HIV infection is associated with high rates of osteopenia and osteoporosis, but the mechanisms involved are unclear. We recently reported that bone loss in the HIV transgenic rat model was associated with upregulation of B cell expression of the key osteoclastogenic cytokine receptor-activator of NF-κB ligand (RANKL), compounded by a simultaneous decline in expression of its physiological moderator, osteoprotegerin (OPG). To clinically translate these findings we performed cross-sectional immuno-skeletal profiling of HIV-uninfected and antiretroviral therapy-naïve HIV-infected individuals. Bone resorption and osteopenia were significantly higher in HIV-infected individuals. B cell expression of RANKL was significantly increased, while B cell expression of OPG was significantly diminished, conditions favoring osteoclastic bone resorption. The B cell RANKL/OPG ratio correlated significantly with total hip and femoral neck bone mineral density (BMD), T- and/or Z-scores in HIV infected subjects, but revealed no association at the lumbar spine. B cell subset analyses revealed significant HIV-related increases in RANKL-expressing naïve, resting memory and exhausted tissue-like memory B cells. By contrast, the net B cell OPG decrease in HIV-infected individuals resulted from a significant decline in resting memory B cells, a population containing a high frequency of OPG-expressing cells, concurrent with a significant increase in exhausted tissue-like memory B cells, a population with a lower frequency of OPG-expressing cells. These data validate our pre-clinical findings of an immuno-centric mechanism for accelerated HIV-induced bone loss, aligned with B cell dysfunction.

Objective To assess the relationship between vitamin D status and diabetic retinopathy Methods A clinic-based, cross-sectional study was conducted at Emory University. A total of 221 subjects were classified into five groups based on diabetes status and retinopathy findings: no diabetes or ocular disease (n = 47), no diabetes with ocular disease (n = 51), diabetes with no background diabetic retinopathy (No BDR; n = 41), nonproliferative diabetic retinopathy (NPDR; n = 40), and proliferative diabetic retinopathy (PDR; n = 42). Key exclusion criteria included type 1 diabetes and those taking > 1000 IU vitamin D daily. Subjects underwent dilated fundoscopic examination and were tested for hemoglobin A1c, serum creatinine, and 25-hydroxy-vitamin D (25(OH)D) between December 2009 and March 2010. Results Between the groups, there was no statistical difference in age, race, sex, or multivitamin use. Diabetic subjects had lower 25(OH)D levels than non-diabetic subjects (22.9 ng/ml versus 30.3 ng/ml, p<0.001). The mean 25(OH)D levels were as follows: No diabetes or ocular disease = 31.9 ng/ml, No diabetes with ocular disease = 28.8 ng/ml, No BDR = 24.3 ng/ml, NPDR = 23.6 ng/ml, PDR = 21.1 ng/ml. Univariate analysis of the 25(OH)D levels demonstrated statistical significance between the study groups, race, body mass index, multivitamin use, hemoglobin A1c, serum creatinine, and estimated glomerular filtration rate. In a multivariate linear model with all potential confounders, only multivitamin use remained significant (p<0.001). Conclusions This study suggests that diabetic subjects, especially those with PDR, have lower 25(OH)D levels than those without diabetes.

Maximal and durable viral load suppression is one of the most important goals of HIV therapy and is directly related to adequate drug exposure. Protease inhibitors (PIs), an important component of the antiretroviral armada, were historically associated with poor oral bioavailability and high pill burden. However, because the PIs are metabolized by cytochrome P450 (CYP) 3A enzymes, intentional inhibition of these enzymes leads to higher drug exposure, lower pill burden, and therefore simplified dosing schedules with this class of drug. This is the basis of pharmacokinetic enhancement. In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat. Both agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir. Unlike ritonavir, cobicistat does not have antiretroviral activity. Cobicistat has been evaluated in clinical trials and was recently approved in the USA as a fixed-dose combination with the integrase inhibitor, elvitegravir and two nucleos(t)ide analogs. Additional studies are examining cobicistat in fixed-dose combinations with various PIs. In this review, we summarize current knowledge of these agents and clinically relevant drug regimens and ongoing trials. Studies with elvitegravir and the novel PI TMC319011 are also discussed.

Background Lopinavir (LPV)/ritonavir (RTV) co-formulation (LPV/RTV) is a widely used protease inhibitor (PI) based regimen to treat HIV-infection. As with all PIs, the trough concentration (Ctrough) is a primary determinant of response, but the optimum exposure remains poorly defined. The primary objective was to develop an integrated LPV population pharmacokinetic model to investigate the influence of α-1-acid glycoprotein (AAG) and link total and free LPV exposure to pharmacodynamic changes in HIV-1 RNA and assess viral dynamic and drug efficacy parameters. Methods Data from 35 treatment-naïve HIV-infected patients initiating therapy with LPV/RTV 400/100 mg orally twice daily across two studies were used for model development and simulations using ADAPT. Total LPV (LPVt) and RTV concentrations were measured by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Free LPV (LPVf) concentrations were measured using equilibrium dialysis and mass spectrometry. Results LPVt typical value of clearance (CLLPVt/F) was 4.73 L/h and distribution volume (VLPVt/F) was 55.7 L. Clearance (CLLPVf/F) and distibution volume (Vf/F) for LPVf were 596 L/h and 6370 L, respectively. Virion clearance rate was 0.0350 h-1. Simulated LPVLPVt Ctrough at 90% (EC90) and 95% (EC95) maximum response were 316 and 726 ng/mL, respectively. Conclusion The pharmacokinetic/pharmacodynamic model provides a useful tool to quantitatively describe the relationship between LPV/RTV exposure and viral response. This comprehensive modeling and simulation approach could be used as a surrogate assessment of ARV where adequate early phase dose-ranging studies are lacking in order to define target trough concentrations and possibly refine dosing recommendations.

HIV-1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross-sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV-1 RNA, and neopterin levels in subjects receiving either ritonavir-boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured by Ampliprep/COBAS® Taqman® 2.0 assay (Roche) and enzyme-linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06–0.12] than DRV, 0.04 (95%CI 0.03–0.06). Unbound CSF concentrations were lower than protein adjusted wild-type inhibitory concentration-50 (IC50) in all ATV and 1 DRV-treated subjects (P < 0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P = 0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation.