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.

Escitalopram for the prevention of peginterferon-α2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.

BACKGROUND: Depression is a major complication during treatment of chronic hepatitis C virus (HCV) infection with interferon-α (IFN-α). It is unclear whether antidepressants can prevent IFN-induced depression in patients without psychiatric risk factors. OBJECTIVE: To examine whether preemptive antidepressant treatment with escitalopram can decrease the incidence or severity of depression associated with pegylated IFN-α in HCV-infected patients without a history of psychiatric disorders. DESIGN: Randomized, multicenter, double-blind, prospective, placebo-controlled, parallel-group trial. (ClinicalTrials.gov registration number: NCT00136318) SETTING: 10 university and 11 academic hospitals in Germany. PATIENTS: 181 HCV-infected patients with no history of psychiatric disorders enrolled between August 2004 and December 2008. INTERVENTION: Escitalopram, 10 mg/d (n = 90), or placebo (n = 91) administered 2 weeks before and for 24 to 48 weeks during antiviral therapy. MEASUREMENTS: The primary end point was the incidence of depression, defined as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 13 or higher. Secondary end points were time to depression, incidence of major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, quality of life, sustained virologic response, tolerability, and safety. RESULTS: 32% (95% CI, 21% to 43%) of the patients in the escitalopram group developed a MADRS score of 13 or higher compared with 59% (CI, 48% to 69%) in the placebo group (absolute difference, 27 percentage points [CI, 12 to 42 percentage points]; P < 0.001). Major depression was diagnosed in 8% of the patients in the escitalopram group and 19% in the placebo group (absolute risk difference, 11 percentage points [CI, 5 to 15 percentage points]; P = 0.031). Tolerability and safety parameters did not differ between the groups. In the escitalopram group, 56% (CI, 46% to 66%) of patients achieved a sustained virologic response compared with 46% (CI, 37% to 57%) in the placebo group (P = 0.21). LIMITATIONS: Results might not be generalizable to patients with previous psychiatric disease. Some patients withdrew or developed temporary elevated MADRS scores after randomization but before the study medication was started. CONCLUSION: Prophylactic antidepressant treatment with escitalopram was effective in reducing the incidence and severity of IFN-associated depression in HCV-infected patients without previous psychiatric disease. PRIMARY FUNDING SOURCE: Roche Pharma and Lundbeck.

Elevated liver enzymes predict morbidity and mortality despite antiviral cure in patients with chronic hepatitis C: Data from the German Hepatitis C-Registry.

While direct-acting antivirals (DAAs) cure chronic hepatitis C virus (HCV) infection in almost all patients, some patients remain at risk of liver disease despite HCV cure. In order to identify risk factors indicating liver-related morbidity and death after viral cure, we included 6982 patients from the national multicenter real-world German Hepatitis C Registry with regular follow-up visits for up to 7 years after DAA therapy. Definitions for normal liver function tests (in women/men) were alanine aminotransferase (ALT; ≤35/≤50 U/L), ALT according to American Association for the Study of Liver Diseases (AASLD; ≤19/≤30 U/L), and gamma-glutamyltransferase (GGT; ≤40/≤60 U/L). In our cohort, 97.4% of patients achieved sustained virologic response (SVR). At 24 weeks after SVR (SVR24), elevated ALT occurred in 657/6982 (9.4%), elevated ALT (AASLD) in 2609/6982 (37.4%), and elevated GGT in 1777/6982 (25.5%) patients. Risk factors for increased ALT at SVR24 were obesity, alcohol, cirrhosis, elevated baseline ALT, and non-SVR. Increased GGT at SVR24 was significantly (p < 0.05) and independently associated with male sex (odds ratio [OR], 2.12), higher body mass index (OR, 1.04), age >50 years (OR, 1.60), liver cirrhosis (OR, 3.97), alcohol consumption (OR, 2.99), diabetes (OR, 1.63), non-SVR (OR, 8.00), and elevated GGT at baseline (OR, 17.12). In multivariate regression analysis, elevated GGT at SVR24, particularly in combination with cirrhosis, was the best predictor for hepatic decompensation, hepatocellular carcinoma development, and death, followed by elevated ALT (AASLD) and standard ALT, which predicted hepatic decompensation. Despite successful HCV therapy, elevated GGT at SVR24 and to a lesser extent ALT are predictive of the future clinical outcome and linked with liver-associated comorbidities. This may highlight the relevance of nonalcoholic fatty liver disease, diabetes mellitus, alcohol, and cirrhosis for the clinical outcome in a vulnerable population, even after HCV cure.

Weight Gain after Interferon-Free Treatment of Chronic Hepatitis C-Results from the German Hepatitis C-Registry (DHC-R).

Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (-0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48%, 31%, and 22% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated.

Influence of gender on cytokine induced depression and treatment: Gender aspects of IFN-α-induced depression.

BACKGROUND: Cytokine treatment with Interferon-alpha (IFN-α) represents a clinical model of immune associated depression, but it remains unclear if it is of the same entity as major depressive disorder (MDD). The study focuses on possible gender differences in IFN-α induced depression and effects of a pre-emptive antidepressant treatment. METHODS: Data from 181 patients with chronic hepatitis C infection (cHC) without history of mental illnesses undergoing treatment with IFN-α 2a and ribavirin were re-analyzed for gender effects. Patients with a pre-emptive antidepressant therapy with Escitalopram (n = 90, verum group) to prevent IFN-induced depression were compared to patients who received placebo (n = 91). Depressive symptoms before and during HCV-treatment were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), Beck's Depression Inventory (BDI) and the Hamilton Anxiety Rating Scale. RESULTS: We found significant differences regarding the incidence and severity of depressive symptoms between men and women for patients without antidepressant pre-treatment (placebo group). Significantly more women without pre-emptive antidepressant therapy suffered from clinically relevant depression (MADRS values ≥ 13, p = 0.041) and self-rated depressive symptoms (BDI ≥ 17, p = 0.024). Antidepressant pre-treatment showed comparable effects regarding the reduction of incidence and severity of depression in both women and men. CONCLUSIONS: Compared to MDD, IFN-alpha-induced depression in patients with cHC is also characterized by gender differences with an increased risk for women but no gender difference regarding the effects of an antidepressant pre-treatment is found. Our data strengthens the hypothesis that Interferon-induced depression serves as a clinical model for immune related depressive disorders.

Outcomes and Costs of Treating Hepatitis C Patients in the Era of First Generation Protease Inhibitors - Results from the PAN Study.

1 OBJECTIVE: Chronic hepatitis C virus infections (HCV) cause a significant public health burden. Introduction of telaprevir (TVR) and boceprevir (BOC) has increased sustained virologic response rates (SVR) in genotype 1 patients but were accompanied by higher treatment costs and more side effects. Aim of the study was to assess outcomes and costs of treating HCV with TVR or BOC in routine care. 2 MATERIAL AND METHODS: Data was obtained from a non-interventional study. This analysis relates on a subset of 1,786 patients for whom resource utilisation was documented. Sociodemografic and clinical parameters as well as resource utilisation were collected using a web-based data recording system. Costs were calculated using official remuneration schemes. 3 RESULTS: Mean age of patients was 49.2 years, 58.6% were male. In treatment-naive patients SVR-rates of 62.2% and 55.7% for TVR and BOC were observed (prior relapser: 68.5% for TVR and 63.5% for BOC; prior non-responder: 45.6% for TVR and 39.1% for BOC). Treatment costs are dominated by costs for pharmaceuticals and range between €39,081 and €53,491. We calculated average costs per SVR of €81,347 (TVR) and €70,163 (BOC) in treatment-naive patients (prior relapser: 78,089 €/SVR for TVR and 82,077 €/SVR for BOC; prior non-responder: 116,509 €/SVR for TVR and 110,156 €/SVR for BOC). Quality of life data showed a considerable decrease during treatment. 4 CONCLUSION: Our study is one of few investigating both, outcomes and costs, of treating HCV in a real-life setting. Data can serve as a reference in the discussion of increasing costs in recently introduced agents.

Performance and Value of IFN-Lambda3 and IFN-Lambda4 Genotyping in Patients with Chronic Hepatitis C (CHC) Genotype 2/3 in a Real World Setting.

BACKGROUND: SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3. METHODS: We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631). RESULTS: Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%). CONCLUSION: IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.

Treatment of naïve patients with chronic hepatitis C genotypes 2 and 3 with pegylated interferon alpha and ribavirin in a real world setting: relevance for the new era of DAA.

Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10-20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources.

Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon-alpha therapy.

BACKGROUND: The efficacy of consensus interferon (CIFN), a synthetic IFN with optimised in vitro activity, was assessed in chronic hepatitis C virus (HCV) patients who had failed the pretreatment with interferon-alpha (IFNalpha) and ribavirin. METHODS: One hundred and three patients after non-response (n=69) or relapse (n=34) to IFNalpha+/-ribavirin were randomly assigned to high-dose induction (CIFN 27-->9 microg daily for 24 weeks, 9 microg t.i.w. for 24 weeks) or low-dose treatment (CIFN 18 microg t.i.w. for 12 weeks, 9 microg t.i.w. for 36 weeks); each with ribavirin 800 mg/day. Follow-up was 24 weeks. RESULTS: Non-responder patients treated with high-dose induction had higher early virological response rates (63% vs. 39%, P<0.05). This initial positive effect was lost during the last 24 weeks of treatment yielding sustained virological response (SVR) rates of 26% in both groups. Relapse patients revealed SVR in 70% and 38% in groups A and B (NS). Treatment was well tolerated with side effect-related preterm discontinuations in 8% and 5%. CONCLUSIONS: CIFN and ribavirin treatment induced considerable SVR rates in patients with non-response or relapse to IFNalpha+/-ribavirin. Viral elimination rates might be further increased by continuous daily administration of CIFN and weight-adjusted ribavirin dosing.