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Minimal impact of sofosbuvir and ribavirin on health related quality of life in Chronic Hepatitis C (CH-C)
Research Article
Minimal impact of sofosbuvir and ribavirin on health related quality of life in Chronic Hepatitis C (CH-C) Zobair M. Younossi1,2,⇑, Maria Stepanova1,2, Linda Henry2, Edward Gane3, Ira M. Jacobson4, Eric Lawitz5, David Nelson6, Fatema Nader1, Sharon Hunt1,2 1
Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA; 2Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA; 3Auckland City Hospital, Auckland, New Zealand; 4Weill Cornell Medical College, New York, NY, USA; 5Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA; 6University of Florida, Gainesville, FL, USA
Background & Aims: Treatment for CH-C contains interferon with substantial associated side effects and health-related quality of life (HRQL) impairment. Currently, there is no published data assessing the impact of interferon-free regimens on HRQL. The aim is to report the HRQL of patients who participated in clinical trials of sofosbuvir (SOF) for CH-C. Methods: CH-C patients were treated with sofosbuvir (SOF), pegylated interferon (PegIFN), ribavirin (RBV), or placebo in different combinations and duration (POSITRON, FISSION, FUSION, and NEUTRINO phase III trials). HRQL was assessed using SF-36 at baseline, during treatment, at the end of treatment, and at follow-up, and compared between treatment arms. Results: HRQL scores decreased over the course of treatment for all treatment arms in all studies; however, patients returned to their baseline score by the end of follow-up. Compared to placebo, SOF and RBV was not associated with HRQL impairment (POSITRON). Compared to SOF and RBV, HRQL was significantly more impaired in the PegIFN and RBV arm (FISSION). For those treated with SOF and RBV, there was no difference in HRQL between 12 weeks or 16 weeks of treatment (FUSION). Multivariate analysis demonstrated that depression, fatigue, and insomnia were important predictors of patients’ HRQL prior, during or after treatment. Additionally, anemia and receiving interferon were predictors of HRQL impairment during treatment. Achieving sustained virologic response after 12 weeks of follow-up (SVR-12) with SOF and RBV was associated with improvement in HRQL scores from baseline. Conclusions: Treatment-related HRQL impairment during SOF and RBV regimen is mild, and does not increase with longer treatment duration. Achieving SVR-12 with SOF and RBV is associated with an improvement in HRQL.
Keywords: Quality of life; Clinical trials; Hepatitis C. Received 17 September 2013; received in revised form 29 November 2013; accepted 4 December 2013; available online 11 December 2013 ⇑ Corresponding author. Address: Betty and Guy Beatty Center for Integrated Research, Claude Moore Health Education and Research Building, 3300 Gallows Road, Falls Church, VA 22042, USA. Tel.: +1 703 776 2540; fax: +1 703 776 4386. E-mail address: [email protected] (Z.M. Younossi).
Ó 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction Patient-reported outcomes (PROs), including health-related quality of life (HRQL), have become increasingly important to assess the total impact of a chronic disease or an intervention on patients’ health and well-being. PROs are considered the gold standard to estimate patients’ experiences with their disease and treatment. Finally, the healthcare consumers, whether patients or payers or policy makers are increasingly interested in how medical intervention impacts PROs such as patient’s HRQL [1–5]. Health-related quality of life is especially important for patients with chronic hepatitis C, who suffer from a variety of symptoms such as fatigue with profound negative impact on their well-being. In addition to disease-related PRO burden, hepatitis C treatment with interferon-containing regimens have been shown to severely exaggerate this HRQL impairment, leading to negative patient experiences and lower adherence to the treatment regimen [6]. Given the expected wave of HCV-related complications and the associated economic burden over the next two decades, better treatment regimens with higher efficacy and better tolerability are on the horizon [7–11]. Highly effective and better tolerated treatment coupled with more effective strategies to screen patients for HCV, may result in identifying and more effectively treating patients who currently suffer from chronic hepatitis C infection. This could potentially change the projected future trajectory of HCV disease and could hopefully lighten its tremendous economic burden [4–8]. In an attempt to develop anti-HCV therapy with higher efficacy, shorter duration and better tolerability, a number of interferon-free regimens are being developed. One such regimen contains a new Direct Anti-viral Agent (DAA), Sofosbuvir (SOF). The efficacy and safety of SOF in patients with chronic hepatitis C were assessed in 4 phase III clinical trials (FISSION, POSITRON, NEUTRINO, and FUSION) [12,13]. The purpose of the present study is to report the impact of these treatment regimens on the study subjects’ health-related quality of life.
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Research Article Patients and methods Patients Patients were included from 4 phase III clinical trials with Sofosbuvir containing regimens: POSITRON (sofosbuvir + ribavirin vs. placebo for 12 weeks), FISSION (sofosbuvir + ribavirin for 12 weeks vs. pegylated interferon + ribavirin for 24 weeks), FUSION (sofosbuvir + ribavirin for 12 vs. 16 weeks) and NEUTRINO (sofosbuvir + ribavirin + pegylated interferon for 12 weeks). The study design for each clinical trial is previously published [12,13]. For the purpose of this study, medical history collected at the time of screening and enrollment provided the clinical data such as a history of depression, fatigue, anxiety, and insomnia. Other clinical and laboratory data were collected during and after treatment as delineated in the Supplementary data [12,13]. For all four studies, Short Form-36 version 2 (SF-36v2) was administered at each study time point to all subjects in patients’ native language. The questionnaire was self-administered by patients in the clinic room prior to initiation of any other study-related activities. To eliminate a possible effect on perceived quality of life, both patients and site staff were blinded to patient’s HCV RNA level measured at the time of each visit. In all studies, SF-36 was administered at baseline and different study time points [FISSION: baseline, week 12, week 24, and week 36, POSITRON: baseline, week 12, and week 16, FUSION: baseline, weeks 4, 12, 16, 20, 24, 28, and 40 (only those with SVR at week 20 were followed-up at subsequent visits) and NEUTRINO: baseline, weeks 12, 16, and 24]. The SF-36 questionnaire includes 8 scores measured on a scale 0–100 with a 100 indicating the best possible health status: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). The two summary scores, namely, Physical Component Summary score (PCS) and Mental Component Summary score (MCS) summarize the physical and mental health components of SF-36. The summary scores were calculated using the individual scores linearly transformed using the population norms to the mean of 50 and a standard deviation of 10. The minimal clinically important difference (MCID) for each of the eight individual scores and he two summary scores (MCS and PCS) have been previously published [14,16]. Statistical analysis In each study, successfully screened patients were randomized into treatment or control. Clinico-demographic parameters as well as all HRQL scales and summary scores were compared between the arms at all applicable time points using Pearson’s Chi-square test for independence or Wilcoxon non-parametric test. Furthermore, the decrements in HRQL with reference to the baseline time point were calculated for each patient at each time point, and Wilcoxon tests were applied to compare them to zero (sign rank) and between the study arms (rank sum). Independent predictors of HRQL summary scores and decrements in those were assessed using multiple linear regression with the arm of the study being used as one of potential predictors of HRQL. Other potential HRQL predictors were age, gender, ethnicity, BMI, location, baseline hemoglobin (at day 1) or treatmentrelated anemia (after the start of treatment), recent history of psychiatric disorders, baseline HCV viral load, ALT, and presence of liver cirrhosis. At the last day of treatment and at all follow-up time points, achieving SVR was also included in the models as a potential predictor of HRQL. Each study was separately approved by each site’s Institutional Review Boards.
Results Health related quality of life from the POSITRON study For the POSITRON study, a total of 278 patients with HCV genotype 2 and 3 were randomized to receive SOF and RBV (target arm, N = 207) or the placebo (controls, N = 71). Of the study cohort, 16% had cirrhosis. The demographic and clinical parameters of the study cohort are given in Supplementary Table 1. No difference at baseline was observed for all studied parameters between the study arms (all p >0.05). The efficacy and safety of POSITRON has been previously published [13]. 742
The first analysis was to compare the summary scores and scales scores of SF-36 between the two arms (SOF + RBV vs. placebo). When the two arms of the study were compared directly, no differences in MCS and PCS scores were observed at all-time points (Table 1A and Fig. 1A, Supplementary Table 1). Considering SF-36 scales separately, only the decrement of 13.86 in the SF scale was found to be significantly higher in the SOF and RBV arm when compared to the placebo arm (p = 0.0104). After 4 weeks of follow-up, no significant decrement in any aspect of HRQL was observed between the two study arms (all p >0.1). The second round of analysis compared HRQL scores of patients in each arm of the study to their own baseline scores. When compared to their own respective baseline scores, HRQL decrements were observed in those receiving SOF + RBV treatment: a decrement of 1.54 for PCS (p = 0.0145) and 5.58 for MCS (p <0.0001). No similar decrements were observed for the placebo group (Table 1A). Considering different SF-36 scales separately, treatment-related decrements in SOF + RBV treated group were observed for PF (a decrement of 7.95), RE (11.95), SF (13.86), MH (8.21), VT (10.31), and PR (7.43), while in the placebo group, only a decrement in VT (5.47) was significant at the last day of treatment (all p <0.05) (Supplementary Table 1). All these decrements in all aspects of HRQL disappeared after follow-up (all p >0.05) (Table 1A and Fig. 1A; Supplementary Table 1 for the individual scales). In multivariate analysis (Supplementary Fig. 1), depression was found to be a major predictor of lower HRQL at all-time points. Additionally, fatigue was associated with lower PCS and insomnia was associated with lower MCS at certain time points. Treatment-related anemia was another independent predictor of physical health, which persisted until week 4 of follow-up. Finally, we noted that insomnia is another major predictor of larger decrement in HRQL during treatment: beta = +4.12 ± 1.84 (p = 0.0268) for MCS, +12.08 ± 5.18 (p = 0.0209) for RE, +6.67 ± 3.04 (p = 0.0311) for MH. At the same time, depression was found to be associated with larger decrement in RE only: beta = +9.67 ± 4.41 (p = 0.0295). Health related quality of life from the FISSION study For the FISSION study, 215 treatment-naive patients with HCV genotype 2 or 3 were randomized to receive either 12 weeks of sofosbuvir and ribavirin (N = 105) or the standard of care which, at the time of the trial, was 24 weeks of pegylated interferon and ribavirin (N = 110). A total of 21% of the study participants had cirrhosis. The demographics of the study cohort are given in Supplementary Table 2. No difference in any clinical or demographic parameters between the two study arms was observed [12]. Similar proportions of patients developed anemia during treatment, and similar SVR-12 rates were observed in the two treatment arms of the study (Supplementary Table 2). Compared to POSITRON, the baseline HRQL scores in FISSION were significantly higher for most of the scales: +3.6 in PF (p = 0.0079), +6.9 in RP (p = 0.0050), +6.5 in BP (p = 0.0106), +4.1 in GH (p = 0.0719), +6.4 in VT (p = 0.0038), +3.5 in SF (p = 0.0615), +6.5 in RE (p = 0.0036). +3.8 in MH (p = 0.0247), and +1.9 in PCS (p = 0.0108), +2.3 in MCS (p = 0.0243). This most likely reflects the nature of the POSITRON study cohort, which included interferon-ineligible and -intolerant subjects with higher baseline co-morbidities such as depression (41.1% in POSITRON vs. 20.9% in FISSION, p <0.0001).
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JOURNAL OF HEPATOLOGY Table 1. Clinico-demographic and HRQL parameters from the POSITRON study (sofosbuvir + ribavirin vs. placebo).
Physical summary scale (PCS)
A
Positron (12 wk of SOF + RBV vs. placebo) SOF + RBV (n = 207) Baseline 48.17 ± 8.50 Last day of treatment 46.91 ± 9.49 Decrement after treatment 1.54 ± 7.22* Wk 4 follow-up 47.85 ± 10.03 Decrement at 4 wk post-treatment 0.78 ± 7.01
Placebo (n = 71) 46.31 ± 9.68 46.56 ± 9.39 0.59 ± 6.47 47.23 ± 9.17 -0.06 ± 7.14**
B
Fission (12 wk of SOF + RBV vs. 24 wk of IFN + RBV) SOF + RBV IFN + RBV (n = 105) (n = 110) Baseline 48.78 ± 9.28 50.37 ± 9.69 Last day of treatment 49.10 ± 10.48 45.70 ± 9.75 Decrement after treatment -0.43 ± 8.35** 4.03 ± 8.71* Wk 12 follow-up 49.28 ± 9.64 50.45 ± 8.88 Decrement at 12 wk post-treatment -1.88 ± 7.95** 0.03 ± 7.02
C
Fusion (SOF + RBV for 12 vs. 16 wk) 16 weeks (n = 98) Baseline 48.51 ± 9.08 Last day of treatment 48.19 ± 8.59 Decrement after treatment 0.09 ± 6.58 Wk 12 follow-up 50.13 ± 8.54 Decrement at 12 wk post-treatment -2.48 ± 6.37*/**
12 weeks (n = 103) 49.23 ± 9.47 47.61 ± 9.95 1.30 ± 6.81 50.37 ± 9.38 -1.51 ± 6.44**
D Neutrino (12 wk of SOF + RBV + IFN) Baseline 50.72 ± 9.41 Last day of treatment 45.00 ± 9.44 Decrement after treatment 5.93 ± 9.05* Wk 12 follow-up 51.10 ± 8.97 Decrement at 12 wk post-treatment -0.28 ± 7.33** ⁄
p value 0.32 0.85 0.75 0.54 0.78 p value 0.16 0.0125 0.0007 0.56 0.17 p value 0.46 0.97 0.24 0.57 0.49
Mental summary scale (MCS) SOF + RBV (n = 207) 48.45 ± 10.37 44.21 ± 11.58 5.58 ± 11.42* 47.33 ± 10.91 1.82 ± 10.81
Placebo (n = 71) 45.83 ± 11.93 44.74 ± 12.61 1.81 ± 8.44 45.07 ± 11.30 2.25 ± 9.70
p value
SOF + RBV (n = 105) 50.28 ± 10.22 47.56 ± 11.84 3.41 ± 10.47* 49.78 ± 10.18 0.65 ± 9.24
IFN + RBV (n = 110) 49.97 ± 9.79 43.07 ± 11.93 7.37 ± 11.68* 48.42 ± 11.44 1.67 ± 9.05
p value
16 weeks (n = 98) 51.13 ± 9.33 47.91 ± 11.42 3.45 ± 9.13* 48.99 ± 11.73 0.33 ± 9.35
12 weeks (n = 103) 49.56 ± 10.52 45.66 ± 11.57 3.69 ± 10.80* 51.04 ± 10.58 0.66 ± 8.22
p value
0.20 0.70 0.09 0.17 0.47
0.68 0.0120 0.0123 0.52 0.41
0.43 0.09 0.52 0.42 0.57
51.31 ± 9.59 44.69 ± 11.198 6.33 ± 9.70* 51.94 ± 9.65 -0.82 ± 9.43**
p <0.05 for the decrement. Negative decrement indicates improvement in HRQL.
⁄⁄
The two arms of the study for patients included in FISSION were compared. This analysis shows that the baseline HRQL scores were similar between the two arms of the study (Table 1B and Fig. 1B). However, at the last day of treatment (week 12 for the SOF and RBV arm and week 24 for the PegIFN and RBV arm) both physical and mental summary scores of SF-36 were profoundly lower in patients who had received interferon. Considering each scale of SF-36 separately, PegIFN containing regimen was associated with significantly lower HRQL scores for GH, VT, SF, RE, and RP (all p values <0.05). Furthermore a trend in lower scores was noted for PF, BP, and MH (all p = 0.08) (Supplementary Table 2). When compared to their own baseline scores, profound decrements in HRQL were noted for both PCS and MCS in the PegIFN and RBV arm (both p <0.05), but only a modest decrement in the MCS score was noted for the SOF and RBV arm (Table 1B). In fact, this decrement in MCS associated with SOF + RBV was significantly smaller when compared to interferon containing regimen (p <0.05) (Table 1B). Considering SF-36 scales separately,
RP, GH, VT, SF, and RE were all significantly lower in the interferon-containing arm at the last day of treatment (Supplementary Table 2). Furthermore, significantly higher decrements in HRQL in the interferon-containing arm was noted as compared to SOF and RBV at the last day of treatment for RP (21.71 ± 31.55 vs. 6.05 ± 29.64), BP (10.61 ± 22.92 vs. 1.59 ± 23.70), GH (5.85 ± 19.10 vs. 3.83 ± 16.31), VT (18.78 ± 24.05 vs. 5.13 ± 24.14), and SF (20.83 ± 30.14 vs. 6.10 ± 26.28) (all p <0.01). Nevertheless, after 12 weeks of follow up, the decrement from baseline in both arms of the study recovered and were no longer significant (p >0.05) (Table 1B and Fig. 1B). In multivariate analysis, similarly to the previous study, depression, insomnia, and fatigue were all associated with lower HRQL scores before, during, and after treatment (Supplementary Fig. 2). Furthermore, during treatment, anemia was associated with mental health impairment. Additionally, during treatment, receiving PegIFN was an independent predictor of both physical and mental health impairment. Specifically, after adjustment
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Fig. 1. Changes in HRQL. (A) Participants of POSITRON, (B) FISSION, (C) FUSION, and (D) NEUTRINO during the study period (baseline, after 12 or 24 weeks of treatment and after 12 or 24 weeks of follow-up). PCS, physical component summary; MCS, mental component summary.
for demographic and clinical confounders, the SOF and RBV arm was associated with 4.24 ± 1.56 higher PCS and 5.36 ± 1.78 higher MCS (both p <0.01) compared to interferon containing regimen (Supplementary Fig. 2).
Health related quality of life from the FUSION study In the FUSION study, 201 treatment-experienced subjects with HCV genotype 2 and 3 were randomized to receive either 12 weeks or 16 weeks of SOF and RBV treatment. For those receiving the 12 week duration, it was followed by 4 weeks of double-blinded placebo, so, for both study arms, the 16 week time point was considered the last day of treatment. The clinical and demographic data for the patients enrolled for this study are depicted in Supplementary Table 3. Of the study participants, 34% had cirrhosis. No difference between the two study arms was found at baseline or during treatment [13]. In this study, HRQL scores were not different between those receiving 12 weeks and those receiving 16 weeks of treatment (Table 1C, Fig. 1C, and Supplementary Table 3 for individual scales). For both arms of the study, mild decrements in MCS were observed over the entire course of treatment regardless of treatment duration, but these decrements vanished after the last day of treatment, also regardless of the treatment arm. In multivariate analysis, similarly to previously described studies, depression, fatigue, and anxiety were the major predictors of HRQL (Supplementary Fig. 3). Again during treatment, anemia predicted physical health impairment. As noted previously, the important finding of this study was the fact that longer duration of treatment regimen (16 weeks) was not associated with HRQL impairment during or after treatment (Supplementary Fig. 3). 744
Health related quality of life from the NEUTRINO study In the NEUTRINO study, treatment-naive genotype 1/4/5/6 patients were receiving 12 weeks of combined triple therapy. The clinico-demographic profile of the cohort is depicted in Supplementary Table 4. Of the study participants, 17% had cirrhosis. The study’s safety and efficacy protocol is published [12]. By the last day of treatment, patients experienced major decrements in HRQL in all SF-36 scales except for GH. The decrement in HRQL was noted as follows: 15.2 in PF compared to baseline, 24.3 in RP, 13.4 in BP, 3.9 in GH, 19.9 in VT, 20.5 in SF, 14.6 in RE, 8.9 in MH, and 5.9 in PCS, 6.3 in MCS (all p <0.0001). In general, at the end of 12 weeks of follow-up, all SF-36 scale scores returned to their baseline levels (all p <0.05) (Fig. 1D and Table 1D, Supplementary Table 4 for individual scales). In multivariate analysis (Supplementary Fig. 4), predictors of lower HRQL were similar to all previously described studies and included anxiety, depression, fatigue, and female gender. Furthermore, at baseline, low HCV viral load (<6 106) and higher hemoglobin were found to be associated with better PCS, while older age was associated with lower PCS. In order to compare the impact of adding SOF to PegIFN and RBV, we compared NEUTRINO to the PegIFN + RBV arm of FISSION. In fact, both double combination and triple combination containing PegIFN + RBV have rapid and profound decline in SF-36 summary scales. Nevertheless, the decline in HRQL scores were similar suggesting that the addition of SOF did not add to the HRQL burden of PegIFN + RBV (Fig. 2). HRQL in patients who achieved SVR-12 To evaluate the change in HRQL associated with SVR-12, we studied those who eventually achieved SVR-12 after each treatment
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JOURNAL OF HEPATOLOGY
Discussion This study sought to determine the impact of oral, interferon-free hepatitis C treatment on patients’ health related quality of life using the data from 4 recent phase 3 clinical trials of sofosbuvir. The studies included different combinations of drugs, various treatment durations as well as different control strategies. First, the HRQL analysis of the FISSION study showed that patients’ HRQL is significantly less impacted when treated with an oral interferon-free than an interferon-based therapy.
PCS: IFN + RBV 24 wk PCS: IFN + RBV 12 wk U.S. population MCS: IFN + RBV 24 wk MCS: IFN + RBV 12 wk
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55
50
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PCS: p = n.s. MCS: p = n.s.
45
PCS: p = n.s. MCS: p = 0.0115
40 First day of treatment Last day of treatment
F/U wk 12
Fig. 2. HRQL in interferon-based regimens: SOF-free (IFN arm of FISSION) vs. SOF-containing (NEUTRINO). In both regimens, decrements from baseline in both PCS and MCS were significant at the last day of treatment (all p <0.05), and not significant at the end of follow-up (all p >0.05). PCS, physical component summary; MCS, mental component summary; IFN, PegIFN; n.s., not significant. p values indicate the difference between the treatment regimens.
PF BP GH VT MH PCS
8 * 6 HRQL scale
regimen separately (the SVR-12 rates were 77.8% in POSITRON, 66.5% in FISSION, 61.0% in FUSION, 90.0% in NEUTRINO). For subjects with SVR-12, we evaluated their HRQL after the last day of treatment and compared that to subjects who did not achieve an SVR-12 where applicable. In POSITRON, which included interferon-ineligible, unwilling and intolerant subjects with or without treatment history, the decrements in HRQL by the last day of treatment were similar between those who did and did not achieve SVR-12 (all p >0.05). At week 4 of follow-up, in both SVR-12 and nonSVR-12 subjects, no HRQL decrement was found when compared to the baseline while significant improvement was detected for the SF scale (+7.1, p = 0.0076) in the SVR-12 group only. In the SOF + RBV treatment arm of FISSION, which included treatment-naive subjects only, by week 12 of follow-up, significant improvements in BP (on average, +5.6 higher compared to the baseline) and GH (+6.7) (all p <0.05 for non-zero location) as well as a borderline improvement in PCS (+2.0, p = 0.0604) were observed in the SVR-12 (Figs. 3 and 4A) but not in the non-SVR-12 group (1.1, +0.8, and +1.4, respectively, all p >0.1). Furthermore, at week 12 of follow-up, a significant decrement from the baseline MH was observed in non-SVR-12 subjects (10.3, p = 0.0361) with no similar decrement among those who achieved SVR-12 (+0.05, p = 0.67). By the week 24, improvement in GH in the SVR group remained significant: +6.3 to the baseline (p = 0.0006). In contrast, in the PegIFN arm of FISSION, among those who achieved SVR-12, no improvement in HRQL was observed by week 12 of follow-up, and all their HRQL scales were not different from those who failed to achieve SVR-12 (Fig. 4B). In the FUSION study where only treatment-experienced subjects were enrolled, at week 4 post-treatment, all HRQL scales were not different from subjects’ own baseline regardless of their SVR-12 status. By week 8 of follow-up, those with SVR-12 showed improvements in VT (+4.0, p = 0.0168), and PCS (+1.6, p = 0.0116) aspects of their quality of life with a tendency to show some improvement in BP (+4.3, p = 0.0796). This improvement in HRQL in patients with sustained viral eradication continued, and by follow-up week 12 improvements in HRQL among SVR-12 patients were much more profound: +3.7 in PF (p = 0.0462), +3.6 in RP (p = 0.0551), +5.5 in BP (p = 0.0069), +5.2 in VT (p = 0.0004) and +2.1 in PCS (p = 0.0017) (Fig. 3). Finally, in the NEUTRINO study, at the end of follow-up at week 12, those who achieved SVR-12 showed significant improvements in comparison to their own baseline level in GH and VT: +2.5 (p = 0.0082) and +4.8 (p <0.0001), respectively. Improvement in the MH was also significant in those with SVR12: +2.1 (p = 0.0244) (Fig. 3). Of those who failed to achieve SVR-12, no meaningful improvement was observed (all p >0.1).
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Fig. 3. Improvements in HRQL by week 12 post-treatment in patients with SVR-12. ⁄p <0.05 when compared to patients’ own baseline level. PF, physical functioning; BP, bodily pain; GH, general health; VT, vitality; MH, mental health; PCS, physical component summary; IFN, PegIFN.
Although there was a mild decline in HRQL with SOF + RBV, the extent of this decline was substantially higher for those receiving PegIFN and RBV. These data support the better tolerability of SOF + RBV when compared to the current standard regimen, which is expected to result in better adherence to treatment and potentially better effectiveness of this regimen in the clinical practice setting. Our analysis from POSITRON again provides evidence that patients treated with oral anti-HCV regimen (SOF + RBV) had a very mild decline in their mental health component during treatment. Of the SF-36 scales, we found that the treated group had mild declines in score in 6 out of the 8 subscales of SF-36 with social functioning being the most affected. We suspect that a major component of this decrement is related to RBV-associated anemia and other related side effects. It was interesting to note that comparing SOF + RBV to placebo at any time point during treatment, HRQL scores were not significantly different between the two arms of the study. This indicated that SOF + RBV do not seem to add a tremendous burden on patients’ HRQL. Furthermore, the mild decrements in HRQL related to SOF + RBV were reversed at 4 weeks after stopping treatment, consistent with
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GH
Fig. 4. HRQL in patients achieving SVR-12. (A) After SOF + RBV and (B) IFN + RBV therapy. PF, physical functioning; PR, role physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role emotional; MH, mental health; n.s., not significant.
the time it takes hemoglobin levels to return to baseline levels after stopping ribavirin. It was also interesting to note that our multivariate analysis indicated that receiving placebo was, in fact, associated with lower PCS during treatment. This data suggested that active treatment may have possibly improved physical health by suppressing the virus. Based on these findings, we hypothesize that in future, with development of IFN-free, RBV-free, all-oral antiHCV therapy, patients may experience improvement of their HRQL early after the initiation of treatment. Nevertheless, future clinical trials of new anti-HCV regimens should assessment of HRQL and other patient-reported outcomes (PROs) as their secondary endpoints. When reviewing the results from the FUSION study, our analyses confirmed that regardless of the duration of SOF + RBV, patients do experience a moderate decrement in their MCS, which disappeared after treatment ended. Nevertheless, the results clearly show that the addition of 4 weeks to the treatment regimen (12 weeks vs. 16 weeks) did not substantially add to the quality of life burden of these patients at the last day of treatment or soon thereafter. The results of the NEUTRINO study confirm that patients receiving the IFN-based regimen experienced a major decrement in HRQL during treatment. Nevertheless, addition of SOF to PegIFN and RBV does not seem to worsen patients’ HRQL (comparison with the PegIFN and RBV arm of the FISSION study). Moreover, we believe that SOF-IFN-RBV triple combination regimen’s substantially shorter duration of treatment (12 weeks vs. 24 weeks of treatment for HCV genotype 1) may lead to an improved total HRQL burden [12]. Nevertheless, it is important to note that absence of a control arm in NEUTRINO does not allow to make definite conclusions about the effect of adding SOF to PegIFN and RBV. Despite this shortcoming, we believe this
746
shorter and highly effective regimen does provide HRQL benefit to patients with chronic hepatitis C. Our multivariate analyses provided further insights about potential drivers of HRQL impairment for patients with CH-C. Our study confirms that having depression, fatigue, or insomnia prior to the initiation of treatment are the major independent predictors of lower HRQL score at all time points, from baseline to the end of post-treatment follow-up. These findings are both not unexpected and consistent with what has been previously reported [15–21]. Specifically, fatigue and depression are common and important symptoms associated with the presence of CH-C infection, although they may be substantially exaggerated by the side effects of interferon and RBV containing regimens during anti-HCV treatment. On the other hand, both fatigue and depression are complex conditions that can arise from a variety of sources including insomnia, anemia, other drug side effects, as well as an individual’s medical history and poor nutritional status [17,18]. Furthermore, depression can be manifested as extreme fatigue – the inability to get things done due to being tired [19]. The impact of these aspects separately cannot be determined from this analysis and requires additional studies. Another interesting finding was the balance of treatmentrelated impairment in physical as opposed to mental well-being. In PegIFN and RBV regimens, PegIFN is usually presumed to be responsible for depression while RBV is known to cause anemia. In our study, we indeed see a proportion of subjects developing anemia, a common RBV-associated side effect. When transformed to the metrics of HRQL, one might expect more impairment in PCS than in MCS given the presence of the risk factor for anemia and absence of that for depression in IFN-free regiments. However, in all studies which included IFN-free regimens, by the last day of treatment, we saw smaller impairment in PCS than in MCS: an average decrement of 0–2 for PCS and 3–5 for MCS, depending on the study and the cohort. Given the proposed MCID for these parameters [14,16], this essentially means that, on average, physical well-being of the study participants undergoes at most a borderline decrement during treatment with sofosbuvir combined with ribavirin. However, there is still a more profound and clinically significant decrement in their mental well-being scores. The reasons for this are not completely clear and may include certain neuropsychiatric side effects of ribavirin which has been suspected [21]. Again, the future ribavirin-free regimens may potentially reduce this HRQL burden. Finally, we assessed the impact of cirrhosis and gender on HRQL before and during treatment. Our analysis did not show significant differences in HRQL between cirrhotics and noncirrhotics in the univariate or multivariate analyses. This finding is important to indicate that patients with early cirrhosis (advanced cirrhotics were excluded from these studies) could tolerate these regimens in a similar fashion to non-cirrhotics. Nevertheless, it is important to perform additional in-depth analyses exploring the impact of cirrhosis on patients’ HRQL. Another interesting finding of this study was the impact of gender on HRQL. Although male gender was associated with higher PCS scores (Supplementary Figs. 3 and 4), the decrements in PCS scores during treatment were not significantly different between males and females (2.1 ± 7.4 vs. 0.7 ± 6.6, p = 0.30, in FUSION; 6.6 ± 10.5 vs. 5.5 ± 8.1, p = 0.60, in NEUTRINO) suggesting that gender is unlikely an effect modifier for the case of sofosbuvir-based regimens.
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JOURNAL OF HEPATOLOGY This study has some limitations. The major shortcoming of this study is the lack of controls for those who achieved SVR after the last day of treatment, since in most studies the patients with detectable HCV RNA at week 4 post-treatment were not asked to come for subsequent visits as they were allowed to start re-treatment or enter a long-term follow-up study. As a result, we were limited in our ability to make conclusions about improvement of HRQL with SVR. Furthermore, because of multidimensionality of the studied HRQL metrics, multiple study cohorts and time points all resulted in multiple testing. However, many of the differences and associations reported in this study, as well as the lack of those, are observed consistently in different studies and also match with prior knowledge about the effect of anti-HCV treatment on HRQL. In summary, our study is the largest HRQL analysis from 4 large multi-national multi-center studies of interferon-free regimens to treat CH-C. Our data shows that treatment with sofosbuvir results in a moderate decrement in HRQL, which is substantially smaller than that for the interferon-containing regimens. Furthermore, longer duration of the interferon-free sofosbuvir-based regimen does not result in additional HRQL impairment while improving the chances of SVR. Overall, regardless of duration, interferon-free regimens are superior to interferon-based regimens in terms of HRQL, resulting in improved patients’ experience, potentially lower risks of treatment discontinuation, and lower overall burden of chronic HCV infection.
Conflict of interest Z.M.Y. is consultant to Gilead sciences and gives advice regarding study design and analysis related to clinical and outcomes research.
Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jhep.2013.12.006.
References [1] Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 1998;27:209–212. [2] Ware Jr JE, Bayliss MS, Mannocchia M, et al. Health-related quality of life in chronic hepatitis C: impact of disease and treatment response. The Interventional Therapy Group. Hepatology 1999;30:550–555. [3] Younossi Z, Kallman J, Kincaid J. The effects of HCV infection and management on health-related quality of life. Hepatology 2007;45:806–816.
[4] Davis GL, Balert LA, Schiff ER, et al. Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile. Clin Ther 1994;16:334–343. [5] Rodger AJ, Jolley D, Thompson SC, et al. The impact of diagnosis of hepatitis C virus on quality of life. Hepatology 1999;30:1299–1301. [6] Bernstein D, Kleinman L, Barker CM, et al. Relationship of health-related quality of life to treatment adherence and sustained response in chronic hepatitis C patients. Hepatology 2002;35:704–708. [7] El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012;142:1264–1273.e1. http://dx.doi.org/10.1053/ j.gastro.2011.12.061. [8] Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): costs of a baby boomer epidemic of liver disease. Available from: http:// publications.milliman.com/research/health-rr/pdfs/consequences-hepatitisc-virus-RR05-18-09.pdf [Last accessed on 17 July 2013]. [9] Hassanein T, Cooksley G, Sulkowski M, et al. The impact of peginterferon alfa-2a plus ribavirin combination therapy on health-related quality of life in chronic hepatitis C. J Hepatol 2004;40:675–681. [10] Rasenack J, Zeuzem S, Feinman SV, et al. Peginterferon alpha-2a (40kD) [Pegasys] improves HR-QOL outcomes compared with unmodified interferon alpha-2a [Roferon-A]: in patients with chronic hepatitis C. Pharmacoeconomics 2003;21:341–349. [11] Younossi ZM, Stepanova M, Afendy M, Lam BP, Mishra A. Knowledge about infection is the only predictor of treatment in patients with chronic hepatitis C. J Viral Hepat 2013;20:550–555. http://dx.doi.org/10.1111/jvh.12080, [Epub 2013 Mar 25]. [12] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878–1887. [13] Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;368:1867–1877. [14] Hays RD, Morales LS. The RAND-36 measure of health-related quality of life. Ann Med 2001;33:350–357. [15] Davis GL, Roberts WL. The healthcare burden imposed by liver disease in aging Baby Boomers. Curr Gastroenterol Rep 2010;12:1–6. http://dx.doi.org/ 10.1007/s11894-009-0087-2. [16] Spiegel BM, Younossi ZM, Hays RD, Revicki D, Robbins S, Kanwal F. Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment. Hepatology 2005;41:790–800. [17] Kallman J, O’Neil MM, Larive B, Boparai N, Calabrese L, Younossi ZM. Fatigue and health-related quality of life (HRQL) in chronic hepatitis C virus infection. Dig Dis Sci 2007;52:2531–2539, [Epub 2007 Apr 4]. [18] Manos MM, Ho CK, Murphy RC, Shvachko VA. Physical, social, and psychological consequences of treatment for hepatitis C: a communitybased evaluation of patient-reported outcomes. Patient 2013;6:23–34. http://dx.doi.org/10.1007/s40271-013-0005-4. [19] Tavakkoli M, Ferrando SJ, Rabkin J, Marks K, Talal AH. Depression and Fatigue in chronic hepatitis C patients with and without HIV co-infection. Psychosomatics 2013. http://dx.doi.org/10.1016/j.psym.2013.02.009, pii: S0033-3182(13)00047-9 [Epub ahead of print]. [20] Younossi ZM, Stepanova M, Henry L, Gane E, Jacobson IM, Lawitz E, et al. Sofosbuvir-based treatment, with and without interferon, on outcome and productivity of patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2013. pii: S1542-3565(13)01838-7. http://dx.doi.org/10.1016/j.cgh.2013.11.032 [Epub ahead of print]. [21] Schaefer M, Capuron L, Friebe A, Diez-Quevedo C, Robaeys G, Neri S, et al. Hepatitis C infection, antiviral treatment and mental health: a European expert consensus statement. J Hepatol 2012;57:1379–1390. http:// dx.doi.org/10.1016/j.jhep.2012.07.037, [Epub 2012 Aug 7].
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Minimal impact of sofosbuvir and ribavirin on health related quality of life in Chronic Hepatitis C (CH-C) Zobair M. Younossi1,2,⇑, Maria Stepanova1,2, Linda Henry2, Edward Gane3, Ira M. Jacobson4, Eric Lawitz5, David Nelson6, Fatema Nader1, Sharon Hunt1,2 1
Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA; 2Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA; 3Auckland City Hospital, Auckland, New Zealand; 4Weill Cornell Medical College, New York, NY, USA; 5Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA; 6University of Florida, Gainesville, FL, USA
Background & Aims: Treatment for CH-C contains interferon with substantial associated side effects and health-related quality of life (HRQL) impairment. Currently, there is no published data assessing the impact of interferon-free regimens on HRQL. The aim is to report the HRQL of patients who participated in clinical trials of sofosbuvir (SOF) for CH-C. Methods: CH-C patients were treated with sofosbuvir (SOF), pegylated interferon (PegIFN), ribavirin (RBV), or placebo in different combinations and duration (POSITRON, FISSION, FUSION, and NEUTRINO phase III trials). HRQL was assessed using SF-36 at baseline, during treatment, at the end of treatment, and at follow-up, and compared between treatment arms. Results: HRQL scores decreased over the course of treatment for all treatment arms in all studies; however, patients returned to their baseline score by the end of follow-up. Compared to placebo, SOF and RBV was not associated with HRQL impairment (POSITRON). Compared to SOF and RBV, HRQL was significantly more impaired in the PegIFN and RBV arm (FISSION). For those treated with SOF and RBV, there was no difference in HRQL between 12 weeks or 16 weeks of treatment (FUSION). Multivariate analysis demonstrated that depression, fatigue, and insomnia were important predictors of patients’ HRQL prior, during or after treatment. Additionally, anemia and receiving interferon were predictors of HRQL impairment during treatment. Achieving sustained virologic response after 12 weeks of follow-up (SVR-12) with SOF and RBV was associated with improvement in HRQL scores from baseline. Conclusions: Treatment-related HRQL impairment during SOF and RBV regimen is mild, and does not increase with longer treatment duration. Achieving SVR-12 with SOF and RBV is associated with an improvement in HRQL.
Keywords: Quality of life; Clinical trials; Hepatitis C. Received 17 September 2013; received in revised form 29 November 2013; accepted 4 December 2013; available online 11 December 2013 ⇑ Corresponding author. Address: Betty and Guy Beatty Center for Integrated Research, Claude Moore Health Education and Research Building, 3300 Gallows Road, Falls Church, VA 22042, USA. Tel.: +1 703 776 2540; fax: +1 703 776 4386. E-mail address: [email protected] (Z.M. Younossi).
Ó 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction Patient-reported outcomes (PROs), including health-related quality of life (HRQL), have become increasingly important to assess the total impact of a chronic disease or an intervention on patients’ health and well-being. PROs are considered the gold standard to estimate patients’ experiences with their disease and treatment. Finally, the healthcare consumers, whether patients or payers or policy makers are increasingly interested in how medical intervention impacts PROs such as patient’s HRQL [1–5]. Health-related quality of life is especially important for patients with chronic hepatitis C, who suffer from a variety of symptoms such as fatigue with profound negative impact on their well-being. In addition to disease-related PRO burden, hepatitis C treatment with interferon-containing regimens have been shown to severely exaggerate this HRQL impairment, leading to negative patient experiences and lower adherence to the treatment regimen [6]. Given the expected wave of HCV-related complications and the associated economic burden over the next two decades, better treatment regimens with higher efficacy and better tolerability are on the horizon [7–11]. Highly effective and better tolerated treatment coupled with more effective strategies to screen patients for HCV, may result in identifying and more effectively treating patients who currently suffer from chronic hepatitis C infection. This could potentially change the projected future trajectory of HCV disease and could hopefully lighten its tremendous economic burden [4–8]. In an attempt to develop anti-HCV therapy with higher efficacy, shorter duration and better tolerability, a number of interferon-free regimens are being developed. One such regimen contains a new Direct Anti-viral Agent (DAA), Sofosbuvir (SOF). The efficacy and safety of SOF in patients with chronic hepatitis C were assessed in 4 phase III clinical trials (FISSION, POSITRON, NEUTRINO, and FUSION) [12,13]. The purpose of the present study is to report the impact of these treatment regimens on the study subjects’ health-related quality of life.
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Research Article Patients and methods Patients Patients were included from 4 phase III clinical trials with Sofosbuvir containing regimens: POSITRON (sofosbuvir + ribavirin vs. placebo for 12 weeks), FISSION (sofosbuvir + ribavirin for 12 weeks vs. pegylated interferon + ribavirin for 24 weeks), FUSION (sofosbuvir + ribavirin for 12 vs. 16 weeks) and NEUTRINO (sofosbuvir + ribavirin + pegylated interferon for 12 weeks). The study design for each clinical trial is previously published [12,13]. For the purpose of this study, medical history collected at the time of screening and enrollment provided the clinical data such as a history of depression, fatigue, anxiety, and insomnia. Other clinical and laboratory data were collected during and after treatment as delineated in the Supplementary data [12,13]. For all four studies, Short Form-36 version 2 (SF-36v2) was administered at each study time point to all subjects in patients’ native language. The questionnaire was self-administered by patients in the clinic room prior to initiation of any other study-related activities. To eliminate a possible effect on perceived quality of life, both patients and site staff were blinded to patient’s HCV RNA level measured at the time of each visit. In all studies, SF-36 was administered at baseline and different study time points [FISSION: baseline, week 12, week 24, and week 36, POSITRON: baseline, week 12, and week 16, FUSION: baseline, weeks 4, 12, 16, 20, 24, 28, and 40 (only those with SVR at week 20 were followed-up at subsequent visits) and NEUTRINO: baseline, weeks 12, 16, and 24]. The SF-36 questionnaire includes 8 scores measured on a scale 0–100 with a 100 indicating the best possible health status: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). The two summary scores, namely, Physical Component Summary score (PCS) and Mental Component Summary score (MCS) summarize the physical and mental health components of SF-36. The summary scores were calculated using the individual scores linearly transformed using the population norms to the mean of 50 and a standard deviation of 10. The minimal clinically important difference (MCID) for each of the eight individual scores and he two summary scores (MCS and PCS) have been previously published [14,16]. Statistical analysis In each study, successfully screened patients were randomized into treatment or control. Clinico-demographic parameters as well as all HRQL scales and summary scores were compared between the arms at all applicable time points using Pearson’s Chi-square test for independence or Wilcoxon non-parametric test. Furthermore, the decrements in HRQL with reference to the baseline time point were calculated for each patient at each time point, and Wilcoxon tests were applied to compare them to zero (sign rank) and between the study arms (rank sum). Independent predictors of HRQL summary scores and decrements in those were assessed using multiple linear regression with the arm of the study being used as one of potential predictors of HRQL. Other potential HRQL predictors were age, gender, ethnicity, BMI, location, baseline hemoglobin (at day 1) or treatmentrelated anemia (after the start of treatment), recent history of psychiatric disorders, baseline HCV viral load, ALT, and presence of liver cirrhosis. At the last day of treatment and at all follow-up time points, achieving SVR was also included in the models as a potential predictor of HRQL. Each study was separately approved by each site’s Institutional Review Boards.
Results Health related quality of life from the POSITRON study For the POSITRON study, a total of 278 patients with HCV genotype 2 and 3 were randomized to receive SOF and RBV (target arm, N = 207) or the placebo (controls, N = 71). Of the study cohort, 16% had cirrhosis. The demographic and clinical parameters of the study cohort are given in Supplementary Table 1. No difference at baseline was observed for all studied parameters between the study arms (all p >0.05). The efficacy and safety of POSITRON has been previously published [13]. 742
The first analysis was to compare the summary scores and scales scores of SF-36 between the two arms (SOF + RBV vs. placebo). When the two arms of the study were compared directly, no differences in MCS and PCS scores were observed at all-time points (Table 1A and Fig. 1A, Supplementary Table 1). Considering SF-36 scales separately, only the decrement of 13.86 in the SF scale was found to be significantly higher in the SOF and RBV arm when compared to the placebo arm (p = 0.0104). After 4 weeks of follow-up, no significant decrement in any aspect of HRQL was observed between the two study arms (all p >0.1). The second round of analysis compared HRQL scores of patients in each arm of the study to their own baseline scores. When compared to their own respective baseline scores, HRQL decrements were observed in those receiving SOF + RBV treatment: a decrement of 1.54 for PCS (p = 0.0145) and 5.58 for MCS (p <0.0001). No similar decrements were observed for the placebo group (Table 1A). Considering different SF-36 scales separately, treatment-related decrements in SOF + RBV treated group were observed for PF (a decrement of 7.95), RE (11.95), SF (13.86), MH (8.21), VT (10.31), and PR (7.43), while in the placebo group, only a decrement in VT (5.47) was significant at the last day of treatment (all p <0.05) (Supplementary Table 1). All these decrements in all aspects of HRQL disappeared after follow-up (all p >0.05) (Table 1A and Fig. 1A; Supplementary Table 1 for the individual scales). In multivariate analysis (Supplementary Fig. 1), depression was found to be a major predictor of lower HRQL at all-time points. Additionally, fatigue was associated with lower PCS and insomnia was associated with lower MCS at certain time points. Treatment-related anemia was another independent predictor of physical health, which persisted until week 4 of follow-up. Finally, we noted that insomnia is another major predictor of larger decrement in HRQL during treatment: beta = +4.12 ± 1.84 (p = 0.0268) for MCS, +12.08 ± 5.18 (p = 0.0209) for RE, +6.67 ± 3.04 (p = 0.0311) for MH. At the same time, depression was found to be associated with larger decrement in RE only: beta = +9.67 ± 4.41 (p = 0.0295). Health related quality of life from the FISSION study For the FISSION study, 215 treatment-naive patients with HCV genotype 2 or 3 were randomized to receive either 12 weeks of sofosbuvir and ribavirin (N = 105) or the standard of care which, at the time of the trial, was 24 weeks of pegylated interferon and ribavirin (N = 110). A total of 21% of the study participants had cirrhosis. The demographics of the study cohort are given in Supplementary Table 2. No difference in any clinical or demographic parameters between the two study arms was observed [12]. Similar proportions of patients developed anemia during treatment, and similar SVR-12 rates were observed in the two treatment arms of the study (Supplementary Table 2). Compared to POSITRON, the baseline HRQL scores in FISSION were significantly higher for most of the scales: +3.6 in PF (p = 0.0079), +6.9 in RP (p = 0.0050), +6.5 in BP (p = 0.0106), +4.1 in GH (p = 0.0719), +6.4 in VT (p = 0.0038), +3.5 in SF (p = 0.0615), +6.5 in RE (p = 0.0036). +3.8 in MH (p = 0.0247), and +1.9 in PCS (p = 0.0108), +2.3 in MCS (p = 0.0243). This most likely reflects the nature of the POSITRON study cohort, which included interferon-ineligible and -intolerant subjects with higher baseline co-morbidities such as depression (41.1% in POSITRON vs. 20.9% in FISSION, p <0.0001).
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JOURNAL OF HEPATOLOGY Table 1. Clinico-demographic and HRQL parameters from the POSITRON study (sofosbuvir + ribavirin vs. placebo).
Physical summary scale (PCS)
A
Positron (12 wk of SOF + RBV vs. placebo) SOF + RBV (n = 207) Baseline 48.17 ± 8.50 Last day of treatment 46.91 ± 9.49 Decrement after treatment 1.54 ± 7.22* Wk 4 follow-up 47.85 ± 10.03 Decrement at 4 wk post-treatment 0.78 ± 7.01
Placebo (n = 71) 46.31 ± 9.68 46.56 ± 9.39 0.59 ± 6.47 47.23 ± 9.17 -0.06 ± 7.14**
B
Fission (12 wk of SOF + RBV vs. 24 wk of IFN + RBV) SOF + RBV IFN + RBV (n = 105) (n = 110) Baseline 48.78 ± 9.28 50.37 ± 9.69 Last day of treatment 49.10 ± 10.48 45.70 ± 9.75 Decrement after treatment -0.43 ± 8.35** 4.03 ± 8.71* Wk 12 follow-up 49.28 ± 9.64 50.45 ± 8.88 Decrement at 12 wk post-treatment -1.88 ± 7.95** 0.03 ± 7.02
C
Fusion (SOF + RBV for 12 vs. 16 wk) 16 weeks (n = 98) Baseline 48.51 ± 9.08 Last day of treatment 48.19 ± 8.59 Decrement after treatment 0.09 ± 6.58 Wk 12 follow-up 50.13 ± 8.54 Decrement at 12 wk post-treatment -2.48 ± 6.37*/**
12 weeks (n = 103) 49.23 ± 9.47 47.61 ± 9.95 1.30 ± 6.81 50.37 ± 9.38 -1.51 ± 6.44**
D Neutrino (12 wk of SOF + RBV + IFN) Baseline 50.72 ± 9.41 Last day of treatment 45.00 ± 9.44 Decrement after treatment 5.93 ± 9.05* Wk 12 follow-up 51.10 ± 8.97 Decrement at 12 wk post-treatment -0.28 ± 7.33** ⁄
p value 0.32 0.85 0.75 0.54 0.78 p value 0.16 0.0125 0.0007 0.56 0.17 p value 0.46 0.97 0.24 0.57 0.49
Mental summary scale (MCS) SOF + RBV (n = 207) 48.45 ± 10.37 44.21 ± 11.58 5.58 ± 11.42* 47.33 ± 10.91 1.82 ± 10.81
Placebo (n = 71) 45.83 ± 11.93 44.74 ± 12.61 1.81 ± 8.44 45.07 ± 11.30 2.25 ± 9.70
p value
SOF + RBV (n = 105) 50.28 ± 10.22 47.56 ± 11.84 3.41 ± 10.47* 49.78 ± 10.18 0.65 ± 9.24
IFN + RBV (n = 110) 49.97 ± 9.79 43.07 ± 11.93 7.37 ± 11.68* 48.42 ± 11.44 1.67 ± 9.05
p value
16 weeks (n = 98) 51.13 ± 9.33 47.91 ± 11.42 3.45 ± 9.13* 48.99 ± 11.73 0.33 ± 9.35
12 weeks (n = 103) 49.56 ± 10.52 45.66 ± 11.57 3.69 ± 10.80* 51.04 ± 10.58 0.66 ± 8.22
p value
0.20 0.70 0.09 0.17 0.47
0.68 0.0120 0.0123 0.52 0.41
0.43 0.09 0.52 0.42 0.57
51.31 ± 9.59 44.69 ± 11.198 6.33 ± 9.70* 51.94 ± 9.65 -0.82 ± 9.43**
p <0.05 for the decrement. Negative decrement indicates improvement in HRQL.
⁄⁄
The two arms of the study for patients included in FISSION were compared. This analysis shows that the baseline HRQL scores were similar between the two arms of the study (Table 1B and Fig. 1B). However, at the last day of treatment (week 12 for the SOF and RBV arm and week 24 for the PegIFN and RBV arm) both physical and mental summary scores of SF-36 were profoundly lower in patients who had received interferon. Considering each scale of SF-36 separately, PegIFN containing regimen was associated with significantly lower HRQL scores for GH, VT, SF, RE, and RP (all p values <0.05). Furthermore a trend in lower scores was noted for PF, BP, and MH (all p = 0.08) (Supplementary Table 2). When compared to their own baseline scores, profound decrements in HRQL were noted for both PCS and MCS in the PegIFN and RBV arm (both p <0.05), but only a modest decrement in the MCS score was noted for the SOF and RBV arm (Table 1B). In fact, this decrement in MCS associated with SOF + RBV was significantly smaller when compared to interferon containing regimen (p <0.05) (Table 1B). Considering SF-36 scales separately,
RP, GH, VT, SF, and RE were all significantly lower in the interferon-containing arm at the last day of treatment (Supplementary Table 2). Furthermore, significantly higher decrements in HRQL in the interferon-containing arm was noted as compared to SOF and RBV at the last day of treatment for RP (21.71 ± 31.55 vs. 6.05 ± 29.64), BP (10.61 ± 22.92 vs. 1.59 ± 23.70), GH (5.85 ± 19.10 vs. 3.83 ± 16.31), VT (18.78 ± 24.05 vs. 5.13 ± 24.14), and SF (20.83 ± 30.14 vs. 6.10 ± 26.28) (all p <0.01). Nevertheless, after 12 weeks of follow up, the decrement from baseline in both arms of the study recovered and were no longer significant (p >0.05) (Table 1B and Fig. 1B). In multivariate analysis, similarly to the previous study, depression, insomnia, and fatigue were all associated with lower HRQL scores before, during, and after treatment (Supplementary Fig. 2). Furthermore, during treatment, anemia was associated with mental health impairment. Additionally, during treatment, receiving PegIFN was an independent predictor of both physical and mental health impairment. Specifically, after adjustment
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54 50 p >0.05
p >0.05
p >0.05
46 42
C
4
8 Week
12
58
p >0.05
p >0.05 p >0.05
46 42 0
4
8
12 16 Week
20
24
28
PCS: Sofosbuvir PCS: Interferon MCS: Sofosbuvir MCS: Interferon
58 54
PCS: p = 0.0101 MCS: p = 0.0215
50 46
PCS: p = 0.0201 p >0.05 MCS: p = 0.0007
p >0.05
42 0
PCS: 16 wk PCS: 12 wk MCS: 16 wk MCS: 12 wk
50
Fission
16
Fusion
54
SF-36 summary scale
PCS: Sofosbuvir PCS: Placebo MCS: Sofosbuvir MCS: Placebo
58
0
SF-36 summary scale
B
Positron
D SF-36 summary scale
SF-36 summary scale
A
12
Week
24
36 PCS: SVR PCS: No SVR MCS: SVR MCS: No SVR
Neutrino 58 54
p >0.05
p >0.05
50
p >0.05
46 42 0
4
8
12 16 Week
20
24
28
Fig. 1. Changes in HRQL. (A) Participants of POSITRON, (B) FISSION, (C) FUSION, and (D) NEUTRINO during the study period (baseline, after 12 or 24 weeks of treatment and after 12 or 24 weeks of follow-up). PCS, physical component summary; MCS, mental component summary.
for demographic and clinical confounders, the SOF and RBV arm was associated with 4.24 ± 1.56 higher PCS and 5.36 ± 1.78 higher MCS (both p <0.01) compared to interferon containing regimen (Supplementary Fig. 2).
Health related quality of life from the FUSION study In the FUSION study, 201 treatment-experienced subjects with HCV genotype 2 and 3 were randomized to receive either 12 weeks or 16 weeks of SOF and RBV treatment. For those receiving the 12 week duration, it was followed by 4 weeks of double-blinded placebo, so, for both study arms, the 16 week time point was considered the last day of treatment. The clinical and demographic data for the patients enrolled for this study are depicted in Supplementary Table 3. Of the study participants, 34% had cirrhosis. No difference between the two study arms was found at baseline or during treatment [13]. In this study, HRQL scores were not different between those receiving 12 weeks and those receiving 16 weeks of treatment (Table 1C, Fig. 1C, and Supplementary Table 3 for individual scales). For both arms of the study, mild decrements in MCS were observed over the entire course of treatment regardless of treatment duration, but these decrements vanished after the last day of treatment, also regardless of the treatment arm. In multivariate analysis, similarly to previously described studies, depression, fatigue, and anxiety were the major predictors of HRQL (Supplementary Fig. 3). Again during treatment, anemia predicted physical health impairment. As noted previously, the important finding of this study was the fact that longer duration of treatment regimen (16 weeks) was not associated with HRQL impairment during or after treatment (Supplementary Fig. 3). 744
Health related quality of life from the NEUTRINO study In the NEUTRINO study, treatment-naive genotype 1/4/5/6 patients were receiving 12 weeks of combined triple therapy. The clinico-demographic profile of the cohort is depicted in Supplementary Table 4. Of the study participants, 17% had cirrhosis. The study’s safety and efficacy protocol is published [12]. By the last day of treatment, patients experienced major decrements in HRQL in all SF-36 scales except for GH. The decrement in HRQL was noted as follows: 15.2 in PF compared to baseline, 24.3 in RP, 13.4 in BP, 3.9 in GH, 19.9 in VT, 20.5 in SF, 14.6 in RE, 8.9 in MH, and 5.9 in PCS, 6.3 in MCS (all p <0.0001). In general, at the end of 12 weeks of follow-up, all SF-36 scale scores returned to their baseline levels (all p <0.05) (Fig. 1D and Table 1D, Supplementary Table 4 for individual scales). In multivariate analysis (Supplementary Fig. 4), predictors of lower HRQL were similar to all previously described studies and included anxiety, depression, fatigue, and female gender. Furthermore, at baseline, low HCV viral load (<6 106) and higher hemoglobin were found to be associated with better PCS, while older age was associated with lower PCS. In order to compare the impact of adding SOF to PegIFN and RBV, we compared NEUTRINO to the PegIFN + RBV arm of FISSION. In fact, both double combination and triple combination containing PegIFN + RBV have rapid and profound decline in SF-36 summary scales. Nevertheless, the decline in HRQL scores were similar suggesting that the addition of SOF did not add to the HRQL burden of PegIFN + RBV (Fig. 2). HRQL in patients who achieved SVR-12 To evaluate the change in HRQL associated with SVR-12, we studied those who eventually achieved SVR-12 after each treatment
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Discussion This study sought to determine the impact of oral, interferon-free hepatitis C treatment on patients’ health related quality of life using the data from 4 recent phase 3 clinical trials of sofosbuvir. The studies included different combinations of drugs, various treatment durations as well as different control strategies. First, the HRQL analysis of the FISSION study showed that patients’ HRQL is significantly less impacted when treated with an oral interferon-free than an interferon-based therapy.
PCS: IFN + RBV 24 wk PCS: IFN + RBV 12 wk U.S. population MCS: IFN + RBV 24 wk MCS: IFN + RBV 12 wk
SF-36 scale
55
50
PCS: p = n.s. MCS: p = n.s.
PCS: p = n.s. MCS: p = n.s.
45
PCS: p = n.s. MCS: p = 0.0115
40 First day of treatment Last day of treatment
F/U wk 12
Fig. 2. HRQL in interferon-based regimens: SOF-free (IFN arm of FISSION) vs. SOF-containing (NEUTRINO). In both regimens, decrements from baseline in both PCS and MCS were significant at the last day of treatment (all p <0.05), and not significant at the end of follow-up (all p >0.05). PCS, physical component summary; MCS, mental component summary; IFN, PegIFN; n.s., not significant. p values indicate the difference between the treatment regimens.
PF BP GH VT MH PCS
8 * 6 HRQL scale
regimen separately (the SVR-12 rates were 77.8% in POSITRON, 66.5% in FISSION, 61.0% in FUSION, 90.0% in NEUTRINO). For subjects with SVR-12, we evaluated their HRQL after the last day of treatment and compared that to subjects who did not achieve an SVR-12 where applicable. In POSITRON, which included interferon-ineligible, unwilling and intolerant subjects with or without treatment history, the decrements in HRQL by the last day of treatment were similar between those who did and did not achieve SVR-12 (all p >0.05). At week 4 of follow-up, in both SVR-12 and nonSVR-12 subjects, no HRQL decrement was found when compared to the baseline while significant improvement was detected for the SF scale (+7.1, p = 0.0076) in the SVR-12 group only. In the SOF + RBV treatment arm of FISSION, which included treatment-naive subjects only, by week 12 of follow-up, significant improvements in BP (on average, +5.6 higher compared to the baseline) and GH (+6.7) (all p <0.05 for non-zero location) as well as a borderline improvement in PCS (+2.0, p = 0.0604) were observed in the SVR-12 (Figs. 3 and 4A) but not in the non-SVR-12 group (1.1, +0.8, and +1.4, respectively, all p >0.1). Furthermore, at week 12 of follow-up, a significant decrement from the baseline MH was observed in non-SVR-12 subjects (10.3, p = 0.0361) with no similar decrement among those who achieved SVR-12 (+0.05, p = 0.67). By the week 24, improvement in GH in the SVR group remained significant: +6.3 to the baseline (p = 0.0006). In contrast, in the PegIFN arm of FISSION, among those who achieved SVR-12, no improvement in HRQL was observed by week 12 of follow-up, and all their HRQL scales were not different from those who failed to achieve SVR-12 (Fig. 4B). In the FUSION study where only treatment-experienced subjects were enrolled, at week 4 post-treatment, all HRQL scales were not different from subjects’ own baseline regardless of their SVR-12 status. By week 8 of follow-up, those with SVR-12 showed improvements in VT (+4.0, p = 0.0168), and PCS (+1.6, p = 0.0116) aspects of their quality of life with a tendency to show some improvement in BP (+4.3, p = 0.0796). This improvement in HRQL in patients with sustained viral eradication continued, and by follow-up week 12 improvements in HRQL among SVR-12 patients were much more profound: +3.7 in PF (p = 0.0462), +3.6 in RP (p = 0.0551), +5.5 in BP (p = 0.0069), +5.2 in VT (p = 0.0004) and +2.1 in PCS (p = 0.0017) (Fig. 3). Finally, in the NEUTRINO study, at the end of follow-up at week 12, those who achieved SVR-12 showed significant improvements in comparison to their own baseline level in GH and VT: +2.5 (p = 0.0082) and +4.8 (p <0.0001), respectively. Improvement in the MH was also significant in those with SVR12: +2.1 (p = 0.0244) (Fig. 3). Of those who failed to achieve SVR-12, no meaningful improvement was observed (all p >0.1).
*
*
4
*
*
* *
2
*
*
0
-2 -4
SOF + RBV
IFN + RBV
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SOF + RBV
SOF + IFN
Fusion
Neutrino
Fig. 3. Improvements in HRQL by week 12 post-treatment in patients with SVR-12. ⁄p <0.05 when compared to patients’ own baseline level. PF, physical functioning; BP, bodily pain; GH, general health; VT, vitality; MH, mental health; PCS, physical component summary; IFN, PegIFN.
Although there was a mild decline in HRQL with SOF + RBV, the extent of this decline was substantially higher for those receiving PegIFN and RBV. These data support the better tolerability of SOF + RBV when compared to the current standard regimen, which is expected to result in better adherence to treatment and potentially better effectiveness of this regimen in the clinical practice setting. Our analysis from POSITRON again provides evidence that patients treated with oral anti-HCV regimen (SOF + RBV) had a very mild decline in their mental health component during treatment. Of the SF-36 scales, we found that the treated group had mild declines in score in 6 out of the 8 subscales of SF-36 with social functioning being the most affected. We suspect that a major component of this decrement is related to RBV-associated anemia and other related side effects. It was interesting to note that comparing SOF + RBV to placebo at any time point during treatment, HRQL scores were not significantly different between the two arms of the study. This indicated that SOF + RBV do not seem to add a tremendous burden on patients’ HRQL. Furthermore, the mild decrements in HRQL related to SOF + RBV were reversed at 4 weeks after stopping treatment, consistent with
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No SVR SVR
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Fig. 4. HRQL in patients achieving SVR-12. (A) After SOF + RBV and (B) IFN + RBV therapy. PF, physical functioning; PR, role physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role emotional; MH, mental health; n.s., not significant.
the time it takes hemoglobin levels to return to baseline levels after stopping ribavirin. It was also interesting to note that our multivariate analysis indicated that receiving placebo was, in fact, associated with lower PCS during treatment. This data suggested that active treatment may have possibly improved physical health by suppressing the virus. Based on these findings, we hypothesize that in future, with development of IFN-free, RBV-free, all-oral antiHCV therapy, patients may experience improvement of their HRQL early after the initiation of treatment. Nevertheless, future clinical trials of new anti-HCV regimens should assessment of HRQL and other patient-reported outcomes (PROs) as their secondary endpoints. When reviewing the results from the FUSION study, our analyses confirmed that regardless of the duration of SOF + RBV, patients do experience a moderate decrement in their MCS, which disappeared after treatment ended. Nevertheless, the results clearly show that the addition of 4 weeks to the treatment regimen (12 weeks vs. 16 weeks) did not substantially add to the quality of life burden of these patients at the last day of treatment or soon thereafter. The results of the NEUTRINO study confirm that patients receiving the IFN-based regimen experienced a major decrement in HRQL during treatment. Nevertheless, addition of SOF to PegIFN and RBV does not seem to worsen patients’ HRQL (comparison with the PegIFN and RBV arm of the FISSION study). Moreover, we believe that SOF-IFN-RBV triple combination regimen’s substantially shorter duration of treatment (12 weeks vs. 24 weeks of treatment for HCV genotype 1) may lead to an improved total HRQL burden [12]. Nevertheless, it is important to note that absence of a control arm in NEUTRINO does not allow to make definite conclusions about the effect of adding SOF to PegIFN and RBV. Despite this shortcoming, we believe this
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shorter and highly effective regimen does provide HRQL benefit to patients with chronic hepatitis C. Our multivariate analyses provided further insights about potential drivers of HRQL impairment for patients with CH-C. Our study confirms that having depression, fatigue, or insomnia prior to the initiation of treatment are the major independent predictors of lower HRQL score at all time points, from baseline to the end of post-treatment follow-up. These findings are both not unexpected and consistent with what has been previously reported [15–21]. Specifically, fatigue and depression are common and important symptoms associated with the presence of CH-C infection, although they may be substantially exaggerated by the side effects of interferon and RBV containing regimens during anti-HCV treatment. On the other hand, both fatigue and depression are complex conditions that can arise from a variety of sources including insomnia, anemia, other drug side effects, as well as an individual’s medical history and poor nutritional status [17,18]. Furthermore, depression can be manifested as extreme fatigue – the inability to get things done due to being tired [19]. The impact of these aspects separately cannot be determined from this analysis and requires additional studies. Another interesting finding was the balance of treatmentrelated impairment in physical as opposed to mental well-being. In PegIFN and RBV regimens, PegIFN is usually presumed to be responsible for depression while RBV is known to cause anemia. In our study, we indeed see a proportion of subjects developing anemia, a common RBV-associated side effect. When transformed to the metrics of HRQL, one might expect more impairment in PCS than in MCS given the presence of the risk factor for anemia and absence of that for depression in IFN-free regiments. However, in all studies which included IFN-free regimens, by the last day of treatment, we saw smaller impairment in PCS than in MCS: an average decrement of 0–2 for PCS and 3–5 for MCS, depending on the study and the cohort. Given the proposed MCID for these parameters [14,16], this essentially means that, on average, physical well-being of the study participants undergoes at most a borderline decrement during treatment with sofosbuvir combined with ribavirin. However, there is still a more profound and clinically significant decrement in their mental well-being scores. The reasons for this are not completely clear and may include certain neuropsychiatric side effects of ribavirin which has been suspected [21]. Again, the future ribavirin-free regimens may potentially reduce this HRQL burden. Finally, we assessed the impact of cirrhosis and gender on HRQL before and during treatment. Our analysis did not show significant differences in HRQL between cirrhotics and noncirrhotics in the univariate or multivariate analyses. This finding is important to indicate that patients with early cirrhosis (advanced cirrhotics were excluded from these studies) could tolerate these regimens in a similar fashion to non-cirrhotics. Nevertheless, it is important to perform additional in-depth analyses exploring the impact of cirrhosis on patients’ HRQL. Another interesting finding of this study was the impact of gender on HRQL. Although male gender was associated with higher PCS scores (Supplementary Figs. 3 and 4), the decrements in PCS scores during treatment were not significantly different between males and females (2.1 ± 7.4 vs. 0.7 ± 6.6, p = 0.30, in FUSION; 6.6 ± 10.5 vs. 5.5 ± 8.1, p = 0.60, in NEUTRINO) suggesting that gender is unlikely an effect modifier for the case of sofosbuvir-based regimens.
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JOURNAL OF HEPATOLOGY This study has some limitations. The major shortcoming of this study is the lack of controls for those who achieved SVR after the last day of treatment, since in most studies the patients with detectable HCV RNA at week 4 post-treatment were not asked to come for subsequent visits as they were allowed to start re-treatment or enter a long-term follow-up study. As a result, we were limited in our ability to make conclusions about improvement of HRQL with SVR. Furthermore, because of multidimensionality of the studied HRQL metrics, multiple study cohorts and time points all resulted in multiple testing. However, many of the differences and associations reported in this study, as well as the lack of those, are observed consistently in different studies and also match with prior knowledge about the effect of anti-HCV treatment on HRQL. In summary, our study is the largest HRQL analysis from 4 large multi-national multi-center studies of interferon-free regimens to treat CH-C. Our data shows that treatment with sofosbuvir results in a moderate decrement in HRQL, which is substantially smaller than that for the interferon-containing regimens. Furthermore, longer duration of the interferon-free sofosbuvir-based regimen does not result in additional HRQL impairment while improving the chances of SVR. Overall, regardless of duration, interferon-free regimens are superior to interferon-based regimens in terms of HRQL, resulting in improved patients’ experience, potentially lower risks of treatment discontinuation, and lower overall burden of chronic HCV infection.
Conflict of interest Z.M.Y. is consultant to Gilead sciences and gives advice regarding study design and analysis related to clinical and outcomes research.
Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jhep.2013.12.006.
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