Table Of ContentBezemeretal.BMCGastroenterology2012,12:11
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RESEARCH ARTICLE Open Access
Long-term effects of treatment and response in
patients with chronic hepatitis C on quality of
life. An international, multicenter, randomized,
controlled study
Geert Bezemer1, Arthur R Van Gool1,2, Elke Verheij-Hart1, Bettina E Hansen1, Yoav Lurie3, Juan I Esteban4,
Martin Lagging5, Francesco Negro6, Stefan Zeuzem7, Carlo Ferrari8, Jean-Michel Pawlotsky9, Avidan U Neumann10,
Solko W Schalm1 and Robert J de Knegt1*, for for the DITTO-HCV Study Group
Abstract
Background: Hepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral
therapy. HRQL improves after successful treatment. This trial explores the course of and factors associated with
HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study).
Methods: The Short Form (SF)-36 Health Survey was administered at baseline (n = 192) and 24 weeks after the
end of therapy (n = 128).
Results: At baseline HRQL was influenced by age, participating center, severity of liver disease and income.
Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased. In
this dimension patients with a relapse or sustained response differed from non-responders. Men and women
differed in the dimension bodily pain. Treatment schedule did not influence the course of HRQL.
Conclusions: Main determinants of HRQL were severity of liver disease, age, gender, participating center and
response to treatment. Our results do not exclude a more profound negative impact of individualized treatment
compared to standard, possibly caused by higher doses and extended treatment duration in the individualized
group. Antiviral therapy might have a more intense and more prolonged negative impact on females.
Keywords: health related quality of life, hepatitis C, peginterferon
Background ongoing addiction and/or psychiatric problems, reflected
Patients chronically infected with hepatitis C virus in lower HRQL. In addition, patients with hepatitis C
(HCV) have a decreased health related quality of life are stigmatized in society and the majority of the popu-
(HRQL) compared to the general population [1,2]. The lation of hepatitis C patients has a lower social eco-
impact of the disorder is comparable with other stressful nomic status compared to the general population [5].
life events and chronic diseases, like diabetes [3]. In part, The reduction of HRQL is probably also due to physi-
the reduction in HRQL is due to the mental compo- cal and psychiatric symptoms as a direct consequence of
nents of HRQL. With regard to these mental compo- this chronic infection and its sequelae (such as cirrho-
nents, patients aware of their diagnosis have a more sis). The chronic inflammation is believed to signal the
reduced HRQL than those who are unaware [4]. brain and to give rise to neurovegetative symptoms (e.g.
Furthermore, many HCV patients have a previous or malaise and fatigue) and to amongst others depression
and concentration difficulties [6]. Possibly, also the brain
*Correspondence:[email protected] itself is infected by HCV [7].
1Dpt.Gastroenterology&Hepatology,ErasmusUniversityMedicalCenter, Finally, treatment of chronic HCV with (peg)inter-
Rotterdam,theNetherlands
feron-alpha ((PEG)IFN) and ribavirin (RBV) further
Fulllistofauthorinformationisavailableattheendofthearticle
©2012Bezemeretal;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
Bezemeretal.BMCGastroenterology2012,12:11 Page2of7
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diminishes HRQL due to its side-effects. The introduc- review boards of the participating centers approved the
tion of PEGIFN provided a significant improvement study. After randomization, 134 patients received stan-
over standard IFN, with the result that the decrease of dard treatment and 136 patients were treated according
HRQL during treatment with PEGIFN is less than with to an individualized treatment schedule depending on
standard IFN [8-11]. In case of successful treatment the response at week 4 and 12 of treatment. 216
(obtaining a sustained virological response (SVR)) an patients completed the treatment per protocol and 249
improvement of HRQL-scores is observed [2,8-10]. patients completed the end of follow up. At t = 0 HRQL
In the Ditto-study [12] a dynamically individualized was measured in 192 patients (not every center partici-
treatment schedule depending on the on-treatment pated in the HRQL-analysis) and at follow up (24 weeks
response was compared to a standard combination ther- after completion of therapy) in 128 patients. In 120
apy with PEGIFN alfa-2a (180 μg qw) plus RBV (1000- patients, HRQL could be assessed at both time points.
1200 mg qd) for 48 weeks (Figure 1). The primary aim
of the Ditto study was to improve the SVR rate by indi- Study Design
vidualizing the treatment schedule, but this could not be This phase III, open-label, randomized, multicenter trial
established. was conducted by the DITTO-HCV study group
This large scale, multi-centre, international trial, between February 2001 and November 2003 at 9 centers
firstly, provides the opportunity to explore a variety of in France, Germany, Greece, Israel, Italy, the Nether-
factors associated with HRQL in HCV patients at base- lands, Spain, Sweden, and Switzerland.
line (treatment naïve; t = 0). Secondly, although type of
treatment, treatment intensity and treatment duration Assessments
were heterogeneous this study enabled us to investigate The Short Form (SF)-36 Health Survey was used to
the course of HRQL during PEGIFN-based treatment measure HRQL. The SF-36 generates a profile of HRQL
and to add to the existing knowledge on the impact of outcomes by measuring health across eight different
cytokine-based antiviral treatment on HRQL. (E.g. do dimensions: physical functioning, role limitation because
patients recover 24 weeks after completion of therapy of physical health, social functioning, vitality, bodily
(follow up) and which factors are associated with the pain, mental health, role limitation because of emotional
course of HRQL?) problems and general health. Responses to each ques-
tion within a dimension are combined to generate a
Methods score from 0 to 100, where 100 indicates “good health”.
Patients The eight multi-item subscales were also converted into
273 patients were included in the study, after informed a physical component summary scale and a mental com-
consent was obtained, and 270 patients were rando- ponent summary scale [13]. Demographic (such as age,
mized after 6 weeks of standard treatment. The ethical gender, and income in Euros) and disease related factors
were assessed before start of treatment. At the moment
the SF-36 was completed at follow up both patients and
Sthtaerrta poyf PEG-IFN alfa-2a + RBV the treating physician were unaware of the response to
week 6 the treatment because HCV-RNA testing results were
RVR SPR FPR NUR
B C not known yet, however non-responders were aware of
week 12 A1 AN2= ST + - ST + - ST D+ - ST their (positive) HCV-RNA status at relevant time points
week 24 20 D D D D during treatment.
B1 B2
N= N= N= N= N= N= N=
week 48 25 25 4 25 1 25 N= 25 Data analysis
3
Power calculation
N=
week 72 150 The HRQL-analysis was part of the main study which
was powered on significant differences in SVR-rates
week 96
between standard and individualized treatment. There-
Assessment of viral kinetics treatment
fore no separate power analysis was performed for this
PEG-IFN alfa-2a 180 μg qw follow-up
PEG-IFN alfa-2a 180 μg qw + RBV 1.0-1.2 g qd treatment interruption analysis.
PEG-IFN alfa-2a 180 μg qw + RBV 1.0-1.2 g qd + histamine +acceleration of viral decay Determinants of HRQL before treatment
PEG-IFN alfa-2a 360 μg qw + RBV 1.0-1.2 g qd -unaffected viral decay
To investigate the influence of different characteristics
Figure 1 Treatment allocation of patients with chronic
hepatitisCaccordingtoinitialvirologicresponsepatternin such as age, grade of fibrosis, and income in Euros, t-
theDittostudy.Abbreviations:Ribavirin(RBV),Rapidviralresponse test analysis for dichotomous categorical, univariate ana-
(RVR),Slowpartialresponse(SPR),Flatpartialresponse(FPR),null lysis for multicategorical and correlation analysis (Spear-
response(NUR),Standardcombinationtherapy(STD).
man) for continuous data were performed (n = 192).
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Course of HRQL limitation because of physical health, general health,
The differences between HRQL at t = 0 and follow up bodily pain, vitality, social functioning and mental health
were investigated with analysis of variance (ANOVA) were all significantly different between the participating
and t-tests for Equality of Means (n = 120). centers (Figure 2).
Explanatory variables on the course of HRQL
a) Effects of response to treatment on the course of Course of HRQL
HRQL The course of HRQL was analyzed separately for General health improved significantly at follow up com-
patients with SVR, relapse or non-response with t-tests. pared to general health at start of treatment (mean
Comparison between patients with SVR, with relapse improvement 3.5, p = .04). The subscale physical func-
and non-response was assessed by means of ANOVA. tioning tended to worsen with a mean decrease of - 3.4
b) Effects of treatment schedule The mean differences (p = .06) compared to t = 0. Other dimensions did not
in quality of life between t = 0 and follow up were com- change.
pared between patients treated with standard and indivi-
dualized treatment using ANOVA and t-tests for Explanatory variables on the differences between HRQL
Equality of Means. Also the mean differences were com- at baseline and at follow up
pared between the groups with RVR (A1, A2 and stan- a) Effect of response to treatment on course of HRQL
dard treatment with RVR) and the groups B2, D and A2 In patients with SVR, as well as with a relapse or non-
(extended versus shortened therapy, see Figure 1). response, HRQL did not change compared to t = 0 after
c) Effects of patient characteristics on the course of treatment with PEGIFN antiviral therapy, except for an
HRQL With t-test analysis for dichotomous categorical, increase in social functioning in sustained viral respon-
univariate analysis for multicategorical and correlation ders (78.8 at baseline, 83.3 at follow up, p = .04).
analysis (Spearman) for continuous data, the influence Among the different groups changes compared to base-
on the differences between HRQL at t = 0 and follow line in the dimensions general health differed signifi-
up was determined for the factors age (< 20, 20-29, 30- cantly (p = .02) between patients with a relapse (+ 5.3),
39, 40-49, 50-59, 60-69 years), gender, participating cen- SVR (+ 6.1) and non-response (- 6.3) to treatment.
ter, presence of cirrhosis, genotype (1, 4, and 5 versus 2 b) Effect of treatment schedule on course of HRQL
and 3) and income in Euros. No significant differences were observed in changes in
d) Multivariate analysis For further exploration of the the different dimensions of the SF-36 between standard
influence of the different factors mentioned above on and individualized treatment. A sub-analysis comparing
the course of HRQL, a multivariate analysis was per- responders and non-responders separately in standard
formed with a correction for age and baseline values of and individualized treatment showed no difference,
the SF-36. either. Patients treated for 24 weeks and patients treated
with double dose PEGIFN showed a decline on the
Results dimensions mental health whereas patients treated for
Baseline host and virus-related variables were similar in 72 weeks had an increase on this dimension: respectively
the standard and the individualized treatment groups - 7.9, - 2.0 and + 18.5.
(data not shown). c) Effects of patient characteristics on course of HRQL
Neither age, genotype nor grade of fibrosis had an influ-
Determinants of HRQL before treatment ence on changes in the different dimensions of HRQL.
HRQL varied with age, participating center, severity of A significant difference was seen between men and
liver disease and income in Euros (Table 1). As might women in the dimensions bodily pain (males: + 4.1,
be expected, younger patients had a better performance females: - 7.2, p = .02), social functioning (males: + 6.3,
compared to older patients, especially on the physical females: - 5.8, p = .008), vitality (males: + 7.2, females: -
components of HRQL. Surprisingly, cirrhotic patients 2.7, p = .03) and role limitations due to emotional pro-
had a better performance than non-cirrhotic patients, blems (males: + 9.3, females: - 8.3, p = .05). There was a
having significantly higher scores on several dimensions weak significant positive correlation between income in
of the SF-36, mostly on mental components. Higher Euros and increase in vitality and mental health between
income in Euros had a weak positive effect on the physi- baseline and follow up: correlation coefficient .30 (p =
cal component summary scale and role limitation .02) for vitality and .21 (p = .03) for mental health. See
because of physical health scale of HRQL, with a corre- Figure 3 and 4.
lation coefficient of 0.30 (p = .003) and 0.23 (p = .002) d) Multivariate analysis
respectively. Finally, HRQL differed among the different Also in a multivariate analysis gender was a significant
participating centers: the mental component summary factor on the course of HRQL. All different dimensions,
scale and the dimensions physical functioning, role except for physical component summary scale and
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Table 1Determinants ofHealth Related Quality ofLife ont =0andcourse ofHealth Related Quality ofLife
Subscale t=0 P-value Course P-value
(followup-t=0)
Age Agecategory(20-29,30-39, Agecategory(20-29,30-39,
40-9,50-59) 40-49,50-59)
Physicalfunctioning 90.6,93.1,86.1,78.1 0.01
Subscale t=0 P-value Course P-value
(followup-t=0)
CirrhosisNo/Yes No Yes No Yes
Mentalcomponentsummaryscale 44.7 53.7 0.001
Generalhealth 61.3 73.5 0.003
Bodilypain 74.2 88.4 0.04
Rolelimitationbecauseofemotionalproblems 68.9 88.1 0.05
Mentalhealth 66.4 80.4 0.0004
Subscale t=0 P-value Course P-value
(followup-t=0)
IncomeinEuros SubscaleSF-36 Correlationcoefficient P-value Correlationcoefficient P-value
Physicalcomponentsummaryscale 0.30 0.003
Rolelimitationbecauseofphysicalhealth 0.23 0.002
Vitality .30 0.02
Bodilypain 0.18 0.07
Mentalhealth .21 0.03
Subscale t=0 P-value Course P-value
(Followup-t=0)
Gender(M/F) M F M F
Bodilypain +4.1 -7.2 0.02
Socialfunctioning +6.3 -5.8 0.008
Vitality +7.2 -2.7 0.03
Rolelimitationbecauseofemotionalproblems +9.3 -8.3 0.05
Resultsofstatisticalanalysisoftheinfluenceofage(ANOVA),presenceofcirrhosis(t-test),gender(t-test)andincomeinEuros(correlationanalysis:Spearman)on
HealthRelatedQualityofLifeatstartoftreatment(t=0)andthecourseofHealthRelatedQualityofLife(scoresat24weeksaftertreatment(Followup)minus
scoresatbaseline).Datawereshownifrelationshipswerestatisticallysignificant.
physical functioning
100,00 role physical functioning
general health
bodily pain
vitality
social functioning
90,00 mroelen teaml hoetiaolnthal
100 physical functioning
80,00 role physical functioning
90
Mean 70,00 80 general health
bodily pain
70
60,00
vitality
60
50,00 social functioning
50
role emotional functioning
40,00 40
mental health
Spain France Switzerland Sweden Italy The Israel N = 8181808180818080 8181798180818180
Netherlands Baseline Folluwup
center
Figure2MeanscoresofthedifferentSF36dimensionsatt=0 Time
fromtheparticipatingcenters.Barcelona;Spain,Paris;France, Figure 3 Mean scores with 95% confidence intervals of the
Geneva;Switzerland,Gothenburg;Sweden,Parma;Italy,Rotterdam; differentdimensionsoftheSF-36inmenatbaselineandat24
TheNetherlands,Rehovot;Israel. weeksaftercompletionoftreatment(followup).
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With regard to the severity of the liver disease, patients
with cirrhosis did better compared to those without cir-
physical
95 functioning
rhosis. We are unable to explain this difference.
90 role physical
functioning In our study almost all dimensions of the SF-36 did
85
not change regardless of response, indicative of a satisfy-
80 general
health ing recovery of patients after cytokine-based therapy.
75
bodily However, a significant increase was found on the sub-
70 pain
65 vitalit scale general health despite a therapy-induced worsening
y
of the subscale physical functioning. This improvement
60
social
functioning was seen in patients with both SVR and relapse, whereas
55
50 role emotional functioning non-responders showed a decrease in general health. In
45 mental our study, interestingly the relapsers who were ignorant
N = 39 37 39 39 38 39 37 38 39 38 38 39 38 39 38 38 health
Baseline Follow up of treatment effect when filling in the questionnaire, had
Time a far more higher score on general health compared to
Figure 4 Mean scores with 95% confidence intervals of the the non-responders who were aware of their previous
differentdimensionsoftheSF-36infemalesatbaselineandat non-response to therapy. This underlines the mental
24weeksaftercompletionoftreatment(followup).
aspects of the impact on HRQL in this disease [14]. The
observed recovery in HRQL is in line with previous stu-
general health, were significantly different between men dies reporting an improvement on (almost) all different
and women (Table 2). Response to treatment was again dimensions of the SF-36 after a successful treatment
significantly influencing general health. with PEGIFN and RBV compared to baseline scores
In the multivariate analysis, individualized treatment [2,8-10].
had a significantly negative influence on the course of The presence of cirrhosis did not influence the course
HRQL on the dimensions physical component summary of HRQL during treatment, but patients with a cirrhosis
scale, bodily pain, vitality and social functioning, com- had higher scores on some, mostly mental, dimensions
pared to patients treated with standard treatment (Table of the SF-36 at t = 0 and at follow up, which is in con-
2). trast with earlier studies [8,15]. Patients with decompen-
The presence or absence of cirrhosis and grade of sated cirrhosis were excluded to participate in the study,
fibrosis did not play a role in the course of HRQL in but still we cannot explain this difference. Higher age
this analysis. Also different kind of genotypes (1, 4 and was associated with a decrease in HRQL, according to
5 versus 2 and 3) did not influence changes in HRQL. literature data [16].
Men and women differed in the course of HRQL with
Discussion an increase on scores for men on several dimensions
In this study we explored the influence of PEGIFN- and women experiencing a decrease. These differences
based antiviral treatment with various regimens and of between men and women were also significant in a mul-
patients characteristics on HRQL before as well as at 24 tivariate analysis for all dimensions except for general
weeks after completion of treatment. Main determinants health. In the general population, men report a higher
of HRQL in this study were the severity of liver disease HRQL [16-18], a finding possibly of relevance for our
(non-cirrhosis vs. cirrhosis), age, gender and participat- findings. But also, therapy with PEGIFN and RBV might
ing center and - to some extent - response to treatment. have a more intense and more prolonged impact on
Table 2Multivariate analysis
Physical Mental Physical Rolelimitation General Bodily Vitality Social Rolelimitation Mental
component component functioning becauseof health pain functioning becauseof health
summary summary physical emotional
scale scale health problems
Gender .043 .050 .030 .006 .009 .001 .024 .023
SVR .047
Standardvs .031 .019 .027 .031 .075
Individualized
treatment
Multivariateanalysis(correctedforbaselinevalueandage)oftheinfluenceofgender,responsetotreatmentandkindoftherapyonthemeandifference
betweenbaselineandfollowup(courseofHealthRelatedQualityofLife)ofthedifferentdimensionsoftheSF-36.
Onlysignificantp-valuesareshowninthistable.
Abbreviations:SustainedVirologicalResponse(SVR).
Bezemeretal.BMCGastroenterology2012,12:11 Page6of7
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females. Studies show more severe anemia in women Hepatology,JohannWolfgangGoetheHospital,Frankfurt,Germany.8Dpt.
during treatment with PEGIFN and RBV [19]. As ane- InfectiousDiseasesandHepatology,AziendaOspedalieradiParma,Parma,
Italy.9Dpt.Virology,HopitalHenriMondor-UniversitéParisXII,Creteil,
mia plays an important role in HRQL during antiviral France.10MinaandEverardGoodmanFacultyofLifeSciences,Bar-Ilan
treatment this could be one of the explanations for the University,Ramat-Gan,Israel.
observed difference [20]. With the fixed doses of
Authors’contributions
PEGIFN women may be treated with higher doses of GBcontributedtothedesignofthestudy,acquiredandanalysedthedata,
PEGIFN per kg, which may contribute to more side- anddraftedthemanuscript;AGcontributedtothedesignofthestudy,
effects and a lower HRQL during treatment and at 24- analysisofthedataandwasinvolvedindraftingthemasnuscript;EVH
contributedtotheanalysisofthedata;BHcontributedtothestatistical
weeks follow-up. To our knowledge, only one study analysisofthedata;YLcontributedtodata-acquirementandrevisionofthe
found sex differences in recovery, with males doing manuscript;JEcontributedtodata-acquirementandrevisionofthe
slightly worse [21]. manuscript;MLcontributedtodata-acquirementandrevisionofthe
manuscript;FNcontributedtodata-acquirementandrevisionofthe
HRQL at baseline was found to be differing between manuscript;SZcontributedtodesignofthestudy,data-acquirementand
the participating centers (in this case different coun- revisionofthemanuscript,CFcontributedtodata-acquirementandrevision
ofthemanuscript;JMPcontributedtodata-acquirementandrevisionofthe
tries/cultural regions). In the study by Ware et al [9] a
manuscript;AUNcontributedtodataacquirementandrevisionofthe
similar observation was made. Although much attention manuscript;SWScontributedtothedesignofthestudy,data-acquirement
has been devoted to assure the comparability between andrevisionofthemanuscript;RJKcontributedtothedesignofthestudy,
different cultures and languages, this observation sug- data-requirementandanalysis,anddraftingthemanuscript.Allauthorshave
readandapprovedthefinalmanuscript.
gests that studies from different countries concerning
side effects (for instance decrease of HRQL, but also Competinginterests
psychopathology) should be interpreted with caution ThisstudywassupportedbytheEuropeanCommunity(QLK2-2000-00836),
HoffmannLa-RocheandMaximPharmaceuticals.
[22,23].
Inadditionandinrelationtothisstudy,theauthorswouldliketodisclose
An important limitation of this study is the large thefollowing:
number of variables in relation to the number of partici- GeertBezemer,nothingtodisclose
ArthurR.VanGool,nothingtodisclose
pants and the many different treatment schedules. Also
ElkeVerheij-Hart,nothingtodisclose
the relative high number of drop-outs with data of 192 BettinaE.Hansen,nothingtodisclose
patients at baseline and of 128 patients at follow up YoavLurie,nothingtodisclose
JuanI.Esteban,nothingtodisclose
could be of importance, however non-responders or
MartinLagging,nothingtodisclose
relapsers were not significantly more non-compliant FrancescoNegro,nothingtodisclose
compared to responders (data not shown). In retrospect StefanZeuzem,nothingtodisclose
CarloFerrari,nothingtodisclose
an additional time point at the end of treatment would
Jean-MichelPwalotsky,nothingtodisclose
have given more insight. AvidanNeumann,nothingtodisclose
SolkoW.Schalm,nothingtodisclose
RobertJ.deKnegt,nothingtodisclose
Conclusion
In conclusion: our findings support the observation, that Received:28July2011 Accepted:31January2012
in general patients exposed to PEGIFN-based treatment Published:31January2012
do recover to their pre-treatment level of baseline, six
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