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Schizophrenia Bulletin vol. 36 no. 1 pp.

165172, 2010
doi:10.1093/schbul/sbn065
Advance Access publication on June 17, 2008

Antiviral Therapy Completion and Response Rates Among Hepatitis C Patients With
and Without Schizophrenia

Marilyn Huckans14, Alex Mitchell2,3, rable with those without SCHZ. Based on these data,
Samantha Ruimy2,3, Jennifer Loftis2,46, and SCHZ should not be considered a contraindication to an-
Peter Hauser27 tiviral therapy for HCV.
2
Northwest Hepatitis C Resource Center and; 3Behavioral Health
and Clinical Neurosciences Division, Portland VA Medical Center; Key words: interferon/mental disorders/psychotic
4
Department of Psychiatry and; 5Department of Behavioral disorders/adverse effects
Neurosciences, Oregon Health and Science University, Portland,
Oregon; 6The J.E.N.S. Laboratory, Portland VA Medical Center;
7
Department of Internal Medicine, Oregon Health and Science
University, Portland 97239, Oregon
Introduction

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Chronic hepatitis C (HCV) infects approximately 1.8% of
Background: Despite disproportionately high rates of hepa- adults and 5.4% of veterans in the United States,1,2 and
titis C (HCV) among patients with severe mental illness, to adults with schizophrenia (SCHZ) or schizoaffective dis-
date, there is scant empirical data available regarding anti- order are at significantly higher risk for HCV. One study
viral therapy outcomes within this population. Objective: prospectively tested 931 individuals with serious mental
To compare antiviral therapy completion and response illness and found that 19.6% were confirmed to have
rates between HCV patients with vs those without schizo- HCV.3,4 Utilizing a Veterans Healthcare Administration
phrenia (SCHZ). Methods: A regional Veterans Health- (VHA) medical record database, our group found that, of
care Administration database was used to identify those tested for HCV, 9.9% (219/2207) of veterans with
veterans meeting criteria for this retrospective chart review. SCHZ and no documented history of substance-use
All patients confirmed to have SCHZ and to have received disorder (SUD) were confirmed to have HCV, compared
antiviral therapy between 1998 and 2006 (n 5 30) were com- with 31.1% (943/3029) of veterans with comorbid SCHZ
pared with a control group of demographically matched and SUD.5
(HCV genotype, age, race, gender) patients with no history Although the prevalence of HCV among seriously
of SCHZ (n 5 30). Results: For HCV patients with geno- mentally ill adults is disproportionately high, many pro-
type 1, antiviral completion, end of treatment response viders are reluctant to treat psychiatric patients with
(ETR), and sustained viral response (SVR) rates did not HCV because of concerns that antiviral therapy may ex-
significantly differ between groups. For those with geno- acerbate psychiatric symptoms or that patients with psy-
types 2 and 3 combined, antiviral therapy completion rates chiatric illness may be less compliant with antiviral
did not significantly differ between groups; however, the therapy.6 In fact, several recent studies demonstrate
SCHZ group was significantly (P < 0.050) more likely that individuals with psychiatric comorbidities are signif-
to achieve an ETR and an SVR. For all genotypes com- icantly less likely to be deemed eligible for or to receive
bined, the SCHZ patients were no more likely than controls antiviral therapy for HCV.810 Our retrospective VHA
to discontinue therapy early for psychiatric symptoms, database study found that patients with comorbid
medical complications, or other adverse events, and groups SCHZ and SUD were significantly less likely to receive
did not significantly differ in terms of hospitalization rates antiviral therapy for HCV relative to controls without
during antiviral therapy. Conclusion: Our retrospective SCHZ or SUD.5 Another VHA database study demon-
chart review suggests that patients with SCHZ complete strated that SUD, major depression, mild depression, bi-
and respond to antiviral therapy for HCV at rates compa- polar disorder, and SCHZ were each independently
predictive of nontreatment for HCV.11
1 Despite high rates of psychiatric disorders among
To whom correspondence should be addressed; Portland VA
Medical Center (P3MHDC), 3710 Southwest US Veterans Hos- patients with HCV, there are limited data on HCV treat-
pital Road, Portland 97239, OR; tel: 503-220-8262 ext. 54689; fax: ment outcomes specific to psychiatric populations. One
503-220-3499; e-mail: marilyn.huckans@va.gov. study of 33 HCV positive veterans treated with antiviral
The Author 2008. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
For permissions, please email: journals.permissions@oxfordjournals.org.
165
M. Huckans et al.

therapy for 6 months found that 6/19 (32%) patients with had been ruled out). Three additional cases were excluded
psychiatric comorbidities developed severe neuropsychi- because they had not yet initiated or completed antiviral
atric side effects leading to antiviral therapy discontinu- therapy. A total of 30 subjects were included in the final
ation, compared with 2/14 (14%) patients without SCHZ group. In several of these cases (n = 5/30), the med-
psychiatric comorbidities; both groups had similar viro- ical record indicated that symptoms of SCHZ were pres-
logical response rates.12 Another prospective study found ent during the study period and that SCHZ was the most
that, compared with nonpsychiatric controls (n = 23), probable working diagnosis throughout the record. In all
patients with psychiatric comorbidities (n = 16) were other cases (n = 25/30), the medical record indicated that
no more likely to drop out of HCV treatment, to expe- there was a definitive diagnosis of SCHZ during the study
rience neuropsychiatric or other side effects, or to be period.
nonresponders.13 A larger retrospective chart review sim- The VISN 20 CHIPS data warehouse was then used to
ilarly revealed that patients with psychiatric and/or SUDs randomly identify a demographically case-matched con-
(n = 294) were as likely as controls without psychiatric trol group (n = 30). We then conducted a thorough med-
disorders (n = 353) to complete and respond to antiviral ical record review to confirm that patients met full
therapy for HCV.14 Each of these studies combined psy- eligibility criteria for the control group: (1) laboratory re-
chiatric diagnoses together, so it remains unclear whether cord and progress notes confirmed that the patient was
specific diagnostic groups yield differential risk for psy- treated for HCV with antiviral therapy and (2) there
chiatric side effects, noncompliance, or poor response. was no evidence within the medical record that the pa-
While several case studies report on individuals with tient ever met criteria for SCHZ. In total, 10 cases
SCHZ who have successfully adhered and responded were reviewed and then excluded because 6 had not

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to antiviral therapy for HCV, larger empirical studies in- yet initiated or completed antiviral therapy and 4 had in-
vestigating HCV treatment outcomes specific to patients sufficient progress notes to allow review. We made every
with SCHZ have not yet been published.15,16 The primary effort to match cases by age (65 years), HCV genotype,
objective of this study was to compare rates of antiviral race, and gender. However, in order to accommodate ge-
completion, reasons for early treatment termination, and notype matching, one SCHZ patient was matched to one
viral response between HCV patients with vs those with- control who was 7 years younger. Also, one African
out SCHZ. American patient with SCHZ was matched to one Cau-
casian control, and one Caucasian with SCHZ was
matched to one African American control. Additionally,
4 patients had unknown genotypes. In 2 of these cases
Methods
(both SCHZ patients), genotyping was completed, but
We conducted a retrospective medical record review of all the results were indeterminate. In the 2 other cases
patients with SCHZ who received antiviral therapy for (one control and one SCHZ), genotyping records were
HCV between 1998 and 2006 at VHA facilities in the Vet- unavailable in the chart. Therefore, the one SCHZ
erans Integrated Service Network 20 (VISN 20) (Oregon, with unavailable genotyping records (recommended for
Washington, Idaho, and Alaska). Using the VISN 20 24 weeks of antiviral therapy) was matched to a control
CHIPS data warehouse, which extracts data from elec- with genotype 3 (recommended for 24 weeks of antiviral
tronic patient medical records at each facility, we first therapy). One SCHZ with indeterminate results (recom-
identified a pool of potential study candidates using mended for 48 weeks of antiviral therapy) was matched
broad search termspatients who had a detectable to the one control with unavailable genotyping records
HCV viral load by polymerase chain reaction, were pre- (recommended for 24 weeks of therapy). The other
scribed antiviral therapy between 1998 and 2006 and had SCHZ with indeterminate results (recommended for 48
a diagnosis of SCHZ on at least one clinic encounter or weeks of therapy) was matched to a control with geno-
their problem list (n = 76). Complete electronic medical type 2 (recommended for 24 weeks of therapy).
records were then reviewed to ensure patients met full el- Complete medical record reviews were conducted us-
igibility criteria for inclusion: (1) laboratory record and ing structured data collection forms to collect data on de-
progress notes confirmed that the patient was treated for mographics, mental health history and treatment,
HCV with antiviral therapy and (2) across the medical psychotropic/antiviral/growth factor prescriptions, liver
record progress notes, qualified providers evidenced rea- biopsy and laboratory results, reasons for incomplete an-
sonable consensus that the patient met criteria for SCHZ. tiviral treatment, end of treatment response (ETR), sus-
Forty-three of the initial 76 cases (56.6%) were excluded tained viral response (SVR), and emergency room visits/
because chart notes revealed they did not have SCHZ (eg, inpatient hospitalizations during antiviral therapy.
although SCHZ had been listed on at least one encounter, In order to ensure the reliability and validity of our
chart notes indicated that the patient had no history of data collection forms and procedures, 7/60 (11.7%, 4
SCHZ, the patient had been clearly diagnosed with other SCHZ, 3 controls) records were reviewed by 2 separate
psychiatric disorders or SUDs, or the diagnosis of SCHZ reviewers, blind to each others responses. Interrater
166
Effects of Schizophrenia on Hepatitis C Antiviral Therapy

agreement on items ranged from 71.4% to 100%; the av- gorical independent variables on a single step, and
erage rate of agreement was 93.3%. SVR entered as the dependent variable.

Definitions
Antiviral therapy included either monotherapy or com- Results
bination therapy with pegylated or nonpegylated inter-
Baseline characteristics for the total sample and for each
feron and, in the case of combination therapy,
group are included in table 1. The total sample (n = 60)
ribavirin. When available, liver biopsy results included
was predominantly male, Caucasian, and middle aged.
both grade of inflammation and stage of liver disease.
Due to case matching, groups did not differ in terms
Reasons for early discontinuation of antiviral therapy
of demographic variables or HCV genotype. Within
were included as described by the treating clinicians
the total sample, 46.7% had genotype 1 and 46.7% had
and were not mutually exclusive. Treatment completion
either genotype 2 or 3. The majority of patients had a life-
was defined as a patient completing either 80% or 100%
time history of alcohol-use disorder (65.0%), but only
(analyzed separately) of the recommended length of an-
7.7% of these patients were using within 6 months of an-
tiviral treatment as indicated by treating providers; typ-
tiviral therapy. Half of the total sample had a lifetime his-
ically, recommended treatment length was 24 weeks for
tory of other SUD (50.0%), and 26.7% of these patients
genotypes 2 and 3 and 48 weeks for genotype 1 and in-
were using within 6 months of antiviral therapy. Groups
determinate genotypes. ETR was defined as an undetect-
did not significantly differ in terms of rates of alcohol-use
able HCV viral load upon treatment termination. SVR
disorders or other SUDs. High rates of active psychiatric

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was defined as an undetectable HCV viral load at least
disorder (other than SCHZ) were present across both
6 months after treatment termination. Psychiatric disor-
groups. As expected, compared with controls, the SCHZ
ders and SUDs were based on definitions in the Diagnos-
group was significantly more likely to have been prescribed
tic and Statistical Manual of Mental Disorders, Fourth
psychotropic medications at baseline and to have been
Edition.17 Alcohol-use disorders included abuse as well
hospitalized for psychiatric reasons within 5 years of anti-
as dependence. SUDs included abuse of or dependence
viral therapy. Only one patient in the SCHZ group had no
on any substance other than alcohol or nicotine. Lifetime
evidence of psychotropic medication prescriptions at base-
history of a disorder was based on evidence of the disor-
line. This patient reportedly declined psychotropic medica-
der at any point in the medical record. Active diagnoses
tions and providers felt this to be acceptable because his
were based on diagnoses addressed in patient progress
course included predominantly negative symptoms and rel-
notes within 6 months of antiviral therapy initiation. Al-
atively few positive symptoms of SCHZ.
cohol and drug use was based on progress notes and urine
As expected in patients receiving antiviral therapy,
drug analysis results. A patient was considered to be re-
most patients within the total sample evidenced abnor-
ceiving alcohol or substance-abuse therapy if they were
mally high alanine aminotransferase (75.0%) and aspar-
followed by any addiction specialist for individual or
tate aminotransferase (70.2%) baseline concentrations.
group therapy or case management (not just medication
Of those with available liver biopsy results within the to-
management) to specifically address SUD. A patient was
tal sample, 51.6% evidenced advanced stages of liver dis-
considered to be receiving mental health services if they
ease (stage 3 or 4) and 39.3% evidenced advanced
were seen by any mental health specialist (eg, psychiatrist,
inflammation (grade 3 or 4). Groups did not significantly
psychiatric nurse practitioner, psychologist, mental
differ in terms of liver functioning laboratory tests or bi-
health therapist, psychiatric social worker). A patient
opsy results.
was considered to be receiving psychotropic medications
Table 2 compares antiviral completion and response
regardless of who prescribed them (eg, primary care
rates across groups, for each genotype subgroup, based
provider).
on intention to treat. For all genotypes combined,
60.0% completed 100% of the recommended treatment
Statistical Analysis length, 61.7% achieved an ETR, and 43.3% achieved
Groups were compared in terms of characteristics before, an SVR. There was a trend toward the SCHZ patients
during, and after antiviral therapy. Antiviral completion being less likely than controls to complete 80% of the rec-
and response rate comparisons were also subgrouped by ommended treatment length, but groups were equally
genotype. For continuous variables, Mann-Whitney U likely to complete 100% of treatment. Groups were
tests were used to account for nonnormal distributions. also equally likely to achieve an ETR, and SCHZ patients
Dichotomous variables were evaluated with chi-square were significantly more likely to achieve an SVR. For ge-
statistics if all expected cell counts exceeded 5; otherwise, notype 1, antiviral completion and response rates did not
Fisher exact tests were used. A post hoc binary logistic significantly differ between groups. For genotypes 2 and
regression with both groups combined was also con- 3 combined, antiviral therapy completion rates were not
ducted, with selected treatment factors entered as cate- significantly different between SCHZ and control
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M. Huckans et al.

Table 1. Baseline Characteristics of Patients Receiving Antiviral Therapy for HCV

Total Sample Controls Schizophrenics P

Total N 60 30 30
Demographics
Age (mean years 6 SD) 50.4 6 4.9 50.7 6 4.7 50.2 6 5.1 1.000
Male gender 58 (96.7%) 29 (96.7%) 29 (96.7%) 1.000
Caucasian 55 (91.7%) 27 (90.0%) 28 (93.3%) 1.000
Vietnam era veteran 47 (78.3%) 21 (70.0%) 26 (86.7%) 0.117
Substance-use history
Lifetime history of
Alcohol-use disorder 39 (65.0%) 18 (60.0%) 21 (70.0%) 0.417
Other drug-use disorder 30 (50.0%) 12 (40.0%) 18 (60.0%) 0.121
Injection drug use 24/27 (88.9%) 9/11 (81.8%) 15/16 (93.8%) 0.549
Prior to antiviral therapy, in remission for at least
6 mo from
Alcohol-use disordera 36/39 (92.3%) 18/18 (100.0%) 18/21 (85.7%) 0.235
Drug-use disorderb 22/30 (73.3%) 8/12 (66.7%) 14/18 (77.8%) 0.678
Psychiatric history
Active diagnoses (6 mo prior to antiviral therapy)
Mood disorders 18 (30.0%) 8 (26.7%) 10 (33.3%) 0.573
PTSD 15 (25.0%) 7 (23.3%) 8 (26.7%) 0.766

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Other anxiety disorders 4 (6.7%) 2 (6.7%) 2 (6.7%) 1.000
Personality disorders 2 (3.3%) 0 (0.0%) 2 (6.7%) 0.492
Psychiatric hospitalizations (5 y prior to antiviral therapy)
Mean number 1.00 6 2.64 0.03 6 0.18 1.97 6 3.50 <0.001***
Any 14 (23.3%) 1 (3.3%) 13 (43.3%) <0.000***
Psychotropic medications (6 mo prior to antiviral therapy) 45 (75.0%) 16 (53.3%) 29 (96.7%) <0.001***
Medical characteristics
ALT (mean U/l 6 SD)/n 118.96 93.5/56 126.26 109.7/28 111.66 75.1/28 0.941
High ALT 42/56 (75.0%) 23/28 (82.1%) 19/28 (67.9%) 0.217
High AST 40/57 (70.2%) 19/29 (65.5%) 21/28 (75.0%) 0.434
Histological grade of inflammation
12 17/28 (60.7%) 7/11 (63.6%) 10/17 (58.8%) 1.000
34 11/28 (39.3%) 4/11 (36.4%) 7/17 (41.2%) 1.000
Histological stage of liver disease
12 15/31 (48.4%) 8/14 (57.1%) 7/17 (41.2%) 0.376
34 16/31 (51.6%) 6/14 (42.9%) 10/17 (58.8%) 0.376
HCV genotyping completed 58 (96.7%) 29 (96.7%) 29 (96.7%) 1.000
Unavailable/indeterminate 4 (6.7%) 1 (3.3%) 3 (10.0%) 0.612
Genotype 1 28 (46.7%) 14 (46.7%) 14 (46.7%) 1.000
Genotype 2 14 (23.3%) 7 (23.3%) 7 (23.3%) 1.000
Genotype 3 14 (23.3%) 8 (26.7%) 6 (20.0%) 0.542
Genotype 2 or 3 28 (46.7%) 15 (50.0%) 13 (43.3%) 0.605

Note: HCV, hepatitis C; SD, standard deviation; PTSD, posttraumatic stress disorder; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; NOS, not otherwise specified; SCHZ, schizophrenia. Data expressed as n, with (%) in terms of n over total N, unless
otherwise indicated. Controls include patients with no history of SCHZ or schizoaffective disorder. Schizophrenics include patients
with diagnoses of SCHZ or schizoaffective disorder. Substance-use and psychiatric disorders were based on definitions in the
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Depressive disorders included major depressive disorders,
dysthymic disorders, depressive disorder NOS, mood disorders due to medical conditions, and mood disorder NOS. PTSD was
recorded separately from other anxiety disorders. Other anxiety disorders included panic disorder, agoraphobia, specific phobias, social
phobias, generalized anxiety disorder, anxiety disorder due to medical conditions, anxiety disorder NOS, and adjustment disorders.
Personality disorders included all subtypes including personality disorder NOS. A psychiatric diagnosis was considered active if
providers documented and therefore addressed the diagnosis in patient progress notes within 6 mo of antiviral therapy initiation.
P values reflect differences between the controls and schizophrenics.
a
Indicates number of patients who abused alcohol during antiviral therapy out of those with lifetime history of an alcohol-use disorder.
b
Indicates number of patients who abused illicit drugs out of those with a lifetime history of a drug-use disorder.
***P  0.001.

groups; however, the SCHZ group was significantly more received combination therapy with ribavirin (96.7%) and
likely than controls to achieve an ETR and an SVR. only 2 patients received monotherapy (one in each
Table 3 compares antiviral therapy course characteris- group). Most patients were prescribed peginterferon
tics across groups. Within the total sample, most patients alfa-2a (58.3%) or peginterferon alfa-2b (10.0%), but
168
Effects of Schizophrenia on Hepatitis C Antiviral Therapy

Table 2. Antiviral Therapy Completion and Response Rates by Genotype for Patients with Hepatitis C

Total Sample Controls Schizophrenics P

All genotypes
Total N 60 30 30
Treatment completion (100%) 36 (60.0%) 20 (66.7%) 16 (53.3%) 0.292
Treatment completion (80%) 39 (65.0%) 23 (76.7%) 16 (53.3%) 0.058
ETR (intention to treat) 37 (61.7%) 16 (53.3%) 21 (70.0%) 0.184
SVR (intention to treat) 26 (43.3%) 9 (30.0%) 17 (56.7%) 0.037*
Genotype 1
Total N 28 14 14
Treatment completion (100%) 14 (50.0%) 8 (57.1%) 6 (42.9%) 0.450
Treatment completion (80%) 15 (53.6%) 9 (64.3%) 6 (42.9%) 0.256
ETR (intention to treat) 12 (42.9%) 6 (42.9%) 6 (42.9%) 1.000
SVR (intention to treat) 8 (28.6%) 3 (21.4%) 5 (35.7%) 0.678
Genotypes 2 and 3
Total N 28 15 13
Treatment completion (100%) 22 (78.6%) 12 (80.0%) 10 (76.9%) 1.000
Treatment completion (80%) 24 (85.7%) 14 (93.3%) 10 (76.9%) 0.311
ETR (intention to treat) 23 (82.1%) 10 (66.7%) 13 (100.0%) 0.044*
SVR (intention to treat) 16 (57.1%) 6 (40.0%) 10 (76.9%) 0.049*

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Note: ETR, end of treatment response; SVR, sustained viral response; SCHZ, schizophrenia. Data expressed as n, with (%) in terms of
n over total N within the genotype grouping. Controls include patients with no history of SCHZ or schizoaffective disorder.
Schizophrenics include patients with active diagnoses of SCHZ or schizoaffective disorder during the study period. Treatment
completion was defined as completion of 80% or 100% (analyzed separately) of the length of treatment recommended by the treating
provider. ETR and SVR rates were calculated based on intention to treat. P values reflect differences between the controls and
schizophrenics.
*P < 0.050.

31.7% were prescribed nonpegylated interferon (inter- adverse events; however, the SCHZ patients were signif-
feron alfacon-1, interferon alfa-2a, or interferon alfa- icantly more likely to discontinue due to noncompliance
2b). Although groups did not differ in terms of rates issues.
of monotherapy vs combination therapy, controls were Relatively few patients in either group required emer-
significantly more likely than SCHZ patients to have re- gency room visits or inpatient hospitalizations during an-
ceived pegylated vs regular interferon. tiviral therapy, with no significant differences between
Table 3 also compares reasons for early discontinua- groups.
tion of antiviral therapy across groups. Of those who Table 3 additionally compares selected treatment fac-
did not complete 100% of the recommended length of an- tors present during antiviral therapy across groups.
tiviral treatment, 20.8% discontinued early for neuropsy- Within the total sample, despite high rates of lifetime al-
chiatric side effects, 37.5% for medical side effects, 25.0% cohol-use disorder and SUD, only one patient was fol-
for noncompliance issues, and 29.2% for inadequate viral lowed by an addiction specialist during antiviral
response early into treatment. Only 3 patients discontin- therapy. During antiviral therapy, 76.7% of patients re-
ued due to serious adverse events. Specifically, one con- ceived mental health services from a mental health spe-
trol discontinued for interferon-induced sarcoidosis and cialist and 61.7% had psychotropic medication dose
one SCHZ patient discontinued for gastrointestinal adjustments. As expected, during antiviral therapy, com-
bleeding. A second SCHZ patient discontinued antiviral pared with the control group, the SCHZ group was sig-
therapy due to HCV-related complications, unrelated to nificantly more likely to have received mental health
antiviral therapy, which led to his death 8 days later. Only services from a mental health specialist and to have
one patient (a control) was lost to follow-up during treat- been prescribed psychotropic medications by any pro-
ment. No patients with a history of alcohol abuse were vider; however, groups did not significantly differ in
known to be drinking during antiviral therapy. Although terms of other selected treatment factors.
16.7% of patients with a history of other SUD were using In order to determine whether patients were more or
illicit substances during antiviral therapy (4 were using less likely to achieve an SVR if our selected treatment fac-
marijuana, one was using nonprescribed morphine), no tors were present during antiviral therapy, a priori chi-
patient discontinued antiviral therapy early due to sub- square and Fisher exact tests were used to compare
stance use. The SCHZ patients were no more likely patients with and without an SVR regardless of diagnostic
than controls to have discontinued treatment early for group. There was one trend (P = 0.059), suggesting
neuropsychiatric symptoms, medical side effects, or other that patients who achieved an SVR were more likely
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M. Huckans et al.

Table 3. Antiviral Therapy Course Characteristics for Patients Treated for Hepatitis C

Total Sample Controls Schizophrenics P

Antiviral therapy type


Total N 60 30 30
Monotherapy 2 (3.3%) 1 (3.3%) 1 (3.3%) 1.000
Combination therapy 58 (96.7%) 29 (96.7%) 29 (96.7%) 1.000
Peginterferon alfa-2a 35 (58.3%) 19 (63.3%) 16 (53.3%) 0.432
Peginterferon alfa-2b 6 (10.0%) 6 (20.0%) 0 (0.0%) 0.024*
Nonpegylated interferon 19 (31.7%) 5 (16.7%) 14 (46.7%) 0.012*
Reasons for early discontinuation from
antiviral therapy
N (patients with early discontinuation) 24 10 14
Neuropsychiatric side effects 5/24 (20.8%) 3/10 (30.0%) 2/14 (14.3%) 0.615
Alcohol/substance-abuse relapse 0/24 (0.0%) 0/10 (0.0%) 0/14 (0.0%) 1.000
Medical side effects 9/24 (37.5%) 3/10 (30.0%) 6/14 (42.9%) 0.678
Serious adverse events 3/24 (12.5%) 1/10 (10.0%) 2/14 (14.3%) 1.000
Noncompliance with treatment 6/24 (25.0%) 0/10 (0.0%) 6/14 (42.9%) 0.024*
Inadequate viral response 7/24 (29.2%) 5/10 (50.0%) 2/14 (14.3%) 0.085
Lost to follow-up 1/24 (3.3%) 1/10 (10.0%) 0/14 (0.0%) 1.000
Adverse events during antiviral therapy
Total N 60 30 30

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Emergency room visits
Psychiatric 2 (3.3%) 0 (0.0%) 2 (6.7%) 0.492
Medical 11 (18.3%) 3 (10.0%) 8 (26.7%) 0.095
Inpatient hospitalization
Psychiatric 2 (3.3%) 0 (0.0%) 2 (6.7%) 0.492
Medical 5 (8.3%) 1 (3.3%) 4 (13.3%) 0.353
Alcohol abusea 0/38 (0.0%) 0 (0.0%) 0 (0.0%) 1.000
Drug abuseb 5/30 (16.7%) 2/12 (16.7%) 3/18 (16.7%) 1.000
Selected treatment factors present during
antiviral therapy
Total N 60 30 30
Alcohol/substance-abuse therapy 1 (1.7%) 0 (0.0%) 1 (3.3%) 1.000
Mental health services 46 (76.7%) 17 (56.7%) 29 (96.7%) <0.001***
Psychotropic medications 51 (85.0%) 22 (73.3%) 29 (96.7%) 0.026*
Psychotropic medication changes 37 (61.7%) 17 (56.7%) 20 (66.7%) 0.426
Antiviral dose adjustments 21 (35.0%) 12 (40.0%) 9 (30.0%) 0.417
Growth factor prescriptions 6 (10.0%) 5 (16.7%) 1 (3.3%) 0.195

Note: Data expressed as n, with (%) in terms of n over total N, unless otherwise indicated; SCHZ, schizophrenia. Controls include
patients with no history of SCHZ or schizoaffective disorder. Schizophrenics include patients with active diagnoses of SCHZ or
schizoaffective disorder during the study period. Monotherapy includes pegylated and regular interferon without ribavirin.
Combination therapy includes ribavirin plus pegylated or regular interferon. Reasons for incomplete treatment are not mutually
exclusive because patients may have had multiple reasons for early discontinuation. Substance-abuse therapy refers to therapy,
counseling, or case management services (not just medication management) by an addiction specialist during antiviral therapy. Mental
health services refer to medication management, therapy, counseling, or case management by a mental health specialist during antiviral
therapy. Psychotropic medications were counted if any provider (eg, mental health specialist, primary care provider) prescribed any
psychotropic medications during antiviral therapy. Psychotropic medication changes refer to any initiation, discontinuation, or dose
adjustment to psychotropic medications during antiviral therapy. Antiviral dose adjustments refer to any dose adjustments to
interferon or ribavirin during antiviral therapy. P values reflect differences between the controls and schizophrenics.
a
Indicates number of patients who abused alcohol during antiviral therapy out of those with lifetime history of an alcohol-use disorder.
b
Indicates number of patients who abused illicit drugs out of those with a lifetime history of a drug-use disorder.
*P < 0.050, ***P < 0.001.

to have received mental health services from a mental (odds ratio = 12.2, confidence interval = 1.2125.2, P =
health specialist during antiviral therapy than patients 0.035); no other treatment factors were significantly pre-
who did not achieve an SVR (88.5% vs 67.6%, P = dictive of SVR.
0.059). Comparisons did not approach significance (P <
0.100) for other selected treatment factors. A post hoc
Discussion
binary logistic regression similarly revealed that patients
who received mental health services during antiviral Our retrospective chart review suggests that patients with
therapy had a higher likelihood of achieving an SVR SCHZ complete and respond to antiviral therapy for
170
Effects of Schizophrenia on Hepatitis C Antiviral Therapy

HCV at rates comparable to patients without SCHZ. Ad- an increasing number of programs have successfully uti-
ditionally, our results indicate that patients with SCHZ lized a multidisciplinary approach to HCV care.18
are no more likely to terminate treatment early due to One question that arises is why patients with SCHZ
psychiatric side effects, substance-abuse relapse, or other had higher SVR rates relative to controls (with differen-
adverse events. Among those who terminated treatment ces reaching significance for all genotypes combined and
early, patients with SCHZ were more likely than controls for genotypes 2 and 3 combined). This finding is partic-
to have noncompliance listed as a reason for early discon- ularly surprising given that SCHZ patients were more
tinuation, but, based on intention to treat, patients with likely than controls to have received regular interferon,
SCHZ were at least as likely as controls to achieve an which has been shown to have lower response rates
ETR and an SVR. In summary, we found no evidence than pegylated interferon. Our study design did not allow
to suggest that a diagnosis of SCHZ uniformly contrain- us to directly test possible explanations, but we did find
dicates antiviral therapy for HCV. Nevertheless, our that patients with SCHZ were more likely than controls
modest sample size limited our power to detect differen- to have received mental health services and psychotropic
ces across groups, and replication of results using larger medications during antiviral therapy. Moreover, we
samples is required to confirm conclusions and further found a trend suggesting that, for both groups combined,
clarify outcomes within this population. patients who achieved an SVR were more likely to have
Although additional studies are clearly needed, our received mental health services from a mental health spe-
data and the disproportionately high rates of HCV cialist during antiviral therapy than those who did not
among patients with SCHZ35 suggest that excluding achieve an SVR. Future studies should examine whether
this population from antiviral therapy is likely not justi- mental health services or other treatment factors help

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fied. Indeed, both the National Institutes of Health and promote completion and response rates in various pop-
the VHA have issued HCV treatment guidelines in which ulations.
they recommend establishment of screening tests for all Our studys primary limitations include its relatively
groups at high risk of HCV infection and the extension small sample size and its reliance on categorical data,
of appropriate treatment to special populations infected which in combination may have limited our power to de-
with HCV, such as those with psychiatric disorders.18 tect group differences. For example, although patients
Our data would, therefore, support treatment of patients with SCHZ did have higher rates of emergency room vis-
with SCHZ who otherwise meet medical criteria for an- its and inpatient hospitalizations during interferon ther-
tiviral therapy. apy than patients without SCHZ, these differences did
Of note, our study design does not directly explore not reach statistical significance, raising the possibility
whether special treatment precautions are necessary to of type II error. Results should, therefore, be interpreted
optimize outcomes and safety for patients with SCHZ. cautiously, and prospective studies are needed to better
Although empirically validated treatment guidelines do explore the effect of interferon therapy on medical and
not exist for this population, several groups provide psychiatric outcomes in patients with SCHZ.
HCV treatment recommendations based on their clinical Our study design has several additional limitations.
expertise with psychiatrically complex patients.1820 In First, the retrospective chart review design precluded
general, these groups recommend that psychiatric use of standardized side effect and symptom rating scales,
patients be offered antiviral therapy for HCV if they so it is unclear to what extent providers may have incon-
are medically eligible, if they are able to attend medical sistently documented adverse events. Second, it is unclear
appointments regularly, and if they are willing to engage to what extent patients who were selected for antiviral
in psychiatric and substance-abuse therapy during anti- therapy may have differed from patients with SCHZ
viral therapy. Education about disease course, treatment who did not receive antiviral therapy. Providers may
efficacy, and side effects is strongly encouraged prior to have had a tendency, eg, to select certain SCHZ patients
treatment initiation; the Northwest Hepatitis C Resource for antiviral therapy because they were psychiatrically
Center at the Portland VA Medical Center, eg, offers stable, more likely to attend medical appointments, or
a one-time HCV education group to individuals initially had stronger psychosocial supports or resources. Lastly,
diagnosed with HCV.21 Mental health and substance- because so few patients with SCHZ have received antivi-
abuse screenings are conducted during this education ral therapy for HCV, we opted to include all patients who
group and prior to treatment initiation. Individuals received any type of monotherapy or combination ther-
who screen positive are referred to psychiatric and sub- apy with ribavirin, including pegylated and regular inter-
stance-abuse treatment programs prior to antiviral ther- ferons. Although response rates appear comparable to
apy initiation and for monitoring of symptoms at regular those found in clinical trials,22,23 they are not specific
intervals throughout antiviral therapy. In general, psy- to one type of interferon therapy, and our small sample
chiatric medication adjustments and increased supports size precludes meaningful subanalyses by interferon type.
may be required throughout antiviral therapy should However, because the percentage of those on combina-
symptom exacerbations or relapses arise. To this end, tion therapy, with the majority being on peginterferon
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M. Huckans et al.

alfa-2a plus ribavirin, did not significantly differ across therapy at initial evaluation in veterans with chronic hepatitis
groups, we believe our conclusion that group outcomes C. J Clin Gastroenterol. 2004;38:530534.
were similar remains valid. 7. Sylvestre DL, Loftis JM, Hauser P, et al. Co-occurring hepa-
titis C, substance use, and psychiatric illness: treatment issues
Despite limitations, our design has certain important and developing integrated models of care. J Urban Health.
strengths. To our knowledge, our study represents the 2004;81:719734.
only published empirical data on HCV treatment out- 8. Rigsby M, Burgess J, Davey V, et al. Patients with chronic
comes for patients with SCHZ. Unlike previous research, hepatitis C: VA treatment recommendations, version 5.0.
our study specifically focuses on patients with SCHZ, Fed Pract. 2003;20:133.
rather than combining patients with diverse psychiatric 9. Bini EJ, Brau N, Currie S, et al. Prospective multicenter study
diagnoses together. In order to ensure validity, we con- of eligibility for antiviral therapy among 4,084 U.S. veterans
with chronic hepatitis C virus infection. Am J Gastroenterol.
firmed all diagnoses by thorough medical record review 2005;100:17721779.
and established high interrater agreement for individual 10. Morrill JA, Shrestha M, Grant RW. Barriers to the treatment
data points and the overall study. Moreover, in addition of hepatitis C. Patient, provider, and system factors. J Gen In-
to case matching by salient demographic features, we tern Med. 2005;20:754758.
demonstrated that our SCHZ and control groups were 11. Butt AA, Justice AC, Skanderson M, Rigsby MO, Good CB,
also equivalent in terms of liver disease severity and sub- Kwoh CK. Rate and predictors of treatment prescription for
stance-abuse history. Thus, we have eliminated impor- hepatitis C. Gut. 2007;56:385389.
tant factors that could have otherwise differentially 12. Ho SB, Nguyen H, Tetrick LL, Opitz GA, Basara ML,
Dieperink E. Influence of psychiatric diagnoses on interferon-
impacted group outcomes. Based on these findings, alpha treatment for chronic hepatitis C in a veteran population.
HCV patients with SCHZ should be considered potential

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Am J Gastroenterol. 2001;96:157164.
candidates for antiviral therapy. 13. Schaefer M, Schmidt F, Folwaczny C, et al. Adherence and
mental side effects during hepatitis C treatment with inter-
feron alfa and ribavirin in psychiatric risk groups. Hepatol-
Funding ogy. 2003;37:443451.
Stanley Medical Research Institute (05R-981). 14. Chainuvati S, Khalid SK, Kancir S, et al. Comparison of hep-
atitis C treatment patterns in patients with and without psy-
chiatric and/or substance use disorders. J Viral Hepat.
Acknowledgments 2006;13:235241.
15. Dobmeier M, Frick E, Frank S, Franke C, Wolfersdorf M.
For their time and expertise, the authors thank the VA Schizophrenic psychosis: a contraindication for treatment of
Hepatitis C Resource Center, Aaron Blackwell, John hepatitis C with interferon alpha? Pharmacopsychiatry. 2000;
Davidson, Larry Dewey, Jason Dominitz, Nancy 33:7274.
Hedrick, David Indest, Emily Kizer, Alex Linke, 16. Mistler LA, Brunette MF, Rosenberg SD, Vidaver RM,
Benjamin Morasco, Julie Nelligan, Laura Parisi, Luckoor R, Iber M. Case report of 3 patients with severe
Byung Park, Murray Raskind, Rebekah Rein, Anna mental illness and chronic hepatitis C virus infection treated
with interferon-alpha. Int J Psychiatry Med. 2006;36:449455.
Sasaki, Robert Socherman, Mark Ward, and Betsy
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