Effectiveness of First-Line Bevacizumab in Metastatic Colorectal Cancer: The Observational Cohort Study GRETA.

BACKGROUND: Scant real-world data exist on the clinical outcomes associated with the use of bevacizumab-containing chemotherapy (B+CT) in patients with metastatic colorectal cancer (mCRC). The primary objective of the GRETA cohort study was to compare the overall survival (OS) of patients with mCRC treated with first-line B+CT versus chemotherapy (CT) alone, in an Italian clinical practice setting. MATERIALS AND METHODS: Incident patients with mCRC were identified during the period 2010-2012 from five population-based cancer registries in Italy. Cases were linked to regional health care utilization databases to obtain the entire spectrum of health services provided to each patient. Patients starting a first-line treatment with B+CT or CT alone within 90 days from the diagnosis were included in the study cohort. A propensity score (PS) method was applied to account for residual confounding. RESULTS: Of 480 patients with mCRC included in the study cohort, 21.0 received first-line B+CT, and 79.0% received CT. Patients receiving B+CT were younger (p < .001) and underwent surgery more frequently (p = .001). The median OS was 22.5 and 14.6 months for B+CT and CT, respectively (p = .011). The corresponding hazard ratios adjusted by multivariate modeling and PS matched analysis were 0.82 (95% confidence interval [CI], 0.62-1.08) and 0.86 (95% CI, 0.56-1.33), respectively. Similar results were observed after subgrouping by age and surgery. CONCLUSION: In this Italian real-world setting of unselected mCRC, the OS of patients treated with B+CT was consistent with previous observational and patient-registry studies. However, definitive evidence of an improvement in OS cannot be drawn. IMPLICATIONS FOR PRACTICE: Bevacizumab is a well-established first-line treatment for metastatic colorectal cancer. However, there is scarce evidence in the literature about its effectiveness in clinical practice. Evaluating this topic should be of interest for both clinicians and regulatory agencies. In this study, the median overall survival of the bevacizumab cohort was strikingly coherent with that reported in large observational series of unselected patients, thus suggesting a consistent and reproducible effect of the drug in clinical practice. Although consistent results were observed both in the overall population and in age and surgery subgroups, the present study did not offer definitive evidence of an improvement in OS.

Obinutuzumab Plus Chemotherapy Compared with Rituximab Plus Chemotherapy in Previously Untreated Italian Patients with Advanced Follicular Lymphoma at Intermediate-High Risk: A Cost-Effectiveness Analysis.

OBJECTIVE: To assess the cost-effectiveness of obinutuzumab (O-chemo) in comparison to rituximab (R-chemo) in patients with untreated advanced follicular lymphoma (FL) at intermediate or high risk from an Italian National Health Service (NHS) perspective. METHODS: A previously developed four-state Markov model was adapted to estimate lifetime clinical outcomes and costs of Italian patients with advanced FL and an FL international predictive index score ≥2 in treatment with O-chemo and R-chemo. Life expectancy was derived from the GALLIUM and PRIMA clinical trials. Progression-free survival (PFS), early progressive disease (PD), and treatment duration were extrapolated by fitting parametric distributions to empirical data in GALLIUM and late PD to data in PRIMA. Expected survival was weighed by published utilities. Costs updated to 2020 Euros and health gains occurring after the first year were discounted at an annual 3% rate. Probabilistic sensitivity analysis (PSA) was carried out. RESULTS: O-chemo was associated with an incremental survival increase (0.97 life-years [LYs]), even when weighted for quality (0.88 quality-adjusted LYs [QALYs]), and incremental costs (around €15,000), driven by longer treatment during PFS state relative to R-chemo. The incremental cost-effectiveness ratio and incremental cost-utility ratio are both widely accepted by the Italian NHS (around €15,500/LY and €17,000/QALY gained, respectively). PSA simulations confirmed the robustness of results given sensible variations in assumptions. CONCLUSION: O-chemo has superior clinical efficacy compared to rituximab, and should be considered a cost-effective option in first-line treatment of patients with advanced FL at intermediate or high risk in Italy. Incremental cost-effectiveness ratios are below the threshold considered affordable by developed countries.

Relationships between Dream and Previous Wake Emotions Assessed through the Italian Modified Differential Emotions Scale.

Despite the increasing interest in sleep and dream-related processes of emotion regulation, their reflection into wake and dream emotional experience remains unclear. Here, we aimed to assess dream emotions and their relationships with wake emotions through the modified Differential Emotions Scale (Fredrickson, 2003), which includes a broad array of both positive and negative emotions. The scale has been first validated on 212 healthy Italian participants, in two versions: a WAKE-2wks form, assessing the frequency of 22 emotions over the past 2 weeks, and a WAKE-24hr form, assessing their intensity over the past 24 h. Fifty volunteers from the wider sample completed the WAKE-24hr mDES for several days until a dream was recalled, and dream emotions were self-reported using the same scale. A bifactorial structure was confirmed for both mDES forms, which also showed good validity and reliability. Though Positive and Negative Affect (average intensity of positive and negative items, PA, and NA, respectively) were balanced in dreams, specific negative emotions prevailed; rmANOVA showed a different pattern (prevalence of PA and positive emotions) in wake (both WAKE-2wks and WAKE-24hr), with a decrease of PA and an increase of NA in the dream compared to previous wake. No significant regression model emerged between waking and dream affect, and exploratory analyses revealed a stable proportion of PA and NA (with prevailing PA) over the 3 days preceding the dream. Our findings highlight a discontinuity between wake and dream affect and suggest that positive and negative emotions experienced during wake may undertake distinct sleep-related regulation pathways.

A genotype-specific baseline score predicts post-treatment response to peginterferon alfa-2a in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: Peginterferon alfa-2a induces durable responses in some hepatitis B e antigen-negative patients, but robust pretreatment predictors are not available to identify likely responders. In this study we aimed to develop genotype-specific baseline scoring systems to predict response. METHODS: Data from 323 hepatitis B e antigen-negative peginterferon alfa-2a recipients from three studies were analyzed. Scoring systems were developed using generalized additive models and multiple logistic regression analysis. Response was defined as hepatitis B virus DNA <2000 IU/mL alone (virological response) or in combination with alanine aminotransferase normalization (combined response) 48 weeks post-treatment. RESULTS: Points were assigned to genotype B/C patients for: age, alanine aminotransferase ratio, genotype B or C, and hepatitis B surface antigen level; and to genotype D patients for age, hepatitis B surface antigen level and hepatitis B virus DNA level. Higher total scores (range 0-5 for B/C; 0-3 for D) indicated a higher likelihood of response. Among genotype B/C patients with scores of 0-1, 2 and ≥3, respectively, virological response rates were 16.7%, 25.8% and 70.2%, and combined response rates were 12.5%, 21.0% and 57.4%. Among genotype D patients with scores of 0-1, 2 and 3, respectively, virological response rates were 10.1%, 28.0% and 50.0%, and combined response rates were 7.8%, 28.0% and 33.3%. CONCLUSION: Genotype-specific baseline scoring systems can identify hepatitis B e antigen-negative patients with low or high likelihood of achieving sustained responses to peginterferon alfa-2a.

Effect of aging, glucose level, and HIV viral load on response to treatment with pegylated interferon plus ribavirin in HIV/HCV co-infected women.

BACKGROUND: This was a post-hoc analysis of the Optimized Pegylated interferons Efficacy and anti-Retroviral Approach (OPERA) study, originally designed to document routine clinical and treatment data in HIV/HCV coinfected patients treated with pegylated interferon/ribavirin (PEG-IFN/RBV). The aim of this study was to define the impact of several variables, such as age, glucose metabolism, and HIV viral load, on PEG-IFN/RBV treatment outcomes, in HIV/HCV coinfected women. METHODS: Female subjects from the OPERA database were retrospectively evaluated and factors associated with sustained virological response (SVR) were assessed and compared to the male population by logistic regression analysis. At baseline, clinical and demographic data were collected. Patients were then administered with PEG-IFN/RBV therapy for 48 weeks. After a 24-week follow-up period, SVR was evaluated. RESULTS: A total of 1523 patients were enrolled in 98 centers across Italy, 1284 of whom were IFN therapy naïve and were included in the post-hoc analysis. In the female group, factors associated with SVR were the presence of HCV genotype 2,3 (adjusted odds ratio [AOR]=6.87, p<0.0001), age ≤45 years (AOR=2.61, p=0.014), ≥80% exposure to PEG-IFN (AOR=3.85, p=0.019) and RBV (AOR=3.94, p=0.015) therapy. Also, increased glucose plasma level negatively correlated with SVR (AOR=0.98, p=0.066). In the male population, undetectable HIV-RNA (AOR=1.47, p=0.033) but not glucose level (AOR=1.0, p=0.95) predicted SVR. CONCLUSIONS: Findings from the present study demonstrate that several factors may be predictive of SVR when pegylated interferon plus ribavirin is used (i.e., age, gender, HIV viral load and HCV genotype) that need to be carefully considered prior to therapeutic intervention, since they may hinder successful therapy. Use of PEG-IFN/RBV with novel direct antiviral agents will likely be still maintained until less expensive and effective interferon-free strategies become available.

Cytopenias during treatment of HIV-HCV-coinfection with pegylated interferon and ribavirin: safety analysis of the OPERA study.

BACKGROUND: Until recently, recommendations for HCV treatment in HIV-coinfected patients have been combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). However, this treatment is often accompanied with cytopenias which lead to drug-dose reduction/discontinuation, therefore influencing sustained virological response (SVR). This study aimed at evaluating incidence and predictors of cytopenias and to define their impact on SVR in Italian HIV-HCV-coinfected patients undergoing PEG-IFN/RBV treatment. METHODS: OPERA was a multicentric, observational study conducted in 98 Italian centres. Patients with HIV-HCV coinfection were administered with PEG-IFN/RBV combination treatment for 48 weeks. Incidence and time of onset of cytopenias and multiple bone marrow toxicity (mBMT) was monitored. Logistic regression analysis assessed factors associated with SVR, anaemia, neutropenia, thrombocytopenia and mBMT. RESULTS: Between 2005 and 2011, 1,523 patients were enrolled. Anaemia (haemoglobin <10 g/dl) occurred in 197 (12.9%) patients and a haemoglobin drop ≥3 g/dl was recorded in 796 (52.3%). Anaemia did not impact on SVR, its rate being 42.1% and 38.1%, respectively, in patients with and without anaemia (P=0.31). Therapy discontinuation due to anaemia occurred in 47 patients (3.1%). Neutropenia (<1,000 neutrophils/mm(3)) occurred in 652 (42.8%) patients, and SVR was higher (P<0.001) for patients with neutropenia (44.8%) compared to without neutropenia (34%). Patients developing neutropenia did not have an increased risk of developing infections. Thrombocytopenia (<100,000 platelets/mm(3)) occurred in 595 (39.1%) patients, SVR was not influenced by it (38.2% versus 38.9% in patients with and without thrombocytopenia, respectively; P=0.79), and 16 patients (1.1%) discontinued therapy due to it. Cirrhosis was found in 148/734 evaluated patients (20.2%) and was significantly associated with thrombocytopenia (P<0.0001). mBMT was found in 417 patients (27.4%). CONCLUSIONS: Cytopenias are frequent side effects of PEG-IFN/RBV combination therapy in HIV-HCV-coinfected patients. However, SVR is not negatively affected by their presence, nor is there an increased risk of infections in patients developing neutropenia. Several predicting factors for the onset of cytopenias have been unravelled, which will help to identify early those patients at high risk of developing cytopenia.

OPERA: use of pegylated interferon plus ribavirin for treating HCV-HIV coinfection in interferon-naive patients.

BACKGROUND: The Optimized Pegylated interferons Efficacy and anti-Retroviral Approach (OPERA) study aimed to assess the efficacy and safety profile of treatment with pegylated interferons (PEG-IFNs) in interferon-naive patients with chronic HCV and HIV infection in routine clinical practice. METHODS: This was a multicentre, prospective observational cohort study conducted at 98 Italian referral centres for the treatment of chronic HCV and HIV coinfection. Adult subjects (n=1,523) with a confirmed diagnosis of HCV and stable HIV coinfection were followed between April 2005 and March 2011; of these, 1,284 were interferon-naive and were the focus of this analysis. Patients received PEG-IFN-α2a or -α2b plus ribavirin combination therapy. The choice of treatment and dose was at the investigator's discretion, according to the summary of product characteristics and current guidelines. The primary efficacy end point was sustained virological response (SVR). Secondary end points included rates of rapid viral response, early viral response and response at end of treatment. RESULTS: SVR was achieved by 40.0% of patients; the highest SVR rate was observed in patients with HCV genotypes 2 and 3. More genotype 2 and 3 than genotype 1 and 4 patients achieved rapid and early viral responses, and end of treatment responses. Higher SVR rates were also associated with ≥80% anti-HCV treatment compliance and lower baseline HCV levels. CONCLUSIONS: The OPERA study results show that PEG-IFN plus ribavirin is an effective treatment for HCV-HIV coinfection in interferon-naive patients. Independent predictors of SVR include HCV genotype, undetectable baseline HIV RNA and baseline HCV RNA<500,000 IU/ml.

Individualized treatment of HBeAg-negative chronic hepatitis B using pegylated interferon-α2a as first-line and week-12 HBV DNA/HBsAg stopping rule: a cost-effectiveness analysis.

BACKGROUND: Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) is the most frequent and difficult-to-treat viral hepatitis worldwide. HBV DNA and hepatitis B surface antigen (HBsAg) serum levels, which help the early identification of non-responders to pegylated interferon (PEG-IFN), prompt more flexible individualized therapeutic strategies exploiting the benefits of both PEG-IFN and nucleoside/nucleotide analogues (NAs). We assessed the cost-effectiveness of week-12 HBV DNA/HBsAg stopping rule for early interruption and switch to currently most effective NA treatments (entecavir [ETV] or tenofovir disoproxil fumarate [TDF]). METHODS: A decision-analytic Markov model was developed in the following health-related states: CHB, compensated cirrhosis (CC) and decompensated cirrhosis, hepatocellular carcinoma, liver transplant, post-liver transplant, death, virological response, relapse and HBsAg clearance. Simulated strategies included: ETV/TDF in CHB; ETV/TDF delayed until CC; first-line PEG-IFN followed by switch to ETV/TDF for either patients meeting the week-12 stopping rule or week-48 null-responders/relapsers; and first-line PEG-IFN followed by switch to ETV/TDF delayed until CC. ETV and TDF were considered alternatively for a total of eight strategies. A lifetime simulation horizon was applied. RESULTS: Early treatment strategies using NAs with or without first-line PEG-IFN provided the highest results (approximately 22 life-years and 15 quality-adjusted life years [QALYs]). Delayed treatments until cirrhosis development resulted in poorer outcomes. The average per-patient lifetime costs ranged from €33,500 (TDF in CC) to €68,900 (TDF in CHB). Costs using ETV were 20-50% higher. First-line PEG-IFN strategies ranged from dominant (that is, more effective and less costly) to highly cost-effective, although differences in QALYs were always very narrow. CONCLUSIONS: The cost-effectiveness of antiviral therapy of HBeAg-negative CHB could be improved significantly using first-line PEG-IFN followed by a switch to NAs in either patients meeting the week-12 HBV DNA/HBsAg stopping rule or week-48 non-responders/relapsers.