Only partial improvement in health-related quality of life after treatment of chronic hepatitis C virus infection with direct acting antivirals in a real-world setting-results from the German Hepatitis C-Registry (DHC-R).

Improvement of health-related quality of life (HRQoL) is frequently reported as a benefit when treating hepatitis C virus infection (HCV) with direct acting antivirals (DAA). As most of the available data were obtained from clinical trials, limited generalizability to the real-world population might exist. This study aimed to investigate the impact of DAA therapy on changes in HRQoL in a real-world setting. HRQoL of 1180 participants of the German Hepatitis C-Registry was assessed by Short-Form 36 (SF-36) questionnaires. Scores at post-treatment weeks 12-24 (FU12/24) were compared to baseline (BL). Changes of ≥2.5 in mental and physical component summary scores (MCS and PCS) were defined as a minimal clinical important difference (MCID). Potential predictors of HRQoL changes were analysed. Overall, a statistically significant increase in HRQoL after DAA therapy was observed, that was robust among various subgroups. However, roughly half of all patients failed to achieve a clinically important improvement in MCS and PCS. Low MCS (p < .001, OR = 0.925) and PCS (p < .001, OR = 0.899) BL levels were identified as predictors for achieving a clinically important improvement. In contrast, presence of fatigue (p = .023, OR = 1.518), increased GPT levels (p = .005, OR = 0.626) and RBV containing therapy regimens (p = .001, OR = 1.692) were associated with a clinically important decline in HRQoL after DAA therapy. In conclusion, DAA treatment is associated with an overall increase of HRQoL in HCV-infected patients. Nevertheless, roughly half of the patients fail to achieve a clinically important improvement. Especially patients with a low HRQoL seem to benefit most from the modern therapeutic options.

Improvement of Hepatic and Extrahepatic Complications from Chronic Hepatitis C After Antiviral Treatment: A Retrospective Analysis of German Sickness Fund Data.

INTRODUCTION: German data regarding the economic burden of chronic hepatitis C (CHC) and potential benefits of CHC treatment are limited. To address this issue, we evaluated the role of treatment in mitigating the economic burden of hepatic and extrahepatic complications (EHCs) from CHC virus infection in Germany. METHODS: This retrospective, cross-sectional study used claims data from the Betriebskrankenkasse German sickness fund (2007-2014) to assess the medical costs of hepatic complications and EHCs, including conditions that are prevalent and behavioral factors associated with CHC. All-cause costs, medical costs related to hepatic and EHCs, and CHC-related and non-CHC-related pharmacy costs (adjusted to the 2016 euro rate) were calculated and compared between CHC patients' treated (n = 1714) and untreated time (n = 7124) and CHC patients that initiated treatment early (i.e., without cirrhosis; n = 1552) vs. late (i.e., with cirrhosis; n = 162). RESULTS: CHC treatment was associated with an average adjusted savings of €1885 in annual all-cause medical costs per patient, with a significant proportion attributed to EHC-related cost savings (adjusted difference, €1363; P < 0.01). Although initiating CHC treatment early was economically beneficial compared with initiating treatment late, the total cost savings were not significantly different (annual average adjusted difference, €3831; P = 0.27). However, nearly 60% of these savings were EHC related (adjusted difference, €2255; P < 0.01). CONCLUSION: CHC is associated with a significant economic burden in Germany, largely due to EHCs. Antiviral treatment may reduce the burden of CHC and result in significant cost savings, even when initiated at earlier stages of liver disease. FUNDING: AbbVie Inc.

Clinical and Economic Burden of Hepatic and Extrahepatic Complications from Chronic Hepatitis C: A Retrospective Analysis of German Sickness Fund Data.

INTRODUCTION: German data regarding the burden of complications from chronic hepatitis C (CHC) virus infection are limited. To address this issue, this study evaluates the clinical and economic burden of hepatic and extrahepatic complications (EHCs) associated with CHC in Germany. METHODS: This retrospective, cross-sectional study used claims data from the Betriebskrankenkasse German sickness fund (2007-2014) to assess the risks and medical costs of hepatic complications and EHCs, including conditions that are prevalent and behavioral factors associated with CHC. Prevalence, incidence, and risks were calculated for 1:1 matched patients with and without CHC (n = 3994). All-cause cost, medical costs related to hepatic and EHCs, as well as CHC-related and non-CHC-related pharmacy costs (adjusted to the 2016 Euro rate), were calculated and compared between 1:5 matched patients with (n = 8425) and without CHC (n = 42,125). RESULTS: Patients with CHC had a 3-fold higher risk for any EHC (OR = 3.0; P < 0.05) and higher EHC-related medical costs (adjusted difference, €1606; P < 0.01) compared with patients without CHC. Total costs (€10,108 vs. €5430), hepatic complication-related medical costs (€1425 vs. €556), EHC-related costs (€3547 vs. €1921), CHC-related pharmacy costs (€577 vs. €116), and non-CHC-related pharmacy costs (€3719 vs. €1479) were all significantly greater for patients with CHC compared with patients without CHC. EHC-related medical costs were a major contributor to the higher all-cause medical (84.4%) and total (44.3%) cost differences between patients with CHC and the matched sample of patients without CHC. CONCLUSION: CHC is associated with substantial clinical and economic burden in Germany, largely due to hepatic complications and EHCs. FUNDING: Abbvie Inc.

Treatment Extension of Pegylated Interferon Alpha and Ribavirin Does Not Improve SVR in Patients with Genotypes 2/3 without Rapid Virological Response (OPTEX Trial): A Prospective, Randomized, Two-Arm, Multicentre Phase IV Clinical Trial.

UNLABELLED: Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A) or additional 12 weeks (total 36 weeks, group B) of 1.5 µg/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B) could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat) analysis, 68% [55%; 81%] in Group A and 57% [43%; 71%] in Group B achieved SVR (p= 0.31). The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70%) was not met. In conclusion, approximately 23% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group. TRIAL REGISTRATION: ClinicalTrials.gov NCT00803309.

Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C.

UNLABELLED: Earlier studies have suggested neurocognitive impairment in patients with chronic hepatitis C virus (HCV) infection even before liver cirrhosis has developed. Since these deficits might be reversible after successful antiviral therapy, we analyzed the long-term course of neurocognitive parameters in HCV patients with and without successful virus elimination by an interferon-based antiviral treatment. In a multicenter study including 168 HCV patients receiving antiviral therapy (peginterferon alpha-2b and ribavirin) we performed a long-term follow-up of neurocognitive performance before and after treatment. Neurocognitive function was psychometrically assessed using the computer-aided TAP (Test Battery of Attentional Performance). When tested at least 12 months after termination of antiviral treatment, patients with sustained virologic response (SVR) had improved significantly as compared to their pretreatment performance in three of five TAP subtasks (vigilance, P < 0.001; shared attention: optical task, P < 0.001; working memory, P < 0.001). Patients who failed to eradicate the virus, however, showed no significant long-term changes in neurocognitive performance in all five subtasks assessed (0.194 < P < 0.804). In the posttreatment evaluation, neurocognitive function was significantly better in responders to the antiviral therapy as compared to nonresponders. CONCLUSION: Successful eradication of HCV leads to a significant improvement of relevant aspects of attentional and neurocognitive performance, indicating that the neurocognitive impairment caused by chronic HCV infection is potentially reversible. This therefore suggests an added therapeutic benefit of antiviral treatment in HCV infection. Improvement of neurocognitive function may be an additional treatment indication in patients with HCV. (HEPATOLOGY 2013;58:497-504).

Platelet serotonin (5-HT) levels in interferon-treated patients with hepatitis C and its possible association with interferon-induced depression.

BACKGROUND & AIMS: Interferon-associated depression is a frequent side effect of antiviral therapy for chronic hepatitis C. The aim of the present study was to investigate the correlation between platelet serotonin (5-hydroxytryptamine, 5-HT) concentrations and IFN-induced depression. METHODS: The study represents a secondary analysis of a previously published trial on the efficacy of SSRI medication in HCV patients on IFN therapy. Ninety-three patients were longitudinally assessed for depression and platelet serotonin. Evaluation time points were: prior to IFN therapy, at weeks 4, 12, and 24 of IFN treatment, and 4 weeks after antiviral treatment. Depression was assessed using the Hospital Anxiety and Depression Scale (HADS). Platelet serotonin concentrations were measured by ELISA. RESULTS: Platelet serotonin concentrations were significantly decreased during interferon therapy (p=0.001) in 74 of the 93 patients (79.6%). Clinically relevant depression occurred in 33.3% of patients - however, IFN-induced depression was not significantly linked to either baseline 5-HT concentrations or kinetics. In the subgroup of patients with IFN-induced depression who received the selective serotonin reuptake inhibitor (SSRI) citalopram (20 mg daily, n=17), serotonin levels declined further during anti-depressant medication, becoming statistically significant within the first 2 weeks (p<0.001) of SSRI treatment. CONCLUSIONS: We demonstrate a significant impact of IFN and SSRI intake on platelet serotonin levels, suggesting a biochemical analogy between 5-HT metabolism in blood platelets and the CNS. Platelet 5-HT levels might serve as a surrogate marker for patient adherence to antiviral and anti-depressant medication. For the prediction of IFN-induced depression, however, platelet 5-HT measurements are not suitable.

Differential effects of PPARgamma activation by the oral antidiabetic agent pioglitazone in Barrett's carcinoma in vitro and in vivo.

BACKGROUND AND PURPOSE: The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a key transcription factor regulating genes involved in adipogenesis, glucose homeostasis and cell differentiation. Moreover, PPARgamma has been demonstrated to control proliferation and apoptosis in various cancer cells. We investigated the biological effects of PPARgamma activation by the oral antidiabetic agent pioglitazone in Barrett's adenocarcinoma cells in vitro and in vivo. RESULTS: PPARgamma mRNA and protein were overexpressed in endoscopic biopsies of Barrett's epithelium and the human Barrett's adenocarcinoma cancer cell line OE33 as compared to normal esophagus and stomach and the esophageal squamous epithelium cancer cell line Kyse-180. PPARgamma activation by pioglitazone in OE33 cells in vitro led to reduced cell growth by induction of apoptosis. Effects of systemic PPARgamma activation by the thiazolidinedione pioglitazone on tumor cell proliferation and apoptosis were then assessed in vivo in nude mice bearing transplantable Barrett's adenocarcinomas derived from OE33 cells. Unexpectedly, enhanced growth of OE33 derived transplantable adenocarcinomas was observed in Balb/c nu/nu mice upon systemic pioglitazone treatment due to increased cell proliferation. CONCLUSION: These results indicate that PPARgamma is involved in the molecular pathogenesis of Barrett's adenocarcinoma formation and growth. However, activation of PPARgamma exerts differential effects on growth of Barrett's adenocarcinoma cells in vitro and in vivo emphasizing the importance of additional cell context specific factors and systemic metabolic status for the modulation of PPARgamma action in vivo.

Psychopathological changes and quality of life in hepatitis C virus-infected, opioid-dependent patients during maintenance therapy.

AIMS: To examine among maintenance patients (methadone or buprenorphine) with and without hepatitis C virus (HCV) infection (i) the frequency of psychopathological symptoms at baseline and 1-year follow-up; (ii) the association between antiviral interferon (IFN) treatment and psychopathological symptoms; and (iii) to explore whether IFN therapy has an effect on 1-year outcome of maintenance treatment. DESIGN: Naturalistic prospective longitudinal cohort design. SETTING: A total of 223 substitution centres in Germany. PARTICIPANTS: A nationally representative sample of 2414 maintenance patients, namely 800 without and 1614 with HCV infection, of whom 122 received IFN therapy. MEASURES: HCV infection (HCV+/HCV-), IFN (IFN+/IFN-) treatment status and clinical measures. Diagnostic status and severity (rated by clinician), psychopathology (BSI--Brief Symptom Inventory) and quality of life (EQ-5D--EuroQol Group questionnaire). FINDINGS: HCV+ patients revealed indications for a moderately increased psychopathological burden and poorer quality of life at baseline and follow-up compared to HCV- patients. HCV+ patients showed a marked deterioration over time only in the BSI subscale somatization (P = 0.002), and the frequency of sleep disorders almost doubled over time (12.8% at baseline; 24.1% at follow-up; P < 0.01). IFN treatment, received by 10% of HCV+ patients, did not impair efficacy or tolerability of maintenance therapy and was associated overall with neither increased psychopathological burden nor reduced quality of life. CONCLUSIONS: Findings suggest no increased risk among HCV+ patients on maintenance therapy for depressive or other psychopathological syndromes. In our patient sample, IFN treatment was not associated with increased psychopathological burden, reduced quality of life or poorer tolerability and efficacy of maintenance treatment.

Deterioration of health-related quality of life and fatigue in patients with chronic hepatitis C: Association with demographic factors, inflammatory activity, and degree of fibrosis.

BACKGROUND/AIMS: Health-related quality of life (HRQoL) is impaired in patients with chronic hepatitis C. We investigated HRQoL and fatigue in patients with chronic hepatitis C virus (HCV) infection in relation to the degree of fibrosis and inflammation, and controlled for the influence of relevant demographic and medical variables. METHODS: We conducted a cross-sectional two-center study including 215 outpatients with chronic hepatitis C applying the Short-Form Health Survey (SF-36) and the Fatigue Impact Scale (FIS-D). The contribution to the variability of these psychometric scores was evaluated for the degree of fibrosis as well as viremia, gender, age, mode of transmission, genotype, and ALT. RESULTS: There was a strong negative association between the degree of liver fibrosis and the physical SF-36 summary score (p=0.016). This was independent of the covariate age, also significantly predicting physical HRQoL (p=0.001). The absolute FIS score was significantly increased in patients with advanced fibrosis (p=0.043). In females, mental SF-36 summary score (p=0.007) and fatigue (p=0.017) were significantly more impaired. CONCLUSIONS: Our study suggests a significant association of physical aspects of HRQoL and fatigue with the extent of fibrosis. Fibrosis stage should be considered for the identification and management of HCV patients at risk for reduced physical HRQoL.

Feasibility and outcome of substitution treatment of heroin-dependent patients in specialized substitution centers and primary care facilities in Germany: a naturalistic study in 2694 patients.

BACKGROUND: In many countries, buprenorphine and methadone are licensed for the maintenance treatment (MT) of opioid dependence. Despite many short-term studies, little is known about the long-term (12-month) effects of these treatments in different settings, i.e. primary care-based (PMC) and specialized substitution centers (SSCs). OBJECTIVES: To describe over a period of 12 months: (1) mortality, retention and abstinence rates; (2) changes in concomitant drug use, somatic and mental health; and (3) to explore differences between different types of provider settings. METHODS: 12-Month prospective-longitudinal naturalistic study with four waves of assessment in a prevalence sample of N=2694 maintenance patients, recruited from a nationally representative sample of N=223 substitution physicians. RESULTS: The 12-month retention rate was 75%; the mortality rate 1.1%. 4.1% of patients became "abstinent" during follow-up. 7% were referred to drug-free addiction treatment. Concomitant drug use decreased and somatic health status improved. No significant improvements were observed for mental health and quality of life. When controlling for initial severity, small PMC settings revealed better retention, abstinence and concomitant drug use rates. CONCLUSION: The study underlines the overall 12-month effectiveness of various forms of agonist MT. Findings reveal relatively high retention rates, low mortality rates, and improvements in most 12-month outcome domains, except for mental health and quality of life. PMC settings appear to be a good additional option to improve access to MTs.

Sustained virological response in the antiviral therapy of chronic hepatitis C: is there a predictive value of interferon-induced depression?

BACKGROUND: The study objective was to determine the contribution of cytokine-induced depression to a predictive model of sustained virological response (SVR) in chronic hepatitis C. METHODS: One hundred and one therapy-naïve hepatitis C virus (HCV) outpatients received treatment with peginterferon alfa-2b and ribavirin. Neuropsychiatric side effects were monitored prospectively (Hospital Anxiety and Depression Scale, DSM-IV criteria for major depression). SVR was defined as a failure to detect HCV by PCR 24 weeks after therapy. RESULTS: SVR rate was 72.3% (73 of 101 patients). Classification data and the extent of interferon-induced depression were not significantly linked to SVR. Virus genotype (p = 0.045) and gender (p = 0.016) contributed significantly to a logistic regression model. Mean (p = 0.811) and maximum (p = 0.744) depression increases were no significant predictors of SVR. Major depression rates (DSM-IV criteria) were 12.3% (9 of 73 patients) in the subgroup with SVR and 10.7% (3 of 28) in patients without SVR. CONCLUSIONS: We found no significant association between depression and the efficacy of antiviral treatment in chronic hepatitis C. Interferon-induced depressive symptoms are important to be monitored and treated if necessary; however, they cannot be used to predict therapy success.

Serotonin-1A receptor gene HTR1A variation predicts interferon-induced depression in chronic hepatitis C.

BACKGROUND & AIMS: Interferon-induced depression is a major complication in antiviral therapy of chronic hepatitis C. Little is known about underlying mechanisms and reliable predictive factors associated with cytokine-induced depressive symptoms. METHODS: In a cohort of 139 hepatitis C-infected outpatients treated with interferon alfa-2b, we investigated the impact of functional gene variants of the cerebral serotonin (5-HT) signalling pathway previously implicated in depression risk. Depression was monitored using the Hospital Anxiety and Depression Scale (HADS). All patients were genotyped for functional variations in the 5-HT(1A) receptor (HTR1A), 5-HT transporter (SLC6A4, 5-HTT), and tryptophan hydoxylase-2 (TPH2). RESULTS: Homozygosity for the HTR1A-1019G variant significantly increased both incidence and severity of interferon-induced depression. Maximum increases in HADS depression scores during antiviral therapy correlated with HTR1A variation (P = .011). Clinically relevant depression was significantly associated with the HTR1A-1019G genotype (P = .017; OR, 2.95). 5-HTT and TPH2 variations did not contribute significantly to the prediction of interferon-induced depression by HTR1A (sensitivity, 35.9%; specificity, 84.0%). CONCLUSIONS: Our findings suggest an impact of allelic variation in 5-HT(1A) receptor expression on the development of interferon alfa-induced depression during antiviral treatment of chronic hepatitis C. Prediction models of interferon-induced depressive symptoms based on HTR1A variation offer a perspective for an antidepressant selective serotonin reuptake inhibitor prophylaxis in patients genetically at risk for interferon-induced depression.

High recurrence rate of Barrett's epithelium during long-term follow-up after argon plasma coagulation.

OBJECTIVE: Several studies have shown that argon plasma coagulation (APC) combined with proton-pump inhibitor (PPI) therapy is a suitable procedure to eradicate Barrett's epithelium for a short-term follow-up. The real impact of this kind of management with respect to cancer risk and durability of squamous regeneration remains unclear. We present the follow-up data for up to 51 months after eradication of Barrett's mucosa. MATERIAL AND METHODS: In 1998-2001, 25 patients with Barrett's esophagus were included in a prospective study. After baseline documentation, Barrett's epithelium was treated with repeated APC until complete squamous restoration was reached. Thereafter, all patients were continuously treated with high-dose PPIs. RESULTS: Each patient underwent a median of four APC sessions. Twenty-one (84%) of the patients had complete squamous regeneration at the end of treatment. During a follow-up of up to 51 months, Barrett's epithelium was found to have recurred in 14/21 (66%) patients. Including the patients with initially incomplete squamous restoration, a long-lasting and complete effect was achieved in only 7 patients (28%) after a mean follow-up period of 30 months. CONCLUSIONS: So far, it is still not proven whether coagulation-induced squamous regeneration reduces the risk of Barrett's carcinoma. Furthermore, the high relapse rate, the procedure-related risk, and the high costs incurred preclude the routine use of APC for the treatment of non-dysplastic Barrett's esophagus. The different recurrence rates between published studies may be due to technical differences and PPI schedule. We suggest that optimal conditions for the procedure must be defined before further studies are undertaken.

Methodological approaches in the assessment of interferon-alfa-induced depression in patients with chronic hepatitis C - a critical review.

In recent years, research on interferon (IFN)-induced depressive symptoms in antivirally treated patients suffering from chronic hepatitis C (CHC) has considerably intensified. Profound scientific knowledge of this complication is of great relevance with regard to adherence, compliance, and premature therapy discontinuation. Presently, there is considerable variability of both, the frequency and extent of IFN-induced depression reported in different cohorts of patients. The aim of the presented study was to systematically review recent literature of research within this field; and particularly (1) to identify to what extent methodological bias contributed to inconsistent results in different studies, (2) to critically appraise methods and results of studies published so far, and (3) to suggest directions for future work, especially with respect to alternative and improved methodological approaches. The results of this critical review suggest that the variability of findings seem to be largely due to different study populations, treatment regimens, methodological approaches, and sometimes arbitrary or at least poorly defined choice of screening instruments for depression, particularly criteria for clinically relevant depression (cut-off criteria). Study designs and methodological approaches to investigate IFN-alfa-induced depression in patients with CHC have been incoherent. Future research in this field needs agreement on the use of standardized assessment of IFN-induced depression in CHC. Furthermore, objective criteria and guidelines for the treatment of IFN-induced depression in these patients are needed in clinical practice.

Physician-patient relationship and disclosure behaviour in chronic hepatitis C in a group of German outpatients.

OBJECTIVES: In chronic hepatitis C infection, the doctor-patient relationship can be burdened for various reasons. Factors associated with the doctor-patient relationship and self-disclosure of hepatitis C virus (HCV) status have not so far been investigated systematically. The goal of the study was to examine self-disclosure of HCV positivity, perceived stigmatization, and potential predictor variables in a German outpatient group. METHODS: In a cross-sectional single-centre study, we included a volunteer sample of 103 HCV outpatients. Patient recruitment was between March 2003 and September 2004. Data were obtained from a fully standardized face-to-face interview [HCV disclosure behaviour (main interview variable), stigmatization, doctor-patient relationship] and psychometric self-assessment questionnaires [Hospital Anxiety and Depression Scale, German version; Symptom Checklist-90 Revised (global severity index); Inventory of Interpersonal Problems (total score)]. RESULTS: The overall general disclosure rate was 44.7% (with respect to all physicians). However, 75% stated revealing their positive serostatus in future physician appointments (P < 0.05). With respect to family/friends, disclosure rates were clearly higher (permanent partner, 99%; average, 76.7%). Patients' disclosure behaviour could not be predicted by sociodemographic variables or personality factors (binary logistic regression, P > 0.05). Similarly, the Hospital Anxiety and Depression Scale and Symptom Checklist-90 subscales were not substantially associated with HCV disclosure. Experiences of stigmatization (rate 38.8%) were more frequent in women (P = 0.014) and patients with higher depression scores (P = 0.029). CONCLUSIONS: There is a need for education in the field of chronic hepatitis C in order to improve the physician-patient relationship. HCV disclosure rates might thus be increased and the frequency of problematic contacts reduced. Importantly, the data show that physicians should explicitly ask for the patients' HCV status because unrequested disclosure cannot be taken for granted.

Prediction of progression to cirrhosis by a glutathione S-transferase P1 polymorphism in subjects with hereditary hemochromatosis.

BACKGROUND: Oxidative stress plays an important pathogenic role in hereditary hemochromatosis (HHC) and chronic hepatitis C virus infection (CHC). Several enzymes involved in the degradation of reactive oxidants and xenobiotics, such as glutathione S-transferase P1 (GSTP1) and manganese superoxide dismutase (MnSOD), reveal polymorphisms that affect their antioxidant capacity and may therefore modulate the progression to cirrhosis. Our objective was to establish the role of the functional polymorphisms of GSTP1 (codon 105 Ile-->Val) and MnSOD (codon 16 of precursor protein Ala-->Val) on the evolution of cirrhosis in patients with HHC and CHC. METHODS: One hundred seventy-two patients with HHC who were homozygous for the C282Y mutation and 285 patients with CHC underwent liver biopsy and genotyping for the GSTP1 and MnSOD polymorphisms. RESULTS: In HHC, the GSTP1 Val/Val genotype was more common in patients with than in those without cirrhosis (14.8% vs 2.1%, P = .009), whereas the distribution of MnSOD variants was not different. Logistic regression analysis identified GSTP1 Val/Val genotype, serum ferritin level, male sex, and age as independent predictors for the presence of cirrhosis. The odds ratio for the GSTP1 Val/Val genotype for the development of cirrhosis was 3.85 (95% confidence interval, 1.18-12.62; P = .03). However, in patients with CHC, the GSTP1 and MnSOD genotypes were not associated with cirrhosis. CONCLUSIONS: Cirrhosis is more likely to develop in C282Y homozygotes with the GSTP1 Val/Val genotype than in those with non-Val/Val genotypes, which in part explains the variable phenotypic expression of HHC and highlights the central role of oxidative stress in its pathogenesis.

Buprenorphine and methadone in the treatment of opioid dependence: methods and design of the COBRA study.

Buprenorphine and methadone are the two established substitution drugs licensed in many countries for the treatment of opioid dependence. Little is known, however, about how these two drugs are applied and how they work in clinical practice. In this paper we present the aims, methods, design and sampling issues of a collaborative multi-stage epidemiological study (COBRA) to address these issues. Based on a nationally representative sample of substitution physicians, the study is designed as an observational, naturalistic study, consisting of three major parts. The first part was a national survey of substitution doctors (prestudy, n = 379 doctors). The second part was a cross-sectional study (n = 223 doctors), which consisted of a target-week assessment of 2,694 consecutive patients to determine (a) the severity and problem profiles and treatment targets; (b) the choice and dosage scheme of the substitution drug; (c) past and current interventions, including treatment of comorbid hepatitis C; and (d) cross-sectional differences between the two drugs with regard to comorbidity, clinical course, acceptance/compliance and social integration. The third part consists of a prospective-longitudinal cohort study of 48 methadone-treated and 48 buprenorphine-treated patients. The cohort is followed up over a period of 12 months to investigate whether course and outcome of the patients differ by type or treatment received in terms of clinical, psychosocial, pharmaco-economic and other related measures. The response rate among substitution doctors was 57.1%; that among eligible patients was 71.7%. Comparisons with the federal registers reveal that the final samples of doctors and patients may be considered nationally representative with regard to regional distribution, training, type of setting as well as the frequency of patients treated with buprenorphine or methadone. The COBRA study provides a unique comprehensive database, informing about the natural allocation and intervention processes in routine care and about the course and outcome of patients treated with buprenorphine or methadone.

Psychiatric side effects of pegylated interferon alfa-2b as compared to conventional interferon alfa-2b in patients with chronic hepatitis C.

AIM: To assess systematically the spectrum and extent of depressive symptoms comparing patient groups receiving peginterferon or conventional interferon. METHODS: Ninety-eight patients with chronic hepatitis C and interferon-based therapy (+ribavirin) were consecutively enrolled in a longitudinal study. Patients were treated with conventional interferon alfa-2b (48/98 patients; 5 MIU interferon alfa-2b thrice weekly) or peginterferon alfa-2b (50/98 patients; 80-150 mug peginterferon alfa-2b) in combination with weight-adapted ribavirin (800-1 200 mg/d). Repeated psychometric testing was performed before, three times during and once after antiviral therapy: Depression was evaluated by the Hospital Anxiety and Depression Scale (HADS), anger/hostility by the Symptom Checklist-90 Items Revised (SCL-90-R). RESULTS: Therapy with pegylated interferon alfa-2b produces comparable scores for depression (ANOVA: P = 0.875) as compared to conventional interferon. Maximums of depression scores were even higher and cases of clinically relevant depression were frequent during therapy with peginterferon. Scores for anger/hostility were comparable for both therapy subgroups. CONCLUSION: Our findings suggest that the extent and frequency of depressive symptoms in total are not reduced by peginterferon. Monitoring and management of neuropsychiatric toxicity especially depression have to be considered as much as in antiviral therapy with unmodified interferon.

Neurocognitive changes in patients with hepatitis C receiving interferon alfa-2b and ribavirin.

BACKGROUND: During antiviral therapy of chronic hepatitis C, patients frequently report impairment of concentration or memory. Therefore we prospectively investigated neurocognitive performance in patients receiving interferon alfa and ribavirin. METHODS: Repeated computer-based testing of neurocognitive function was performed in 70 patients with chronic hepatitis C receiving interferon alfa-2b (pegylated or conventional) and ribavirin. In addition, depression scores were obtained (Hospital Anxiety and Depression Scale). RESULTS: Reaction times were significantly increased during treatment (mean reaction time increase after 3 months of therapy: alertness, 46.76 ms [95% confidence interval (CI)], 26.86-66.66 ms), P < .001; divided attention, 47.04 ms [95% CI, 26.44-67.64 ms], P < .001; vigilance, 60.78 ms [95% CI, 29.24-92.32 ms], P < .001; and working memory, 38.53 ms [95% CI, 1.22-75.83], P = .34). Accuracy measures (number of false reactions) were affected for the working-memory task exclusively. Cognitive performance returned to pretreatment values after the end of therapy. Cognitive impairment was not significantly correlated with the degree of concomitant depression (0.04 < r [absolute value] < 0.10, P > .390). CONCLUSIONS: Interferon-based combination therapy of chronic hepatitis C causes significant but reversible impairment of neurocognitive performance. Consequences for the requirements of an active life in patients with chronic hepatitis C receiving antiviral therapy need to be assessed.