Jnl of Hepatology Article In Press, corrected proof
"......it was notable that more cirrhotics had worse fatigue than those with minimal fibrosis....."
After treatment results
Once therapy terminated, the proportion of patients who admitted to feeling fatigued decreased. By 12weeks after discontinuation, the proportion of patients with fatigue was lower than that at baseline (36% in responders, 42% non-responders vs. 52% at baseline, Fig. 1A). The median fatigue VAS scores were also lower (11mm in responders, 17mm in non-responders vs. 25mm at baseline: Fig. 1B).
The improvement in fatigue was greater among patients who achieved an SVR than in those who never became HCV RNA negative (non-responders). Overall, the proportion of SVR patients who admitted to having fatigue decreased from 53% at baseline to 33%, 24weeks after treatment (p<0.0001; n=161), and the median VAS fatigue score decreased from 27mm to 13mm (p<0.0001; n=158). These changes were especially profound in patients who at baseline had severe levels of fatigue (fatigue VAS score >40mm), in whom the median fatigue VAS score decreased from 64mm at baseline to 21mm at follow-up week 24 (p<0.0001, n=66; Fig. 3A). Among non-responders, the presence and severity of fatigue decreased but not significantly between baseline and 24weeks after treatment regardless of the initial score (p>0.05, Fig. 3B). Furthermore, there was no significant change in fatigue presence or severity among patients who had virologic relapse (n=60) or breakthrough (n=21) (data not shown).
As expected, fatigue score was associated with depression, (Spearman correlation coefficients, rs=0.53 at baseline; 0.66 at treatment week 24; and 0.73 at follow-up week 24; all p<0.0001). Controlling for the presence of depression did not alter the significance of the changes in fatigue severity after successful completion of therapy compared to baseline (p<0.0001).
Fig 3. Severity of fatigue categorized by baseline fatigue status in responders and non-responders (NR). Severity of fatigue by baseline fatigue status in (A) responders and (B) NR patients.
Discussion
Fatigue is perhaps the most common symptom among patients with chronic hepatitis C and is a troublesome side effect of its therapy [1], [2], [4], [7], [9], [34], [35]. In this study, half of the patients enrolled in a study of antiviral therapy of HCV admitted that they had some degree of fatigue, of whom two-thirds rated it as moderate or severe. The current literature suggests that the presence and severity of fatigue correlate poorly with disease activity although it may be somewhat more common and severe in patients with cirrhosis [1], [9], [19], [36]. In the current study, the differences in frequency and severity of fatigue in patients with cirrhosis compared to those with lesser degrees of fibrosis were not statistically significant; however, the data were limited by numbers of patients with more advanced disease (n=29: 7% of the cohort) but it was notable that more cirrhotics had worse fatigue than those with minimal fibrosis.
As expected, fatigue became more troublesome during interferon therapy [9], [14], [15], [18]. Fatigue worsened during the first 4weeks of therapy, then plateaued, and did not completely resolve or return to baseline until 12weeks after stopping therapy. The cause of fatigue induced from interferon therapy is likely multifactorial, but may include the systemic effects of cytokines, secondary effects of treatment-related side effects such as anemia [37], [38], [39], [40], as well as the psychosocial stress of having to maintain occupational and family responsibilities while undergoing medical treatment. Thus, although attributing the cause of fatigue to a specific set of genes or proteins is an attractive and parsimonious notion, an interlinked pathway involving multiple genetic, biochemical, and environmental processes is a more realistic probability [41], and an area for future research.
Importantly, the presence and severity of fatigue ultimately declined in patients with sustained clearance of HCV. The results remained consistent even after controlling for depression, a common cofounder of fatigue. These findings indicate that therapy of HCV can result in significant and sustained improvement in clinical symptoms, and that the measurement of fatigue using VASs is successful in capturing these changes. Improvements in fatigue were most convincing in patients with moderate to severe levels of fatigue at baseline. Thus, patients with relatively non-significant biochemical or histologic disease, but who have troublesome symptoms such as fatigue, should be considered for antiviral therapy.
The likely cause for the improvement of fatigue with eradication of HCV is unclear. It is also unclear whether certain aspects of fatigue (i.e., physical, mental or cognitive) fare better, as the VAS is a quantitative measure rather than a qualitative one. While patient awareness of virological response could have a beneficial psychological effect on perceptions of fatigue, fatigue assessments were obtained before the results of virological testing were known, and improvements in fatigue were achieved well before knowledge of SVR was given to patients.
A few limitations of this study should be noted. The cohort tested was a relatively biased sample of patients with HCV infection, as these subjects all had genotype 1 and all were sufficiently motivated to undergo a rigorous, prolonged medical therapy with notable adverse side effects. Another caveat to consider is that the improvements in fatigue scores were observed predominantly among patients who had moderate or severe levels of fatigue before treatment, and there was little or no improvement in patients who initially reported minimal fatigue. Such findings suggest that there is little room for improvement in fatigue among those with lower levels at baseline, or that the VAS is not sensitive enough to detect minor improvements.
In conclusion, use of a simple fatigue VAS demonstrated that at least half of the patients with chronic hepatitis C who participated in a clinical trial had complaints of fatigue at baseline, however, fatigue significantly improved in those who achieved viral eradication. Further analyses of the quality of fatigue in chronic liver disease, as well as the biologic and psychosocial pathways associated with this subjective symptom are needed to improve management of chronic liver disease and assessment of the benefits of antiviral therapy, whether curative or ameliorative in nature.
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