Antidepressant effects of direct-acting antivirals against hepatitis C virus-Results from a pilot study

Background and Aims The new direct-acting antiviral agents (DAA) have revolutionized the treatment of patients with chronic hepatitis C virus (HCV) infection. This study investigates to which extent DAA affect fatigue and mood and, if so, whether this results from changes to tryptophan (TRP) metabolism, as reflected by two critical biosynthetic pathways, serotonin (SRT) generation from TRP and TRP degradation through kynurenines (KYN) via indoleamine 2,3-dioxygenase (IDO). Methods Results This study assessed 24 patients with chronic HCV infection, before (T1), during (T2: at 4 weeks) and 12 weeks post-treatment with DAA (T3) with respect to viral load, fatigue and depressive symptoms (BDI-II questionnaire), physical activity (actigraph) and plasma serotonin-tryptophan metabolites (LC/MS). The KYN:TRP ratio reflected IDO activity. All participants achieved sustained virological response (SVR12) with DAA treatment (79% sofosbuvir-based). Fatigue (scores at T1:0.83 +/- 0.70, T2:0.48 +/- 0.70, T3:0.30 +/- 0.50; P = 0.023) and depressive symptoms (scores at T1:9.8 +/- 10.2, T2:6.0 +/- 7.3, T3:5.0 +/- 7.6; P = 0.005) improved significantly on therapy, whereas no changes were noted in five untreated controls. TRP plasma concentrations markedly decreased (T1:306 +/- 179 mg/L, T2:283 +/- 84 mg/L), whereas 5-HTP levels increased (T1:0.08 +/- 0.01 mg/L, T2:0.10 +/- 0.06 mg/L). KYN concentrations (T1:2.4 +/- 2.0 mg/L, T2:3.7 +/- 1.4 mg/L, P = 0.003) increased significantly during treatment, as did IDO activity (T1:0.008 +/- 0.006 mg/L, T2:0.014 +/- 0.004 mg/L; P < 0.001). Conclusions In this study, DAA exert positive and persistent effects on both fatigue and mood in patients with chronic HCV infection. These extrahepatic benefits are, at least in part, related to the modulation of TRP metabolism. The robust elevation of KYN concentrations challenges the current paradigm of low KYN levels as prerequisite for mental health.