High adherence to all-oral directly acting antiviral HCV therapy among an inner-city patient population in a phase 2a study

Background

As treatment for chronic hepatitis C (HCV) virus has evolved to all-oral, interferon-free directly acting antiviral (DAA) therapy, the impact of these improvements on patient adherence has not been described.

Methods

Medication adherence was measured in 60 HCV, genotype-1, treatment-naïve participants enrolled in a phase 2a clinical trial at the National Institutes of Health and community clinics. Participants received either ledipasvir/sofosbuvir (LDV/SOF) (90 mg/400 mg) (one pill) daily for 12 weeks, LDV/SOF + GS-9451 (80 mg/day) (two pills) daily for 6 weeks, or LDV/SOF + GS-9669 (500 mg twice daily; three pills, two in the morning, one in the evening) for 6 weeks. Adherence was measured using medication event monitoring system (MEMS) caps, pill counts and patient report.

Results

Overall adherence to DAAs was high. Adherence declined over the course of the 12-week treatment (p = 0.04). While controlled psychiatric disease or symptoms of depression did not influence adherence, recent drug use was a risk factor for non-adherence to 12-week (p = 0.01), but not 6-week regimens. Adherence as measured by MEMS was lower than by patient report.

Conclusions

Adherence to short courses of DAA therapy with 1–3 pills a day was excellent in an urban population with multiple risk factors for non-adherence.

     

Shwachman syndrome: Exocrine pancreatic dysfunction and variable phenotypic expression

BACKGROUND & AIMS: Shwachman syndrome is an inherited condition with multisystemic abnormalities, including exocrine pancreatic dysfunction. The aim of this study was to evaluate the occurrence and progression of features in a large cohort of patients. METHODS: Clinical records of 25 patients with Shwachman syndrome were reviewed. RESULTS: Mean birth weight (2.92 +/- 0.51 kg) was at the 25th percentile. However, by 6 months of age, mean heights and weights were less than the 5th percentile. After 6 months of age, growth velocity was normal. Severe fat maldigestion due to pancreatic insufficiency was present in early life (fecal fat, 26% +/- 17% of fat intake; age, < 2 years). Serial assessment of exocrine pancreatic function showed persistent deficits of enzyme secretion, but 45% of patients showed moderate age-related improvements leading to pancreatic sufficiency. Neutropenia was the most common hematologic abnormality (88%), but leukopenia, thrombocytopenia, and anemia were also frequently encountered. Patients with hypoplasia of all three bone marrow cellular lines (n = 11) had the worst prognosis; 5 patients died, 2 of sepsis and 3 of acute myelogenous leukemia. Other findings included hepatomegaly and/or abnormal liver function test results and skeletal abnormalities. CONCLUSIONS: A wide and varied spectrum of phenotypic abnormalities among patients with Shwachman syndrome is described. Pancreatic acinar dysfunction is an invariable abnormality. Patients with severe bone marrow involvement may have a guarded prognosis. (Gastroenterology 1996 Dec;111(6):1593-602)     

Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women

Previous studies indicate that leptin secretion is regulated by insulin-mediated glucose metabolism. Because fructose, unlike glucose, does not stimulate insulin secretion, we hypothesized that meals high in fructose would result in lower leptin concentrations than meals containing the same amount of glucose. Blood samples were collected every 30-60 min for 24 h from 12 normal-weight women on 2 randomized days during which the subjects consumed three meals containing 55, 30, and 15% of total kilocalories as carbohydrate, fat, and protein, respectively, with 30% of kilocalories as either a fructose-sweetened [high fructose (HFr)] or glucose-sweetened [high glucose (HGl)] beverage. Meals were isocaloric in the two treatments. Postprandial glycemic excursions were reduced by 66 +/- 12%, and insulin responses were 65 +/- 5% lower (both P < 0.001) during HFr consumption. The area under the curve for leptin during the first 12 h (-33 +/- 7%; P < 0.005), the entire 24 h (-21 +/- 8%; P < 0.02), and the diurnal amplitude (peak - nadir) (24 +/- 6%; P < 0.0025) were reduced on the HFr day compared with the HGl day. In addition, circulating levels of the orexigenic gastroenteric hormone, ghrelin, were suppressed by approximately 30% 1-2 h after ingestion of each HGl meal (P < 0.01), but postprandial suppression of ghrelin was significantly less pronounced after HFr meals (P < 0.05 vs. HGl). Consumption of HFr meals produced a rapid and prolonged elevation of plasma triglycerides compared with the HGl day (P < 0.005). Because insulin and leptin, and possibly ghrelin, function as key signals to the central nervous system in the long-term regulation of energy balance, decreases of circulating insulin and leptin and increased ghrelin concentrations, as demonstrated in this study, could lead to increased caloric intake and ultimately contribute to weight gain and obesity during chronic consumption of diets high in fructose.     

Evidence for functional endothelial cell damage in early diabetic retinopathy

Summary Two aspects of endothelial cell function were examined in two matched groups of male insulin-dependent diabetics, six with background retinopathy and seven without retinopathy. Leakage of fluorescein from the retinal capillaries was estimated by vitreous fluorophotometry. In addition, factors VIII/von Willebrand (vWF) and VIII-related antigen (VIII-RAG), which are synthesized by the endothelial cells, were measured, together with VIII-antihaemophilic factor (VIII-AHF). The patients without retinopathy had normal leakage of fluorescein in the macula (mean ± SEM: 1.10±0.10 g × 10^-8/ml) and the posterior vitreous (0.45±0.11 g × 10^-8/ml), and normal circulating levels of vWF (123% of a normal reference plasma ± 18%), VIII-RAG (137±14%) and VIII-AHF (112±18%). In contrast, the patients with background retinopathy showed higher leakage of fluorescein in the macula (6.34±1.74 g ×10^-8/ml; p<0.01), and the posterior vitreous (3.09±0.94 g ×10^-8/ml; p<0.02), as well as increased levels of vWF (177±16%; p<0.05). There was a trend towards increased VIII-RAG (195±24%; p<0.1), but not VIII-AHF (126 ±13%). Alterations of endothelial cell function thus accompany the development of retinopathy. It cannot be said from the present study whether these alterations also precede the appearance of retinopathy.     

Release of neurotensin by selective perfusion of the jejunum with oleic acid in dogs

Plasma neurotensin concentrations are rapidly elevated after oral ingestion or intraduodenal infusion of fat, apparently before fat reaches the ileum where neurotensin is highly concentrated. The purpose of this study was to investigate the site of neurotensin release and to determine whether neurotensin is released by direct luminal stimulation by fat in conscious dogs. Dogs were prepared with isolated jejunal or ileal segments and portal vein catheters. Release of neurotensin into the portal venous blood was examined by selective perfusion of each intestinal segment with sodium oleáte. The results of this study show that selective perfusion of the jejunum, but not the ileum, with sodium oleate, caused a significant release of neurotensin. We speculate that release of ileal neurotensin is not due to direct luminal stimulation, but is mediated by local neural or humoral intermediates.     

Mechanisms of the trophic actions of bombesin on the pancreas

Bombesin has both direct and indirect effects [mediated through release of cholecystokinin (CCK)] on pancreatic secretion. Polyamine biosynthesis, essential for DNA synthesis, is increased in the pancreas after CCK stimulation. The purpose of this study was to examine the trophic effects of bombesin and to determine whether the mechanism of bombesin-induced pancreatic growth is mediated through synthesis of polyamines. The time course of bombesin-stimulated polyamine biosynthesis was defined. Rats were studied in groups of six and received intraperitoneal (i.p.) injections every 8 h of either saline, bombesin (10 micrograms/kg), CR1409 (2.5 mg/kg) (a CCK-receptor antagonist), or both to define the effects on pancreatic growth and polyamine biosynthesis. Rats were killed at 14 days and the pancreas was excised, weighed, and analyzed for protein, RNA, and DNA content. We found that bombesin produced significant pancreatic hyperplasia (increased pancreatic weight, protein, and DNA content) after 14 days. CR1409 inhibited only bombesin-stimulated DNA content. Bombesin stimulated polyamine biosynthesis as early as 2 h after administration of bombesin, but CR1409 had no effect. The trophic actions of bombesin are both direct and indirect (mediated through CCK), and the direct effects of bombesin are mediated by polyamine biosynthesis.     

Geographic and ecologic distributions of the Anopheles gambiae complex predicted using a genetic algorithm

The distribution of the Anopheles gambiae complex of malaria vectors in Africa is uncertain due to under-sampling of vast regions. We use ecologic niche modeling to predict the potential distribution of three members of the complex (A. gambiae, A. arabiensis, and A. quadriannulatus) and demonstrate the statistical significance of the models. Predictions correspond well to previous estimates, but provide detail regarding spatial discontinuities in the distribution of A. gambiae s.s. that are consistent with population genetic studies. Our predictions also identify large areas of Africa where the presence of A. arabiensis is predicted, but few specimens have been obtained, suggesting under-sampling of the species. Finally, we project models developed from African distribution data for the late 1900s into the past and to South America to determine retrospectively whether the deadly 1929 introduction of A. gambiae sensu lato into Brazil was more likely that of A. gambiae sensu stricto or A. arabiensis.