Both renal disease and systemic inflammation predict non-AIDS events and overall mortality in HIV-infected patients. Here we sought to determine the relationships between renal disease and circulating inflammation markers.
We performed a secondary analysis of AIDS Clinical Trials Group study A5224s to determine if markers of renal disease [urine protein/creatinine (uPCR); urine albumin/creatinine (uACR); estimated glomerular filtration rate, eGFR, using CKD-EPI creatinine and cystatin C-creatinine] were associated with markers of systemic inflammation [high sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, soluble receptors of TNF-α (sTNFRI and II), soluble vascular cellular and intercellular adhesion molecules]. We correlated these renal and inflammatory markers prior to antiretroviral initiation and at 96 weeks of therapy.
We found that estimated eGFR (using CKD-EPI cystatin C-creatinine), uPCR, and uACR were significantly correlated with most assessed markers of systemic inflammation prior to antiretroviral initiation. uPCR and eGFR (using CKD-EPI cystatin C-creatinine), but not uACR, remained significantly correlated with most of the assessed inflammatory markers after 96 weeks of ART. Most of these correlations, although statistically significant, were under 0.50. eGFR using CKD-EPI creatinine was much less frequently associated with inflammation markers and only significantly correlated with sTNFR1 at Week 0 and with sTNFRI and II at Week 96.
Renal disease and function are associated with systemic inflammation in HIV both before and after ART. Systemic inflammation may partially explain the relationships between proteinuria, albuminuria, and reduced renal function and future adverse outcomes.
HIV-1; nephropathy; inflammation; albuminuria; proteinuria
The relationships between HIV infection, monocyte activation, and endothelial colony forming cells (ECFCs) are unknown. We compared ECFC, intermediate monocytes (CD14+CD16+), and non-classical monocytes (CD14dimCD16++) levels in HIV-infected participants virologically-suppressed on antiretroviral therapy, HIV-infected treatment-naïve participants, and HIV-uninfected healthy controls. ECFC levels were significantly higher in the HIV-infected, virologically-suppressed group compared to the uninfected controls. CD14+CD16+ percentages (but not CD14dimCD16++ cells) were significantly higher in both HIV-infected groups vs uninfected controls. In the HIV-infected groups, ECFCs and CD14+CD16+ intermediate monocytes were significantly and inversely correlated. Lower availability of ECFCs may partly explain the relationship between greater intermediate monocytes and atherosclerosis in HIV.
endothelial progenitor cell; endothelial colony forming cells; non-classical monocyte; intermediate monocyte; HIV; flow-mediated dilation
We sought to determine the relationships among intrarenal and systemic inflammation and renal disease in HIV. We compared paired serum and urinary levels (normalized to urine creatinine) of monocyte chemotactic protein-1 (MCP-1), regulated on activation normal T cell expressed and secreted (RANTES), interferon-γ-induced protein-10 (IP-10), interleukin-8 (IL-8), and β2-microglobulin (B2M) between two groups of HIV-infected subjects not receiving antiretroviral therapy (ART) [A: not expecting to initiate ART immediately due to having CD4 cell counts ≥350/μl, N=26; B: about to initiate ART, N=19], a group of HIV-infected subjects receiving virologically suppressive antiretroviral therapy [C, N=30], and a group of HIV-uninfected, healthy volunteers [D, N=45]. We then correlated these inflammatory biomarker levels with urine protein/creatinine ratios (uPCR), urine albumin/creatinine ratios (uACR), and estimated glomerular filtration rates (eGFR). Urine inflammatory biomarker levels were highest in Group B. When combining all four study groups, statistically significant positive correlations included uPCR with urine IL-8, urine MCP-1, urine IP-10, and serum IP-10 and uACR with urine IL-8, urine B2M, serum IP-10, and serum B2M. eGFR was statistically significantly negatively correlated with serum MCP-1 and serum B2M. Paired serum and urine levels of IP-10 and B2M (but not IL-8, RANTES, or MCP-1) were significantly correlated with each other in the overall group. The levels of urine inflammatory markers tested differed by HIV status and use of virologically suppressive ART. These urine and serum inflammatory markers were differentially correlated with uPCR, uACR, and eGFR, suggesting that different intrarenal and systemic inflammatory pathways may contribute to different measures of nephropathy.
The HIV NNRTI rilpivirine is being evaluated as a possible agent for HIV pre-exposure prophylaxis. We have recently shown that the NNRTI efavirenz may impair endothelial function assessed as flow-mediated dilation (FMD), but whether this impairment is also found with rilpivirine is unknown. We sought to compare cardiovascular risk profiles between efavirenz and rilpivirine in healthy volunteers.
We performed a prospective, randomized, open-label trial in 40 HIV-uninfected healthy volunteers who were randomized 1: 1 to either efavirenz or rilpivirine. Vascular indices, metabolic parameters, inflammatory biomarkers and oxidative stress were measured before and after 4 weeks of treatment. This study is registered at ClinicalTrials.gov (NCT01585038).
There were no significant differences in 4 week mean (SD) changes in FMD between efavirenz and rilpivirine [0.089 (3.65)% versus 0.63 (2.42)%; P = 0.77]. There were also no significant differences in 4 week changes in high-sensitivity C-reactive protein, IL-6, soluble vascular cell adhesion molecule-1, HDL-cholesterol, triglycerides or homeostasis model assessment–insulin resistance. However, efavirenz led to significant increases in total cholesterol [19.39 (23.9) versus −5.78 (16.5) mg/dL; P < 0.001], LDL-cholesterol [13.29 (19.5) versus −2.24 (13.4) mg/dL; P = 0.009] and F2-isoprostanes [92.7 (178.6) versus −101.4 (215.7) pg/mL; P = 0.019] compared with rilpivirine. Two participants from each study group discontinued prematurely for adverse events.
There were no significant differences in the changes in endothelial function over 1 month between the efavirenz and rilpivirine groups, although efavirenz had worse lipid changes compared with rilpivirine. Longer-term studies are required for confirmation.
The effects of antiretrovirals on cystatin C-based renal function estimates are unknown.
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.
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.
Antiretroviral-associated changes in renal function vary in magnitude and direction based on the estimating equation used.
atazanavir; creatinine; cystatin C; HIV-1; nephropathy; tenofovir
Among patients with HIV-infection, changes in the kidney filtration marker cystatin C after initiation of antiretroviral therapy (ART) may be related to changes in body composition or biomarkers of inflammation.
ACTG A5224s was a substudy of A5202 which randomly assigned ART-naïve HIV-infected subjects to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r). This analysis explored changes in cystatin C from 0 to 96 weeks.
Of the 269 subjects, 85% were male and 66% White non-Hispanics; baseline mean CD4 count was 236 cells/mm3 and cystatin C was 0.89 mg/L. Cystatin C decreased significantly within each arm; however, ATV/r attenuated the beneficial effects of ART on cystatin C compared to EFV. Compared to ABC/3TC, TDF/FTC led to a marginally significant attenuation for percent change analyses only. Higher baseline BMI and HIV RNA were associated with larger reductions in cystatin C in multivariable models. At baseline, cystatin C was positively correlated with high sensitivity C-reactive protein (Spearman r=0.25), interleukin-6 (r=0.34), soluble intercellular adhesion molecule (r=0.36), soluble vascular cell adhesion molecule (r=0.54), tumor necrosis factor-α (r=0.57), and soluble TNF-α receptor-I (r=0.70, all p<0.001). Reductions in cystatin C from 0 to 96 weeks correlated with reductions in all inflammatory biomarkers (r=0.39 to 0.58, p<0.001) except for hs-CRP (r=0.01, p=0.89) and IL-6 (r=0.08, p=0.24).
The beneficial effect of ART on cystatin C concentrations is attenuated by boosted ATV when compared to EFV. Reductions in cystatin C after ART are associated with reductions in systemic inflammation.
kidney; glomerular filtration rate; cystatin C; antiretroviral therapy; inflammation
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.
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.
Supplemental Digital Content is Available in the Text.
Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with improved renal and bone safety compared with TDF-containing regimens. We report the 48 week safety and efficacy of a once-daily single tablet regimen of elvitegravir 150 mg (E), cobicistat 150 mg (C), emtricitabine 200 mg (F), and TAF 10 mg (E/C/F/TAF) in HIV-1-infected patients with mild to moderate renal impairment.
We enrolled virologically suppressed HIV-1-infected subjects with estimated creatinine clearance (CrCl) 30–69 mL/min in a single-arm, open-label study to switch regimens to E/C/F/TAF. The primary endpoint was the change from baseline in glomerular filtration rate estimated using various formulae. This study is registered with ClinicalTrials.gov, number NCT01818596.
We enrolled and treated 242 patients with mean age 58 years, 18% Black, 39% hypertension, 14% diabetes. Through week 48, no significant change in estimated CrCl was observed. Two patients (0.8%) discontinued study drug for decreased creatinine clearance, neither had evidence of renal tubulopathy and both had uncontrolled hypertension. Subjects had significant improvements in proteinuria, albuminuria, and tubular proteinuria (P < 0.001 for all). Hip and spine bone mineral density significantly increased from baseline to week 48 (mean percent change +1.47 and +2.29, respectively, P < 0.05). Ninety-two percent (222 patients) maintained HIV-1 RNA <50 copies per milliliter at week 48.
Switch to E/C/F/TAF was associated with minimal change in GFR. Proteinuria, albuminuria and bone mineral density significantly improved. These data support the efficacy and safety of once daily E/C/F/TAF in HIV+ patients with mild or moderate renal impairment without dose adjustment.
tenofovir alafenamide; emtricitabine; chronic kidney disease; bone mineral density; HIV
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.
HIV-1; Endothelium; Inflammation; Pentoxifylline
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.
HIV-1; proteinuria; renal failure; nephropathy; immune activation
We report here the novel finding that HIV-negative factor (Nef) protein is present in considerable numbers of peripheral blood mononuclear cells (PBMCs) from viremic HIV-infected patients not on antiretroviral therapy (ART) and also in patients receiving virologically suppressive ART, though to a smaller degree. Interestingly, these Nef-positive PBMCs constitute predominantly uninfected bystander cells. These results may explain systemic pathology in HIV patients, even in those receiving ART.
Tenofovir disoproxil fumarate (TDF) is a widely used antiretroviral agent with favorable efficacy, safety and tolerability profiles. However, renal adverse events, including rare Fanconi syndrome (FS), may occur in a small subset of HIV-infected treated patients.
The aim of this study was to identify genetic variants that may associate with TDF-associated FS (TDF-FS).
DNA samples collected from a 19 cases with TDF-FS and 36 matched controls were sequenced and genetic association studies were performed in eight candidate genes: ATP-binding cassette (ABC) transporters ABCC2 (MRP2) and ABCC4 (MRP4), solute carrier family members SLC22A6 (OAT1) and SLC22A8 (OAT3), adenylate kinases 2 (AK2) and 4 (AK4), chloride transporter CIC-5 CLCN5, and Lowe syndrome protein OCRL. Functional effects of a SNP predicted to alter transport of tenofovir were then investigated in cells expressing an identified variant or ABCC4.
Overall, the case group showed a trend towards a higher proportion of rare alleles. Six SNPs in ABCC2 (3 SNPs), ABCC4 (1 SNP) and OCRL (2 SNPs) were associated with TDF-FS case status, but did not remain significant after correction for multiple testing. Six SNPs, in OCRL (4 SNPs) and ABCC2 (2 SNPs), were significantly associated with increased serum creatinine levels in the cases, and remained significant after multiple test correction (P < 2 × 10−04). One synonymous SNP in ABCC2 (rs8187707; P=2.10 ×10−04; β =−73.3 ml/min/1.73m2)) was also significantly associated with decreased estimated glomerular filtration rate of creatinine in the cases. However, these results were driven by rare SNPs present in a small number of severely affected cases. A previously uncharacterized, non-synonymous SNP, rs11568694, that was predicted to alter MRP4 function, had no significant effect on tenofovir cellular accumulation in vitro.
While no single predictive genetic marker for the development of TDF-FS was identified, these findings suggest that multiple rare variants in multiple genes involved in renal handling of tenofovir and/or renal cell homeostasis may be associated with increased susceptibility to TDF-FS.
Fanconi Syndrome; tenofovir; HIV; transporter; pharmacogenetics
To evaluate the pharmacokinetics and pharmacogenomics of efavirenz (EFV) and lopinavir/ritonavir (LPV/RTV) in HIV-infected persons requiring hemodialysis.
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).
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.
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.
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.
Pharmacokinetics; Pharmacogenomics; Renal Failure; Dialysis; HIV; Efavirenz; Lopinavir; Ritonavir
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.
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.
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.
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.
HIV; Proteinuria; Antiretroviral Therapy; Nephropathy
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.
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.
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.
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.
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.
interferon alfa-2b; pegylation; pharmacokinetics; renal insufficiency
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.
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.
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.
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.
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.
desloratadine; dose; paediatric; pharmacokinetics; safety
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.
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.
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).
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.
albuminuria; antiretroviral therapy; cardiovascular disease; cardiovascular risk; HIV; protease inhibitors
HIV; Proteinuria; Albuminuria; Endothelial Function; Lopinavir/ritonavir
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.
HIV-1; chronic kidney disease; clinical practice guideline; HIV-associated nephropathy; kidney transplantation
Antiretroviral therapy (ART) is associated with improved kidney function; however, the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been associated with decreased kidney function and proteinuria.
We examined changes in urine protein:creatinine (UPCR) and albumin:creatinine (UACR) ratios in 245 ART-naïve participants in A5202 randomized in a substudy to blinded NRTI (abacavir/lamivudine, ABC/3TC, n=124 or TDF/emtricitabine, TDF/FTC, n=121) with open-label protease inhibitor (PI) atazanavir/ritonavir (ATV/r) or non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV).
At baseline, 18% of participants had clinically significant proteinuria (UPCR ≥ 200 mg/g) and 11% had clinically significant albuminuria (UACR ≥ 30 mg/g). The prevalence of clinically significant proteinuria and albuminuria decreased from baseline to week 96 in all treatment groups. In intention-to-treat analyses, there was a significant effect of NRTI component on fold-change in UPCR (p=0.011) and UACR (p=0.018) from baseline to week 96, with greater improvements in participants randomized to ABC/3TC. There was no significant effect of NNRTI/PI component on fold-change in UPCR (p=0.23) or UACR (p=0.88), and no significant interactions between NRTI and NNRTI/PI components.
In this pre-specified secondary analysis, ART initiation was associated with improvements in proteinuria and albuminuria, with significantly greater improvements in participants randomized to ABC/3TC versus TDF/FTC. These are the first data from a randomized trial to suggest that initiation of TDF/FTC may not be associated with the same degree of improvement in proteinuria and albuminuria that have been reported with other regimens. Future studies should consider the long-term clinical significance of these findings.