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1.
Clin Infect Dis ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31606734

RESUMO

BACKGROUND: Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation. METHODS: We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naïve people with HIV (PWH) initiating ART between 2003-2015, comprising over 5,000 participants and 10,000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation. FINDINGS: Weight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4, higher HIV-1 RNA, no injection drug use, female sex and black race. Integrase strand transfer inhibitors (INSTIs) were associated with more weight gain than protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTI), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine. INTERPRETATION: Weight gain is ubiquitous in clinical trials of ART initiation, and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens contributing. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.

2.
J Anal Methods Chem ; 2019: 1648782, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396433

RESUMO

Dendranthema indicum var. aromaticum is a new species with strong fragrance and is used as a herbal medicine by Chinese folks. The abundant flavonoids play important roles in its pharmacological activities. In this study, an ultrasound-assisted method was used to extract total flavonoids (TF) from D. indicum var. aromaticum by response surface methodology. A quadratic model was developed to optimize the extraction conditions, whose accuracy was verified by statistic analysis. Ethanol and acetic acid at the volume ratio of 70% : 2% were selected as the extract solvent. The optimized extraction conditions were as follows: extraction time, 40 min; solid/liquid ratio, 1 : 23 g/mL; and temperature, 60°C. This is the first report of an efficient and easy-operating method for TF extraction from D. indicum var. aromaticum. Besides, this study provides reference for future pharmacological research on D. indicum var. aromaticum and extraction of bioactive components from other herbs.

3.
Sci Rep ; 9(1): 7745, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123283

RESUMO

Dendranthema indicum var. aromaticum plant has been widely used as herbal medicine in China, however, the material basis responsible for the therapeutic benefits remains largely unclear. This study aimed to provide an optimized method for extracting and characterizing phenolic compounds in D. indicum var. aromaticum flower. Firstly, an ultrasound-assisted method combined with central composite circumscribed (CCC) design was applied to optimize phenolic compound extraction. Ethanol-acetic acid (70%:2%, v/v) was selected as solvent, and the optimal extraction condition was: extraction temperature, 57 °C; solid/liquid ratio, 1:30 g/mL; extraction time, 20 min. Secondly, an effective and economic HPLC-PDA-ESI-MSn method was established and validated for phenolic compound characterization and quantification. As a result, 14 phenolic compounds were identified, including 8 phenolic acids and 6 flavonoids, and for the first time, oleuropein derivatives, chrysoeriol, and tricin are reported in D. indicum var. aromaticum flower. The content of phenolics identified by HPLC-MSn was 6.42 ± 0.32 mg/g DW. The optimized method for extraction and characterization of phenolic compounds has significant meaning to future pharmaceutical and medicinal research on D. indicum var. aromaticum, and the results in this study can provide references for herbal research.

4.
AIDS ; 33(9): 1455-1465, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30932951

RESUMO

OBJECTIVE: Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has been associated with improvement in markers of renal dysfunction in individual randomized trials; however, the comparative incidence of clinically significant renal events remains unclear. DESIGN: We used a pooled data approach to increase the person-years of drug exposure analysed, maximizing our ability to detect differences in clinically significant outcomes. METHODS: We pooled clinical renal safety data across 26 treatment-naive and antiretroviral switch studies to compare the incidence of proximal renal tubulopathy and discontinuation due to renal adverse events between participants taking TAF-containing regimens vs. those taking TDF-containing regimens. We performed secondary analyses from seven large randomized studies (two treatment-naive and five switch studies) to compare incidence of renal adverse events, treatment-emergent proteinuria, changes in serum creatinine, creatinine clearance, and urinary biomarkers (albumin, beta-2-microglobulin, and retinol binding protein-to-creatinine ratios). RESULTS: Our integrated analysis included 9322 adults and children with HIV (n = 6360 TAF, n = 2962 TDF) with exposure of 12 519 person-years to TAF and 5947 to TDF. There were no cases of proximal renal tubulopathy in participants receiving TAF vs. 10 cases in those receiving TDF (P < 0.001), and fewer individuals on TAF (3/6360) vs. TDF (14/2962) (P < 0.001) discontinued due to a renal adverse event. Participants initiating TAF-based vs. TDF-based regimens had more favourable changes in renal biomarkers through 96 weeks of therapy. CONCLUSION: These pooled data from 26 studies, with over 12 500 person-years of follow-up in children and adults, support the comparative renal safety of TAF over TDF.

5.
J Acquir Immune Defic Syndr ; 78(4): 465-472, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29649076

RESUMO

BACKGROUND: Tenofovir alafenamide (TAF), a prodrug of the nucleotide analogue tenofovir (TFV), is an antiretroviral (ARV) agent approved either as a complete regimen [elvitegravir/cobicistat/emtricitabine (F)/TAF, rilpivirine/F/TAF, bictegravir/F/TAF], or for use with other ARVs (F/TAF), for treatment of HIV. TAF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Disposition of TAF may be altered by comedications that can inhibit or induce P-gp or BCRP transporters. The effects of ARVs on the pharmacokinetics of TAF were evaluated in 3 studies. METHODS: Healthy participants received TAF administered alone or with rilpivirine in study 1, with dolutegravir, ritonavir-boosted atazanavir (ATV + RTV), lopinavir (LPV/RTV), or darunavir (DRV + RTV) in study 2, and with the pharmacokinetic enhancer cobicistat or efavirenz in study 3. RESULTS: Across the 3 studies, 98 participants received treatment with TAF and a coadministered agent (n = 10-34/cohort). All study treatments were well tolerated. TAF and TFV exposures were unaffected after co-administration with rilpivirine and dolutegravir. Coadministration with P-gp/BCRP inhibitors such as cobicistat or PI-based regimens (ATV + RTV, LPV/r, or DRV + RTV) resulted in a range of 6%-183% increases in TAF and 105%-316% increases in TFV exposure, whereas coadministration with a P-gp inducer, efavirenz, resulted in a 15%-24% decrease in TAF and TFV exposure. CONCLUSIONS: Evaluation of the drug interaction between TAF and other commonly prescribed boosted and unboosted ARVs provides characterization of the susceptibility of TAF and/or TFV pharmacokinetics to inhibitors or inducers of P-gp/BCRP transporters.


Assuntos
Adenina/análogos & derivados , Antirretrovirais/farmacocinética , Interações de Medicamentos , Adenina/administração & dosagem , Adenina/farmacocinética , Adolescente , Adulto , Antirretrovirais/administração & dosagem , Quimioterapia Combinada/métodos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
AIDS ; 32(8): 1053-1057, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29424783

RESUMO

OBJECTIVE: Assess the performance of HIV-1 RNA repeat testing of stored samples in cases of low-level viremia during clinical trials. DESIGN: Prospective and retrospective analysis of randomized clinical trial samples and reference standards. METHODS: To evaluate assay variability of the Cobas AmpliPrep/Cobas TaqMan HIV-1 Test, v2.0, three separate sources of samples were utilized: the World Health Organization (WHO) HIV reference standard (assayed using 50 independent measurements at six viral loads <200 copies/ml), retrospective analysis of four to six aliquots of plasma samples from four clinical trial participants, and prospective repeat testing of 120 samples from participants in randomized trials with low-level viremia. RESULTS: The TaqMan assay on the WHO HIV-1 RNA standards at viral loads <200 copies/ml performed within the expected variability according to assay specifications. However, standards with low viral loads of 36 and 18 copies/ml reported values of ≥ 50 copies/ml in 66 and 18% of tests, respectively. In participants treated with antiretrovirals who had unexpected viremia of 50-200 copies/ml after achieving <50 copies/ml, retesting of multiple aliquots of stored plasma found <50 copies/ml in nearly all cases upon retesting (14/15; 93%). Repeat testing was prospectively implemented in four clinical trials for all samples with virologic rebound of 50-200 copies/ml (n = 120 samples from 92 participants) from which 42% (50/120) had a retest result of less than 50 copies/ml and 58% (70/120) retested ≥ 50 copies/ml. CONCLUSION: The TaqMan HIV-1 RNA assay shows variability around 50 copies/ml that affects clinical trial results and may impact clinical practice. In participants with a history of viral load suppression, unexpected low-level viremia may be because of assay variability rather than low drug adherence or true virologic failure. Retesting a stored aliquot of the same sample may differentiate between assay variability and virologic failure as the source of viremia. This retesting strategy could save time, money, and anxiety for patients and their providers, as well as decrease follow-up clinic visits without increasing the risk of virologic failure and resistance development.


Assuntos
Infecções por HIV/virologia , HIV-1/isolamento & purificação , RNA Viral/sangue , Carga Viral/métodos , Humanos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Padrões de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos
7.
J Acquir Immune Defic Syndr ; 74(2): 193-200, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27753684

RESUMO

BACKGROUND: HIV-infected, treatment-experienced adults with a history of prior resistance and regimen failure can be virologically suppressed but may require multitablet regimens associated with lower adherence and potential resistance development. METHODS: We enrolled HIV-infected, virologically suppressed adults with 2-class to 3-class drug resistance and at least 2 prior regimen failures into this phase 3, open-label, randomized study. The primary endpoint was the percentage of participants with HIV-1 RNA <50 copies per milliliter at week 24 [Food and Drug Administration (FDA) snapshot algorithm]. RESULTS: For 135 participants [elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) plus darunavir (DRV), n = 89; baseline regimen, n = 46], most of whom were taking a median of 5 tablets/d, simplification to E/C/F/TAF plus DRV was noninferior to continuation of baseline regimens at week 24 (plasma HIV-1 RNA <50 copies per milliliter: 96.6% vs. 91.3%, difference 5.3%, 95.001% CI: -3.4% to 17.4%). E/C/F/TAF plus DRV met prespecified criteria for noninferiority and superiority at week 48 for the same outcome. E/C/F/TAF plus DRV was well tolerated and had an improved renal safety profile compared with baseline regimens, with statistically significant differences between groups in quantitative total proteinuria and markers of proximal tubular proteinuria. Compared with baseline regimens, participants who switched to E/C/F/TAF plus DRV reported higher mean treatment satisfaction scale total scores and fewer days with missed doses. CONCLUSIONS: This study demonstrated that regimen simplification from a 5-tablet regimen to the 2-tablet, once-daily combination of E/C/F/TAF plus DRV has durable maintenance of virologic suppression and improvements in specific markers of renal safety. Such a strategy may lead to greater adherence and improved quality of life.


Assuntos
Antirretrovirais/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Resposta Viral Sustentada , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Carga Viral , Adulto Jovem
8.
Phys Chem Chem Phys ; 18(45): 31323-31329, 2016 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-27824178

RESUMO

Molecular dynamics simulations demonstrate that the cut defect can induce and guide the self-assembly of an isolated graphene nanoring (GNR) to form multi-layered funnel morphology. The vdW force is the driving force; the tangent component drives the self-assembly of GNR and the normal component adjusts and maintains the vertical distance between graphene layers, which is two times of the vdW radius. Moreover, the offset π-π stacking aids the adjacent layers to achieve the lowest energy of AB stacking. With different diameters of the annular GNRs, the final configurations experience multilayered cone, funnel and tube-shaped structures. It also illustrates the influence of temperature in the funnel-forming process. The wide gap with two edges beyond the cutoff distance of vdW force can utilize fullerenes to help and induce the assembly of the GNR. Cutting defect fissure would be a new way to induce the self-assembly of isolated graphene to design and fabricate new carbon nanostructures without impurities.

9.
Food Chem ; 210: 541-50, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27211680

RESUMO

Rose hip fruit, which contains high concentration of carotenoids is commonly used for different food products in Europe and it is considered to have medical properties. In this study, a simple, rapid and efficient HPLC-DAD-APCI(+)-MS method was developed and applied to identify and quantify the carotenoids in rose hip fruit of four rose species, including both unsaponified and saponified extract. In the unsaponified extract 23 carotenoid esters were detected, in which either rubixanthin ester or violaxanthin ester was the dominant component of the ester composition. In the saponified extract 21 carotenoids, including 11 xanthophylls and 10 carotenes were detected. This is the first time the total carotenoid composition, including the carotenoid esters in rose hip fruit were identified and quantified. This work reveals the potential of rose hip fruit to be utilized as a healthy dietary material and give chemical information for the possible future development in the pharmacology field.


Assuntos
Carotenoides/análise , Cromatografia Líquida de Alta Pressão/métodos , Ésteres/análise , Frutas/química , Rosa/química , Europa (Continente) , Espectrometria de Massas/métodos , Saponinas , Xantofilas
10.
J Acquir Immune Defic Syndr ; 72(1): 58-64, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26829661

RESUMO

In 2 double-blinded Phase 3 trials, 1733 antiretroviral-naive participants were randomized to tenofovir alafenamide (TAF), a tenofovir prodrug versus tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir/cobicistat/emtricitabine (E/C/F). At 96 weeks, 86.6% in the TAF arm and 85.2% in the TDF arm had HIV-1 RNA <50 c/mL [difference 1.5%; (95% CI: -1.8% to 4.8%)]. With TAF, there are smaller declines in bone mineral density and more favorable changes in proteinuria, albuminuria, and tubular proteinuria, and no cases of proximal tubulopathy compared with 2 for TDF. These longer-term data support E/C/F/TAF as a safe, well-tolerated, and durable regimen for initial HIV-1 treatment.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Cobicistat/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Quinolonas/uso terapêutico , Tenofovir/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Albuminúria/patologia , Fármacos Anti-HIV/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Contagem de Linfócito CD4 , Cobicistat/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Emtricitabina/efeitos adversos , Feminino , HIV-1/efeitos dos fármacos , Humanos , Masculino , Proteinúria/patologia , Quinolonas/efeitos adversos , RNA Viral/sangue , Tenofovir/efeitos adversos
11.
J Am Chem Soc ; 138(5): 1490-3, 2016 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-26797173

RESUMO

We discovered an organic weak acid, 3,4,9,10-perylene tetracarboxylic acid (PTCA), confined on the electrode surface, revealing a reversible and ultrafast protonation/deprotonation non-Faradaic process but exhibiting analogous voltammetric peaks (capacitive peaks). A further synthesized PTCA-graphene supramolecular nanocomplex discloses a wide voltage window (1.2 V) and ultrahigh specific capacitance up to 143 F g(-1) at an ultrafast charge-discharge density of 1000 A g(-1) (at least 1 order of magnitude faster than present speeds). The capacitance retention maintained at 73% after 5000 cycles. This unique capacitive voltammetric behavior suggests a new type of charge-storage modes, which may offer a way for overcoming the present difficulties of supercapacitors.

12.
Clin Infect Dis ; 62(7): 929-934, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26689956

RESUMO

BACKGROUND: The COBAS AMPLICOR HIV-1 MONITOR Test, version 1.5 (Amplicor) has been replaced with the COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, version 2.0 (TaqMan 2.0), a real-time polymerase chain reaction human immunodeficiency virus type 1 (HIV-1) assay with higher sensitivity and broader dynamic range. HIV-1 RNA values at the 50 copies/mL cutoff drive major patient management decisions and clinical study outcomes. METHODS: A total of 2217 samples were collected from 1922 HIV-1-infected subjects taking antiretroviral therapy for at least 48 weeks and had at least 2 consecutive samples with HIV-1 RNA <50 copies/mL by Amplicor from 7 recent clinical trials. HIV-1 RNA results were obtained from the Amplicor and TaqMan 2.0 assays in parallel by a reference laboratory. RESULTS: The overall concordance between assay results was 96% at the cutoff of 50 copies/mL. However, statistically significant discordance at the 50 copies/mL cutoff was found between the assays for 3.9% of samples (n = 87). By TaqMan 2.0, virologic failure defined as HIV-1 RNA ≥ 50 copies/mL was reported for 2.8% more samples than Amplicor. Of these 87 samples, 68 samples fell within the predicted range of assay variability. Retesting of HIV-1 RNA by TaqMan 2.0 confirmed the discordance in only 28 of the 87 samples. CONCLUSIONS: The TaqMan 2.0 assay reports fewer subjects below the clinical endpoint of HIV-1 RNA <50 copies/mL in HIV clinical trials than the Amplicor assay. This difference must be considered when assessing disease progression, designing clinical trials, and comparisons with historical trials that used the Amplicor assay.


Assuntos
Infecções por HIV/diagnóstico , Infecções por HIV/virologia , HIV-1/genética , Técnicas de Diagnóstico Molecular/normas , RNA Viral/sangue , Reação em Cadeia da Polimerase em Tempo Real/normas , Carga Viral/normas , Adulto , Feminino , Humanos , Masculino , Técnicas de Diagnóstico Molecular/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Viremia/diagnóstico , Viremia/virologia
13.
J Clin Pharmacol ; 56(6): 723-32, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26449283

RESUMO

Elvitegravir (EVG) is an HIV strand transfer integrase inhibitor approved for the treatment of HIV infection as a part of antiretroviral regimens containing cobicistat (COBI) or ritonavir (RTV) as a booster. The population pharmacokinetics of EVG in treatment-naive and -experienced HIV patients was determined, and the effects of demographic, biometric, and formulation covariates on EVG pharmacokinetics (PK) were evaluated. Data from 31 clinical studies (25 in healthy subjects, 6 phase 1b to phase 3 in HIV-1-infected patients) with COBI-boosted EVG studies (as EVG/co or EVG/COBI/FTC/TDF single-tablet regimen) or RTV-boosted EVG studies (EVG/r) were analyzed using NONMEM. The effect of the covariates age, sex, race, health status (healthy volunteers vs HIV patients), weight, body mass index (BMI), body surface area (BSA), creatinine clearance (estimated GFR), and formulation were evaluated. EVG PK, with COBI or RTV, was described by a 2-compartment model, with first-order absorption and elimination and an absorption lag time. A statistically significant, but not clinically relevant, effect of BSA on EVG clearance (CL) was observed. Coadministration of atazanavir or lopinavir with EVG/r had an effect on EVG CL consistent with the known interaction with these agents. No other covariate had a meaningful effect on EVG PK. EVG PK was well described in a population PK model with HIV-infected patients, with low PK variability and no relevant effect of demographic or biometric covariates.


Assuntos
Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/sangue , Quinolonas/administração & dosagem , Quinolonas/sangue , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Criança , Quimioterapia Combinada , Feminino , Integrase de HIV/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Small ; 11(43): 5814-25, 2015 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-26413807

RESUMO

Meeting proteins is regarded as the starting event for nanostructures to enter biological systems. Understanding their interactions is thus essential for a newly emerging field, nanomedicine. Chemically converted graphene (CCG) is a wonderful two-dimensional (2D) material for nanomedicine, but its stability in biological environments is limited. Systematic probing on the binding of proteins to CCG is currently lacking. Herein, we report a comprehensive study on the interactions between blood proteins and stabilized CCG (sCCG). CCG nanosheets are functionalized by monolayers of perylene leading to significant improvement in their resistance to electrolyte salts and long-term stability, but retain their core structural characteristics. Five types of model human blood proteins including human fibrinogen, γ-globulin, bovine serum albumin (BSA), insulin, and histone are tested. The main driving forces for blood protein binding involve the π-π interacations between the π-plane of sCCG and surface aromatic amonic acid (sAA) residues of proteins. Several key binding parameters including the binding amount, Hill coefficient, and binding constant are determined. Through a detailed analysis of key controlling factors, we conclude that the protein binding to sCCG is determined mainly by the protein size, the number, and the density of the sAA.


Assuntos
Materiais Biocompatíveis/química , Proteínas Sanguíneas/química , Grafite/química , Nanopartículas/química , Mapeamento de Interação de Proteínas/métodos , Adsorção , Sítios de Ligação , Proteínas Sanguíneas/ultraestrutura , Teste de Materiais , Nanopartículas/ultraestrutura , Ligação Proteica
15.
Lancet ; 385(9987): 2606-15, 2015 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-25890673

RESUMO

BACKGROUND: Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens. METHODS: In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445. FINDINGS: We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2·0%, 95% CI -0·7 to 4·7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0·08 vs 0·12 mg/dL; p<0·0001), significantly less proteinuria (median % change -3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86; p<0·0001) and hip (-0·66 vs -2·95; p<0·0001) at 48 weeks. INTERPRETATION: Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile. FUNDING: Gilead Sciences.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Carbamatos/administração & dosagem , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , Organofosfonatos/administração & dosagem , Quinolonas/administração & dosagem , Tiazóis/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adulto , Fármacos Anti-HIV/efeitos adversos , Artralgia/induzido quimicamente , Densidade Óssea/efeitos dos fármacos , Contagem de Linfócito CD4 , Carbamatos/efeitos adversos , Cobicistat , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Emtricitabina , Feminino , Infecções por HIV/virologia , Cefaleia/induzido quimicamente , Humanos , Rim/efeitos dos fármacos , Masculino , Náusea , Organofosfonatos/efeitos adversos , Quinolonas/efeitos adversos , Transtornos Respiratórios/induzido quimicamente , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Tenofovir , Tiazóis/efeitos adversos , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
16.
Nanoscale ; 6(18): 10516-23, 2014 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-25089855

RESUMO

We report a new method for controlling H- and J-stacking in supramolecular self-assembly. Graphene nanosheets act as structure inducers to direct the self-assembly of a versatile organic dye, perylene into two distinct types of functional nanostructures, i.e. one-dimensional nanotubes via J-stacking and two-dimensional branched nanobuds through H-stacking. Graphene integrated supramolecular nanocomposites are highly stable and show significant enhancement of photocurrent generation in these two configurations of photosensing devices, i.e. solid-state optoelectronic constructs and liquid-junction solar cells.

17.
AIDS Patient Care STDS ; 28(4): 168-75, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24660840

RESUMO

The once daily, single-tablet regimen (STR) combining rilpivirine (RPV), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) provides a simplified treatment option for antiretroviral therapy (ART)-naïve patients with baseline HIV-1 RNA (BLVL) of ≤100,000 copies/mL. The aim of this analysis is to compare long-term efficacy, safety, and tolerability of RPV+FTC/TDF vs. efavirenz (EFV)+FTC/TDF as individual components in subjects with BLVL ≤100,000 copies/mL. Week 96 efficacy and safety data from subjects with BLVL ≤100,000 copies/mL, who received daily RPV 25 mg or EFV 600 mg with FTC/TDF in the phase 3, randomized, double-blind, double-dummy, active-controlled, registrational trials ECHO and THRIVE, were analyzed. Virologic response was evaluated by intent-to-treat, time to loss of virological response (ITT-TLOVR), and Snapshot algorithms. Through Week 96, RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF (84% vs. 81%, respectively; ITT-TLOVR) in 543 subjects with BLVL ≤100,000 copies/mL, and overall rates of virologic failure (VF) were 5.9% vs. 2.4%, respectively. Resistance development was lower in Year 2 than Year 1. Subjects in both arms with suboptimal adherence (≤95%) had lower virologic responses (63% vs. 62%, respectively). Treatment with RPV+FTC/TDF was associated with significantly fewer treatment-related adverse events (AEs), grade 2-4 AEs, neurological and psychiatric AEs (including dizziness and abnormal dreams/nightmares), and rash. Additionally, grade 2-4 treatment-emergent laboratory abnormalities and grade 1-3 lipid abnormalities were significantly less common with RPV+FTC/TDF than EFV+FTC/TDF. RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF in ART-naïve subjects with BLVL ≤100,000 copies/mL and was associated with a higher rate of VF but a more favorable safety and tolerability profile through Week 96.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Antivirais/uso terapêutico , Benzoxazinas/uso terapêutico , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Nitrilos/uso terapêutico , Organofosfonatos/uso terapêutico , Pirimidinas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adenina/administração & dosagem , Adenina/uso terapêutico , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Antivirais/administração & dosagem , Benzoxazinas/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Emtricitabina , Feminino , Infecções por HIV/virologia , HIV-1/genética , HIV-1/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilos/administração & dosagem , Organofosfonatos/administração & dosagem , Pirimidinas/administração & dosagem , RNA Viral , Inibidores da Transcriptase Reversa/administração & dosagem , Rilpivirina , Tenofovir , Fatores de Tempo , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Adulto Jovem
18.
J Antimicrob Chemother ; 69(5): 1362-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24508897

RESUMO

BACKGROUND: Tenofovir alafenamide (formerly GS-7340) is a new oral prodrug of tenofovir, a nucleotide analogue that inhibits HIV-1 reverse transcription. Unlike the currently marketed tenofovir prodrug, tenofovir disoproxil fumarate, tenofovir alafenamide is stable in plasma and then rapidly converted into tenofovir once inside cells. METHODS: The pharmacokinetics, safety and antiviral activity of 40 or 120 mg of tenofovir alafenamide compared with 300 mg of tenofovir disoproxil fumarate when administered as monotherapy once daily for 14 days in HIV-1-infected, treatment-naive subjects was studied. RESULTS: Administration of 40 mg of tenofovir alafenamide for 14 days resulted in lower tenofovir Cmax (13 versus 207 ng/mL) and lower systemic exposures (AUC0-t, 383 versus 1810 ng ·â€Šh/mL) compared with subjects who received tenofovir disoproxil fumarate. There were higher intracellular tenofovir concentrations within peripheral blood mononuclear cells with both 40 mg of tenofovir alafenamide (8.2 µM) and 120 mg of tenofovir alafenamide (16.9 µM) compared with 300 mg of tenofovir disoproxil fumarate (0.9 µM). The most commonly observed adverse events were headache, nausea and flatulence, which occurred similarly across the three groups. After 14 days, the mean changes in HIV-1 RNA were -0.94 log10copies/mL for the tenofovir disoproxil fumarate group, -1.57 log10 copies/mL for the 40 mg of tenofovir alafenamide group and -1.71 log10 copies/mL for the 120 mg of tenofovir alafenamide group. The mean first-phase HIV-1 RNA decay slopes were -0.36, -0.63 and -0.64 for the tenofovir disoproxil fumarate group, the 40 mg of tenofovir alafenamide group and the 120 mg of tenofovir alafenamide group, respectively. No resistance mutations to either tenofovir alafenamide or tenofovir disoproxil fumarate were detected. CONCLUSIONS: Tenofovir alafenamide, a new once-daily oral prodrug of tenofovir, showed more potent anti-HIV-1 activity and higher intracellular tenofovir levels compared with tenofovir disoproxil fumarate, while maintaining lower plasma tenofovir exposure at 40 mg with good tolerability over 14 days of monotherapy.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , Pró-Fármacos/farmacologia , Pró-Fármacos/farmacocinética , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/farmacocinética , Adenina/farmacologia , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Área Sob a Curva , Feminino , Infecções por HIV/virologia , Transcriptase Reversa do HIV , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Plasma/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Adulto Jovem
19.
J Acquir Immune Defic Syndr ; 63(4): 449-55, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23807155

RESUMO

OBJECTIVE: To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of short-term monotherapy with tenofovir alafenamide (TAF), a next-generation tenofovir (TFV) prodrug. DESIGN: A phase 1b, randomized, partially blinded, active- and placebo-controlled, dose-ranging study. METHODS: Treatment-naive and experienced HIV-1-positive adults currently off antiretroviral therapy were randomized to receive 8, 25, or 40 mg TAF, 300 mg tenofovir disoproxil fumarate (TDF), or placebo, each once daily for 10 days. RESULTS: Thirty-eight subjects were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all TAF dose groups compared with placebo (P < 0.01), with a median decrease of 1.08-1.73 log10 copies per milliliter, including a dose-response relationship for viral load decrease up to 25 mg. At steady state, 8, 25, and 40 mg TAF yielded mean TFV plasma exposures [area under the plasma concentration-time curve (AUCtau)] of 97%, 86%, and 79% lower, respectively, as compared with the TFV exposures observed with 300 mg TDF. For 25 and 40 mg TAF, the mean intracellular peripheral blood mononuclear cell tenofovir diphosphate AUCtau was ∼7-fold and ∼25-fold higher, relative to 300 mg TDF. CONCLUSIONS: Compared with 300 mg TDF, TAF demonstrated more potent antiviral activity, higher peripheral blood mononuclear cell intracellular tenofovir diphosphate levels, and lower plasma TFV exposures, at approximately 1/10th of the dose. This may translate into greater antiviral efficacy, a higher barrier to resistance, and an improved safety profile relative to TDF, supporting further investigation of TAF dosed once daily in HIV-infected patients.


Assuntos
Adenina/análogos & derivados , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , RNA Viral/sangue , Adenina/efeitos adversos , Adenina/sangue , Adenina/farmacocinética , Adenina/farmacologia , Adenina/uso terapêutico , Adulto , Antirretrovirais/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Fadiga/induzido quimicamente , Feminino , Infecções por HIV/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Organofosfatos/sangue , Organofosfonatos/farmacocinética , Organofosfonatos/farmacologia , Organofosfonatos/uso terapêutico , Método Simples-Cego , Estatísticas não Paramétricas , Tenofovir , Carga Viral , Adulto Jovem
20.
J Infect Dis ; 208(1): 32-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23532097

RESUMO

BACKGROUND: Cobicistat (COBI) is a pharmacoenhancer with no antiretroviral activity in vitro. METHODS: An international, randomized, double-blind, double-dummy, active-controlled trial was conducted to evaluate the efficacy and safety of COBI versus ritonavir (RTV) as a pharmacoenhancer of atazanavir (ATV) in combination with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) in treatment-naive patients. The primary end point was a human immunodeficiency virus type 1 (HIV-1) RNA load of <50 copies/mL at week 48 by the Food and Drug Administration snapshot algorithm; the noninferiority margin was 12%. RESULTS: A total of 692 patients were randomly assigned to a treatment arm and received study drug (344 in the COBI group vs 348 in the RTV group). At week 48, virologic success was achieved in 85% of COBI recipients and 87% of RTV recipients (difference, -2.2% [95% confidence interval, -7.4% to 3.0%]); among patients with a baseline HIV-1 RNA load of >100 000 copies/mL, rates were similar (86% vs 86%). Similar percentages of patients in both groups had serious adverse events (10% of COBI recipients vs 7% of RTV recipients) and adverse events leading to discontinuation of treatment with the study drug (7% vs 7%). Median increases in the serum creatinine level were 0.13 and 0.09 mg/dL, respectively, for COBI and RTV recipients. CONCLUSIONS: COBI was noninferior to RTV in combination with ATV plus FTC/TDF at week 48. Both regimens achieved high rates of virologic success. Safety and tolerability profiles of the 2 regimens were comparable. Once-daily COBI is a safe and effective pharmacoenhancer of the protease inhibitor ATV.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Carbamatos/uso terapêutico , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Oligopeptídeos/uso terapêutico , Organofosfonatos/uso terapêutico , Piridinas/uso terapêutico , Ritonavir/uso terapêutico , Tiazóis/uso terapêutico , Adenina/administração & dosagem , Adenina/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Sulfato de Atazanavir , Carbamatos/administração & dosagem , Cobicistat , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Emtricitabina , Feminino , Inibidores da Protease de HIV/administração & dosagem , HIV-1/efeitos dos fármacos , Humanos , Masculino , Oligopeptídeos/administração & dosagem , Organofosfonatos/administração & dosagem , Piridinas/administração & dosagem , Ritonavir/administração & dosagem , Tenofovir , Tiazóis/administração & dosagem , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
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