measures showed a bimodal distribution with some patients reporting no symptoms while
others reported mild to severe symptoms. T-scores over 55 are 1/2 standard deviation worse than
the general US population and considered a clinically meaningful difference in other medical
Fig 2. Histograms of PROMIS symptom T-scores. The vertical line in each histogram shows the proportion of patients reporting no symptoms or responses at
the minimum score.
13 / 26
Neuropsychiatric symptom cluster. Approximately 60-80% of patients endorsed
symptoms in the neuropsychiatric symptom cluster (Fig 2). Bivariate correlations and unadjusted
mean group differences are summarized in Table 3. Of the sociodemographic variables, the
largest correlations with this symptom cluster were with employment (.19 r .28), health
insurance (.13 r .19), and income (.09 r .18), such that disability, unemployment, low
income, and public health insurance were associated with worse symptoms. Correlations
between the neuropsychiatric symptom cluster and liver-related markers were quite small
(0 r .07).
In multivariable models, severity of the neuropsychiatric symptom cluster was frequently
associated with being disabled, unemployed, and use of psychiatric medications (Table 5).
Patients who were disabled, unemployed, white, single and with past or current psychiatric
medication use had 6% to 18% higher depression scores. Anger severity decreased with age and
was 4% to 8% higher in patients who were disabled, unemployed, using psychiatric
medications and abusing prescription drugs. Anxiety severity decreased with age and was 6% to 11%
higher in patients who were disabled, of other race, uninsured, taking psychiatric medications,
or had a history of psychiatric diagnosis. Severity in cognitive concerns was 4% to 9% higher in
patients who were disabled, unemployed, on psychiatric medications, and history of
Somatic symptom cluster. Almost all patients endorsed some level of fatigue and sleep
disturbance, evidenced by the histograms in Fig 2 and 65% reported pain interference.
Bivariate correlations and unadjusted mean differences between the somatic symptom cluster and
patient characteristics are summarized in Table 3. In general, the largest correlations with the
Currently on Psych
Hx of Psych Meds
Hx of Psych diagnosis
Hx of Psych
somatic symptom cluster were the sociodemographic and psychiatric variables. Patients who
had lower income, were unemployed or disabled, or on public health insurance had worse
somatic symptoms (.13 r .42) Patients with psychiatric markers were also observed to
experience worse pain, sleep, and fatigue (.11 r .29). By contrast, correlations between the
somatic symptom cluster and liver-related markers were small (.01 r .11).
Multivariable models demonstrated that fatigue severity was worse among patients who
were female (6% higher), White or other race (9%-10% higher), disabled (9% higher) and
those taking psychiatric medications (7% higher) (Table 4). Sleep disturbance severity was
higher in patients who were unemployed (10% higher), disabled (11% higher), using
psychiatric medications (7%-8% higher) (Table 4). Patients with lower income (5% higher), disabled
(13% higher), unemployed (8% higher), with psychiatric medication use (5% higher) reported
more severe pain interference (Table 5). No liver-related markers were identified as validated
predictors of the somatic symptom cluster.
Gastrointestinal symptom cluster. Approximately half of the cohort reported symptoms
in the GI cluster, including abdominal pain (50%), nausea/vomiting (50%), and diarrhea
(40%) (Fig 2). Bivariate correlations between the GI symptom cluster and patient
characteristics are summarized in Table 3. Correlations were smaller with the GI cluster than with other
symptom clusters. In general, the sociodemographic variables had the largest correlations with
the GI cluster (.07 r .27), followed by correlations with the psychiatric markers (.10 r
.20), and liver-related markers (0 r .11).
In multivariable models, nausea/vomiting severity was worse in patients who were disabled,
unemployed or abusing prescription medications (14% to 23% higher) (Table 5). Abdominal
Symptom severity, frequency and distress are reported as percentages of those who endorsed the symptom presence.
a Severity ranges from slight, moderate, severe, very severe; data shown is % reporting moderate, severe, very severe
b Frequency ranges from rarely, occasionally, frequently, almost constantly; data shown is % reported frequently or
c Distress or bothersome ranges from not at all, a little bit, somewhat, quite a bit, very much; data shown is %
reporting symptoms as somewhat, quite a bit, or very much distressing.
15 / 26
pain severity was worse in patients who were disabled, unemployed, and with psychiatric
diagnosis and psychiatric medication use (5% to 18% higher). Diarrhea severity was worse in
patients who were disabled, taking psychiatric medications, and with a history of psychiatric
diagnosis and hospitalization (7% -19% higher).
Overall symptom burden and associations with patient characteristics
On the MSAS, individual symptoms reported by at least 25% of participants are listed in
Table 6 (S3 Table). The median TMSAS score was 0.4 (mean = 0.6, SD = 0.5, range: 0±3.1).
The most common symptoms were lack of energy, pain, and difficulty sleeping. These
symptoms were also the most severe and frequent.
As shown in Table 3, higher overall symptom burden (higher TMSAS scores) was
correlated with sociodemographics (.15 r .36; being female; lower income; disabled; uninsured;
having public health insurance), lab biomarkers (.12 r .16; lower albumin, lower
hemoglobin) and psychiatric markers (.23 r .35). Correlations with alcohol and substance abuse
were lower (0 r .12). In multivariable regressions, symptom burden was higher in patients
who were female (13% higher), disabled (41% higher), unemployed (29% higher), and taking
psychiatric medications (33% higher) (Table 4).
HCV-specific functional well-being
The mean HCV-PRO total score was 72 (median = 77, SD = 22; range = 0-100), a score
consistent with a previous Phase II clinical trial where patients had a mean baseline HCV-PRO of 78
]. As shown in Table 3, patients with lower functional well-being tended to be younger;
other race; lower income, disabled, unemployed, or on public insurance. Low functional
well-being was also correlated with the mental health markers (.24 r .38). In contrast, the
correlations between HCV-PRO scores and liver-related markers were quite small, with the
strongest correlations being with albumin, APRI >2, and MELD 12 (.07 r .09). In
multivariable regression models, functional well-being was lower in patients who had worse liver
disease (APRI >2) (6% lower), were unemployed (11% lower), disabled (15% lower), and taking
psychiatric medications (11% lower).
Sensitivity analyses and diagnostics were used to evaluate the robustness of the reported main
results in Tables 4 and 5 to reasonable perturbations of the statistical methods and assumptions
used. These auxiliary analyses were used to guide our level of trust in the main results. The
various sensitivity analyses produced results similar to the main results. For example: (1) For
Table 5, similar results were obtained when using a zero-inflated negative binomial (ZINB)
model instead of the zero-inflated Poisson (ZIP) model, albeit with wider confidence intervals
as expected. The two approaches identified the same predictor variables but ZINB classified
fewer as ªvalidatedº. In terms of the Akaiki Information Criterion, the ZINB fit was slightly
better for some PRO measures. (2) For Table 4, similar results were obtained when using a
generalized linear model with identity link function instead of the Poisson model. (3) Results
in Tables 4 and 5 were supported when we explored inclusion or exclusion of selected
candidate predictor variables. (4) Finally, the results in Tables 4 and 5 relied on multiple imputation
(MI) of missing values for patient characteristics using a two-step approach:
Markov-chainMonte-Carlo estimation followed by use of parametric regressions. Closely similar versions of
Tables 4 and 5 were obtained when relying on an alternative MI method in which the second
step was a nonparametric propensity scores method.
16 / 26
With recent advances in the treatment of HCV using highly potent DAAs and resultant
changes to demographics of patients initiating DAA treatment, a contemporary and
comprehensive assessment of the symptom burden of HCV-infected individuals in a real world
setting, outside of carefully selected clinical trials populations, was needed. Towards this end, we
conducted an in-depth analysis of patient-reported symptom burden including
HCV-associated specific symptoms, medical comorbidities and functional well-being in a large
multicenter cohort initiating DAA therapy. We also took the opportunity to thoroughly describe the
cohort with regard to several sociodemographics, liver-related features, and mental health and
drug and alcohol use parameters of the current treatment population. Through a rigorous
analytical approach, we identified and validated key patient characteristics associated with each
PRO. Our analysis has three key findings. First, many patients with chronic HCV, although
not all, had a large number of medical comorbidities and high symptom burden, with the most
common being fatigue, sleep disturbance, pain interference and neuropsychiatric symptoms.
Second, most PROs were strongly associated with just a handful of patient characteristics;
namely, disability, unemployment and current use of psychiatric medications. Other predictor
variables for each PRO were identified, but with lower frequency and strength of association.
Third, laboratory biomarkers and clinical markers of liver disease severity were not strong
predictors of most PROs. These findings will lay the groundwork for subsequent longitudinal
investigations of symptoms and comorbid conditions that may change over the course of
DAA therapy and after viral eradication.
This study provides extensive sociodemographic information regarding the chronic HCV
population currently being treated in the US. The study cohort was 61% White and 39%
nonWhite (33% identified as Black/African-American, 6% identified as Other Race), in contrast to
industry-sponsored clinical trials that under-represent minority populations (i.e., majority are
>80% White (range: 66%-97%)[49±51]. The vast majority of patients initiating treatment had
low educational attainment (not exceeding high school) and low household income (less or
equal to $40,000 per year), well below the average income cited in the 2016 Census survey[
Over 50% were recipients of disability benefits, applying for disability benefits, or unemployed
and looking for work. The majority was receiving public health insurance or was uninsured.
Employment status, including disability and unemployment, as well as low income and lack of
insurance were common patient features associated with high symptom burden and
comorbidities, consistent with the larger literature on social and economic determinants of poor
health in other medical populations). Recognizing the impact of SDoH on the health and
treatment outcomes of the HCV population has both clinical and health policy implications. While
the emphasis has been on viral eradication to improve liver-related outcomes, our results
highlight the need to acknowledge the high burden of concomitant chronic health conditions
among the chronic HCV population. In fact, HCV therapy initiation presents a window of
opportunity for patients to re-engage with the healthcare system and address other health
conditions. Improving the overall health of the HCV population will require improvements and
innovation at multiple levels of healthcare including enhanced coordination of care between
hepatologists and other subspecialists, multidisciplinary teams, co-location of mental health
and addiction specialists, patient navigation, and innovative telehealth models [21, 53±63].
Nearly half of the cohort had cirrhosis and 12% had evidence of advanced cirrhosis
(MELD 12). We suspect that state Medicaid restrictions during the enrollment period
partially influenced variability of liver disease severity in this cohort by limiting access to
treatment to patients with higher stages of fibrosis and denying treatment to those with minimal
17 / 26
Psychiatric disorders were common comorbidities among HCV-infected individuals in the
], and this trend continues. Almost half of the patients reported a
psychiatric diagnosis (44%), utilizing mental health treatment or services (41%), or psychiatric
medication use (50%), with 30% currently on psychiatric medications. Eighteen percent (n = 287)
of the cohort reported a past history of inpatient psychiatric hospitalizations, a proxy for severe
psychopathology. The prevalence of these mental health indicators far exceeds the prevalence
in the general US population. A total of 36% of patients were still using alcohol at time of
treatment initiation and at least 20% had used street drugs and 9% reported using prescription
medications in an abusive fashion in the previous year. While these data are alarming, it is
likely that patients under-reported these behaviors due to social desirability and fear of
treatment being rescinded. In this study, we attempted to mitigate under-reporting by highlighting
the confidential nature of data collection and separation of research team and clinical staff.
The high prevalence of psychiatric disorders and moderate drug and alcohol use has clinical
relevance for all practitioners, as these patients will be at risk for long-term poor health
outcomes, beyond liver disease.
The vast majority of patients suffer from multiple chronic health conditions. Patients
reported up to 15 comorbid conditions and an average of four. A greater number of
comorbidities was found for patients who are disabled and older. Many of the prevalent medical
conditions could represent biologically plausible inflammatory conditions, or extrahepatic disorders
(EHDs) related to HCV, such as diabetes[
]. Recent literature suggests that EHDs are
underestimated because they are non-specific, but may compromise overall health outcomes
and result in an estimated economic burden of $1.5 billion per year[
]. The diagnostic
guidelines published by the International Study Group of Extrahepatic Manifestations Related to
HCV recommend evaluating all patients with HCV for potential EHDs to ensure that the
entire spectrum of HCV-related disorders are identified and properly treated[
patients with all stages of liver disease should be treated for HCV and not delayed until fibrosis
advances, as studies indicate that clinical and economic burden of EHDs can be reduced
through viral eradication[
Like comorbidities, many, but not all patients reported experiencing specific symptoms.
For each of the specific neuropsychiatric, somatic and GI symptoms, a proportion of patients
did not experience that particular symptom (e.g., 50-60% had no GI symptoms), but the
majority reported mild to severe symptoms. For instance, fatigue and sleep disturbance were
ubiquitous problems in the entire cohort. With regard to the neuropsychiatric cluster
(depression, anxiety, anger, cognitive concerns), about 60-80% endorsed mild to severe symptoms,
with severe neuropsychiatric symptoms experienced by patients who were disabled,
unemployed, and on psychiatric medications, among other factors. Over 60% of patients endorsed
pain interference and 30% endorsed joint/muscle pain, which is consistent with previous
reports of pain disorders in patients with chronic HCV[6, 15, 72±74]. Over 90% of patients
reporting some level of sleep disturbance; 31% reported a sleep disorder. Estimates from the
literature suggest that up to 60% of patients with chronic HCV may have sleep problems,
including restless leg syndrome, although confounding effects of other comorbidities has been
difficult to tease apart[
]. Disability, unemployment, and psychiatric medication use were
the prominent predictors of the pain, sleep interference, and fatigue cluster. Finally, 40-50% of
patients endorsed GI symptoms (nausea/vomiting, abdominal pain, diarrhea) and similarly,
disability, unemployment and psychiatric markers including psychiatric medication use were
associated with more severe GI symptoms.
A comprehensive analysis of symptom prevalence in the chronic HCV population has not
been conducted since the work of Lang et al. in 2006[
]; therefore, this study provides a
contemporary perspective of the most prevalent, severe, and distressing symptoms in the chronic
18 / 26
HCV population. The majority of symptoms endorsed by at least 20% of patients in this cohort
overlap considerably with Lang et al.'s findings, validating our results. We also identified new
symptoms (e.g., numbness and tingling in hands and feet, dry mouth, cough, feeling bloated,
shortness of breath, and lack of sexual interest) that were prevalent and require further
investigation. This information can help clinicians identify and better care for these patients and
observe changes in symptoms after viral eradication.
The functional well-being of the current cohort was comparable to that obtained from the
original HCV-PRO analysis embedded in a Phase II clinical trial[
]. Items endorsed on the
HCV-PRO most often included ªHaving Hepatitis C was very stressful to meº, ªI had difficulty
sleeping or slept too muchº, and ªI needed to pace myself to finish what I had plannedº.
HCVspecific functional well-being was worse in patients with advanced liver disease (APRI > 2),
and those disabled, unemployed and on psychiatric medications. The HCV-PRO is a
contemporary disease-specific instrument developed with rigorous methods and we would
recommend it for use in future HCV investigations; unfortunately, no other studies have been
published to date, therefore cross-study comparisons are unable to be conducted.
Not surprisingly, we found that laboratory biomarkers and markers of liver disease severity
were not strong predictors of the PROs investigated in this study. We observed differences in
the unadjusted means between high and low MELD subgroups by 2 to 7 points across the
PROs, reflecting possible clinically significant differences in patients with advanced cirrhosis
on symptoms such as sleep disturbance and the GI symptom cluster. However, MELD was not
a strong predictor in confirmatory models. There were small differences between patients with
high versus low APRI, FIB-4, albumin and creatinine, but only APRI was validated as a
predictor of functional well-being in multivariable models. Our findings are consistent with a large
body of HrQOL literature from the interferon treatment era that found negligible associations
between liver disease parameters and PROs once other variables were accounted for[15, 76±
81]. Most of these studies have found psychiatric and/or medical conditions to be the strongest
predictors of PROs in multivariate models, especially depression and pain-related conditions
[15, 80±82]. Many clinical researchers have speculated that HCV exerts a deleterious effect on
PROs through medical and psychiatric comorbidities, which could represent underlying
HCV-induced EHDs [
15, 80, 81
]. These speculations require further investigation.
Limitations of this study should be noted, particularly regarding the generalizability of
these results. Our findings may not apply to other subpopulations or clinical settings, including
younger people who inject drugs, persons receiving medication-assisted treatment for opioid
use disorders with methadone or buprenorphine/naloxone, Veterans, and those incarcerated.
These subgroups may represent the primary treatment groups in years to come if the opioid
epidemic is not controlled[
]. We found no substantial differences between patients enrolled
and not enrolled in this study, therefore we can presume generalizability to similar patients
treated in similar settings. Social desirability and response bias issues could have occurred,
especially in response to alcohol and drug use questions. However, it's important to appreciate
the necessity of capturing data directly from patients when they are uniquely positioned to
assess an outcome (i.e., pain), as research shows that clinicians tend to under-report the
frequency and severity of patients' symptoms[
]. Finally, minimal clinical data were extracted
from medical records, thus we are unable to verify patient-reporting of medical comorbidities,
psychiatric medications and other clinical information.
Future research should build upon our observations to directly inform clinical knowledge
and decision-making for various stakeholders (patients, clinicians, policy makers). There is a
critical need to tease apart and elucidate the causal pathways that may influence health
outcomes in the HCV population (i.e., psychiatric illness, EHDs, number of medical
comorbidities, liver disease, symptoms); this may be achieved through sophisticated path analyses and
19 / 26
structural equation modeling[
]. We identified a new predictor of worse PROs, namely
employment status, which should be included in future predictive models of HCV-related
PROs. Health services research is needed to examine the most effective models to integrate
healthcare for liver disease, mental health, and addiction[21, 55±57, 60±63]. More studies
derived from real world clinical settings, outside of clinical trials, need to examine changes in
overall symptom burden and specific symptom clusters over time, during DAA therapy, after
virologic cure, and during long-term follow-up. Comparisons between the DAA regimens and
how they affect PROs would provide stakeholders with information to guide treatment
decision-making. Importantly, it remains unclear if overall symptom burden lessens after virologic
cure or if only specific symptom clusters improve. Therefore, the exploratory work herein to
identify and validate the most robust predictors of PROs is fundamental to future PRO
research in chronic HCV.
Our findings have a number of strengths and highlight clinical relevance for multiple
stakeholders. This study is unique and notably the largest investigation of PROs in the current
population of HCV patients seeking DAA therapy outside of clinical trials. We have identified
some of the most challenging sociodemographic features, common comorbidities, potentially
EHDs, and troublesome symptoms experienced by HCV-infected individuals. More black
Americans have been recruited than any previously conducted clinical trial and thus provided
an opportunity for a robust evaluation. Interestingly, Black patients reported the lowest levels
of symptom burden and neuropsychiatric symptoms. Consistent with many prior studies, we
found that laboratory biomarkers and liver disease severity were not helpful in identifying
patients with diminished PROs, such as HrQOL, when other variables were accounted for[80±
82]. It is also noteworthy that PROP UP is a highly patient-centered study. Patients affected by
HCV were engaged since its inception and helped to identify the study outcomes and select
PRO measures to ensure the study findings were salient and meaningful to people with HCV.
Finally, given the large sample size, we were able to conduct cross-validation analyses to
rigorously identify and confirm predictors, essentially conducting two separate identical studies,
and then followed up with sensitivity analyses to confirm that perturbations in modeling,
missing data, and assumptions did not alter our findings. These methods serve to instill a higher
level of trust in the conclusions drawn from this study. Consequently, we hope the
comprehensive data provided herein serves as reference guide for future investigations of PROs in the
chronic HCV patient population.
S1 Table. Full names of each subsite's local approving IRBs.
S2 Table. Complete list of self-reported medical comorbidities. a Each participant only
counted once in combined column.
S3 Table. Complete list of MSAS symptoms. Symptom severity, frequency and distress are
reported as percentages of those who endorsed the symptom presence. a Severity ranges from
slight, moderate, severe, very severe; data shown is % reporting moderate, severe, very severe
symptoms. b Frequency ranges from rarely, occasionally, frequently, almost constantly; data
shown is % reported frequently or almost constantly. c Distress or bothersome ranges from not
at all, a little bit, somewhat, quite a bit, very much; data shown is % reporting symptoms as
somewhat, quite a bit, or very much distressing.
20 / 26
The authors would like to acknowledge the contributions of the following people: Alan
Franciscus of www.HCVadvocate.org, Anquenette Sloan, Summer Wadsworth-Delciotto, Scott
Kixmiller, Larry Huston, Finton Brown (UNC Patient Engagement Group); Virginia Sharpless,
Ken Berquist, Herleesha Anderson, Courtenay Pierce, Jenn Barr, Bryonna Jackson, Jane Giang,
Jama Darling, Paul Hayashi, Steven Zacks, A. Sidney Barritt IV, Scott Elliot, Dawn Harrison,
Danielle Cardona (University of North Carolina); Patrick Horne (University of Florida); Kelly
Borges, Danielle Ciuffetelli (University of Pennsylvania); Chrissy Ammons, Kathleen Genther,
Jessica Mason (Virginia Commonwealth University); Lelani Fetrow, Vicki Shah (Rush
University); Theresa Cattoor, Alisha McLendon (Saint Louis University); Mariechristi Candido, Sophia
Zaragoza, Sandeep Dhaliwal, Patricia Poole, Rebecca Hluahanich, Kathleen Haight, (University
of California, Davis); Andrea Gajos, Elizabeth Wu, Carrie Bergmans (University of Michigan);
AnnMarie Liapakis, MD, Kristine Drozd, Carol Eggers, Hong Chau and Claudia Bertuccio
(Yale University). William Harlan, Roberta Golden, Kylee Diaz(Asheville Gastroenterology
Associates), William King, Megan Marles (Wilmington Gastroenterology Associates).
Conceptualization: Donna M. Evon, Paul W. Stewart, Carol E. Golin, Bryce B. Reeve, David
R. Nelson, Michael W. Fried.
Data curation: Paul W. Stewart, Jipcy Amador.
Formal analysis: Paul W. Stewart, Jipcy Amador.
Funding acquisition: Donna M. Evon, Carol E. Golin, Michael W. Fried.
Investigation: Donna M. Evon, Marina Serper, Anna S. Lok, Richard K. Sterling, Souvik
Sarkar, Carol E. Golin, David R. Nelson, Nancy Reau, Joseph K. Lim, K. Rajender Reddy,
Adrian M. Di Bisceglie, Michael W. Fried.
Methodology: Donna M. Evon, Paul W. Stewart, Jipcy Amador.
Project administration: Donna M. Evon, Anna S. Lok, Richard K. Sterling, Souvik Sarkar,
David R. Nelson, Nancy Reau, Joseph K. Lim, K. Rajender Reddy, Adrian M. Di Bisceglie.
Software: Paul W. Stewart, Jipcy Amador.
Supervision: Donna M. Evon, Anna S. Lok, Richard K. Sterling, Souvik Sarkar, Nancy Reau,
Joseph K. Lim, K. Rajender Reddy, Adrian M. Di Bisceglie.
Validation: Paul W. Stewart.
Visualization: Paul W. Stewart, Jipcy Amador.
Writing ± original draft: Donna M. Evon, Paul W. Stewart, Jipcy Amador, Marina Serper,
Anna S. Lok, Richard K. Sterling, Souvik Sarkar, Carol E. Golin, Bryce B. Reeve, David R.
Nelson, Michael W. Fried.
Writing ± review & editing: Donna M. Evon, Paul W. Stewart, Jipcy Amador, Marina Serper,
Anna S. Lok, Richard K. Sterling, Souvik Sarkar, Carol E. Golin, Bryce B. Reeve, David R.
Nelson, Nancy Reau, Joseph K. Lim, K. Rajender Reddy, Adrian M. Di Bisceglie, Michael
21 / 26
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international journal of quality of life aspects of treatment, care and rehabilitation. 2014; 23(3):877±86.
Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple
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