Conclusion.This pooled analysis demonstrated that eravacycline 1 mg/kg IV q12h was generally well tolerated for the treatment of cIAI when compared with ertapenem and meropenem.Results of the analysis are consistent with those of individual clinical studies and no new safety signals were identified.
The practical application of gene therapy as a treatment for cystic fibrosis is limited by poor gene transfer efficiency with vectors applied to the apical surface of airway epithelia. Recently, folate receptor alpha (FR alpha), a glycosylphosphatidylinositol-linked surface protein, was reported to be a cellular receptor for the filoviruses. We found that polarized human airway epithelia expressed abundant FR alpha on their apical surface. In an attempt to target these apical receptors, we pseudotyped feline immunodeficiency virus (FIV)-based vectors by using envelope glycoproteins (GPs) from the filoviruses Marburg virus and Ebola virus. Importantly, primary cultures of well-differentiated human airway epithelia were transduced when filovirus GP-pseudotyped FIV was applied to the apical surface. Furthermore, by deleting a heavily O-glycosylated extracellular domain of the Ebola GP, we improved the titer of concentrated vector severalfold. To investigate the folate receptor dependence of gene transfer with the filovirus pseudotypes, we compared gene transfer efficiency in immortalized airway epithelium cell lines and primary cultures. By utilizing phosphatidylinositol-specific phospholipase C (PI-PLC) treatment and FR alpha-blocking antibodies, we demonstrated FR alpha-dependent and -independent entry by filovirus glycoprotein-pseudotyped FIV-based vectors in airway epithelia. Of particular interest, entry independent of FR alpha was observed in primary cultures of human airway epithelia. Understanding viral vector binding and entry pathways is fundamental for developing cystic fibrosis gene therapy applications.
Introduction: Sustained virologic response (SVR) after treatment of chronic hepatitis C virus (HCV) reduces the risk for fibrosis progression. The 3 direct-acting antiviral regimen of ombitasvir (OBV), paritaprevir (identified by AbbVie and Enanta, co-dosed with ritonavir [PTV/r]), and dasabuvir (DSV) with or without ribavirin (RBV) has shown high SVR rates in HCV genotype (GT) 1 infected patients with or without cirrhosis. We assessed factors predictive of improvements in fibrosis from baseline as measured by FibroTest. Methods: TURQUOISE-II (GT1 with compensated cirrhosis) and TOPAZ-II (GT1 with or without compensated cirrhosis) patients treated with OBV/PTV/r + DSV ± RBV for 12 or 24 weeks,with FibroTest scores at baseline and at least one post-treatment week (PTW) visit were included. Stepwise logistic regression assessed the relative contribution of baseline factors, including fibrosis stage, sex, age, BMI, achievement of SVR, prior HCV treatment status, platelet count, ALT, and albumin on improvement from baseline in FibroTest score. FibroTest-derived fibrosis stage change from baseline was evaluated. The upper thresholds for METAVIR F0-1, F2, and F3 were 0.48, 0.58, and 0.72, respectively. Results: FibroTest scores at baseline and at one post-treatment visit were available for 882 patients, of whom 413 (47%) had F4 baseline METAVIR scores. For patients with PTW12 data, fibrosis stage regression occurred in 197/396 (50%) F4 patients, 73/114 (64%) F3 patients, 59/86 (69%) F2 patients, and was stable in 250/260 (96%) F0-1 patients (Table). In patients achieving SVR subgrouped by baseline METAVIR score, FibroTest least square mean changes from baseline were significantly different from no change. These changes were statistically different from those in patients that did not achieve SVR (F4: -0.17 vs -0.11; F3: -0.15 vs +0.05; F2: -0.13 vs +0.23; F0-1: -0.05 vs +0.07 for SVRs vs non-SVRs respectively). Achievement of SVR was strongly associated with FibroTest score improvement and patients with BL F4 fibrosis were more likely to have improvement than patients with F0-1, though not compared to patients with F2 or F3 fibrosis. Conclusion: Improvements in mean FibroTest score were observed in patients treated with OBV/PTV/r + DSV ± RBV and achieving SVR, irrespective of baseline score. Achievement of SVR was a predictor of improvement in FibroTest score and led to FibroTest-derived fibrosis stage regression for the majority with baseline F2 - F4 fibrosis.Table 1: Cross-Tabulation of Number and Proportion of Patients by Baseline and PTW12 FibroTest-Derived METAVIR Scores, n (%)
Direct-acting antiviral (DAA) therapy is highly effective in curing hepatitis C virus (HCV) infection in people who inject drugs (PWID). Previous studies showed declining persistence to DAA therapy over the course of treatment. This study compares real-world medication persistence to prescription refills for 8- versus 12-week DAA in treatment-naïve PWID with chronic HCV with compensated cirrhosis or without cirrhosis.Symphony Health's claims database was used to collect data from patients with chronic HCV aged ≥ 12 years who were prescribed 8- or 12-week DAA therapy between August 2017 and November 2020 and had a diagnosis of addicted drug use within 6 months prior to index date. Eligible patients had medical/pharmacy claims in the 6 months before and 3 months after the first index medication fill date (i.e., index date). Patients completing all refills (8-week = 1 refill, 12-week = 2 refills) were deemed persistent. The percentage of persistent patients in each group, and at each refill step, was determined; outcomes were also assessed in a subgroup of Medicaid-insured patients.This study assessed 7203 PWID with chronic HCV (8-week, 4002; 12-week, 3201). Patients prescribed 8-week DAA treatment were younger (42.9 ± 12.4 vs 47.5 ± 13.2, P < 0.001) and had fewer comorbidities (P < 0.001). Patients receiving 8- versus 12-week DAA had greater refill persistence (87.9% vs 64.4%, P < 0.001). Similar percentages of patients missed their first refill (8-week, 12.1% vs 12-week, 10.8%); nearly 25% of patients receiving 12-week DAA missed their second refill. After baseline characteristics were controlled, patients prescribed 8- versus 12-week DAA were more likely to be persistent (odds ratio [95% confidence interval] 4.3 [3.8, 5.0]). Findings in the Medicaid-insured subgroup were consistent.Patients prescribed 8- vs 12-week DAA therapy had significantly greater prescription refill persistence. Most nonpersistence was due to missed second refills, highlighting the potential benefit of shorter treatment durations in this population.
Abstract Sustained virologic response at posttreatment Week 12 (SVR12) is the widely accepted efficacy endpoint for direct‐acting antiviral agents. Those with hepatitis C virus (HCV) are presenting younger with milder liver disease, potentially reducing need for long‐term liver posttreatment monitoring. This analysis aimed to determine the positive predictive value (PPV) of SVR at posttreatment Week 4 (SVR4) for achieving SVR12 in patients with HCV, without cirrhosis or with compensated cirrhosis, receiving glecaprevir/pibrentasvir (G/P) in clinical trials. An integrated dataset from 20 Phase 2 and 3 clinical trials of G/P was evaluated in patients with 8‐, 12‐ or 16‐week treatment duration consistent with the current label (label‐consistent group), and in all patients regardless of treatment duration consistency with the current label (overall group). Sensitivity analyses handled missing data either by backward imputation or were excluded. SVR4 PPV, negative predictive value (NPV), sensitivity and specificity were calculated for achieving SVR12 in both groups, and by treatment duration in the label‐consistent group. SVR was defined as HCV ribonucleic acid <lower limit of quantification. The label‐consistent group and overall group included 2890 and 4390 patients, respectively. PPV of SVR4 for SVR12 was >99% in both groups regardless of treatment duration. Not achieving SVR4 had 100% NPV and sensitivity for all groups. SVR4 measure had 79.5% specificity for identifying patients who did not achieve SVR12. Across 20 Phase 2/3 clinical trials of G/P, SVR4 was highly predictive of SVR12. Long‐term follow‐up to confirm SVR may not be necessary for certain populations of patients with HCV.
Introduction: Glecaprevir, an NS3/4A protease inhibitor (developed by AbbVie and Enanta) and pibrentasvir (NS5A inhibitor), collectively G/P, is a once-daily, pangenotypic, direct-acting antiviral (DAA) regimen shown to be efficacious in the treatment of all major genotypes (GT) of hepatitis C virus (HCV). Here, we present an integrated efficacy and safety analysis of 8-, 12-, and 16-week durations of G/P in non-cirrhotic HCV GT 1-6 patients, including those with HIV co-infection. Methods: Data were pooled from the SURVEYOR-I and -II and ENDURANCE-1, -2, -3, and -4, and EXPEDITION-2 and -4 studies. Patients were either treatment-naïve or treatment-experienced with interferon (IFN), pegIFN ± ribavirin (RBV), or sofosbuvir (SOF) + RBV ± pegIFN. Patients with experience to a DAA other than SOF were excluded. Patients with GT1, 2, 4, 5, and 6 infection received 8 or 12 weeks of G/P regardless of treatment history, whereas treatment-experienced GT3-infected patients received 16 weeks of G/P. Efficacy was evaluated as the rate of sustained virologic response (HCV RNA < lower limit of quantification) at 12 weeks post-treatment (SVR12) using a modified intent-to-treat analysis excluding those not achieving SVR for reasons other than virologic failure. Safety was assessed in all patients. Results: In total, 2063 chronic HCV patients without cirrhosis were included in the analysis comprised of 55% (1135/2063) males, 79% (1639/2063) white race, 24% (494/2063) treatment experienced, and 8% (170/2063) HIV co-infected. SVR12 rates are shown in Figure 1 according to treatment duration and genotype. In the modified intent-to-treat (mITT) population, overall SVR12 rates were 99.1% for the 8-week (943/952) and 99.6% for the 12-week groups (1060/1064). The SVR12 rate was 95% (21/22) for treatment-experienced GT3 patients receiving 16-weeks of G/P. In patients with HIV co-infection, 100% (169/169) of patients achieved SVR12. Overall, G/P was well-tolerated with 1 (< 0.1%) DAA-related serious adverse events and 10 (0.5%) adverse events leading to treatment discontinuation.Figure: mITT Analysis of Integrated Efficacy for 8-, 12-, and 16-week G/P treatment.Conclusion: G/P for 8, 12, and 16 weeks in chronic HCV GT1-6 infected patients without cirrhosis was well-tolerated and achieved high SVR12 rates. These data suggest that the majority of patients without cirrhosis can be treated for 8 weeks with G/P.
INTRODUCTION: Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment. METHODS: Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1–6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis). RESULTS: Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0–4: 100%; weeks 5–8: 98.3%; and weeks 9–12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%–100%; <80%: 83.3%–100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred. DISCUSSION: These findings support the impact of treatment duration on adherence rates and further reinforce the concept of “treatment forgiveness” with direct-acting antivirals.
Progress towards achieving hepatitis C virus (HCV) elimination in Florida has been hampered by barriers to screening, linkage to care, and treatment. This study aims to describe the HCV care cascade and patient characteristics in Florida. This analysis combined HCV-related laboratory data and patient characteristics from two, large US laboratory datasets that included individuals tested for HCV antibody (Ab) and HCV ribonucleic acid (RNA) viral load between January 2015 and December 2019. A decline in sequential HCV RNA viral loads was used to impute HCV treatment. Machine-learning algorithms were used to identify cured patients. The actual number of individuals with HCV Ab screening, and the number and percentage of persons who were HCV RNA-positive and treated, were calculated. The number of persons in Florida diagnosed as HCV RNA-positive was 31,659 in 2019. The number of individuals HCV Ab screened in 2019 was 1,024,379, an increase of 82.5% from 2015. The percentage of HCV Ab-positive individuals was 4.1%, demonstrating a 16.2% decrease from 2015. The percentage of HCV RNA-positive patients who were treated was 27.0%, a 10.5% decrease from 2015 to 2019. An Ab positivity rate > 4-times higher than national estimates with increased screening among baby boomers, but decreased screening among younger individuals, suggests risk-based screening is still common practice in Florida, despite universal screening recommendations. Public health efforts to decrease barriers to screening, linkage to care, and treatment are needed to reduce the burden of HCV in Florida and to ensure progress toward virus elimination.
Glecaprevir/pibrentasvir (G/P) was approved on 26 September 2019 by the US Food and Drug Administration for 8-week duration in treatment-naïve (TN) hepatitis C virus (HCV)-infected patients with compensated cirrhosis (CC). Evidence from the EXPEDITION-8 study demonstrated that 8 weeks of G/P achieved a 98% intent-to-treat (ITT) sustained virologic response rate 12 weeks post treatment (SVR12) in 343 TN/CC patients. The aim of this study is to demonstrate the first US real-world effectiveness of G/P 8-week treatment in genotype 1–6 TN/CC HCV patients. Data from 73 TN/CC patients who initiated 8 weeks of G/P treatment between August 2017 and November 2018 were collected electronically from providers and specialty pharmacies of the Trio Health network and analyzed. Cirrhosis was determined by FIB-4 > 5.2 or was physician reported. The primary outcome was Per Protocol (PP) SVR12. The majority (60%) of patients were male, with (mean values): age 59 years, body mass index (BMI) of 30, aspartate aminotransferase (AST) 105, and alanine aminotransferase (ALT) 101 IU/ml. HCV genotypes (GT) were: GT1 81% (59/73), GT2 10% (7/73), GT3 5% (4/73), GT4 3% (2/73), and GT6 1% (1/73). Eight percent (6/73) of patients had concurrent proton pump inhibitor (PPI) use, and 15% (11/72) had a baseline viral load > 6 MM IU/ml. Zero patients discontinued, two patients were reported as lost to follow-up, and there was one virologic failure. PP sustained virologic response at 12 weeks (SVR12) rate was 99% (70/71), and the intent-to-treat (ITT) SVR12 rate was 96% (70/73). Early real-world experience indicates high effectiveness of the 8-week G/P regimen in a diverse treatment-naïve, compensated cirrhotic US population.
