Showing papers by "Jeffrey L. Lennox published in 2014"

Clinical Practice Guideline for the Management of Chronic Kidney Disease in Patients Infected With HIV: 2014 Update by the HIV Medicine Association of the Infectious Diseases Society of America

Abstract: It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Efficacy and Tolerability of 3 Nonnucleoside Reverse Transcriptase Inhibitor–Sparing Antiretroviral Regimens for Treatment-Naive Volunteers Infected With HIV-1: A Randomized, Controlled Equivalence Trial

Abstract: Nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. This phase 3, open-label study evaluated 3 NNRTI-spa...

Dysregulated B cell expression of RANKL and OPG correlates with loss of bone mineral density in HIV infection.

Abstract: 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-naive 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 naive, 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.

Metabolomics of Bronchoalveolar Lavage Differentiate Healthy HIV-1-Infected Subjects from Controls

Abstract: Despite antiretroviral therapy, pneumonias from pathogens such as pneumococcus continue to cause significant morbidity and mortality in HIV-1-infected individuals. Respiratory infections occur despite high CD4 counts and low viral loads; therefore, better understanding of lung immunity and infection predictors is necessary. We tested whether metabolomics, an integrated biosystems approach to molecular fingerprinting, could differentiate such individual characteristics. Bronchoalveolar lavage fluid (BALf ) was collected from otherwise healthy HIV-1-infected individuals and healthy controls. A liquid chromatography-high-resolution mass spectrometry method was used to detect metabolites in BALf. Statistical and bioinformatic analyses used false discovery rate (FDR) and orthogonally corrected partial least-squares discriminant analysis (OPLS-DA) to identify groupwise discriminatory factors as the top 5% of metabolites contributing to 95% separation of HIV-1 and control. We enrolled 24 subjects with H...

Anti-retroviral therapy is associated with decreased alveolar glutathione levels even in healthy HIV-infected individuals.

Abstract: Objective Lung infections are a leading cause of death in HIV-infected individuals. Measuring redox in HIV-infected individuals may identify those with chronic oxidative stress who are at increased risk for lung infection. We sought to estimate the association between HIV infection and oxidative stress in the lung, as reflected by decreased levels of glutathione and cysteine in the epithelial lining fluid. Methods Bronchoalveolar lavage (BAL) fluid was collected from healthy HIV-infected subjects and controls. Individuals were excluded if they had evidence of major medical co-morbidities, were malnourished or smoked cigarettes. Results We enrolled 22 otherwise healthy HIV and 21 non-HIV subjects. Among the HIV-infected subjects, 72.7% were on anti-retroviral therapy (ART) with a median CD4 count of 438 (279.8–599) and viral load of 0 (0–1.0) log copies/mL. There were no significant differences in median BAL fluid glutathione and cysteine levels between HIV and HIV-uninfected subjects. However, BAL glutathione was significantly higher in HIV-infected subjects on anti-retroviral therapy (ART) compared to those not on ART [367.4 (102–965.3) nM vs. 30.8 (1.0–112.1) nM, p = 0.008]. Further, HIV infection with ART was associated with an OR of 2.02 for increased BAL glutathione when adjusted for age and body mass index, whereas HIV infection without ART was associated with an OR of 2.17 for decreased BAL glutathione. Conclusion HIV infection without ART was associated with increased oxidative stress, as reflected by decreased alveolar glutathione levels, in otherwise healthy HIV-infected individuals. Further study needs to be done identify predictors of lung health in HIV and to address the role of ART in improving lung immunity.

Effect of protein binding on unbound atazanavir and darunavir cerebrospinal fluid concentrations.

Abstract: Despite highly active antiretroviral therapy (HAART), human immunodeficiency virus-1 (HIV-1) continues to elude eradication. Even in the setting of plasma virologic suppression, HIV-1 RNA can be found in peripheral blood mononuclear cells (PBMCs), genital secretions, gastrointestinal lymphoid tissue, and cerebrospinal fluid (CSF).1,2 Limited penetration of antiretrovirals (ARVs) into these sites may play a role in viral persistence.2,3 HIV-1 invades the central nervous system (CNS) early after infection via macrophages, monocytes, and dendritic cells.4 Over time, HIV-associated neurocognitive disorders (HAND) can develop,5 contributing significantly to morbidity6 and early mortality.7 While severity of HAND has decreased, prevalence remains unchanged since the pre-HAART era: 36.2–44.8%,6 prompting a concern for suboptimal CNS control of HIV. This is supported by reports of elevated neopterin, an inflammatory biomarker, and measurable HIV RNA in the CSF of patients on long term HAART,8,9 both predictive markers for development of HIV-associated dementia.10,11 Some studies suggest that limited CNS penetration by ARVs is associated with HAND.12,13 Molecular size, lipophilicity, affinity for efflux pump transporters, and degree of plasma protein binding are factors that impact drug CNS penetration.14 Lipophilic drugs, including HIV protease inhibitors (PIs), are highly bound to plasma protein, predominantly alpha1-acid glycoprotein (AAG). The plasma unbound (free) drug component is considered pharmacologically active and readily crosses the blood–brain and blood–CSF barriers15,16 therefore highly bound drugs such as PIs may have limited CNS penetration. Two PIs, atazanavir (ATV) and darunavir (DRV), are recommended by the Department of Health and Human Services (DHHS) as part of first-line once daily regimens for ARV-naive patients when boosted with ritonavir (RTV) and given with a backbone of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC).17 Both PIs have characteristics that could impede tissue and CNS penetration, including large molecular size and affinity for efflux pump transporters. However, they differ in their affinity for plasma AAG: ATV is 86% plasma protein bound in vitro whereas DRV is 95% bound.18,19 The degree to which they successfully penetrate the CNS remains unclear. Best et al showed low or undetectable CSF ATV levels in nearly 25% of study participants.20 but measured only total drug concentrations with a lower quantitation limit of 5 ng/mL. In contrast, 3 prior studies have shown that DRV can attain drug concentrations in the CSF exceeding IC50 21–23 ; however, the single study measuring unbound drug concentrations22 examined participants receiving twice daily DRV rather than the DHHS recommended once daily dosing schedule for patients without history of DRV resistance.17 Additionally, measuring random total drug concentrations rather than troughs limited all previous studies. To address these limitations, we evaluated the CSF penetration of once daily DRV relative to ATV, both boosted with RTV and administered with the same background TDF/FTC regimen. We hypothesized that ATV, a PI with lower degree of plasma protein binding, would achieve a higher CSF/plasma unbound drug concentration ratio than DRV. In addition, we compared unbound CSF PI concentrations to their drug-specific IC50 and assessed relationships with CSF HIV-1 RNA and neopterin.

Integrated Population Pharmacokinetic/Viral Dynamic Modelling of Lopinavir/Ritonavir in HIV-1 Treatment-Naive Patients

Abstract: 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 (C trough) 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 and link total and free LPV exposure to pharmacodynamic changes in HIV-1 RNA and assess viral dynamic and drug efficacy parameters. Data from 35 treatment-naive 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 with ultraviolet (UV) detection. Free LPV (LPVf) concentrations were measured using equilibrium dialysis and mass spectrometry. The LPVt typical value of clearance ( $$ {\text{CL}}_{{{\text{LPV}}_{\text{t}} }} /F $$ ) was 4.73 L/h and the distribution volume ( $$ V_{{{\text{LPV}}_{\text{t}} }} /F $$ ) was 55.7 L. The clearance ( $$ {\text{CL}}_{{{\text{LPV}}_{\text{f}} }} /F $$ ) and distribution volume (V f/F) for LPVf were 596 L/h and 6,370 L, respectively. The virion clearance rate was 0.0350 h−1. The simulated $$ {\text{LPV}}_{{{\text{LPV}}_{\text{t}} }} $$ C trough values at 90 % (EC90) and 95 % (EC95) of the maximum response were 316 and 726 ng/mL, respectively. The pharmacokinetic–pharmacodynamic model provides a useful tool to quantitatively describe the relationship between LPV/RTV exposure and viral response. This comprehensive modelling and simulation approach could be used as a surrogate assessment of antiretroviral (ARV) activity where adequate early-phase dose-ranging studies are lacking in order to define target trough concentrations and possibly refine dosing recommendations.