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Online Submissions: wjg.wjgnet.com                                          World J Gastroenterol 2008 October 28; 14(40): 6195-6203
   wjg@wjgnet.com                                                                World Journal of Gastroenterology ISSN 1007-9327
   doi:10.3748/wjg.14.6195                                                                  © 2008 The WJG Press. All rights reserved.



                                                                                                 RAPID COMMUNICATION

Patient education improves adherence to peg-interferon
and ribavirin in chronic genotype 2 or 3 hepatitis C virus
infection: A prospective, real-life, observational study



Patrice Cacoub, Denis Ouzan, Pascal Melin, Jean-Philippe Lang, Michel Rotily, Thierry Fontanges,
Marina Varastet, Michel Chousterman, Patrick Marcellin

Patrice Cacoub, Department of Internal Medicine, Pitié-           self-reported over the past 4 wk (peg-interferon) or
Salpêtrière Hospital, AP HP, Paris 75651, France; Pierre and      7 d (ribavirin). Adherence to bitherapy was defined
Marie Curie (Paris 6) University, CNRS UMR 7087, Paris            as adherence to the two drugs for ≥ 20 wk. SVR was
75651, France                                                     defined as undetectable RNA ≥ 12 wk after the end of
Denis Ouzan, Department of Hepato-Gastroenterology, Arnault       treatment.
Tzanck Institute, Saint Laurent du Var 06721, France
                                                                  RESULTS: 370/674 patients received education during
Pascal Melin, Department of Polyvalent Medicine, Hospital of
Saint Dizier, Saint Dizier 52115, France                          the first 3 mo of treatment. After 6 mo, adherence to
Jean-Philippe Lang, Department of Psychiatry and Addiction,       bitherapy was higher in educated patients (61% vs
Hospital of Erstein, Erstein 67152, France                        47%, P = 0.01). Adherence to peg-interferon was 78%
Michel Rotily, Marina Varastet, ClinSearch, Bagneux 92220,        vs 69% (P = 0.06). Adherence to ribavirin was 70% vs
France                                                            56% (P = 0.006). The SVR (77% vs 70%, P = 0.05)
Thierry Fontanges, Department of Hepato-Gastroenterology,         and relapse (10% vs 16%, P = 0.09) rates tended to
General Hospital of Bourgoin, Bourgoin Jailleu 38317, France      be improved. After adjustment for baseline differences,
Michel Chousterman, Department of Hepato-Gastroentrology,         education improved adherence [Odds ratio (OR) 1.58,
Hospital of Créteil (CHIC), Créteil 94010, France                 P = 0.04] but not the SVR (OR 1.54, P = 0.06).
Patrick Marcellin, Department of Hepatology, Beaujon              CONCLUSION: In genotype 2/3 patients, therapeutic
Hospital, Pôle des Maladies de l'Appareil Digestif, Clichy
                                                                  education helped maintain real-life adherence to
92118, France; and INSERM U 773, CRB3, University of Paris
VII, Beaujon Hospital, Clichy 92118, France                       bitherapy.
Author contributions: Cacoub P, Ouzan D, Melin P, Lang JP,
Rotily M, Fontanges T, Chousterman M, and Marcellin P (The        © 2008 The WJG Press. All rights reserved.
Scientific Committee) designed the research, reviewed the data,
supervised the analysis and interpreted the results; Varastet M   Key words: Viral hepatitis; Adherence; Therapeutic
helped analysing the data, interpreting the results, and wrote    education; Real life; Peg-interferon; Ribavirin
the paper; All authors helped writing, critically reviewed and
approved the paper.                                               Peer reviewer: Raymund Rabe Razonable, PhD, Division of
Supported by Schering-Plough France                               Infectious Diseases, Mayo Clinic Institution, 200 First Street
Correspondence to: Patrice Cacoub, Professor, Department          SW, Rochester 55905, United States
of Internal Medicine, Pitié-Salpêtrière Hospital, 47-83
boulevard de l'Hôpital, Paris cedex 13 F-75651,                   Cacoub P, Ouzan D, Melin P, Lang JP, Rotily M, Fontanges T,
France. patrice.cacoub@psl.aphp.fr
                                                                  Varastet M, Chousterman M, Marcellin P. Patient education
Telephone: +33-142-178027 Fax: +33-142-178033
                                                                  improves adherence to peg-interferon and ribavirin in chronic
Received: June 19, 2008         Revised: September 16, 2008
Accepted: September 23, 2008                                      genotype 2 or 3 hepatitis C virus infection: A prospective,
Published online: October 28, 2008                                real-life, observational study. World J Gastroenterol 2008;
                                                                  14(40): 6195-6203 Available from: URL: http://www.wjgnet.
                                                                  com/1007-9327/14/6195.asp DOI: http://dx.doi.org/10.3748/
                                                                  wjg.14.6195
Abstract
AIM: To evaluate the impact of therapeutic education
on adherence to antiviral treatment and sustained
                                                                  INTRODUCTION
virological response (SVR) in a real-life setting in
genotype 2/3 hepatitis C, as there are few adherence              As pointed out by the WHO [1] , poor adherence
data in genotype 2/3 infection, even from randomized              to treatment is a worldwide issue in all chronic
trials.                                                           conditions, which results in poor health outcomes and
METHODS: This prospective survey included genotype                increased health care costs [2,3]. Even in clinical trials,
2/3 patients who received peg-interferon alfa-2b and              mean adherence rates are low (43%-78%) in chronic
ribavirin. There was no intervention. Adherence was               conditions[4-6]. In clinical practice, adherence rates of

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about 50% are usually reported[7].                             to previous therapy. In accordance with French law, the
    Adherence to therapy is critical in the treatment of       Ethics Committee’s approval was not required as the
chronic hepatitis C virus (HCV) infection. The current         protocol was strictly observational and usual practice was
gold standard therapy is a combination of peg-interferon       unchanged. However, all patients gave informed consent
alfa and ribavirin[8,9]. Patients with genotype 1 infection    to participate.
have a 42%-51% likelihood of achieving a sustained                  Included patients saw their physician at a frequency
virological response (SVR) after 48 wk of therapy;             corresponding to the usual practice in the center. The
78%-82% of patients with genotype 2 or 3 infection             investigator and the patient completed a questionnaire
respond to 24 wk of treatment, whereas patients with           each at inclusion, at the visits occurring approximately
genotype 3 infection and high viral load are difficult to      every 3 mo during treatment, and at the visit occurring
treat (< 70% responders)[10,11]. Non-responders to prior       approximately 6 mo after the end of treatment. Patients
standard bitherapy respond to retreatment in 13% of the        filled in their questionnaires in the waiting room and
cases (29% in non-1 genotype), and relapsers in 58.5%          either gave it back to the investigator in a sealed envelope
of the cases[12]. Therapy requires weekly subcutaneous         or returned it using a prepaid envelope.
injections, twice-daily oral dosing and frequent visits,            The investigators recorded socio-demographic
with blood tests. Side effects occur in nearly all patients.   data, history of HCV infection (including previous
As a result, 15%-20% of patients in clinical trials and >      treatments), risk factors, comorbidities, patient
25% in clinical practice discontinue therapy.                  therapeutic education (provided or not), planned/
    In clinical trials, SVR was significantly improved         prescribed hepatitis C treatment, modification of
in those patients with HCV genotype 1 infection who            treatment during follow-up, concomitant medications,
received > 80% of their total peg-interferon dose              and adverse events. The virological status, documented
and > 80% of their ribavirin dose for > 80% of the             by qualitative PCR (Amplicor™, Roche) and test date,
scheduled treatment duration, in comparison with those         was recorded at the last visit.
who failed these adherence criteria[13]. A review of the            The patient questionnaires concerned adherence
2002-2007 literature confirmed that treatment response         to peg-interferon and ribavirin, and the persons
is influenced not only by HCV genotype and viral load,         involved in the management of their disease (e.g. health
but also by patient-related factors including adherence[14].   professionals of any discipline, patient associations).
Moreover, optimal HCV healthcare requires further              The following parameters relating to the past 4 wk were
efforts from providers in communicating with patients,         recorded to evaluate adherence to peg-interferon: date
as advocated in France by hepatitis C experts and the          of injections (or reason for not having an injection),
Health Ministry[15,16], and shown in studies using patient     frequency of and reason for taking peg-interferon at
questionnaires in North America[17,18].                        a higher/lower dose than prescribed. The following
    We carried out a large survey named CheObs to              parameters relating to the past 7 d were recorded to
evaluate adherence to chronic hepatitis C treatment in         evaluate adherence to ribavirin: number of (200 mg)
the real-life setting in France. We observed that some         capsules prescribed morning and evening, date of
patients received therapeutic education by a third party       dosing and number of capsules taken in the morning
(other than the investigator), at the discretion of the        and evening, reasons for missing doses, reasons for and
investigators, during the study period. According to the       frequency of taking more/less capsules than prescribed.
consensus that efforts to boost treatment adherence                 As for any survey, there was no protocol-specific
improve SVR rates, we performed the present analysis           intervention. Therapeutic education was defined by
to evaluate the impact of patient education on real-life       intervention of a third party (healthcare professionals
adherence and response to treatment with peg-interferon        other than the prescribing physician) and distribution
alfa-2b and ribavirin. This analysis was carried out in        of support documents and educational material during
patients with genotype 2/3 HCV infection (one third of         individual sessions. It was provided at the discretion of
the CheObs cohort), as there are few adherence data for        the physician. No instruction was given related to which
these patients even from randomized trials, and because        patient should be considered or how education should
their data were available before those of patients with        be provided.
other genotypes, due to shorter treatment duration.                 Adherence to bitherapy was defined as adherence to
                                                               both peg-interferon and ribavirin over a sufficient time
                                                               period, as self-reported by the patients. According to
MATERIALS AND METHODS                                          the “80/80/80” criteria previously defined[13], patients
The prospective, multicenter, CheObs sur vey was               were considered to have adhered to peg-interferon if
carried out in teaching hospitals, non-teaching hospitals,     they had received three or four injections during the
and private practice offices highly involved in the            past 4 wk, and to have adhered to ribavirin if they had
management of hepatitis C in France, and supervised            taken at least 22 (200 mg) capsules over the past week.
by a Scientific Committee. Consecutive patients aged           Patients were considered to have adhered to bitherapy
≥ 18 years with chronic hepatitis C were enrolled if           if they had adhered to the two drugs for at least 20 wk.
initiation of bitherapy with peg-interferon alfa-2b and        These rules were defined according to the recommended
ribavirin was scheduled. They could be naive for any           number of peg-interferon injections (one per week), the
chronic hepatitis C therapy or non-responders/relapsers        recommended ribavirin daily dose (at least 800 mg/d),

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Cacoub P et al . Real-life adherence to HCV treatment                                                                            6197


and the recommended duration of bitherapy in                             Chronic HCV
genotype 2/3 HCV infection (24 wk).                                        infection
    SVR was defined as undetectable HCV RNA in the                        n = 2001
                                                                                                  Genotype non-2 and non-3         n = 1296
serum 12 wk after the end of treatment or later. This
time interval was considered to be sufficient for this                  Genotype 2 or 3
                                                                                                 Excluded from analysis              n = 31
evaluation, since relapse after 12 wk of follow-up is                      n = 705
                                                                                                 Due to:
rarely (2%) observed whatever the HCV genotype[19], and                                               Monotherapy                    n =5
the dates of the visits and laboratory tests could not be                    Analysed                 Bitherapy end date not available n = 26
forced in this observational protocol. Non-response was                      n = 674

defined as detectable RNA at the end of treatment, and
relapse as undetectable RNA at the end of treatment but          Without                   With
                                                               therapeutic              therapeutic
detectable at a later time point.
                                                                education                education
                                                                n = 304                  n = 370
Statistical analysis
Due to the lack of data in the literature, the CheObs         Figure 1 Patient flow.
sample size calculation was based on real-life adherence
observed in chronic conditions other than chronic
HCV infection, such as HIV infection[20], diabetes[21], or    but a similar body mass index (BMI) (Table 1). They
hypertension[22]. A total of 1537 patients were required      more frequently had a past history of depression (P
to estimate a 50% adherence rate, with a precision of         = 0.01) and current psychiatric disorders (P = 0.04,
2.5% and a type Ⅰ error of 0.05. Assuming 25%-30% of          mainly depression and anxiety), though there was
patients were lost to follow-up or discontinued treatment     no difference for the nature or proportion of each
early, approximately 2000 patients were included overall.     disorder. Educated patients were also more frequently
    The present analysis was carried out in the subset        psychoactive drug users (P = 0.02, mainly cocaine
of patients with genotype 2/3 HCV infection from the          and heroin), but the profile of consumption (injecting
CheObs cohort. Statistical analysis was conducted using       behavior and frequency of abuse) was similar. Regarding
SAS 8.2 (SAS Institute Inc, Cary, NC, USA). Tests were        HCV infection, although educated patients had more
two-sided and type Ⅰ error was set at 0.05. Descriptive       frequently significant liver fibrosis than those without
statistics were performed using all available data. Group     therapeutic education (P = 0.04), the proportion of
comparisons were carried out using Kruskal-Wallis or          cirrhotic patients was similar (13% and 15%).
Fisher’s exact tests. The relationships between adherence
or virological response and a set of potential explanatory    Treatment
variables were analysed by forward stepwise logistic          A 24-wk bitherapy was scheduled in most patients
regressions. These variables included not only those for      (571/667, 86%), with no marked difference between
which groups differed significantly at baseline (P < 0.05),   groups (Table 2). Treatment for 48 wk was more
but also those expected to have a significant impact          frequently planned in non-responders/relapsers to
according to the literature.                                  previous therapy (43/125, 34%) than in naive patients
                                                              (49/542, 9%, P < 0.001). The planned weekly dose of
                                                              peg-interferon was higher in educated patients (P =
RESULTS                                                       0.01), at 1.5 μg/kg per week in most cases (82% vs 75%)
Patients' characteristics                                     whereas patients without therapeutic education were
Between 2002 and 2006, 184 investigators enrolled 2001        more frequently prescribed lower doses. However there
HCV patients in the CheObs survey, including 705              was no difference between the groups for the proportion
patients infected with the genotype 2/3 HCV (Figure 1).       of retreated patients (Table 1) or that of relapsers/
Of these, 674 patients were analyzed. We observed that        non-responders to previous treatment (P = 0.95). The
370/674 (55%) patients received therapeutic education         ribavirin dose prescribed was similar in both groups. It
during the first 3 mo of treatment and 304 (45%) did          was 800 mg/d in half of the patients (344/669, 51%)
not. Among the 82 centers which included the analyzed         and < 800 mg/d in 18 (3%) patients.
population, 24 (29%) did not educate any patient, 18              The actual duration of bitherapy was shorter than
(22%) educated > 0 to 50% of their patients, 19 (23%)         20 wk in 85/674 (13%) patients (P = 0.20 between
educated > 50% to < 100% of their patients, and 21            groups, Table 2), with an average of 11.1 ± 4.9 wk
(26%) educated 100% of their patients. The 31 patients        (median 12) in these patients. Reasons for premature
excluded from analysis were similar to the analyzed           discontinuation were: lost to follow-up (n = 28), safety
population for the therapeutic education rate (58%)           (n = 27), patient’s request (n = 14), virological (HCV
and all other baseline variables, except for the Metavir      RNA detectable or decrease < 2 log, n = 7), unknown
activity score, which was more frequently A2/A3 (78%          (n = 3), investigator’s request (n = 2), and other (n = 4).
vs 50%, P = 0.009).                                           They were similar in nature and occurrence (P = 0.79)
    In the analyzed population, educated patients had         in both groups. These patients, who were not included
a higher body weight (70.5 ± 14.0 kg vs 67.9 ± 14.3 kg,       in the analysis of virological response, did not differ
P = 0.02) than patients without therapeutic education,        significantly from those who received a longer bitherapy

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6198      ISSN 1007-9327           CN 14-1219/R            World J Gastroenterol      October 28, 2008          Volume 14       Number 40


 Table 1 Baseline characteristics of the patients (n = 674):                  Table 2 Treatment planned and actually received (n = 674):
 Univariate analysis                                                          Univariate analysis

                                            Therapeutic education                                                   Therapeutic education
                                           No             Yes          P                                    No (n = 304) Yes (n = 370)           P
                                       (n = 304)       (n = 370)               Duration of bitherapy (wk)1
 Socio-demography                                                               Planned                      27.7 ± 8.9        27.1 ± 8.2       0.49
  Men                                  170/303 (56)    229/370 (62)   0.14      Actual                       28.4 ± 12.7       30.3 ± 14.2      0.25
  Age (yr)                               44.1 ± 11.4    44.9 ± 11.4   0.16      Premature discontinuation    44/304 (15)       41/370 (11)      0.20
  Body mass index (kg/m2)                23.5 ± 4.1     24.1 ± 4.2    0.06      (< 20 wk)
 Employment status                                                             Peginterferon weekly dose (μg/kg)
  Professional activity                190/303 (63)    220/370 (59)   0.59      Planned                      1.35 ± 0.29       1.41 ± 0.22     0.01
  Unemployed                            48/303 (16)     69/370 (19)             Actual at 3 mo2              1.31 ± 0.30       1.38 ± 0.25     0.006
  Other                                 65/303 (22)     81/370 (22)             Actual at 6 mo2              1.18 ± 0.35       1.25 ± 0.31     0.02
 Educational level                                                             Ribavirin daily dose (mg)
  Low                                  182/300 (61)    223/365 (61)   0.94      Planned                       897 ± 147         906 ± 154       0.67
  High                                 118/300 (39)    142/365 (39)             Actual at 3 mo2               871 ± 166         885 ± 175       0.25
 Origin of incomes                                                              Actual at 6 mo2               771 ± 201         803 ± 209       0.06
  Paid employment                      166/298 (56)    183/368 (50)   0.24
  Unemployment incomes                  48/298 (16)     60/368 (16)          Data are expressed as mean ± SD, or proportions of patients. 1Date of end
  Other                                 84/298 (28)    125/368 (34)          of bitherapy minus date of inclusion; 2Cumulated over the past 3 mo (AUC,
 Debts                                                                       investigator report).
  Difficult to manage                    8/232 (4)      27/315 (9)    0.02
  None or easily managed               224/232 (97)    288/315 (91)
 Comorbidities                                                               with regards to the main variables.
  Past psychiatric history
    Depression                          67/303 (22)    113/370 (31)   0.01
                                                                                 Physicians modified the peg-interferon dose less
    Suicide attempt                     23/302 (8)      29/368 (8)    0.81   frequently in educated patients (16% vs 22% without
    Hospitalisation for mental          25/301 (8)      36/369 (10)   0.59   therapeutic education, P = 0.046), whereas the
    disease                                                                  ribavirin dose was changed in similar proportions of
  Psychiatric disorder                  60/300 (20)     98/367 (27)   0.04   patients in both groups (17% vs 18%, P = 0.28) nearly
  Chronic disease                       64/298 (22)     89/366 (24)   0.41
 Risk factors
                                                                             always because of adverse effects and weight loss and
  Alcohol consumption > 20 g/d           10/70 (14)     24/100(24)    0.17   depression in particular. The difference in the dose
  Tobacco consumption                  167/299 (56)    187/366 (51)   0.24   between groups remained constant for peg-interferon
 Drug abuse                                                                  whereas it increased over time for ribavirin, in particular
  None                                 139/303 (46)    172/368 (47)   0.02
                                                                             after the third month of treatment (Table 2). The
  Former                               158/303 (52)    174/368 (47)
  Current                                6/303 (2)      22/368 (6)
                                                                             occurrence of adverse events over the whole study was
 HCV infection                                                               82% of patients in each group (P = 0.92).
  Source of HCV infection1
    Transfusion                         62/304 (20)     76/370 (21)   1.00
                                                                             Adherence to bitherapy
    Injection or intranasal drug       157/304 (52)    193/370 (52)   0.94
    abuse
                                                                             Overall adherence to bitherapy was 64% (301/468)
    Other                               86/304 (29)    100/370 (27)   0.86   at 3 mo and 55% (209/383) at 6 mo of treatment.
  Duration of HCV infection (year)       20.4 ± 8.4     20.0 ± 8.9    0.85   Adherence to peg-interferon (80% and 74% at 3 and
  Serum HCV-RNA                                                              6 mo, respectively) was higher than to ribavirin (72%
    ≤ 800 000 IU/mL or equivalent      121/193 (63)    162/265 (61)   0.77
                                                                             and 64%, respectively). Patients prescribed high doses
    > 800 000 IU/mL or equivalent       72/193 (37)    103/265 (39)
  HCV genotype                                                               of ribavirin (≥ 1000 mg/d) did not differ significantly
    2                                   85/304 (28)    117/370 (32)   0.31   from those with lower doses with respect to premature
    3                                  219/304 (72)    253/370 (68)   0.31   treatment discontinuation and adherence to peg-
  Coinfection                                                                interferon and/or ribavirin.
    Human immunodeficiency virus 12/303 (4)             14/369 (4)    1.00
    Hepatitis B virus2                    3/301 (1)      6/369 (2)    0.63
                                                                                 At 3 mo, the proportion of adherents to both drugs
  Metavir activity grade or equivalent                                       was 66% with therapeutic education and 63% without
    A0 or A1                           119/226 (53)    131/272 (48)   0.32   therapeutic education (non-significant difference)
    A2 or A3                           107/226 (47)    141/272 (52)          (Figure 2 and Table 3). At 6 mo, this proportion was
  Metavir fibrosis stage or equivalent                                       still 61% in educated patients, whereas it dropped
    F0 or F1                           110/227 (49)    109/272 (40)   0.04
    F2 or F3                            82/227 (36)    129/272 (47)
                                                                             down to 47% without therapeutic education (P = 0.01).
    F4                                  35/227 (15)     34/272 (13)          Multivariate analysis showed that, after adjustment,
  Knodell score                           7.9 ± 3.0      8.4 ± 3.5    0.19   therapeutic education increased the probability of
  Previous anti-HCV treatment course                                         adhering to bitherapy at 6 mo by a factor of 1.58 (95% CI:
    None                               242/303 (80)    303/370 (82)   0.74
                                                                             1.02 to 2.46).
    One or more                         61/303 (20)     67/370 (18)
                                                                                 At 6 mo, the adherence rate was still 78% for peg-
Data are expressed as mean ± SD, or proportions of patients. 1One patient
                                                                             interferon and 70% for ribavirin in educated patients,
could have more than one presumed source of infection. 2Hepatitis B          whereas it was reduced to 69% (P = 0.06) and 56% (P
antigen positivity.                                                          = 0.006), respectively, in patients without therapeutic



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Cacoub P et al . Real-life adherence to HCV treatment                                                                                         6199


 Table 3 Adherence to treatment, virological response (univariate analysis) and their association with therapeutic education
 (multivariate analysis)

                                                                                    Therapeutic education
                                                    Univariate analysis                                               Multivariate analysis
                               No (n = 304)           Yes (n = 370)                P                    OR                  95% CI                   P
  Adherence1 at 3 mo
   Bitherapy                     137/218 (63)          164/250 (66)               0.56                  1.04               0.69 to 1.56             0.87
   Peginterferon                 175/218 (80)          201/250 (80)               1.00                  0.94               0.57 to 1.53             0.79
   Ribavirin                     152/218 (70)          186/250 (74)               0.30                  1.13               0.72 to 1.77             0.59
  Adherence1 at 6 mo
   Bitherapy                      83/175 (47)          126/208 (61)               0.01                  1.58               1.02 to 2.46             0.04
   Peginterferon                 121/175 (69)          162/208 (78)               0.06                  1.78               1.07 to 2.96             0.03
   Ribavirin                      98/175 (56)          145/208 (70)               0.006                 1.67               1.05 to 2.65             0.03
  Virological response2
   SVR                           171/246 (70)          230/298 (77)               0.05                  1.543              0.99 to 2.40             0.06
   Nonresponse                    37/246 (15)           37/298 (12)               0.38
   Relapse                        38/246 (16)           31/298 (10)               0.09


Data are expressed as proportions of patients. Multivariate analyses were adjusted for sex, weight, BMI, educational level (adherence only), history of
depression, psychiatric disorders, alcohol consumption, drug abuse, duration of HCV infection, previous anti-HCV treatment, HCV genotype (SVR only),
and peginterferon dose prescribed at inclusion. 1≥ 3 peginterferon injections during the last 4 wk and/or ≥ 22 ribavirin capsules of 200 mg each during the
last 7 d (self-report); 2≥ 12 wk after the end of treatment; 3The rate of SVR was used as dependent variable.



education. After adjustment, therapeutic education                              (P = 0.047) rates was observed, but the sample size was
increased the probability of adherence by a factor of 1.78                      small (n = 80).
for peg-interferon and 1.67 for ribavirin after 6 mo of                             Moreover, although favorable trends were observed,
bitherapy.                                                                      therapeutic education had no significant impact on the
    Educated patients more frequently re por ted                                virological response in patients treated for the first time
contacting persons in the hospital for management of                            (P = 0.27) or in non-responders/relapsers to previous
their disease, with a median of three persons vs two for                        therapy (P = 0.22).
patients without therapeutic education during the first
3 mo of treatment (P=0.016), and three persons vs one
during the next 3 mo (P = 0.003). Conversely, patients                          DISCUSSION
without therapeutic education reported more frequent                            We evaluated the impact of patient therapeutic education
contacts with office-based persons, with a median of                            by a third party on adherence and virological response
two persons vs one in educated patients during the first                        to peg-interferon alfa-2b and ribavirin in 674 patients
3 mo (P = 0.012), and two persons vs none during the                            with chronic genotype 2/3 HCV infection. This is the
next 3 mo (P < 0.001).                                                          first time that adherence has been evaluated in patients
                                                                                carrying these genotypes, and also the first time that
Virological response                                                            adherence has been assessed in a real-life setting.
The overall SVR rate was 74% (401/544). There were                                  Therapeutic education given during the first 3 mo
13.6% of non-responders and 12.7% of relapsers. The                             of treatment significantly improved the proportion of
virological response was better, though not significantly,                      patients adhering to bitherapy at 6 mo (OR 1.58, P =
in educated patients (Figure 2 and Table 3). The SVR                            0.01 after adjustment for sex, weight, BMI, educational
rate was higher (77% vs 70%, P = 0.05) and the rate                             level, history of depression, psychiatric disorders,
of relapse was lower (10% vs 16%, P = 0.09) in these                            alcohol consumption, drug abuse, duration of HCV
patients than in patients without therapeutic education.                        infection, previous anti-HCV treatment, and peg-
Multivariate analysis confirmed that, after adjustment,                         interferon dose prescribed at inclusion). The proportion
the relationship between SVR and therapeutic education                          of adherents was stable above 60% until the sixth month
was borderline significant (P = 0.06). Response was                             of treatment in educated patients, whereas it dropped
better in patients whose ribavirin dose was not reduced                         by more than 10% between the third and sixth month
during the first 3 mo of treatment (P < 0.001), mostly                          of treatment when there was no therapeutic education.
due to an increased SVR rate (362/473, 77% vs 37/67,                            The virological response was also improved in educated
55%, P = 0.001) and a decreased rate of non-response                            patients, with an increased SVR rate (77% vs 70%) and a
(51/473, 11% vs 21/67, 31%, P < 0.001).                                         lower relapse rate (10% vs 16%), though this effect was
    The virological response is shown taking into account                       statistically not significant (P = 0.06 after adjustment
genotype and baseline viral load (> or ≤ 800 000 IU/mL)                         for sex, weight, BMI, history of depression, psychiatric
in Figure 3. Though this effect was not significant,                            disorders, alcohol consumption, drug abuse, duration
therapeutic education was found to have a beneficial                            of HCV infection, previous anti-HCV treatment,
impact in all patients. In those with genotype 2 and low                        HCV genotype, and peg-interferon dose prescribed at
viral load, an impact on the SVR (P = 0.038) and relapse                        inclusion). Since a 12-wk treatment may be very effective


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6200   ISSN 1007-9327           CN 14-1219/R           World J Gastroenterol   October 28, 2008    Volume 14     Number 40


A                                          Without therapeutic education (n = 218)   for obtaining an SVR [23]. A positive impact was also
                                           With therapeutic education (n = 250)      observed on adherence to peg-interferon, showing that
                                               P =1
                                                                   P = 0.30
                                                                                     an improvement can still be obtained.
                                              80    80
                80      P = 0.56
                                                                         74               Our results are consistent with the general consensus
                                                                  70
                       63         66                                                 that patient therapeutic education in clinical practice
                60                                                                   effectively improves adherence to treatment in chronic
% of patients




                                                                                     disease [2,15,16] and that adherence, even to placebo, is
                40
                                                                                     essential to achieve health outcome goals[3]. It should be
                20
                                                                                     noted however, that education required the cooperation
                                                                                     of specialists and nursing staff, and therefore probably
                 0                                                                   affected both patient-related and health care team-related
                       Bitherapy           Peg-interferon         Ribavirin          factors, which are recognized to improve adherence.
                                       Adherence at 3 mo
                                                                                          The adherence rate to bitherapy (64%) was low
                                                                                     compared to the rates of > 70% reported in clinical
B                                          Without therapeutic education (n = 175)   trials[13]. The SVR rate observed here (72%) was however,
                                           With therapeutic education (n = 208)
                                              P = 0.06
                                                                                     in line with that reported in clinical trials (80%) in
                80                                  78              P = 0.006        genotype 2/3 HCV patients treated with similar therapy[24].
                        P = 0.01                                         70
                                  61
                                             69                                      Apart from the fact that results are usually more marked
                                                                                     in randomized trials, our population included a high
% of patients




                60                                                56
                       47
                                                                                     proportion of patients with psychiatric disorders and/or
                40
                                                                                     drug addicts. This suggests that in real-life situations
                20                                                                   such comorbidities and high-risk behavior do not have
                                                                                     an impact on adherence or response to treatment, so that
                 0
                       Bitherapy           Peg-interferon         Ribavirin          they may not be as difficult to treat as usually believed.
                                       Adherence at 6 mo                                  Unlike during clinical trials, patients in this
                                                                                     observational study were not selected or obliged to
C                       P = 0.05           Without therapeutic education (n = 246)   follow specific procedures and physicians were not
                80                77       With therapeutic education (n = 298)      instructed on which patient should be considered for
                       70
                                                                                     therapeutic education. This may be considered to be a
                60                                                                   weakness of the study, as comparisons were performed
% of patients




                                                                                     on non-randomized groups. The CheObs study was not
                40
                                              P = 0.38             P = 0.09
                                                                                     designed to perform comparisons, but aimed to provide
                20                            15                  16                 a picture of the real-life setting. The use of multivariate
                                                    12                   10
                                                                                     analysis in the present evaluation reduced such bias by
                 0                                                                   taking into account the differences between groups
                            SVR              Non-response          Relapse
                                       Virological response
                                                                                     observed at baseline.
                                                                                          The method used to assess adherence may also be
Figure 2 Impact of patient therapeutic education on adherence to                     criticized. When the study was designed, we chose to use
treatment (A and B) and virological response (C). At 3 mo of treatment, the          data reported by patients rather than by investigators,
proportion of patients adhering to treatment (patient self-report) was similar in    to best ref lect the real-life situation. However,
the two groups. At 6 mo, the proportion of adherents dropped in patients without     asking patients to fill a diary each day would have
therapeutic education only. The virological response was better in educated
patients, with an increased rate of SVR and a lower relapse rate.
                                                                                     influenced their behavior and led to an unquantifiable
                                                                                     overestimation of our primary endpoint. Adherence
                                                                                     data were therefore collected over limited time periods.
in naive genotype 2/3 patients, the fact that adherence                              We also chose not to take into account body weight
was the same over 12 wk may explain why adherence                                    when calculating adherence to ribavirin. Theoretically,
in the later part did not translate to significantly higher                          we overestimated adherence to ribavirin in patients over
SVR rates. As suggested by the borderline P value, this                              65 kg body weight, i.e. in approximately half the study
might also be due to the fact that inclusion of one-third                            population at baseline. This bias was however reduced,
of the CheObs cohort in this analysis limited the power                              as weight is known to decrease markedly over time in
to detect statistical significance.                                                  most treated patients and, as expected, dose reductions
    The overall adherence rate to ribavirin (64%-72%)                                occurred for safety reasons in a large proportion of
was consistently lower than that to peg-interferon                                   patients (17%-18%) in both groups.
(74%-80%), as expected from their regimen. The                                            Our results demonstrate that, although patients with
ribavirin regimen is somewhat complex (twice-daily                                   HCV genotype 2/3 are those who usually show the best
oral dosing) whereas peg-interferon alfa-2b adherence                                response rates, further efforts may be made to improve
is facilitated by the low frequency of administration                                outcomes. There is more than one barrier preventing
(weekly injections) and availability of an injecting pen                             patients from optimal compliance to their treatment
device. Therapeutic education significantly enhanced                                 regimen[1]. Five interacting dimensions affect adherence:
adherence to ribavirin, which is particularly important                              social and economic factors, and factors related to the


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Cacoub P et al . Real-life adherence to HCV treatment                                                                                       6201

A                                                                         Genotype 2
                                                                                                                  Without therapeutic education (n = 66)
                                                                                                                  With therapeutic education (n = 101)

                                                                                                                        82
                             77                                      79
                 80                                           75
                      70
                                                                                                                60
                 60
% of patients




                 40


                                                                                       18                                       20                20
                 20                   17    15     14                          17                                                      14
                                                        8                                       8
                                                                                                      4                                                 4
                  0
                           SVR      Nonresponse    Relapse         SVR       Nonresponse        Relapse           SVR        Nonresponse          Relapse

                                   All (n = 167)                          High viral load (n = 40)                      Low viral load (n = 80)


B                                                                         Genotype 3
                                                                                                                  Without therapeutic education (n = 180)
                                                                                                                  With therapeutic education (n = 197)
                                                                                                                        86
                 80          77                                                                                 75
                      69                                             69
                                                              63
                 60
% of patients




                 40

                                                                               21      19
                 20                                16                                          16
                                      14                12                                            12                        13                12
                                            11                                                                                         10
                                                                                                                                                        4
                  0
                           SVR      Nonresponse    Relapse         SVR       Nonresponse        Relapse           SVR        Nonresponse          Relapse

                                  All (n = 377)                           High viral load (n = 101)                     Low viral load (n = 146)


Figure 3 Virological response in patients infected with genotype 2 (A) or genotype 3 (B), and according to viral load (> or ≤ 800 000 IU/mL). Although not
statistically significant, patient therapeutic education was beneficial in all patient subgroups, especially in those with genotype 2 and low viral load, with a marked
impact on the SVR (SVR, P = 0.038) and relapse (P = 0.047) rates.


health care team and system, the condition, treatment, and                              Mercier (Stat Process, Pont Mort, France), who analysed
the patient[2,15,16]. Increasing the impact of interventions                            the data, as well as all investigators for participating in
aimed at patient-related factors and/or health care team-                               this study (the CheObs Study Group).
related factors is essential. Methods that have been shown                                  The CheObs Study Group (France): Laurent Alric
to be effective in improving therapy include: educational                               (Toulouse), Tony Andreani (Paris), Michel Antoni
interventions involving patients[25,26]; strategies to improve                          (Orange), Jean-Pierre Arpurt (Avignon), Tarik Asselah
dosing schedules[6]; interventions that enlist ancillary health                         (Clichy), Yannick Bacq (Tours), François Bailly (Lyon),
care providers such as pharmacists, behavioral specialists,                             Axel Balian (Clamart), Xavier Ballorain (Châtellerault),
and nursing staff[27,28]; and enhancing communication                                   Christelle Bapin (Montpellier), Jean-Claude Barbare
between physicians and patients[29-31].                                                 (Compiègne), Didier Barbereau (Tours), Marc Bardou
    To conclude, in the real-life setting, therapeutic                                  (Dijon), Jean-Luc Baroni (Martigues), Eric Barriere
education helped maintain adherence to bitherapy in                                     (Limoges), Marc Bary (Paris), Guy Bellaiche (Aulnay-
patients with genotype 2/3 infection. There was a trend                                 sous-Bois), Serge Bellon (Avignon), Souaad Benali
for a benefit on virological response. This analysis of                                 (Marseille), Serge Benhaim (Marseille), Sylvain Beorchia
the real-life impact of patient education by a third party                              (Lyon), Pierre Bernard (Pessac), Brigitte Bernard-Chabert
on health outcomes may help to further improve patient                                  (Reims), Isabelle Besson (La Rochelle), Louis Bettan
quality of life and outcome. The importance of adherence                                (Villeneuve-St-Georges), Isabelle Beurton (Besançon),
and the role of education should now be studied in a                                    Daniel Bianchi (Nice), Pierre Blanc (Montpellier), Alain
randomized controlled trial in genotype 1/4 infection.                                  Blanchi (Le Mans), Gilles Bommelaer (Clermont-Ferrand),
                                                                                        Cyril Bonaventure (Lyon), Corinne Bonny (Clermont-
                                                                                        Ferrand), Daniele Botta-Fridlund (Marseille), James
ACKNOWLEDGMENTS                                                                         Boulant (Grasse), Guy Boulay (Arles), Marc Bourliere
The authors are grateful to Ceri Medical (Garches,                                      (Marseille), Nathalie Boyer (Clichy), Slim Bramli (Avignon),
France), who helped in field monitoring, Florence Colin-                                Jean-Pierre Bronowicki (Vandoeuvre-les-Nancy), Maud

                                                                                                                                                  www.wjgnet.com
6202    ISSN 1007-9327       CN 14-1219/R      World J Gastroenterol       October 28, 2008             Volume 14           Number 40


Brung-Lefebvre (Elbeuf), Yvon Calmus (Paris), Jean-Yves        (Chambéry), Rolland Rollux (Thonon-les-Bains), Isabelle
Canva (Roubaix), Valèrie Canva-Delcambre (Lille), Jean         Rosa (Créteil), Françoise Roudot-Thoraval (Créteil),
Cassigneul (Toulouse), Laurent Castera (Pessac), Xavier        Faouzi Saliba (Villejuif), Thierry Sapey (Châteauroux),
Causse (La Source), Jean-Michel Cayla (Saint Brice),           Olivier Savary (Brest), Olivia Scalone (Lyon), Mathieu
Catherine Chevalier (Limoges), Philippe Chevassus (Gap),       Schnee (La-Roche-sur-Yon), Maud Schoeny (Saint-
Renè Chiari (Perpignan), Ariane Chryssostalis (Crèteil),       Dizier), Lawrence Serfaty (Paris), Jeanne Serpaggi (Paris),
Jean-Marc Combis (Toulouse), Filomena Conti (Paris),           Eric Sgro (Carcassonne), Si Nafa Si Ahmed (La Source),
Denis Corcos (Narbonne), Olivier Croizet (Toulouse),           Claude Souvignet (La Tronche), Nathalie Szostak-
Emmanuel Cuillerier (Dreux), Bella Czernichow                  Talbodec (Tourcoing), Jean-Claude Tellaroli (Thionville),
(Sarreguemines), Louis D’Alteroche (Tours), Hélène             Dominique Thabut (Paris), Gilles Tordjman (Aulnay-
Danielou (Rennes), Odile Danne (Pontoise), Manh-               sous-Bois), Christian Trepo (Lyon), Régine Truchi (Nice),
Thuong Dao (Caen), Cécilia D’Arondel de Haye (Paris),          Claire Vanlemmens (Besançon), René-Louis Vitte (Poissy),
Patrick Delasalle (Grasse), Pierre Deltenre (Lille), Jacques   Jean-Pierre Zarski (La Tronche).
Denis (Corbeil-Essonnes), Salem Dernaika (Paris), Hervé
Desmorat (Toulouse), Jacques Doll (Le Chesnay), Sylva
Doumet (Villeneuve-St-Georges), Jean-Charles Duclos-            COMMENTS
Vallee (Villejuif), Michel Duffaut (Toulouse), Samouh          Background
Elfadel (Caen), Gilbert Eschmann (Grasse), Claude              Adherence to therapy is critical in the treatment of chronic hepatitis C virus
Eugene (Poissy), Roger Faroux (La Roche-sur-Yon),              (HCV) infection. The current gold standard therapy is a combination of peg-
                                                               interferon alfa and ribavirin. Patients with genotype 2 or 3 infection have a
Laetitia Fartoux Heymann (Paris), Abdelaziz Fatisse            78%-82% likelihood of achieving a sustained virological response (SVR) after
(Belfort), Bernard Filoche (Lomme), Antoine Fleury             24 wk of therapy, whereas patients with genotype 3 infection and high viral load
(Pontoise), Isabelle Fouchard-Hubert (Angers), Juliette        are difficult to treat (< 70% responders). Therapy requires weekly subcutaneous
Foucher (Pessac), Serge Fratte (Belfort),Valérie Garcia        injections, twice-daily oral dosing and frequent visits, with blood tests. Side
(Montpellier), Dany Gargot (Blois), Jean-Louis Gaudin          effects occur in nearly all patients. As a result, 15%-20% of patients in clinical
                                                               trials and over 25% in clinical practice discontinue therapy.
(Le Puy-en-Velay), Nathalie Giuily (Clichy), Odile Goria
                                                               Research frontiers
(Rouen), Alain Gourlaouen (Morlaix), Stéphane Grimaldi         In clinical trials, the SVR rate was significantly improved in those patients with
(Carcassonne), Catherine Guillemard (Caen), Anne               HCV genotype 1 infection who received > 80% of their total peg-interferon dose
Guillygomarc’H (Rennes), Dominique Guyader (Rennes),           and > 80% of their ribavirin dose for > 80% of the scheduled treatment duration.
François Habersetzer (Strasbourg), Sadia Hachemane             A review of the 2002-2007 literature confirmed that treatment response is
(Montpellier), Nabil Haddad (Villejuif), Hervé Hagege          influenced not only by HCV genotype and viral load, but also by patient-related
                                                               factors including adherence.
(Créteil), Najia Haioun (Cavaillon), Bertrand Hanslik
                                                               Innovations and breakthroughs
(Montpellier), Cyril Hatem (Dijon), Marie-Laure Hemery         The authors evaluated, perhaps for the first time, the impact of patient therapeutic
(Montpellier), Pascale Hervio (Pontoise), Christophe           education by a third party on adherence and virological response to peg-interferon
Hezode (Créteil), Noëlle Hilleret (La Tronche), Patrick        alfa-2b and ribavirin. The analysis was carried out in the 674 patients with chronic
Hillon (Dijon), Valérie Hyrailles (Béziers), Jean-Paul         genotype 2/3 HCV infection from the CheObs cohort. Therapeutic education given
Jacques (Toulouse), Pascal Kitmacher (La Rochelle),            during the first 3 mo of treatment significantly improved the proportion of patients
                                                               adhering to bitherapy at 6 mo (odds ratio 1.58). Though not significantly, the
Alain Landau (Dreux), Emmanuel Lapoile (Villeneuve-            virological response was also improved in educated patients, with an increased
St-Georges), Dominique Larrey (Montpellier), Olivier           SVR rate (77% vs 70%) and a lower relapse rate (10% vs 16%). Therapeutic
Larroque (Hyères), Sophie Le Calvez (Paris), Pascal            education significantly enhanced adherence to ribavirin, which is particularly
Lebray (Paris), Olivier Lejeune (St-Priest-en-Jarez), Alain    important for obtaining a SVR. A positive impact was also observed on adherence
Lemoine (Nevers), Stéphane Levy (Reims), Fabrice Longo         to peg-interferon, showing that an improvement can still be obtained.
(Fréjus), Véronique Loustaud Ratti (Limoges), Hervé            Applications
                                                               This analysis of the real-life impact of patient therapeutic education by a third
Louvet (Reims), Damien Lucidarme (Lomme), Catherine
                                                               party on health outcomes may help to further improve patient quality of life and
Mathieu-Chandelier (Lille), Philippe Mathurin (Lille),         outcome. Five interacting dimensions affect adherence: social and economic
Marianne Maynard (Lyon), Sophie Metivier (Toulouse),           factors, and factors related to the health care team and system, the condition,
Jean-Philippe Miguet (Besançon), Anne Minello (Dijon),         treatment, and the patient. Methods that have been shown to be effective
François Mion (Lyon), Joseph Moussalli (Paris), Bernard        in improving therapy include: educational interventions involving patients;
                                                               strategies to improve dosing schedules; interventions that enlist ancillary health
Nalet (Montélimar), Jean-Baptiste Nousbaum (Brest),            care providers such as pharmacists, behavioral specialists, and nursing staff;
Frédéric Oberti (Angers), Valérie Oules (Marseille),           and enhancing communication between physicians and patients.
Georges Philippe Pageaux (Montpellier), Jean-Louis             Peer review
Payen (Montauban), Christophe Pilette (Le Mans), Didier        This is a subgroup analysis of a bigger project. Since the a priori power
Pillon (Bourg-en-Bresse), Isabelle Portal (Marseille),         calculation was based on 2000 subjects for meaningful statistical analysis,
Philippe Pouderoux (Nîmes), Claude Raffanel (Nîmes),           the inclusion of only 630 or so patients in this study clearly limits the power to
                                                               detect statistical significance.
Baboojaswan Ramgoolam (Apt), Karine Randl (Clermont-
Ferrand), Vlad Ratziu (Paris), Corinne Regimbeau (Paris),
André-Jean Remy (Perpignan), Christophe Renou (Hyères),        REFERENCES
Ghassian Riachi (Rouen), Didier Ribard (Nîmes), Olivier
                                                               1     Sabate E. Adherence to long-term therapies. Evidence for
Ribiere (Rambouillet), Jean-Philippe Richardet (Créteil),            action. Geneva: World Health Organization; 2003. Available
Marie-Pierre Ripault (Clichy), Bruno Roche (Villejuif),              from URL: http://whqlibdoc.who.int/publications/2003/9
Christine Roche (Clermont-Ferrand), Olivier Rogeaux                  241545992.pdf


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Cacoub P et al . Real-life adherence to HCV treatment                                                                                6203

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Patient education improves adherence to HCV therapy -the CHEOBS Study

  • 1. Online Submissions: wjg.wjgnet.com World J Gastroenterol 2008 October 28; 14(40): 6195-6203 wjg@wjgnet.com World Journal of Gastroenterology ISSN 1007-9327 doi:10.3748/wjg.14.6195 © 2008 The WJG Press. All rights reserved. RAPID COMMUNICATION Patient education improves adherence to peg-interferon and ribavirin in chronic genotype 2 or 3 hepatitis C virus infection: A prospective, real-life, observational study Patrice Cacoub, Denis Ouzan, Pascal Melin, Jean-Philippe Lang, Michel Rotily, Thierry Fontanges, Marina Varastet, Michel Chousterman, Patrick Marcellin Patrice Cacoub, Department of Internal Medicine, Pitié- self-reported over the past 4 wk (peg-interferon) or Salpêtrière Hospital, AP HP, Paris 75651, France; Pierre and 7 d (ribavirin). Adherence to bitherapy was defined Marie Curie (Paris 6) University, CNRS UMR 7087, Paris as adherence to the two drugs for ≥ 20 wk. SVR was 75651, France defined as undetectable RNA ≥ 12 wk after the end of Denis Ouzan, Department of Hepato-Gastroenterology, Arnault treatment. Tzanck Institute, Saint Laurent du Var 06721, France RESULTS: 370/674 patients received education during Pascal Melin, Department of Polyvalent Medicine, Hospital of Saint Dizier, Saint Dizier 52115, France the first 3 mo of treatment. After 6 mo, adherence to Jean-Philippe Lang, Department of Psychiatry and Addiction, bitherapy was higher in educated patients (61% vs Hospital of Erstein, Erstein 67152, France 47%, P = 0.01). Adherence to peg-interferon was 78% Michel Rotily, Marina Varastet, ClinSearch, Bagneux 92220, vs 69% (P = 0.06). Adherence to ribavirin was 70% vs France 56% (P = 0.006). The SVR (77% vs 70%, P = 0.05) Thierry Fontanges, Department of Hepato-Gastroenterology, and relapse (10% vs 16%, P = 0.09) rates tended to General Hospital of Bourgoin, Bourgoin Jailleu 38317, France be improved. After adjustment for baseline differences, Michel Chousterman, Department of Hepato-Gastroentrology, education improved adherence [Odds ratio (OR) 1.58, Hospital of Créteil (CHIC), Créteil 94010, France P = 0.04] but not the SVR (OR 1.54, P = 0.06). Patrick Marcellin, Department of Hepatology, Beaujon CONCLUSION: In genotype 2/3 patients, therapeutic Hospital, Pôle des Maladies de l'Appareil Digestif, Clichy education helped maintain real-life adherence to 92118, France; and INSERM U 773, CRB3, University of Paris VII, Beaujon Hospital, Clichy 92118, France bitherapy. Author contributions: Cacoub P, Ouzan D, Melin P, Lang JP, Rotily M, Fontanges T, Chousterman M, and Marcellin P (The © 2008 The WJG Press. All rights reserved. Scientific Committee) designed the research, reviewed the data, supervised the analysis and interpreted the results; Varastet M Key words: Viral hepatitis; Adherence; Therapeutic helped analysing the data, interpreting the results, and wrote education; Real life; Peg-interferon; Ribavirin the paper; All authors helped writing, critically reviewed and approved the paper. Peer reviewer: Raymund Rabe Razonable, PhD, Division of Supported by Schering-Plough France Infectious Diseases, Mayo Clinic Institution, 200 First Street Correspondence to: Patrice Cacoub, Professor, Department SW, Rochester 55905, United States of Internal Medicine, Pitié-Salpêtrière Hospital, 47-83 boulevard de l'Hôpital, Paris cedex 13 F-75651, Cacoub P, Ouzan D, Melin P, Lang JP, Rotily M, Fontanges T, France. patrice.cacoub@psl.aphp.fr Varastet M, Chousterman M, Marcellin P. Patient education Telephone: +33-142-178027 Fax: +33-142-178033 improves adherence to peg-interferon and ribavirin in chronic Received: June 19, 2008 Revised: September 16, 2008 Accepted: September 23, 2008 genotype 2 or 3 hepatitis C virus infection: A prospective, Published online: October 28, 2008 real-life, observational study. World J Gastroenterol 2008; 14(40): 6195-6203 Available from: URL: http://www.wjgnet. com/1007-9327/14/6195.asp DOI: http://dx.doi.org/10.3748/ wjg.14.6195 Abstract AIM: To evaluate the impact of therapeutic education on adherence to antiviral treatment and sustained INTRODUCTION virological response (SVR) in a real-life setting in genotype 2/3 hepatitis C, as there are few adherence As pointed out by the WHO [1] , poor adherence data in genotype 2/3 infection, even from randomized to treatment is a worldwide issue in all chronic trials. conditions, which results in poor health outcomes and METHODS: This prospective survey included genotype increased health care costs [2,3]. Even in clinical trials, 2/3 patients who received peg-interferon alfa-2b and mean adherence rates are low (43%-78%) in chronic ribavirin. There was no intervention. Adherence was conditions[4-6]. In clinical practice, adherence rates of www.wjgnet.com
  • 2. 6196 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol October 28, 2008 Volume 14 Number 40 about 50% are usually reported[7]. to previous therapy. In accordance with French law, the Adherence to therapy is critical in the treatment of Ethics Committee’s approval was not required as the chronic hepatitis C virus (HCV) infection. The current protocol was strictly observational and usual practice was gold standard therapy is a combination of peg-interferon unchanged. However, all patients gave informed consent alfa and ribavirin[8,9]. Patients with genotype 1 infection to participate. have a 42%-51% likelihood of achieving a sustained Included patients saw their physician at a frequency virological response (SVR) after 48 wk of therapy; corresponding to the usual practice in the center. The 78%-82% of patients with genotype 2 or 3 infection investigator and the patient completed a questionnaire respond to 24 wk of treatment, whereas patients with each at inclusion, at the visits occurring approximately genotype 3 infection and high viral load are difficult to every 3 mo during treatment, and at the visit occurring treat (< 70% responders)[10,11]. Non-responders to prior approximately 6 mo after the end of treatment. Patients standard bitherapy respond to retreatment in 13% of the filled in their questionnaires in the waiting room and cases (29% in non-1 genotype), and relapsers in 58.5% either gave it back to the investigator in a sealed envelope of the cases[12]. Therapy requires weekly subcutaneous or returned it using a prepaid envelope. injections, twice-daily oral dosing and frequent visits, The investigators recorded socio-demographic with blood tests. Side effects occur in nearly all patients. data, history of HCV infection (including previous As a result, 15%-20% of patients in clinical trials and > treatments), risk factors, comorbidities, patient 25% in clinical practice discontinue therapy. therapeutic education (provided or not), planned/ In clinical trials, SVR was significantly improved prescribed hepatitis C treatment, modification of in those patients with HCV genotype 1 infection who treatment during follow-up, concomitant medications, received > 80% of their total peg-interferon dose and adverse events. The virological status, documented and > 80% of their ribavirin dose for > 80% of the by qualitative PCR (Amplicor™, Roche) and test date, scheduled treatment duration, in comparison with those was recorded at the last visit. who failed these adherence criteria[13]. A review of the The patient questionnaires concerned adherence 2002-2007 literature confirmed that treatment response to peg-interferon and ribavirin, and the persons is influenced not only by HCV genotype and viral load, involved in the management of their disease (e.g. health but also by patient-related factors including adherence[14]. professionals of any discipline, patient associations). Moreover, optimal HCV healthcare requires further The following parameters relating to the past 4 wk were efforts from providers in communicating with patients, recorded to evaluate adherence to peg-interferon: date as advocated in France by hepatitis C experts and the of injections (or reason for not having an injection), Health Ministry[15,16], and shown in studies using patient frequency of and reason for taking peg-interferon at questionnaires in North America[17,18]. a higher/lower dose than prescribed. The following We carried out a large survey named CheObs to parameters relating to the past 7 d were recorded to evaluate adherence to chronic hepatitis C treatment in evaluate adherence to ribavirin: number of (200 mg) the real-life setting in France. We observed that some capsules prescribed morning and evening, date of patients received therapeutic education by a third party dosing and number of capsules taken in the morning (other than the investigator), at the discretion of the and evening, reasons for missing doses, reasons for and investigators, during the study period. According to the frequency of taking more/less capsules than prescribed. consensus that efforts to boost treatment adherence As for any survey, there was no protocol-specific improve SVR rates, we performed the present analysis intervention. Therapeutic education was defined by to evaluate the impact of patient education on real-life intervention of a third party (healthcare professionals adherence and response to treatment with peg-interferon other than the prescribing physician) and distribution alfa-2b and ribavirin. This analysis was carried out in of support documents and educational material during patients with genotype 2/3 HCV infection (one third of individual sessions. It was provided at the discretion of the CheObs cohort), as there are few adherence data for the physician. No instruction was given related to which these patients even from randomized trials, and because patient should be considered or how education should their data were available before those of patients with be provided. other genotypes, due to shorter treatment duration. Adherence to bitherapy was defined as adherence to both peg-interferon and ribavirin over a sufficient time period, as self-reported by the patients. According to MATERIALS AND METHODS the “80/80/80” criteria previously defined[13], patients The prospective, multicenter, CheObs sur vey was were considered to have adhered to peg-interferon if carried out in teaching hospitals, non-teaching hospitals, they had received three or four injections during the and private practice offices highly involved in the past 4 wk, and to have adhered to ribavirin if they had management of hepatitis C in France, and supervised taken at least 22 (200 mg) capsules over the past week. by a Scientific Committee. Consecutive patients aged Patients were considered to have adhered to bitherapy ≥ 18 years with chronic hepatitis C were enrolled if if they had adhered to the two drugs for at least 20 wk. initiation of bitherapy with peg-interferon alfa-2b and These rules were defined according to the recommended ribavirin was scheduled. They could be naive for any number of peg-interferon injections (one per week), the chronic hepatitis C therapy or non-responders/relapsers recommended ribavirin daily dose (at least 800 mg/d), www.wjgnet.com
  • 3. Cacoub P et al . Real-life adherence to HCV treatment 6197 and the recommended duration of bitherapy in Chronic HCV genotype 2/3 HCV infection (24 wk). infection SVR was defined as undetectable HCV RNA in the n = 2001 Genotype non-2 and non-3 n = 1296 serum 12 wk after the end of treatment or later. This time interval was considered to be sufficient for this Genotype 2 or 3 Excluded from analysis n = 31 evaluation, since relapse after 12 wk of follow-up is n = 705 Due to: rarely (2%) observed whatever the HCV genotype[19], and Monotherapy n =5 the dates of the visits and laboratory tests could not be Analysed Bitherapy end date not available n = 26 forced in this observational protocol. Non-response was n = 674 defined as detectable RNA at the end of treatment, and relapse as undetectable RNA at the end of treatment but Without With therapeutic therapeutic detectable at a later time point. education education n = 304 n = 370 Statistical analysis Due to the lack of data in the literature, the CheObs Figure 1 Patient flow. sample size calculation was based on real-life adherence observed in chronic conditions other than chronic HCV infection, such as HIV infection[20], diabetes[21], or but a similar body mass index (BMI) (Table 1). They hypertension[22]. A total of 1537 patients were required more frequently had a past history of depression (P to estimate a 50% adherence rate, with a precision of = 0.01) and current psychiatric disorders (P = 0.04, 2.5% and a type Ⅰ error of 0.05. Assuming 25%-30% of mainly depression and anxiety), though there was patients were lost to follow-up or discontinued treatment no difference for the nature or proportion of each early, approximately 2000 patients were included overall. disorder. Educated patients were also more frequently The present analysis was carried out in the subset psychoactive drug users (P = 0.02, mainly cocaine of patients with genotype 2/3 HCV infection from the and heroin), but the profile of consumption (injecting CheObs cohort. Statistical analysis was conducted using behavior and frequency of abuse) was similar. Regarding SAS 8.2 (SAS Institute Inc, Cary, NC, USA). Tests were HCV infection, although educated patients had more two-sided and type Ⅰ error was set at 0.05. Descriptive frequently significant liver fibrosis than those without statistics were performed using all available data. Group therapeutic education (P = 0.04), the proportion of comparisons were carried out using Kruskal-Wallis or cirrhotic patients was similar (13% and 15%). Fisher’s exact tests. The relationships between adherence or virological response and a set of potential explanatory Treatment variables were analysed by forward stepwise logistic A 24-wk bitherapy was scheduled in most patients regressions. These variables included not only those for (571/667, 86%), with no marked difference between which groups differed significantly at baseline (P < 0.05), groups (Table 2). Treatment for 48 wk was more but also those expected to have a significant impact frequently planned in non-responders/relapsers to according to the literature. previous therapy (43/125, 34%) than in naive patients (49/542, 9%, P < 0.001). The planned weekly dose of peg-interferon was higher in educated patients (P = RESULTS 0.01), at 1.5 μg/kg per week in most cases (82% vs 75%) Patients' characteristics whereas patients without therapeutic education were Between 2002 and 2006, 184 investigators enrolled 2001 more frequently prescribed lower doses. However there HCV patients in the CheObs survey, including 705 was no difference between the groups for the proportion patients infected with the genotype 2/3 HCV (Figure 1). of retreated patients (Table 1) or that of relapsers/ Of these, 674 patients were analyzed. We observed that non-responders to previous treatment (P = 0.95). The 370/674 (55%) patients received therapeutic education ribavirin dose prescribed was similar in both groups. It during the first 3 mo of treatment and 304 (45%) did was 800 mg/d in half of the patients (344/669, 51%) not. Among the 82 centers which included the analyzed and < 800 mg/d in 18 (3%) patients. population, 24 (29%) did not educate any patient, 18 The actual duration of bitherapy was shorter than (22%) educated > 0 to 50% of their patients, 19 (23%) 20 wk in 85/674 (13%) patients (P = 0.20 between educated > 50% to < 100% of their patients, and 21 groups, Table 2), with an average of 11.1 ± 4.9 wk (26%) educated 100% of their patients. The 31 patients (median 12) in these patients. Reasons for premature excluded from analysis were similar to the analyzed discontinuation were: lost to follow-up (n = 28), safety population for the therapeutic education rate (58%) (n = 27), patient’s request (n = 14), virological (HCV and all other baseline variables, except for the Metavir RNA detectable or decrease < 2 log, n = 7), unknown activity score, which was more frequently A2/A3 (78% (n = 3), investigator’s request (n = 2), and other (n = 4). vs 50%, P = 0.009). They were similar in nature and occurrence (P = 0.79) In the analyzed population, educated patients had in both groups. These patients, who were not included a higher body weight (70.5 ± 14.0 kg vs 67.9 ± 14.3 kg, in the analysis of virological response, did not differ P = 0.02) than patients without therapeutic education, significantly from those who received a longer bitherapy www.wjgnet.com
  • 4. 6198 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol October 28, 2008 Volume 14 Number 40 Table 1 Baseline characteristics of the patients (n = 674): Table 2 Treatment planned and actually received (n = 674): Univariate analysis Univariate analysis Therapeutic education Therapeutic education No Yes P No (n = 304) Yes (n = 370) P (n = 304) (n = 370) Duration of bitherapy (wk)1 Socio-demography Planned 27.7 ± 8.9 27.1 ± 8.2 0.49 Men 170/303 (56) 229/370 (62) 0.14 Actual 28.4 ± 12.7 30.3 ± 14.2 0.25 Age (yr) 44.1 ± 11.4 44.9 ± 11.4 0.16 Premature discontinuation 44/304 (15) 41/370 (11) 0.20 Body mass index (kg/m2) 23.5 ± 4.1 24.1 ± 4.2 0.06 (< 20 wk) Employment status Peginterferon weekly dose (μg/kg) Professional activity 190/303 (63) 220/370 (59) 0.59 Planned 1.35 ± 0.29 1.41 ± 0.22 0.01 Unemployed 48/303 (16) 69/370 (19) Actual at 3 mo2 1.31 ± 0.30 1.38 ± 0.25 0.006 Other 65/303 (22) 81/370 (22) Actual at 6 mo2 1.18 ± 0.35 1.25 ± 0.31 0.02 Educational level Ribavirin daily dose (mg) Low 182/300 (61) 223/365 (61) 0.94 Planned 897 ± 147 906 ± 154 0.67 High 118/300 (39) 142/365 (39) Actual at 3 mo2 871 ± 166 885 ± 175 0.25 Origin of incomes Actual at 6 mo2 771 ± 201 803 ± 209 0.06 Paid employment 166/298 (56) 183/368 (50) 0.24 Unemployment incomes 48/298 (16) 60/368 (16) Data are expressed as mean ± SD, or proportions of patients. 1Date of end Other 84/298 (28) 125/368 (34) of bitherapy minus date of inclusion; 2Cumulated over the past 3 mo (AUC, Debts investigator report). Difficult to manage 8/232 (4) 27/315 (9) 0.02 None or easily managed 224/232 (97) 288/315 (91) Comorbidities with regards to the main variables. Past psychiatric history Depression 67/303 (22) 113/370 (31) 0.01 Physicians modified the peg-interferon dose less Suicide attempt 23/302 (8) 29/368 (8) 0.81 frequently in educated patients (16% vs 22% without Hospitalisation for mental 25/301 (8) 36/369 (10) 0.59 therapeutic education, P = 0.046), whereas the disease ribavirin dose was changed in similar proportions of Psychiatric disorder 60/300 (20) 98/367 (27) 0.04 patients in both groups (17% vs 18%, P = 0.28) nearly Chronic disease 64/298 (22) 89/366 (24) 0.41 Risk factors always because of adverse effects and weight loss and Alcohol consumption > 20 g/d 10/70 (14) 24/100(24) 0.17 depression in particular. The difference in the dose Tobacco consumption 167/299 (56) 187/366 (51) 0.24 between groups remained constant for peg-interferon Drug abuse whereas it increased over time for ribavirin, in particular None 139/303 (46) 172/368 (47) 0.02 after the third month of treatment (Table 2). The Former 158/303 (52) 174/368 (47) Current 6/303 (2) 22/368 (6) occurrence of adverse events over the whole study was HCV infection 82% of patients in each group (P = 0.92). Source of HCV infection1 Transfusion 62/304 (20) 76/370 (21) 1.00 Adherence to bitherapy Injection or intranasal drug 157/304 (52) 193/370 (52) 0.94 abuse Overall adherence to bitherapy was 64% (301/468) Other 86/304 (29) 100/370 (27) 0.86 at 3 mo and 55% (209/383) at 6 mo of treatment. Duration of HCV infection (year) 20.4 ± 8.4 20.0 ± 8.9 0.85 Adherence to peg-interferon (80% and 74% at 3 and Serum HCV-RNA 6 mo, respectively) was higher than to ribavirin (72% ≤ 800 000 IU/mL or equivalent 121/193 (63) 162/265 (61) 0.77 and 64%, respectively). Patients prescribed high doses > 800 000 IU/mL or equivalent 72/193 (37) 103/265 (39) HCV genotype of ribavirin (≥ 1000 mg/d) did not differ significantly 2 85/304 (28) 117/370 (32) 0.31 from those with lower doses with respect to premature 3 219/304 (72) 253/370 (68) 0.31 treatment discontinuation and adherence to peg- Coinfection interferon and/or ribavirin. Human immunodeficiency virus 12/303 (4) 14/369 (4) 1.00 Hepatitis B virus2 3/301 (1) 6/369 (2) 0.63 At 3 mo, the proportion of adherents to both drugs Metavir activity grade or equivalent was 66% with therapeutic education and 63% without A0 or A1 119/226 (53) 131/272 (48) 0.32 therapeutic education (non-significant difference) A2 or A3 107/226 (47) 141/272 (52) (Figure 2 and Table 3). At 6 mo, this proportion was Metavir fibrosis stage or equivalent still 61% in educated patients, whereas it dropped F0 or F1 110/227 (49) 109/272 (40) 0.04 F2 or F3 82/227 (36) 129/272 (47) down to 47% without therapeutic education (P = 0.01). F4 35/227 (15) 34/272 (13) Multivariate analysis showed that, after adjustment, Knodell score 7.9 ± 3.0 8.4 ± 3.5 0.19 therapeutic education increased the probability of Previous anti-HCV treatment course adhering to bitherapy at 6 mo by a factor of 1.58 (95% CI: None 242/303 (80) 303/370 (82) 0.74 1.02 to 2.46). One or more 61/303 (20) 67/370 (18) At 6 mo, the adherence rate was still 78% for peg- Data are expressed as mean ± SD, or proportions of patients. 1One patient interferon and 70% for ribavirin in educated patients, could have more than one presumed source of infection. 2Hepatitis B whereas it was reduced to 69% (P = 0.06) and 56% (P antigen positivity. = 0.006), respectively, in patients without therapeutic www.wjgnet.com
  • 5. Cacoub P et al . Real-life adherence to HCV treatment 6199 Table 3 Adherence to treatment, virological response (univariate analysis) and their association with therapeutic education (multivariate analysis) Therapeutic education Univariate analysis Multivariate analysis No (n = 304) Yes (n = 370) P OR 95% CI P Adherence1 at 3 mo Bitherapy 137/218 (63) 164/250 (66) 0.56 1.04 0.69 to 1.56 0.87 Peginterferon 175/218 (80) 201/250 (80) 1.00 0.94 0.57 to 1.53 0.79 Ribavirin 152/218 (70) 186/250 (74) 0.30 1.13 0.72 to 1.77 0.59 Adherence1 at 6 mo Bitherapy 83/175 (47) 126/208 (61) 0.01 1.58 1.02 to 2.46 0.04 Peginterferon 121/175 (69) 162/208 (78) 0.06 1.78 1.07 to 2.96 0.03 Ribavirin 98/175 (56) 145/208 (70) 0.006 1.67 1.05 to 2.65 0.03 Virological response2 SVR 171/246 (70) 230/298 (77) 0.05 1.543 0.99 to 2.40 0.06 Nonresponse 37/246 (15) 37/298 (12) 0.38 Relapse 38/246 (16) 31/298 (10) 0.09 Data are expressed as proportions of patients. Multivariate analyses were adjusted for sex, weight, BMI, educational level (adherence only), history of depression, psychiatric disorders, alcohol consumption, drug abuse, duration of HCV infection, previous anti-HCV treatment, HCV genotype (SVR only), and peginterferon dose prescribed at inclusion. 1≥ 3 peginterferon injections during the last 4 wk and/or ≥ 22 ribavirin capsules of 200 mg each during the last 7 d (self-report); 2≥ 12 wk after the end of treatment; 3The rate of SVR was used as dependent variable. education. After adjustment, therapeutic education (P = 0.047) rates was observed, but the sample size was increased the probability of adherence by a factor of 1.78 small (n = 80). for peg-interferon and 1.67 for ribavirin after 6 mo of Moreover, although favorable trends were observed, bitherapy. therapeutic education had no significant impact on the Educated patients more frequently re por ted virological response in patients treated for the first time contacting persons in the hospital for management of (P = 0.27) or in non-responders/relapsers to previous their disease, with a median of three persons vs two for therapy (P = 0.22). patients without therapeutic education during the first 3 mo of treatment (P=0.016), and three persons vs one during the next 3 mo (P = 0.003). Conversely, patients DISCUSSION without therapeutic education reported more frequent We evaluated the impact of patient therapeutic education contacts with office-based persons, with a median of by a third party on adherence and virological response two persons vs one in educated patients during the first to peg-interferon alfa-2b and ribavirin in 674 patients 3 mo (P = 0.012), and two persons vs none during the with chronic genotype 2/3 HCV infection. This is the next 3 mo (P < 0.001). first time that adherence has been evaluated in patients carrying these genotypes, and also the first time that Virological response adherence has been assessed in a real-life setting. The overall SVR rate was 74% (401/544). There were Therapeutic education given during the first 3 mo 13.6% of non-responders and 12.7% of relapsers. The of treatment significantly improved the proportion of virological response was better, though not significantly, patients adhering to bitherapy at 6 mo (OR 1.58, P = in educated patients (Figure 2 and Table 3). The SVR 0.01 after adjustment for sex, weight, BMI, educational rate was higher (77% vs 70%, P = 0.05) and the rate level, history of depression, psychiatric disorders, of relapse was lower (10% vs 16%, P = 0.09) in these alcohol consumption, drug abuse, duration of HCV patients than in patients without therapeutic education. infection, previous anti-HCV treatment, and peg- Multivariate analysis confirmed that, after adjustment, interferon dose prescribed at inclusion). The proportion the relationship between SVR and therapeutic education of adherents was stable above 60% until the sixth month was borderline significant (P = 0.06). Response was of treatment in educated patients, whereas it dropped better in patients whose ribavirin dose was not reduced by more than 10% between the third and sixth month during the first 3 mo of treatment (P < 0.001), mostly of treatment when there was no therapeutic education. due to an increased SVR rate (362/473, 77% vs 37/67, The virological response was also improved in educated 55%, P = 0.001) and a decreased rate of non-response patients, with an increased SVR rate (77% vs 70%) and a (51/473, 11% vs 21/67, 31%, P < 0.001). lower relapse rate (10% vs 16%), though this effect was The virological response is shown taking into account statistically not significant (P = 0.06 after adjustment genotype and baseline viral load (> or ≤ 800 000 IU/mL) for sex, weight, BMI, history of depression, psychiatric in Figure 3. Though this effect was not significant, disorders, alcohol consumption, drug abuse, duration therapeutic education was found to have a beneficial of HCV infection, previous anti-HCV treatment, impact in all patients. In those with genotype 2 and low HCV genotype, and peg-interferon dose prescribed at viral load, an impact on the SVR (P = 0.038) and relapse inclusion). Since a 12-wk treatment may be very effective www.wjgnet.com
  • 6. 6200 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol October 28, 2008 Volume 14 Number 40 A Without therapeutic education (n = 218) for obtaining an SVR [23]. A positive impact was also With therapeutic education (n = 250) observed on adherence to peg-interferon, showing that P =1 P = 0.30 an improvement can still be obtained. 80 80 80 P = 0.56 74 Our results are consistent with the general consensus 70 63 66 that patient therapeutic education in clinical practice 60 effectively improves adherence to treatment in chronic % of patients disease [2,15,16] and that adherence, even to placebo, is 40 essential to achieve health outcome goals[3]. It should be 20 noted however, that education required the cooperation of specialists and nursing staff, and therefore probably 0 affected both patient-related and health care team-related Bitherapy Peg-interferon Ribavirin factors, which are recognized to improve adherence. Adherence at 3 mo The adherence rate to bitherapy (64%) was low compared to the rates of > 70% reported in clinical B Without therapeutic education (n = 175) trials[13]. The SVR rate observed here (72%) was however, With therapeutic education (n = 208) P = 0.06 in line with that reported in clinical trials (80%) in 80 78 P = 0.006 genotype 2/3 HCV patients treated with similar therapy[24]. P = 0.01 70 61 69 Apart from the fact that results are usually more marked in randomized trials, our population included a high % of patients 60 56 47 proportion of patients with psychiatric disorders and/or 40 drug addicts. This suggests that in real-life situations 20 such comorbidities and high-risk behavior do not have an impact on adherence or response to treatment, so that 0 Bitherapy Peg-interferon Ribavirin they may not be as difficult to treat as usually believed. Adherence at 6 mo Unlike during clinical trials, patients in this observational study were not selected or obliged to C P = 0.05 Without therapeutic education (n = 246) follow specific procedures and physicians were not 80 77 With therapeutic education (n = 298) instructed on which patient should be considered for 70 therapeutic education. This may be considered to be a 60 weakness of the study, as comparisons were performed % of patients on non-randomized groups. The CheObs study was not 40 P = 0.38 P = 0.09 designed to perform comparisons, but aimed to provide 20 15 16 a picture of the real-life setting. The use of multivariate 12 10 analysis in the present evaluation reduced such bias by 0 taking into account the differences between groups SVR Non-response Relapse Virological response observed at baseline. The method used to assess adherence may also be Figure 2 Impact of patient therapeutic education on adherence to criticized. When the study was designed, we chose to use treatment (A and B) and virological response (C). At 3 mo of treatment, the data reported by patients rather than by investigators, proportion of patients adhering to treatment (patient self-report) was similar in to best ref lect the real-life situation. However, the two groups. At 6 mo, the proportion of adherents dropped in patients without asking patients to fill a diary each day would have therapeutic education only. The virological response was better in educated patients, with an increased rate of SVR and a lower relapse rate. influenced their behavior and led to an unquantifiable overestimation of our primary endpoint. Adherence data were therefore collected over limited time periods. in naive genotype 2/3 patients, the fact that adherence We also chose not to take into account body weight was the same over 12 wk may explain why adherence when calculating adherence to ribavirin. Theoretically, in the later part did not translate to significantly higher we overestimated adherence to ribavirin in patients over SVR rates. As suggested by the borderline P value, this 65 kg body weight, i.e. in approximately half the study might also be due to the fact that inclusion of one-third population at baseline. This bias was however reduced, of the CheObs cohort in this analysis limited the power as weight is known to decrease markedly over time in to detect statistical significance. most treated patients and, as expected, dose reductions The overall adherence rate to ribavirin (64%-72%) occurred for safety reasons in a large proportion of was consistently lower than that to peg-interferon patients (17%-18%) in both groups. (74%-80%), as expected from their regimen. The Our results demonstrate that, although patients with ribavirin regimen is somewhat complex (twice-daily HCV genotype 2/3 are those who usually show the best oral dosing) whereas peg-interferon alfa-2b adherence response rates, further efforts may be made to improve is facilitated by the low frequency of administration outcomes. There is more than one barrier preventing (weekly injections) and availability of an injecting pen patients from optimal compliance to their treatment device. Therapeutic education significantly enhanced regimen[1]. Five interacting dimensions affect adherence: adherence to ribavirin, which is particularly important social and economic factors, and factors related to the www.wjgnet.com
  • 7. Cacoub P et al . Real-life adherence to HCV treatment 6201 A Genotype 2 Without therapeutic education (n = 66) With therapeutic education (n = 101) 82 77 79 80 75 70 60 60 % of patients 40 18 20 20 20 17 15 14 17 14 8 8 4 4 0 SVR Nonresponse Relapse SVR Nonresponse Relapse SVR Nonresponse Relapse All (n = 167) High viral load (n = 40) Low viral load (n = 80) B Genotype 3 Without therapeutic education (n = 180) With therapeutic education (n = 197) 86 80 77 75 69 69 63 60 % of patients 40 21 19 20 16 16 14 12 12 13 12 11 10 4 0 SVR Nonresponse Relapse SVR Nonresponse Relapse SVR Nonresponse Relapse All (n = 377) High viral load (n = 101) Low viral load (n = 146) Figure 3 Virological response in patients infected with genotype 2 (A) or genotype 3 (B), and according to viral load (> or ≤ 800 000 IU/mL). Although not statistically significant, patient therapeutic education was beneficial in all patient subgroups, especially in those with genotype 2 and low viral load, with a marked impact on the SVR (SVR, P = 0.038) and relapse (P = 0.047) rates. health care team and system, the condition, treatment, and Mercier (Stat Process, Pont Mort, France), who analysed the patient[2,15,16]. Increasing the impact of interventions the data, as well as all investigators for participating in aimed at patient-related factors and/or health care team- this study (the CheObs Study Group). related factors is essential. Methods that have been shown The CheObs Study Group (France): Laurent Alric to be effective in improving therapy include: educational (Toulouse), Tony Andreani (Paris), Michel Antoni interventions involving patients[25,26]; strategies to improve (Orange), Jean-Pierre Arpurt (Avignon), Tarik Asselah dosing schedules[6]; interventions that enlist ancillary health (Clichy), Yannick Bacq (Tours), François Bailly (Lyon), care providers such as pharmacists, behavioral specialists, Axel Balian (Clamart), Xavier Ballorain (Châtellerault), and nursing staff[27,28]; and enhancing communication Christelle Bapin (Montpellier), Jean-Claude Barbare between physicians and patients[29-31]. (Compiègne), Didier Barbereau (Tours), Marc Bardou To conclude, in the real-life setting, therapeutic (Dijon), Jean-Luc Baroni (Martigues), Eric Barriere education helped maintain adherence to bitherapy in (Limoges), Marc Bary (Paris), Guy Bellaiche (Aulnay- patients with genotype 2/3 infection. There was a trend sous-Bois), Serge Bellon (Avignon), Souaad Benali for a benefit on virological response. This analysis of (Marseille), Serge Benhaim (Marseille), Sylvain Beorchia the real-life impact of patient education by a third party (Lyon), Pierre Bernard (Pessac), Brigitte Bernard-Chabert on health outcomes may help to further improve patient (Reims), Isabelle Besson (La Rochelle), Louis Bettan quality of life and outcome. The importance of adherence (Villeneuve-St-Georges), Isabelle Beurton (Besançon), and the role of education should now be studied in a Daniel Bianchi (Nice), Pierre Blanc (Montpellier), Alain randomized controlled trial in genotype 1/4 infection. Blanchi (Le Mans), Gilles Bommelaer (Clermont-Ferrand), Cyril Bonaventure (Lyon), Corinne Bonny (Clermont- Ferrand), Daniele Botta-Fridlund (Marseille), James ACKNOWLEDGMENTS Boulant (Grasse), Guy Boulay (Arles), Marc Bourliere The authors are grateful to Ceri Medical (Garches, (Marseille), Nathalie Boyer (Clichy), Slim Bramli (Avignon), France), who helped in field monitoring, Florence Colin- Jean-Pierre Bronowicki (Vandoeuvre-les-Nancy), Maud www.wjgnet.com
  • 8. 6202 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol October 28, 2008 Volume 14 Number 40 Brung-Lefebvre (Elbeuf), Yvon Calmus (Paris), Jean-Yves (Chambéry), Rolland Rollux (Thonon-les-Bains), Isabelle Canva (Roubaix), Valèrie Canva-Delcambre (Lille), Jean Rosa (Créteil), Françoise Roudot-Thoraval (Créteil), Cassigneul (Toulouse), Laurent Castera (Pessac), Xavier Faouzi Saliba (Villejuif), Thierry Sapey (Châteauroux), Causse (La Source), Jean-Michel Cayla (Saint Brice), Olivier Savary (Brest), Olivia Scalone (Lyon), Mathieu Catherine Chevalier (Limoges), Philippe Chevassus (Gap), Schnee (La-Roche-sur-Yon), Maud Schoeny (Saint- Renè Chiari (Perpignan), Ariane Chryssostalis (Crèteil), Dizier), Lawrence Serfaty (Paris), Jeanne Serpaggi (Paris), Jean-Marc Combis (Toulouse), Filomena Conti (Paris), Eric Sgro (Carcassonne), Si Nafa Si Ahmed (La Source), Denis Corcos (Narbonne), Olivier Croizet (Toulouse), Claude Souvignet (La Tronche), Nathalie Szostak- Emmanuel Cuillerier (Dreux), Bella Czernichow Talbodec (Tourcoing), Jean-Claude Tellaroli (Thionville), (Sarreguemines), Louis D’Alteroche (Tours), Hélène Dominique Thabut (Paris), Gilles Tordjman (Aulnay- Danielou (Rennes), Odile Danne (Pontoise), Manh- sous-Bois), Christian Trepo (Lyon), Régine Truchi (Nice), Thuong Dao (Caen), Cécilia D’Arondel de Haye (Paris), Claire Vanlemmens (Besançon), René-Louis Vitte (Poissy), Patrick Delasalle (Grasse), Pierre Deltenre (Lille), Jacques Jean-Pierre Zarski (La Tronche). Denis (Corbeil-Essonnes), Salem Dernaika (Paris), Hervé Desmorat (Toulouse), Jacques Doll (Le Chesnay), Sylva Doumet (Villeneuve-St-Georges), Jean-Charles Duclos- COMMENTS Vallee (Villejuif), Michel Duffaut (Toulouse), Samouh Background Elfadel (Caen), Gilbert Eschmann (Grasse), Claude Adherence to therapy is critical in the treatment of chronic hepatitis C virus Eugene (Poissy), Roger Faroux (La Roche-sur-Yon), (HCV) infection. The current gold standard therapy is a combination of peg- interferon alfa and ribavirin. Patients with genotype 2 or 3 infection have a Laetitia Fartoux Heymann (Paris), Abdelaziz Fatisse 78%-82% likelihood of achieving a sustained virological response (SVR) after (Belfort), Bernard Filoche (Lomme), Antoine Fleury 24 wk of therapy, whereas patients with genotype 3 infection and high viral load (Pontoise), Isabelle Fouchard-Hubert (Angers), Juliette are difficult to treat (< 70% responders). Therapy requires weekly subcutaneous Foucher (Pessac), Serge Fratte (Belfort),Valérie Garcia injections, twice-daily oral dosing and frequent visits, with blood tests. Side (Montpellier), Dany Gargot (Blois), Jean-Louis Gaudin effects occur in nearly all patients. As a result, 15%-20% of patients in clinical trials and over 25% in clinical practice discontinue therapy. (Le Puy-en-Velay), Nathalie Giuily (Clichy), Odile Goria Research frontiers (Rouen), Alain Gourlaouen (Morlaix), Stéphane Grimaldi In clinical trials, the SVR rate was significantly improved in those patients with (Carcassonne), Catherine Guillemard (Caen), Anne HCV genotype 1 infection who received > 80% of their total peg-interferon dose Guillygomarc’H (Rennes), Dominique Guyader (Rennes), and > 80% of their ribavirin dose for > 80% of the scheduled treatment duration. François Habersetzer (Strasbourg), Sadia Hachemane A review of the 2002-2007 literature confirmed that treatment response is (Montpellier), Nabil Haddad (Villejuif), Hervé Hagege influenced not only by HCV genotype and viral load, but also by patient-related factors including adherence. (Créteil), Najia Haioun (Cavaillon), Bertrand Hanslik Innovations and breakthroughs (Montpellier), Cyril Hatem (Dijon), Marie-Laure Hemery The authors evaluated, perhaps for the first time, the impact of patient therapeutic (Montpellier), Pascale Hervio (Pontoise), Christophe education by a third party on adherence and virological response to peg-interferon Hezode (Créteil), Noëlle Hilleret (La Tronche), Patrick alfa-2b and ribavirin. The analysis was carried out in the 674 patients with chronic Hillon (Dijon), Valérie Hyrailles (Béziers), Jean-Paul genotype 2/3 HCV infection from the CheObs cohort. Therapeutic education given Jacques (Toulouse), Pascal Kitmacher (La Rochelle), during the first 3 mo of treatment significantly improved the proportion of patients adhering to bitherapy at 6 mo (odds ratio 1.58). Though not significantly, the Alain Landau (Dreux), Emmanuel Lapoile (Villeneuve- virological response was also improved in educated patients, with an increased St-Georges), Dominique Larrey (Montpellier), Olivier SVR rate (77% vs 70%) and a lower relapse rate (10% vs 16%). Therapeutic Larroque (Hyères), Sophie Le Calvez (Paris), Pascal education significantly enhanced adherence to ribavirin, which is particularly Lebray (Paris), Olivier Lejeune (St-Priest-en-Jarez), Alain important for obtaining a SVR. A positive impact was also observed on adherence Lemoine (Nevers), Stéphane Levy (Reims), Fabrice Longo to peg-interferon, showing that an improvement can still be obtained. (Fréjus), Véronique Loustaud Ratti (Limoges), Hervé Applications This analysis of the real-life impact of patient therapeutic education by a third Louvet (Reims), Damien Lucidarme (Lomme), Catherine party on health outcomes may help to further improve patient quality of life and Mathieu-Chandelier (Lille), Philippe Mathurin (Lille), outcome. Five interacting dimensions affect adherence: social and economic Marianne Maynard (Lyon), Sophie Metivier (Toulouse), factors, and factors related to the health care team and system, the condition, Jean-Philippe Miguet (Besançon), Anne Minello (Dijon), treatment, and the patient. Methods that have been shown to be effective François Mion (Lyon), Joseph Moussalli (Paris), Bernard in improving therapy include: educational interventions involving patients; strategies to improve dosing schedules; interventions that enlist ancillary health Nalet (Montélimar), Jean-Baptiste Nousbaum (Brest), care providers such as pharmacists, behavioral specialists, and nursing staff; Frédéric Oberti (Angers), Valérie Oules (Marseille), and enhancing communication between physicians and patients. Georges Philippe Pageaux (Montpellier), Jean-Louis Peer review Payen (Montauban), Christophe Pilette (Le Mans), Didier This is a subgroup analysis of a bigger project. Since the a priori power Pillon (Bourg-en-Bresse), Isabelle Portal (Marseille), calculation was based on 2000 subjects for meaningful statistical analysis, Philippe Pouderoux (Nîmes), Claude Raffanel (Nîmes), the inclusion of only 630 or so patients in this study clearly limits the power to detect statistical significance. Baboojaswan Ramgoolam (Apt), Karine Randl (Clermont- Ferrand), Vlad Ratziu (Paris), Corinne Regimbeau (Paris), André-Jean Remy (Perpignan), Christophe Renou (Hyères), REFERENCES Ghassian Riachi (Rouen), Didier Ribard (Nîmes), Olivier 1 Sabate E. Adherence to long-term therapies. Evidence for Ribiere (Rambouillet), Jean-Philippe Richardet (Créteil), action. Geneva: World Health Organization; 2003. Available Marie-Pierre Ripault (Clichy), Bruno Roche (Villejuif), from URL: http://whqlibdoc.who.int/publications/2003/9 Christine Roche (Clermont-Ferrand), Olivier Rogeaux 241545992.pdf www.wjgnet.com
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[Compliance in 16 Plan National Hépatites Virales C et B (2002-2005). 2002. schizophrenia: predictive factors, therapeutical considerations Available from URL: http://www.sante.gouv.fr/htm/ and research implications] Encephale 2002; 28: 266-272 actu/hepatites/sommaire.htm 31 Ross FM. Patient compliance--whose responsibility? Soc Sci 17 Balfour L, Cooper C, Tasca GA, Kane M, Kowal J, Garber Med 1991; 32: 89-94 S- Editor Li DL L- Editor Negro F E- Editor Lin YP www.wjgnet.com