Sustainable and equivalent improvements in symptoms and functional well-being following viral cure from ledipasvir/sofosbuvir versus elbasvir/grazoprevir for chronic hepatitis C infection: Findings from the randomized PRIORITIZE trial.

The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.

A Pragmatic, Randomized Controlled Trial of Oral Antivirals for the Treatment of Chronic Hepatitis C: The PRIORITIZE Study.

BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.

Linkage of resistance-associated substitutions in GT1 sofosbuvir + NS5A inhibitor failures treated with glecaprevir/pibrentasvir.

BACKGROUND & AIMS: Retreatment with glecaprevir/pibrentasvir (G/P) resulted in a rate of sustained virologic response 12 weeks after treatment completion (SVR12) of >90% in HCV genotype 1 (GT1) patients who previously failed a regimen of sofosbuvir plus an NS5A inhibitor (NS5Ai). This study investigated the prevalence and impact of baseline NS3 and NS5A resistance-associated substitutions (RASs) on the efficacy of G/P in prior GT1 sofosbuvir+NS5Ai failures and the persistence of treatment-emergent RASs. METHODS: Longitudinal samples from 177 patients enrolled in a phase IIIb, randomized pragmatic clinical trial were analyzed. Patients without cirrhosis were randomized to 12 or 16 weeks of G/P, and patients with compensated cirrhosis were randomized to G/P and ribavirin for 12 weeks or G/P for 16 weeks. Linkage of RAS was identified using Primer-ID next-generation sequencing at a 15% cut-off. RESULTS: Of 177 patients, 169 (95.5%) were PI-naïve. All 33 GT1b-infected patients achieved SVR12. In GT1a-infected patients, baseline NS5A RASs were prevalent (74.5%, 105/141) but NS3 RASs were uncommon. Baseline NS3 RASs had no impact on G/P efficacy and patients with baseline NS5A RASs showed a numerically but not statistically significantly lower SVR12 rate compared to those without NS5A RASs (89% vs. 97%). SVR12 was achieved in 34 of 35 (97%) patients without NS5A baseline substitution, and 53 of 57 (93%), 35 of 40 (88%), 5 of 8 (63%) with single, double-linked, and triple-linked NS5A substitutions, respectively. Among 13 patients with virologic failure, 4 acquired treatment-emergent NS3 RASs and 10 acquired NS5A RASs. CONCLUSION: Baseline NS5A RASs were highly prevalent. The presence of an increasing number of linked NS5A RASs in GT1a showed a trend in decreasing SVR12 rates, although no specific NS5A RASs or their linkage pattern were associated with lower SVR12 rates. LAY SUMMARY: Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C infection, but treatment failure occurs in some patients. Retreatment of patients who previously failed a regimen consisting of sofosbuvir and an NS5A inhibitor with a regimen of glecaprevir and pibrentasvir (G/P) is >90% effective. Herein, we analyzed samples from these patients and showed that retreatment efficacy with G/P is lower in patients with double- or triple-linked NS5A resistance mutations than in patients with single or no NS5A resistance mutations. CLINICAL TRIAL NUMBER: NCT03092375.

Efficacy of Glecaprevir and Pibrentasvir in Patients With Genotype 1 Hepatitis C Virus Infection With Treatment Failure After NS5A Inhibitor Plus Sofosbuvir Therapy.

BACKGROUND & AIMS: Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. METHODS: We performed a phase 3b, open-label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n = 78, group A) or 16 weeks (n = 49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n = 21, group C) or G/P for 16 weeks (n = 29, group D). The primary end point was a sustained virologic response 12 weeks after treatment. Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions in NS3 and NS5A. RESULTS: Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with sustained virologic response 12 weeks after treatment in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 (7.3%) patients with HCV genotype 1a infection, 6 (7.9%) in group A, 3 (6.1%) in group B, 3 (6.1%) in group C (6.1%), and 1 (3.4%) in group D. Most patients had baseline resistance-associated substitutions in NS5A. Treatment-emergent resistance-associated substitutions in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. CONCLUSIONS: In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced sustained virologic response 12 weeks after treatment in >90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT03092375.

Associations Between Environmental Conditions and Executive Cognitive Functioning and Behavior During Late Childhood: A Pilot Study.

Numerous studies have established the influence of detrimental home conditions on child cognition and behavior; however, fewer have assessed these outcomes in the context of relatively "normal" range of home environmental conditions. Given the exquisite sensitivity to the environment of the neural substrates that undergird executive functioning (EF) and behavioral self-regulation in children, it is possible that a range of conditions within the home, even in the absence of maltreatment or economic deprivation, may impact these outcomes. The purpose of the present exploratory investigation was to further define the relationship between features of the home environment using the HOME inventory (a structured interview and observation of parent and child) and several dimensions of child EF and behavioral problems. In addition, this study sought to elucidate potentially differential associations between home and parent-reported neighborhood conditions-a hypothetically less direct influence on cognition in this age group-and level of child functioning. A battery of EF performance tasks and a widely-used checklist of behavioral problems were administered to 66 children, 8-11 years old from a lower middle income, working class sample. Results showed significant relationships between the home environment and several dimensions of EF and behavioral problems. In contrast, neighborhood conferred additional effects only on rule-breaking and aggression, not cognition, which is consistent with evidence that externalizing behavior in this age group becomes increasingly oriented toward outside influences. These findings warrant follow-up studies to establish causality. A broader program of research designed to delve further into the relationship between nuanced influences from the home and child cognition and behavior has implications for parenting strategies that foster healthy development. Neighborhood contexts should also be considered during early and mid-adolescent years based on existing studies and findings reported herein suggesting that this period of newfound autonomy and the heightened significance of peer relationships may influence externalizing behaviors, with implications for protective courses of action.

Safety and Effectiveness of Ledipasvir and Sofosbuvir, With or Without Ribavirin, in Treatment-Experienced Patients With Genotype 1 Hepatitis C Virus Infection and Cirrhosis.

BACKGROUND & AIMS: We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi-center, prospective, observational cohort study (HCV-TARGET). METHODS: We collected data from 667 treatment-experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel. Information was collected from medical records and abstracted into a unique centralized data core. Independent monitors systematically reviewed data entries for completeness and accuracy. Demographic, clinical, adverse event, and virologic data were collected every 12 weeks during treatment and during the follow-up period. The primary efficacy endpoint was sustained virologic response, defined as a level of HCV RNA below the lower limit of quantification or undetectable at a minimum 64 days after the end of treatment (SVR12). The per-protocol population (n = 610) was restricted to patients who completed 12 or 24 weeks of treatment (±2 weeks) and had final virologic outcomes available. RESULTS: The per-protocol analysis revealed that 579 patients (93.8%) achieved an SVR12, including 50/51 patients who received ledipasvir and sofosbuvir for 12 weeks (98%), 384/408 patients who received ledipasvir and sofosbuvir for 24 weeks (94.1%), 68/70 patients who received ledipasvir and sofosbuvir with ribavirin for 12 weeks (97.1%), and 57/60 patients who received ledipasvir and sofosbuvir with ribavirin for 24 weeks (95%). On multivariate analysis, neither treatment duration nor the addition of ribavirin was associated with SVR12. Compensated cirrhosis (odds ratio [OR] compared to decompensated cirrhosis, 2.41; 95% CI, 1.16-5.02), albumin ≥ 3.5 g/dL (OR, 3.15; 95% CI 1.46-6.80), or total bilirubin ≤ 1.2 mg/dL (OR 3.34; 95% CI, 1.59-7.00) were associated with SVR12. CONCLUSIONS: In an analysis of safety and effectiveness data from the HCV-TARGET study, we found treatment with ledipasvir and sofosbuvir, with or without ribavirin, to be effective and well tolerated by treatment-experienced patients with genotype 1 HCV infection and compensated cirrhosis. There were no significant differences in rate of SVR12 among patients treated with ledipasvir and sofosbuvir for 12 or 24 weeks, with or without ribavirin. Patients with decompensated cirrhosis appear to benefit from the addition of ribavirin or extension of ledipasvir and sofosbuvir treatment to 24 weeks. ClinicalTrials.gov no: NCT10474811.

Estimation of pyrethroid pesticide intake using regression modeling of food groups based on composite dietary samples.

Population-based estimates of pesticide intake are needed to characterize exposure for particular demographic groups based on their dietary behaviors. Regression modeling performed on measurements of selected pesticides in composited duplicate diet samples allowed (1) estimation of pesticide intakes for a defined demographic community, and (2) comparison of dietary pesticide intakes between the composite and individual samples. Extant databases were useful for assigning individual samples to composites, but they could not provide the breadth of information needed to facilitate measurable levels in every composite. Composite sample measurements were found to be good predictors of pyrethroid pesticide levels in their individual sample constituents where sufficient measurements are available above the method detection limit. Statistical inference shows little evidence of differences between individual and composite measurements and suggests that regression modeling of food groups based on composite dietary samples may provide an effective tool for estimating dietary pesticide intake for a defined population.

Dietary intakes of pesticides based on community duplicate diet samples.

The calculation of dietary intake of selected pesticides was accomplished using food samples collected from individual representatives of a defined demographic community using a community duplicate diet approach. A community of nine participants was identified in Apopka, FL from which intake assessments of organophosphate (OP) and pyrethroid pesticides were made. From these nine participants, sixty-seven individual samples were collected and subsequently analyzed by gas chromatography/mass spectrometry. Measured concentrations were used to estimate dietary intakes for individuals and for the community. Individual intakes of total OP and pyrethroid pesticides ranged from 6.7 to 996 ng and 1.2 to 16,000 ng, respectively. The community intake was 256 ng for OPs and 3430 ng for pyrethroid pesticides. The most commonly detected pesticide was permethrin, but the highest overall intake was of bifenthrin followed by esfenvalerate. These data indicate that the community in Apopka, FL, as represented by the nine individuals, was potentially exposed to both OP and pyrethroid pesticides at levels consistent with a dietary model and other field studies in which standard duplicate diet samples were collected. Higher levels of pyrethroid pesticides were measured than OPs, which is consistent with decreased usage of OPs. The diversity of pyrethroid pesticides detected in food samples was greater than expected. Continually changing pesticide usage patterns need to be considered when determining analytes of interest for large scale epidemiology studies. The Community Duplicate Diet Methodology is a tool for researchers to meet emerging exposure measurement needs that will lead to more accurate assessments of intake which may enhance decisions for chemical regulation. Successfully determining the intake of pesticides through the dietary route will allow for accurate assessments of pesticide exposures to a community of individuals, thereby significantly enhancing the research benefit realized from epidemiological exposure studies.

Community duplicate diet methodology: a new tool for estimating dietary exposures to pesticides.

An observational field study was conducted to assess the feasibility of a community duplicate diet collection method; a dietary monitoring tool that is population-based. The purpose was to establish an alternative procedure to duplicate diet sampling that would be more efficient for a large, defined population, e.g., in the National Children's Study (NCS). Questionnaire data and food samples were collected in a residence so as not to lose the important component of storage, preparation, and handling in a contaminated microenvironment. The participants included nine Hispanic women of child bearing age living in Apopka, FL, USA. Foods highly consumed by Hispanic women were identified based on national food frequency questionnaires and prioritized by permethrin residue concentrations as measured for the Pesticide Data Program. Participants filled out questionnaires to determine if highly consumed foods were commonly eaten by them and to assess the collection protocol for the food samples. Measureable levels of permethrin were found in 54% of the samples. Questionnaire responses indicated that the collection of the community duplicate diet was feasible for a defined population.

Concentrations of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and their associations with human semen quality measurements.

A total of 256 men were studied to evaluate whether serum concentrations of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) impacted semen quality or reproductive hormones. Blood and semen were collected and analyzed for perfluorochemicals and reproductive and thyroid hormones. Semen quality was assessed using standard clinical methods. Linear and logistic modeling was performed with semen profile measurements as outcomes and PFOS and PFOA in semen and plasma as explanatory variables. Adjusting for age, abstinence, and tobacco use, there was no indication that PFOA or PFOS was significantly associated with volume, sperm concentration, percent motility, swim-up motility and concentration, and directional motility (a function of motility and modal progression). Follicle-stimulating hormone was not associated with either PFOA or PFOS. Luteinizing hormone was positively correlated with plasma PFOA and PFOS, but not semen PFOS. Important methodological concerns included the lack of multiple hormonal measurements necessary to address circadian rhythms.

Pesticides on household surfaces may influence dietary intake of children.

The physical and chemical environment influences children's exposures to pesticides in and around the home. Children's activities, which increase their potential for exposure especially during eating, have been captured in the Children's Dietary Intake Model (CDIM). In addition to the chemical exposure associated with the food itself, this model incorporates excess dietary exposures due to handling of food during consumption. To stochastically evaluate CDIM, distributions of measured, and in some cases estimated, model factors were determined from measurements of permethrin, chlorpyrifos, and diazinon derived from assembled databases and laboratory experiments. Using the distributions of these factors, Monte Carlo simulations were performed to obtain distributions of total dietary intake of pesticides. To target the sources of pesticide contamination that were influencing total dietary intake, each factor was evaluated. We found pesticide surface concentration to be highly influential. By excluding surface concentration, we were also able to determine the influence of the other factors based on the F-statistic. Transfer efficiencies, followed by pesticide residue in consumed foods and amount of food consumed, were the next most influential factors within the model. With these distributions for model inputs, CDIM has the potential to more accurately predict total dietary intake of a contaminant by a child.

Cost/variance optimization for human exposure assessment studies.

The National Human Exposure Assessment Survey (NHEXAS) field study in EPA Region V (one of three NHEXAS field studies) provides extensive exposure data on a representative sample of 249 residents of the Great Lakes states. Concentration data were obtained for both metals and volatile organic compounds (VOCs) from multiple environmental media and from human biomarkers. A variance model for the logarithms of concentration measurements is used to define intraclass correlations between observations within primary sampling units (PSUs) (nominally counties) and within secondary sampling units (SSUs) (nominally Census blocks). A model for the total cost of the study is developed in terms of fixed costs and variable costs per PSU, SSU, and participant. Intraclass correlations are estimated for media and analytes with sufficient sample sizes. We demonstrate how the intraclass correlations and variable cost components can be used to determine the sample allocation that minimizes cost while achieving pre-specified precision constraints for future studies that monitor environmental concentrations and human exposures for metals and VOCs.

Limitations on the uses of multimedia exposure measurements for multipathway exposure assessment--Part II: Effects of missing data and imprecision.

Multimedia data from two probability-based exposure studies were investigated in terms of how missing data and measurement-error imprecision affected estimation of population parameters and associations. Missing data resulted mainly from individuals'refusing to participate in certain measurement activities, rather than from field or laboratory problems; it suggests that future studies should focus on methods for maximizing participation rates. Measurement error variances computed from duplicate-sample data were small relative to the inherent variation in the populations; consequently, adjustments in nonparametric percentile estimates to account for measurement imprecision were small. Methods of adjustment based on lognormality assumptions, however, appeared to perform poorly.