RESUMO
BACKGROUND: The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug-drug interactions with concomitantly used ART. OBJECTIVES: To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and isoniazid for TB prevention in people living with HIV. METHODS: Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/isoniazid was calculated. RESULTS: Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13-66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266-9302) ng/mL; week 2, 5537 (3552-8462) ng/mL; and week 4, 5388 (3516-8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/isoniazid, 2.03 (1.58-2.58) L/h; and during rifapentine/isoniazid, 2.62 (1.81-3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26-1.33). CONCLUSIONS: The CL/F of nevirapine significantly increased with concomitant rifapentine/isoniazid. The decrease in nevirapine trough concentrations during rifapentine/isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug-drug interaction suggests daily rifapentine/isoniazid for TB prevention should not be co-administered with nevirapine-containing ART.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , Antituberculosos/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , Isoniazida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nevirapina/uso terapêutico , Rifampina/análogos & derivados , Adulto JovemRESUMO
OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum. METHODS: International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography-mass spectrometry (LC-MS). The target area under the concentration versus time curve from time 0 to 24 h post dose (AUC) was ≥ 1.99 µg h/mL (nonpregnant historical control 10th percentile). RESULTS: The median tenofovir AUC was decreased during the second (1.9 µg h/mL) and third (2.4 µg h/mL; P = 0.005) trimesters versus postpartum (3.0 µg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women [73%; 95% confidence interval (CI) 56%, 86%] in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P > 0.05). Median second/third-trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median third-trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2 kg, respectively; P = 0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected. CONCLUSIONS: This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90 kg) or inadequate HIV RNA response.
Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Complicações Infecciosas na Gravidez/tratamento farmacológico , Tenofovir/farmacocinética , Adolescente , Adulto , Fármacos Anti-HIV/uso terapêutico , Área Sob a Curva , Feminino , Infecções por HIV/metabolismo , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Humanos , Masculino , Período Pós-Parto , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Tenofovir/uso terapêutico , Adulto JovemRESUMO
Accelerator mass spectrometry (AMS) is an ultrasensitive technique to detect radiolabeled compounds. We administered a microdose (100 µg) of (14)C-labeled zidovudine (ZDV) with or without a standard unlabeled dose (300 mg) to healthy volunteers. Intracellular ZDV-triphosphate (ZDV-TP) concentration was measured using AMS and liquid chromatography-tandem mass spectrometry (LC/MS/MS). AMS analysis yielded excellent concordance with LC/MS/MS and was 30,000-fold more sensitive. The kinetics of intracellular ZDV-TP formation changed several-fold over the dose range studied (100 µg-300 mg). AMS holds promise as a tool for quantifying intracellular drug metabolites and other biomediators in vivo.
Assuntos
Líquido Intracelular/metabolismo , Leucócitos Mononucleares/metabolismo , Espectrometria de Massas em Tandem/métodos , Zidovudina/metabolismo , Adulto , Cromatografia Líquida/métodos , Sistemas de Liberação de Medicamentos/métodos , Humanos , Líquido Intracelular/química , Leucócitos Mononucleares/química , Leucócitos Mononucleares/citologia , Masculino , Pessoa de Meia-Idade , Zidovudina/análise , Zidovudina/sangueRESUMO
Drug development involves learning and confirming in healthy volunteers and ultimately in patients. This approach should apply to drug-drug interactions because requirements to extrapolate pharmacokinetic and pharmacodynamic findings from healthy volunteers to patients are not uniformly met, and the designs of interaction studies often have little relevance to actual clinical use. Guidance to health-care professionals on a safe and effective dose for individual patients should include information from drug-drug interaction studies in the intended patients.
Assuntos
Ensaios Clínicos como Assunto , Interações Medicamentosas , Medicina Baseada em Evidências , Humanos , Farmacocinética , Guias de Prática Clínica como Assunto , Projetos de Pesquisa , Medição de RiscoRESUMO
We determined the effects of lopinavir/ritonavir on tenofovir renal clearance. Human immunodeficiency virus-infected subjects taking tenofovir disoproxil fumarate (TDF) were matched on age, race, and gender and were enrolled into one of the following two groups: group 1: subjects taking TDF plus lopinavir/ritonavir plus other nucleoside reverse transcriptase inhibitors (NRTIs); group 2: subjects taking TDF plus NRTIs and/or non-NRTIs but no protease inhibitors. Twenty-four-hour blood and urine collections were carried out in subjects for tenofovir quantification. Drug transporter genotype associations with tenofovir pharmacokinetics were examined. In 30 subjects, median (range) tenofovir apparent oral clearance, renal clearance, and fraction excreted in urine were 34.6 l/h (20.6-89.5), 11.3 l/h (6.2-22.6), and 0.33 (0.23-0.5), respectively. After adjusting for renal function, tenofovir renal clearance was 17.5% slower (P=0.04) in subjects taking lopinavir/ritonavir versus those not taking a protease inhibitor, consistent with a renal interaction between these drugs. Future studies should clarify the exact mechanism and whether there is an increased risk of nephrotoxicity.
Assuntos
Adenina/análogos & derivados , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacologia , Rim/efeitos dos fármacos , Organofosfonatos/farmacocinética , Pirimidinonas/farmacologia , Inibidores da Transcriptase Reversa/farmacocinética , Ritonavir/farmacologia , Adenina/administração & dosagem , Adenina/farmacocinética , Adenina/urina , Administração Oral , Adulto , Terapia Antirretroviral de Alta Atividade , Estudos de Casos e Controles , Interações Medicamentosas , Feminino , Genótipo , Infecções por HIV/genética , Infecções por HIV/metabolismo , Inibidores da Protease de HIV/administração & dosagem , Humanos , Rim/metabolismo , Lopinavir , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/genética , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Organofosfonatos/administração & dosagem , Organofosfonatos/urina , Pirimidinonas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/urina , Ritonavir/administração & dosagem , Tenofovir , Resultado do TratamentoRESUMO
Fifty human immunodeficiency virus (HIV)-infected children participated in an area-under-the plasma concentration-time curve (AUC)-controlled trial of efavirenz and nelfinavir. Pharmacokinetic evaluations were performed at weeks 2, 6, and 56. Efavirenz and nelfinavir doses were adjusted to achieve AUC values of 60-120 and > or = 10 mg h/l, respectively. Thirty-seven (74%) children met the efavirenz target and 41 (82%) the nelfinavir by week 10. Children with AUC values for both drugs above the first quartile were more likely to reach < 400 copies/ml of HIV RNA at week 8. Efavirenz and nelfinavir oral clearance increased 37 and 62% from weeks 2 to 56, respectively, in 34 children who continued on therapy at week 56. AUC values at week 56 were not different between children who did or did not have HIV RNA < 400 copies/ml. Dose adjustment to achieve specific AUC values in these children reduced the risk of suboptimal exposure and achieved high rates of virologic suppression.
Assuntos
Benzoxazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Nelfinavir/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Administração Oral , Adolescente , Alcinos , Área Sob a Curva , Benzoxazinas/administração & dosagem , Ciclopropanos , Quimioterapia Combinada , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , Humanos , Taxa de Depuração Metabólica , Nelfinavir/administração & dosagem , RNA Viral/sangue , Inibidores da Transcriptase Reversa/administração & dosagem , Resultado do Tratamento , Estados Unidos , Replicação Viral/efeitos dos fármacosRESUMO
OBJECTIVES: To evaluate the pharmacokinetics, tolerance, safety and antiviral activity of the HIV protease inhibitor, saquinavir, formulated as soft gelatin capsules (SQV-SGC), given in combination with nucleoside antiretroviral agents (NRTIs) with or without nelfinavir in HIV-infected children. METHODS: This was an open label study of HIV-infected children ages 3 to 16 years, conducted in two parts. In Part 1 of the study 14 children were treated orally with SQV-SGC (initially given in three 33-mg/kg doses daily; dosage adjusted to 50 mg/kg three times daily based on initial pharmacokinetics) and two NRTIs. Addition of nelfinavir was permitted for children who did not achieve a predetermined steady state target plasma saquinavir exposure. In Part 2 a new group of 13 children received SQV-SGC (33 mg/kg three times daily) in combination with nelfinavir and one or two NRTIs. Pharmacokinetics were assessed after the first dose and 4 weeks into treatment (steady state). Patients were treated for 72 and 48 weeks in Parts 1 and 2, respectively. RESULTS: Most adverse events were mild; the most commonly reported were diarrhea, abdominal discomfort and headache. Two children were withdrawn from the study because of adverse events (one each of nausea and dysphagia) related to the study treatment. There were no deaths or serious adverse events attributed to the study medication. Steady state saquinavir area under the plasma concentration vs. time curves (AUC24) were 6,210 and 11,010 ng/h/ml for Parts 1 and 2, respectively. Compared with baseline measurements median changes in plasma HIV RNA concentrations were -2.12 log10 copies/ml [5 of 14 (36%) with HIV RNA <50 copies/ml) (Week 72)] and -2.58 log10 copies/ml [8 of 13 (62%) <50 copies/ml) (Week 48)] in Parts 1 and 2, respectively. The median changes in CD4+ lymphocyte count were +292 and +154 cells/microl for Parts 1 and 2, respectively. Genotypic resistance assays revealed a low frequency of saquinavir-associated resistance mutations after 48 weeks of therapy, with only 2 of 27 children having substitutions at positions 48V and/or 90M. CONCLUSIONS: Combination therapy with SQV-SGC was well-tolerated and safe in HIV-infected children, and antiviral activity was observed. Saquinavir plasma concentrations were lower than expected, particularly for Part 1 (SQV-SGC plus NRTIs), but addition of nelfinavir increased saquinavir exposures.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Saquinavir/uso terapêutico , Administração Oral , Adolescente , Terapia Antirretroviral de Alta Atividade/métodos , Cápsulas , Criança , Pré-Escolar , Feminino , Gelatina , Infecções por HIV/diagnóstico , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Humanos , Masculino , Nelfinavir/uso terapêutico , Prognóstico , Inibidores da Transcriptase Reversa/uso terapêutico , Saquinavir/administração & dosagem , Saquinavir/efeitos adversosRESUMO
Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naïve subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Indinavir/uso terapêutico , Lamivudina/uso terapêutico , Zidovudina/uso terapêutico , Adulto , Algoritmos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Área Sob a Curva , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Meia-Vida , Humanos , Indinavir/administração & dosagem , Indinavir/farmacocinética , Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Zidovudina/administração & dosagem , Zidovudina/farmacocinéticaRESUMO
OBJECTIVE: To quantify unbound indinavir concentrations and characterize indinavir plasma protein binding in HIV-infected adults. DESIGN: Pharmacokinetic study in antiretroviral-naive, HIV-infected persons with CD4 T lymphocytes > 100 x 10(6) cells/L and HIV-RNA in plasma >5000 copies/ml at baseline who were participating in an open-label study of zidovudine, lamivudine and indinavir therapy. METHODS: Eight men underwent 8 h intensive pharmacokinetic studies for indinavir on two occasions 6 months apart. Unbound indinavir was separated by ultra-filtration, and unbound and total concentrations were quantified by a validated high-performance liquid chromatography method. RESULTS: Overall indinavir protein binding was 61+/-6%, with a range among the profiles of 54 to 70%. Indinavir binding was higher at the 8 h post-dose concentration compared with the 1 h post-dose concentration (66 versus 57%, P = 0.0006). CONCLUSIONS: The mean 61% protein binding for indinavir in these HIV-infected persons is similar to the in vitro report of 60%. However, the fraction bound was concentration-dependent, and considerable variability in binding was present among patients. Quantification of unbound protease inhibitor concentrations opens new avenues of research to advance our understanding of the pharmacologically-relevant moieties of antiretroviral agents and thereby the pharmacotherapy of HIV infection.
Assuntos
Proteínas Sanguíneas/metabolismo , Infecções por HIV/tratamento farmacológico , HIV-1 , Indinavir/farmacocinética , Adulto , Inibidores da Protease de HIV/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Ligação ProteicaRESUMO
This study examined the rate of decline in plasma human immunodeficiency virus type 1 (HIV-1) RNA levels to <400 and <50 copies/mL in children receiving highly active antiretroviral therapy (HAART) consisting of efavirenz, nelfinavir, and 1 or 2 nucleoside reverse-transcriptase inhibitors. Children receiving HAART achieved a plasma HIV-1 RNA level <400 copies/mL by a median of 4 weeks after initiation of therapy and a decline to <50 copies/mL by 20 weeks. Baseline plasma HIV-1 RNA levels affected the likelihood of achieving potent and sustained virus suppression, and children whose CD4 lymphocyte counts increased >70 cells/microL by 20 weeks on therapy were more likely to achieve durable virological and immunological benefit. These data provide time frames for virus suppression after the initiation of HAART that should be useful in evaluating the potential efficacy and durability of response of newly instituted combination antiretroviral therapy in HIV-1-infected children.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1/isolamento & purificação , RNA Viral/sangue , Inibidores da Transcriptase Reversa/uso terapêutico , Adolescente , Alcinos , Terapia Antirretroviral de Alta Atividade , Benzoxazinas , Criança , Pré-Escolar , Ciclopropanos , Infecções por HIV/virologia , HIV-1/genética , Humanos , Nelfinavir/uso terapêutico , Oxazinas/uso terapêutico , Fatores de TempoRESUMO
The use of recombinant CD4-IgG2 in pediatric human immunodeficiency virus type 1 (HIV-1) infection was evaluated by single and multidose intravenous infusions in 18 children in a phase 1/2 study. The study drug was well tolerated, and dose proportionality was observed in terms of area under time-concentration curve and peak serum concentration. Acute decreases of >0.7 log(10) copies/mL in serum HIV-1 RNA concentration were seen in 4 of the 6 children treated with 4 weekly 10 mg/kg doses. At 14 days after treatment, 3 children had sustained reductions in serum HIV-1 RNA; the other children had rebounded to baseline levels or above. By 28 days after therapy, the peak HIV-1 cellular infectious units was reduced in all 6 children, including the 2 who had experienced an earlier transient increase in values. Thus, recombinant CD4-IgG2 treatment of HIV-1-infected children appears to be well tolerated and capable of reducing HIV-1 burden.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Imunoadesinas CD4/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Proteínas Recombinantes de Fusão/uso terapêutico , Adolescente , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Imunoadesinas CD4/administração & dosagem , Criança , Pré-Escolar , Feminino , Infecções por HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Infusões Intravenosas , Leucócitos Mononucleares/virologia , Masculino , RNA Viral/sangue , Proteínas Recombinantes de Fusão/administração & dosagem , Carga ViralRESUMO
OBJECTIVE: To quantitate intracellular concentrations of zidovudine and lamivudine triphosphate and explore relationships with virologic and immunologic responses to antiretroviral therapy. DESIGN: Eight antiretroviral-naive, HIV-infected persons with CD4 T cell counts > 100 x 10(6) cells/l, and HIV RNA in plasma > 5000 copies/ml participating in a prospective, randomized, open-label study of standard dose versus concentration-controlled therapy with zidovudine, lamivudine, and indinavir. METHODS: Peripheral blood mononuclear cells and plasma were collected frequently throughout the study for quantitation of intracellular zidovudine triphosphate and lamivudine triphosphate concentrations, and zidovudine and lamivudine concentrations in plasma. CD4 T cells and HIV RNA in plasma (Roche Amplicor Ultrasensitive Assay) were measured at baseline and every 4 weeks throughout the study. Relationships among intracellular and plasma concentrations, and CD4 T cells and HIV RNA in plasma were investigated with regression analyses. RESULTS: Significant relationships were observed between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate and the baseline level of CD4 cells. Lamivudine triphosphate concentrations were related in a linear manner to the apparent oral clearance of lamivudine from plasma. A direct linear relationship was found between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. The percent change in CD4 cells during therapy and the rate of decline in HIV RNA in plasma were related to the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. CONCLUSION: These studies into the intracellular clinical pharmacology of nucleoside reverse transcriptase inhibitors illustrate potential clinical implications as determinants of therapeutic success. Moreover, these findings provide several leads and a strong impetus for future investigations with nucleoside reverse transcriptase inhibitors particularly when given in combination and sequentially.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Citidina Trifosfato/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV , Lamivudina/uso terapêutico , Nucleotídeos de Timina/uso terapêutico , Zidovudina/uso terapêutico , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/farmacocinética , Contagem de Linfócito CD4 , Citidina Trifosfato/análogos & derivados , Citidina Trifosfato/farmacocinética , Didesoxinucleotídeos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Humanos , Lamivudina/análogos & derivados , Lamivudina/farmacocinética , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/análise , Análise de Regressão , Inibidores da Transcriptase Reversa/uso terapêutico , Nucleotídeos de Timina/farmacocinética , Zidovudina/análogos & derivados , Zidovudina/farmacocinéticaRESUMO
This study compared antiretroviral activity among 6 "salvage" therapy regimens. The study was a prospective, randomized, 2x3 factorial, multicenter study of the AIDS Clinical Trials Group. The study enrolled 277 human immunodeficiency virus (HIV)-infected patients naive to nonnucleoside analogues who had taken indinavir >6 months. The patients had 2000-200,000 HIV RNA copies/mL. Patients received saquinavir with ritonavir or nelfinavir together with delavirdine and/or adefovir and were followed for safety and antiretroviral response between baseline and week 16. At week 16, 30% (77/254) of patients had =500 HIV RNA copies/mL. Virologic response did not differ significantly between pooled ritonavir and nelfinavir groups (28% vs. 33%; P=.50) or between pooled delavirdine and delavirdine/adefovir groups (40% vs. 33%; P=.42). Pooled delavirdine groups had a greater virologic response rate than did adefovir groups (40% vs. 18%; P=.002). Overall, one-third of patients who experienced virologic failure on an indinavir-containing regimen suppressed virus load levels while they were taking a new salvage regimen.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Organofosfonatos , Adenina/administração & dosagem , Adenina/análogos & derivados , Adulto , Fármacos Anti-HIV/efeitos adversos , Contagem de Linfócito CD4 , Delavirdina/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Nelfinavir/administração & dosagem , Estudos Prospectivos , RNA Viral/análise , Ritonavir/administração & dosagem , Saquinavir/administração & dosagemRESUMO
Defining the source of HIV-1 RNA in cerebrospinal fluid (CSF) will facilitate studies of treatment efficacy in the brain. Four antiretroviral drug-naive adults underwent two 48-hr ultraintensive CSF sampling procedures, once at baseline and again beginning on day 4 after initiating three-drug therapy with stavudine, lamivudine, and nelfinavir. At baseline, constant CSF HIV-1 RNA concentrations were maintained by daily entry of at least 10(4) to 10(6) HIV-1 RNA copies into CSF. Change from baseline to day 5 ranged from -0.38 to -1.18 log(10) HIV-1 RNA copies/ml in CSF, and from -0.80 to -1.33 log(10) HIV-1 RNA copies/ml in plasma, with no correlation between CSF and plasma changes. There was no evidence of genotypic or phenotypic viral resistance in either CSF or plasma. With regard to pharmacokinetics, mean CSF-to-plasma area-under-the-curve (AUC) ratios were 38.9% for stavudine and 15.3% for lamivudine. Nelfinavir and its active M8 metabolite could not be accurately quantified in CSF, although plasma M8 peak level and AUC(0-8hr) correlated with CSF HIV-1 RNA decline. This study supports the utility of ultraintensive CSF sampling for studying HIV-1 pathogenesis and therapy in the CNS, and provides strong evidence that HIV-1 RNA in CSF arises, at least in part, from a source other than plasma.
Assuntos
Sistema Nervoso Central/virologia , Infecções por HIV/virologia , HIV-1/genética , RNA Viral/líquido cefalorraquidiano , Adulto , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/líquido cefalorraquidiano , Fármacos Anti-HIV/farmacocinética , Resistência Microbiana a Medicamentos , Variação Genética , Infecções por HIV/sangue , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/líquido cefalorraquidiano , Inibidores da Protease de HIV/farmacocinética , HIV-1/efeitos dos fármacos , Humanos , Lamivudina/sangue , Lamivudina/líquido cefalorraquidiano , Lamivudina/farmacocinética , Nelfinavir/sangue , Nelfinavir/líquido cefalorraquidiano , Nelfinavir/farmacocinética , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/líquido cefalorraquidiano , Inibidores da Transcriptase Reversa/farmacocinética , Estavudina/sangue , Estavudina/líquido cefalorraquidiano , Estavudina/farmacocinética , Fatores de TempoRESUMO
The objective of this article is to review and evaluate risks and benefits associated with the use of acyclovir in the treatment and prophylaxis of common manifestations of herpes simplex virus (HSV) infections in immunocompetent and immunocompromised patients. Information was found through a MEDLINE search using keywords: herpes simplex virus, genital herpes, herpes labialis, acyclovir and acyclovir. Selected articles were randomised, double-blind, placebo-controlled, clinical trials. 30 such trials involving 3364 persons were evaluated. All articles were reviewed by the authors and the data were extracted and summarised. In both immunocompetent and immunocompromised hosts, acyclovir therapy demonstrated a high degree of clinical efficacy. None of the studies reported statistically significant differences between acyclovir and placebo for mild or major adverse events. This evaluation found that acyclovir is both effective and well tolerated for treatment and prophylaxis of genital, oral and mucocutaneous HSV infections in immunocompetent and immunocompromised patients. In most clinical scenarios. the benefit of acyclovir exceeded any risks by a comfortable margin. The availability of acyclovir as a generic preparation further improves the benefit to cost ratio.
Assuntos
Aciclovir/efeitos adversos , Antivirais/efeitos adversos , Herpes Simples/tratamento farmacológico , Herpes Simples/prevenção & controle , Humanos , Hospedeiro Imunocomprometido , RiscoRESUMO
STUDY OBJECTIVE: To characterize the concentration-time profiles of zidovudine and zidovudine-glucuronide in semen and serum of men infected with the human immunodeficiency-1 virus (HIV-1). DESIGN: Open-label observational study. SETTING: University-affiliated teaching hospital and research center. PATIENTS: Four asymptomatic HIV-1-infected men. INTERVENTIONS: Zidovudine administration was followed by an 8-hour intensive pharmacokinetic study on day 1. Over the next 8 days, a dose administration and timed single-sample strategy was employed to determine serum and semen concentration time profiles simultaneously. MEASUREMENTS AND MAIN RESULTS: Zidovudine and zidovudine-glucuronide concentrations were uniformly higher in semen than in serum except at 1 hour after the dose. The median area under the curve ratio (semen AUC0-48:serum AUC0-infinity) was 3.31 for zidovudine and 15.04 for zidovudine-glucuronide. CONCLUSION: Zidovudine and zidovudine-glucuronide reach high levels in seminal plasma relative to serum. The virologic, pharmacodynamic, and public health implications of distribution to this compartment require further study.
Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/metabolismo , HIV-1 , Sêmen/metabolismo , Zidovudina/farmacocinética , Adolescente , Adulto , Fármacos Anti-HIV/sangue , Área Sob a Curva , Glucuronídeos/sangue , Glucuronídeos/metabolismo , Infecções por HIV/sangue , Humanos , Masculino , Zidovudina/sangueRESUMO
PRO 542 (CD4-IgG2) is a recombinant antibody-like fusion protein wherein the Fv portions of both the heavy and light chains of human IgG2 have been replaced with the D1D2 domains of human CD4. Unlike monovalent and divalent CD4-based proteins, tetravalent PRO 542 potently neutralizes diverse primary human immunodeficiency virus (HIV) type 1 isolates. In this phase 1 study, the first evaluation of this compound in humans, HIV-infected adults were treated with a single intravenous infusion of PRO 542 at doses of 0.2-10 mg/kg. PRO 542 was well tolerated, and no dose-limiting toxicities were identified. Area under the concentration-time curve, and peak serum concentrations increased linearly with dose, and a terminal serum half-life of 3-4 days was observed. No patient developed antibodies to PRO 542. Preliminary evidence of antiviral activity was observed as reductions in both plasma HIV RNA and plasma viremia. Sustained antiviral effects may be achieved with repeat dosing with PRO 542.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Imunoadesinas CD4/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Imunoadesinas CD4/efeitos adversos , Imunoadesinas CD4/sangue , Imunoadesinas CD4/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/fisiologia , Humanos , Infusões Intravenosas , RNA Viral/sangue , RNA Viral/efeitos dos fármacos , Carga Viral , Viremia/etiologiaRESUMO
Many factors are involved in the success or failure of antiretroviral therapy. Recent data suggest that there are significant differences in drug absorption and disposition for the protease inhibitor class of antiretroviral drugs, and relationships between plasma concentrations and their antiviral effect have been described. Consequently, the issue of whether therapeutic drug monitoring should be employed for patients receiving treatment with these drugs has arisen. Several criteria must be met before a drug is considered a candidate for therapeutic drug monitoring. These criteria include pharmacological, clinical, and analytic components. Although not all the necessary criteria have yet been met, some of these components have been defined, and additional data are being generated. However, prospectively designed clinical trials must be completed to determine if monitoring protease inhibitor plasma concentrations provides additional clinical benefit to the patient.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Infecções por HIV/metabolismo , Inibidores da Protease de HIV/sangue , HumanosRESUMO
The use of human immunodeficiency virus (HIV) protease inhibitors in children has lagged behind that in adults because of the lack of suitable pediatric formulations and information on safe and effective dosing regimens. This study was designed to obtain pharmacokinetic information on indinavir, administered to HIV-infected children also receiving therapy with two nucleoside agents, and to explore relationships between pharmacokinetic parameters and anti-HIV effect. Indinavir was initiated at a dose of 500 mg/m(2) every 8 h. Plasma indinavir concentrations were measured every 4 weeks; the dose or dosing interval was adjusted to maintain trough concentrations of > or =0.1 mg/liter. All children were evaluated clinically at baseline and every 4 weeks. Plasma HIV RNA was quantitated at baseline and at weeks 4, 12, and 24. Eighteen children participated in this study. The average daily dose of indinavir was 2,043 mg/m(2); nine children received indinavir at 6-h intervals. Pharmacokinetic characteristics of indinavir (mean +/- standard deviation) were the following: oral clearance, 1.4 +/- 0.5 liters/h/kg; half-life, 1.1 +/- 0.43 h; and trough concentration, 0. 29 +/- 0.32 mg/liter. In nine children that completed 24 weeks of therapy, the baseline-to-week-24 change in HIV RNA level was related to indinavir trough concentration and didanosine area under the curve. This study illustrates the ability to obtain pharmacokinetic information from children during routine clinic visits and to use this information to provide a safeguard against underdosing. The incorporation of pharmacologic knowledge with virologic, immunologic, and behavioral considerations should result in improved clinical outcomes for children infected with HIV.
Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Didanosina/farmacocinética , Didanosina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Indinavir/farmacocinética , Indinavir/uso terapêutico , Estavudina/farmacocinética , Estavudina/uso terapêutico , Área Sob a Curva , Criança , Cromatografia Líquida de Alta Pressão , Quimioterapia Combinada , Infecções por HIV/virologia , Meia-Vida , Humanos , Espectrofotometria Ultravioleta , Fatores de TempoRESUMO
The clinical, immunologic, and virologic effects and the pharmacokinetics of human immunodeficiency virus (HIV) human hyperimmune immunoglobulin (HIVIG) were assessed in 30 HIV-infected children aged 2-11 years. All had moderately advanced disease with an immune complex-dissociated (ICD) p24 antigen >70 pg/mL and were on stable antiviral therapy. Three groups of 10 children received 6 monthly infusions of 200, 400, or 800 mg/kg of HIVIG, and serial immunologic and virologic assays were performed. HIVIG doses as high as 800 mg/kg were safe and well tolerated. The half-life of HIVIG, determined by serial p24 antibody titers, was 13-16 days, the volume of distribution was 102-113 mL/kg, and clearance was 5.6-6.0 mL/kg/day. Plasma ICD p24 decreased during the infusions, but CD4 cell levels, plasma RNA copy number, cellular virus, immunoglobulin levels, and neutralizing antibody titers were minimally affected by the infusions. Clinical status did not change during the 6-month infusion and 3-month follow-up periods.