Whether the presence of cirrhosis influences patient-reported outcomes (PROs), including health-related quality of life, during treatment with newly available anti-HCV (hepatitis C virus) regimens is unclear. Our aim was to assess the association of cirrhosis with PROs in patients treated with sofosbuvir (SOF)-containing regimens. Four PRO questionnaires (Short Form-36 [SF-36], Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F], Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV), and the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem [WPAI-SHP]) were administered to subjects receiving SOF and ribavirin (RBV; FUSION trial, N = 201, 34% cirrhosis; VALENCE trial: N = 333, 21% cirrhosis) and SOF, RBV, and pegylated interferon (Peg-IFN; NEUTRINO trial: N = 327, 17% cirrhosis). HCV patients with cirrhosis showed significant impairment of PROs before initiation of treatment. During treatment, patients with cirrhosis treated with the IFN-free regimen experienced moderate decline in their PRO scores (0.6%-5.2% on a normalized scale of the summary scores; all P > 0.02). In contrast, patients with cirrhosis treated with IFN-containing regimen showed decline in PRO scores that ranged from 3.4% to 16.0% (all P < 0.005). Nevertheless, by follow-up week 12, no PRO decrement from baseline was observed in patients with cirrhosis regardless of the treatment regimen. Furthermore, in patients with cirrhosis with HCV who achieved sustained virological response at 12 weeks (SVR-12), some improvement in PROs from baseline was observed. During treatment, changes in PRO scores were similar between patients with and without cirrhosis for both treatment regimens (all P > 0.05). Independent predictors of lower PROs in patients with cirrhosis included baseline depression, anxiety, fatigue, high HCV viral load, female gender, and receiving IFN-containing treatment. Conclusions: Treatment with SOF+RBV with or without Peg-IFN is tolerated by HCV patients with and without cirrhosis in terms of their PRO scores. After achieving SVR-12 with the IFN-free regimen, patients with cirrhosis showed improvement in some aspects of their PROs. (Hepatology 2014;59:2161–2169)
Chronic hepatitis C (CHC) is the most common cause of cirrhosis and its complications (hepatocellular carcinoma) in the United States and the Western world.[1-9] CHC has been associated with increased mortality and resource utilization as well as impairment of patients' well-being. Although hepatitis C virus (HCV), by itself, can negatively affect patient-reported outcomes (PROs), presence of cirrhosis, especially in its advanced form, can further deteriorate this impairment.[5-8]
Until recently, treatment of CHC was based on interferon (IFN) with substantial side effects, which could negatively affect patients' well-being.[10, 11] The recent approval of new anti-HCV regimens, including IFN-free regimens, not only has led to significant improvement in efficacy, but also has provided patients with a more tolerable regimen with shorter treatment duration. Furthermore, these regimens have been shown to be cost-effective and improve patients' health-related quality of life (HRQL) and other PROs.[12-14] Given further impairment of HRQL in patients with cirrhosis, it becomes critical to assess the effect of these regimens on PROs of CHC patients with cirrhosis who are treated with these new regimens.
Therefore, the aim of this study was to assess the effect of cirrhosis on PROs as well as the changes in PRO scores during treatment with sofosbuvir (SOF) with ribavirin (RBV) with or without IFN.
In this study, we address two important issues related to PROs in patients with HCV-related cirrhosis. First, we attempt to ascertain the effect of cirrhosis on PROs before initiation of any anti-HCV treatment-related activities. Our data show that baseline HRQL, measured by both the generic SF-36 and the disease-specific CLDQ-HCV, documents significant impairment of HRQL in CHC patients with cirrhosis. The most profound decrements in PROs were related to activity, energy, vitality, and fatigue issues represented by the role physical and vitality domains of SF-36 and the respective domains of CLDQ-HCV and FACIT-F. Given these data, it is not unexpected that even compensated cirrhosis negatively influences issues related to work productivity measured by both presenteeism while working and performing activities other than work (both measured by the WPAI instrument). In fact, CHC patients with cirrhosis had lower PRO scores even after adjustment for baseline demographic data, such as age and gender.
The second important issue addressed by our study was related to the effect of SOF-containing regimens on PROs of CHC patients with cirrhosis during treatment and after achieving SVR. Our data show that IFN-free regimens have a modest negative effect on PROs, and this effect of treatment is not higher in patients with cirrhosis, when compared to patients without cirrhosis. Furthermore, these impairments in PROs are resolved shortly after discontinuation of the IFN-free regimen. Patients with cirrhosis who achieve SVR with IFN-free regimens show significant improvement in vitality, fatigue, activity/energy, worry, and other disease-specific aspects of HRQL. This is important because patients with cirrhosis at baseline suffer from substantial impairment of patient-reported outcomes. Furthermore, viral eradication may play an important role in improving these outcomes that are critical from patients' perspective.
Looking at the same variables for CHC patients with cirrhosis treated with SOF in an IFN-containing regimen, the decline in PRO scores was expectedly more profound, as compared to the IFN-free arm. Given the side-effect profile of IFN, these impairments are expected and are also similar to the previously reported values.[13, 14, 22, 23] Nevertheless, the relatively short duration of this treatment (12 weeks) and complete posttreatment recovery of all the PRO scores in patients with cirrhosis suggest that the IFN-containing SOF-based regimen can be well tolerated by patients with HCV with cirrhosis. Although some improvement was noted in patients with cirrhosis who achieved SVR with the IFN-containing regimen, these changes were not as consistent as those observed in patients with cirrhosis who achieved SVR-12 with the IFN-free regimens. This supports the notion that IFN-related side effects may take longer than 12 weeks to fully resolve. In fact, the role emotional component of SF-36 continued to show some deficit in patients with cirrhosis with SVR as late as 12 weeks after the end of treatment. This is consistent with the long-term side-effect profile of IFN exemplified by the reports of cases of depression months after discontinuation of IFN.[23, 24]
Our study also assessed predictors of PROs in CHC patients with cirrhosis who were treated with IFN-free or IFN-containing regimens. As previously reported, depression, fatigue, and anxiety are the most consistent independent predictors of PROs at any time point.[23-26] In a pooled multivariate analysis, having cirrhosis was also associated with lower PROs while being off-treatment (i.e., at baseline or during posttreatment follow-up). On the other hand, during treatment, having cirrhosis was no longer associated with additional PRO impairment. This gives further support to the premise that well-compensated CHC patients with cirrhosis can tolerate SOF-containing regimens in a similar fashion to CHC patients without cirrhosis.
Our data also suggest that patients with cirrhosis with low albumin and platelets also can tolerate SOF-containing treatment reasonably well. In fact, 17 CHC patients with cirrhosis had the reported unfavorable safety profiles for treatment with triple combinations containing the first generation direct antiviral agents (DAAs) (albumin below 3.5 g/dL and platelets below 100,000/mL). Nevertheless, in our study, for these patients, the rate of treatment-related anemia was significantly lower (47.1% vs. 82.9% in other patients with cirrhosis; P = 0.0005), likely because of lower baseline hemoglobin (14.0 ± 1.3 vs. 15.0 ± 1.2; P = 0.0040), whereas other non-PRO parameters and baseline PROs were similar, as was the SVR rate (all P > 0.05). Because only 2 of those patients were treated with the IFN-containing regimen, we studied on-treatment PROs only in those receiving the IFN-free treatment. In those patients, of their PROs during treatment, only PF and PCS of SF-36 declined more substantially, compared to other patients with cirrhosis: by −17.1 versus −3.4 (P = 0.0229) and by −4.38 versus −0.87 (P = 0.0269). Both of these aspects of PROs returned to their baseline levels as early as week 4 posttreatment and were no longer different from the rest of the patients with cirrhosis. Thus, patients with compensated cirrhosis who were advanced enough to make them ineligible for triple therapy with IFN and first generation DAAs, without compromising their PROs.
To the study limitations, the data used for this analysis came from the multicenter clinical trials, so these results may not necessarily be generalizable to all facilities or the general population of patients with cirrhosis with CHC. In fact, patients with decompensated cirrhosis were excluded from these trials, whereas the effect of anti-HCV treatment may be substantially different for these populations; further studies are needed to assess this effect in those patients. We also could not contrast post-SVR PRO improvements to those who did not achieve SVR because of the lack of the necessary follow-up data. Nevertheless, this is the largest PRO study in patients with cirrhosis with CHC treated with IFN-free and IFN-containing regimens. The careful assessment of PROs with multiple validated instruments and longitudinal assessments provides substantial information about outcomes that are important to patients with CHC.
In conclusion, patients with CHC and cirrhosis who participated in the recent phase III clinical trials of SOF-based treatment experienced some decrement in their PROs before initiation of treatment. However, IFN-free regimens were associated with minimal PRO decrements. Although PROs were more substantially affected by the IFN-containing SOF-based treatment, these impairments were similar between patients with and without cirrhosis, whereas the short duration of treatment (12 weeks) does provide advantage to these patients. Finally, patients with cirrhosis who achieved SVR-12 after treatment, especially with the IFN-free SOF-based regimens, enjoyed significant improvement of some of their PRO scores. It is important that future studies of decompensated patients with cirrhosis treated with IFN-free regimens are to be assessed not only for efficacy and safety, but also for the effect of these regimens on PROs.