Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virologic response rates in adherent patients

Abstract

  Reluctance has been expressed about treating chronic hepatitis C in active intravenous (IV) drug users (IDUs), and this is found in both international guidelines and routine clinical practice. However, the medical literature provides no evidence for an unequivocal treatment deferral of this risk group. We retrospectively analyzed the direct effect of IV drug use on treatment outcome in 500 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study. Patients were eligible for the study if they had their serum hepatitis C virus (HCV) RNA tested 6 months after the end of treatment and at least one visit during the antiviral therapy, documenting the drug use status. Five hundred patients fulfilled the inclusion criteria (199 were IDU and 301 controls). A minimum exposure to 80% of the scheduled cumulative dose of antivirals was reached in 66.0% of IDU and 60.5% of controls (P = NS). The overall sustained virological response (SVR) rate was 63.6%. Active IDU reached a SVR of 69.3%, statistically not significantly different from controls (59.8%). A multivariate analysis for treatment success showed no significant negative influence of active IV drug use. In conclusion, our study shows no relevant direct influence of IV drugs on the efficacy of anti-HCV therapy among adherent patients.

Full text

Active intravenous drug use during chronic hepatitis C therapy
does not reduce sustained virological response rates in
adherent patients
P. Bruggmann,
1
L. Falcato,
1
S. Dober,
1
B. Helbling,
2
O. Keiser,
3
F. Negro
4
and D. Meili
1
on
behalf of the Swiss Hepatitis C Cohort Study
1
ARUD Zurich, Association for Risk Reduction in the Use of Drugs, Zurich;
2
Department of Gastroenterology and Hepatology, Stadtspital Waid, Zurich;
3
SCCS Cohort Centre, University Hospital CHUV, Lausanne;
4
Services de
Gastroente
´rologie et dÕHe
´patologie et de Pathologie Clinique, Ho
ˆpitaux Universitaires, Gene
`ve, Switzerland
Received January 2008; accepted for publication April 2008
SUMMARY. Reluctance has been expressed about treating
chronic hepatitis C in active intravenous (IV) drug users
(IDUs), and this is found in both international guidelines and
routine clinical practice. However, the medical literature
provides no evidence for an unequivocal treatment deferral
of this risk group. We retrospectively analyzed the direct
effect of IV drug use on treatment outcome in 500 chronic
hepatitis C patients enrolled in the Swiss Hepatitis C Cohort
Study. Patients were eligible for the study if they had their
serum hepatitis C virus (HCV) RNA tested 6 months after the
end of treatment and at least one visit during the antiviral
therapy, documenting the drug use status. Five hundred
patients fulfilled the inclusion criteria (199 were IDU and
301 controls). A minimum exposure to 80% of the scheduled
cumulative dose of antivirals was reached in 66.0% of IDU
and 60.5% of controls (P= NS). The overall sustained
virological response (SVR) rate was 63.6%. Active IDU
reached a SVR of 69.3%, statistically not significantly
different from controls (59.8%). A multivariate analysis for
treatment success showed no significant negative influence
of active IV drug use. In conclusion, our study shows no
relevant direct influence of IV drugs on the efficacy of anti-
HCV therapy among adherent patients.
Keywords: drug use, hepatitis C, intravenous drug users,
outcome, treatment.
INTRODUCTION
Intravenous (IV) drug users (IDUs) make up the largest risk
group among patients with chronic hepatitis C [1,2]. The
prevalence of anti-hepatitis C virus (HCV) antibodies among
IDUs in Western Europe varies between 33% and 98% [3].
IDUs are destined to be one of the largest groups of patients
with end-stage liver disease in the future, contributing
therefore a significant number of liver transplant candidates
[4].
Despite the proved effectiveness of methadone therapy in
reducing heroin use, active IV drug use under methadone
maintenance is common [5]. On the contrary, patients on
methadone replacement therapy show similarly good ther-
apeutic response to hepatitis C treatment when compared
with patients who are not dependent on drugs [6–9].
However, current guidelines contain restrictive recom-
mendations for hepatitis C therapy in patients actively
injecting drugs [10]. In practice, these patients are usually
excluded from the therapy.
Based on our personal experience, we postulated that
IDUs receiving therapy for chronic hepatitis C could have
a comparable outcome to patients without active drug use.
We assumed that in active IDUs, HCV therapy success is
depending on the setting. According to our daily work
with IDUs, HCV treatment embedded in an intensive
setting with high frequent contacts could adjust imbalances
in adherence. We therefore wanted to analyse the direct
influence of the often mentioned exclusion criterion
Ôongoing IV drug useÕon sustained virological response
(SVR) rate.
PATIENTS AND METHODS
Patients
The Swiss Hepatitis C Cohort Study (SCCS) collects prospec-
tive information on adults with confirmed HCV infection
through standardized questionnaires, clinical examination
Abbreviations: HCV, hepatitis C virus; IDUs, intravenous drug users;
IFN-a, interferon-a; RBV, ribavirin; SCCS, Swiss Hepatitis C Cohort
Study; SVR, sustained virological response.
Correspondence: Philip Bruggmann, ARUD Zurich, Poliklinik Zokl1,
Sihlhallenstr 30, CH 8026 Zurich, Switzerland. E-mail: p.bruggman
n@arud-zh.ch
Journal of Viral Hepatitis, 2008, 15, 747–752 doi:10.1111/j.1365-2893.2008.01010.x
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd

and laboratory investigations conducted yearly at eight
centres providing specialist treatment across Switzerland
[11]. From September 1, 2000, the start of recruitment, until
May 31, 2006, a total of 2535 persons had been enrolled into
the cohort, contributing a total of 4318 person-years of
follow-up. At each follow-up visit, enrolled patients were
asked about IV drug use since the previous visit. Follow-up
visits took place every 6 months until 2005. From then on,
cohort participants were followed-up yearly. In order to be
eligible for enrolment in the present study, patients had to
fulfil the following criteria:
1. Chronic hepatitis C treatment based on the combination
of standard or pegylated interferon-a(IFN-a) and ribavi-
rin (RBV);
2. Serum HCV RNA assay performed 6 months after the end
of treatment;
3. At least one follow-up visit within 6 months before the
start of HCV treatment and 6 months after the end of
HCV treatment;
4. A declaration about IV drug use in the above-mentioned
visit during or close to the HCV therapy.
Patients with self-reported IV drug use in one or more of
the follow-up visits during the above-defined period of
interest were assigned to the IDU group (from now called
ÔIDUsÕ). Cohort participants not involved in IV drug use
during the therapy were allocated to the control group (from
now called ÔcontrolsÕ).
Type of anti HCV medication used, duration of therapy
and cumulative dose were assessed for each patient. A suf-
ficient exposure to antiviral treatment was defined as at
least 80% of the prescribed cumulative dose of each drug
and at least 80% of the scheduled therapy duration. In all
patients, factors with potential influence on the therapy
were recorded at the last follow-up before treatment start.
These factors included HCV genotype, HCV viral load,
presence of anti-HIV and ⁄or of anti-HBc antibodies and ⁄or
HBsAg, treatment for depression or other psychiatric ther-
apy, liver cirrhosis, alcohol use of more than 40 g per day
and opioid maintenance treatment with methadone or
buprenorphine (for detailed description of the SCCS proto-
col, see ref. 11).
Statistical methods
We used cross-tabulations to examine differences between
IDUs and controls in terms of their socio-demographic
characteristics, their HCV therapy outcome (measured as
SVR) and the above-mentioned factors potentially influenc-
ing the outcome. Chi-square-coefficients (FisherÕs exact test)
were calculated and tested for two-sided statistical signifi-
cance on the 0.05 alpha level. In a second step, we com-
pared the outcome of IDUs to controls in a bivariate analysis,
additionally considering the HCV genotype. Finally, a mul-
tiple logistic regression model was calculated for SVR as
dependent variable. We included IV drug use during the
HCV therapy, opioid substitution treatment, HCV genotype,
age, sex, medication type, the cumulative dose and alcohol
use during the therapy to predict HCV therapy outcome.
To examine the simultaneous influence of these variables on
the outcome, the odds ratio for each parameter value was
calculated and tested for significance. Overall, 362 cases had
valid data for all variables in the model. All data transfor-
mations and analysis were carried out with SPSSx Version
12 for Windows.
RESULTS
Sociodemographic characteristics
Overall, 500 patients fulfilled the inclusion criteria in the
present study: 199 patients belonged to the IDU group
(40%), whereas 301 were not injecting drugs during the
therapy. The majority of the patients were male, Caucasian
and weighed less then 85 kg, but there were no statistically
significant differences between the two groups (Table 1).
Patients in the control group were older than IDUs (42.7%
over 50 years vs 5.6%, P< 0.001).
Type of anti-HCV medication, cumulative dose and
duration of therapy
The percentage of the type of IFN used did slightly differ
between IDUs and controls (Table 2). IDUs (60.3%) vs con-
trols (69.4%) (P= 0.043) were treated with pegylated IFN-
a2a and RBV, 31.7% vs 23.3% (P= 0.039) with pegylated
IFN-a2b and RBV and 7.0% vs 5.6% with standard
recombinant IFN-aand RBV.
As far as drug exposure was concerned, 66.0% of IDUs
received 80% or more of the prescribed cumulative dose
of each of the antiviral drugs vs 60.5% in the control group.
As many as 87.9% of IDUs and 86.0% of controls reached at
least 80% of the scheduled treatment duration. None of these
differences were statistically significant.
Table 1 Sociodemographic features of 500 chronic
hepatitis C patients included in the present study
Variable
Reported
category
IDUs %
(n= 199)
Controls %
(n= 301) P(v
2
)
Gender Male 70.4 63.1 NS
Age <30 years 12.6 6.7 <0.001
30–39 years 41.9 22.3
40–49 years 39.9 28.3
‡50 years 5.6 42.7
Body weight ‡85 kg 27.1 24.6 NS
Ethnicity Caucasian 98.0 95.0 NS
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
748 P. Bruggmann et al.

Therapy outcome
The overall unadjusted SVR rate was 63.6%. The therapy
outcome in the IDU group (69.3%) was significantly better
than in the controls group (59.8%) (P= 0.037) (Fig. 1).
Stratifying outcome according to genotype showed slightly
better rates for the IDU group with genotype 1 (53.3% vs
47.2%), 3 (77.2% vs 67.8%) and 4 (72.7% vs 50.0%)
(Fig. 2). Genotype 2 was more often successfully treated in
the controls than in the IDU group (83.3% vs 60.0%,
respectively) (Fig. 2). However, none of these differences
reached statistical significance. Considering only patients
having been exposed to least 80% of the scheduled cumu-
lative dose for at least 80% of the scheduled therapy duration
(n= 307), IDUs achieved an SVR in 76.2% of cases as
opposed to 65.0% of controls (P= 0.023).
Other features potentially affecting SVR
Genotype 3 (61.8% vs 28.9%, P< 0.001) was significantly
more frequent, whereas genotypes 1 (30.2% vs 47.2%,
P< 0.001) and 2 (2.5% vs 17.9%, P< 0.001) were signif-
icantly less frequent in the IDU group. Genotype 4 did not
differ between the two groups. Other parameters influencing
SVR are presented in Table 3.
Multiple logistic regression analysis
The multiple logistic regression analysis showed that geno-
type and age influenced treatment outcome. Neither active
IV drug use during the therapy nor opioid substitution had a
significant influence on the SVR rate (Table 4).
Table 2 Treatment characteristics of
HCV therapies of the study sample Variable Reported category
IDUs %
(n= 199)
Controls %
(n= 301) P(v
2
)
Medication Ribavirin + P40 60.3 69.4 0.043
Ribavirin + P12 31.7 23.3 0.039
Ribavirin + recombinant
interferon
7.0 5.6 NS
Other ⁄unknown 1.0 1.7 NS
Cumulative
dosage
sufficient 66.0 60.5 NS
Duration sufficient 87.9 86.0 NS
P40: pegylated interferon alpha-2a; P12: pegylated interferon alpha-2b.
59.8
69.3
0
10
20
30
40
50
60
70
80
90
100
Controlls (n = 301)IDU (n = 199)
%
Fig. 1 Sustained virological response (SVR) in active IV
drug users (IDUs) did not significantly differ from the
controls.
SVR according to genotype
50.0
67.8
83.3
47.2
72.7
77.2
60.0
53.3
0
10
20
30
40
50
60
70
80
90
100
Type 4 (n = 29) ; NSType 3 (n = 210); NSType 2 (n = 59); NSType 1 (n = 202) ; NS
%
Controls (n = 301)
IDU (n = 199)
Fig. 2 Therapy outcome stratified
according to genotype did not show a
significant difference between patients
with ongoing IV drug use during the
HCV treatment (IDUs) and controls.
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
Hepatitis C treatment and active IV drug use 749

DISCUSSION
Intravenous drug use can have a negative impact on
adherence. In our study, we have therefore only chosen
adherent patients to show the direct impact of IV drug use
on treatment. The included patients had to be adherent
enough to go through a full course of antiviral therapy and
to come to the scheduled cohort visits during and after the
therapy.
Our results show that IV drug use does not have a neg-
ative, direct influence on the efficacy of antiviral treatment
in adherent chronic hepatitis C patients. In addition, IDUs
received a sufficient dose of antivirals and for a sufficient
duration of time as controls. By multivariate analysis,
ongoing IV drug use had no negative influence on SVR rate.
When stratified by genotype (Fig. 2), the SVR rates were
similar in both the groups independent of the viral genotype.
The overall SVR rates in this study were comparable to the
results in the major clinical trials using pegylated IFN-a
[12,13]. Previous studies reported lower SVR rates for active
IDUs [14,15]. These studies were conducted with standard
recombinant IFN-a, whereas the vast majority of the patients
in our study received the pegylated form of IFN-a. Still, a
direct comparison to other studies is not justified, because
our data – in contrast to the studies mentioned above – do
not comply with a classical intention-to-treat or per-protocol
analysis. We included only adherent patients and we did not
know how many patients followed at the same centres and
treated for their hepatitis C were not included in the cohort,
which is a frequent occurrence (patientsÕrefusal). Thus, for
us it was impossible to calculate how many patients com-
pleted the protocol out of the total treated in the same setting
(i.e. a classical intention-to-treat analysis).
The most feared effect of ongoing drug use is its negative
impact on adherence. On the basis of the results of our study,
therapy should not be denied simply based on ongoing IV
drug use. Methadone and buprenorphine maintenance
treatment likewise did not influence therapy outcome in the
multivariate analysis, confirming existing data on similar
SVR rates between methadone patients and controls
[6,9,14].
Patients who have received antidepressant or other psy-
chiatric treatment are likely to be suffering from some form
of mental disorder. It is not surprising to find this type of
treatment more often in IDUs, as mental disorders are a
frequent co-morbidity in this group, the most common
among them being personality, affective and anxiety disor-
ders [16,17]. However, stable mental disorders under psy-
chopharmacological treatment are not considered to be a
contraindication for chronic hepatitis C therapy [18,19].
From the SCCS, as a multicentre cohort with an obser-
vational period over almost 6 years, we were able to obtain
treatment data from 199 IDUs which is quite a large number
when compared with similar previous studies [7,8]. Another
reason for the comparable high number of evaluated IDUs is
the special situation concerning methadone and heroin
therapy in Switzerland. As mentioned in the introduction,
opioid maintenance therapy offers a favourable setting
for successful HCV therapy [6–9]. The treatment capacity
for opiate addicts in Switzerland is sufficient for 60% of
those in need, compared to 15% in the United States [20,21].
In Swiss methadone maintenance and heroin prescribing
programmes side use of IV drugs does not lead to an
exclusion of the patient from the programme. That is why it
is possible to treat active IDUs for hepatitis C in such a
programme.
The main limitation of this study is the restricted infor-
mation about baseline and endpoint data of the patients in
the two groups. As our study was observational, we could
only assess the data routinely collected in the cohort. As it
Table 3 Other features potentially
affecting SVR
Variable Valid n
Reported
category
IDUs %
(n= 199)
Controls %
(n= 301) P(v
2
)
HCV genotype 500 1 30.2 47.2 <0.001
2 2.5 17.9 <0.001
3 61.8 28.9 <0.001
4 5.5 6.0 NS
HCV RNA 321 >2 ·10
6
IU ⁄mL 26.1 21.9 NS
Alcohol 368 >40 g ⁄day 3.0 3.4 NS
Anti-HIV 383 Positive 3.7 3.6 NS
HBsAg 360 Positive 2.6 2.9 NS
Anti-HBc 466 Positive 54.8 35.4 <0.001
Cirrhosis 212 Yes 10.6 19.5 NS
Treatment for
depression
215 Yes 31.6 14.2 0.003
Other psychiatric
treatment
215 Yes 21.1 6.7 0.001
Opioid substitution
treatment
500 Yes 53.8 4.7 <0.001
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
750 P. Bruggmann et al.

was not part of the standard cohort questionnaire, nothing
could be said about safety endpoints like severe adverse
events or other side-effects. Information about IV drug use
and kind of opioids used in substitution therapy is missing
for the same reason. As IV drug use without any further
differentiation is an exclusion criterion in many guidelines
and for many practitioners, the findings of this study are of
value [10].
No urine analyses for heroin or cocaine were provided by
the cohort. The group allocation was based on self-reported
IV drug use, which is a shortcoming of the presented data.
Self-reported heroin use compared with urine analysis has
been shown to have a sensitivity of 82% and a specificity of
87.5% [22,23].
Our study only reflects the state of drug use at the time of
HCV therapy. Thus, nothing is said about the prior history of
IV drug use in the control group, although due to its
frequency among HCV patients the rate of IV drug use as a
path of infection must also be considered common in these.
In summary, we can conclude that IV drug use per se does
not affect treatment outcome or treatment quality in
adherent patients. Further studies with a prospective design
and a differentiation of IDUs are needed to confirm our data.
ACKNOWLEDGEMENTS
The Swiss Hepatitis C Cohort Study is supported by the
following grants: number 3347C0_108782 ⁄1 from the
Swiss National Science Foundation, number 03.0599 from
the Swiss Federal Office for Education and Sciences,
and number LSHM-CT-2004-503359 from the European
Commission.
Table 4 Multiple logistic regression
model for successful HCV therapy
(n= 362) Variable Category Frequency
Odds
ratio Significance
HCV genotype 362 0.000
1 152 Ref.*
2 43 5.09 0.000
3 145 2.46 0.001
4 22 1.91 0.184
Age (years) 362 0.005
<30 30 Ref.
30–39 106 0.46 0.157
40–49 115 0.27 0.016
50 and more 111 0.18 0.003
Sex 362 NS
Male 238 Ref.
Female 124 1.05 0.860
Medication 362 NS
Ribavirin +
P40 interferon
240 Ref.
Ribavirin +
P12 interferon
98 1.01 0.972
Ribavirin +
recombinant
interferon
24 0.523 0.194
Study group 362 NS
Controls 227 Ref.
IDUs 135 0.928 0.810
Cumulative dose 362 NS
Not sufficient 141 Ref.
Sufficient 221 1.02
Substitution treatment 362 NS
No 281 Ref.
Yes 81 1.23 0.565
Alcohol >20 g ⁄day 362 NS
No 330 Ref.
Yes 32 0.561 0.153
Constant 362 3.29 0.043
*Category of reference.
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
Hepatitis C treatment and active IV drug use 751

CONFLICTS OF INTERESTS
(i) P. Bruggmann has served as a speaker for Roche Pharma
Switzerland, Essex Chemie Switzerland and Schering Plough
Norway.
(ii) B. Helbling has served as a speaker, a consultant and an
advisory board member for Roche Pharma Switzerland and
Essex Chemie Switzerland.
(iii) F. Negro has served as a speaker, a consultant and an
advisory board member for Roche Pharma Switzerland,
Essex Chemie, Novartis, Debiopharm and Vertex, and has
received research funding from Roche Pharma Switzerland,
Takeda International and Essex Chemie.
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