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Adherence to treatment and quality of life during hepatitis C therapy:a prospective, real-life, observational study by Patrick Marcellin, Michel Chousterman, Thierry Fontanges, Denis Ouzan, Michel …

Adherence to treatment and quality of life during hepatitis C therapy:a prospective, real-life, observational study by Patrick Marcellin, Michel Chousterman, Thierry Fontanges, Denis Ouzan, Michel Rotily, Marina Varastet,Jean-Philippe Lang, Pascal Melin and Patrice Cacoub, for the CheObs Study Group published in Liver Int 2011

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  • 1. Liver International ISSN 1478-3223CLINICAL STUDIESAdherence to treatment and quality of life during hepatitis C therapy:a prospective, real-life, observational studyPatrick Marcellin1, Michel Chousterman2, Thierry Fontanges3, Denis Ouzan4, Michel Rotily5, Marina Varastet5,Jean-Philippe Lang6, Pascal Melin7 and Patrice Cacoub8, for the CheObs Study Group1 Department of Hepatology, University of Paris 7, INSERM U 773, CRB3, Beaujon Hospital, Clichy, France ´ ´2 Department of Hepato-Gastroentrology, Hospital of Creteil (CHIC), Creteil, France3 Department of Hepato-Gastroenterology, General Hospital of Bourgoin, Bourgoin Jailleu, France4 Department of Hepato-Gastroenterology, Arnault Tzanck Institute, Saint Laurent du Var, France5 Department of Epidemiology and Public Health, ClinSearch, Bagneux, France6 Department of Psychiatry and Addiction, Hospital of Erstein, Erstein, France7 Department of Polyvalent Medicine, Hospital of Saint Dizier, Saint Dizier, France ´ ˆ `8 Department of Internal Medicine, Pierre and Marie Curie (Paris 6) University, UMR 7211 (UPMC/CNRS), U 959 (INSERM), AP HP, Pitie-SalpetriereHospital, Paris, FranceKeywords Abstractadherence to treatment – chronic hepatitis C Background: Adherence is important for therapy of chronic diseases, but has– compliance – peginterferon a-2b – quality still not been well studied in real life in chronic hepatitis C. Aims: To assessof life – real life – ribavirin adherence to hepatitis C combination therapy in routine clinical practice and to identify factors associated with imperfect adherence. Methods: This cohort study included unselected chronic hepatitis C patients initiating peginterferonCorrespondence ´ a-2b plus ribavirin. 100% adherence was defined by taking all the prescribedPr Patrick Marcellin, Service d’Hepatologie, ˆ ´ ´Hopital Beaujon, 100 Boulevard du General doses of both drugs for the full initially intended duration, as declared by theLeclerc, 92110 Clichy, France patient or believed by the physician. Quality of life was assessed using theTel: 133 140 87 53 38 short-form health survey (SF-36) questionnaire. Results: 1860 patients wereFax: 133 147 30 94 40 analysed, including 72% treatment-naive, 36% genotype 2/3, 23% psychiatric,e-mail: patrick.marcellin@bjn.aphp.fr 44% drug addicts and 3% human immunodeficiency virus (HIV)-positive patients. Early treatment discontinuation occurred in 30% of patients. Overall,Received 27 August 2010 38% of patients reported 100% adherence. Patient- and physician-reportedAccepted 30 December 2010 adherences were discordant, with a 20–30% overestimation by physicians. HIV co-infection [odds ratio (OR) 2.52, 95% confidence interval (CI)DOI:10.1111/j.1478-3231.2011.02461.x 1.36–4.67], no drug use during follow-up (2.37, 1.30–4.31), genotype 3 (1.55, 1.20–2.00) and treatment-naive (1.32, 1.03–1.69) were associated with 100% adherence. Quality of life worsened during treatment but returned to baseline after the end of treatment. Conclusions: Imperfect adherence to combination therapy is common in routine patients. Adherence is markedly overestimated by physicians and is associated with some patient’s baseline characteristics. Knowledge of these factors might help identify patients who are most in need of intervention and plan more frequent and accurate follow-up.The current standard of care for chronic hepatitis C is the trials who received Z80% of both their total peginterfer-antiviral combination therapy with peginterferon a and on and ribavirin doses for Z80% of the expectedribavirin (1, 2). Peginterferon is administered subcuta- duration of therapy (7). However, adverse effects ofneously once a week and ribavirin orally twice daily. interferon-based therapy – mainly flu-like symptoms,Successful treatment, i.e. achievement of a sustained neuropsychiatric disorders, anaemia and neutropenia –virological response, has been obtained in 79–93% of are significant, justify frequent dose reduction of pegin-genotype 2 or 3 hepatitis C virus (HCV) patients after 24 terferon and ribavirin and represent one major cause ofweeks of treatment; as well as in 41–52% of genotype 1 premature treatment discontinuation (8). Shortenedpatients and 77% of genotype 4 patients after 48 weeks of antiviral therapy may be considered in some patientstreatment in clinical trials (3–6). Good adherence to depending on genotype, baseline viral load and viraltreatment is believed to enhance the rate of sustained kinetics (9–11), but only a minority of patients arevirological response, as shown in patients from prior concerned in routine practice, at least in France. Liver International (2011)516  c 2011 John Wiley & Sons A/S
  • 2. Marcellin et al. Real-life adherence to HCV treatment These data originate from randomised, controlled documented by quantitative PCR (AmplicorTM, Rocheclinical trials. However, many patients in routine clinical Diagnostics, France), HCV genotype, liver fibrosis andpractice are nonresponders or relapsers to previous necro-inflammation (Metavir, FibroTest-ActiTests (22),interferon-based therapy and the majority present with Knodell score) and previous antiviral treatment. Processa wide spectrum of comorbidities. In particular, the high of care included the intended antiviral treatment regimenprevalence of psychiatric or substance abuse disorders in (drug doses and duration), any subsequent treatmentpatients with chronic HCV infection is well known (12). modification (dose modification or treatment disconti-Conversely, people with chronic psychiatric disorders nuation), the reason for modification and patient’s(13, 14) and intravenous drug users (15–17) are far more therapeutic education. Patients recorded the antivirallikely to be infected with HCV compared with the general medication actually taken and self-assessed their qualitypopulation. In addition, one-fourth to one-third of hu- of life using the validated French translation of the MOSman immunodeficiency virus (HIV)-infected patients 36-item short-form health survey (SF-36) questionnaireare co-infected with HCV (18, 19). Besides strict contra- (23). Each SF-36 subscore ranges from 0 (worse) to 100indications, such diagnoses have constituted the most (best), except health transition, which ranges from 0common reason patients have been denied treatment for (best) to 100 (worse).HCV infection, not only in clinical trials (3, 4) but also,until recently, in the real life (20, 21). Outcomes We performed a cohort study in chronic hepatitis Cpatients to evaluate the adherence to peginterferon a-2b At each visit under treatment, patients reported theand ribavirin combination therapy and to identify factors number of missed peginterferon injections in the pastassociated with good adherence in a real-life setting. We month (the last four injections) or missed ribavirinalso assessed the coherence between patient-reported and intakes in the past week (the last 14 intakes). To estimatephysician-reported adherence, and the health-related patient-reported adherence at a given time point, wequality of life. took into account the ‘actual’ doses as reported by the patient at each visit and compared it with the most recent physician prescription (thus integrating modifications ofPatients and methods prescription that could have occurred over time). ToThis prospective, multicentre, observational study was estimate the patient-reported overall adherence, we tookcarried out in University hospitals, non-University hos- into account the adherence estimated at each visit, thepitals and private practice offices involved in the manage- actual treatment duration and the treatment durationment of hepatitis C in France. All patients aged Z18 initially intended by the physician. As a result, patientsyears with chronic hepatitis C and initiating combination who declared having taken all the prescribed doses oftherapy with peginterferon a-2b and ribavirin were both products for the full initially intended treatmentproposed to participate in the survey, whether naive for duration were classified as 100% adherent. Those whohepatitis C therapy or not. In accordance with the French declared having taken Z80% of at least one product forlaw, Ethics Committee’s approval was not required as the Z80% of the initially planned duration were classified asprotocol was strictly observational and usual practice was Z80% adherent.unchanged. However, all patients gave informed consent Physician-reported adherence at a given visit andto participate. Approval of the ‘Commission Nationale overall was estimated similarly, using the response to the ´de l’Informatique et des Libertes’ was obtained, ensuring following questions: ‘In your opinion, how many timesthat patient data were kept confidential according to the did the patient missed a peginterferon injection in theFrench regulation. past month (the last 4 administrations)?’ or ‘In your As for all observational studies, there were no proto- opinion, how many times did the patient missed acol-specific procedures or study visits. Patients saw their ribavirin intake in the past week (the last 14 intakes)?’.physician as per usual practice in the centre. The inves-tigator and the patient completed an anonymous ques- Statistical analysistionnaire each at inclusion, every 3 months duringtreatment and 6 months after the end of treatment. Statistical analysis was conducted using SAS 8.2 (SASPatients filled in their questionnaires in the waiting room Institute Inc., Cary, NC, USA). Tests were two-sided andand either gave it back to the physician in a sealed type I error was set at 0.05. Descriptive statistics wereenvelope or returned it using a prepaid envelope. performed using all available data. Bivariate group com- Physicians recorded the socio-demographical charac- parisons were carried out using the Kruskal–Wallis,teristics, history of hepatitis C, selected comorbidities, chi-square or Fisher’s exact test as appropriate. Theprocess of care, concomitant treatments and adverse relationships between adherence and a set of potentialevents. Comorbidities included past and current psychia- explanatory variables were analysed by forward stepwisetric history, HIV or HBsAg positivity, chronic diseases logistic regressions. These variables included those forand use of psychoactive products. History of hepatitis C which the groups differed significantly (P o 0.05) atincluded source and duration of infection, viral load baseline in bivariate analyses (100 vs. o 100% adherenceLiver International (2011)c 2011 John Wiley & Sons A/S 517
  • 3. Real-life adherence to HCV treatment Marcellin et al.and/or Z80 vs. o 80% adherence), and variables ex- Table 1. Continuedpected to be related to adherence. The quality of life data All patientswere analysed as recommended in the SF-36 manual and (n = 1860)interpretation guide (23). Debts difficult to manage 100/1509 (7) Hepatitis C history Source of HCV infectionResults Transfusion 496/1860 (27)Patients Injection or intranasal drug abuse 792/1860 (43) Other 579/1860 (31)A total of 184 investigators enrolled and followed up Duration of HCV infection (years) 20.7 Æ 9.0 (20)2001 HCV patients in the survey between November Serum HCV RNA 4 800 000 IU/ml or 586/1382 (42)2002 and January 2005. Of these patients, 141 were equivalentexcluded from analysis because they did not receive HCV genotypecombination therapy with peginterferon a-2b and riba- 1 1019/1860 (55)virin combination therapy (n = 37), duration of combi- 2 202/1860 (11) 3 472/1860 (25)nation therapy was not available (n = 79) or virological 4 136/1860 (7)data were not available (n = 25). Compared with the 5 28/1860 (2)analysed population, excluded patients were more often 6 3/1860 (0.2)genotype 1 carriers (66 vs. 55%, P = 0.013) and less often Metavir activity grade or equivalentgenotype 3 carriers (185 vs. 25%, P = 0.072). They had A0 or A1 723/1572 (46)more severe liver disease (Metavir A2–A3: 66 vs. 54%, A2 or A3 849/1572 (54)P = 0.022; F3–F4: 47 vs. 34%, P = 0.007), and had Metavir fibrosis stage or equivalentreceived more often a previous HCV treatment (43 vs. F0 or F1 549/1580 (35)28%, P o 0.001). All other baseline data were not sig- F2 or F3 792/1580 (50)nificantly different. F4 239/1580 (15) Knodell score 8.4 Æ 3.1 (8) The analysed population included 1860 patients. Their Previous HCV treatment 516/1857 (28)baseline characteristics are provided in Table 1. Most of Comorbiditiesthem (72%) were naive for hepatitis C therapy and 36% Psychiatric historyhad genotype 2 or 3 HCV infection. Liver disease was Previous depression 453/1856 (24)assessed by biopsy in the majority of patients (n = 1606, Suicide attempt 124/1850 (7)86%) and estimated using noninvasive markers in the Past hospitalisation for mental disease 156/1848 (8)remaining patients. Two-thirds of patients had signifi- Current psychiatric disorder 403/1839 (22)cant fibrosis (F2, F3, F4: 65%), including 15% of Addictionscirrhotics. Alcohol consumption 458/1856 (25) Comorbidities were frequent. The cohort included Alcohol consumption 4 20 g/day 101/449 (23) Tobacco consumption 859/1832 (47)22% of psychiatric patients, 44% of drug users and 3% Drug use (ever) 821/1855 (44)of HIV-co-infected patients. Current psychiatric disor- Drug use (active) 60/1855 (3)ders were diagnosed by a psychiatrist in 62% of the cases Co-infectionsand included mainly depressive (n = 203, 11%), anxiety HIV positive 63/1854 (3) HBsAg positive 24/1841 (1) Other current chronic disease 491/1830 (27)Table 1. Patients’ baseline characteristics Quality of life (SF-36)Ã Physical functioning 78.7 Æ 23.2 (85) All patients Role physical 65.7 Æ 42.1 (100) (n = 1860) Bodily pain 66.5 Æ 28.1 (64)Socio-demography General health 54.1 Æ 19.6 (55)Men 1138/1856 (61) Vitality 45.8 Æ 21.4 (45)Age (years) 46.6 Æ 11.8 (45) Social functioning 65.5 Æ 25.2 (63)Body mass index (kg/m2) 24.5 Æ 4.4 (24) Role emotional 66.9 Æ 42.4 (100)Employment status Mental health 58.4 Æ 19.0 (60) Professional activity 1098/1857 (59) Health transition 53.3 Æ 21.6 (50) Unemployed 272/1857 (15) Mental composite score 41.3 Æ 10.7 (42) Other 487/1857 (26) Physical composite score 46.7 Æ 9.3 (48)Educational level Low 1089/1834 (59) Data are expressed as mean values Æ standard deviation (median), or n/N High 745/1834 (41) (%) of patients. ÃScore range: 0 (worse) to 100 (best) points for all domains except healthOrigin of incomes Paid employment 902/1842 (49) transition, which ranges from 0 (best) to 100 (worse) points. Unemployment incomes 254/1842 (14) HCV, hepatitis C virus; HIV, human immunodeficiency virus; RNA, Other 686/1842 (37) ribonucleic acid. Liver International (2011)518  c 2011 John Wiley & Sons A/S
  • 4. Marcellin et al. Real-life adherence to HCV treatment(n = 129, 7%), psychotic (n = 19, 1%) and bipolar (n = 8, 100% adherence ≥80% adherence0.4%) disorders. Other comorbid chronic diseases were 80hypertension (n = 176, 36%), diabetes mellitus (n = 107, 66 64 66 66 55 56 5822%) and asthma (n = 42, 9%). Health-related quality of % of patients 60 54life was altered, each SF-36 subscore being moderatelylower than that in the general population in France (23). 40 20Antiviral treatment 0The mean dose regimen initially prescribed was 1.37 mg/ Month 3 Month 6 Month 9 Month 12kg/week (median 1.5, n = 1837) for peginterferon a-2b (n =1145) (n =973) (n =549) (n =505)and 922 mg/day (median 1000, n = 1820) for ribavirin. A Fig. 1. Proportion of patients with 100% and Z80% adherence tototal of 1089 (58.5%) patients received various forms of combination therapy (patient report).therapeutic education at the discretion of the physicianduring the first 3 months of treatment. The average doseof both drugs progressively decreased over time, reaching A Patient report Physician report0.89 mg/kg/week (median 0.8, n = 1729) for peginterferon Peginterferon alfa-2band 595 mg/day (median 545, n = 1728) for ribavirin atmonth 12. According to the physician, 915/1860 (49%) 100 97 97 98 98patients did not complete therapy as intended initially. 79 78 76 77 80 % of patientsThe main reason for not doing so was virological criteria(n = 302, 16%), lost to follow-up (n = 244, 13%), safety 60(n = 182, 10%), patient’s request (n = 78, 4%), another 40reason (n = 51) or not specified (n = 58). However, as 20calculated subsequently, only 563 (30%) patients had‘insufficient’ treatment duration, i.e. o 80% of the 0 Month 3 Month 6 Month 9 Month 12recommended duration (24 weeks with genotype 2 or 3, (n =1145) (n =973) (n =549) (n =505)48 weeks with the other genotypes). Adverse events werereported in 1598 (86%) patients overall. B Ribavirin 100 92 95 91 90Adherence to treatment 80 66 % of patients 64 62 65Patient-reported adherence to combination therapy was 60100% for the full initially intended treatment duration(overall adherence) in 580/1510 (38%) patients; it was 40Z80% in 747 (50%) patients. The proportion of patientswith good adherence at a given time point was stable over 20time, at 53–58% for 100% adherence and 64–66% for 0Z80% adherence (Fig. 1). Month 3 Month 6 Month 9 Month 12 Patient- and physician-reported adherences to treat- (n =1145) (n =973) (n =549) (n =505)ment were discordant. As shown quarterly in Figure 2, Fig. 2. Proportion of patients with 100% adherence to (A)the proportion of patients reporting a 100% adherence to peginterferon a-2b and (B) ribavirin over time, as reported by thepeginterferon at a given time point was 76–79%, whereas patient and as perceived by the physician.physicians believed it was above 97%. Moreover, theproportion of patients reporting a 100% adherence toribavirin was 62–66%, whereas physicians believed it wasabove 90%. physician office (P = 0.001). They were more often geno- Adherence to ribavirin was always worse than adher- type 2 or 3 HCV carriers (P = 0.009) and naive forence to peginterferon (Fig. 2) and adherence to both antiviral HCV therapy (P = 0.037). In addition, they hadproducts (Fig. 1) was always worse than adherence to less frequent diabetes (P = 0.026), they consumed lowerribavirin. Therefore, most patients with imperfect adher- alcohol amounts at baseline (P = 0.023) and they wereence to one product were different from those with less often regular drug users (P = 0.017), but were moreimperfect adherence to the other product. often HIV co-infected (P = 0.003). They also used illicit Bivariate comparison of patients who took 100% of drugs less frequently during follow-up (P = 0.007) and,both products for the full initially intended treatment although not significantly, drunk less frequently 4 20duration with those who did not is provided in Table 2. g/day alcohol (P = 0.053). They did not differ markedlyThey differed significantly for the following items. 100% for the HCV treatment actually received and occurrenceadherent patients had longer transport time to the of adverse events.Liver International (2011)c 2011 John Wiley & Sons A/S 519
  • 5. Real-life adherence to HCV treatment Marcellin et al.Table 2. Comparison of patients reporting 100% adherence to both products for the full initially intended treatment duration (100%adherence) with those who did not (adherence o 100%) Adherence o 100% (n = 930) 100% adherence (n = 580) P-valueSocio-demography Men 544/929 (59) 358/580 (62) 0.235 Age (years) 47.1 Æ 12.0 (45) 46.7 Æ 11.6 (45) 0.831 Body mass index (kg/m2) 24.8 Æ 4.5 (23.9) 24.3 Æ 4.2 (23.8) 0.111 Employment status 0.666 Professional activity 551/927 (59) 356/580 (61) Unemployed 125/927 (14) 79/580 (14) Other 251/927 (27) 145/580 (25) Educational level 0.957 Low 542/915 (59) 338/572 (59) High 373/915 (41) 234/572 (41) Origin of incomes 0.345 Paid employment 450/918 (49) 298/575 (52) Unemployment incomes 116/918 (13) 78/575 (14) Other 352/918 (38) 199/575 (35) Debts difficult to manage 51/747 (7) 31/476 (7) 0.907 Transport time to the centre (min) 35.2 Æ 38.6 (25) 39.4 Æ 34.5 (30) 0.001Hepatitis C history Source of HCV infection Transfusion 247/930 (27) 160/580 (28) 0.677 Injection or intranasal drug abuse 377/930 (41) 233/580 (40) 0.914 Other 308/930 (33) 189/580 (33) 0.866 Duration of HCV infection (years) 20.8 Æ 8.9 (20) 21.1 Æ 8.9 (21) 0.601 Serum HCV RNA 4 800 000 IU/ml or equivalent 277/670 (41) 196/670 (44) 0.322 HCV genotype 0.009 1 538/930 (58) 292/580 (50) 2 105/930 (11) 67/580 (12) 3 202/930 (22) 170/580 (29) 4 68/930 (7) 38/580 (7) 5 14/930 (2) 13/580 (2) 6 3/930 (0.3) 0/580 (0) Metavir activity grade or equivalent 0.793 A0 or A1 368/797 (46) 218/480 (45) A2 or A3 429/797 (54) 262/480 (55) Metavir fibrosis stage or equivalent 0.123 F0 or F1 267/798 (34) 178/484 (37) F2 or F3 422/798 (53) 228/484 (47) F4 109/798 (14) 78/484 (16) Knodell score 8.3 Æ 3.2 (8) 8.6 Æ 3.2 (8) 0.326 Previous HCV treatment 270/929 (29) 140/580 (24) 0.037Comorbidities Psychiatric disorder (at baseline) 209/921 (22.7) 113/573 (19.7) 0.196 Addictions Alcohol 4 20 g/day At baseline 56/224 (25) 24/138 (17) 0.117 During study follow-up 43/930 (5) 15/580 (3) 0.053 Tobacco (at baseline) 406/913 (45) 269/573 (47) 0.363 Drug use (ever) 391/927 (42) 239/572 (41) 0.359 At baseline 33/927 (4) 13/572 (2) 0.168 During study follow-up 51/930 (6) 15/580 (3) 0.007 Co-infections HIV positive 18/927 (2) 27/577 (5) 0.003 HBsAg positive 11/920 (1) 10/572 (2) 0.376 Other chronic disease (at baseline) 260/913 (29) 152/572 (27) 0.439Current HCV treatment Initial peginterferon dose (mg/kg/week) 1.36 Æ 0.28 (1.5) 1.40 Æ 0.25 (2) 0.003 Initial ribavirin dose (mg/day) 929 Æ 172 (1000) 915 Æ 160 (1000) 0.097 Intended treatment duration (weeks) 40.9 Æ 11.4 (48) 38.6 Æ 12.3 (48) o 0.001 Therapeutic education within the first 3 months 519/930 (56) 344/580 (59) 0.182 Adverse events during study follow-up 835/930 (90) 525/580 (90) 0.660Data are expressed as mean values Æ standard deviation (median), or n/N (%) of patients.HCV, hepatitis C virus; HIV, human immunodeficiency virus; RNA, ribonucleic acid. Liver International (2011)520  c 2011 John Wiley & Sons A/S
  • 6. Marcellin et al. Real-life adherence to HCV treatmentTable 3. Factors independently associated with 100% adherence to the combination therapy Reference P-value Odds ratio 95% Confidence intervalHIV co-infection No 0.003 2.521 1.362–4.668No drug use during follow-up Drug use 0.005 2.370 1.304–4.310HCV genotype 3 Gen. 1 0.016 1.553 1.203–2.005Naive for HCV treatment No 0.028 1.321 1.031–1.692Transport time to the centre (min) – 0.024 1.003 1.000–1.006 10 change from baseline of the mental and physical compo- 5 site scores, which integrate all SF-36 domains except health transition, was, respectively, À 6.4 and À 6.5 Mean change from baseline (point) 0 points at month 6, and À 5.7 and À 5.3 points at month –5 12. The health transition score, which estimates the change of perceived health condition compared with 1 –10 year before, also worsened during treatment as shown by –15 a mean change from baseline at 16.6 points at month 6 and 15.5 points at month 12. After the end of treatment, –20 quality of life was returned above the pretreatment level; –25 the mean change from baseline was 12.6, 12.4 and À 6.2 points for the mental composite score, physical –30 composite scores and health transition score respectively. –35 Almost all SF-36 domains were significantly worse at –40 baseline in patients who reported an adherence o 100% Month 3 Month 6 Month 12 6 months after compared with patients with 100% adherence (P o 0.05 (n =1058) (n =881) (n =403) end of treatment for PF, BP, GH, VT, SF, MH, PCS and HT; not significant (n =565) for RP, RE and MCS). During and after treatment,Fig. 3. Mean change from baseline of SF-36 subscores (point). changes of quality of life were parallel in both groups;MCS, mental composite score; PCS, physical composite score. there were no significant differences between groups forPhysical domains: BP, bodily pain; GH, general health; PF, physical the change from baseline of each SF-36 subscore, what-functioning; RP, role physical. Mental domains: MH, mental health; ever the time point.RE, role emotional; SF, social functioning; VT, vitality. HT, healthtransition. Discussion To our knowledge, this is the largest study assessing The potential explanatory variables proposed to the adherence to HCV therapy using data on dose taking.multivariate model included genotype, remoteness of the Imperfect adherence was common. Overall, only 38% ofcentre (transport time), Metavir activity and fibrosis our routine patients reported strict adherence to pegin-scores, sex, age, BMI, previous HCV treatment, serum terferon a-2b and ribavirin, i.e. full-dose, persistentHCV RNA, HIV co-infection, psychiatric disorders (ever therapy as initially intended by the physician. In addi-and at baseline), diabetes, alcohol consumption 4 20 tion, 76–79% of patients on treatment reported havingg/day (at baseline and during follow-up), drug use (at taken all peginterferon doses in the last 4 weeks; 62–66%baseline and during follow-up) and therapeutic education. reported having taken all ribavirin doses in the lastAs a result (Table 3), the factors significantly associated 7 days; and 53–58% reported having taken all doses ofwith 100% adherence to combination therapy were HIV both drugs at months 3, 6, 9 and 12. We also provideco-infection, no illicit drug use during follow-up, HCV information on adherence in terms of early treatmentgenotype 3, HCV treatment-naive and, to a lower extent discontinuation (30%) and dose decreases, as usually(odds ratio close to 1), remoteness of the centre. referred to by clinicians in HCV infection. Our results add to the literature as among the few studies that assessed adherence in terms of dose taking,Quality of life none did so in the whole population of routine HCVThe change from baseline of SF-36 subscores is displayed patients and over the whole treatment period. In ain Figure 3. During the treatment period (up to month clinical trial including 401 mono-infected HCV patients12), all physical and mental domains progressively wor- (24), at least 95% of patients reported having taken allsened, in particular those reflecting problems at work or peginterferon doses in the past 4 weeks at months 1, 3, 6,in daily activities that result from the physical (role 9 and 12; the rate of patients who reported having takenphysical) and mental (role emotional) status. The mean all ribavirin doses in the past 4 days decreased from 91%Liver International (2011)c 2011 John Wiley & Sons A/S 521
  • 7. Real-life adherence to HCV treatment Marcellin et al.at month 1 to 43% at month 12. In a cross-sectional psychiatric disorders, suggesting that these conditionsstudy involving 180 routine HCV patients (25), 7% of should no longer limit access to HCV antiviral therapy. Inpatients reported having missed at least one peginterfer- addition, treating intravenous drug users should have aon dose in the last 4 weeks and 21% having missed at positive impact on prevention of transmission, with aleast one ribavirin dose in the last 7 days. Patients were chance of reducing the incidence of new cases. Knowl-under treatment since 19.3 Æ 13.4 weeks in average. In a edge of factors predictive of poor adherence is a usefulretrospective study where adherence was estimated using resource for physicians to help identify patients who arepharmacy refill data in 188 HCV US Veterans (26), 73% most in need of intervention and plan more frequent andof patients were found with at least 100% adherence to accurate follow-up.peginterferon and 68% with at least 100% adherence to Careful assessment of health-related quality of life wasribavirin during the initial 3 months of treatment. Lastly, regularly performed in our patients using a validatedin a cohort of 63 HCV/HIV-co-infected patients (27), questionnaire. As expected, quality of life was impaired23% of patients discontinued treatment early and 98% of before treatment initiation compared with the generalthose on treatment reported having taken all peginterfer- population (23, 35) and both the mental and physicalon and ribavirin doses in the past 2 weeks at months 3, 6 domains worsened during treatment. However, 6 monthsand 12. Such a high adherence is not surprising as dose- after the end of treatment, it was returned to baseline,taking adherence is nowadays routinely stressed in HIV even slightly better than before treatment. Quality of lifepatient care. changes were parallel in patients with perfect and im- However, the ability of physicians to recognise non- perfect adherence. These results confirm previous reportsadherence was poor. Our study physicians markedly of temporary worsening (36, 37). Therefore, physiciansoverestimated adherence to combination therapy, by should reassure patients and encourage them to persist20–30% compared with patient self-report. This phe- with therapy despite frequent side effects and worsenednomenon has already been shown in other chronic quality of life.diseases such as HIV infection or diabetes but not yet in In conclusion, this cohort study brings potentialchronic HCV infection (28, 29). Several reasons exist clinically relevant information by emphasising the fol-including for example poor or judgemental provider– lowing points. Imperfect adherence to combinationpatient communication (30, 31). Moreover, in this therapy with peginterferon plus ribavirin is common inindication, electronic monitoring has provided much routine chronic hepatitis C patients. Adherence is mark-lower rates of adherence than self-reported adherence edly overestimated by physicians and is associated with(24), suggesting that patients also overestimate adher- some patient’s baseline characteristics. These findingsence to combination therapy. This medication-taking suggest that assessment of adherence to HCV combina-behaviour is also well known in other chronic disorders tion therapy by physicians should be improved. This(30). Therefore, healthcare providers should be more could be easily carried out by the wide use of standar-vigilant about adherence to HCV combination therapy in dised adherence measurement tools such as a self-their daily management, especially in terms of missed questionnaire, keeping in mind that patients may over-ribavirin doses. Indeed, standard ribavirin dosing is estimate the true figures. The need to enhance commu-complex and ribavirin dose reductions, at least in the nication would be triggered by discordance between thefirst weeks of treatment, may alter virological outcome physician and patient assessments. Knowledge of baseline(26, 32–34). Patient-related reasons for nonadherence characteristics associated with adherence might helpmay include forgetfulness, the decision to omit doses, adjust the monitoring in a subset of patients at higherlack of information and emotional factors (30). Clin- risk of nonadherence.ician-related reasons may include, in addition to poorcommunication with the patient, failing to explain thetreatment benefits and side effects and not giving con- Acknowledgementssideration to a patient’s lifestyle. More flexibility inindication for treatment could have a positive impact on The authors are grateful to Ceri Medical (Garches,the individual prognosis of patients and the overall France), who helped in field monitoring, Florencecontrol of the disease burden. Although there is no Colin-Mercier (Stat Process, Pont Mort, France), whoperfect method to assess adherence to medication, pa- analysed the data, as well as all investigators (the CheObstient self-report is probably the simplest and most Study Group) for participating in this study.effective method of measurement. Statement of interests: This research was funded in This study provides other clinically relevant informa- full by Schering-Plough France.tion. Patients who did not present with the following P. Marcellin, M. Chousterman, T. Fontanges, D.baseline characteristics of HCV infection, HIV co-infec- Ouzan, J.P. Lang, P. Melin and P. Cacoub have served astion, HCV genotype 3 and HCV treatment-naive, and speaker, consultant and/or advisory board member forpatients who used illicit drugs during HCV treatment Schering-Plough France, and have received researchwere at higher risk of imperfect adherence. Interestingly, funding from Schering-Plough France. M. Rotily is aadherence was not associated with history of addiction or former employee of ClinSearch; he now serves as a Liver International (2011)522  c 2011 John Wiley & Sons A/S
  • 8. Marcellin et al. Real-life adherence to HCV treatmentconsultant for ClinSearch. M. Varastet is an employee of Bavaria: risk factors for seropositivity. Eur J EpidemiolClinSearch. 2003; 18: 563–8. Clinical trial registration: Not applicable. 16. Crofts N, Jolley D, Kaldor J, van Beek I, Wodak A. Epidemiology of hepatitis C virus infection among inject- ing drug users in Australia. J Epidemiol Community Health 1997; 51: 692–7. 17. Galeazzi B, Tufano A, Barbierato E, Bortolotti F. HepatitisReferences C virus infection in Italian intravenous drug users: epide- 1. National Institutes of Health. National Institutes of Health miological and clinical aspects. Liver 1995; 15: 209–12. Consensus Development Conference Statement: manage- 18. Bonacini M. Liver injury during highly active antiretroviral ment of hepatitis C:2002–June 10–12, 2002. Hepatology therapy: the effect of hepatitis C coinfection. Clin Infect Dis 2002; 36: S3–20. 2004; 38(Suppl. 2): S104–8. 2. Dhumeaux D. Consensus conference. Treatment of hepatitis 19. Rockstroh JK, Mocroft A, Soriano V, et al. Influence of C. Gastroenterol Clin Biol 2002; 26(Spec No. 2): B303–20. hepatitis C virus infection on HIV-1 disease progression 3. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon and response to highly active antiretroviral therapy. J Infect alfa-2a plus ribavirin for chronic hepatitis C virus infection. Dis 2005; 192: 992–1002. N Engl J Med 2002; 347: 975–82. 20. Hatem C, Minello A, Bresson-Hadni S, et al. Is the manage- 4. Manns MP, McHutchison JG, Gordon SC, et al. Peginter- ment of hepatitis C patients appropriate? A population- feron alfa-2b plus ribavirin compared with interferon alfa- based study. Aliment Pharmacol Ther 2005; 21: 1007–15. 2b plus ribavirin for initial treatment of chronic hepatitis C: 21. Cacoub P, Rosenthal E, Halfon P, et al. Treatment of a randomised trial. Lancet 2001; 358: 958–65. hepatitis C virus and human immunodeficiency virus 5. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon- coinfection: from large trials to real life. J Viral Hepat alpha2a and ribavirin combination therapy in chronic 2006; 13: 678–82. hepatitis C: a randomized study of treatment duration and 22. Imbert-Bismut F, Ratziu V, Pieroni L, et al. Biochemical ribavirin dose. Ann Intern Med 2004; 140: 346–55. markers of liver fibrosis in patients with hepatitis C virus 6. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. infection: a prospective study. Lancet 2001; 357: 1069–75. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C 23. ` Leplege A, Cosse E, Pouchot J, Coste J, Perneger T. Le virus infection in HIV-infected patients. N Engl J Med 2004; questionnaire MOS SF-36. Manuel de l’utilisateur et guide 351: 438–50. ´ d’interpretation des scores. Paris: Editions Estem, 2001. 7. McHutchison JG, Manns M, Patel K, et al. Adherence to 24. Smith SR, Wahed AS, Kelley SS, et al. Assessing the validity combination therapy enhances sustained response in geno- of self-reported medication adherence in hepatitis C treat- type-1-infected patients with chronic hepatitis C. Gastro- ment. Ann Pharmacother 2007; 41: 1116–23. enterology 2002; 123: 1061–9. 25. Weiss JJ, Bhatti L, Dieterich DT, et al. Hepatitis C patients’ 8. Manns MP, Wedemeyer H, Cornberg M. Treating viral self-reported adherence to pegylated interferon and riba- hepatitis C: efficacy, side effects, and complications. Gut virin. Aliment Pharmacol Ther 2008; 28: 289–93. 2006; 55: 1350–9. 26. Lo Re V III, Amorosa VK, Localio AR, et al. Adherence to 9. Zeuzem S, Buti M, Ferenci P, et al. Efficacy of 24 weeks hepatitis C virus therapy and early virologic outcomes. Clin treatment with peginterferon alfa-2b plus ribavirin in Infect Dis 2009; 48: 186–93. patients with chronic hepatitis C infected with genotype 1 27. Fumaz CR, Munoz-Moreno JA, Ballesteros AL, et al. and low pretreatment viremia. J Hepatol 2006; 44: 97–103. Influence of the type of pegylated interferon on the onset10. Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a of depressive and neuropsychiatric symptoms in HIV-HCV and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. coinfected patients. AIDS Care 2007; 19: 138–45. N Engl J Med 2007; 357: 124–34. 28. Walshe L, Saple DG, Mehta SH, et al. Physician estimate of11. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, antiretroviral adherence in India: poor correlation with management, and treatment of hepatitis C: an update. patient self-report and viral load. AIDS Patient Care STDS Hepatology 2009; 49: 1335–74. 2010; 24: 189–95.12. Loftis JM, Matthews AM, Hauser P. Psychiatric and sub- 29. Moreau A, Aroles V, Souweine G, et al. Patient versus stance use disorders in individuals with hepatitis C: epide- general practitioner perception of problems with treatment miology and management. Drugs 2006; 66: 155–74. adherence in type 2 diabetes: from adherence to concor-13. Cividini A, Pistorio A, Regazzetti A, et al. Hepatitis C virus dance. Eur J Gen Pract 2009; 15: 147–53. infection among institutionalised psychiatric patients: a 30. Osterberg L, Blaschke T. Adherence to medication. N Engl J regression analysis of indicators of risk. J Hepatol 1997; 27: Med 2005; 353: 487–97. 455–63. 31. Zickmund S, Hillis SL, Barnett MJ, Ippolito L, LaBrecque14. Dinwiddie SH, Shicker L, Newman T. Prevalence of hepa- DR. Hepatitis C virus-infected patients report communica- titis C among psychiatric patients in the public sector. Am J tion problems with physicians. Hepatology 2004; 39: Psychiatry 2003; 160: 172–4. 999–1007.15. Backmund M, Meyer K, Wachtler M, Eichenlaub D. 32. Reddy KR, Shiffman ML, Morgan TR, et al. Impact of Hepatitis C virus infection in injection drug users in ribavirin dose reductions in hepatitis C virus genotype 1Liver International (2011)c 2011 John Wiley & Sons A/S 523
  • 9. Real-life adherence to HCV treatment Marcellin et al. patients completing peginterferon alfa-2a/ribavirin treat- 35. Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C ment. Clin Gastroenterol Hepatol 2007; 5: 124–9. virus infection causes a significant reduction in quality of33. Shiffman ML, Ghany MG, Morgan TR, et al. Impact of life in the absence of cirrhosis. Hepatology 1998; 27: 209–12. reducing peginterferon alfa-2a and ribavirin dose during 36. Foster GR. Quality of life considerations for patients with retreatment in patients with chronic hepatitis C. Gastro- chronic hepatitis C. J Viral Hepat 2009; 16: 605–11. enterology 2007; 132: 103–12. 37. Zickmund SL, Bryce CL, Blasiole JA, et al. Majority of34. Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa- patients with hepatitis C express physical, mental, and 2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or social difficulties with antiviral treatment. Eur J Gastroen- 3. N Engl J Med 2005; 352: 2609–17. terol Hepatol 2006; 18: 381–8. Liver International (2011)524  c 2011 John Wiley & Sons A/S