Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
1.
J Infect Dis ; 205(1): 87-96, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22180621

RESUMO

BACKGROUND: The benefits of antiretroviral therapy during early human immunodeficiency virus type 1 (HIV-1) infection remain unproved. METHODS: A5217 study team randomized patients within 6 months of HIV-1 seroconversion to receive either 36 weeks of antiretrovirals (immediate treatment [IT]) or no treatment (deferred treatment [DT]). Patients were to start or restart antiretroviral therapy if they met predefined criteria. The primary end point was a composite of requiring treatment or retreatment and the log(10) HIV-1 RNA level at week 72 (both groups) and 36 (DT group). RESULTS: At the June 2009 Data Safety Monitoring Board (DSMB) review, 130 of 150 targeted participants had enrolled. Efficacy analysis included 79 individuals randomized ≥72 weeks previously. For the primary end point, the IT group at week 72 had a better outcome than the DT group at week 72 (P = .005) and the DT group at week 36 (P = .002). The differences were primarily due to the higher rate of progression to needing treatment in the DT group (50%) versus the IT (10%) group. The DSMB recommended stopping the study because further follow-up was unlikely to change these findings. CONCLUSIONS: Progression to meeting criteria for antiretroviral initiation in the DT group occurred more frequently than anticipated, limiting the ability to evaluate virologic set point. Antiretrovirals during early HIV-1 infection modestly delayed the need for subsequent treatment. CLINICAL TRIALS REGISTRATION: NCT00090779.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Lopinavir/uso terapêutico , Organofosfonatos/uso terapêutico , Ritonavir/uso terapêutico , Carga Viral , Adenina/uso terapêutico , Adulto , Desoxicitidina/uso terapêutico , Progressão da Doença , Esquema de Medicação , Combinação de Medicamentos , Quimioterapia Combinada , Emtricitabina , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , RNA Viral/sangue , Tenofovir , Resultado do Tratamento
2.
PLoS Med ; 7(8)2010 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-20711481

RESUMO

BACKGROUND: Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients. METHODS AND FINDINGS: Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median -0.2 and -0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus -44 cells/mm(3), p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood. CONCLUSION: In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT00515827


Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Pirrolidinonas/uso terapêutico , Viremia/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Infecções por HIV/sangue , HIV-1/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinonas/farmacologia , Raltegravir Potássico , Carga Viral/métodos , Viremia/sangue
3.
AIDS Res Hum Retroviruses ; 35(8): 691-697, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31099252

RESUMO

AMD11070 binds to the chemokine receptor CXCR4, with anti-HIV-1 activity in vitro and in vivo. We conducted a phase IB/IIA proof-of-concept dose-escalating, open-label study to determine safety and antiviral activity of AMD11070 administered over 10 days to HIV-1-infected participants who harbored CXCR4-tropic virus. Primary endpoints were ≥1 log10 rlu (relative luminescence units) reduction in CXCR4-tropic virus during 10 days of AMD11070 treatment or in the 7 days following treatment discontinuation, rlu changes over 10 days of treatment, and safety. Plasma pharmacokinetic parameters, HIV-1 RNA, and safety labs were obtained over 90 days of study. The study was stopped early due to emerging AMD11070 animal toxicity data. Six HIV-infected participants with plasma HIV-1 RNA ≥5,000 copies/mL on no antiretroviral therapy for 14 days before entry were treated. AMD11070 was well-tolerated when administered at 200 mg orally every 12 h for 10 days. All enrolled participants had dual/mixed (D/M) viruses. Reductions of almost 1 log10 rlu or more in CXCR4 virus were seen in three of six participants after 10 days of treatment. No participants had ≥1 log10 decline in plasma HIV-1 RNA from baseline at day 10. No clear relationship between pharmacokinetic parameters and response to therapy (X4 log rlu reduction) was observed. AMD11070 demonstrated in vivo activity as measured by reductions in CXCR4 rlu signal. Despite the finding of discordant rlu and plasma HIV RNA responses in these participants with D/M viruses, exploration of other HIV-1 CXCR4 antagonist therapies is possible.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel/farmacologia , Receptores CXCR4/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos , Adulto , Aminoquinolinas , Fármacos Anti-HIV/efeitos adversos , Benzimidazóis , Butilaminas , Linfócitos T CD4-Positivos/virologia , Feminino , HIV-1/genética , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Humanos , Masculino , Estudo de Prova de Conceito , RNA Viral/sangue , Receptores CXCR4/metabolismo , Estados Unidos
4.
AIDS ; 26(11): 1345-54, 2012 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-22441252

RESUMO

OBJECTIVE: To evaluate virologic response rates of lopinavir/ritonavir (LPV/r) monotherapy as second-line antiretroviral treatment (ART) among adults in resource-limited settings (RLSs). DESIGN: An open-label pilot study of LPV/r monotherapy in participants on first-line nonnucleoside reverse transcriptase inhibitor three-drug combination ART with plasma HIV-1 RNA 1000-200 000  copies/ml. METHODS: Participants were recruited from five sites in Africa and Asia within the AIDS Clinical Trials Group (ACTG) network. All participants received LPV/r 400/100  mg twice daily. The primary endpoint was remaining on LPV/r monotherapy without virologic failure at week 24. Participants with virologic failure were offered addition of emtricitabine and tenofovir (FTC/TDF) to LPV/r. RESULTS: Mutations associated with drug resistance were encountered in nearly all individuals screened for the study. One hundred and twenty-three participants were enrolled, and 122 completed 24 weeks on study. A high proportion remained on LPV/r monotherapy without virologic failure at 24 weeks (87%). Archived samples with HIV-1 RNA levels less than 400  copies/ml at week 24 (n=102) underwent ultrasensitive assay. Of these individuals, 62 had levels less than 40  copies/ml and 30 had levels 40-200  copies/ml. Fifteen individuals experienced virologic failure, among whom 11 had resistance assessed and two had emergent protease inhibitor mutations. Thirteen individuals with virologic failure added FTC/TDF and one individual added FTC/TDF without virologic failure. At study week 48, 11 of 14 adding FTC/TDF had HIV-1 RNA levels less than 400  copies/ml. CONCLUSION: In this pilot study conducted in diverse RLS, LPV/r monotherapy as second-line ART demonstrated promising activity.


Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Desoxicitidina/análogos & derivados , Lopinavir/administração & dosagem , Organofosfonatos/administração & dosagem , RNA Viral/efeitos dos fármacos , Ritonavir/administração & dosagem , Síndrome da Imunodeficiência Adquirida/epidemiologia , Síndrome da Imunodeficiência Adquirida/imunologia , Adenina/administração & dosagem , Adulto , África/epidemiologia , Desoxicitidina/administração & dosagem , Esquema de Medicação , Quimioterapia Combinada , Emtricitabina , Feminino , Recursos em Saúde/provisão & distribuição , Humanos , Índia/epidemiologia , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Projetos Piloto , RNA Viral/imunologia , Inibidores da Transcriptase Reversa/efeitos adversos , Inquéritos e Questionários , Tenofovir , Tailândia/epidemiologia , Falha de Tratamento , Carga Viral
5.
J Acquir Immune Defic Syndr ; 59(3): 229-35, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22083073

RESUMO

BACKGROUND: Controversy continues regarding the extent of ongoing viral replication in HIV-1-infected patients on effective antiretroviral therapy (ART). Adding an additional potent agent, such as raltegravir, to effective ART in patients with low-level residual viremia may reveal whether there is ongoing HIV-1 replication. METHODS: We previously reported the outcome of a randomized placebo-controlled study of raltegravir intensification in patients on ART with HIV-1 RNA <50 copies per milliliter that showed no effect on residual viremia measured by single copy assay. We now report the effects of raltegravir intensification in that trial on other potential measures of ongoing HIV-1 replication as follows: 2-LTR HIV-1 circles, total cellular HIV-1 DNA, and T-cell activation. RESULTS: Of 50 patients tested, 12 (24%) had 2-LTR circles detected at baseline. Patients who were 2-LTR-positive had higher plasma HIV-1 RNA and HIV-1 DNA levels than 2-LTR-negative individuals. At week 12 of raltegravir intensification, there was no change from baseline in 2-LTR circles, in total HIV-1 DNA or in the ratio of 2-LTR circles to total HIV-1 DNA. There was also no change in markers of T-cell activation. CONCLUSIONS: In HIV-1-infected individuals on effective ART, we find no evidence of ongoing viral replication in the blood that is suppressible by raltegravir intensification. The results imply that raltegravir intensification alone will not eradicate HIV-1 infection.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/fisiologia , Pirrolidinonas/administração & dosagem , Replicação Viral/efeitos dos fármacos , Contagem de Linfócito CD4 , DNA Viral/sangue , DNA Viral/química , DNA Viral/genética , Infecções por HIV/sangue , Infecções por HIV/imunologia , Repetição Terminal Longa de HIV/efeitos dos fármacos , HIV-1/genética , Humanos , Ativação Linfocitária/efeitos dos fármacos , Reação em Cadeia da Polimerase , RNA Viral/sangue , RNA Viral/genética , Raltegravir Potássico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Viremia/sangue , Viremia/tratamento farmacológico , Viremia/imunologia , Viremia/virologia
6.
Antimicrob Agents Chemother ; 51(7): 2351-8, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17452489

RESUMO

AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P < or = 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0- to 2.1-fold) in an E(max) model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070.


Assuntos
Compostos Heterocíclicos com 1 Anel/administração & dosagem , Compostos Heterocíclicos com 1 Anel/farmacocinética , Receptores CXCR4/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Aminoquinolinas , Área Sob a Curva , Benzimidazóis , Butilaminas , Estudos de Coortes , Relação Dose-Resposta a Droga , Jejum , Meia-Vida , Cefaleia/induzido quimicamente , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/sangue , Compostos Heterocíclicos com 1 Anel/urina , Humanos , Leucócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
7.
Biomarkers ; 8(3-4): 187-203, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12944172

RESUMO

Subjects enrolled in studies are not always screened for routine habits such as smoking. Personal history is not always reliable and therefore an objective biomarker is necessary to screen for smokers. The objectives of this article were to review the metabolism of nicotine and other metabolic considerations associated with smoking; to review some of the routine methods used to assess exposure to nicotine-containing products; to revisit cotinine breakpoints utilized to distinguish smokers from non-smokers during screening for clinical trials; to assess the utility of screening questions regarding smoking practices; and to recommend standards for clinical pharmacology studies. The results indicated that cotinine levels serve as a useful biomarker of tobacco exposure; racial issues may be clinically relevant in determining smoking status; cessation of smoking should occur at least 14 days prior to the start of the study; adverse effects from nicotine withdrawal such as craving, hunger and weight gain may persist for more than 6 months; potential metabolic interactions via cytochrome P2A6 and P1A2 need to be considered when designing a study; and the use of a single calibrator as a breakpoint is acceptable if a categorical outcome such as 'smoker' versus 'non-smoker' is desired. Nicotine from food products is not expected to impact assay sensitivity or to be clinically relevant; a serum cotinine concentration of 10 ng ml(-1) be employed as a breakpoint for non-smokers versus smokers; other non-invasive alternatives are collection of urine, saliva, or hair (with suggested breakpoints of 200 ng ml(-1), 5 ng ml(-1) and 0.3 ng mg(-1), respectively; screening questions be accompanied by testing for cotinine; and the inclusion of smokers in studies should be considered once the impact of smoking on the targeted population is understood.


Assuntos
Cotinina/análise , Fumar/metabolismo , Biomarcadores/análise , Interações Medicamentosas , Humanos , Nicotina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA