A Prospective, Multicenter, Observational Study on Adherence With Viral Hepatitis C Treatments (CHEOBS Study): Impact of

Past Psychiatric Disorders on Sustained Virologic Response (SVR)J. P. Lang,1 P. Melin,2 D. Ouzan,3 L. Cattan,4 M. Chousterman,5 J. M. Rotily,6 T. Fontanges,7 P. Marcellin,8 P. Cacoub9

1Centre Hospitalier Erstein, Erstein, France; 2Hôpital Général, Saint Dizier, France; 3Institut Arnaud Tzanck, Saint Laurent du Var, France; 4Private Practice, Paris, France; 5Hôpital de Créteil, Créteil, France; 6INSERM, Bagneux, France; 7Centre de l’Appareil Digestif, Bourgoin Jallieu, France; 8Hôpital Beaujon, Clichy, France; 9Hôpital Pitié-Salpêtrière, Paris, France

Presented at the 42nd Annual Meeting of the European Association for the Study of the Liver; 11-15 April 2007; Barcelona, Spain

AbstractBackground: The French multicenter, prospective, observational CHEOBS study was designed toevaluate adherence to peginterferon α-2b (PegIFN) plus ribavirin (RBV) combination in patients withchronic hepatitis C virus (HCV).

Aim: In this sub-analysis, we assessed the impact of past psychiatric disorders (PPDs) on treatmentadherence and SVR in patients with genotype 2 or 3 (G2/3) infection.

Methods: From Jan 2003 to Dec 2004, 702 out of 2000 patients included were infected with G2/3 virus,among which 641 had sufficient data to be analyzed: 460 patients without PPDs and 181 with PPDs.PPDs were defined by depression (169, 93%) and/or attempted suicide (49, 27%) and/or psychiatrichospitalization (58, 32%). Baseline characteristics, impact of PPD on adherence (=3 injections of PegIFNduring the past 4 weeks and =800 mg/d of RBV during the past week), and SVR (=21 weeks afterstopping therapy) were assessed.

Results: At baseline, both groups did not differ significantly for most socio-demographic, virological,and histological characteristics. The rate of patients who received a therapeutic education was similarbetween PPD+ and PPD– patients (61% vs. 53%, p=0.08). Unemployment (30% vs. 12%, p=0.015),indebtedness (11% vs. 4%, p=0.005), lower study level (67% vs. 58%, p=0.025), former drug abuse(66% vs. 42%, p=0.001), current psychiatric disorders (64% vs. 8%, p=0.001), and the number of G3(82% vs. 66%, p=0.001) were significantly more frequent in PPD+ patients. Current psychiatric disorderswere depression (63%), anxiety (53%), chronic psychosis (6%), bipolar depression (3%), and others(2%). They were diagnosed by a psychiatrist in 71% of patients. The mean duration of treatment(28.4 ± 12.3 vs. 29.4 ± 13.8 weeks, p=0.88), the rate of early discontinuations of treatment (13% vs. 13%, p=0.89), the adherence to RBV plus PegIFN at month 6 (140/259, 54% vs. 54/107, 51%,p=0.56), and the SVR (88/101, 92% vs. 231/286, 83%, p=0.151) did not differ significantly betweenPPD+ and PPD– patients, respectively.

Conclusion: In the real-life, for patients infected with genotype 2 or 3 treated with peginterferon α-2b plus ribavirin, past psychiatric disorders were not a contraindication to HCV treatment, neithera risk of nonadherence nor nonsustained virological response.

Background• Adherence is an important component in treating patients with chronic hepatitis C with pegylated

interferon (PEG-IFN) plus ribavirin (RBV), particularly because these drugs are associated withadverse effects.

• Adherence is generally defined by the 80:80:80 rule, whereby at least 80% of the planned PEG-IFNalfa and 80% of the planned RBV doses are taken for at least 80% of the duration of the plannedtreatment.1

• Clinical trial data indicate that adherence differentially affects response to therapy, depending on hepatitis C virus (HCV) genotype.

— For genotype 1 (G1) patients, adherence is closely related to treatment outcome, with highersustained virologic response (SVR) rates reported in adherent patients.1

— For genotype 2 or 3 (G2/3) patients, SVR rates are similar among G2/3 patients who meet the80:80:80 rule and among those who are less adherent.1,2

• The impact of adherence among G2/3 patients in real-world clinical practice is unknown, particularlyin those with comorbid or past psychiatric disorders (PPDs).

Aim • To assess the impact of PPDs on treatment adherence and SVR rates among patients with chronic

hepatitis C infected with G2/3 HCV.

Patients and MethodsPatients• Only patients with G2/3 HCV infection were included in this analysis.

• Included were patients 18 years or older with chronic hepatitis C who were treated with PEG-IFNalfa-2b (PegIntron®) (1.5 µg/kg/wk), alone or in combination with weight-based RBV (800 mg/d,1000 mg/d, or 1200 mg/d, depending on body weight).

• Patients could be treatment naive or nonresponsive to or have relapsed after previous therapy.

• PPD was indicated by a previous diagnosis of depression, a documented suicide attempt, a hospitalstay because of a psychiatric condition, or any combination of these.

Study Design• CHEOBS is a French, prospective, multicenter, observational study designed to evaluate adherence

with PEG-IFN alfa-2b (1.5 µg/kg/wk) and weight-based RBV (800-1200 mg/d) combination therapyin patients with chronic hepatitis C in a real-world, community-based setting.

• 100 centers in France that specialize in the management of hepatitis C were invited to participatein the study.

Questionnaires• Some patients in the study participated in a therapeutic education program, defined as intervention

by a third person (eg, nurse, behavioral specialist), during the first 3 months of therapy to optimize tolerance to and efficacy of PEG-IFN alfa-2b and RBV.

• Every 3 months during treatment and 6 months after treatment cessation, investigator and patientquestionnaires were completed.

• The investigator questionnaire collected information on the following:

— Patient sociodemographic data.

— History of HCV infection.

— History of psychoactive drug consumption.

— Hepatitis C therapy received before inclusion in the CHEOBS study.

— Therapeutic education provided to the patient.

— Planned hepatitis C treatment.

— Treatment modifications during follow-up.

— Virologic status of the patient 6 months after treatment cessation.

• The patient self-questionnaire collected information on the following:

— Nature and source of therapeutic education received for chronic hepatitis C and associatedtreatment.

— Responses to quality-of-life assessment (Short Form-36).

— Self-reported adherence to PEG-IFN alfa-2b and RBV treatment.

Assessments• Treatment adherence was assessed at month 3 and month 6 during treatment and was defined as

the patient having

— 3 to 4 injections of PEG-IFN alfa-2b during the past 4 weeks.

— At least 800 mg/d of RBV during the past week.

• Virologic response was defined as

— Nonresponse (detectable HCV RNA at the end of treatment).

— Sustained response (undetectable HCV RNA for at least 21 weeks after treatment cessation).

— Relapse (undetectable HCV RNA at the end of treatment and detectable HCV RNA during the 6 months of follow-up).

• Virologic status was determined by qualitative and quantitative polymerase chain reaction.

Statistical Analysis• Group comparisons were performed with use of the Kruskal-Wallis test and logistic regression,

where α = 5% and β = 80%.

ResultsPatient Disposition• From January 2003 to December 2004, a total of 2000 patients with chronic hepatitis C were

included in the CHEOBS study (Figure 1).

— 702 had G2/3 HCV infection; 641 were eligible for inclusion in this analysis.■ 61 received monotherapy or their treatment end date was unavailable.

• Overall, 28% (181/641) of G2/3 patients had at least 1 PPD (depression, 93%; attempted suicide,27%; psychiatric hospitalization, 32%; Figure 1).

• Proportions of patients who were PPD+ (at least 1 PPD) or PPD– (no PPDs) and who were enrolledin the therapeutic education program were similar between groups (61% vs 53%, respectively; P = .08).

Figure 1. Patient disposition

Baseline Characteristics • Employment status, debt management, educational level, current psychiatric diagnosis, tobacco

consumption, and drug abuse profiles were significantly different between PPD+ and PPD– patients(Table 1).

• Proportions of patients with a history of injection or intranasal drug abuse, G3 HCV infection, or HIVcoinfection were significantly higher in the PPD+ group than in the PPD– group (Table 2).

Table 1. Sociodemographic Baseline Characteristics

Baseline Characteristic PPD+ PPD– P(n = 181) (n = 460)

Men, n/N (%) 107/181 (59) 273/459 (59) .92

Mean age ± SD, y 42.9 ± 9.6 45.2 ± 12 .08

Mean body mass index ± SD, kg/m2 23.7 ± 4.2 23.9 ± 4.2 .46

Employment status, n/N (%) <.001

Professional activity 95/181 (52) 296/459 (64)

Unemployed 54/181 (30) 56/459 (12)

Other 32/181 (18) 107/459 (23)

Educational level, n/N (%) .02

<High school 122/181 (67) 261/452(58)

≥High school 59/181 (33) 191/452 (42)

Origin of income, n/N (%) <.001

Employment 73/178 (41) 258/455 (57)

Unemployment 44/178 (25) 55/455 (12)

Other 61/178 (34) 142/455 (31)

Indebtedness, n/N (%) .005

Difficult to manage 17/153 (11) 16/371 (4)

None or easily managed 136/153 (89) 355/371 (96)

Current psychiatric disorder, n/N (%) 115/181 (64) 35/453 (8) <.001

Depression 69/110 (63) 3/24 (13)

Anxiety 58/110 (53) 22/24 (92)

Chronic psychosis 6/110 (5) —

Bipolar depression 3/110 (3) —

Other 2/110 (2) 1/24 (4)

Chronic disease, n/N (%) 43/178 (24) 104/455 (23) .75

Alcohol consumption >14 glasses/wk, n/N (%) 11/64(17) 21/100 (21) .687

Tobacco consumption, n/N (%) 136/181 (75) 200/451 (44) <.001

Drug abuse, n/N (%) <.001

None 47/181 (26) 251/457 (55)

Former 120/181 (66) 192/457 (42)

Current 14/181 (8) 14/457 (3)PPD = past psychiatric disorder.

Table 2. Hepatitis C History

Baseline Characteristic PPD+ PPD– P(n = 181) (n = 460)

Source of HCV infection, n/N (%)

Transfusion 28/181 (15) 103/460 (22) .051

Injection or intranasal drug abuse 129/181 (71) 201/460 (44) <.001

Other 25/181 (14 ) 156/460 (34) <.001

Mean duration of HCV infection ± SD, y 19.8 ± 7.5 20.1 ± 8.6 .84

Serum HCV RNA, n/N (%)

≥800,000 IU/mL 71/125 (57) 199/308 (65) .15

>800,000 IU/mL 54/125 (43) 109/308 (35)

HCV genotype, n/N (%) <.001

G2 32/181 (18) 157/460 (34)

G3 149/181 (82) 303/460 (66)

Coinfection, n/N (%)

HIV 13/181 (7) 14/458 (3) .028

Hepatitis B virus surface antigen positive 2/181 (1) 3/458 (1) .44

METAVIR activity grade, n/N (%) .21

A0 or A1 59/131 (45) 176/342 (51)

A2 or A3 72/131 (55) 166/342 (49)

METAVIR fibrosis stage, n/N (%) .14

F0 or F1 51/131 (39) 156/342 (46)

F2 or F3 65/131 (50) 136/342 (40)

F4 15/131 (11) 50/342 (15)

Mean Knodell score ± SD 8.9 ± 3.6 7.8 ± 3.1 .034

Previous anti–HCV treatment course, n/N (%) .262

None 142/181 (78) 378/459 (82)

One or more 39/181 (22) 81/459 (18)HCV = hepatitis C virus; PPD = past psychiatric disorder.

Patient-Reported Adherence and Virologic Response• Adherence was similar at months 3 and 6 in PPD+ and PPD– patients (Figure 2).

• SVR rates were also similar between PPD+ and PPD– patients (Figure 3).

Figure 2. Patient-reported treatment adherence at 6 months (univariate analysis)

Figure 3. Virologic response rates (univariate analysis)

Treatment Dosing and Duration• Mean number of PEG-IFN alfa-2b injections and RBV capsules (in milligrams) was similar in the

PPD+ and PPD– groups (Figure 4).

• Mean duration of PEG-IFN alfa-2b and RBV therapy was approximately 29 weeks in each group, asreported by the investigator (Table 3).

• Mean duration of HCV treatment, rate of early discontinuation, and dose of PEG-IFN alfa-2b and ofRBV were similar in both groups (Table 3).

Figure 4. Patient-reported mean number of PEG-IFN alfa-2b injections administered and RBV capsules consumed at 6 months of treatment

Table 3. Investigator-Reported Treatment Doses and Duration

PPD+ PPD– P(n = 181) (n = 460)

Mean duration ± SD, wk* 28.4 ± 12.3 29.4 ± 13.8 .88

Early discontinuation (<20 wk), n/N (%) 24/181 (13) 59/460 (13) .89

PEG-IFN alfa-2b weekly dose, µg/kg† 1.4 ± 0.26 1.3 ± 0.3 .58

RBV daily dose, mg† 858 ± 159 870.6 ± 163.2 .30PEG-IFN = pegylated interferon; PPD = past psychiatric disorder; RBV = ribavirin.*Date of end of combination therapy minus date of study entry.†As reported by the investigator at the last visit under treatment.

Conclusions• This is the first prospective, community-based study to evaluate treatment adherence among

patients with G2/3 HCV infection.

• Patients with at least 1 PPD reported rates of adherence to treatment and attained sustainedresponse rates similar to those of patients without previous psychiatric diagnoses.

— The presence of 1 or more PPDs should, therefore, not be considered a contraindication toHCV treatment with PEG-IFN alfa-2b and RBV.

References1. McHutchison JG, et al. Gastroenterology. 2002;123:1061-1069.

2. Zeuzem S, et al. J Hepatol. 2004;40:993-999.

Supported by Schering-Plough.

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G = genotype; HCV = hepatitis C virus; PPD = past psychiatric disorder.

Patients with HCV N = 2000

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