Adherence to treatment and quality of life during hepatitis C therapy:a prospective, real-life, observational study - CHEOBS Study

Liver International ISSN 1478-3223

CLINICAL STUDIES

Adherence to treatment and quality of life during hepatitis C therapy:
a prospective, real-life, observational study
Patrick Marcellin1, Michel Chousterman2, Thierry Fontanges3, Denis Ouzan4, Michel Rotily5, Marina Varastet5,
Jean-Philippe Lang6, Pascal Melin7 and Patrice Cacoub8, for the CheObs Study Group
1 Department of Hepatology, University of Paris 7, INSERM U 773, CRB3, Beaujon Hospital, Clichy, France
´ ´
2 Department of Hepato-Gastroentrology, Hospital of Creteil (CHIC), Creteil, France
3 Department of Hepato-Gastroenterology, General Hospital of Bourgoin, Bourgoin Jailleu, France
4 Department of Hepato-Gastroenterology, Arnault Tzanck Institute, Saint Laurent du Var, France
5 Department of Epidemiology and Public Health, ClinSearch, Bagneux, France
6 Department of Psychiatry and Addiction, Hospital of Erstein, Erstein, France
7 Department of Polyvalent Medicine, Hospital of Saint Dizier, Saint Dizier, France
´ ˆ `
8 Department of Internal Medicine, Pierre and Marie Curie (Paris 6) University, UMR 7211 (UPMC/CNRS), U 959 (INSERM), AP HP, Pitie-Salpetriere
Hospital, Paris, France

Keywords Abstract
adherence to treatment – chronic hepatitis C Background: Adherence is important for therapy of chronic diseases, but has
– compliance – peginterferon a-2b – quality still not been well studied in real life in chronic hepatitis C. Aims: To assess
of life – real life – ribavirin adherence to hepatitis C combination therapy in routine clinical practice and
to identify factors associated with imperfect adherence. Methods: This cohort
study included unselected chronic hepatitis C patients initiating peginterferon
Correspondence
´
a-2b plus ribavirin. 100% adherence was defined by taking all the prescribed
Pr Patrick Marcellin, Service d’Hepatologie,
ˆ ´ ´
Hopital Beaujon, 100 Boulevard du General
doses of both drugs for the full initially intended duration, as declared by the
Leclerc, 92110 Clichy, France
patient or believed by the physician. Quality of life was assessed using the
Tel: 133 140 87 53 38 short-form health survey (SF-36) questionnaire. Results: 1860 patients were
Fax: 133 147 30 94 40 analysed, including 72% treatment-naive, 36% genotype 2/3, 23% psychiatric,
e-mail: patrick.marcellin@bjn.aphp.fr 44% drug addicts and 3% human immunodeficiency virus (HIV)-positive
patients. Early treatment discontinuation occurred in 30% of patients. Overall,
Received 27 August 2010 38% of patients reported 100% adherence. Patient- and physician-reported
Accepted 30 December 2010 adherences were discordant, with a 20–30% overestimation by physicians.
HIV co-infection [odds ratio (OR) 2.52, 95% confidence interval (CI)
DOI:10.1111/j.1478-3231.2011.02461.x 1.36–4.67], no drug use during follow-up (2.37, 1.30–4.31), genotype 3 (1.55,
1.20–2.00) and treatment-naive (1.32, 1.03–1.69) were associated with 100%
adherence. Quality of life worsened during treatment but returned to baseline
after the end of treatment. Conclusions: Imperfect adherence to combination
therapy is common in routine patients. Adherence is markedly overestimated
by physicians and is associated with some patient’s baseline characteristics.
Knowledge of these factors might help identify patients who are most in need
of intervention and plan more frequent and accurate follow-up.

The current standard of care for chronic hepatitis C is the trials who received Z80% of both their total peginterfer-
antiviral combination therapy with peginterferon a and on and ribavirin doses for Z80% of the expected
ribavirin (1, 2). Peginterferon is administered subcuta- duration of therapy (7). However, adverse effects of
neously once a week and ribavirin orally twice daily. interferon-based therapy – mainly flu-like symptoms,
Successful treatment, i.e. achievement of a sustained neuropsychiatric disorders, anaemia and neutropenia –
virological response, has been obtained in 79–93% of are significant, justify frequent dose reduction of pegin-
genotype 2 or 3 hepatitis C virus (HCV) patients after 24 terferon and ribavirin and represent one major cause of
weeks of treatment; as well as in 41–52% of genotype 1 premature treatment discontinuation (8). Shortened
patients and 77% of genotype 4 patients after 48 weeks of antiviral therapy may be considered in some patients
treatment in clinical trials (3–6). Good adherence to depending on genotype, baseline viral load and viral
treatment is believed to enhance the rate of sustained kinetics (9–11), but only a minority of patients are
virological response, as shown in patients from prior concerned in routine practice, at least in France.

Liver International (2011)
516
c 2011 John Wiley Sons A/S

Marcellin et al. Real-life adherence to HCV treatment

These data originate from randomised, controlled documented by quantitative PCR (AmplicorTM, Roche
clinical trials. However, many patients in routine clinical Diagnostics, France), HCV genotype, liver fibrosis and
practice are nonresponders or relapsers to previous necro-inflammation (Metavir, FibroTest-ActiTests (22),
interferon-based therapy and the majority present with Knodell score) and previous antiviral treatment. Process
a wide spectrum of comorbidities. In particular, the high of care included the intended antiviral treatment regimen
prevalence of psychiatric or substance abuse disorders in (drug doses and duration), any subsequent treatment
patients with chronic HCV infection is well known (12). modification (dose modification or treatment disconti-
Conversely, people with chronic psychiatric disorders nuation), the reason for modification and patient’s
(13, 14) and intravenous drug users (15–17) are far more therapeutic education. Patients recorded the antiviral
likely to be infected with HCV compared with the general medication actually taken and self-assessed their quality
population. In addition, one-fourth to one-third of hu- of life using the validated French translation of the MOS
man immunodeficiency virus (HIV)-infected patients 36-item short-form health survey (SF-36) questionnaire
are co-infected with HCV (18, 19). Besides strict contra- (23). Each SF-36 subscore ranges from 0 (worse) to 100
indications, such diagnoses have constituted the most (best), except health transition, which ranges from 0
common reason patients have been denied treatment for (best) to 100 (worse).
HCV infection, not only in clinical trials (3, 4) but also,
until recently, in the real life (20, 21).
Outcomes
We performed a cohort study in chronic hepatitis C
patients to evaluate the adherence to peginterferon a-2b At each visit under treatment, patients reported the
and ribavirin combination therapy and to identify factors number of missed peginterferon injections in the past
associated with good adherence in a real-life setting. We month (the last four injections) or missed ribavirin
also assessed the coherence between patient-reported and intakes in the past week (the last 14 intakes). To estimate
physician-reported adherence, and the health-related patient-reported adherence at a given time point, we
quality of life. took into account the ‘actual’ doses as reported by the
patient at each visit and compared it with the most recent
physician prescription (thus integrating modifications of
Patients and methods
prescription that could have occurred over time). To
This prospective, multicentre, observational study was estimate the patient-reported overall adherence, we took
carried out in University hospitals, non-University hos- into account the adherence estimated at each visit, the
pitals and private practice offices involved in the manage- actual treatment duration and the treatment duration
ment of hepatitis C in France. All patients aged Z18 initially intended by the physician. As a result, patients
years with chronic hepatitis C and initiating combination who declared having taken all the prescribed doses of
therapy with peginterferon a-2b and ribavirin were both products for the full initially intended treatment
proposed to participate in the survey, whether naive for duration were classified as 100% adherent. Those who
hepatitis C therapy or not. In accordance with the French declared having taken Z80% of at least one product for
law, Ethics Committee’s approval was not required as the Z80% of the initially planned duration were classified as
protocol was strictly observational and usual practice was Z80% adherent.
unchanged. However, all patients gave informed consent Physician-reported adherence at a given visit and
to participate. Approval of the ‘Commission Nationale overall was estimated similarly, using the response to the
´
de l’Informatique et des Libertes’ was obtained, ensuring following questions: ‘In your opinion, how many times
that patient data were kept confidential according to the did the patient missed a peginterferon injection in the
French regulation. past month (the last 4 administrations)?’ or ‘In your
As for all observational studies, there were no proto- opinion, how many times did the patient missed a
col-specific procedures or study visits. Patients saw their ribavirin intake in the past week (the last 14 intakes)?’.
physician as per usual practice in the centre. The inves-
tigator and the patient completed an anonymous ques-
Statistical analysis
tionnaire each at inclusion, every 3 months during
treatment and 6 months after the end of treatment. Statistical analysis was conducted using SAS 8.2 (SAS
Patients filled in their questionnaires in the waiting room Institute Inc., Cary, NC, USA). Tests were two-sided and
and either gave it back to the physician in a sealed type I error was set at 0.05. Descriptive statistics were
envelope or returned it using a prepaid envelope. performed using all available data. Bivariate group com-
Physicians recorded the socio-demographical charac- parisons were carried out using the Kruskal–Wallis,
teristics, history of hepatitis C, selected comorbidities, chi-square or Fisher’s exact test as appropriate. The
process of care, concomitant treatments and adverse relationships between adherence and a set of potential
events. Comorbidities included past and current psychia- explanatory variables were analysed by forward stepwise
tric history, HIV or HBsAg positivity, chronic diseases logistic regressions. These variables included those for
and use of psychoactive products. History of hepatitis C which the groups differed significantly (P o 0.05) at
included source and duration of infection, viral load baseline in bivariate analyses (100 vs. o 100% adherence


c 2011 John Wiley Sons A/S 517

Real-life adherence to HCV treatment Marcellin et al.

and/or Z80 vs. o 80% adherence), and variables ex- Table 1. Continued
pected to be related to adherence. The quality of life data All patients
were analysed as recommended in the SF-36 manual and (n = 1860)
interpretation guide (23). Debts difficult to manage 100/1509 (7)
Hepatitis C history
Source of HCV infection
Results Transfusion 496/1860 (27)
Patients Injection or intranasal drug abuse 792/1860 (43)
Other 579/1860 (31)
A total of 184 investigators enrolled and followed up Duration of HCV infection (years) 20.7 Æ 9.0 (20)
2001 HCV patients in the survey between November Serum HCV RNA 4 800 000 IU/ml or 586/1382 (42)
2002 and January 2005. Of these patients, 141 were equivalent
excluded from analysis because they did not receive HCV genotype
combination therapy with peginterferon a-2b and riba- 1 1019/1860 (55)
virin combination therapy (n = 37), duration of combi- 2 202/1860 (11)
3 472/1860 (25)
nation therapy was not available (n = 79) or virological
4 136/1860 (7)
data were not available (n = 25). Compared with the 5 28/1860 (2)
analysed population, excluded patients were more often 6 3/1860 (0.2)
genotype 1 carriers (66 vs. 55%, P = 0.013) and less often Metavir activity grade or equivalent
genotype 3 carriers (185 vs. 25%, P = 0.072). They had A0 or A1 723/1572 (46)
more severe liver disease (Metavir A2–A3: 66 vs. 54%, A2 or A3 849/1572 (54)
P = 0.022; F3–F4: 47 vs. 34%, P = 0.007), and had Metavir fibrosis stage or equivalent
received more often a previous HCV treatment (43 vs. F0 or F1 549/1580 (35)
28%, P o 0.001). All other baseline data were not sig- F2 or F3 792/1580 (50)
nificantly different. F4 239/1580 (15)
Knodell score 8.4 Æ 3.1 (8)
The analysed population included 1860 patients. Their
Previous HCV treatment 516/1857 (28)
baseline characteristics are provided in Table 1. Most of Comorbidities
them (72%) were naive for hepatitis C therapy and 36% Psychiatric history
had genotype 2 or 3 HCV infection. Liver disease was Previous depression 453/1856 (24)
assessed by biopsy in the majority of patients (n = 1606, Suicide attempt 124/1850 (7)
86%) and estimated using noninvasive markers in the Past hospitalisation for mental disease 156/1848 (8)
remaining patients. Two-thirds of patients had signifi- Current psychiatric disorder 403/1839 (22)
cant fibrosis (F2, F3, F4: 65%), including 15% of Addictions
cirrhotics. Alcohol consumption 458/1856 (25)
Comorbidities were frequent. The cohort included Alcohol consumption 4 20 g/day 101/449 (23)
Tobacco consumption 859/1832 (47)
22% of psychiatric patients, 44% of drug users and 3%
Drug use (ever) 821/1855 (44)
of HIV-co-infected patients. Current psychiatric disor- Drug use (active) 60/1855 (3)
ders were diagnosed by a psychiatrist in 62% of the cases Co-infections
and included mainly depressive (n = 203, 11%), anxiety HIV positive 63/1854 (3)
HBsAg positive 24/1841 (1)
Other current chronic disease 491/1830 (27)
Table 1. Patients’ baseline characteristics Quality of life (SF-36)Ã
Physical functioning 78.7 Æ 23.2 (85)
All patients Role physical 65.7 Æ 42.1 (100)
(n = 1860) Bodily pain 66.5 Æ 28.1 (64)
Socio-demography General health 54.1 Æ 19.6 (55)
Men 1138/1856 (61) Vitality 45.8 Æ 21.4 (45)
Age (years) 46.6 Æ 11.8 (45) Social functioning 65.5 Æ 25.2 (63)
Body mass index (kg/m2) 24.5 Æ 4.4 (24) Role emotional 66.9 Æ 42.4 (100)
Employment status Mental health 58.4 Æ 19.0 (60)
Professional activity 1098/1857 (59) Health transition 53.3 Æ 21.6 (50)
Unemployed 272/1857 (15) Mental composite score 41.3 Æ 10.7 (42)
Other 487/1857 (26) Physical composite score 46.7 Æ 9.3 (48)
Educational level
Low 1089/1834 (59) Data are expressed as mean values Æ standard deviation (median), or n/N
High 745/1834 (41) (%) of patients.
ÃScore range: 0 (worse) to 100 (best) points for all domains except health
Origin of incomes
Paid employment 902/1842 (49) transition, which ranges from 0 (best) to 100 (worse) points.
Unemployment incomes 254/1842 (14) HCV, hepatitis C virus; HIV, human immunodeficiency virus; RNA,
Other 686/1842 (37) ribonucleic acid.

518


(n = 129, 7%), psychotic (n = 19, 1%) and bipolar (n = 8, 100% adherence ≥80% adherence
0.4%) disorders. Other comorbid chronic diseases were 80
hypertension (n = 176, 36%), diabetes mellitus (n = 107, 66 64 66 66
55 56 58
22%) and asthma (n = 42, 9%). Health-related quality of

% of patients
60 54
life was altered, each SF-36 subscore being moderately
lower than that in the general population in France (23). 40

20
Antiviral treatment
0
The mean dose regimen initially prescribed was 1.37 mg/ Month 3 Month 6 Month 9 Month 12
kg/week (median 1.5, n = 1837) for peginterferon a-2b (n =1145) (n =973) (n =549) (n =505)
and 922 mg/day (median 1000, n = 1820) for ribavirin. A Fig. 1. Proportion of patients with 100% and Z80% adherence to
total of 1089 (58.5%) patients received various forms of combination therapy (patient report).
therapeutic education at the discretion of the physician
during the first 3 months of treatment. The average dose
of both drugs progressively decreased over time, reaching
A Patient report Physician report
0.89 mg/kg/week (median 0.8, n = 1729) for peginterferon Peginterferon alfa-2b
and 595 mg/day (median 545, n = 1728) for ribavirin at
month 12. According to the physician, 915/1860 (49%) 100 97 97 98 98
patients did not complete therapy as intended initially. 79 78 76 77
80

% of patients
The main reason for not doing so was virological criteria
(n = 302, 16%), lost to follow-up (n = 244, 13%), safety 60
(n = 182, 10%), patient’s request (n = 78, 4%), another 40
reason (n = 51) or not specified (n = 58). However, as
20
calculated subsequently, only 563 (30%) patients had
‘insufficient’ treatment duration, i.e. o 80% of the 0
Month 3 Month 6 Month 9 Month 12
recommended duration (24 weeks with genotype 2 or 3, (n =1145) (n =973) (n =549) (n =505)
48 weeks with the other genotypes). Adverse events were
reported in 1598 (86%) patients overall. B Ribavirin
100 92 95
91 90
Adherence to treatment 80
66
% of patients

64 62 65
Patient-reported adherence to combination therapy was 60
100% for the full initially intended treatment duration
(overall adherence) in 580/1510 (38%) patients; it was 40
Z80% in 747 (50%) patients. The proportion of patients
with good adherence at a given time point was stable over 20
time, at 53–58% for 100% adherence and 64–66% for 0
Z80% adherence (Fig. 1). Month 3 Month 6 Month 9 Month 12
Patient- and physician-reported adherences to treat- (n =1145) (n =973) (n =549) (n =505)
ment were discordant. As shown quarterly in Figure 2, Fig. 2. Proportion of patients with 100% adherence to (A)
the proportion of patients reporting a 100% adherence to peginterferon a-2b and (B) ribavirin over time, as reported by the
peginterferon at a given time point was 76–79%, whereas patient and as perceived by the physician.
physicians believed it was above 97%. Moreover, the
proportion of patients reporting a 100% adherence to
ribavirin was 62–66%, whereas physicians believed it was
above 90%. physician office (P = 0.001). They were more often geno-
Adherence to ribavirin was always worse than adher- type 2 or 3 HCV carriers (P = 0.009) and naive for
ence to peginterferon (Fig. 2) and adherence to both antiviral HCV therapy (P = 0.037). In addition, they had
products (Fig. 1) was always worse than adherence to less frequent diabetes (P = 0.026), they consumed lower
ribavirin. Therefore, most patients with imperfect adher- alcohol amounts at baseline (P = 0.023) and they were
ence to one product were different from those with less often regular drug users (P = 0.017), but were more
imperfect adherence to the other product. often HIV co-infected (P = 0.003). They also used illicit
Bivariate comparison of patients who took 100% of drugs less frequently during follow-up (P = 0.007) and,
both products for the full initially intended treatment although not significantly, drunk less frequently 4 20
duration with those who did not is provided in Table 2. g/day alcohol (P = 0.053). They did not differ markedly
They differed significantly for the following items. 100% for the HCV treatment actually received and occurrence
adherent patients had longer transport time to the of adverse events.




Table 2. Comparison of patients reporting 100% adherence to both products for the full initially intended treatment duration (100%
adherence) with those who did not (adherence o 100%)
Adherence o 100% (n = 930) 100% adherence (n = 580) P-value
Socio-demography
Men 544/929 (59) 358/580 (62) 0.235
Age (years) 47.1 Æ 12.0 (45) 46.7 Æ 11.6 (45) 0.831
Body mass index (kg/m2) 24.8 Æ 4.5 (23.9) 24.3 Æ 4.2 (23.8) 0.111
Employment status 0.666
Professional activity 551/927 (59) 356/580 (61)
Unemployed 125/927 (14) 79/580 (14)
Other 251/927 (27) 145/580 (25)
Educational level 0.957
Low 542/915 (59) 338/572 (59)
High 373/915 (41) 234/572 (41)
Origin of incomes 0.345
Paid employment 450/918 (49) 298/575 (52)
Unemployment incomes 116/918 (13) 78/575 (14)
Other 352/918 (38) 199/575 (35)
Debts difficult to manage 51/747 (7) 31/476 (7) 0.907
Transport time to the centre (min) 35.2 Æ 38.6 (25) 39.4 Æ 34.5 (30) 0.001
Hepatitis C history
Source of HCV infection
Transfusion 247/930 (27) 160/580 (28) 0.677
Injection or intranasal drug abuse 377/930 (41) 233/580 (40) 0.914
Other 308/930 (33) 189/580 (33) 0.866
Duration of HCV infection (years) 20.8 Æ 8.9 (20) 21.1 Æ 8.9 (21) 0.601
Serum HCV RNA 4 800 000 IU/ml or equivalent 277/670 (41) 196/670 (44) 0.322
HCV genotype 0.009
1 538/930 (58) 292/580 (50)
2 105/930 (11) 67/580 (12)
3 202/930 (22) 170/580 (29)
4 68/930 (7) 38/580 (7)
5 14/930 (2) 13/580 (2)
6 3/930 (0.3) 0/580 (0)
Metavir activity grade or equivalent 0.793
A0 or A1 368/797 (46) 218/480 (45)
A2 or A3 429/797 (54) 262/480 (55)
Metavir fibrosis stage or equivalent 0.123
F0 or F1 267/798 (34) 178/484 (37)
F2 or F3 422/798 (53) 228/484 (47)
F4 109/798 (14) 78/484 (16)
Knodell score 8.3 Æ 3.2 (8) 8.6 Æ 3.2 (8) 0.326
Previous HCV treatment 270/929 (29) 140/580 (24) 0.037
Comorbidities
Psychiatric disorder (at baseline) 209/921 (22.7) 113/573 (19.7) 0.196
Addictions
Alcohol 4 20 g/day
At baseline 56/224 (25) 24/138 (17) 0.117
During study follow-up 43/930 (5) 15/580 (3) 0.053
Tobacco (at baseline) 406/913 (45) 269/573 (47) 0.363
Drug use (ever) 391/927 (42) 239/572 (41) 0.359
At baseline 33/927 (4) 13/572 (2) 0.168
During study follow-up 51/930 (6) 15/580 (3) 0.007
Co-infections
HIV positive 18/927 (2) 27/577 (5) 0.003
HBsAg positive 11/920 (1) 10/572 (2) 0.376
Other chronic disease (at baseline) 260/913 (29) 152/572 (27) 0.439
Current HCV treatment
Initial peginterferon dose (mg/kg/week) 1.36 Æ 0.28 (1.5) 1.40 Æ 0.25 (2) 0.003
Initial ribavirin dose (mg/day) 929 Æ 172 (1000) 915 Æ 160 (1000) 0.097
Intended treatment duration (weeks) 40.9 Æ 11.4 (48) 38.6 Æ 12.3 (48) o 0.001
Therapeutic education within the first 3 months 519/930 (56) 344/580 (59) 0.182
Adverse events during study follow-up 835/930 (90) 525/580 (90) 0.660

Data are expressed as mean values Æ standard deviation (median), or n/N (%) of patients.
HCV, hepatitis C virus; HIV, human immunodeficiency virus; RNA, ribonucleic acid.

520


Table 3. Factors independently associated with 100% adherence to the combination therapy
Reference P-value Odds ratio 95% Confidence interval
HIV co-infection No 0.003 2.521 1.362–4.668
No drug use during follow-up Drug use 0.005 2.370 1.304–4.310
HCV genotype 3 Gen. 1 0.016 1.553 1.203–2.005
Naive for HCV treatment No 0.028 1.321 1.031–1.692
Transport time to the centre (min) – 0.024 1.003 1.000–1.006

10 change from baseline of the mental and physical compo-
5
site scores, which integrate all SF-36 domains except
health transition, was, respectively, À 6.4 and À 6.5
Mean change from baseline (point)

0 points at month 6, and À 5.7 and À 5.3 points at month
–5 12. The health transition score, which estimates the
change of perceived health condition compared with 1
–10 year before, also worsened during treatment as shown by
–15 a mean change from baseline at 16.6 points at month 6
and 15.5 points at month 12. After the end of treatment,
–20 quality of life was returned above the pretreatment level;
–25 the mean change from baseline was 12.6, 12.4 and
À 6.2 points for the mental composite score, physical
–30
composite scores and health transition score respectively.
–35 Almost all SF-36 domains were significantly worse at
–40
baseline in patients who reported an adherence o 100%
Month 3 Month 6 Month 12 6 months after compared with patients with 100% adherence (P o 0.05
(n =1058) (n =881) (n =403) end of treatment for PF, BP, GH, VT, SF, MH, PCS and HT; not significant
(n =565)
for RP, RE and MCS). During and after treatment,
Fig. 3. Mean change from baseline of SF-36 subscores (point). changes of quality of life were parallel in both groups;
MCS, mental composite score; PCS, physical composite score. there were no significant differences between groups for
Physical domains: BP, bodily pain; GH, general health; PF, physical the change from baseline of each SF-36 subscore, what-
functioning; RP, role physical. Mental domains: MH, mental health;
ever the time point.
RE, role emotional; SF, social functioning; VT, vitality. HT, health
transition.
Discussion
To our knowledge, this is the largest study assessing
The potential explanatory variables proposed to the adherence to HCV therapy using data on dose taking.
multivariate model included genotype, remoteness of the Imperfect adherence was common. Overall, only 38% of
centre (transport time), Metavir activity and fibrosis our routine patients reported strict adherence to pegin-
scores, sex, age, BMI, previous HCV treatment, serum terferon a-2b and ribavirin, i.e. full-dose, persistent
HCV RNA, HIV co-infection, psychiatric disorders (ever therapy as initially intended by the physician. In addi-
and at baseline), diabetes, alcohol consumption 4 20 tion, 76–79% of patients on treatment reported having
g/day (at baseline and during follow-up), drug use (at taken all peginterferon doses in the last 4 weeks; 62–66%
baseline and during follow-up) and therapeutic education. reported having taken all ribavirin doses in the last
As a result (Table 3), the factors significantly associated 7 days; and 53–58% reported having taken all doses of
with 100% adherence to combination therapy were HIV both drugs at months 3, 6, 9 and 12. We also provide
co-infection, no illicit drug use during follow-up, HCV information on adherence in terms of early treatment
genotype 3, HCV treatment-naive and, to a lower extent discontinuation (30%) and dose decreases, as usually
(odds ratio close to 1), remoteness of the centre. referred to by clinicians in HCV infection.
Our results add to the literature as among the few
studies that assessed adherence in terms of dose taking,
Quality of life
none did so in the whole population of routine HCV
The change from baseline of SF-36 subscores is displayed patients and over the whole treatment period. In a
in Figure 3. During the treatment period (up to month clinical trial including 401 mono-infected HCV patients
12), all physical and mental domains progressively wor- (24), at least 95% of patients reported having taken all
sened, in particular those reflecting problems at work or peginterferon doses in the past 4 weeks at months 1, 3, 6,
in daily activities that result from the physical (role 9 and 12; the rate of patients who reported having taken
physical) and mental (role emotional) status. The mean all ribavirin doses in the past 4 days decreased from 91%




at month 1 to 43% at month 12. In a cross-sectional psychiatric disorders, suggesting that these conditions
study involving 180 routine HCV patients (25), 7% of should no longer limit access to HCV antiviral therapy. In
patients reported having missed at least one peginterfer- addition, treating intravenous drug users should have a
on dose in the last 4 weeks and 21% having missed at positive impact on prevention of transmission, with a
least one ribavirin dose in the last 7 days. Patients were chance of reducing the incidence of new cases. Knowl-
under treatment since 19.3 Æ 13.4 weeks in average. In a edge of factors predictive of poor adherence is a useful
retrospective study where adherence was estimated using resource for physicians to help identify patients who are
pharmacy refill data in 188 HCV US Veterans (26), 73% most in need of intervention and plan more frequent and
of patients were found with at least 100% adherence to accurate follow-up.
peginterferon and 68% with at least 100% adherence to Careful assessment of health-related quality of life was
ribavirin during the initial 3 months of treatment. Lastly, regularly performed in our patients using a validated
in a cohort of 63 HCV/HIV-co-infected patients (27), questionnaire. As expected, quality of life was impaired
23% of patients discontinued treatment early and 98% of before treatment initiation compared with the general
those on treatment reported having taken all peginterfer- population (23, 35) and both the mental and physical
on and ribavirin doses in the past 2 weeks at months 3, 6 domains worsened during treatment. However, 6 months
and 12. Such a high adherence is not surprising as dose- after the end of treatment, it was returned to baseline,
taking adherence is nowadays routinely stressed in HIV even slightly better than before treatment. Quality of life
patient care. changes were parallel in patients with perfect and im-
However, the ability of physicians to recognise non- perfect adherence. These results confirm previous reports
adherence was poor. Our study physicians markedly of temporary worsening (36, 37). Therefore, physicians
overestimated adherence to combination therapy, by should reassure patients and encourage them to persist
20–30% compared with patient self-report. This phe- with therapy despite frequent side effects and worsened
nomenon has already been shown in other chronic quality of life.
diseases such as HIV infection or diabetes but not yet in In conclusion, this cohort study brings potential
chronic HCV infection (28, 29). Several reasons exist clinically relevant information by emphasising the fol-
including for example poor or judgemental provider– lowing points. Imperfect adherence to combination
patient communication (30, 31). Moreover, in this therapy with peginterferon plus ribavirin is common in
indication, electronic monitoring has provided much routine chronic hepatitis C patients. Adherence is mark-
lower rates of adherence than self-reported adherence edly overestimated by physicians and is associated with
(24), suggesting that patients also overestimate adher- some patient’s baseline characteristics. These findings
ence to combination therapy. This medication-taking suggest that assessment of adherence to HCV combina-
behaviour is also well known in other chronic disorders tion therapy by physicians should be improved. This
(30). Therefore, healthcare providers should be more could be easily carried out by the wide use of standar-
vigilant about adherence to HCV combination therapy in dised adherence measurement tools such as a self-
their daily management, especially in terms of missed questionnaire, keeping in mind that patients may over-
ribavirin doses. Indeed, standard ribavirin dosing is estimate the true figures. The need to enhance commu-
complex and ribavirin dose reductions, at least in the nication would be triggered by discordance between the
first weeks of treatment, may alter virological outcome physician and patient assessments. Knowledge of baseline
(26, 32–34). Patient-related reasons for nonadherence characteristics associated with adherence might help
may include forgetfulness, the decision to omit doses, adjust the monitoring in a subset of patients at higher
lack of information and emotional factors (30). Clin- risk of nonadherence.
ician-related reasons may include, in addition to poor
communication with the patient, failing to explain the
treatment benefits and side effects and not giving con-
Acknowledgements
sideration to a patient’s lifestyle. More flexibility in
indication for treatment could have a positive impact on The authors are grateful to Ceri Medical (Garches,
the individual prognosis of patients and the overall France), who helped in field monitoring, Florence
control of the disease burden. Although there is no Colin-Mercier (Stat Process, Pont Mort, France), who
perfect method to assess adherence to medication, pa- analysed the data, as well as all investigators (the CheObs
tient self-report is probably the simplest and most Study Group) for participating in this study.
effective method of measurement. Statement of interests: This research was funded in
This study provides other clinically relevant informa- full by Schering-Plough France.
tion. Patients who did not present with the following P. Marcellin, M. Chousterman, T. Fontanges, D.
baseline characteristics of HCV infection, HIV co-infec- Ouzan, J.P. Lang, P. Melin and P. Cacoub have served as
tion, HCV genotype 3 and HCV treatment-naive, and speaker, consultant and/or advisory board member for
patients who used illicit drugs during HCV treatment Schering-Plough France, and have received research
were at higher risk of imperfect adherence. Interestingly, funding from Schering-Plough France. M. Rotily is a
adherence was not associated with history of addiction or former employee of ClinSearch; he now serves as a

522


consultant for ClinSearch. M. Varastet is an employee of Bavaria: risk factors for seropositivity. Eur J Epidemiol
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Clinical trial registration: Not applicable. 16. Crofts N, Jolley D, Kaldor J, van Beek I, Wodak A.
Epidemiology of hepatitis C virus infection among inject-
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17. Galeazzi B, Tufano A, Barbierato E, Bortolotti F. Hepatitis
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