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Study Finds Quality of Life for Pegasys-Ribavirin Better Than for Interferon-Ribavirin and It Improves For Sustained Viral Responders
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"The impact of peginterferon alfa-2a (Pegasys) plus ribavirin combination therapy on health-related quality of life in chronic hepatitis C"
Journal of Hepatology 40 (April 2004) 675--681
Tarek Hassanein1,*, Graham Cooksley2, Mark Sulkowski3, Coleman Smith4, George Marinos5, Ming-Yang Lai6, Giuseppe Pastore7, Rafael Trejo-Estrada8, Ana Horta e Vale9, Neil Wintfeld10, Jesse Green10 1Department of Medicine, Division of Gastroenterology and Hepatology, University of California, San Diego, USA 2Royal Brisbane Hospital, Brisbane, Qld, Australia 3Johns Hopkins University, Baltimore, MD, USA 4Minnesota Clinical Research Center, St Paul, MN, USA 5Prince of Wales Hospital, Randwick, NSW, Australia 6National Taiwan University Hospital, Taipei, Taiwan 7Universita Di Bari, Bari, Italy 8Centro Medico Nacional Siglo XXI, Mexico, D.F. Mexico 9Clinica Diagnostico Medico Integral, Vila Nova de Gaia, Portugal10Hoffmann-La Roche Inc., Nutley, NJ, USA
"...Patients receiving peginterferon alfa-2a plus placebo reported better quality of life and less fatigue than those taking either of the combination therapies that included ribavirin: peginterferon alfa-2a plus ribavirin or interferon alfa-2b plus ribavirin. In addition, patients taking peginterferon alfa-2a plus ribavirin reported better quality of life and less fatigue than patients receiving interferon alfa-2b plus ribavirin..."
"...At the end of follow-up period (week 72) patients who attainedsustained viral response (SVR) reported improvements in all SF-36 and FSS scores (quality of life measures) that were significantly greater than those reported by patients who did not attain SVR..."
"...This improved quality of life and fatigue may be due to the sustainedserum levels produced by the weekly dosing schedule of peginterferon alfa-2a compared with the peaks and troughs associated with thrice weekly dosing of interferon alfa-2b. These results are also consistent with the lower rates of influenza-like symptoms and depression seen with peginterferonalfa-2a plus ribavirin vs. interferon alfa-2b plus ribavirin..."
Better quality of life for patients on Pegasys/RBV compared to IFN/RBV was more prominent during the first two weeks. This was characterized by superior QOL in more domains during the first 2 weeks than in subsequent weeks. But there were domains during the remainder of the study in which Pegasys/RBV performed better. QOL during the first few weeks has a special importance. Full adherence during the first 12 weeks is crucial, and improved QOL early in treatment may help to encourage patients to remain on therapy.
CHANGES FROM BASELINE IN HRQOL SCORES BY SVR STATUS
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Domain
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MEAN SF-36 and FSS score
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SVR
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Non-SVR
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Difference
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Physical function
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3.6
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-1.9
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5.5*
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Role limitation physical
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5.8
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0.1
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5.7**
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Bodily pain
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4.4
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0.3
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4.1**
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General health
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7.4
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-1.2
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8.6*
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Vitality
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8.0
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1.7
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6.3
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Social functioning
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3.0
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2.8
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5.8*
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Role emotional
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7.4
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-1.9
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9.3*
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Mental health
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3.1
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-1.9
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5.0*
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Physical component score
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2.0
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-0.2
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2.2*
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Mental component score
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2.2
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-0.4
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2.6*
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Total fatigue
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2.7
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-0.6
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3.3*
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Fatigue severity score
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10.3
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2.9
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7.4*
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*p<=0.01
**p<=0.05
ABSTRACT
Peginterferon alfa-2a plus ribavirin improves sustained virological responses compared with interferon alfa-2b and ribavirin, or peginterferon alfa-2a alone in chronic hepatitis C. We examined the impact of these treatments on health related quality of life (HRQOL).
Patients (n 5 1121) were randomized to peginterferon alfa-2a weekly plus ribavirin or placebo, or interferon alfa-2b thrice weekly plus ribavirin. HRQOL was assessed with the SF-36 Health Survey and Fatigue Severity Scale (FSS).
Patients receiving peginterferon alfa-2a (Pegasys) plus ribavirin reported better HRQOL than those receiving interferon alfa-2b plus ribavirin. These differences were statistically significant for three SF-36 domains and both FSSscores (p < 50.05). Patients receiving peginterferon alfa-2a plus placebo had the least impairment; adding ribavirin significantly decreased five domains of the SF-36 and both FSS scores. Sustained virological response was associatedwith improvement at follow-up on all SF-36 and FSS scores.
The effects of combination therapy on HRQOL and fatigue are less with peginterferon alfa-2a plus ribavirin than interferon alfa-2b plus ribavirin. Each medication in combination therapy with interferon and ribavirin, affects patients' quality of life differently. Understanding the relationship of specific therapeutic options to HRQOL may help physicians minimize the impact of therapy on HRQOL.
In particular, peginterferon alfa-2a plus ribavirin therapy was associated with significantly less bodily pain, more energy, less disabling fatigue, and fewer limitations in social functioning during 48 weeks of treatment, compared withconventional interferon alfa-2b plus ribavirin in patients with chronic hepatitis C. These HRQOL advantages of peginterferon alfa-2a plus ribavirin in comparison with interferon alfa-2b plus ribavirin were seen as early as thefirst post-baseline visit and maintained throughout therapy. This early difference could impact patients' compliance especially during the first 12 weeks of therapy. The results of this study also confirm previous researchthat found an association between SVR and improved HRQOL. These confirmatory findings support the conclusion that reductions in HRQOL produced by HCV can be overcome with successful treatment.
INTRODUCTION
Hepatitis C virus (HCV) is an important cause of chronic liver disease worldwide. In the United States alone, nearly 4 million individuals are infected with this virus. Currently, hepatitis C is responsible for anestimated 8000--10,000 deaths annually, and without effective intervention, that number is postulated to triple in the next 10--20 years. Hepatitis C is now the leading reason for liver transplantation in the United States. Patients with chronic hepatitis C also have more impaired health-related quality of life (HRQOL) than the general population. In addition, soon after the onset of treatment with interferon monotherapy or interferon plus ribavirin, patients report increased incidence and severity of fatigue, pain, and mood changes that interfere with physical and emotional well-being, work productivity, and activities of daily living. These changes in HRQOL might adversely affect adherence and result in early discontinuation of therapy. Previous research on hepatitisCtherapy has shown that such declines in HRQOL increase the risk of premature treatment discontinuation.
In a randomized clinical trial, peginterferon alfa-2a has demonstrated increased efficacy (sustained virological response rate after completion of treatment) in monotherapy compared with conventional interferon alfa-2a. Analysis of HRQOL in that trial found that patients in the peginterferon alfa-2a group reported significantly less impairment of HRQOL during therapy than those in the conventional interferon alfa-2a group. The current standard of care for patients with chronic hepatitis C is combination therapy using interferon and ribavirin.
In a recent multinational, randomized trial, combination therapy with peginterferon alfa-2a plus ribavirin demonstrated increased efficacy compared with peginterferon alfa-2a alone (56 vs. 29%, P <=0.001) andinterferon alfa-2b plus ribavirin (56 vs. 44%, P <=0.001). The study also found significantly lower rates of influenza-like symptoms (fever, headache, myalgia, and rigors) with peginterferon alfa-2a plus ribavirin vs. interferon alfa-2b plus ribavirin. Lower rates of these adverse events may contribute to less impairment of HRQOL during therapy with peginterferon alfa-2a plus ribavirin vs. interferon alfa-2b plus ribavirin.
The present study examined differences in HRQOL experienced by patients randomized to 48 weeks of treatment with either peginterferon alfa-2a plus placebo, peginterferon alfa-2a plus ribavirin, or interferon alfa-2b plus ribavirin. The purpose of the study was threefold. First, to determine whether peginterferon alfa-2a plus ribavirin was associated with lessimpairment of HRQOL and less fatigue burden than interferon alfa-2b plus ribavirin. Second to test previous findings that successful treatment of HCV is associated with significant improvements in patient quality of life. Third, tocompare the HRQOL experienced by patients in the peginterferon alfa-2a plus placebo and peginterferon alfa-2a plus ribavirin groups in order to examine the specific effects of both peginterferon alfa-2a and ribavirin when used in combination, on HRQOL.
This study was based on data from an international, multicenter, openlabel, openlabel, randomized, parallel, efficacy and safety study comparing peginterferon alfa-2a (Pegasysw, Roche) plus ribavirin (Copegusw, Roche) orplacebo, or interferon alfa-2b plus ribavirin (Rebetrone, Schering-PloughCorporation, Kenilworth, NJ, USA). Peginterferon alfa-2a was administered as a once-weekly subcutaneous injection of 180 mg, while interferon alfa-2b was administered as a subcutaneous injection of 3 million units thrice weekly. Ribavirin was given orally at a dose of 1000--1200 mg per day administered in two split doses. Subjects were treated for 48 weeksand followed for an additional 24 weeks after therapy was discontinued.Randomization was stratified by HCV genotype (1 vs. non-1) and bycountry. Details of this clinical trial have been published elsewhere.
HRQOL assessments
The self-administered version of the Short Form (SF)-36 Health Surveywas included to comprehensively measure HRQOL. The SF-36 is a generic health status measure that consists of 36 items and eight domain scales. Domain scale scores are linearly transformed into a 0 (worst health) to 100 (best health) scale. Mental component summary and physical component summary scores were also generated. The SF-36 has demonstrated good reliability and validity in chronic disease populations, including patients with chronic hepatitis C.
Since fatigue is a prominent symptom of chronic hepatitis C and a commonly reported side-effect of treatment, we also included the 10-item Fatigue Severity Scale (FSS), a self-administered instrument developed to assess the impact and severity of fatigue in our study. Nine items are combined into a total fatigue score. The FSS also includes a visual analog scale which represents fatigue severity as a 100 mm horizontal line anchored at 'no fatigue' and 'fatigue as bad as it could be'. For consistency with the SF-36, FSS scores were transformed so that higher scores indicate better health, in terms of a lower burden of fatigue. The FSS has been shown to have excellent psychometric properties in CHC.
The FSS and SF-36 were available in the relevant languages at all clinical centers. Standard validated techniques for translation and culturalvalidation were employed. To ensure that patients responded independently of the clinical evaluations, they were asked to complete the SF-36 and the FSS (in this order) prior to any clinical procedures or consultations. The HRQOL instruments were self-administered by patients at baseline, during treatment at weeks 2, 12, 24, and 48 and at posttreatment follow-up (week 72).
Results
Patient demographics
A total of 1121 patients were randomized and received at least one dose of either peginterferon alfa-2a plus placebo, peginterferon alfa-2a plus ribavirin or interferon alfa-2b plus ribavirin. There were no significant differencesbetween treatment groups for any baseline demographic or clinical characteristic. The baseline SF-36 and FSS scores also did not significantly differ by treatment group. The mean age of the patients was 43 years; 71% were males, and the mean body mass index was 27 kg/m2. The majority of patients (65%) were infected with HCV genotype 1 and 87% had no histological evidence of cirrhosis.
Quality of life during treatment
Patients receiving peginterferon alfa-2a plus placebo reported better HRQOLand less fatigue than those taking either of the combination therapies that included ribavirin: peginterferon alfa-2a plus ribavirin or interferon alfa-2b plus ribavirin. In addition, patients taking peginterferon alfa-2a plus ribavirin reported better HRQOL and less fatigue than patients receiving interferon alfa-2b plus ribavirin.
The incremental effects of adding ribavirin to peginterferon alfa-2a are reflected in the lower HRQOL scores in the peginterferon alfa-2a plus ribavirin arm compared with the peginterferon alfa-2a plus placebo arm (Fig. 1). These differences were statistically significant for five out of eightdomains of the SF-36: physical function (p <0.01); physical role limitations (p <0.01); vitality (p <0.01); social functioning (p <0.05); mental health (p <0.05) and for both the total fatigue (p <0.01) and fatigue severity scores (p <0.01) of the FSS.
Comparison of the two combination treatments that included ribavirin revealed differences in HRQOL between peginterferon alfa-2a plus ribavirin and interferon alfa-2b plus ribavirin. These differences (favoring peginterferon alfa-2a) were significant for the SF-36 domains: bodily pain (p <=0:01); vitality (p <=0:05); social functioning (p <=0:05) and for both the total fatigue (p <=0:05) and fatigue severity (p <=0:05) scores of the FSS Analysis of the SF-36 and FSS scores by week of treatment indicated that most of the on-treatment differences between peginterferon alfa-2a plus ribavirin and interferon alfa-2b plus ribavirin were statistically significant by the second week of treatment. These were role limitations—physical (p <0:01); bodily pain (p <0:01); vitality (p <0:01); physical component score (p <0.01) and the total fatigue and fatigue severity scores (p <0.01) of the FSS. At posttreatment followup (week 72),HRQOL scores had returned tobaseline levels or better in all groups.
The negative difference scores indicate that during therapy, HRQOL declined from baseline in all treatment groups. The impact of peginterferonalfa-2a alone on HRQOL during treatment was most prominent for the SF-36 domains of role limitations— physical, bodily pain, social functioning, role limitations— emotional, and vitality as well as for the fatigue severityscore of the FSS. The largest incremental effects of adding ribavirin to peginterferon alfa-2a were seen in the SF-36 physical functioning, role limitations—physical, and vitality scores, and in the fatigue severity score of the FSS. At the end of follow-up period (week 72) patients who attainedSVR reported improvements in all SF-36 and FSS scores that were significantly greater than those reported by patients who did not attain SVR.
Discussion
Combination therapy with interferon and ribavirin for CHC has become increasingly effective, however, patients continue to report difficulties with HRQOL during treatment. In this study combination therapy with peginterferon alfa-2a plus ribavirin was associated with better HRQOLand less burden of fatigue than interferon alfa-2b plus ribavirin across a broad spectrum of HRQOL domains. This improved HRQOL and fatigue may be due to the sustained serum levels produced by the weekly dosing schedule of peginterferon alfa-2a compared with the peaks and troughs associated with thrice weekly dosing of interferon alfa-2b. These results are also consistent with the lower rates of influenza-like symptoms and depression seen with peginterferon alfa-2a plus ribavirin vs. interferon alfa-2b plusribavirin.
In particular, peginterferon alfa-2a plus ribavirin therapy was associated with significantly less bodily pain, more energy, less disabling fatigue, and fewer limitations in social functioning during 48 weeks of treatment, compared withconventional interferon alfa-2b plus ribavirin in patients with chronic hepatitis C. These HRQOL advantages of peginterferon alfa-2a plus ribavirin in comparison with interferon alfa-2b plus ribavirin were seen as early as thefirst post-baseline visit and maintained throughout therapy. This early difference could impact patients' compliance especially during the first 12 weeks of therapy.
The results of this study also confirm previous research that found an association between SVR and improved HRQOL. These confirmatory findings support the conclusion that reductions in HRQOL produced byHCV can be overcome with successful treatment.
Specific effects of interferon and ribavirin on HRQOL
The inclusion of peginterferon alfa-2a plus placebo and peginterferon alfa-2a plus ribavirin therapy arms enabled us to describe the individual components of the combination therapy (interferon and ribavirin) on HRQOL. This type ofinformation may be useful to physicians in understanding the likely source of patients' specific complaints about limited activities, fatigue, or other HRQOL problems. For example, the worsening of bodily pain associated withtherapy seems to be due primarily to the interferon rather than the ribavirin and is substantially worse with conventional interferon than with peginterferon alfa-2a. Impairment of physical functioning (such as difficulty with running, lifting, or other physical activities) is partly attributable to interferon but is substantially exacerbated by ribavirin, as is the case with limitations in role function such as work related activities and problems due to fatigue.
Limitations
In this study, patients were informed of their HCV RNA status at intervals during the trial. Such knowledge may have potentially influenced HRQOL scores. However, the first PCR result that patients and physicians were aware of, was after week 12, yet significant differences between treatments in some of the HRQOL scores were detected at weeks 2 and 12. As with all clinical trials, caution should be exercised in generalizing the results of this study to the overall population of patients with chronic hepatitis C, asenrolled patients were required to meet certain inclusion andexclusion criteria.
Conclusion
Previous studies in patients with chronic hepatitis C have demonstrated that interferon therapy has a negative effect on HRQOL, as measured by the SF-36 during the initial 12--24 weeks of treatment. Although patient functioning and well-being eventually return to pre-treatment levels at the end of therapy, the worsening HRQOL while on treatment may negatively influence compliance and ultimately contribute to an unfavorable clinical outcome. When choosing optimal therapy for patients with chronic hepatitis C, health-related quality of life issues should be considered in conjunction with safety and efficacy concerns.
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