Ellen Lentz

Histologic outcomes in hepatitis C–infected patients with varying degrees of virologic response to interferon‐based treatments

Patients with chronic hepatitis C with partial virologic response or nonresponse to interferon‐based therapies can experience treatment‐related improvements in liver histology. This retrospective analysis assessed the histologic response to treatment in patients with varying degrees of virologic response (sustained virologic response [SVR], breakthrough, relapse, or nonresponse), time to hepatitis C virus (HCV) RNA undetectability, and duration of viral suppression. Patients (HCV genotypes 1‐6) with baseline and follow‐up liver biopsies from eight phase 2 to phase 4 interferon‐based trials were analyzed. Blinded biopsies were evaluated by a single pathologist. Improvements or worsening of METAVIR necroinflammatory activity and fibrosis were defined as increase or decrease of ≥1 grading category from baseline to 24 weeks after end of treatment. A majority of the 1571 patients with paired biopsy data were white, male, with HCV genotype 1/4, baseline HCV RNA levels >800,000 IU/mL, and baseline alanine aminotransferase levels ≤3 × upper limit of the normal range; mean baseline activity and fibrosis scores were 1.8 and 1.7, respectively. Overall, 80% of patients received peginterferon alfa‐2a monotherapy or peginterferon alfa‐2a/ribavirin combination therapy. Mean treatment duration was 46 weeks. There was a positive correlation between the degree of virologic response and improvements in METAVIR activity and fibrosis, and an inverse correlation with worsening activity and fibrosis (all comparisons, P < 0.0001). Patients with SVR had the greatest histologic benefit. As a combined group, relapsers and patients with breakthrough had significantly greater benefits than nonresponders (activity, P = 0.0001; fibrosis, P = 0.003). Consistent with these results, a better histologic response was correlated with a shorter time to undetectable HCV RNA and a longer duration of viral suppression (all comparisons, P < 0.0001). Conclusion: In patients with chronic hepatitis C who were treated with interferon‐based therapies, histologic benefits may be observed even in the absence of an SVR. (HEPATOLOGY 2010;)

Peginterferon α-2a Plus Ribavirin in Latino and Non-Latino Whites With HCV Genotype 1: Histologic Outcomes and Tolerability From the LATINO Study

OBJECTIVES:We sought to compare the histologic response, safety, and tolerability in Latino and non-Latino patients with hepatitis C virus (HCV) genotype 1 treated with peginterferon α-2a plus ribavirin (LATINO study).METHODS:LATINO was a prospective, open-label, multicenter study that enrolled 269 Latinos and 300 non-Latinos receiving peginterferon α-2a 180 μg/week and ribavirin 1,000/1,200 mg/day for 48 weeks. Liver biopsies were obtained within 18 months of baseline and at week 72. Improved or worsened liver fibrosis and necroinflammatory activity were assessed by the Ishak-modified histologic activity index scoring system. Efficacy and safety parameters were monitored during treatment and the 24-week follow-up period.RESULTS:The primary study results published elsewhere showed a higher sustained virologic response (SVR) rate among non-Latinos than Latinos (49% vs. 34%; P<0.001). Paired biopsy data were available for 157 Latinos and 201 non-Latinos. At baseline, more Latinos vs. non-Latinos had alanine aminotransferase (ALT) >3 × the upper limit of normal (20% vs. 18%) and cirrhosis (13% vs. 10%). Both groups experienced improvement in Ishak activity at week 72, although the improvement rates were higher in non-Latinos than Latinos (59% vs. 47%; P=0.03). For both groups, more patients with SVR compared with non-responders had improved Ishak fibrosis scores. In both groups, baseline Ishak activity score (P<0.0001 for both) was predictive of Ishak activity response. Additional predictors in Latinos were age (P=0.0023), body mass index (BMI) (P=0.068), baseline ALT quotient (P=0.031), and baseline Ishak fibrosis scores (P=0.021). There were no significant differences in steatosis changes between the two groups. Adverse events (AEs) and withdrawals due to AEs were more frequent in non-Latinos.CONCLUSIONS:Significant proportions of patients in both groups had histologic response to peginterferon α-2a plus ribavirin. However, histologic response was higher in non-Latinos than in Latinos regardless of virologic response. This study highlights the need for additional strategies to improve virologic response in Latinos.

The Management of Schizophrenia in Clinical Practice (MOSAIC) Registry: A focus on patients, caregivers, illness severity, functional status, disease burden and healthcare utilization

BACKGROUND The Management of Schizophrenia in Clinical Practice (MOSAIC), a disease-based registry of schizophrenia, was initiated in December 2012 to address important gaps in our understanding of the impact and burden of schizophrenia and to provide insight into the current status of schizophrenia care in the US. Recruitment began in December 2012 with ongoing assessment continuing through May 2014. METHODS Participants were recruited from a network of 15 centralized Patient Assessment Centers supporting proximal care sites. Broad entry criteria included patients diagnosed with schizophrenia, schizophreniform or schizoaffective disorder, presenting within the normal course of care, in usual treatment settings, aged ≥18years and able to read and speak English. RESULTS By May 2014, 550 participants (65.8% male, 59.8% White, 64.4% single, mean age 42.9years), were enrolled. The majority had a diagnosis of schizophrenia (62.0%). Mean illness duration at entry was 15.0years. Common comorbidities at entry were high lipid levels (26.9%), hypertension (23.1%) and type II diabetes (13%). Participants were categorized by baseline overall Clinical Global Impression-Schizophrenia Severity Score as minimally (9.1%), mildly (25.3%), moderately (39.9%), markedly (22.3%) and severely (3.4%) ill. Most commonly used second generation antipsychotics at entry were risperidone (17.8%), clozapine (16.5%), olanzapine (14.0%), aripiprazole (13.6%) and quetiapine (5.6%). CONCLUSIONS No large-scale patient registry has been conducted in the US to longitudinally follow patients with schizophrenia and describe symptom attributes, support network, care access and disease burden. These data provide important epidemiological, clinical and outcome insights into the burden of schizophrenia in the US.

Association of host pharmacodynamic effects with virologic response to pegylated interferon alfa-2a/ribavirin in chronic hepatitis C.

Patients receiving therapy for chronic hepatitis C virus (HCV) infection frequently experience cytopenias and weight loss. We retrospectively assessed the pharmacodynamic effects of pegylated interferon (PEG‐IFN) alfa‐2a and ribavirin by evaluating the relationship between changes in hematologic parameters, body weight, and virologic response. Patients with HCV genotypes 1, 4, 5, or 6 receiving 24 or 48 weeks of PEG‐IFN alfa‐2a and ribavirin therapy were pooled from four phase 3/4 trials. Maximum decreases in hemoglobin level, neutrophil count, platelet count, and weight during therapy were assessed according to virologic response category (sustained virologic response [SVR], relapse, breakthrough, and nonresponder) and race/ethnicity. Of 1,778 patients analyzed, more than half were male, non‐Hispanic Caucasian, and infected with HCV genotype 1; had a baseline HCV RNA >800,000; and had alanine aminotransferase levels ≤3 × the upper limit of normal. Virologic responders (SVR, relapse, and breakthrough) experienced greater maximum decreases from baseline in hemoglobin level, neutrophil count, platelet count, and weight compared with nonresponders; however, no clear trend was observed between SVR, relapse, and breakthrough. After adjusting for drug exposure and treatment duration, only decreases in neutrophil count remained associated with virologic response. Significantly greater declines in neutrophil (P < 0.0001) and platelet (P < 0.005) count were observed at weeks 4, 12, and 24 of therapy in virologic responders compared with nonresponders. This difference between responders and nonresponders was also observed among racial/ethnic groups, although statistical significance was not consistent across all groups. Conclusion: This post hoc analysis of HCV patients treated with PEG‐IFN alfa‐2a and ribavirin shows that maximum decreases from baseline in hematologic parameters and weight loss were associated with virologic response. However, after adjusting for drug exposure and accounting for duration of therapy, only neutropenia was independently associated with virologic response. (HEPATOLOGY 2010;)

Examining the reliability and validity of the Clinical Assessment Interview for Negative Symptoms within the Management of Schizophrenia in Clinical Practice (MOSAIC) multisite national study

The current study sought to expand on prior reports of the validity and reliability of the CAINS (CAINS) by examining its performance across diverse non-academic clinical settings as employed by raters not affiliated with the scales developers and across a longer test-retest follow-up period. The properties of the CAINS were examined within the Management of Schizophrenia in Clinical Practice (MOSAIC) schizophrenia registry. A total of 501 participants with a schizophrenia spectrum diagnosis who were receiving usual care were recruited across 15 national Patient Assessment Centers and evaluated with the CAINS, other negative symptom measures, and assessments of functioning, quality of life and cognition. Temporal stability of negative symptoms was assessed across a 3-month follow-up. Results replicated the two-factor structure of the CAINS reflecting Motivation and Pleasure and expression symptoms. The CAINS scales exhibited high internal consistency and temporal stability. Convergent validity was supported by significant correlations between the CAINS subscales with other negative symptom measures. Additionally, the CAINS was significantly correlated with functioning and quality of life. Discriminant validity was demonstrated by small to moderate associations between the CAINS and positive symptoms, depression, and cognition (and these associations were comparable to those found with other negative symptom scales). Findings suggest that the CAINS is a reliable and valid tool for measuring negative symptoms in schizophrenia across diverse clinical samples and settings.

535 Virologic and Metabolic Responses in Chronic Hepatitis C (CHC) Patients With Insulin Resistance (IR) Treated With Pioglitazone and Peginterferon Alfa-2a Plus Ribavirin

Background In CHC patients with IR, improving insulin sensitivity may increase the response to anti-HCV therapy. The Sensitize study is designed to compare virologic and metabolic responses in CHC patients with IR who were randomized to receive peginterferon alfa-2a plus ribavirin (PEG-2a/RBV) alone or PEG-2a/RBV plus pioglitazone (PIO). Methods This is a multicenter, randomized, open-label study designed to treat 240 CHC patients with HCV genotype 1 and IR. Patients stratified by homeostasis model assessment score (HOMA) of >2- 3×ULN (22% vs 15%), and had HCV RNA ≥800,000 IU/mL (83% vs 77%). Glycemic variables were similar between arms. In the control arm vs PIO arm, the median log10 changes in HCV RNA from baseline to Wks 4 and 12 of anti-HCV therapy were -2.1 vs -2.0 IU/mL and -4.2 vs -4.0 IU/mL; the proportion of patients achieving undetectable HCV RNA (<28 IU/mL) at Wk 4 was 16% (11/70) vs 8% (5/59), and at Wk 12 was 54% (36/67) vs 49% (19/39). Median changes in HOMA score, insulin, and glucose concentrations from baseline to Wk 12 of anti-HCV therapy were -0.5, -10.5 pmol/L, and -0.2 mmol/L in the control arm vs -1.2, -37.5 pmol/L, and -0.4 mmol/L in the PIO arm, respectively. Median change in adiponectin levels was greater in the PIO arm vs the control arm (10.0 vs 0 μg/ mL). No clinically relevant changes in lipid variables were observed in the PIO arm. Four patients (5%) in the control arm and 5 (6%) in the PIO arm withdrew due to adverse events while 26 (34%) controls and 31 (39%) treated with PIO withdrew for non-safety reasons. Conclusions Improvements in several glycemic variables with PIO treatment prior to and during anti-HCV therapy may not improve virologic responses in CHC patients with IR treated for 12 weeks. This ongoing study will determine whether this trend extends over the long-term.