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Liver International ISSN 1478-3223

CLINICAL STUDIES

Factors associated with treatment failure of patients with psychiatric
diseases and injecting drug users in the treatment of genotype 2 or 3
hepatitis C chronic infection
Gerardo Alvarez-Uria1,2, Jeremy N. Day1,3, Anisa J. Nasir1, Susan K. Russell1 and Francisco Javier Vilar1
1 Monsall Unit, Department of Infectious Diseases, North Manchester General Hospital, Manchester, UK
2 Departament de Medicina, Universitat Autonoma de Barcelona, Barcelona, Spain
3 Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam

Keywords
antidepressive agents – depression – liver
cirrhosis – peginterferon – psychotic disorders

Correspondence
Gerardo Alvarez-Uria, Monsall Unit,
Department of Infectious Diseases, North
Manchester General Hospital, Delaunays Road,
Manchester M8 5RB, UK
Tel: 144 161 720 2730
Fax: 144 161 720 2680
e-mail: gerardouria@gmail.com
Received 20 September 2008
Accepted 6 November 2008
DOI:10.1111/j.1478-3231.2008.01958.x

Abstract
Background: Genotype 2/3 hepatitis C virus (HCV) has a good response to
treatment with peginterferon and ribavirin. Patients with psychiatric disorders
and injecting drug users (IDUs) are considered ‘difficult to treat’ and are often
excluded from treatment despite the lack of evidence supporting this decision.
Aims: To investigate the outcome and factors associated with treatment failure
in these groups. Methods: This is an observational study of a cohort of
patients infected by genotype 2/3 HCV. IDUs and patients with psychiatric
diseases were not excluded from treatment. We performed an intention-totreat analysis to evaluate factors related to treatment failure. Results: A
sustained virological response (SVR) was achieved in 91 of the 125 patients
treated (72.8%). Patients with chronic psychotic disorders or former IDUs had
SVR rates similar to other groups. After multivariate analysis, independent
factors associated with treatment failure were liver cirrhosis [odds ratio (OR)
3.4, 95% confidence interval (CI) 1.1–10.4], a history of depression and not
being on antidepressants at the commencement of HCV treatment (OR 4.4,
95% CI 1.2–16) and active IDUs (OR 7.3, 95% CI 1.77–30.4). Conclusions: Patients with a history of depression who were not receiving antidepressants
and active IDUs are more likely to fail treatment for genotype 2/3 HCV and
will need additional support.

Hepatitis C virus (HCV) chronic infection is a common
disease worldwide and may lead to liver cirrhosis and
hepatocellular carcinoma (1). Patients with genotype 2 or
3 HCV have better response rates to combination treatment with peginterferon and ribavirin than patients with
other genotypes. Studies have shown sustained virological responses (SVRs) of 74–82% (1).
The prevalence of injecting drug users (IDUs) and
psychiatric illnesses is high in patients infected by HCV
(2, 3). A recent literature review found at least a 50%
HCV prevalence in IDUs in 49 countries (4). HCV
prevalence among patients with psychiatric diseases is
not well known. In a Psychiatry Unit in Melbourne,
Australia, psychiatric inpatients had a 19.4% prevalence
of HCV seropositivity and high rates of risk behaviour
(5). Some physicians are reluctant to treat these patients
because of concerns regarding the risk of psychiatric side
effects of interferon, an expectation of poor adherence or
a risk of re-infection (6–8), and many of these patients
are excluded from receiving HCV treatment (9). However, the evidence supporting this exclusion is not strong
Liver International (2008)
c 2008 Blackwell Publishing Ltd
2008 The Authors. Journal compilation


c

and some of these patients will die of cirrhosis or
hepatocellular carcinoma.
It is particularly important to determine the safety and
efficacy of treating patients with psychiatric diseases or
IDUs who have genotype 2 or 3 HCV chronic infection
because of the high SVR rate and the shorter duration of
treatment compared with other HCV genotypes (1). The
benefits of treatment for these individuals may outweigh
the potential risks of a psychiatric decompensation.
Moreover, treatment success in IDUs may lead to a
reduction of HCV transmission.
In our Infectious Diseases Unit, we follow a policy of
no exclusion of patients with psychiatric diseases and
active IDUs as long as patients do not share drug
paraphernalia. They receive treatment under the same
conditions as other patients, with no additional support
other than that provided by their drug or psychiatric
services. The purpose of this observational study is to
assess whether being an IDU or having a psychiatric
disease is associated with having a poorer response to
treatment against genotype 2 or 3 HCV chronic infection

1051

HCV treatment in ‘difficult’ patients

and to investigate the factors associated with treatment
failure.
Patients and methods
Setting

This study was conducted in the Infectious Diseases Unit
at North Manchester General Hospital, Manchester, UK.
Patients

All patients with genotype 2 or 3 HCV chronic infection
who received treatment with peginterferon and ribavirin
from November 2003 until August 2006 were included in
this study.
Study design

The primary endpoint for analysis was the SVR, defined
as a negative HCV RNA 6 months after finishing treatment. Patients with undetectable HCV RNA at the end of
the treatment but in whom HCV RNA was not available 6
months after finishing treatment were excluded from the
analysis. HIV-co-infected patients were also excluded.
The history of psychiatric diseases and use of intravenous
drugs were assessed using a structured interview and
questionnaire on every patient.
Liver cirrhosis was defined as an Ishak fibrosis score of
5 or 6 on the liver biopsy or radiological signs of
cirrhosis. Current IDU was defined as use of injecting
drugs within 4 months of starting treatment or during
HCV treatment. A history of depression was defined as
previous depressive symptoms that required antidepressant drugs. Patients with a decrease in HCV RNA of
o 100-fold at the 12th week of treatment or a positive
HCV RNA at the 24th week or 6 months after finishing
treatment were considered treatment failures. Those who
failed to follow-up during treatment were also considered as failures.

Alvarez-Uria et al.

Results

One hundred and thirty-eight patients were treated
during the period of this study. Two patients with HIV
co-infection, and 11 patients who achieved undetectable
HCV RNA during treatment but who but did not have an
HCV RNA determination 6 months after the end of
treatment were excluded. Thus, 125 patients were included
in the analysis. Ninety-one patients (72.8%) achieved an
SVR. Analysis of the factors associated with treatment
failure is shown in Table 1. The group who did not achieve
an SVR was older. No significant differences were seen
between the different ethnic groups. A history of depression in the past was associated with treatment failure but
only in those patients not receiving antidepressant drugs at
the time of starting HCV treatment. Four patients who
had chronic psychotic disorders were treated, and all of
them achieved an SVR. The diagnosis of chronic psychotic
disorder was made previously by a psychiatrist and all four
patients were receiving depot administration of antipsychotic drugs. Active IDUs had a poorer response to
treatment but not former IDUs. Having liver cirrhosis or
having received previous treatment with peginterferon and
ribavirin were also related to treatment failure. After
multivariate analysis, significant differences persisted only
in those patients with previous episodes of depression who
were not on antidepressants, active IDUs and those with
liver cirrhosis.
Outcomes of treatment of the different subgroups are
presented in Table 2. Patients with no cirrhosis, no
history of depression and no history of IDU had a high
rate of SVR (86.4%) and only one patient (2.3%) did not
complete the treatment. The highest rate of dropout was
seen in patients with a history of depression who were
not receiving antidepressants when HCV treatment was
started. Active IDUs had the highest rate of relapse after
completing treatment.
Discussion

Treatment

Patients received peginterferon a-2a 180 mg/week or
peginterferon a-2b 1.5 mg/kg/week and ribavirin,
800 mg/day if o 65 kg, 1000 mg/day if between 65 and
85 kg and 1200 mg/day if 4 85 kg, regardless of the type
of peginterferon. Treatment duration was 24 weeks.
Statistical analysis

All data were analysed using the statistical package SPSS
(version 13.0, SPSS Inc., Chicago, IL, USA). The twosided Fisher’s exact test or the w2 test was used to
compare categorical variables as appropriate. The Student t-test was used to compare continuous variables if
normality criteria were met. Differences were considered
significant if P o 0.05. For multivariate analysis, those
variables significantly related to treatment failure on
univariate analysis were included in a model using
logistic regression analysis.

1052

The results of this study provide new information about
the safety and efficacy of the treatment with peginterferon in patients with psychiatric diseases and IDUs.
In our study, patients who reported previous depressive symptoms but were not receiving antidepressants at
the commencement of HCV treatment were less likely to
achieve an SVR and were more likely to fail to complete
their treatment. It has been reported that patients treated
with peginterferon and ribavirin can experience moderate to severe depressive symptoms in 39% of cases (10).
Antidepressant drugs are used to ease these symptoms
but patients may need 2–4 weeks to feel an improvement
(11).
Some small clinical trials have shown reduction of
related depressive symptoms when antidepressants were
given before starting HCV treatment (12–14). Although
we have to be cautious because of the observational
nature of this study, our results support the use of
antidepressants before treatment not only for easing


c

Liver International (2008)
c 2008 Blackwell Publishing Ltd
2008 The Authors. Journal compilation

Alvarez-Uria et al.

HCV treatment in ‘difficult’ patients

Table 1. Univariate and multivariate analyses of factors associated with treatment failure

Females
Age (years); mean (SD)
Weight 4 85 kg
Ethnic groups
Caucasians
Indian subcontinent
Afro-Caribbean
Diabetes mellitus
History of depression
Receiving antidepressants
Not receiving antidepressants
Chronic psychotic disorder
Injecting drug use
Former
Active
Genotype 3
Liver cirrhosis
Previous treatment with
peginterferon and ribavirin

Global (n = 125)

Sustained
virological
response (n = 91)

Failure
(n = 34)

P

37 (29.6)
41.3 (9.3)
26 (20.8)

30 (33)
40.2 (9.2)
17 (18.7)

7 (20.6)
44.1 (9.1)
9 (26.5)

0.17
0.038
0.34

76 (60.8)
46 (36.8)
3 (2.4)
9 (7.2)
34 (27.2)
21 (16.8)
13 (10.4)
4 (3.2)

54 (59.3)
35 (38.5)
2 (2.2)
8 (8.8)
20 (22)
14 (15.4)
6 (6.6)
4 (4.4)

22 (64.7)
11 (32.4)
1 (2.9)
1 (2.9)
14 (41.2)
7 (20.6)
7 (20.6)
0

0.58
0.53
1.0
0.44
0.032
0.49
0.042
0.57

60 (48)
10 (8)
113 (90.4)
20 (16)
5 (4)

44 (48.4)
4 (4.4)
81 (89)
10 (11)
1 (1.1)

16 (47.1)
6 (17.6)
32 (94.1)
10 (29.4)
4 (11.8)

0.9
0.024
0.51
0.012
0.019

Adjusted OR (95%
confidence interval)
1.03 (0.98–1.08)

4.4 (1.21–16)

7.34 (1.77–30.4)
3.43 (1.12–10.45)
1.41 (0.75–2.65)

Data are number (%) of patients, unless otherwise indicated.
Ishak fibrosis score of 5 or 6 in the liver biopsy or radiological signs of cirrhosis. Thirty-two patients did not have a liver biopsy.
OR, odds ratio; SD, standard deviation.

Table 2. Outcomes of hepatitis C virus treatment presented by subgroups
Sustained virological No response at
Relapse during the Relapse after completing Treatment not
response (n = 91)
12th week (n = 1) treatment (n = 5) the treatment (n = 10)
completed (n = 18)
No cirrhosis, no IDUs and no history
of depression (n = 44)
History of depression (n = 34)
On antidepressants (n = 21)
Not on antidepressants (n = 13)
IDUs (n = 70)
Former (n = 60)
Active (n = 10)
Liver cirrhosis (n = 20)

38 (86.4)

0

2 (4.5)

3 (6.8)

1 (2.3)

20 (58.8)
14 (66.7)
6 (42.6)
48 (68.6)
44 (73.3)
4 (40)
10 (50)

1 (2.9)
0
1 (7.7)
0
0
0
0

2 (5.9)
2 (9.5)
0
3 (4.3)
2 (3.3)
1 (10)
2 (10)

3 (8.8)
2 (9.5)
1 (7.7)
4 (5.7)
2 (3.3)
2 (20)
3 (15)

8 (23.5)
3 (14.3)
5 (38.5)
15 (21.4)
12 (20)
3 (30)
5 (25)

Data are number (%) of patients within the different subgroups.
IDUs, injecting drug users.

depressive symptoms but also for increasing the likelihood of treatment success. Unfortunately, we did not
administer a depression scale to patients at baseline. It is
uncertain whether all patients with a history of depression would benefit from pre-emptive antidepressive
treatment or only those with depressive symptoms at
baseline. Raison et al. (10) described a higher risk of
developing depressive symptoms in patients with higher
scores on a depression scale at baseline. However, this
was not seen in units with a multidisciplinary approach,
with high numbers of patients on antidepressants before
starting peginterferon and ribavirin (15). Larger studies
are needed to determine which group of patients would
benefit from pre-emptive treatment with antidepressants.
Liver International (2008)
c 2008 Blackwell Publishing Ltd
2008 The Authors. Journal compilation


c

Four patients with chronic psychotic disorders were
treated and all achieved an SVR without psychiatric
complications. Patients with chronic psychotic disorders
are frequently excluded from treatment based on a
hypothetical risk of psychiatric decompensation. Some
case reports describe psychotic episodes in patients
treated with interferon (16–20). Nevertheless, this is a
rare side effect of peginterferon (21) and treatment of
HCV with interferon and ribavirin in patients with
psychotic disorders has proved to be safe (22). In a recent
publication by Schaefer et al. (15), 14 patients with
psychotic disorders were treated with peginterferon and
ribavirin and none had any exacerbation of their psychotic condition. These data support the fact that patients
with chronic psychotic disorders should not be excluded

1053

HCV treatment in ‘difficult’ patients

from HCV treatment if patients are stable and have a
supportive environment. However, it is crucial to work
together with a psychiatric team who must be aware of
the theoretical risk of psychotic decompensation (23),
although this is probably uncommon.
Despite the high prevalence of HCV infection among
IDUs, only a small proportion of IDUs receive treatment
(8). However, previous studies have shown similar compliance and response to treatment compared with other
patients with HCV infection (24–26). This was confirmed in our study. Physicians are usually reluctant to
treat HCV infection in current IDUs (9). Although the
number of patients is small, in this study 40% of active
IDUs achieved an SVR, which is a response rate similar to
patients infected with genotype 1 HCV. Besides, previous
studies have shown a low risk of re-infection in IDUs
(27). However, this group had the highest rate of relapse
after finishing treatment. We do not know whether this
was because of a re-infection or poor adherence during
the treatment. We believe that rather than excluding
these patients from HCV treatment, additional support
should be offered to help them to complete their treatments (28). Ideally, these patients should be treated
before the development of liver cirrhosis because cirrhosis is associated with a poorer response to treatment.
This study has some limitations. Patients were not
assessed by a psychiatrist before the commencement of
HCV treatment. The definition of a history of depression
was made if patients referred previous depressive symptoms that required antidepressant drugs. Probably not all
these episodes of depressive symptoms fulfilled the DSMIV criteria for the diagnosis of a major depressive
disorder. However, searching for diagnostic criteria of
past episodes of major depressive disorders can be
challenging in many of these patients, and this less
exigent definition can be easily used in any clinical setting
without the requirement of a psychiatrist. Identification
of active IDUs was based on direct questioning of the
patients. Most of the former IDUs were receiving opioid
substitution treatment and we did not perform urinary
drug controls during the treatment. It is possible that
some of the patients classified as former IDUs were
currently using injecting drugs. A liver biopsy was not
performed in 32 patients. They were considered not to
have liver cirrhosis based on the clinical examination and
the lack of signs of portal hypertension in the liver
ultrasonography. It is possible that some of these patients
had compensated liver cirrhosis. However, the possibility
of a bias in the results of this study is small because the
SVR rate in this group was 71.9%, which is very similar
to the SVR rate for all the patients in this study.
In conclusion, this study provides information for a
better characterization of patients with psychiatric disorders and IDUs when we consider commencing combination therapy with peginterferon and ribavirin for
genotype 2 or 3 HCV. Patients with a previous history of
depression are more likely to experience depressive
symptoms during the treatment, and subsequently are

1054

Alvarez-Uria et al.

more likely to stop their treatment. However, this is
partially ameliorated if they are receiving antidepressant
drugs before starting HCV treatment. Patients with
chronic psychotic disorders or a past history of IDU have
similar treatment response rates than other groups. Even
in active IDUs, treatment is feasible and there is a
significant response rate. ‘Difficult-to-treat’ patients
should be individualized before treatment and provided
close supervision and extra support. Physicians and
hepatitis nurses must work alongside drug workers and
psychiatrists with experience in opioid addiction in the
setting of a multidisciplinary programme to serve these
patients more effectively.
Acknowledgements

We thank Jayne Dodd for her support to the patients and
help with the collection of data, and Dr Leann Johnson
for her comments on the article.
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1055


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