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1.  Cystatin C-Based Renal Function Changes After Antiretroviral Initiation: A Substudy of a Randomized Trial 
Open Forum Infectious Diseases  2014;1(1):ofu003.
Background.
 The effects of antiretrovirals on cystatin C-based renal function estimates are unknown.
Methods.
 We analyzed changes in renal function using creatinine and cystatin C-based estimating equations in 269 patients in A5224s, a substudy of study A5202, in which treatment-naive patients were randomized to abacavir/lamivudine or tenofovir/emtricitabine with open-label atazanavir/ritonavir or efavirenz.
Results.
 Changes in renal function significantly improved (or declined less) with abacavir/lamivudine treatment compared with tenofovir/emtricitabine using the Cockcroft-Gault formula (P = .016) and 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI; P = .030) and 2012 CKD-EPI cystatin C-creatinine (P = .025). Renal function changes significantly improved (or declined less) with efavirenz compared with atazanavir/ritonavir (P < .001 for all equations). Mean (95% confidence interval) renal function changes specifically for tenofovir/emtricitabine combined with atazanavir/ritonavir were −8.3 (−14.0, −2.6) mL/min with Cockcroft-Gault; −14.9 (−19.7, −10.1) mL/min per 1.732 with Modification of Diet in Renal Disease; −12.8 (−16.5, −9.0) mL/min per 1.732 with 2009 CKD-EPI; +8.9 (4.2, 13.7) mL/min per 1.732 with 2012 CKD-EPI cystatin C; and −1.2 (−5.1, 2.6) mL/min per 1.732 with 2012 CKD-EPI cystatin C-creatinine. Renal function changes for the other treatment arms were more favorable but similarly varied by estimating equation.
Conclusions.
 Antiretroviral-associated changes in renal function vary in magnitude and direction based on the estimating equation used.
doi:10.1093/ofid/ofu003
PMCID: PMC4324191  PMID: 25734077
atazanavir; creatinine; cystatin C; HIV-1; nephropathy; tenofovir
2.  Neither Proteinuria Nor Albuminuria Is Associated With Endothelial Dysfunction in HIV-Infected Patients Without Diabetes or Hypertension 
The Journal of Infectious Diseases  2011;204(12):1946-1950.
It is unknown whether systemic endothelial dysfunction underlies the association between nephropathy and cardiovascular disease (CVD) in persons infected with human immunodeficiency virus (HIV). Spot urine protein to creatinine ratio, spot urine albumin to creatinine ratio, creatinine clearance, estimated glomerular filtration rate, and flow-mediated dilation (FMD) of the brachial artery were evaluated in 123 study participants infected with HIV (58 receiving antiretroviral therapy [ART] and 65 not receiving ART) with no history of diabetes or hypertension. None of the renal markers, modeled as either continuous or categorical variables, correlated with FMD. Contrary to expectations, endothelial dysfunction may not be the link between nephropathy and CVD in HIV.
doi:10.1093/infdis/jir668
PMCID: PMC3209818  PMID: 22013226
3.  Endothelial, Inflammatory, Coagulation, Metabolic Effects and Safety of Etravirine in HIV-Uninfected Volunteers 
AIDS Patient Care and STDs  2011;25(6):327-331.
Abstract
The innate proatherosclerotic properties of non-nucleoside reverse transcriptase inhibitors have not previously been examined. Therefore, we performed a pilot study of etravirine (ETR) in healthy volunteers over 28 days. This investigation also allowed us to evaluate the safety of ETR over a period commonly used for HIV postexposure prophylaxis. ETR 200 mg twice daily was given to 28 healthy HIV-uninfected volunteers over 28 days. Flow-mediated dilation (FMD) of the brachial artery and circulating markers of inflammation, coagulation, and metabolism were measured at entry and at day 28. These circulating markers were also measured at day 35. Of the initial 28 subjects, 23 completed both entry and day 28 procedures. Two subjects were discontinued due to development of rash. No other major toxicities developed. The change in FMD over 28 days was minimal and not significant (0.03 [−3.21, 0.97] %; p=0.36). The post hoc estimated detectable absolute change in FMD with the 23 subjects in our study was 2.26%, which is an effect size that has been associated with future cardiovascular event rates in the general population; thus our study had sufficient power to find clinically relevant changes in FMD. In addition, there were no significant changes in any of the circulating markers from entry to day 28 or from day 28 to day 35. ETR did not demonstrate any innate proatherosclerotic properties over 28 days in these HIV-uninfected volunteers. ETR was generally well tolerated. Larger studies are warranted to confirm that ETR can be used safely as part of HIV postexposure prophylaxis regimens.
doi:10.1089/apc.2011.0011
PMCID: PMC3143389  PMID: 21470045
4.  Anti-Inflammatory Treatment with Pentoxifylline Improves HIV-Related Endothelial Dysfunction: A Pilot Study 
AIDS (London, England)  2010;24(9):1377-1380.
We performed a single-arm, open-label pilot trial of the anti-inflammatory drug pentoxifylline to reduce systemic inflammation and improve endothelial function, measured by flow-mediated dilation of the brachial artery, in HIV-infected patients not requiring antiretroviral therapy. Pentoxifylline significantly reduced circulating levels of vascular cell adhesion molecule-1 and interferon-gamma-induced protein and significantly improved endothelial function during the 8 week trial. Pentoxifylline may reverse HIV-related endothelial dysfunction by directly inhibiting the endothelial leukocyte adhesion pathway.
doi:10.1097/QAD.0b013e3283396024
PMCID: PMC2891092  PMID: 20559042
HIV-1; Endothelium; Inflammation; Pentoxifylline
5.  Proteinuria, CrCl, and Immune Activation in Antiretroviral-Naïve HIV-Infected Subjects 
The Journal of infectious diseases  2009;200(4):614-618.
Because both renal disease and immune activation predict progression to AIDS, we evaluated the relationships between dipstick proteinuria ≥1+ [7% of 1012 subjects], CrCl <90mL/min [18% of 1071 subjects], and percentages of peripheral activated CD8 cells (CD8+CD38+HLA-DR+) in antiretroviral-naïve, HIV-infected subjects enrolled into AIDS Clinical Trials Group studies 384 and A5095. Proteinuria, but not CrCl, was associated with higher percentages of CD8+CD38+HLA-DR+ cells [55% vs. 50%; P=0.01], with even more pronounced differences in men and among Blacks and Hispanics. Proteinuria may be a surrogate measure of greater immune activation in HIV-infected patients initiating antiretroviral therapy.
doi:10.1086/600890
PMCID: PMC2858634  PMID: 19591572
HIV-1; proteinuria; renal failure; nephropathy; immune activation
6.  The Pharmacokinetics and Pharmacogenomics of Efavirenz and Lopinavir/Ritonavir in HIV-Infected Persons Requiring Hemodialysis 
AIDS (London, England)  2008;22(15):1919-1927.
Objective
To evaluate the pharmacokinetics and pharmacogenomics of efavirenz (EFV) and lopinavir/ritonavir (LPV/RTV) in HIV-infected persons requiring hemodialysis.
Design
Prospective, observational study of HIV-infected hemodialysis subjects receiving one 600mg tablet daily of EFV (N=13) or three 133.3/33.3mg capsules twice daily of LPV/RTV (N=13).
Methods
24-hour EFV and 12-hour LPV/RTV pharmacokinetics were assessed. Geometric mean ratios were calculated using historical controls with normal renal function. The effects of several candidate gene polymorphisms were also explored.
Results
The geometric mean (95% CI, %CV) Cmin, Cmax, and AUC for the EFV group were 1.81µg/mL (0.93, 3.53; 103%), 5.04µg/mL (3.48, 7.29; 72%), and 71.5µg·h/mL (43.2, 118.3; 93%), respectively. These parameters were 2.76µg/mL (1.86, 4.11; 53%), 8.45µg/mL (6.41, 11.15; 52%), and 69.6µg·h/mL (55.6, 87.2; 37%) for LPV and 0.08µg/mL (0.05, 0.14; 63%), 0.58µg/mL (0.44, 0.76; 41%), and 3.74µg·h/mL (2.91, 4.80; 37%) for RTV. The AUC geometric mean ratios (90% CI) for EFV, LPV, and RTV were 132% (89, 197), 81% (67, 97), and 92% (76, 111), respectively. LPV Cmin was lower than expected in the hemodialysis group. Higher EFV concentrations were associated with the CYP2B6 516G>T polymorphism.
Conclusions
The pharmacokinetics of EFV and LPV/RTV in hemodialysis suggest that no dosing adjustments are necessary in treatment-naïve patients. As HIV-infected hemodialysis patients are disproportionately black, the increased frequency of the CYP2B6 516G>T polymorphism may lead to higher EFV levels. The potentially lower LPV trough levels in this population suggest that LPV/RTV should be used with caution in protease inhibitor-experienced patients.
doi:10.1097/QAD.0b013e32830e011f
PMCID: PMC2675161  PMID: 18784455
Pharmacokinetics; Pharmacogenomics; Renal Failure; Dialysis; HIV; Efavirenz; Lopinavir; Ritonavir
7.  The Effects of HIV-1 Viral Suppression and Non-Viral Factors on Quantitative Proteinuria in the HAART Era 
Antiviral therapy  2009;14(4):543-549.
Background
Proteinuria is associated with progressive renal disease and overall mortality in HIV-infected patients. However, the prevalence and correlates of quantitative proteinuria in the HAART era are unknown.
Methods
Spot urine protein to creatinine (P/Cr) ratios, an accepted measure of quantitative daily proteinuria, were measured annually since 2002 in participants of the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) cohort. We used linear regression models with general estimating equations to identify factors associated with the abnormal P/Cr thresholds of ≥0.2 and ≥1.0.
Results
2857 participants, most of whom were receiving antiretroviral therapy, were analyzed. 16% and 3% had P/Cr levels ≥0.2 and ≥1.0, respectively, at first measurement. P/Cr levels did not change during a median follow-up of 3 (IQR 2, 4) years. Factors associated with P/Cr ≥0.2 at any measurement included greater age, lower glomerular filtration rate, female sex, antiretroviral therapy prior to entry into parent randomized trial, HIV-1 RNA level ≥ 400copies/ml, lower CD4 cell count, and history of hypertension, diabetes, or hepatitis C co-infection (all P<0.04). Black race and higher non-HDL-C levels were associated with P/Cr levels ≥1.0 but not with P/Cr levels ≥0.2. Hepatitis B co-infection and current use of adefovir, indinavir, and tenofovir were not associated with either P/Cr threshold.
Conclusions
Both HIV and non-HIV-related factors are associated with abnormal levels of proteinuria and identify those who are at greater risk of worse clinical outcomes. Several of these factors are differentially associated with lower and higher proteinuria thresholds.
PMCID: PMC2720522  PMID: 19578239
HIV; Proteinuria; Antiretroviral Therapy; Nephropathy
8.  Multiple-dose pharmacokinetics of peginterferon alfa-2b in patients with renal insufficiency 
What is already known about this subject?Current therapy for hepatitis C typically consists of pegylated interferon (PEG-IFN) alfa in combination with ribavirin.Pegylation of IFN alfa-2b confers a 10-fold increase in elimination half-life and a 30% reduction in volume of distribution compared with non-PEG-IFN alfa-2b.A single-dose pharmacokinetic study conducted in patients with chronic renal dysfunction has shown that renal elimination accounts for 30% of total PEG-IFN alfa-2b clearance and that PEG-IFN alfa-2b exposure increases with severity of renal insufficiency.What this study addsBecause the primary mechanism of IFN clearance is catabolism in the kidney, appropriate dosing of IFN-based therapies in patients with renal insufficiency is an important issue.This multiple-dose pharmacokinetic study shows that exposure to PEG-IFN alfa-2b is increased in patients with renal insufficiency, suggesting that doses of the drug should be reduced by 50% in patients with severe renal insufficiency and by 25% in those with moderate insufficiency.PEG-IFN alfa-2b was well tolerated in all patient groups during the 4-week treatment period, with similar adverse events occurring in patients with renal insufficiency and in those with normal renal function.
Aim
To evaluate the safety, tolerability and multiple-dose pharmacokinetics of pegylated interferon (PEG-IFN) alfa-2b in patients with moderate or severe renal insufficiency and in those with normal renal function.
Methods
In an open-label study, subjects with normal renal function (creatinine clearance >80 ml min−1 per 1.73 m2) and patients with moderate (30–50 ml min−1 per 1.73 m2) or severe (10–29 ml−1 min−1 per 1.73 m2) renal impairment received weekly injections of PEG-IFN alfa-2b (1.0 µg kg−1) for 4 weeks. Safety assessments were made before each injection and blood samples were taken up to 168 h after the final dose.
Results
Renal insufficiency increased PEG-IFN alfa-2b exposure. Area under the curve for 0–τ (dosing interval of 168 h), AUCτ, was increased 30% and 120% in patients with moderate or severe renal insufficiency, respectively. Mean maximum serum concentration was almost doubled in patients with severe insufficiency [1305.8 pg ml−1; 95% confidence interval (CI) 825, 1786] compared with subjects with normal renal function (731.4 pg ml−1; 95% CI 407, 1056), whereas the apparent volume of distribution was reduced (0.80 l kg−1vs. 1.28 l kg−1, respectively). Elimination half-life was extended in patients with moderate and severe renal insufficiency (65.6 h and 64.9 h, respectively) compared with subjects with normal renal function (51.5 h). Significant differences were observed in the AUC and Cmax values of patients with severe renal dysfunction, compared with those who had normal renal function (P< 0.05; Kruskal–Wallis test). PEG-IFN alfa-2b was well tolerated and adverse events were similar in both treatment groups.
Conclusions
Exposure to PEG-IFN alfa-2b is increased in patients with renal insufficiency, suggesting that doses of the drug should be reduced by 50% in patients with severe renal insufficiency and by 25% in those with moderate insufficiency.
doi:10.1111/j.1365-2125.2007.02950.x
PMCID: PMC2198783  PMID: 17555463
interferon alfa-2b; pegylation; pharmacokinetics; renal insufficiency
9.  Desloratadine dose selection in children aged 6 months to 2 years: comparison of population pharmacokinetics between children and adults 
What is already known about this subject
According to recent literature, the pathophysiologies of allergic rhinitis and chronic idiopathic urticaria are thought to be similar in adults and children. In addition, the response to antihistamine treatment is similar in adults and children, suggesting a similar concentration-response relationship.
However, an appropriate dose selection and the pharmacokinetics of desloratadine in children of ≥6 months−≤2 years old have never been addressed in the literature.
What this study adds
This study demonstrated that desloratadine syrup offers a safe treatment option for allergic conditions in young children.
A suitable dose for children aged ≥6 months−<1 year is 1.0 mg, while the corresponding predicted dose for children aged ≥1 year−≤2 years is 1.25 mg. These paediatric doses yielded similar systemic desloratadine exposures (AUC) to those seen with a typical adult dose of 5.0 mg.
Aims
The aim of this study was to identify the dose of desloratadine in children aged ≥6 months−≤2 years that would yield a single-dose target exposure (AUC) comparable with that in adults taking 5 mg desloratadine as syrup.
Methods
In a phase 1, single-dose, open-label, pharmacokinetic study in 58 children aged ≥6 months−<1 year and ≥1 year−≤2 years were randomly assigned to desloratadine syrup 0.625 mg (1.25 ml) and 1.25 mg (2.5 ml), respectively. Because the volume of blood that could be collected from individual subjects was limited, a population pharmacokinetic approach was used to estimate the pharmacokinetics of desloratadine. Safety was assessed based on results of screening and postdose physical examinations, laboratory safety tests, vital signs, and adverse events.
Results
The apparent clearance (CL/F) of desloratadine, population estimate (%CV), in children aged ≥6 months−<1 year was 27.8 l h−1 (35) and corresponding values in children ≥1 year−≤2 years was 35.5 l h−1 (51), compared with 137 l h−1 (58) for adults. The CL/F ratios (children to adults) indicated that doses of 1 mg for ≥6 months−<1 year and 1.25 mg for ≥1 year−≤2 years would result in similar systemic exposure to that observed in adults receiving the recommended 5 mg dose. Desloratadine was well tolerated with no safety issues.
Conclusions
Doses of 1.0 and 1.25 mg in children aged ≥6 months−≤2 years should result in an exposure to desloratadine similar to that of adults receiving doses of 5 mg.
doi:10.1111/j.1365-2125.2007.02859.x
PMCID: PMC2000635  PMID: 17324243
desloratadine; dose; paediatric; pharmacokinetics; safety
10.  The effects of highly active antiretroviral therapy on albuminuria in HIV-infected persons: results from a randomized trial 
Background
Human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) regimens, especially those containing protease inhibitors (PIs), are at increased risk for cardiovascular events. Albuminuria is a known independent predictor for the development of cardiovascular disease and may potentially increase in patients receiving PIs. Alternatively, albuminuria may improve with HAART as a result of treating renal parenchymal HIV infection. Longitudinal studies have not been performed previously addressing the effects of HAART on albuminuria.
Methods
We evaluated the effects of HAART on albumin to creatinine ratios (ACRs) during the initial 64 weeks of therapy in 68 previously untreated HIV-infected subjects, without pre-existing diagnosed diabetes or hypertension, enrolled in a randomized trial comparing PI-based (n = 32) with non-PI-based (n = 36) HAART regimens. We also estimated the prevalence of albuminuria, defined as an ACR ≥3.4 mg/mmol, in these subjects prior to initiation of HAART.
Results
The changes in ACR over the initial 64 weeks of therapy in those receiving PIs [0.0 mg/mmol (−0.4, 0.3)] and in those not receiving PIs [0.0 mg/mmol (−0.5, 0.3)] were not significantly different. There was also no significant difference in the change in the ACR in the group as a whole. However, albuminuria at baseline was found in seven (10%) subjects. Five of these seven subjects had substantial improvements in ACR, ranging from 45 to 95%, with HAART use; three subjects had resolution of albuminuria. ACR at baseline significantly correlated with the baseline HIV-1 RNA level (r = 0.25; P = 0.04) and negatively with CD4 cell count (r = 0.25; P = 0.04).
Conclusion
Albuminuria in HIV-infected, treatment-naïve patients was found more frequently than expected and may be influenced by baseline immune status. Although we did not observe an effect of HAART on ACR during the first 64 weeks of therapy, we cannot exclude the possibility that HAART may be beneficial in those patients with significant albuminuria prior to treatment. Research in larger cohorts is required to investigate more definitively the associations between immune status, antiretroviral therapies and renal function in HIV-infected patients.
doi:10.1093/ndt/gfi053
PMCID: PMC1586248  PMID: 16105869
albuminuria; antiretroviral therapy; cardiovascular disease; cardiovascular risk; HIV; protease inhibitors
11.  Proteinuria and Endothelial Dysfunction in Stable HIV-Infected Patients: A Pilot Study 
doi:10.1097/QAI.0b013e318061d2fa
PMCID: PMC2041805  PMID: 17704684
HIV; Proteinuria; Albuminuria; Endothelial Function; Lopinavir/ritonavir
12.  Midnight Haemoptyses 
British Medical Journal  1960;1(5184):1505.
PMCID: PMC1967316
15.  Microbial Translocation and Metabolic and Body Composition Measures in Treated and Untreated HIV Infection 
Abstract
Circulating levels of microbial products such as lipopolysaccharide (LPS) are increased in HIV infection. Microbial translocation promotes obesity, insulin resistance, and dyslipidemia in other settings. We examined data from 178 subjects: an Indiana University (IU) cross-sectional study [N=49 on antiretroviral therapy (ART), N=47 not on ART], and a 24 week prospective study of ART initiation ACTG 5152s (N=82). Pearson correlations were used to describe relationships of plasma LPS levels and soluble CD14 (sCD14), a marker of monocyte activation, with metabolic and body composition measures. HOMA-IR (a measure of insulin resistance) and LPS were correlated for the combined cohorts (r=0.19, p=0.02), particularly in the 5152s ART-naive cohort (r=0.41, p<0.01). Triglycerides were correlated with LPS in the combined cohort (r=0.32, p<0.01), and all subsets excluding the IU on ART subset. There were negative correlations between sCD14 and high-density lipoprotein (HDL) cholesterol in all subjects (r=−0.21, p<0.01), as well as the IU subset not on ART (r=−0.32, p=0.04). Large particle HDL as measured by NMR spectroscopy, but not HDL cholesterol, was negatively correlated with LPS (r=−0.18, p=0.02), particularly among the IU subset receiving ART (r=−0.33, p=0.03). In the combined cohorts, sCD14 was negatively correlated with lean mass as well as trunk and limb fat. There is a relationship between microbial translocation markers and metabolic effects, particularly lipoproteins. During prolonged ART, microbial translocation was associated with an adverse effect on large HDL and thus may contribute to the increased cardiovascular disease risk observed during chronic treatment of HIV.
doi:10.1089/aid.2013.0162
PMCID: PMC3938948  PMID: 24033288
16.  Effects of Switching from Efavirenz to Raltegravir on Endothelial Function, Bone Mineral Metabolism, Inflammation, and Renal Function: A Randomized, Controlled Trial 
We performed a randomized, controlled trial in 30 HIV-infected participants to either continue tenofovir/emtricitabine/efavirenz (Continuation Group) or switch to tenofovir/emtricitabine/raltegravir (Switch Group) for 24 weeks. There were no significant differences in the changes in flow-mediated dilation, 25(OH)vitamin D, or parathyroid hormone levels. Total cholesterol, high sensitivity C-reactive protein, serum alkaline phosphatase, sCD14 levels, and renal function significantly declined in the Switch Group compared to the Continuation Group; however, sCD163 levels significantly increased in the Switch Group. These findings suggest that raltegravir is not inherently more beneficial to endothelial function compared to efavirenz but may impact renal function and monocyte activation.
PMCID: PMC4091630  PMID: 24278992
Efavirenz; raltegravir; endothelial function; vitamin D; monocyte activation; renal function
17.  Substantial Effect of Efavirenz Monotherapy on Bilirubin Levels in Healthy Volunteers 
Background
Efavirenz exhibits multiple interactions with drug-metabolizing enzymes and transporters, and for this reason efavirenz-based HIV therapy is associated with altered pharmacokinetics of coadministered drugs. Probably by the same mechanism, efavirenz-based HIV therapy affects the disposition of endogenous compounds, but this effect is difficult to directly link with efavirenz because it is used in combination with other drugs.
Objectives
To explore the effect of efavirenz monotherapy on biochemical laboratory values in a clinical trial of healthy volunteers.
Methods
Men and women (aged 18–49 years) with body mass index ≤32 who were assessed to be healthy based on medical history, physical examination, and standard laboratory screening received a single (600 mg) and multiple doses (600 mg/d for 17 days) of efavirenz orally. This trial was designed to determine the pharmacokinetics and drug interactions of efavirenz. As part of this study, analysis of serum chemistries that were measured at study entry (screening) and 1 week after completion of the multiple dose study (exit) is reported.
Results
Data from 60 subjects who fully completed and 13 subjects who partially completed the study are presented. Total bilirubin was substantially reduced at exit (by ~30%, with large intersubject variability) compared with screening values (P < 0.0001). The percent changes were in part explained by the intersubject differences in baseline total bilirubin because there was a significant correlation between baseline (screening) values and percent change at exit (r = 0.50; P < 0.0001). Hemoglobin and absolute neutropenia were also substantially decreased at exit compared with screening, but this may be due to intensive blood sampling rather than direct effect of efavirenz on these parameters. No significant correlation was found between percent change in hemoglobin versus percent change in bilirubin, indicating the effect of efavirenz on bilirubin is independent of its effects on hemoglobin.
Conclusions
Efavirenz monotherapy significantly lowers plasma total bilirubin concentration in healthy volunteers independent of its effect on hemoglobin, probably through its effects on bilirubin metabolism and transport (uptake and efflux). These findings help explain reversal by efavirenz of hyperbilirubinemia induction observed by some protease inhibitor antiretroviral drugs (eg, atazanavir). Besides its well-documented role on drug interactions, efavirenz may alter the disposition of endogenous compounds relevant in physiologic homeostasis through its interaction with drug metabolizing enzymes and/or drug transporters. ClinicalTrials.gov identifier: NCT00668395.
doi:10.1016/j.curtheres.2014.05.002
PMCID: PMC4209507  PMID: 25352936
anemia; bilirubin disposition; drug interactions; efavirenz; monotherapy; neutropenia
18.  Fanconi Syndrome Accompanied by Renal Function Decline with Tenofovir Disoproxil Fumarate: A Prospective, Case-Control Study of Predictors and Resolution in HIV-Infected Patients 
PLoS ONE  2014;9(3):e92717.
Objective
The predictors of Fanconi syndrome (FS) accompanied by renal function decline with use of the antiretroviral tenofovir disoproxil fumarate (TDF) have not been assessed. In addition, the natural history of renal recovery from FS after TDF discontinuation is not well-described.
Design
We prospectively enrolled HIV-infected patients receiving TDF with newly identified FS (defined as at least two markers of proximal tubulopathy and either a >25% decline in creatinine clearance (CrCl) from pre-TDF values or a CrCl <60 mL/min in those without a known pre-TDF CrCl) in a multicenter observational study. These case participants were matched 1∶2 to controls; characteristics between the two groups were compared. Case participants with known pre-TDF CrCl values were then followed over 48 weeks to assess renal recovery.
Results
Nineteen cases and 37 controls were enrolled. In multivariable analysis, previous or concurrent use of lopinavir/ritonavir [OR 16.37, 95% CI (2.28, 117.68); P = 0.006] and reduced creatinine clearance prior to initiation of TDF [OR 1.44 for every 5 mL/min reduction, 95% CI (1.09, 1.92); P = 0.012; OR 19.77 for pre-TDF CrCl lower than 83 mL/min, 95% CI (2.24, 174.67); P = 0.007] were significantly associated with FS. Of the 14 cases followed for resolution, 7 (50%) achieved at least partial resolution (defined as recovering CrCl >70% of pre-TDF values) although most participants had full normalization of proximal tubulopathy markers within two months of TDF discontinuation.
Conclusions
FS, defined by specific CrCl decreases and markers of tubulopathy, is more likely in those who have received or are currently receiving concomitant lopinavir/ritonavir or who had lower CrCl prior to TDF initiation. Half of those with protocol-defined FS had CrCl recover to near pre-TDF values during the first year after TDF discontinuation.
doi:10.1371/journal.pone.0092717
PMCID: PMC3961428  PMID: 24651857
19.  Transfer of Intracellular HIV Nef to Endothelium Causes Endothelial Dysfunction 
PLoS ONE  2014;9(3):e91063.
With effective antiretroviral therapy (ART), cardiovascular diseases (CVD) are emerging as a major cause of morbidity and death in the aging HIV-infected population. To address whether HIV-Nef, a viral protein produced in infected cells even when virus production is halted by ART, can lead to endothelial activation and dysfunction, we tested Nef protein transfer to and activity in endothelial cells. We demonstrated that Nef is essential for major endothelial cell activating effects of HIV-infected Jurkat cells when in direct contact with the endothelium. In addition, we found that Nef protein in endothelial cells is sufficient to cause apoptosis, ROS generation and release of monocyte attractant protein-1 (MCP-1). The Nef protein-dependent endothelial activating effects can be best explained by our observation that Nef protein rapidly transfers from either HIV-infected or Nef-transfected Jurkat cells to endothelial cells between these two cell types. These results are of in vivo relevance as we demonstrated that Nef protein induces GFP transfer from T cells to endothelium in CD4.Nef.GFP transgenic mice and Nef is present in chimeric SIV-infected macaques. Analyzing the signal transduction effects of Nef in endothelial cells, we found that Nef-induced apoptosis is mediated through ROS-dependent mechanisms, while MCP-1 production is NF-kB dependent. Together, these data indicate that inhibition of Nef-associated pathways may be promising new therapeutic targets for reducing the risk for cardiovascular disease in the HIV-infected population.
doi:10.1371/journal.pone.0091063
PMCID: PMC3946685  PMID: 24608713
20.  Pentoxifylline Reduces Tumor Necrosis Factor-α and HIV-Induced Vascular Endothelial Activation 
AIDS Research and Human Retroviruses  2012;28(10):1207-1215.
Abstract
Untreated HIV infection is associated with endothelial dysfunction and subsequent cardiovascular disease, likely due to both direct effects of the virus and to indirect effects of systemic inflammation on the vasculature. We have recently shown that treatment with the antiinflammatory agent pentoxifylline (PTX) improved in vivo endothelial function and reduced circulating levels of the inflammatory markers vascular cell adhesion molecule-1 (VCAM-1) and interferon-gamma-induced protein (IP-10) in HIV-infected patients. To delineate the mechanisms underlying this therapeutic effect, we tested whether clinically relevant concentrations of PTX suppress VCAM-1 or IP-10 release in cultivated human lung microvascular endothelial cells. Indeed, we found that tumor necrosis factor (TNF)-α-induced VCAM-1 was reduced with concentrations of PTX in the low nanomolar range, comparable to plasma levels in PTX-treated groups. We also investigated the effect of HIV proteins and found that HIV transactivator of transcription (HIV-Tat) and HIV-envelope-derived recombinant gp120 enhanced TNF-α-induced VCAM-1 gene expression in lung microvascular and coronary macrovascular endothelial cells, respectively. In addition, PTX and a NF-κB-specific inhibitor reduced this enhanced VCAM-1 gene induction in microvascular and macrovascular endothelial cells. These results provide novel insights in how the antiinflammatory agent PTX can directly reduce HIV-associated proinflammatory endothelial activation, which may underlie vascular dysfunction and coronary vascular diseases.
doi:10.1089/aid.2011.0385
PMCID: PMC3448099  PMID: 22463742
21.  Pentoxifylline, Inflammation, and Endothelial Function in HIV-Infected Persons: A Randomized, Placebo-Controlled Trial 
PLoS ONE  2013;8(4):e60852.
Background
Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy.
Methods
We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed.
Results
The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [−1.06 (1.45)%] and PTX [−1.93 (3.03)%] groups was not significant (P = 0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [−83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; P = 0.03]. PTX was generally well-tolerated.
Conclusions
PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population.
Trial Registration
ClinicalTrials.gov NCT00796822
doi:10.1371/journal.pone.0060852
PMCID: PMC3621886  PMID: 23593327
22.  Suppression of HIV-1 replication by antiretroviral therapy improves renal function in persons with low CD4 cell counts and chronic kidney disease 
AIDS (London, England)  2008;22(4):481-487.
Objective
To examine the association between changes in glomerular filtration rates (GFR) and antiretroviral therapy (ART)-mediated suppression of plasma HIV-1 viremia.
Design
Observational, prospective, multicenter cohort study.
Intervention
ART regimens or treatment strategies in HIV-1-infected subjects were implemented through randomized clinical trials; 1776 ambulatory subjects from these trials also enrolled in this cohort study.
Method
The association between suppression of viremia and GFR changes from baseline was examined using the abbreviated Modification of Diet and Renal Disease equation in mixed effects linear models.
Results
GFR improvement was associated with ART-mediated suppression of plasma viremia in subjects with both chronic kidney disease stage ≥2 and low baseline CD4 cell counts (< 200 cells/µl). In this subset, viral suppression (by > 1.0 log10 copies/ml or to < 400 copies/ml) was associated with an average increase in GFR of 9.2 ml/min per 1.73 m2 from baseline (95% confidence interval, 1.6–16.8; P = 0.02) over a median follow-up of 160 weeks. The magnitude of this association increased in subjects who had greater baseline impairment of renal function, and it did not depend on race or sex.
Conclusions
Viral suppression was associated with GFR improvements in those with both low CD4 cell counts and impaired baseline renal function, supporting an independent contribution of HIV-1 replication to chronic renal dysfunction in advanced HIV disease. GFR improvement not associated with viral suppression also was observed in subjects with higher CD4 cell counts.
doi:10.1097/QAD.0b013e3282f4706d
PMCID: PMC3529361  PMID: 18301060
antiretroviral therapy; chronic kidney disease; HIV-1 viremia; HIV-associated nephropathy
23.  Metabolic Effects of Darunavir/Ritonavir Versus Atazanavir/Ritonavir in Treatment-Naive, HIV Type 1-Infected Subjects over 48 Weeks 
AIDS Research and Human Retroviruses  2012;28(10):1184-1195.
Abstract
We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4+ cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, –0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted.
doi:10.1089/aid.2011.0327
PMCID: PMC3448095  PMID: 22352336
24.  Worsening Endothelial Function with Efavirenz Compared to Protease Inhibitors: A 12-Month Prospective Study 
PLoS ONE  2012;7(9):e45716.
Objective
Changes in endothelial function, measured as flow-mediated dilation (FMD) of the brachial artery, has not been systematically assessed beyond 6 months of initiation of antiretroviral therapy (ART) when drug-related effects might offset initial improvements with virologic control.
Design
We assessed 6 and 12 month changes in FMD [presented as median (quartile 1, quartile 3)] and circulating HIV and cardiovascular biomarkers in 23 subjects initiating ART.
Results
There were no significant changes in FMD at 6 or 12 months overall despite significant increases in CD4 cell count and HDL-C and reductions in HIV RNA level, MCP-1, IP-10, sVCAM-1, sTNFR2, and sCD14. However, there were significant differences (P = 0.04) in the changes in FMD between those receiving efavirenz [N = 12; −3.50% (−4.90%, 0.68%)] vs. protease inhibitors at 12 months [N = 11; 1.50% (−0.86%, 4.56%)]. The differences in changes in FMD between those receiving and not receiving emtricitabine/tenofovir/efavirenz were more pronounced and were significantly different at both 6 and 12 months (P<0.02 for both). Additional studies showed no significant differences in changes in 25-(OH)-vitamin D, PTH, FGF-23, of F2-isoprostane levels between efavirenz and PI use or between those receiving and not receiving emtricitabine/tenofovir/efavirenz.
Conclusion
Efavirenz use was associated with reduced FMD at 12 months compared to PI-based regimens while emtricitabine/tenofovir/efavirenz was associated with reduced FMD at both 6 and 12 months compared to those not receiving this combination. Long-term effects of antiretrovirals on endothelial function may play an important role in the risk of cardiovascular disease in HIV-infected patients.
doi:10.1371/journal.pone.0045716
PMCID: PMC3447812  PMID: 23029197
25.  Relationship between Microbial Translocation and Endothelial Function in HIV Infected Patients 
PLoS ONE  2012;7(8):e42624.
Background
Circulating levels of microbial products are increased in HIV infection, and provoke endothelial dysfunction in other disease settings.
Methodology/Principal Findings
We examined data from a cross-sectional single site study at Indiana University (Indiana, N = 85) and a 24- week multicenter prospective study of antiretroviral therapy (ART) initiation (ACTG 5152s, N = 75). Brachial artery flow-mediated dilation (FMD) was measured by ultrasound. Plasma lipopolysaccharide (LPS) and soluble CD14 (sCD14) levels were measured from stored specimens and correlated with FMD values using Pearson correlations. The Indiana subjects were 63% male with a mean age of 39 years and a median CD4 count of 406 cells/mm3 (388 not on ART, 464 on ART). The 5152s subjects were 92% were male with a mean age of 35 years and a median CD4 count of 251 cells/mm3 at entry which increased to 396 cells/mm3 on ART. When analyzing the two cohorts individually or in combination neither sCD14 nor LPS correlated significantly with FMD. In a pre-specified subgroup analysis of the Indiana subjects receiving ART (N = 46, mean ART duration 40 months) LPS was inversely correlated with FMD (r = −0.33, p = 0.02), but not sCD14 (r = −0.01, p = 0.9). Multivariate analysis confirmed LPS as an independent predictor of FMD in this subgroup (p = 0.02).
Conclusions/Significance
In HIV- infected individuals on prolonged ART, higher LPS levels are associated with worse endothelial function but not in untreated subjects or at 24 weeks after ART initiation. Persistent microbial translocation may contribute to arterial dysfunction and the increased cardiovascular disease risk observed in individuals on long-term ART.
doi:10.1371/journal.pone.0042624
PMCID: PMC3431387  PMID: 22952600

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