Healthcare utilization and direct costs of non-infectious comorbidities in HIV-infected patients in the USA

Objective: To estimate the incremental healthcare utilization and costs associated with common non-infectious comorbid conditions among commercially and Medicaid-insured HIV-infected patients in the US.

Methods: US administrative claims were used to select adult HIV patients with chronic kidney disease (CKD), cardiovascular disease (CVD) events, or fracture/osteoporosis, three common comorbidities that have been associated with HIV and HIV treatment, between 1 January 2004 and 30 June 2013. Propensity score matched controls with no CKD, no CVD events, and no fracture/osteoporosis were identified for comparison. All-cause healthcare utilization and costs were reported as per patient per month (PPPM).

Results: The commercial cohort comprised 381 CKD patients, 624 patients with CVD events, and 774 fracture/osteoporosis patients, and 1013, 1710, and 2081 matched controls, respectively; while the Medicaid HIV cohort comprised 207 CKD and 271 CVD cases, and 516 and 735 matched controls, respectively. There was insufficient Medicaid data for fracture analyses. Across both payers, HIV patients with CKD or CVD events had significantly higher healthcare utilization and costs than controls. The average incremental PPPM costs in HIV patients with CKD were $1403 in the commercial cohort and $3051 in the Medicaid cohort. In those with CVD events, the incremental costs were $2655 (commercial) and $4959 (Medicaid) for HIV patients compared to controls (p?Conclusions: The results suggested a considerable increase in healthcare utilization and costs associated with CKD, CVD and fracture/osteoporosis comorbidities among HIV patients in the past decade. Because these conditions have been associated with treatment, it is critical to consider their impact on costs and outcomes when optimizing patient care.     

First-in-Human Phase 1b Trial of Quinacrine Plus Capecitabine in Patients With Refractory Metastatic Colorectal Cancer

BackgroundQuinacrine plus a fluoropyrimidine has in vivo efficacy against metastatic colorectal cancer (mCRC). This phase 1b trial evaluated the combination of quinacrine plus capecitabine in patients with treatment-refractory mCRC.Patients and MethodsUsing a modified Simon accelerated titration design, adults with treatment-refractory mCRC were treated with capecitabine 1000 mg/m² twice daily for 14/21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg twice daily, and 200 mg twice daily for 21 days. The primary endpoint was identifying the maximum tolerated dose, determining tolerability and safety. In an expansion cohort, it was overall response rate and time to tumor progression (TTP).ResultsTen patients (median age of 60 years) were treated in phase 1b. The first 2 quinacrine dosing levels were well tolerated. Dose-limiting toxicities were seen in 3 patients treated with quinacrine 200 mg twice daily. Five additional patients tolerated quinacrine 100 mg twice daily without further dose-limiting toxicities, thus establishing the maximum tolerated dose. Seven additional expansion-cohort patients enrolled onto the study before quinacrine manufacturing ceased within the United States. Five patients experienced stable disease, 1 partial response, and 10 disease progression. Median TTP overall was 2.12 months and median overall survival 5.22 months for the 17 patients.ConclusionCapecitabine and quinacrine can be safely administered at the maximum tolerated dose of capecitabine 1000 mg/m² by mouth twice daily on days 1-14 and quinacrine 100 mg by mouth twice daily on days 1-21 of a 21-day cycle in mCRC patients. Although the expansion study was halted early, TTP was in line with other studies of refractory mCRC, suggesting activity of this regimen in heavily pretreated patients.     

Virtual inhibitory quotient predicts response to ritonavir boosting of indinavir-based therapy in human immunodeficiency virus-infected patients with ongoing viremia

Depending on the degree of underlying resistance present, optimization of the pharmacokinetics of protease inhibitors may result in improved virologic suppression. Thirty-seven human immunodeficiency virus (HIV)-infected subjects who had chronic detectable viremia and who were receiving 800 mg of indinavir three times a day (TID) were switched to 400 mg of indinavir BID with 400 mg of ritonavir two times a day (BID) for 48 weeks. Full pharmacokinetic evaluations were obtained for 12 subjects before the switch and 3 weeks after the switch. Combination therapy increased the indinavir predose concentrations in plasma by 6.47-fold, increased the minimum concentration in serum by 3.41-fold, and reduced the maximum concentration in serum by 57% without significantly changing the area under the plasma concentration-time curve at 24 h. At week 3, 58% (21 of 36) of the subjects for whom postbaseline measurements were available achieved a viral load in plasma of <50 copies/ml or a reduction from the baseline load of > or =0.5 log(10) copies/ml. Of these subjects, 82% (14 of 17) whose viruses had three or fewer protease inhibitor mutations and 88% (14 of 16) whose viruses had an indinavir virtual phenotypic susceptibility test of more than sixfold less than that for the baseline isolate were considered virologic responders. The indinavir virtual inhibitory quotient, which is a function of baseline indinavir phenotypic resistance (estimated by virtual phenotype) and the indinavir predose concentration in plasma achieved with indinavir-ritonavir combination therapy, was the best predictor of a viral load reduction. Sixteen subjects discontinued the study by week 48 due to adverse events, predominantly related to hyperlipidemia. Pharmacokinetic intensification of indinavir-based therapy with ritonavir reduced the viral loads in subjects but added toxicity. The virtual inhibitory quotient, which incorporates both baseline viral resistance and the level of drug exposure in plasma, was superior to either baseline resistance or drug exposure alone in predicting the virologic response.     

Neural androgen receptor overexpression affects cell number in the spinal nucleus of the bulbocavernosus

The spinal nucleus of the bulbocavernosus (SNB) is a sexually dimorphic neuromuscular system in which the masculinisation of cell number is assumed to depend on the action of perinatal androgen in non‐neural targets, whereas the masculinisation of cell size is assumed to depend primarily on the action of adult androgen on SNB cells themselves. To test these hypotheses, we characterised the SNB of Cre/loxP transgenic mice that overexpress androgen receptor (AR) throughout the body (CMV‐AR) or in neural tissue only (Nestin‐AR). Additionally, we examined the effects of androgen manipulation in male mutants and wild‐type (WT) controls. We reproduced the expected sex differences in both motoneurone number and size, as well as the expected adult androgen dependence of SNB size. We found effects of genotype such that both Nestin‐AR and CMV‐AR have more SNB motoneurones than WT littermates and also that CMV‐AR females have larger SNB motoneurones than Nes‐AR or WT females. These results raise the possibility that AR can act in neurones and/or glia to rescue SNB motoneurones, as well as on non‐neural AR to increase SNB cell size.     

Metabolic changes in glutathione and metallothionein in newborn rat liver

Metallothionein (MT) and glutathione (GSH) both contain 30% cysteine and they have distinct developmental profiles in perinatal rat liver. The metabolic relationships between these two cysteine pools were investigated in newborn rats under various experimental conditions. Injection of 2-day-old rat pups with buthionine sulfoximine, phorone or diethylmaleate decreased hepatic GSH levels without any change in high basal levels of MT or zinc. Similarly injection of L-oxothiazolidine carboxylate increased hepatic GSH levels but no changes in MT or zinc levels were observed. Administration of buthionine sulfoximine in drinking water to pregnant rats from day 14 of gestation decreased hepatic GSH concentrations in both the dams and pups with little change observed in neonatal hepatic zinc and MT levels or in gamma-glutamyltranspeptidase activity. The induction of MT synthesis by zinc salts in newborn rats was not affected by the in utero reduction of GSH levels. Although maternal hepatic GSH levels can be decreased by a sulfhydryl-deficient diet, no changes were observed in GSH, MT or zinc levels in newborn rat liver. Reduction of perinatal hepatic MT levels by in utero zinc deficiency had little effect on GSH levels. However, inhibition of the cystathionase pathway in newborn rats with propargylglycine decreased hepatic levels of MT, zinc and GSH. The results suggest that whereas there is little interaction between these two pools of cysteine, inhibition of cystathionase activity can decrease hepatic concentrations of both GSH and MT.     

Parametric reverse correlation reveals spatial linearity of retinotopic human V1 BOLD response

Many experiments measuring blood oxygen level dependent (BOLD) signal in functional magnetic resonance imaging (fMRI) data assume that the BOLD signal is predominantly linear in space and time. Previous investigations of temporal linearity have reported that the temporal BOLD response contains both linear and nonlinear components. Here, we used a novel method to investigate spatial linearity of BOLD within area V1. The visual field was divided into regions shaped like wedges, rings, or the intersections of the wedges and rings. The appearance of a flickering checkerboard texture within each region was governed by an independent M-sequence. fMRI data were acquired as the human subjects maintained visual fixation on a central cross. The time series data from each voxel were cross-correlated with every stimulus sequence to estimate each voxel's BOLD responses to all independent regions of the visual field. Linearity by spatial summation was assessed directly by comparing responses to wedges and rings with sums of responses to component patches. The BOLD responses of voxels responding positively to stimuli, measured with independent stimuli subtending several degrees of visual angle, were well predicted by linear spatial summation.