Effects of escitalopram prophylaxis during antiviral treatment for chronic hepatitis C in patients with a history of intravenous drug use and depression.

OBJECTIVE: We aimed to identify those patients with hepatitis C virus who benefit most from prophylactic treatment with selective serotonin reuptake inhibitors (SSRIs) during antiviral therapy. METHOD: We performed post hoc analyses on a prospective randomized controlled trial (n = 79) of escitalopram versus placebo during antiviral therapy with pegylated interferon and ribavirin, conducted between August 2005 and June 2008. Our primary outcome measure was the association of baseline characteristics with the development of depression and/or depressive symptoms. Further, we studied effects of prophylactic escitalopram on depressive symptoms. Presence of a major depression was diagnosed using Mini-International Neuropsychiatric Interview (MINI), a short, structured interview used to diagnose DSM-IV-TR and ICD-10 disorders. Depressive symptoms were monitored during treatment by using the depression scale of Symptom Checklist-90 (SCL-90), Montgomery-Asberg Depression Rating Scale (MADRS), and Beck Depression Inventory (BDI) at baseline and weeks 4, 12, and 24 of antiviral therapy. RESULTS: Depression occurred in 14 patients receiving placebo and in 5 patients receiving escitalopram (Pearson χ², P = .01). Combination of history of depression and intravenous drug use was associated with depression (odds ratio = 12.60; 95% CI, 2.47-64.34; P < .01). Moreover, treatment with selective serotonin reuptake inhibitor compared to placebo was associated with a significant reduction in estimated mean depressive symptoms measured by SCL-90 (P = .03) and BDI (P = .048), but not with MADRS (P = .64). CONCLUSIONS: Patients infected by hepatitis C virus with a history of depression and intravenous drug use carry the highest risk to develop interferon-induced depression. In this subset of patients, prophylaxis with escitalopram results in the most substantial decrease of interferon-induced depressive symptoms on the SCL-90 depression scale and the BDI.

Natural killer cell activity and function in chronic HCV-infected patients during peg interferon and ribavirin: early effects of active substance use.

In Western countries, chronic hepatitis C virus (HCV)-infection mostly affects former and active substance users. The effect of active substance use on interferon (IFN)-responsiveness and therapy efficacy is not well understood. In this study, we compared natural killer (NK) cell activity and function in healthy controls and chronic HCV-infected patients with and without active substance use, as well as the early effects of antiviral therapy with peg-IFN and ribavirin. No differences were observed between chronic HCV patients and healthy individuals in the number and frequencies of CD56(dim) and CD56(bright) NK cells. Also, IL-12/18-induced IFN-gamma production by NK cells was comparable between all groups, whereas the cytotoxic ability of NK cells (granzyme and CD107a levels) was more potent in HCV-infected patients as compared to healthy controls, and highest in non-substance users. Moreover, at baseline, the activation of NK cells was significantly lower in HCV-infected patients who used substances, when compared to healthy individuals. Therapy-induced viral load reduction assessed early at day 7 showed a similar decline in substance users and non-substance use HCV patients, with 25% substance users and 17% non-substance users testing HCV-RNA negative at day 7. Furthermore, early during IFN-based therapy, NK cells from HCV patients remained responsive to IFN, and only a minor decline in the degree of STAT-1 phosphorylation was observed irrespective of substance use. These findings were further supported by comparable in vitro p-STAT-1 induction in all three experimental groups. Despite subtle differences at baseline between healthy individuals and chronic HCV patients, we observed that active substance use in chronic HCV-infected patients did not affect the immune responsiveness to IFN early after start of treatment, and thus, we found no evidence - from an immunological point of view - that antiviral therapy of our cohort of HCV-infected patients with active substance use is less efficient.

Potent immune activation in chronic hepatitis C patients upon administration of an oral inducer of endogenous interferons that acts via Toll-like receptor 7.

BACKGROUND: ANA773, an oral prodrug of a small-molecule Toll-like receptor (TLR)7 agonist, induces a dose-related decrease in serum HCV RNA levels in chronic hepatitis C patients. METHODS: The prodrug ANA773 was administered to healthy individuals and chronic hepatitis C patients. At different time points during the course of treatment, modulation of the phenotype and function of peripheral leukocytes were evaluated to determine the role of distinct immune cells on the clinical outcome of therapy. RESULTS: Early after administration of the TLR7 agonist, a mild transient reduction of the number of lymphocytes was observed in both healthy individuals and chronic hepatitis C patients. Moreover, repeated administration of ANA773 resulted in transiently reduced numbers of myeloid and plasmacytoid dendritic cells (DC) in blood. Interestingly, reduced plasmacytoid DC numbers as well as increased serum interferon (IFN)-α and IFN-γ inducible protein (IP)-10 levels were observed only in virological responders (≥1 log(10) IU/ml reduction of HCV RNA levels upon ANA773 treatment), but were absent in virological non-responders. In vitro stimulation of peripheral blood mononuclear cells from virological responders showed a high frequency of IFN-α-producing plasmacytoid DC upon stimulation in vitro with ANA773, whereas no IFN-α was induced in non-responders. CONCLUSIONS: These findings indicate that the viral load decline in chronic hepatitis C patients treated with the TLR7 agonist ANA773 is likely due to intrinsic differences in the induction of endogenous IFNs and IFN-stimulated gene products (IFN-α and IP-10) upon TLR7 ligation.

Pharmacokinetics and antiviral activity of PHX1766, a novel HCV protease inhibitor, using an accelerated Phase I study design.

BACKGROUND: PHX1766 is a novel HCV NS3/4 protease inhibitor with robust potency and high selectivity in replicon studies (50% maximal effective concentration 8 nM). Two clinical trials investigated the safety, tolerability, pharmacokinetics and antiviral activity of PHX1766 in healthy volunteers (HV) and chronic hepatitis C patients, by use of a dose-adaptive overlapping clinical trial design. METHODS: Two randomized, double-blind, placebo-controlled clinical trials were conducted. Single doses of PHX1766 or placebo were administered to 25 HV and six HCV genotype 1-infected patients (50 mg once daily -1,000 mg once daily, 250 mg twice daily and 100 mg of a new formulation of PHX1766 once daily). Multiple doses of PHX1766 or placebo were administered to 32 HV and seven HCV genotype 1-infected patients (50 mg once daily -800 mg twice daily). RESULTS: Oral administration of PHX1766 was safe and well tolerated at all dose levels with rapid absorption (time at which concentration maximum is reached of 1-4 h) and with mean terminal half-lives of 4-23 h. Multiple doses of PHX1766 800 mg twice daily in HCV patients produced an area under the plasma concentration-time curve from time of drug administration to the last time point with a measurable concentration after dosing accumulation ratio of 2.3. The mean maximal observed HCV RNA decline was 0.6 log(10) IU/ml in the first 24 h in the single-dose protocol and 1.5 log(10) IU/ml after 6 days of PHX1766 dosing. CONCLUSIONS: An overlapping, dose-adaptive single-dose and multiple-dose escalating design in HV and HCV-infected patients proved to be highly efficient in identifying a therapeutic dose. Although in vitro replicon studies indicated a robust HCV RNA viral decline of PHX1766, the study in HCV patients demonstrated only modest viral load reduction.