Geert Robaeys

IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity

Studies show that administration of interferon (IFN)-α causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN-α-induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN-α treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood–brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN-α treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN-α-induced depressive symptoms, through its induction of neurotoxic KYN metabolites.

Hepatitis C infection, antiviral treatment and mental health: A European expert consensus statement

Mental health problems frequently occur in chronic infection with the hepatitis C virus (HCV) and during antiviral treatment with pegylated interferon-alpha (PegIFNα) and ribavirin. Depression is one of the most important complications during antiviral treatment of chronic hepatitis C infection. However, an increased prevalence of depression, fatigue, and cognitive disturbances has also been reported in untreated HCV-positive patients. Patients with psychiatric disorders or drug addiction also have an increased risk of HCV infection. Furthermore, because of possible drug-drug interactions, new antivirals administered together with PegIFNα and ribavirin may complicate psychiatric side effect management, even if no specific psychiatric adverse events are known so far for these new drugs. The European liver patients organization (ELPA) organised a European expert conference to review the literature and develop expert recommendations for the management of mental health problems in HCV infected patients. This paper results from the output of the 2011 EASL meeting and subsequent dialogue with patient groups and relevant experts in Europe. It summarises the current knowledge of HCV infection and the brain; prevalence, course, and neurobiology of IFN-α associated psychiatric side effects; possible risk factors for IFN-α associated depression and suicide attempts; psychiatric management of HCV infected patients before and during antiviral treatment; prevention of IFN- α associated psychiatric side effects; and psychiatric aspects of the new antivirals. The summarised current knowledge about mental health changes before and during antiviral treatment should improve interdisciplinary management of HCV infected patients.

Recommendations for the management of hepatitis C virus infection among people who inject drugs

In high income countries, the majority of new and existing hepatitis C virus (HCV) infections occur among people who inject drugs (PWID). In many low and middle income countries large HCV epidemics have also emerged among PWID populations. The burden of HCV-related liver disease among PWID is increasing, but treatment uptake remains extremely low. There are a number of barriers to care which should be considered and systematically addressed, but should not exclude PWID from HCV treatment. The rapid development of interferon-free direct-acting antiviral (DAA) therapy for HCV infection has brought considerable optimism to the HCV sector, with the realistic hope that therapeutic intervention will soon provide near optimal efficacy with well-tolerated, short duration, all oral regimens. Further, it has been clearly demonstrated that HCV treatment is safe and effective across a broad range of multidisciplinary healthcare settings. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment and treatment in this group are urgently needed. These recommendations demonstrate that treatment among PWID is feasible and provide a framework for HCV assessment and care. Further research is needed to evaluate strategies to enhance testing, linkage to care, treatment, adherence, viral cure, and prevent HCV reinfection among PWID, particularly as new interferon-free DAA treatments for HCV infection become available.

Meeting ReportHepatitis C infection, antiviral treatment and mental health: A European expert consensus statement

Mental health problems frequently occur in chronic infection with the hepatitis C virus (HCV) and during antiviral treatment with pegylated interferon-alpha (PegIFNα) and ribavirin. Depression is one of the most important complications during antiviral treatment of chronic hepatitis C infection. However, an increased prevalence of depression, fatigue, and cognitive disturbances has also been reported in untreated HCV-positive patients. Patients with psychiatric disorders or drug addiction also have an increased risk of HCV infection. Furthermore, because of possible drug-drug interactions, new antivirals administered together with PegIFNα and ribavirin may complicate psychiatric side effect management, even if no specific psychiatric adverse events are known so far for these new drugs. The European liver patients organization (ELPA) organised a European expert conference to review the literature and develop expert recommendations for the management of mental health problems in HCV infected patients. This paper results from the output of the 2011 EASL meeting and subsequent dialogue with patient groups and relevant experts in Europe. It summarises the current knowledge of HCV infection and the brain; prevalence, course, and neurobiology of IFN-α associated psychiatric side effects; possible risk factors for IFN-α associated depression and suicide attempts; psychiatric management of HCV infected patients before and during antiviral treatment; prevention of IFN- α associated psychiatric side effects; and psychiatric aspects of the new antivirals. The summarised current knowledge about mental health changes before and during antiviral treatment should improve interdisciplinary management of HCV infected patients.

Recommendations for the Management of Hepatitis C Virus Infection Among People Who Inject Drugs

In the developed world, the majority of new and existing hepatitis C virus (HCV) infections occur among people who inject drugs (PWID). The burden of HCV-related liver disease in this group is increasing, but treatment uptake among PWID remains low. Among PWID, there are a number of barriers to care that should be considered and systematically addressed, but these barriers should not exclude PWID from HCV treatment. Furthermore, it has been clearly demonstrated that HCV treatment is safe and effective across a broad range of multidisciplinary healthcare settings. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment and treatment in this group are urgently needed. These recommendations demonstrate that treatment among PWID is feasible and provides a framework for HCV assessment, management, and treatment. Further research is needed to evaluate strategies to enhance assessment, adherence, and SVR among PWID, particularly as new treatments for HCV infection become available.

Baseline Immune Activation as a Risk Factor for the Onset of Depression During Interferon-Alpha Treatment

BACKGROUND Major depression has been associated cross-sectionally with increased cell-mediated immune activation but causality has been difficult to establish. This study prospectively investigated the hypothesis that baseline level of immune activation predicts the development of depression during interferon-alpha (IFN-alpha) treatment. METHODS Sixteen hepatitis C patients without psychiatric disorder underwent IFN-alpha treatment. Proinflammatory and anti-inflammatory cytokines were determined before starting treatment. Presence of a major depressive disorder (MDD) was assessed at baseline and several times during treatment. RESULTS Baseline soluble interleukin-2 receptor (sIL-2r), interleukin-6 (IL-6), and interleukin-10 (IL-10) concentrations were significantly increased in the five subjects that developed MDD during treatment compared with those that did not, with standardized effect sizes of 1.08, 1.16, and 1.25, respectively, controlling for marijuana use, cigarette smoking, and baseline level of depressive symptoms. CONCLUSIONS Results suggest that increased immune activation, rather than an epiphenomenon, is a causal risk factor for the development of MDD.

Similar compliance and effect of treatment in chronic hepatitis C resulting from intravenous drug use in comparison with other infection causes.

Objectives There is some reluctance to treat intravenous drug users (IVDUs) with chronic hepatitis C (CHC) because of presumed lower compliance and response to antiviral therapy. We intended to evaluate the compliance and response to antiviral treatment for CHC in IVDUs compared with non-IVDUs. Methods A retrospective cohort study — secondary analysis of the results of a treatment trial — was performed in Belgium and The Netherlands. A total of 406 previously untreated CHC patients, including 98 (24%) IVDUs, were studied for compliance (presentation at the end of treatment), complete response (alanine aminotransferase within normal limits and serum hepatitis C virus polymerase chain reaction negative) at the end of therapy and sustained virological response (SVR). Results Non-compliance (8.2%) in IVDUs was not different from non-IVDUs (6.8%) (relative risk=1.20; 95% confidence interval=0.55–2.62). Complete response after controlling for hepatitis C virus was similar (relative risk=1.19; 95% confidence interval=0.89–1.60). Controlling for treatment arm, age, sex, presence of cirrhosis or hepatitis C virus viral load before treatment did not change these results. There was a marginally significant difference in the sustained virological response between IVDUs (46.6%) and non-IVDUs (34.6%) (relative risk=1.35; 95% confidence interval=1.00–1.81), also disappearing after adjusting for genotype. No difference in compliance or sustained virological response was found between active and non-active IVDUs or between IVDU patients in or without a methadone maintenance program. Conclusions In this group of Benelux patients, IVDUs showed similar compliance and response to treatment with interferon and ribavirin compared with other patients with CHC infection. Therefore, it is no longer justifiable to withhold treatment to chronic hepatitis C patients who use intravenous drugs.

Treatment of acute hepatitis C with interferon alpha-2b: early initiation of treatment is the most effective predictive factor of sustained viral response

Aim : To evaluate the efficacy of early interferon α‐2b in non‐post‐transfusion acute hepatitis C virus: a prospective study with historical comparison.

Depressive symptoms following interferon-a therapy: mediated by immune-induced reductions in brain-derived neurotrophic factor?

Interferon-α (IFN-α) therapy for the treatment of hepatitis C is known to induce depressive symptoms and major depression in a substantial proportion of patients. While immune activation and disturbances in peripheral tryptophan catabolism have been implicated, the exact underlying mechanism remains unknown. A role for brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders has recently emerged. This study examined whether depressive symptoms over time are associated with changes in serum BDNF concentration in hepatitis C patients treated with IFN-α, and whether BDNF mediates the effects of IFN-α-induced immune activation on depressive symptoms. For this purpose, 17 hepatitis C patients received IFN-α treatment with ribavirin. Patients were assessed before and at 1, 2, 4, 8, 12 and 24 wk after start of treatment. Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). In addition, cytokine concentrations and serum BDNF levels were measured at all time-points. Serum levels of BDNF decreased during the course of treatment, and were significantly and inversely associated with total MADRS score. Furthermore, pro-inflammatory cytokine levels predicted lower subsequent BDNF levels, whereas low BDNF levels, as well as increased cytokine levels, were independently associated with the development of depressive symptoms during IFN-α treatment. These findings suggest that the effect of IFN-α-induced immune activation on depression may be explained in part by alterations in neuroprotective capacity, reflected by decreases in serum BDNF following IFN-α treatment.

Molecular epidemiology of hepatitis C among drug users in Flanders, Belgium: association of genotype with clinical parameters and with sex- and drug-related risk behaviours

The aim of this study was to determine the genotypic variation of hepatitis C among drug users in Flanders and to relate the distribution of genotypes to the characteristics of the population. Hepatitis C virus RNA (HCV-RNA) quantification and genotyping was performed on stored samples from 161 anti-HCV-positive injecting and non-injecting drug users. Information on sociodemographic status, drug-related risk behaviour and sexual risk behaviour was available for each drug user. HCV-RNA was present in 152 of 161 samples (94.4%). Genotype 1 was predominant (48.7%), followed by genotype 3 (41.2%), genotype 4 (8.8%) and genotype 2 (1.4%). In the multivariate analysis, lack of a history of injecting drug use was confirmed as a statistically significant predictor for infection with genotype 1. Predictors for infection with genotype 3 were the presence of anti-HBc antibodies and a history of injecting drug use. Being tattooed emerged as a statistically significant predictor for infection with genotype 4. The 94.4% prevalence of HCV-RNA among anti-HCV-positive drug users was considerably higher than the 54–86% chronicity rate found globally among HCV-infected patients. The results of this study suggest the existence of separate transmission networks for injecting drug users and non-injecting drug users. Finally, the results suggest that tattooing practices play a role in the spread of HCV among drug users.