Virological and Social Outcomes of HIV-Infected Adolescents and Young Adults in The Netherlands Before and After Transition to Adult Care.

BACKGROUND: As a result of effective combination antiretroviral therapy (cART) and advanced supportive healthcare, a growing number of human immunodeficiency virus (HIV)-infected children survive into adulthood. The period of transition to adult care is often associated with impaired adherence to treatment and discontinuity of care. We aimed to evaluate virological and social outcomes of HIV-infected adolescents and young adults (AYAs) before and after transition, and explore which factors are associated with virological failure. METHODS: We included 59 HIV-infected AYAs from the Netherlands who had entered into pediatric care and transitioned from pediatric to adult healthcare. We used HIV RNA load and cART data from the Dutch Stichting HIV Monitoring database (1996-2014), and collected social and treatment data from patients' medical records from all Dutch pediatric HIV treatment centers and 14 Dutch adult treatment centers involved. We evaluated risk factors for virological failure (VF) in a logistic regression model adjusted for repeated measurements. RESULTS: HIV VF occurred frequently during the study period (14%-36%). During the transition period (from 18 to 19 years of age) there was a significant increase in VF compared with the reference group of children aged 12-13 years (odds ratio, 4.26 [95% confidence interval, 1.12-16.28]; P = .03). Characteristics significantly associated with VF were low educational attainment and lack of autonomy regarding medication adherence at transition. CONCLUSIONS: HIV-infected AYAs are vulnerable to VF, especially during the transition period. Identification of HIV-infected adolescents at high risk for VF might help to improve treatment success in this group.

Two pathways for biliary copper excretion in the rat. The role of glutathione.

To evaluate the role of glutathione in biliary copper excretion, we studied this process in control Wistar rats and in mutant Wistar rats (GY rats), in which the secretion of glutathione into bile is deficient. For comparison, biliary zinc excretion was determined simultaneously. In spite of the markedly reduced bile flow (-45%) in GY rats, biliary output rates of endogenous copper were virtually identical in GY and control rats. In contrast, zinc output was drastically reduced in GY rats compared to controls (-80%). Biliary excretion patterns after intravenous administration of copper, in doses ranging from 65 to 2265 nmol/100 g/body wt, showed a distinct rapid and slow phase in control rats. In GY rats, on the other hand, the rapid phase in copper excretion was absent but the slow phase appeared to be unaffected. Pretreatment of rats with diethylmaleate to deplete hepatic and biliary glutathione abolished the rapid phase of copper excretion in control rats, while the slow phase remained unaffected. No significant effect of diethylmaleate on the hepatic handling of exogenous copper was observed in GY rats. The maximal capacity of the slow copper excretion pathway was 40-45 nmol/hr/100 g body wt, both in control and GY rats; the capacity of rapid excretion pathway depended on the administered copper load. Intravenous injection of copper induced the biliary excretion of a substantial amount of zinc in control rats, but not in GY rats. These results indicate the existence of at least two distinct biliary excretory pathways for copper in the rat, i.e. a slow and a rapid pathway, with a glutathione dependency of the latter only. The basal excretion of (endogenous) copper, in contrast to that of zinc, can proceed independently of glutathione excretion. However, glutathione appears to be involved in the rapid secretion of excess copper.

Bile secretion of trace elements in rats with a congenital defect in hepatobiliary transport of glutathione.

Bile secretion of trace elements, analyzed by proton-induced x-ray emission, was studied in rats with a congenital defect in hepatobiliary transport of organic anions [Groningen Yellow (GY) rats], in which the process of bile secretion resembles that of the neonatal period. Bile flow (-41%) and biliary glutathione secretion (-99%) were drastically impaired in GY rats compared with controls. Plasma concentrations of all detectable trace elements (Fe, Cu, Zn, Mo, Br, and Se), as well as that of simultaneously determined Ca, were similar in GY and age-matched control Wistar rats. Bile concentrations of Fe, Mo, Br, and Ca were also similar in both groups, resulting in a approximately 40% reduction of their secretion rates in GY rats. The concentrations of Zn (-62%) and Mn (-64%) were significantly lower in GY rats in contrast to that of Cu, which was 50% higher. Se could not be detected in bile of either group. Recovery in bile (% dose/3 h) after i.v. injection of MnCl2, CuSO4, or SeO2 (1 mg metal/kg) was lower in GY rats than in controls: Mn, 26 and 35%; Cu, 2.6 and 5%; and Se, 1.5 and 5%, respectively. Injection of ZnSO4 did not lead to increased Zn secretion in GY rats, and only 1.1% of the dose was recovered in controls. Thus, the hepatic handling of different endogenous and exogenously administered trace metals is affected to a variable extent in the GY rat. For a number of metals (e.g. Fe, Mo), this may be related to the reduced bile flow; for others (e.g. Zn, Mn, Cu), other regulatory factors appear to be responsible.

The role of glutathione in bile secretion of endogenous trace elements in rats.

To evaluate the role of glutathione in biliary secretion of endogenous trace elements, we quantitated trace element output rates by proton-induced x-ray emission under various conditions with altered biliary glutathione secretion and hepatic glutathione content in the rat. Treatment with phenobarbital (80 mg/kg body weight, 4 days), ethanol (0.9 gm/kg body weight, 4 days), or diethylmaleate (3.9 mmol/kg body weight) resulted in changes in biliary glutathione secretion of +114%, -56%, and -95%, respectively, and in hepatic glutathione content of -0%, +25%, and -86%, respectively, when compared with control values. Biliary glutathione level was below detection limits in mutant Groningen Yellow Wistar rats, whereas hepatic glutathione content was increased by 114% in these animals. Glutathione secretion showed a linear relationship with bile flow when data from all experiments were included in the analysis; the apparent choleretic activity of glutathione was 67 microliters/mumol. Six trace elements (iron, zinc, copper, manganese, molybdenum, bromine) could always be detected in bile. Potassium and calcium were measured for comparative purposes. No relation was found between biliary trace element secretion and hepatic glutathione content. Biliary output rates of iron, molybdenum, and bromine correlated, albeit poorly, with biliary glutathione efflux (r values: iron, 0.67; molybdenum, 0.40; bromine, 0.53; respectively). Copper, manganese, and zinc secretion did not show any consistent relationship with glutathione secretion. The secretion rates of iron, molybdenum, and bromine, like that of calcium, showed a highly significant correlation with bile flow (r values: iron, 0.89; molybdenum, 0.75; bromine, 0.80; and calcium, 0.90; respectively, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Biliary secretion of trace elements and minerals in the rat. Effects of bile flow variation and diurnal rhythms.

Effects of bile flow variations on bile secretion of trace elements were systematically evaluated by Proton-Induced X-ray Emission (PIXE) in the unanesthetized rat: (i) longitudinally for a 9 day-period of bile drainage; (ii) continuously for a period of 24 h, to include circadian rhythm and (iii) during exogenous bile salt administration. Potassium and Ca were determined for comparative purposes. In rat bile, six trace elements could always be detected by PIXE (Fe, Zn, Cu, Mo, Mn, Br); occasionally some V, Cr, Sr and Pb was found. Se could not be detected in bile. Bile-plasma concentration ratios of the elements could arbitrarily be divided into three groups: Fe, Zn and Se less than 1; Ca, K, Cu, Mo and Br approx. 1 and Mn much greater than 1. After interruption of the enterohepatic circulation, bile flow and bile salt concentration dropped sharply within 4 h to 36% and 4% of their initial values, respectively. Output rates of K, Ca, Mo, Br, Zn and Fe closely followed the decrease in bile flow; bile secretion of Mn and Cu, on the other hand, was minimally affected. A circadian rhythm was observed for all detectable elements; during the night period, secretion rates of Zn, Fe, Ca and K increased maximally by 60-80% and that of Mn, Mo, Br and Cu by 30-50%. Bile salt output and bile flow increased maximally by 70% and 50%, respectively, in the same time interval.(ABSTRACT TRUNCATED AT 250 WORDS)