Temporal changes and regional differences in treatment
uptake of hepatitis C therapy in EuroSIDA*
D Grint,
1
L Peters,
2
C Schwarze-Zander,
3
M Beniowski,
4
C Pradier,
5
M Battegay,
6
D Jevtovic,
7
V Soriano,
8
JD Lundgren,
2
JK Rockstroh,
3
O Kirk
2,9
and A Mocroft
1
for EuroSIDA in EuroCoord
†
1
University College London, London, UK,
2
University of Copenhagen, Copenhagen, Denmark,
3
University of Bonn, Bonn,
Germany,
4
Specialised Hospital, Chorzow, Poland,
5
Hospital de l’Archet, Nice, France,
6
University Hospital Basel,
Basel, Switzerland,
7
University of Belgrade, Belgrade, Serbia,
8
Hospital Carlos III, Madrid, Spain and
9
Rigshospitalet,
Copenhagen, Denmark
Objectives
All HIV/hepatitis C virus (HCV)-coinfected patients with chronic HCV infection and ⱖ F2 fibrosis
should be considered for HCV therapy. This study aimed to determine the rate of HCV treatment
uptake among coinfected patients in Europe.
Methods
EuroSIDA patients with viraemic HCV infection were included in the study. Poisson regression
was used to identify temporal changes and regional differences in HCV treatment uptake.
Results
A total of 1984 patients were included in the study, with a median follow-up time of 168
months [interquartile range (IQR) 121–204 months]. To date, 501 (25.3%) HIV/HCV-coinfected
patients have received HCV therapy. Treatment incidence rose from 0.33 [95% confidence
interval (CI) 0.16–0.50] per 100 person-years of follow-up (PYFU) in 1998 to 5.93 (95% CI
4.49–7.38) in 2007, falling to 3.78 (95% CI 2.50–5.07) in 2009. After adjustment, CD4 cell count
> 350 cells/mL [incidence rate ratio (IRR) 1.33 (95% CI 1.06–1.67) vs. CD4 count 200-350
cells/mL] and ⱖF2 liver fibrosis [IRR 1.60 (95% CI 1.14–2.25; P = 0.0065) vs. < F2 fibrosis] were
predictors of anti-HCV treatment initiation. However, 22% of patients who remain untreated for
HCV, with fibrosis data available, had ⱖF2 fibrosis and should have been considered for
treatment, while only 36% of treated patients had ⱖF2 fibrosis.
Conclusions
Although treatment incidence for HCV has increased, there remain a large proportion of patients
indicated for treatment who have yet to be treated.
Keywords: EuroSIDA, HIV/HCV coinfection, PEG-interferon, ribavirin, treatment completion
Accepted 21 May 2013
Introduction
The substantial declines in HIV-related mortality, as a con-
sequence of the introduction of combination antiretroviral
therapy (cART), have seen liver-related mortality assume
increasing importance among HIV-positive individuals
[1–3]. Progression of liver disease is common with hepatitis
C virus (HCV) infection and known to be accelerated in the
presence of HIV [4,5]. According to current guidelines, all
Correspondence: Mr Daniel Grint, HIV Epidemiology & Biostatistics
Group, Research Department of Infection and Population Health, UCL –
Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. Tel: 020
7794 0500 ext. 34684; fax: 020 7794 1224; e-mail: d.grint@ucl.ac.uk
*This work was presented in part at the 11th International Congress on
Drug Therapy in HIV Infection, Glasgow, UK, November 2012, as an oral
presentation (Abstract O243).
†
See Appendix S1 for the EuroSIDA study group.
DOI: 10.1111/hiv.12068© 2013 The Authors. HIV Medicine published by John Wiley & Sons Ltd
on behalf of British HIV Association. HIV Medicine (2013), 14, 614–623
ORIGINAL RESEARCH
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and
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614
coinfected patients with chronic HCV infection and signifi-
cant fibrosis (ⱖF2) should be considered for HCV therapy
given their increased risk of death from liver disease [6,7].
HCV treatment should preferentially be offered to patients
with controlled HIV infection, and therefore it is recom-
mended when CD4 cell counts are above 350 cells/mL and
often deferred when counts are below 200 cells/mL [7].
However, patients with CD4 cell counts below 200 cells/mL
have been shown to respond well to HCV treatment when
HIV replication is suppressed [8]. Despite these recommen-
dations, the extent to which HIV/HCV-coinfected patients
start HCV therapy is not well documented in Europe. Pre-
vious studies from 2003–2006, including a EuroSIDA
study, have shown that a low proportion of patients are
initiating anti-HCV therapy, typically less than 10% [9–12].
This study includes data up to 2010, when the gold
standard treatment for HCV infection was a combination
of pegylated interferon (peg-IFN) and ribavirin [6]. How-
ever, HCV treatment is not generally well tolerated and
response-guided therapy is used to determine whether
treatment should continue for the full duration [7].
The aims of this study were to describe the temporal
changes and regional differences in the uptake of anti-
HCV therapy and to identify factors associated with treat-
ment across Europe, documenting the rate of completion
of full treatment duration and factors that predict com-
pleting therapy. In a subset of patients with available data,
we also aimed to identify whether patients with significant
fibrosis, in most urgent need of treatment, were selected
for treatment.
Study participants
The EuroSIDA study is a large prospective, observational
cohort study of 18 295 HIV-positive individuals in 105
centres across Europe, Israel and Argentina. The study has
been described in detail previously [13]. HCV antibody
(HCVAb) status has been collected since 1997; persons
who died or were lost to follow-up before this date did
not routinely have HCVAb status collected. Centres that
have determined HCV genotype or measured HCV RNA are
requested to provide that information to the coordinating
centre. Information on the collection of HCVAb, HCV RNA
and genotype data has been given in detail elsewhere
[14,15].
Data on alanine transaminase (ALT), aspartate transami-
nase (AST) and platelet counts have been collected since
1999 and 2005, respectively, while data on liver biopsy
and Fibroscan® (Echosens S.A.S.U, Paris, France) [16] have
been collected since 2010, with sites requested to list all
previous test results where liver biopsy was graded using
the METAVIR scoring system [17] and return the histologi-
cal report for internal validation. Plasma hyaluronic acid
(HA) has been measured in all HCVAb-positive patients
with stored plasma samples; HA data collection is described
elsewhere [18].
Statistical methods
All HCVAb-positive individuals positive for quantitative
HCV RNA were included in these analyses. Baseline was
defined as the date of first HCVAb-positive test result
or recruitment to EuroSIDA, whichever occurred later. In
analyses with the outcome of initiating HCV therapy,
patients were followed up to their last visit, death or the
date of starting HCV therapy, defined as treatment with at
least interferon-a (peg-IFN) plus or minus ribavirin.
Trends over time in starting HCV therapy were described
using Poisson regression models. Factors associated with
HCV treatment uptake were investigated in univariable
analyses and those that were significant with P < 0.1 were
included in multivariable models. Investigated factors
included age, gender, ethnic group, region of Europe,
HIV transmission risk group, prior AIDS diagnosis, time-
updated CD4 cell count, time-updated HIV RNA, time-
updated HCV RNA, HCV genotype, time-updated hepatitis
B virus surface antigen (HBsAg) status, starting cART,
calendar year and time-updated alanine transaminase
(ALT) levels.
Fibrosis levels among treated and untreated patients
were summarized. As fibrosis progression rates have been
shown to be slow in this population [19], fibrosis markers
up to 2 years prior to initiation of HCV treatment were
included, along with the last available measurement in
those who remained untreated. The proportions of treated
and untreated patients with significant fibrosis were
compared using a combined definition of ⱖF2 fibrosis
from biopsy and Fibroscan, HA > 100 ng/mL and an AST
to platelet ratio index (APRI [20]) > 1.5, which have
been shown to be accurate markers of significant fibrosis
[21,22]. A Fibroscan reading of > 7.6 kPa was used to
identify ⱖF2 fibrosis, in accordance with a recent review of
the subject [23].
Completion of a full course of HCV therapy is defined
dependent on HCV genotype, with a ‘full course’ considered
to have been completed after a minimum of 48 weeks for
genotype 1 or 4 and after a minimum of 24 weeks for
genotype 2 or 3 [6]. However, because patients may have
shorter treatment duration in the clinical setting, we also
considered patients who completed at least 80% of the
expected minimum treatment duration to have completed
therapy, in line with previous studies concerning HCV
treatment duration (i.e. 38.4 weeks for genotype 1 or 4 and
19.2 weeks for genotype 2 or 3) [24,25]. The median length
Treatment uptake of hepatitis C therapy 615
© 2013 The Authors. HIV Medicine published by John Wiley & Sons Ltd
on behalf of British HIV Association.
HIV Medicine (2013), 14, 614–623
of treatment duration by HCV genotype, along with the
percentage of patients completing a full course of treatment,
were determined in patients with known HCV genotype and
sufficient follow-up to have completed 80% of treatment.
Predictors of completing a full course of HCV therapy
were determined using logistic regression models adjusted
for age, gender, ethnic group, HIV transmission group,
region of Europe, baseline cART use, prior AIDS diagnoses,
HCV genotype, CD4 cell count at treatment initiation, HIV
viral load at treatment initiation, HCV viral load at treat-
ment initiation and calendar year of treatment initiation.
All analyses were performed using
SAS (version 9.2; SAS
Institute, Cary, NC).
Results
Of the 4224 HCVAb-positive patients in EuroSIDA, 2633 had
available HCV RNA measurements, of whom 2008 (76.3%)
were HCV RNA positive and 1984 either never received
HCV therapy or did so after baseline and were eligible
for inclusion in this analysis. Median follow-up time was
168 months [interquartile range (IQR) 121–204 months]. In
multivariable logistic regression, HCVAb-positive patients
without HCV RNA data available compared to those with
HCV RNA data available had lower CD4 cell counts at
baseline [adjusted odds ratio (aOR) 0.91 (95% confidence
interval (CI) 0.87–0.96; P = 0.0002) per doubling], were
more likely to come from Eastern Europe [aOR 6.45 (95% CI
4.63–8.99; P < 0.0001) compared with Southern Europe] and
were recruited to EuroSIDA later [aOR 1.09 (95% CI 1.07–
1.12; P < 0.0001) per year later].
Table 1 shows the patient characteristics at baseline and
at the date of HCV treatment initiation or last follow-up
according to whether treated for HCV infection. A higher
proportion of treated patients resided in Southern Europe
(41.1% vs. 33.0% for untreated patients; P = 0.0039) and
belonged to the men who have sex with men (MSM) HIV
transmission group (12.1% vs. 8.4%, respectively), while a
lower proportion of treated patients belonged to the inject-
ing drug use (IDU) HIV transmission group (68.9% vs.
74.5%, respectively; global P = 0.09). At the time of anti-
HCV treatment initiation or last follow-up for those not
Table 1 Patient characteristics at baseline and date of last follow-up or hepatitis C virus (HCV) treatment
At baseline At last follow-up or treatment
Untreated
(
n
= 1483)
Treated
(
n
= 501)
P
-value*
Untreated
(
n
= 1483)
Treated
(
n
= 501)
P
-value*
Age (years) [median (IQR)] 33 (28-38) 32 (28–37) 0.29 44 (37–49) 41 (35–46) < 0.0001
Male (%) 67.9 72.6 0.048
White (%) 91.5 93.1 0.27
Region of Europe (%) South 33 41.1 0.0039
West Central 21.6 18.1
North 17.5 12.9
East Central 16.2 17.7
East 11.7 10.3
HIV transmission group (%) MSM 8.4 12.1 0.09
IDU 74.5 68.9
Haemophiliac 3.6 4.2
Heterosexual 10.4 11.7
Other 3.1 3.2
HCV genotype (%) 1 45.2 41.2 0.084
2 2.8 2.2
3 23.4 28.8
4 11.9 13.5
Unknown 16.7 14.5
HBsAg status (%) Negative 60.8 65.1 0.21 85 88.7 0.12
Positive 4.3 4.2 8.3 6.2
Unknown 34.9 30.8 6.7 5.2
Started cART (%) 21.1 26.4 0.014 86.7 86.3 0.85
ALT [units/litre (U/L)] n (%) 418 (28.2) 38 (7.6) 1308 (88.2) 409 (81.6)
Median (IQR) 51 (26–83) 49.5 (30–106) 0.44 44 (37–49) 76 (49–120) < 0.0001
CD4 count (cells/mL) [median (IQR)] 268.5 (145–400) 290 (158.5–429) 0.017 391 (227–614) 479 (349–650) < 0.0001
HIV RNA < 500 copies/mL [% (95% CI)] 26.8 (24.5–29.1) 34.3 (30.2–38.5) 0.0013 71.2 (68.8–73.5) 80.3 (76.7–83.9) < 0.0001
HCV RNA < 800 000 IU/mL [% (95% CI)] 57.8 (55.3–60.3) 59.7 (55.4–64.0) 0.45 55.9 (53.4–58.5) 57.9 (53.2–62.6) 0.46
ALT, alanine transaminase; cART, combination antiretroviral therapy; CI, confidence interval; HBsAg, hepatitis B virus surface antigen; IDU, injecting drug
use; IQR, interquartile range; MSM, men who have sex with men.
*P-values for comparison of proportions or medians.
616 D Grint et al.
© 2013 The Authors. HIV Medicine published by John Wiley & Sons Ltd
on behalf of British HIV Association.
HIV Medicine (2013), 14, 614–623
yet treated, ALT levels were higher in treated patients
[median 76 (IQR 49-120) vs. 44 (37–49) U/L for untreated
patients; P < 0.0001], as were CD4 cell counts [median 479
(IQR 349– 650) vs. 391 (227–614) cells/mL, respectively;
P < 0.0001].
Uptake of HCV therapy
In total, 501 of 1984 patients (25.3%) have so far received
HCV therapy in 18 303 person-years of follow-up (PYFU),
giving an overall incidence of treatment of 2.74 per 100
PYFU (95% CI 2.50–2.97). Figure 1 shows how the inci-
dence of treatment has changed over time. The overall
incidence of treatment increased from 0.33 per 100 PYFU
(0.16–0.50) in 1998 to 5.93 (4.49–7.38) in 2007 before
falling to 3.78 (2.50–5.07) in 2009. In univariable Poisson
regression models, the incidence of treatment increased
by 27% per year (95% CI 23–31%; P < 0.0001) between
1998 and 2007, and fell by 12% per year (95% CI 2-21%;
P = 0.020) between 2007 and 2010.
Table 2 shows univariable and multivariable Poisson
regression parameter estimates for predictors of HCV treat-
ment. In multivariable models, patients selected for treat-
ment were more likely than untreated patients to reside
in Southern Europe [incidence rate ratio (IRR) 1.38 (95%
CI 1.06–1.82; P = 0.019) compared with Western Europe]
and belong to the MSM HIV transmission group [IRR 1.36
(95% CI 1.00–1.83; P = 0.046) compared with IDU]. Treated
patients were also more likely to have current CD4
cell counts > 350 cells/mL [IRR 1.33 (95% CI 1.06–1.67;
P = 0.013) compared with CD4 counts between 200 and 350
cells/mL] and less likely to have CD4 cell counts < 200
cells/mL [IRR 0.42 (0.27–0.65; P = 0.0001) compared with
CD4 counts between 200 and 350 cells/mL].
Compared with untreated patients, treated patients more
often had current HIV RNA levels below 500 HIV-1 RNA
copies/mL [IRR 1.39 (95% CI 1.07–1.80; P = 0.012) compared
with HIV RNA > 500 copies/mL], indicating well-controlled
HIV infection with cART. At the time of treatment, treated
patients were also more likely than untreated patients to
0.33
1.00
1.70
2.22
2.61
3.83
4.32
3.41
4.93
5.93
5.89
3.78
4.71
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
1998 2000 2002 2004 2006 2008 2010
Incidence per 100 PYFU (95% CI)
Year
1998–2007: unadjusted IRR 1.27 (95% CI 1.23–1.31; P < 0.0001) per year
2007–2010: unadjusted IRR 0.88 (95% CI 0.79–0.98; P = 0.020) per year
Fig. 1 Temporal change in the incidence of uptake of hepatitis C virus (HCV) treatment. The incidence rate ratio (IRR) was calculated from univariable
Poisson regression. CI, confidence interval; PYFU, person-years of follow-up.
Treatment uptake of hepatitis C therapy 617
© 2013 The Authors. HIV Medicine published by John Wiley & Sons Ltd
on behalf of British HIV Association.
HIV Medicine (2013), 14, 614–623
have HCV RNA > 800 000 IU/mL [IRR 1.21 (95% CI 1.00–
1.47; P = 0.049) compared with HCV RNA between 616 and
800 000 IU/mL] and raised ALT levels [upper normal range
(uNR) < ALT < 3 times uNR, IRR 2.33 (95% CI 1.83–2.96;
P < 0.0001); ALT > 3 times uNR, IRR 3.56 (95% CI 2.61–4.86;
P < 0.0001) compared with ALT within the normal range]. In
the multivariable model, the calendar year effect was similar
to that shown in Figure 1, with the incidence of treatment
increasing until the years 2007–2008 before falling in
2009–2010. However, in the multivariable model, taking
changes in patient characteristics into account, changes in
the incidence of treatment from 2003/2004 onwards were
not significant [2005/2006, IRR 0.97 (95% CI 0.73–1.29;
P = 0.85); 2007/2008, IRR 1.28 (95% CI 0.98–1.68; P =
0.074), and 2009/2010, IRR 0.82 (95% CI 0.61–1.11; P = 0.20)
compared with 2003/2004].
The proportion of patients treated for HCV infection did
not differ greatly for HCV genotypes 1 to 4 (23.6, 21.2, 29.5
and 27.8%, respectively; P = 0.084). Removing patients
who contracted HIV infection via the MSM route, on the
assumption that they were acutely infected with HCV, did
not change the proportions treated (23.2, 20.9, 28.0 and
26.2%, respectively; P = 0.29), and in the multivariable
model HCV genotype was not significantly associated with
treatment initiation (Table 2).
Interactions between calendar year and region of Europe
(P = 0.48) and calendar year and HIV transmission group
(P = 0.80) were both nonsignificant, indicating that there
were no significant differences in the increasing incidence
of HCV treatment uptake across regions of Europe and HIV
transmission groups, although the power to detect such
differences was limited.
Liver fibrosis levels
Fibrosis markers were available in 800 of 1984 patients
(40.3%) included in this study and are summarized in
Table 3. Patients without fibrosis data were more likely to
be MSM [odds ratio (OR) 1.53 (95% CI 1.07–2.18; P = 0.019)
vs. IDU], reside in Northern Europe [OR 1.54 (95% CI
1.12–2.13; P = 0.0007) vs. Western Europe] and have
lower CD4 cell counts at treatment or last follow-up
[OR 0.72 (95% CI 0.67–0.79; P < 0.0001) per doubling].
Similar proportions of treated and untreated patients with
biopsy/Fibroscan data available had ⱖF2 fibrosis (43.9%
Table 2 Univariable and multivariable Poisson parameter estimates for factors associated with anti-hepatitis C virus (HCV) treatment initiation
Variable
Univariable Multivariable
Estimate
95% confidence
interval
P
-value Estimate
95% confidence
interval
P
-value
Calendar year: 1998 vs. 2003–2004 0.07 (0.04–0.12) < 0.0001 0.11 (0.06–0.21) < 0.0001
1999–2000 vs. 2003–2004 0.48 (0.34–0.68) < 0.0001 0.43 (0.29–0.65) 0.0001
2001–2002 vs. 2003–2004 0.89 (0.68–1.16) 0.39 0.65 (0.47–0.89) 0.0074
2005–2006 vs. 2003–2004 1.72 (1.37–2.15) < 0.0001 0.97 (0.73–1.29) 0.85
2007–2008 vs. 2003–2004 2.65 (2.15–3.27) < 0.0001 1.28 (0.98–1.68) 0.074
2009–2010 vs. 2003–2004 1.68 (1.33–2.12) < 0.0001 0.82 (0.61–1.11) 0.20
South vs. West Central Europe 1.17 (0.98–0.40) 0.081 1.38 (1.06–1.82) 0.019
North vs. West Central Europe 0.74 (0.57–0.95) 0.021 1.02 (0.73–1.44) 0.89
East Central vs. West Central Europe 1.20 (0.96–1.51) 0.12 1.03 (0.74–1.43) 0.85
East vs. West Central Europe 1.38 (1.03–1.84) 0.030 1.18 (0.78–1.78) 0.45
Started cART* 3.29 (2.54–4.26) < 0.0001 1.33 (0.93–1.90) 0.12
CD4 count < 200 cells/mL* vs. CD4 count 200-350 cells/mL 0.21 (0.14–0.32) < 0.0001 0.42 (0.27–0.65) 0.0001
CD4 > 350 cells/mL* vs. CD4 count 200-350 cells/mL 2.86 (2.35–3.48) < 0.0001 1.33 (1.06–1.67) 0.013
HIV RNA < 500 copies/mL* vs. ⱖ 500 copies/mL 3.08 (2.51–3.78) < 0.0001 1.39 (1.07–1.80) 0.012
HCV RNA > 800 000 IU/mL* vs. HCV RNA 616 to 800 000 IU/mL 1.90 (1.59–2.29) < 0.0001 1.21 (1.00–1.47) 0.049
MSM vs. IDU 1.48 (1.13–1.94) 0.0042 1.36 (1.00–1.83) 0.046
Heterosexual vs. IDU 1.17 (0.89–1.53) 0.27 1.19 (0.90–1.59) 0.22
Other vs. IDU 1.07 (0.76–1.51) 0.68 1.25 (0.88–1.78) 0.21
HCV genotype 2 vs. HCV genotype 1 0.75 (0.41–1.36) 0.35 1.05 (0.56–1.94) 0.89
HCV genotype 3 vs.
HCV genotype 1 1.26 (1.04–1.53) 0.018 1.20 (0.96–1.49) 0.11
HCV genotype 4 vs. HCV genotype 1 1.09 (0.84–1.41) 0.51 1.20 (0.90–1.59) 0.21
HCV genotype unknown vs. HCV genotype 1 0.92 (0.72–1.19) 0.53 1.02 (0.77–1.34) 0.91
NR < ALT < 3 times NR vs. upper limit NR 2.93 (2.46–3.49) < 0.0001 2.33 (1.83–2.96) < 0.0001
ALT > 3 times NR vs. upper limit NR 3.39 (2.65–4.34) < 0.0001 3.56 (2.61–4.86) < 0.0001
ALT unknown vs. upper limit NR 0.25 (0.20–0.31) < 0.0001 1.62 (1.17–2.25) 0.0039
The model was also adjusted for age, gender, race and hepatitis B virus surface antigen (HBsAg) status.
ALT, alanine transaminase; cART, combination antiretroviral therapy; IDU, injecting drug use; MSM, men who have sex with men; NR, normal range for ALT,
defined as < 50 U/L for men and < 40 U/L for women; 3 times NR, 3 times the normal range.
*Time-updated variable.
618 D Grint et al.
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on behalf of British HIV Association.
HIV Medicine (2013), 14, 614–623
