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1.
Arch Intern Med ; 167(6): 597-605, 2007 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-17389292

RESUMO

BACKGROUND: Interleukin 2 (IL-2) administration increases CD4 counts in persons with higher counts. This study investigated persons with moderately advanced human immunodeficiency virus infection receiving highly active antiretroviral therapy (HAART). METHODS: Two hundred four patients with CD4 T-cell counts from 50/microL to 350/microL who were treatment naive or had been treated only with reverse transcriptase inhibitors began a specified protease inhibitor HAART regimen. Virologic responders (< or =5000 copies/mL) at 12 weeks were randomized to open-label continuous-infusion IL-2 (IV IL-2), subcutaneous IL-2 (SC IL-2), or HAART alone. Thirty were not randomized and 15 enrolled in a substudy, leaving 159 for analysis. Subjects continued HAART alone for 72 weeks (n = 52) or with IV IL-2 (n = 53) or SC IL-2 (n = 54) for 5 days every 8 weeks. The IV IL-2 subjects could switch to SC IL-2 if their CD4 T-cell count increased by 100/microL or by 25%. RESULTS: Patients receiving IV or SC IL-2 had greater increases in CD4 cell counts. At week 84, median increases were 459/microL, 312/microL, and 102/microL. Increases of greater than 50% at week 60 (primary end point) were achieved in 39 patients (81%) and 32 (67%) in the IV and SC IL-2 arms, respectively, compared with 13 (29%) in the HAART arm (P<.001 for both). Treatment with IL-2 did not increase plasma human immunodeficiency virus RNA levels. There were fewer new AIDS-defining events in the IV (P = .006) and SC (P = .03) IL-2 groups than in the HAART group (0, 1, and 7, respectively). Drug-related adverse events were more frequent with IL-2 treatment. CONCLUSION: Addition of IL-2 to HAART can significantly expand CD4 T-cell counts in moderately advanced human immunodeficiency virus infection, without loss of virologic control.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Interleucina-2/uso terapêutico , Adolescente , Adulto , Idoso , Contagem de Linfócito CD4 , Esquema de Medicação , Feminino , Infecções por HIV/mortalidade , Infecções por HIV/virologia , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Fatores de Tempo
2.
AIDS ; 21(7): 813-23, 2007 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-17415036

RESUMO

OBJECTIVE: To compare a quadruple-nucleoside with an efavirenz-containing regimen for treatment of HIV-1 infection. DESIGN: A randomized, open-label study of the AIDS Clinical Trials Group (ACTG). METHODS: Subjects receiving zidovudine/lamivudine/abacavir on ACTG 5095 with HIV-1 RNA less than 200 copies/ml were randomly assigned to intensify either with tenofovir or efavirenz. Subjects were followed for time to treatment failure, defined as either virological failure or treatment discontinuation. Analyses were intent-to-treat. RESULTS: One hundred and seventy subjects (21% women; 56% non-white) entered the study. At baseline, 95 and 73% had HIV-1-RNA levels less than 200 and 50 copies/ml, respectively; the median CD4 cell count was 453 cells/microl. Over a median 79 weeks follow-up, 165 (97%) completed the study, three (2%) discontinued, and two (1%) died. Treatment failure occurred in 31 subjects: 18 (21%) (quadruple nucleosides) and 13 (15%) (efavirenz-containing regimen); however the failure-time curves crossed and demonstrated a non-constant treatment effect over time, characterized by more early treatment failures on the efavirenz-containing regimen and more late treatment failures on the four-nucleoside regimen. HIV-1 RNA remained suppressed in more than 88% of subjects to less than 200 copies/ml and in more than 78% to less than 50 copies/ml at weeks 24, 48, and 72, without differences by treatment arm. There were no significant differences between the regimens in CD4 cell increases, time to new grade 3/4 adverse events, or adherence. CONCLUSION: The safety, tolerability, and efficacy of the four-nucleoside regimen were not significantly different from the efavirenz-containing regimen. These pilot data support further investigation of the quadruple-nucleoside regimen.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Organofosfonatos/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Adulto , Idoso , Alcinos , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Benzoxazinas/efeitos adversos , Contagem de Linfócito CD4 , Ciclopropanos , Farmacorresistência Viral , Feminino , Genótipo , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/efeitos adversos , Cooperação do Paciente , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir , Resultado do Tratamento , Carga Viral
3.
N Engl J Med ; 350(18): 1850-61, 2004 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-15115831

RESUMO

BACKGROUND: Regimens containing three nucleoside reverse-transcriptase inhibitors offer an alternative to regimens containing nonnucleoside reverse-transcriptase inhibitors or protease inhibitors for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection, but data from direct comparisons are limited. METHODS: This randomized, double-blind study involved three antiretroviral regimens for the initial treatment of subjects infected with HIV-1: zidovudine-lamivudine-abacavir, zidovudine-lamivudine plus efavirenz, and zidovudine-lamivudine-abacavir plus efavirenz. RESULTS: We enrolled a total of 1147 subjects with a mean baseline HIV-1 RNA level of 4.85 log10 (71,434) copies per milliliter and a mean CD4 cell count of 238 per cubic millimeter were enrolled. A scheduled review by the data and safety monitoring board with the use of prespecified stopping boundaries led to a recommendation to stop the triple-nucleoside group and to present the results in the triple-nucleoside group in comparison with pooled data from the efavirenz groups. After a median follow-up of 32 weeks, 82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 of those in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001). This difference was observed regardless of the pretreatment HIV-1 RNA stratum (at least 100,000 copies per milliliter or below this level; P< or =0.001 for both comparisons). Changes in the CD4 cell count and the incidence of grade 3 or grade 4 adverse events did not differ significantly between the groups. CONCLUSIONS: In this trial of the initial treatment of HIV-1 infection, the triple-nucleoside combination of abacavir, zidovudine, and lamivudine was virologically inferior to a regimen containing efavirenz and two or three nucleosides.


Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1 , Nucleosídeos/uso terapêutico , Oxazinas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Idoso , Alcinos , Benzoxazinas , Contagem de Linfócito CD4 , Ciclopropanos , Didesoxinucleosídeos/efeitos adversos , Didesoxinucleosídeos/uso terapêutico , Método Duplo-Cego , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Seguimentos , HIV-1/genética , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxazinas/efeitos adversos , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversos , Zidovudina/efeitos adversos , Zidovudina/uso terapêutico
4.
J Pharm Biomed Anal ; 44(1): 188-95, 2007 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-17391891

RESUMO

The availability of buprenorphine (BUP) provides an alternative approach to the treatment of opioid addiction with methadone, an agent that has many drug-drug interactions when combined with antiretroviral therapy (ART). However, due to limited long-term pharmacokinetic studies in HIV-infected patients, the clinical use of BUP, a CYP450-3A4 substrate, will require that studies be conducted to examine safety, tolerability and pharmacokinetics when these drugs are taken for chronic treatment. One clinical approach could include plasma concentration monitoring to avoid under- or overdosing BUP secondary to drug interactions with ART. The measurement of BUP and its active metabolite, norbuprenorphine (NBUP) facilitates the addition of BUP to ART in an attempt to avoid drug toxicity as described in a recent report by Bruce et al. Therefore, our objective was to validate a BUP assay and integrate its application into an ongoing antiretroviral (ARV) plasma concentration monitoring program. A chromatographic method for monitoring BUP and its active metabolite, NBUP was investigated. An assay was developed that would facilitate BUP and ARV measurement from a single 3 mL blood sample (0.75 mL plasma required) in conjunction with a previously validated multiple ARV HPLC method. The method measures BUP and NBUP over the range from 0.25 to 50 ng/mL with mass spectrometry detection. Inter- and intra-assay variation was

Assuntos
Buprenorfina/sangue , Infecções por HIV/sangue , HIV-1 , Antagonistas de Entorpecentes/sangue , Transtornos Relacionados ao Uso de Substâncias/sangue , Alcinos , Sulfato de Atazanavir , Benzoxazinas/sangue , Benzoxazinas/farmacocinética , Benzoxazinas/uso terapêutico , Bioensaio , Buprenorfina/química , Buprenorfina/farmacocinética , Buprenorfina/uso terapêutico , Calibragem , Cromatografia Líquida/métodos , Ciclopropanos , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/uso terapêutico , Humanos , Espectrometria de Massas/métodos , Estrutura Molecular , Antagonistas de Entorpecentes/química , Antagonistas de Entorpecentes/farmacocinética , Antagonistas de Entorpecentes/uso terapêutico , Oligopeptídeos/sangue , Oligopeptídeos/farmacocinética , Oligopeptídeos/uso terapêutico , Piridinas/sangue , Piridinas/farmacocinética , Piridinas/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos
5.
J Immunol Methods ; 312(1-2): 126-36, 2006 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-16712866

RESUMO

The combination of flow cytometry and carboxyl fluorescent succinimidyl ester (CFSE) labeling techniques has been widely used in the study of cellular proliferation, including measurement of the percentage of proliferated cells and the number of cell divisions undergone by proliferated cells. However, the smallest numbers that represent true cell division rather than experimental variation are not known. To define a threshold that separates true proliferation from experimental variation, we performed a large number of replicate CFSE labeling experiments using polyclonal stimulation, obtained the percentages of proliferated cells using ModFit software, and then analyzed these data using several statistical methods. Our results indicate that the threshold of proliferation lies between 0.071% (95% confidence) and 0.114% (99% confidence) of total CFSE-labeled cells under our laboratory conditions. We offer our methods presented here for other investigators to calculate a threshold in their own CFSE-labeling experiments.


Assuntos
Divisão Celular , Proliferação de Células , Fluoresceínas/química , Corantes Fluorescentes/química , Succinimidas/química , Interpretação Estatística de Dados , Citometria de Fluxo , Humanos , Leucócitos Mononucleares/citologia , Coloração e Rotulagem
6.
Pharmacotherapy ; 26(9): 1255-61, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16945047

RESUMO

STUDY OBJECTIVES: To determine if quercetin, a bioflavonoid that inhibits p-glycoprotein, alters plasma saquinavir concentrations, and to explore the potential influence on intracellular concentrations. DESIGN: Prospective pharmacokinetic analysis. SETTING: University-affiliated general clinical research center. SUBJECTS: Ten healthy adults (four women, six men) with a mean +/- SD age of 30.7 +/- 9.4 years. INTERVENTION: All subjects received saquinavir 1200 mg 3 times/day with food on days 1-11 and quercetin 500 mg 3 times/day with food on days 4-11. MEASUREMENTS AND MAIN RESULTS: On days 4 and 11, nine blood samples and four peripheral blood mononuclear cell samples were drawn during a steady-state dosing interval. Pharmacokinetic parameters were calculated by using standard noncompartmental techniques. Plasma saquinavir concentrations were similar regardless of quercetin administration. Geometric mean ratios for the area under the concentration-time curve during an 8-hour dosing interval (AUC0-8), maximum concentration in the dosing interval, and minimum concentration in the dosing interval were 0.99 (95% confidence interval [CI] 0.65-1.50), 0.99 (95% CI 0.64-1.54), and 1.06 (95% CI 0.68-1.67), respectively. Intracellular saquinavir concentrations displayed substantial intra- and intersubject variability, which limited the ability to determine the influence of quercetin coadministration (geometric mean ratio for AUC0-8 = 0.51 [95% CI 0.14-1.95], six patients). CONCLUSION: Quercetin coadministration did not influence plasma saquinavir concentrations. Because of substantial inter- and intrasubject variability, more study is necessary to determine if saquinavir intracellular concentrations are altered by coadministration of quercetin.


Assuntos
Inibidores da Protease de HIV/farmacocinética , Quercetina/farmacologia , Saquinavir/farmacocinética , Adulto , Feminino , Inibidores da Protease de HIV/sangue , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Saquinavir/sangue
7.
JAMA ; 296(7): 769-81, 2006 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-16905783

RESUMO

CONTEXT: Three-drug antiretroviral regimens are standard of care for initial treatment of human immunodeficiency virus 1 (HIV-1) infection, but a 4-drug regimen could improve antiretroviral activity and be more effective than a 3-drug regimen. OBJECTIVE: To compare the safety/efficacy of 3-drug vs 4-drug regimens for initial treatment of HIV-1 infection. DESIGN: The AIDS Clinical Trials Group (ACTG) A5095 study, a randomized, double-blind, placebo-controlled study with enrollment and follow-up conducted from March 22, 2001, to March 1, 2005, and enrolling treatment-naive, HIV-1-infected patients with HIV-1 RNA levels of 400 copies/mL or greater from US clinical trials units of the ACTG. INTERVENTIONS: Zidovudine/lamivudine plus efavirenz (3-drug regimen) vs zidovudine/lamivudine/abacavir plus efavirenz (4-drug regimen). MAIN OUTCOME MEASURES: Time to virologic failure (defined as time to first of 2 successive HIV-1 RNA levels > or =200 copies/mL at or after week 16), CD4 cell count changes, and grade 3 or 4 adverse events. HIV-1 RNA data were intent-to-treat, regardless of treatment changes. RESULTS: Seven hundred sixty-five patients with a baseline mean HIV-1 RNA level of 4.86 log10 (72,444) copies/mL and CD4 cell count of 240 cells/mm3 were randomized. After a median 3-year follow-up, 99 (26%) of 382 and 94 (25%) of 383 patients receiving the 3-drug and 4-drug regimens, respectively, reached protocol-defined virologic failure; time to virologic failure was not significantly different (hazard ratio, 0.95; 97.5% confidence interval, 0.69-1.33; P = .73). In planned subgroup analyses, increased risk for virologic failure was seen in non-Hispanic black patients (adjusted hazard ratio, 1.66; 95% confidence interval, 1.18-2.34; P = .003). At 3 years, the HIV-1 RNA level was less than 200 copies/mL in 152 (90%) of 169 and 143 (92%) of 156 patients receiving the 3-drug and 4-drug regimens, respectively (P = .59), and less than 50 copies/mL in 144 (85%) of 169 and 137 (88%) of 156 patients (P = .39). CD4 cell count increases and grade 3 or 4 adverse events were not significantly different. CONCLUSIONS: In treatment-naive patients, there were no significant differences between the 3-drug and 4-drug antiretroviral regimens; overall, at least approximately 80% of patients had HIV-1 RNA levels less than 50 copies/mL through 3 years. These results support current guidelines recommending 2 nucleosides plus efavirenz for initial treatment of HIV-1 infection; adding abacavir as a fourth drug provided no additional benefit. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov Identifier: NCT00013520.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Adulto , Idoso , Alcinos , Fármacos Anti-HIV/administração & dosagem , Benzoxazinas , Contagem de Linfócito CD4 , Ciclopropanos , Didesoxinucleosídeos/administração & dosagem , Método Duplo-Cego , Feminino , Infecções por HIV/sangue , HIV-1/genética , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oxazinas/administração & dosagem , RNA Mensageiro/sangue , Carga Viral , Zidovudina/administração & dosagem
8.
Diabetes ; 52(4): 918-25, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12663461

RESUMO

The mechanisms responsible for the deterioration in glucose tolerance associated with protease inhibitor-containing regimens in HIV infection are unclear. Insulin resistance has been implicated as a major factor, but the affected tissues have not been identified. Furthermore, beta-cell function has not been evaluated in detail. The present study was therefore undertaken to assess the effects of protease inhibitor-containing regimens on hepatic, muscle, and adipose tissue insulin sensitivity as well as pancreatic beta-cell function. We evaluated beta-cell function in addition to glucose production, glucose disposal, and free fatty acid (FFA) turnover using the hyperglycemic clamp technique in combination with isotopic measurements in 13 HIV-infected patients before and after 12 weeks of treatment and in 14 normal healthy volunteers. beta-Cell function and insulin sensitivity were also assessed by homeostasis model assessment (HOMA). Treatment increased fasting plasma glucose concentrations in all subjects (P < 0.001). Insulin sensitivity as assessed by HOMA and clamp experiments decreased by approximately 50% (P < 0.003). Postabsorptive glucose production was appropriately suppressed for the prevailing hyperinsulinemia, whereas glucose clearance was reduced (P < 0.001). beta-Cell function decreased by approximately 50% (P = 0.002), as assessed by HOMA, and first-phase insulin release decreased by approximately 25%, as assessed by clamp data (P = 0.002). Plasma FFA turnover and clearance both increased significantly (P < 0.001). No differences at baseline or in responses after treatment were observed between drug naïve patients who were started on a nucleoside reverse transcriptase inhibitor (NRTI) plus a protease inhibitor and patients who had been on long-term NRTI treatment and had a protease inhibitor added. The present study indicates that protease inhibitor-containing regimens impair glucose tolerance in HIV-infected patients by two mechanisms: 1) inducement of peripheral insulin resistance in skeletal muscle and adipose tissue and 2) impairment of the ability of the beta-cell to compensate.


Assuntos
Intolerância à Glucose/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Tecido Adiposo/efeitos dos fármacos , Adulto , Glicemia/análise , Composição Corporal , Constituição Corporal , Peptídeo C/sangue , Contagem de Linfócito CD4 , Ácidos Graxos não Esterificados/sangue , Feminino , Glucagon/sangue , Técnica Clamp de Glucose , Hemoglobinas Glicadas/análise , Glicerol/sangue , Infecções por HIV/sangue , Homeostase , Humanos , Insulina/sangue , Insulina/farmacologia , Resistência à Insulina , Ilhotas Pancreáticas/fisiopatologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Proinsulina/sangue , Carga Viral
9.
J Virol Methods ; 123(2): 131-40, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15620394

RESUMO

To evaluate immune responses in large-scale clinical studies, it is crucial to use assays that are not only sensitive and specific, but also standardized and easily transferable. To this end, an intracellular cytokine staining (ICS) assay for quantifying HIV-specific CD8+ T cells has been established and its performance characteristics determined. PBMCs were stimulated using recombinant vaccinia expressing HIV-Env, -Gag, -Pol and -Nef proteins, or a protein from Escherichia coli (Eco); CD8+ T cell responses were assessed by intracellular IFN-gamma staining and flow cytometric (FC) analysis. In 15 HIV seronegative and 11 HIV seropositive individuals, a minimal background IFN-gamma staining was found after Eco stimulation with a median [inter-quartile range (IQR)] of 0.005% (0.000%, 0.030%) irrespective of HIV infection status. Recent smallpox vaccination was associated with a small but significant increase in background staining [0.02% (0.02%, 0.04%) versus 0.0% (0.0%, 0.01%) (p=0.039)] in HIV seronegative individuals. This assay detected moderate (>0.10%) HIV-specific responses in 64% (7/11) of HIV seropositive individuals. The results suggest that this ICS assay format is sensitive and specific, and is amenable to standardization for screening for HIV-specific CD8+ T cells in clinical trials.


Assuntos
Infecções por HIV/metabolismo , Interferon gama/análise , Coloração e Rotulagem/métodos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Ensaios Clínicos como Assunto , Citocinas/análise , Citometria de Fluxo , Soropositividade para HIV , Humanos , Vaccinia virus/genética
10.
Pharmacotherapy ; 23(7): 866-70, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12885100

RESUMO

STUDY OBJECTIVE: To determine if milk thistle (silymarin) alters the pharmacokinetics of indinavir. DESIGN: Sequential crossover trial. SETTING: General clinical research center. SUBJECTS: Ten healthy subjects. INTERVENTION: Indinavir 800 mg 3 times/day was given for four doses on days 1 and 2. Silymarin 160 mg 3 times/day was given on days 3-15. On day 16 and for one dose on day 17, both drugs were given at the same dosages. MEASUREMENTS AND MAIN RESULTS: Indinavir's pharmacokinetic parameters were evaluated at steady state both before and after administration of 14 days of silymarin. Blood samples were collected -0.25, 0.5, 1, 2, 3, 4, and 5 hours after indinavir dosing and assayed by high-performance liquid chromatography. The final pharmacokinetic model had first-order absorption after a lag time, and two compartments with first-order elimination from the central compartment. When given alone and combined with silymarin, respectively, the geometric mean (95% confidence interval [CI]) steady-state indinavir area under the plasma concentration-time curve was 20.7 hr x mg/L (15.3-28.2 hr x mg/L) and 19.4 hr x mg/L (15.8-23.6 hr x mg/L) and the trough plasma concentration was 0.340 mg/L (0.232-0.497 mg/L) and 0.232 mg/L (0.129-0.419 mg/L). CONCLUSION: Silymarin has no apparent effect on indinavir plasma concentrations.


Assuntos
Inibidores da Protease de HIV/farmacocinética , Indinavir/farmacocinética , Substâncias Protetoras/farmacologia , Silimarina/farmacologia , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Interações Medicamentosas , Feminino , Inibidores da Protease de HIV/sangue , Humanos , Indinavir/sangue , Masculino , Pessoa de Meia-Idade , Silybum marianum/química
11.
Clin Drug Investig ; 23(5): 323-8, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-17535044

RESUMO

BACKGROUND: Delavirdine is a non-nucleoside reverse transcriptase inhibitor with pH-dependent absorption characteristics that has received accelerated approval for the treatment of patients with HIV-1 infection. In a prior single-dose study concurrent administration of delavirdine mesylate and didanosine (buffered formulation) resulted in up to a 31% decrease in the area under the plasma delavirdine concentration versus time curve (AUC) compared with when both drugs were taken separately. OBJECTIVE: To evaluate the interaction of these two agents at steady state. STUDY DESIGN AND PATIENTS: A total of 11 HIV-infected subjects who were previously stabilised on didanosine were enrolled into a randomised, open-labelled crossover study. Nine subjects continued to receive their prescribed dose and schedule of didanosine, with each dose of didanosine taken either together with or 1 hour after delavirdine mesylate (400mg every 8 hours). Pharmacokinetic studies at baseline, day 14 and day 28 were conducted and the plasma concentrations of delavirdine and didanosine were determined. RESULTS: A lower delavirdine maximum plasma concentration (C(max)) [22.4 +/- 11 vs 35.5 +/- 17muM; p = 0.045] was noted when delavirdine and didanosine were taken together. However, no significant difference was noted for delavirdine AUC (114 +/- 56 muM.h compared with 153 +/- 79 muM.h [p = 0.181]). In addition, no differences were noted for didanosine pharmacokinetic parameters between treatments. CONCLUSION: These data indicate that patients receiving didanosine and delavirdine as part of a combination regimen during long-term therapy can be instructed to take them together in an attempt to enhance adherence to treatment with both antiretroviral agents.

14.
Biopharm Drug Dispos ; 29(2): 91-101, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18041735

RESUMO

The combination of efavirenz with HIV-1 protease inhibitors (PI) results in complex interactions secondary to mixed induction and inhibition of oxidative metabolism. ACTG A5043 was a prospective, open-label, controlled, two-period, multiple-dose study with 55 healthy volunteers. The objective of the present study was to evaluate the potential pharmacokinetic interaction between efavirenz and dual PIs. The subjects received a daily dose of 600 mg efavirenz for 10 days with amprenavir 600 mg twice daily added at day 11 and were randomized to receive nelfinavir, indinavir, ritonavir, saquinavir, or no second PI on days 15-21. Intensive pharmacokinetic studies were conducted on day 14 and 21. Efavirenz plasma concentrations were fit to candidate models using weighted non-linear regression. The disposition of efavirenz was described by a linear two-compartment model with first order absorption following a fitted lag time. Apparent clearance (CLt/F), volume of distribution at steady state (Vss/F), inter-compartmental clearance, and the central and peripheral volume of distribution were estimated. The mean CLt/F and Vss/F of efavirenz were 0.126 l/h/kg and 4.412 l/kg, respectively. Both AUC and CLt/F of efavirenz remained unchanged after 7 days of dual PI dosing. The mean Vss/F of efavirenz increased an average of 89% across arms, ranging from 52% (nelfinavir) to 115% (indinavir) relative to efavirenz with amprenavir alone. Increases were also observed in Vp/F after the addition of nelfinavir, indinavir, ritonavir and saquinavir by 85%, 170%, 162% and 111%, respectively. In conclusion, concomitant administration of dual PIs is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2B6 substrates in general or oral efavirenz specifically.


Assuntos
Benzoxazinas/farmacocinética , Inibidores da Protease de HIV/farmacologia , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Alcinos , Hidrocarboneto de Aril Hidroxilases/fisiologia , Benzoxazinas/efeitos adversos , Ciclopropanos , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP3A/fisiologia , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredutases N-Desmetilantes/fisiologia , Estudos Prospectivos
15.
J Infect Dis ; 198(9): 1345-52, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18771406

RESUMO

BACKGROUND: The current goal of human immunodeficiency virus type 1 (HIV-1) therapy is to maximally suppress viral replication. Securing this goal requires new drugs and treatment classes. The chemokine receptor CCR5 provides an entry portal for HIV-1, and PRO 140 is a humanized monoclonal antibody that binds to CCR5 and potently inhibits CCR5-tropic (R5) HIV-1 in vitro. METHODS: A randomized, double-blind, placebo-controlled, dose-escalating study was conducted in 39 individuals with HIV-1 RNA levels or =5000 copies/mL, CD4(+) cell counts > or =250 cells/microL, no antiretroviral therapy for 3 months, and only R5 HIV-1 detectable. Cohorts were randomized 3:10 to receive placebo or doses of PRO 140 of 0.5, 2, or 5 mg/kg. Subjects were monitored for 58 days for safety, antiviral effects, and serum concentrations of PRO 140. RESULTS: PRO 140 was generally well tolerated and demonstrated potent, rapid, prolonged, and dose-dependent antiviral activity. Mean reductions in HIV-1 RNA level of 0.58 log(10), 1.20 log(10) (P= .0002) and 1.83 log(10) (P= .0001) were observed for the 0.5-, 2-, and 5-mg/kg dose groups, respectively. Reductions in mean viral load of > or =10-fold were observed within 4 days and persisted for 2-3 weeks after treatment. CONCLUSIONS: This trial established clear proof of concept for PRO 140 as a potent antiretroviral agent with extended activity after a single dose. TRIAL REGISTRATION: ISRCTN Register: ISRCTN45537485 .


Assuntos
Fármacos Anti-HIV/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/sangue , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais Humanizados , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Farmacorresistência Viral , Feminino , Anticorpos Anti-HIV/sangue , HIV-1/efeitos dos fármacos , Humanos , Contagem de Linfócitos , Linfócitos/imunologia , Masculino , RNA Viral/sangue , Receptores CCR5 , Fatores de Tempo
16.
Metab Syndr Relat Disord ; 5(2): 163-73, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18007962

RESUMO

BACKGROUND: HIV-infected patients treated with antiretroviral medications (ARVs) develop undesirable changes in lipid and glucose metabolism that mimic the metabolic syndrome and may be proatherogenic. Antiretroviral drug levels and their interactions may contribute to these metabolic alterations. METHODS: Fifty six HIV-seronegative adults were enrolled in an open-label, randomized, pharmacokinetic interaction study, and received a nonnucleoside reverse transcriptase inhibitor (efavirenz on days 1-21) plus a protease inhibitor (PI; amprenavir on days 11-21), with a second PI on days 15-21 (saquinavir, nelfinavir, indinavir, or ritonavir). Fasting triglycerides, total LDL-and HDL-cholesterol, glucose, insulin, and C-peptide levels were measured on days 0, 14, 21, and 2-3 weeks after discontinuing drugs. Regression models were used to estimate changes in these parameters and associations between these changes and circulating levels of study drugs. RESULTS: Short-term efavirenz and amprenavir administration significantly increased cholesterol, triglycerides, and glucose levels. Addition of a second protease inhibitor further increased triglycerides, total and LDL-cholesterol levels. Higher amprenavir levels predicted larger increases in triglycerides, total, and LDL-cholesterol. Two weeks after all study drugs were stopped, total, LDL-, and HDL-cholesterol remained elevated above baseline. CONCLUSIONS: ARV regimens that include a nonnucleoside reverse transcriptase inhibitor plus single or boosted PIs are becoming more common, but the pharmacodynamic interactions associated with these regimens can result in persistent, undesirable alterations in serum lipid/lipoprotein levels. Additional pharmacodynamic studies are needed to examine the metabolic effects of ritonavir-boosted regimens, with and without efavirenz.

17.
Ther Drug Monit ; 29(1): 103-9, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17304157

RESUMO

Atazanavir (ATV) is a widely used human immunodeficiency virus (HIV)-1 protease inhibitor (PI) that, like other approved PIs, has been considered as a candidate for therapeutic drug monitoring (TDM). To provide ATV assay results that can be applied to patient management through TDM, the assay would need to perform in a manner consistent with Clinical Laboratory Improvement Amendments (CLIA) standards. To quantitate ATV concentrations in human plasma, the authors added ATV to a previously published reversed-phase high-performance liquid chromatography (HPLC) method from their laboratory. Detection was effected with use of a photodiode-array detector (PDA) collecting spectra at 248 nm. This method allows for detection of ATV to a lower limit of quantitation of 0.05 microg/mL, with an intra-assay coefficient of variation (CV%) of 8.9% or less over 5 days of testing and an interassay CV% ranging from 1.4 to 6.4%. The assay has met passing requirements for interlaboratory proficiency testing for 2 years nationally and internationally, with accuracy within +/-15% over all test samples. During 2 years, more than 100 batches of analyses have been performed and have proved the method is rugged, specific, and accurate. This assay method is currently used in the authors' clinical research program in TDM.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Inibidores da Protease de HIV/uso terapêutico , Oligopeptídeos/uso terapêutico , Piridinas/uso terapêutico , Espectrofotometria Ultravioleta/métodos , Sulfato de Atazanavir , Calibragem , Cromatografia Líquida de Alta Pressão/instrumentação , Monitoramento de Medicamentos/métodos , Quimioterapia Combinada , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/sangue , Humanos , Lopinavir , Oligopeptídeos/sangue , Oligopeptídeos/normas , Piridinas/sangue , Piridinas/normas , Pirimidinonas/uso terapêutico , Controle de Qualidade , Padrões de Referência , Reprodutibilidade dos Testes , Ritonavir/uso terapêutico , Espectrometria de Massas por Ionização por Electrospray/métodos , Fatores de Tempo
18.
Antimicrob Agents Chemother ; 51(5): 1822-6, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17283195

RESUMO

Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring.


Assuntos
Fármacos Anti-HIV/farmacocinética , Carbamatos/farmacocinética , Sulfonamidas/farmacocinética , Administração Oral , Adulto , Idoso , Carbamatos/administração & dosagem , Feminino , Furanos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Sulfonamidas/administração & dosagem
19.
Pharmacogenomics ; 8(3): 227-35, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17324111

RESUMO

INTRODUCTION: HIV-infected patients receiving protease inhibitors may benefit from therapeutic drug monitoring-assisted dose adjustment to achieve target plasma concentrations. However, efflux pumps such as permeability-glycoprotein, which is encoded by the multidrug resistance (MDR)1 gene, may decrease intracellular drug concentrations, thus reducing the amount of drug at the site of action. Plasma concentrations of protease inhibitors and CD4 cell count response have been associated with the T allele at the MDR1 C3435T locus. We examined MDR1 single nucleotide polymorphisms in a cohort of patients in whom therapeutic drug monitoring is ongoing through a research protocol. METHODS: In a multicenter study, genotypic analyses at two MDR1 loci, C3435T and G2677T, were performed by a real-time polymerase chain reaction method using DNA from 103 patients categorized as substance users or nonusers on atazanavir or lopinavir as the primary antiretrovirals. Allelic frequencies were determined as a function of racial/ethnic background, substance use status and trough concentrations of atazanavir and lopinavir. RESULTS: The C/T and G/T alleles at the MDR1 C3435T and G2677T loci were equally frequent in the Caucasian population, but the wild-type alleles were more prevalent in the African-American population (59% homozygous [CC] and 32% heterozygous [CT] for C3435T; 80% homozygous [GG] and 16% heterozygous [GT] for G2677T). The frequencies in the Hispanic population were 46% CC and 38% CT for C3435T, and 58% GG and 38% GT for G2677T. No significant differences were seen in allele frequencies for MDR1 polymorphisms in substance user versus nonuser groups. Trough plasma concentrations of atazanavir or lopinavir were not correlated with the variant T allele. CONCLUSIONS: These data confirm the higher prevalence of wild-type alleles of the MDR1 gene in African-Americans and the linkage disequilibrium between C3435T and G2677T loci. The T allele at the MDR1 C3435T and G2677T loci was not associated with higher atazanavir or lopinavir trough concentrations.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Infecções por HIV/genética , Oligopeptídeos/uso terapêutico , Polimorfismo Genético/genética , Piridinas/uso terapêutico , Pirimidinonas/uso terapêutico , Adulto , Idoso , Sulfato de Atazanavir , Feminino , Frequência do Gene/genética , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Lopinavir , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/sangue , Piridinas/sangue , Pirimidinonas/sangue
20.
J Infect Dis ; 195(8): 1169-76, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17357053

RESUMO

OBJECTIVE: We sought to compare clearance rates of plasma human immunodeficiency virus type 1 (HIV-1) RNA in men and women starting triple-nucleoside-based versus efavirenz (EFV)-based regimens. METHODS: First- and second-phase decay rates of plasma HIV-1 were compared in men and women initiating a triple nucleoside reverse-transcriptase inhibitor (NRTI) regimen versus regimens that included EFV plus an NRTI. Subjects (n=64) were randomized to receive zidovudine/lamivudine/abacavir (triple-nucleoside regimen), zidovudine/lamivudine plus EFV (3-drug EFV regimen) or zidovudine/lamivudine/abacavir plus EFV (4-drug EFV regimen). Plasma HIV-1 RNA levels were fitted to a biexponential viral-dynamics model using a nonlinear mixed-effects model. Nonparametric Wilcoxon tests compared empirical Bayes estimates of first- and second-phase viral decay rates between treatment arms and sex. RESULTS: Median first-phase viral decay rates were significantly faster in subjects receiving the 3-drug EFV regimen (0.67/day), compared with those receiving the triple-nucleoside regimen (0.56/day; P=.02). The second-phase viral decay rate was also faster in the 3-drug EFV group than in the triple-nucleoside group (P=.09). Decay rates in the 4-drug EFV group were intermediate. Viral decay rates were not significantly different in men and women. CONCLUSIONS Faster initial viral decay in subjects randomized to a 3-drug EFV-based regimen corresponded to the overall superior efficacy of that regimen. Viral decay rates did not differ by sex.


Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , RNA Viral/sangue , Alcinos , Fármacos Anti-HIV/administração & dosagem , Benzoxazinas/administração & dosagem , Benzoxazinas/farmacologia , Ciclopropanos , Didesoxinucleosídeos/administração & dosagem , Didesoxinucleosídeos/farmacologia , Quimioterapia Combinada , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/genética , Humanos , Lamivudina/administração & dosagem , Lamivudina/farmacologia , Masculino , Estudos Prospectivos , Análise de Regressão , Fatores de Tempo , Zidovudina/administração & dosagem , Zidovudina/farmacologia
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