relationship of health-related quality of life to treatment adherence and sustained response in...

Relationship of Health-Related Quality of Life toTreatment Adherence and Sustained Response in Chronic

Hepatitis C PatientsDavid Bernstein,1 Leah Kleinman,2 Chris M. Barker,3 Dennis A. Revicki,2 and Jesse Green4

Interferon therapy may exacerbate health-related quality of life (HRQL) deficits associatedwith hepatitis C virus (HCV) early in the course of therapy. Treatment with polyethyleneglycol–modified interferon (peginterferon) alfa-2a (40 kd) provides improved sustainedresponse over interferon alfa-2a, but its effect on HRQL is unknown. The objective of thisstudy was to (1) evaluate the effect of sustained virologic response on HRQL in patients withHCV and (2) determine whether impairment of HRQL during treatment contributes to earlytreatment discontinuation. Data consisted of a pooled secondary analysis of patients (n 51,441) across 3 international, multicenter, open-label, randomized studies that comparedpeginterferon alfa-2a (40 kd) with interferon alfa-2a. ANCOVA was used to examine theeffect of sustained virologic response on HRQL. Repeated-measures mixed-modelsANCOVA was used to compare Fatigue Severity Scale (FSS) and SF-36 scores during treat-ment by treatment group. Logistic regression analysis was used to examine the associationbetween changes at baseline in on-treatment HRQL and early treatment discontinuation.Sustained virologic response was associated with marked improvements from baseline to endof follow-up in all subjects, including patients with cirrhosis. During treatment, patientsreceiving peginterferon alfa-2a (40 kd) had statistically significantly better scores on both theSF-36 and FSS. Baseline to 24-week changes in fatigue and SF-36 mental and physicalsummary scores significantly predicted treatment discontinuation. In conclusion, sustainedvirologic response is associated with improvements in quality of life in patients with orwithout advanced liver disease. This parameter may be an important consideration in max-imizing treatment adherence. (HEPATOLOGY 2002;35:704-708.)

The perception in the medical community is that most peo-ple infected with hepatitis C virus (HCV) feel well and thatthe disease has no impact on their quality of life. This

perception comes from literature describing chronic hepatitis C(CHC) infection as an asymptomatic disease, with less than 20%of patients experiencing clinical symptoms such as fatigue, muscu-loskeletal pain, abdominal pain, concentration defects, and head-ache.1 Recently, however, several studies have shown an impairedhealth-related quality of life (HRQL) in patients with CHC.2-4

Several therapies are currently approved for the treatment ofpatients with CHC, including monotherapy with interferon alfa-2b, interferon alfa-2a, and interferon alfacon-15,6; polyethylene

glycol–modified interferon (peginterferon) alfa-2b; combinationinterferon alfa-2b plus ribavirin; and combination peginterferonalfa-2b plus ribavirin.7 These treatments, however, produce vary-ing degrees of adverse effects, such as fatigue, myalgia, influenza-like symptoms, and alterations in mood, ability to concentrate, andlibido, which may negatively affect a patient’s vitality, social inter-action, and ability to perform work and other activities. The sig-nificant adverse-event profiles of these treatments are critical to thetreating physician’s and patient’s decision to initiate therapy anddiscontinue treatment before completion of a full course of ther-apy. Discontinuation of therapy before completion of an adequatecourse of treatment is an indication of patient intolerance and mayreflect the impact of treatment-related adverse effects on HRQL.8

Several studies have suggested that the percentage of subjectswhose HCV therapy is discontinued due to patient intoleranceranges from 3.8% to 27.1%, depending on the type and durationof therapy.9,10

Although interferon-based therapies negatively affect HRQL ofpatients with CHC during the initial 12 to 24 weeks of therapy, animproved HRQL has been seen in patients with a sustained re-sponse to antiviral therapy, regardless of the specific type of inter-feron.2-4,11,12 However, most of the patients in these studies didnot have cirrhosis. The effects of sustained virologic response onHRQL in patients with CHC and cirrhosis have not been de-scribed.

Abbreviations: HCV, hepatitis C virus; CHC, chronic hepatitis C; HRQL, health-related quality of life; peginterferon, polyethylene glycol–modified interferon; FSS, Fa-tigue Severity Scale.

From 1North Shore University Hospital, Manhasset, NY; 2Center for Health Out-comes Research, MEDTAP International Inc., Bethesda, MD; 3Hoffmann-La Roche,Palo Alto, CA; and 4Hoffmann-La Roche, Nutley, NJ.

Received May 10, 2001; accepted November 29, 2001.Supported by a grant from F. Hoffmann-La Roche Ltd., Basel, Switzerland.Address reprint requests to: David Bernstein, M.D., North Shore University Hospi-

tal, 300 Community Drive, Manhasset, NY 11030. E-mail: [email protected]; fax:516-562-1688.

Copyright © 2002 by the American Association for the Study of Liver Diseases.0270-9139/02/3503-0028$35.00/0doi:10.1053/jhep.2002.31311

704

Recently, it was shown that treatment with peginterferonalfa-2a (40 kd) produced sustained virologic responses in a signif-icantly higher proportion of previously untreated patients withCHC than unmodified interferon alfa-2a while maintaining acomparable safety profile.10 In this study, we performed a pooledanalysis of data from 3 recent randomized trials that compared theefficacy of peginterferon alfa-2a (40 kd) with interferon alfa-2a.The primary objective of our analysis was to examine the relation-ship between sustained virologic response and HRQL. We alsoevaluated whether changes in HRQL during treatment were asso-ciated with premature discontinuation of treatment and comparedHRQL during treatment with peginterferon alfa-2a (40 kd) versusinterferon alfa-2a.

Patients and MethodsThis study included 1,441 patients enrolled in 3 international,

multicenter, open-label, randomized clinical trials designed tocompare the safety and efficacy of peginterferon alfa-2a (40 kd)(Pegasys; F. Hoffmann-La Roche Ltd., Basel, Switzerland) withinterferon alfa-2a (Roferon-A; F. Hoffmann-La Roche Ltd.).These trials were conducted in Australia, Canada, France, Ger-many, Mexico, New Zealand, Spain, Switzerland, Taiwan, theUnited Kingdom, and the United States. Pooled data analysis wasdeemed appropriate because the clinical trials had similar researchprotocols, inclusion and exclusion criteria, and the same activetreatment comparator, data collection schedule, and HRQL in-struments. By pooling data from 3 clinical trials and increasing thesample size, the risks and benefits of treatment could be assessedwith a high degree of confidence.

Adult patients were included in the clinical trials if they had notpreviously been treated for CHC with interferon-based therapies,had a positive hepatitis C antibody in the serum, had persistentlyelevated serum alanine aminotransferase levels, and had a positiveHCV RNA detected by polymerase chain reaction in the serum.Subjects with previous interferon-based therapy, other chronicliver diseases, significant comorbid conditions (e.g., cardiovasculardisease, chronic renal disease, and cancer), pregnancy, or evidenceof substance abuse within 1 year were excluded from the clinicaltrials. One clinical trial was restricted to patients with cirrhosis orbridging fibrosis secondary to CHC infection.

Treatment Groups. Patients were randomized into 2 treat-ment groups. Group I received 90, 135, or 180 mg peginterferonalfa-2a (40 kd) once weekly. Group II received interferon alfa-2a ata dosage of either (1) 6 MIU thrice weekly for 12 weeks followed by3 MIU thrice weekly for 36 weeks or (2) 3 MIU thrice weekly for48 weeks. All patients were monitored for a follow-up period of 24additional weeks after completing therapy.

Sustained Virologic Response. A sustained virologic responsewas defined as an undetectable plasma HCV RNA (AmplicorHCV Test, V. 2.0, with a lower limit of detection ,100 copies/mL) at the end-of-treatment follow-up period (week 72).

HRQL. The SF-36 Health Survey13 and the Fatigue SeverityScale (FSS)14 were used to evaluate HRQL. Subjects completed theSF-36 and the FSS at baseline and at weeks 2, 12, 24, 48, and 72.Instruments were available in the relevant languages for all coun-tries where the clinical trials were conducted. Patients completedthe SF-36 and the FSS (in this order) before any clinical procedures

or consultations to ensure that their responses were not influencedby their clinical evaluations.

The SF-36 was used to measure generic health status and con-sists of 36 items measuring 8 domains: physical function, rolelimitations-physical, vitality, general health perceptions, pain, so-cial function, role limitations-emotional, and mental health.13

Mental and physical component summary scores were calculat-ed.15 The SF-36 has been shown to have good reliability and va-lidity in primary care and chronic disease populations, includingCHC.3,4,12,16,17

The FSS was developed to measure disabling fatigue14 and wasincluded in the clinical trials because fatigue is a common symp-tom of CHC; it is also a common side effect of therapy,8 andfatigue-related effects may result in early discontinuation of treat-ment.2,4,12 The 9 items scored are combined into a total score,which indicates a smaller effect of fatigue on everyday life. The FSSalso includes a visual analogue scale measured as a 100-mm hori-zontal line anchored by “no fatigue” and “fatigue as bad as it couldbe,” which provides a single-item measure of overall severity offatigue. The FSS has been shown to have excellent psychometricproperties in CHC.18

Data Analysis. ANCOVA controlling for baseline score andregion was used to examine the impact of sustained virologic re-sponse on 72-week endpoint HRQL scores. A separate analysis bystatus of cirrhosis was also performed using the same ANCOVAmodel. Only patients with baseline and follow-up HRQL end-point data (95%) were included in these analyses. Repeated-mea-sures mixed-model ANCOVA was used to compare FSS andSF-36 scores during therapy by treatment group. The treatmentperiod was limited to the first 24 weeks of therapy to minimize theimpact of patients’ knowledge of their HCV RNA status onHRQL. The mixed models included fixed effects of treatment,country, visit, treatment-by-country interaction, and the baselinescore as a covariate. Patients without baseline HRQL scores orwithout any postbaseline HRQL scores were not included in theanalyses.

Logistic regression was used to estimate the impact of worseningHRQL and fatigue scores during treatment on premature discon-tinuation of therapy. The change in scores was defined as thedifference from baseline to week 24 or to discontinuation if earlier.Odds ratios representing the effect of worsening scores on the riskof premature termination were calculated based on the interquar-tile range. Specifically, if patients are ranked from least to mostimpaired according to the change from baseline, the odds ratiosindicate the additional risk of discontinuation from being at the75th versus the 25th percentile.

ResultsBaseline patient demographic and disease characteristics are

summarized in Table 1. Patients included 987 men (68%) and 454women (32%); 59% were older than 40 years. Thirty-two percentof patients had cirrhosis or bridging fibrosis. As noted, patientswith significant comorbidity were excluded from the trial, andexamination of baseline HRQL scores showed no significant dif-ferences in comorbidity among treatment groups.

Sustained Virologic Response and HRQL. Sustained viro-logic response was associated with improvement in HRQL and

HEPATOLOGY, Vol. 35, No. 3, 2002 BERNSTEIN ET AL. 705

fatigue for all domains (P , .01) (Table 2). This effect was primar-ily due to improvement from baseline to end of follow-up inHRQL among responders in all domains and secondarily toHRQL declines from baseline to week 72 among nonresponders.The largest improvements for responders were seen in role limita-tions-physical, general health, and vitality scores.

Similar results were seen when patients were classified accordingto histology. Among noncirrhotic patients, changes in HRQLfrom baseline to week 72 were significantly better for responderscompared with nonresponders on all FSS and SF-36 scores (Table3). Among patients with cirrhosis or bridging fibrosis, sustainedvirologic response was associated with improved HRQL on 5 of 8

SF-36 domains (physical function, role limitations-physical, gen-eral health, vitality, and social function) and the 2 SF-36 summaryscores (physical and mental component summary) as well as on theFSS visual analogue scale and FSS total scores (Table 4).

On-Treatment HRQL and Therapy Group. During treat-ment, patients receiving peginterferon alfa-2a (40 kd) reportedbetter HRQL and less fatigue than those taking interferon alfa-2ain 7 of 8 SF-36 domains, both SF-36 summary scores, and the FSStotal and FSS visual analogue scale scores (Table 5). The largestdifferences on the SF-36 were in the 2 role-limitations domains(physical and emotional), which pertain to the impact of health onwork and other productive activities.

HRQL and Premature Discontinuation of Treatment. Atotal of 141 subjects (10%) discontinued treatment before 24weeks of therapy. Worsening fatigue scores and declines in SF-36mental and physical component summary scores were significantpredictors of treatment discontinuation (Table 6). FSS total scorehad the largest impact on the odds of treatment discontinuation(odds ratio 5 1.48; P , .001).

DiscussionThis study shows that sustained virologic response to CHC

therapy is associated with significant improvements in patient en-ergy levels, general functioning, and well-being, as reported onvalidated HCV HRQL instruments. These results are consistentwith other reports of an association between HRQL and sustainedvirologic response in patients with CHC.2-4,12

Confirmation of these findings is important, because they im-ply that the decreased quality of life associated with HCV infectioncan be improved with successful therapy. This study also indicates

Table 1. Baseline Demographic and Clinical Characteristics byTreatment Regimen

Baseline CharacteristicsAll Treatment Arms(n 5 1,441) (%)

Male 987 (68)Female 454 (32)Age

40 years or younger 588 (41)Older than 40 years 853 (59)

White 1,244 (86)Alanine aminotransferase quotient*

,3 864 (60)$3 577 (40)

Histologic diagnosisNoncirrhosis 984 (68)Cirrhosis/bridging fibrosis 456 (32)Missing 1 (,1)

*Defined as the average of 2 serum alanine aminotransferase values divided byupper limit of normal range.

Table 2. Baseline to 72-Week Mean Changes in HRQL forVirologic Responders and Nonresponders

HRQL Scores

VirologicResponders* Virologic Nonresponders

NMean

Change (SE) NMean

Change (SE) Difference†

FSS¶Total score 275 20.4 (0.1) 708 0.1 (0.1) 20.5\

VAS 269 29.1 (1.7) 697 2.4 (1.0) 211.5\

SF-36#Physical function 277 2.4 (1.0) 712 22.2 (0.7) 4.6\

Role limitations-physical 273 8.2 (2.3) 703 21.6 (1.4) 9.8\

Bodily pain 278 2.8 (1.4) 714 20.1 (0.8) 2.9§General health 272 8.5 (1.0) 707 23.6 (0.6) 9.1\

Vitality 277 9.2 (1.3) 714 20.4 (0.7) 9.6\

Social function 278 4.6 (1.3) 716 21.6 (0.8) 6.2\

Role limitations-emotional 272 4.5 (2.3) 703 23.9 (1.5) 8.4§

Mental health 277 2.5 (1.0) 714 22.1 (0.6) 4.6\

PCS 264 2.2 (0.5) 685 20.6 (0.3) 2.8\

MCS 264 2.0 (0.6) 685 21.0 (0.4) 3.0\

Abbreviations: VAS, visual analog scale; PCS, physical component summary; MCS,mental component summary.

*Sustained virologic response at week 72.†Two-tailed P value from ANCOVA model: §P , .01, \P , .001.¶For FSS scores, negative changes indicate improvements in fatigue.#For SF-36 scores, positive changes indicate improvements in health status.

Table 3. Baseline to 72-Week Mean Changes in HRQL byResponder Status in Patients With CHC Without Cirrhosis

HRQL Scores


NMean

Change (SE) NMean


FSS¶Total score 214 20.5 (0.1) 460 0.1 (0.1) 20.6\

VAS 209 210.0 (1.9) 454 1.2 (1.1) 211.2\

SF-36#Physical function 215 2.7 (1.2) 461 21.2 (0.9) 3.9§Role limitations-

physical 211 8.9 (2.5) 454 21.3 (1.7) 10.2§Bodily pain 216 2.7 (1.5) 463 20.5 (1.0) 3.2‡General health 210 8.9 (1.2) 459 23.2 (0.8) 12.1\

Vitality 215 9.8 (1.4) 465 20.4 (0.9) 10.2\

Social function 216 5.1 (1.5) 465 21.0 (1.0) 6.1§Role limitations-

emotional 211 7.0 (2.7) 455 22.7 (1.7) 9.7‡Mental health 215 3.1 (1.1) 465 21.7 (0.7) 4.8§PCS 203 2.1 (0.5) 442 20.5 (0.4) 2.6\

MCS 203 2.5 (0.7) 442 20.8 (0.4) 3.3§


*Sustained virologic response at week 72.†Two-tailed P value from ANCOVA model: ‡P , .05, §P , .01, \P , .001.¶For FSS scores, negative changes indicate improvements in fatigue.#For SF-36 scores, positive changes indicate improvements in health status.

706 BERNSTEIN ET AL. HEPATOLOGY, March 2002

that HRQL benefits of sustained response also occur among pa-tients with advanced liver disease.

Research on the SF-36 suggests that some of the improvementsin patient functioning and well-being associated with attaining asustained virologic response to CHC therapy were clinically mean-ingful. A meta-analysis by Samsa et al.19 showed that 3 to 5 pointsin SF-36 scores represents a minimum clinically important differ-ence. Beyond that threshold, Ware et al.13 suggest that 10 pointsrepresents a moderate effect on patients’ HRQL. By these criteria,sustained virologic response had clinically important effects on

several HRQL domains, especially role limitations-physical, gen-eral health perceptions, and vitality. Among patients with cirrhosisor bridging fibrosis, improvements in these domains were alsoclinically important.

On-Treatment HRQL. Previous reports based on these trialsdocumented the significantly better efficacy of peginterferonalfa-2a (40 kd) compared with unmodified interferon alfa-2a in thetreatment of patients with CHC.10,20,21 This analysis indicates thatthe benefits of peginterferon alfa-2a (40 kd) also extend to HRQL.Peginterferon alfa-2a (40 kd) was associated with significantly lessimpairment of HRQL and less fatigue during the initial 24 weeksof treatment than unmodified interferon alfa-2a. On some do-mains of the SF-36 (role limitations-physical, general health, vital-ity, social function, and role limitations-emotional), the differ-ences were not only statistically significant but also clinicallymeaningful.

Discontinuation of Treatment. The fatigue scores andHRQL summary measures of mental and physical well-being as-sessed in this study were significantly associated with early discon-tinuation of treatment. Studies suggest that the adverse impact oftherapy on HRQL lessens after 12 to 24 weeks and eventuallyreturns to baseline.3,4 The finding that HRQL during treatment isnot as impaired with peginterferon alfa-2a (40 kd) as with inter-feron alfa-2a suggests that choice of treatment may have an impacton adherence.

Limitations. Patients were informed of their HCV RNA sta-tus at intervals during the trials. Such knowledge may potentiallyinfluence HRQL scores. However, HCV RNA results only becameavailable after a visit. Thus, any knowledge patients had at the timeof HRQL assessment was from the previous visit (8-10 weeksearlier). In the case of the follow-up visit at week 72, their knowl-edge would be from the end-of-treatment visit some 24 weeksearlier. In addition, during therapy, the impact of HCV RNAstatus before week 24 seemed to have little impact on patients’expectations, as expressed in their willingness to continue therapy.The only patients who discontinued treatment due to nonresponsedid so after 24 weeks of treatment. Consequently, we confined ouranalyses of HRQL during treatment to the first 24 weeks. Finally,the fact that our findings applied both to the physical and emo-tional domains makes it less likely that disappointment with newsabout HCV RNA status was a major confounding factor.

Table 4. Baseline to 72-Week Mean Changes in HRQL byResponder Status in Patients With Cirrhosis or

Bridging Fibrosis

HRQL Scores


NMean

Change (SE) NMean


FSS¶Total score 61 20.1 (0.2) 248 0.2 (0.1) 20.3‡VAS 60 26.0 (3.6) 243 4.8 (1.8) 11.1\

SF-36#Physical function 62 1.4 (1.4) 251 24.0 (1.2) 5.4§Role limitations-

physical 62 5.8 (5.4) 249 22.0 (2.4) 7.8‡Bodily pain 62 2.9 (3.1) 251 20.5 (1.4) 3.4General health 62 7.1 (2.1) 248 24.2 (1.1) 11.3\

Vitality 62 7.1 (3.1) 249 20.3 (1.2) 7.4\

Social function 62 3.0 (2.8) 251 22.7 (1.5) 5.7‡Role limitations-

emotional 61 23.8 (4.4) 248 26.2 (2.7) 2.4Mental health 62 0.4 (1.8) 249 22.7 (1.0) 3.1PCS 61 2.2 (1.1) 243 20.8 (0.5) 3.0§MCS 61 0.2 (1.1) 243 21.4 (0.7) 1.6‡


*Sustained virologic response at week 72.†Two-tailed P value from ANCOVA model: ‡P , .05, §P , .01, \P , .001.¶For FSS scores, negative changes indicate improvements in fatigue.#For SF-36 scores, positive changes indicate improvements in health status.

Table 5. On-Treatment HRQL: Difference Between PeginterferonAlfa-2a (40 kilodaltons) and Interferon Alfa-2a

HRQL Domain Difference (SE) P

FSSFSS total score 20.2 (0.10) .02FSS VAS 5.1 (1.0) .001

SF-36 domainsPhysical function 2.0 (1.4) .14Role limitations-physical 6.7 (2.4) .005Bodily pain 2.9 (1.5) .05General health 3.2 (1.4) .02Vitality 3.0 (1.4) .03Social function 3.1 (1.5) .04Role limitations-emotional 4.8 (2.2) .03Mental health 2.6 (1.1) .02

SF-36 summary scoresPCS 1.2 (0.6) .04MCS 1.5 (0.6) .02


Table 6. Association Between HRQL Scores and PrematureDiscontinuation of Treatment

HRQL DomainOdds Ratio*

(95% CI) P

FSSFSS total score 1.48 (1.18-1.85) ,.001FSS VAS 1.45 (1.16-1.81) ,.001

SF-36 summary scoresPCS 1.35 (1.08-1.68) ,.01MCS 1.28 (1.05-1.56) ,.05


*Odds ratios represent the difference between the 25th and 75th percentile interms of “worse” fatigue (higher FSS score) or worse quality of life (lower SF-36 score).

HEPATOLOGY, Vol. 35, No. 3, 2002 BERNSTEIN ET AL. 707

These findings apply to a population of patients with CHC whomet inclusion and exclusion criteria of these clinical trials. There-fore, caution should be exercised in making generalizations.

ConclusionSustained virologic response is associated with improvements in

disabling fatigue and patient functioning and well-being in pa-tients with CHC with and without evidence of cirrhosis as mea-sured by both the SF-36 and FSS scales. It is noteworthy thatadvanced liver disease did not prevent patients with CHC whoattained sustained virologic response from experiencing significantimprovements in HRQL, regardless of their fibrosis stage. Becausepeginterferon alfa-2a (40 kd) has recently been shown to producesignificantly more sustained virologic responses in patients withcirrhosis compared with unmodified interferon (30% vs. 8%),10

peginterferon alfa-2a (40 kd) may also improve HRQL in thesepatients. Maintaining an acceptable HRQL on therapy is vital topatient compliance and acceptance of these therapies. Minimizingthe adverse impact of therapy on HRQL should help lessen thedegree of early treatment discontinuation. Peginterferons seem tooffer an advantage over standard therapies in maintaining an ac-ceptable HRQL. HRQL issues should be considered in conjunc-tion with safety and efficacy concerns in choosing optimal therapyfor the treatment of patients with CHC.

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