RESUMO
Multiple subcutaneous immunoglobulin (SCIG) products are available to treat primary antibody deficiency (PAD). The efficacy and tolerability of 16% SCIG (Vivaglobin(®) ) was compared with 20% SCIG (Hizentra(®) ) in PAD subjects. The study was a prospective, single-centre, open-label study of PAD subjects transitioning Vivaglobin to equivalent Hizentra doses, rounded to the nearest vial size. Comparisons included immunoglobulin (Ig)G levels; tetanus, varicella and Streptococcus pneumoniae titres; adverse events (AEs), annual infection rate and quality of life during 8 weeks of Vivaglobin and 24 weeks of Hizentra. Thirty-two subjects (aged 2-75 years) participated. Rounding to the nearest Hizentra vial size resulted in a 12·8% (± 2·9%) increase in SCIG dose. Median immunoglobulin (Ig)G level following 8 weeks of Vivaglobin was similar to 24 weeks of Hizentra (1050 versus 1035 mg/dl, respectively; P = 0·77). Both products had similar protective titres to tetanus, varicella and serotypes of S. pneumoniae, which were variable but well above protective levels. After 12 weeks of Hizentra, subjects reported fewer local site reactions compared with Vivaglobin. Switching products resulted in increased systemic AEs in some subjects but, overall, not significantly higher than during Vivaglobin treatment. Average infusion time decreased from 104·7 min (3·3 sites) with Vivaglobin to 70·7 min (2·2 sites) with Hizentra (P = 0·0005). Acute serious bacterial infections were similar. Treatment satisfaction was superior with Hizentra. Hizentra and Vivaglobin have similar pharmacokinetics and efficacy. Although transition to a different SCIG product initially increased AEs, Hizentra is well tolerated and can be infused more rapidly and with fewer sites compared to Vivaglobin.
Assuntos
Infecções Bacterianas/prevenção & controle , Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Adolescente , Adulto , Idoso , Infecções Bacterianas/imunologia , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Feminino , Febre/induzido quimicamente , Cefaleia/induzido quimicamente , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Imunoglobulina G/uso terapêutico , Imunoglobulinas/administração & dosagem , Imunoglobulinas/efeitos adversos , Síndromes de Imunodeficiência/imunologia , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
To reduce the risk of infection in adults and children with primary immunodeficiencies, replacement therapy with IgG, which can be administered to patients intravenously or subcutaneously, is required. Although intravenous administration of IgG (IVIG) has been the therapy of choice in the US and widely used in Europe for many years, subcutaneous administration of IgG (SCIG) has recently gained considerable acceptance among patients and doctors. SCIG therapy achieves high and stable serum IgG levels, is well tolerated, and can be self-administered. Hizentra (IgPro20; CSL Behring, Berne, Switzerland) is the first, ready-to-use 20% liquid preparation of human IgG specifically formulated for subcutaneous infusions. The high concentration (20%) might allow shorter infusion times due to smaller infusion volumes, with potential improvement in the convenience of SCIG therapy. Hizentra is well tolerated and has been shown to protect adult and pediatric primary immunodeficiency patients against serious bacterial infections. In addition, it is easy to handle and can be stored at a temperature up to 25°C. In summary, Hizentra is an advance in the field of immunoglobulin replacement therapy, which might offer benefits for home therapy patients.
Assuntos
Imunoglobulina G/administração & dosagem , Imunoglobulinas Intravenosas/administração & dosagem , Síndromes de Imunodeficiência/tratamento farmacológico , Adolescente , Adulto , Infecções Bacterianas/imunologia , Infecções Bacterianas/prevenção & controle , Criança , Pré-Escolar , Humanos , Síndromes de Imunodeficiência/imunologia , Infusões Subcutâneas , Resultado do TratamentoRESUMO
The objective of this study is to determine if immune reconstitution of FOXP3+ T regulatory cells correlates with clinical improvement of IPEX syndrome following allogeneic hematopoietic stem cell transplant. An 8-months-old male infant with a mutation in the polyadenylation site of FOXP3 gene, absence of FOXP3 protein expression and clinical manifestations of IPEX syndrome, including eczema, colitis, failure to thrive, TPN requirement, and elevated serum IgE, underwent matched unrelated hematopoietic stem cell transplant. After reduced-intensity conditioning with alemtuzumab followed by fludarabine and melphalan the patient's neutrophils engrafted day +15 and platelets day +29. Patient was a full donor chimera day +28 and +60. Intracellular FOXP3 protein expression in CD4+ T cells was absent pre-HSCT. After transplantation, percentage CD4+ T cells expressing FOXP3+CD25 bright phenotype quickly increased from 4.5 (day +29) to 23% (day +90) and continued in this trend. Foxp3 mRNA expression confirmed flow cytometry data. Serum IgE levels decreased from 5,000 IU/ml pre-transplant to 6 IU/ml on day +90, eczema resolved, and secretory diarrhea and feeding intolerance improved. T regulatory cell reconstitution is evident soon after HSCT following reduced-intensity conditioning correlating with development of full donor chimerism. Increased FOXP3 expression correlates with correction of clinical and laboratory manifestations of IPEX syndrome providing direct evidence that HSCT is a curative procedure for this disorder.
Assuntos
Doenças Autoimunes/cirurgia , Transplante de Medula Óssea , Fatores de Transcrição Forkhead/biossíntese , Linfócitos T Reguladores/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/cirurgia , Alemtuzumab , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/administração & dosagem , Anticorpos Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/genética , Fatores de Transcrição Forkhead/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoglobulina E/sangue , Lactente , Subunidade alfa de Receptor de Interleucina-7/imunologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Masculino , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Condicionamento Pré-Transplante , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/tratamento farmacológico , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genéticaRESUMO
The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and >or=18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults.
Assuntos
Didesoxinucleosídeos/administração & dosagem , Didesoxinucleosídeos/farmacocinética , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Adolescente , Fatores Etários , Feminino , Humanos , Masculino , Adulto JovemRESUMO
This paper presents findings of a multi-site study designed to document: (1) caregivers' regimen knowledge; (2) barriers to adherence; and (3) the relationships between adherence, regimen knowledge and barriers. Fifty-one predominantly female, African American parents and caregivers of HIV-infected children completed the Treatment Interview Protocol (TIP), a brief, structured interview designed to assess regimen knowledge and barriers to adherence. TIP data were compared to information obtained from medical records and pharmacy refill histories. Forty-nine per cent of children were considered adherent, defined as > or = 90% refill rate, which was significantly associated with virologic response. Significant regimen knowledge deficits were observed among caregivers, and inaccurate identification of prescribed medications was significantly associated with adherence. Caregivers identified 21 barriers to adherence, and poor adherence was significantly related to the number of barriers reported. Results indicate that the TIP is a successful tool for identifying regimen knowledge, potential adherence barriers and adherence problems. Results suggest that the TIP could be integrated into clinical practice as a quick, effective tool to identify poor adherers and guide interventions and treatment decision making.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/psicologia , Infecções por HIV/tratamento farmacológico , Cooperação do Paciente , Cuidadores , Criança , Pré-Escolar , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Pais , Reprodutibilidade dos Testes , Carga Viral/métodosRESUMO
METHODS: We examined monocyte prostaglandin synthase 2 (PGS2/COX2) expression in individuals at risk for or with type 1 diabetes including: (i) 58 established type 1 and 2 diabetic patients; (ii) 34 autoantibody positive (AA+) children and adults; (iii) 164 infants and young children with insulin-dependent diabetes mellitus (IDDM) susceptibility human leukocyte antigen (HLA) alleles; and (iv) 37 healthy control individuals, over a 5-yr period. RESULTS: Established type 1 diabetic patients (1 month to 30+ yr post-disease onset) had significantly higher PGS2 expression than healthy controls; by contrast, insulin-treated type 2 diabetic patients had significantly lower PGS2 expression than healthy controls. Longitudinal studies of AA+ subjects at risk for type 1 diabetes indicated that 73% (11/15) of individuals who developed this disease during the study period expressed high levels of PGS2 prior to or after onset. We also found high level PGS2 expression in genetically at-risk infants and young children that correlated with having a first-degree relative with type 1 diabetes, but not with age, gender, or HLA genotype. In this population, high level PGS2 expression coincided with or preceded autoantibody detection in 30% (3/10) of subjects. CONCLUSIONS: These findings suggest that high level monocyte PGS2 expression, although subject to fluctuation, is present in at-risk subjects at an early age and is maintained during progression to and after type 1 diabetes onset.
Assuntos
Diabetes Mellitus Tipo 1/enzimologia , Isoenzimas/sangue , Monócitos/enzimologia , Prostaglandina-Endoperóxido Sintases/sangue , Adulto , Autoanticorpos/sangue , Pré-Escolar , Ciclo-Oxigenase 2 , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/enzimologia , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos HLA/genética , Humanos , Lactente , Masculino , Proteínas de MembranaRESUMO
Evaluation of the T-cell immune response following primary antigenic challenge with a neoantigen is a critical aspect of assessment of the cellular immune response. While many antigens can be used to accurately assess in vitro T-cell proliferation to a recall antigen, only a few neoantigens have been tested for their capacities to measure T-cell responses in vitro to a primary immunization. Rabies vaccination is an excellent candidate for the testing of T-cell proliferation responses to a primary immunization because few individuals have been exposed to rabies virus antigens. In the present study 14 rabies vaccine-naïve, healthy adult volunteers were immunized against rabies virus, and T-cell proliferation and antibody responses were measured before and after vaccination. Optimal lymphocyte proliferation to soluble rabies virus antigen occurred after 8 days in culture. The average level of uptake of tritiated thymidine postimmunization was 29,620 +/- 4,448 cpm, whereas preimmunization levels were 12,660 +/- 3,448 cpm (P = 0.002). All individuals showed increases in rabies virus antibody titers from <0.05 to 5.59 +/- 1.64 IU/ml. The degree of proliferation to tetanus toxoid as a recall antigen was similar to the response to rabies virus antigen among the cohort. Due to high levels of preimmunization proliferation, four subjects failed to demonstrate a twofold increase in response to rabies virus antigen. The high levels of T-cell responses may be due to a viral superantigen effect in some individuals. Rabies vaccination offers a safe and effective means for measurement of both T- and B-cell immune responses to a neoantigen in healthy and immune suppressed individuals.
Assuntos
Antígenos Virais/imunologia , Ativação Linfocitária/imunologia , Vacina Antirrábica/imunologia , Vírus da Raiva/imunologia , Linfócitos T/imunologia , Adulto , Divisão Celular/imunologia , Feminino , Humanos , Esquemas de Imunização , Masculino , Raiva/prevenção & controle , Vacina Antirrábica/uso terapêutico , Linfócitos T/virologia , Toxoide Tetânico/imunologiaRESUMO
OBJECTIVE: During the 2 decades in which effective antiviral therapies have been available for neonatal herpes simplex virus (HSV) disease, changes have been documented not only in the outcomes of infected infants, but also in the natural history of the disease itself. Numerous studies previously have reported that early institution of antiviral therapy is beneficial to the outcome of the disease. The objective of this study was to provide an update of neonatal HSV disease to identify means by which future improvements in the management of HSV-infected neonates can be made. DESIGN/METHODS: Neonates enrolled in 2 studies of parenteral acyclovir for the treatment of neonatal HSV disease provided the data source. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted the studies between 1981 and 1997. A total of 186 patients are summarized, all of whom were treated with acyclovir. Demographic and clinical characteristics of these patients are reported. RESULTS: Comparisons between patients treated in the periods between 1981-1988 and 1989-1997 according to extent of disease revealed that the mean time between the onset of disease symptoms and initiation of therapy has not changed significantly from the early 1980s to the late 1990s. Of all patients evaluated, 40% had fetal scalp monitors during the delivery process. A significant minority of patients did not have skin vesicles at the time of their presentation and did not develop them during the acute HSV disease (39% of patients with disseminated disease; 32% of patients with central nervous system [CNS] disease; and 17% of patients with skin, eye, and/or mouth disease). Among patients with CNS disease, mortality was associated with prematurity. Among patients with disseminated HSV disease treated with acyclovir at 30 mg/kg/d, mortality was associated with aspartate transaminase elevations of >/=10 times the upper limit of normal at the time of initiation of acyclovir therapy. Mortality was also associated with lethargy at initiation of antiviral therapy for patients with disseminated disease. Patients' morbidity status was associated with the extent of disease (skin, eye, and/or mouth disease vs CNS vs disseminated). For those patients with CNS disease, morbidity was also associated with seizures at initiation of antiviral therapy. CONCLUSION: Data presented in the current comparison of neonatal HSV disease over the 2 periods (1981-1988 vs 1989-1997) demonstrate that no progress has been made in decreasing the interval between onset of HSV symptoms and initiation of antiviral therapy. Additional strides in the improvement of disease outcome may occur only if the interval between onset of symptoms and initiation of therapy is shortened. The means by which this will be accomplished lie in increased consideration of neonatal HSV infections in acutely ill infants. Specific data and recommendations to facilitate this goal are contained within.
Assuntos
Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Herpes Simples/tratamento farmacológico , Aciclovir/administração & dosagem , Antivirais/administração & dosagem , Aspartato Aminotransferases/sangue , Diagnóstico Diferencial , Diagnóstico por Imagem , Eletroencefalografia/estatística & dados numéricos , Herpes Simples/diagnóstico , Herpes Simples/microbiologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/isolamento & purificação , Herpesvirus Humano 2/efeitos dos fármacos , Herpesvirus Humano 2/isolamento & purificação , Humanos , Lactente , Recém-Nascido , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/tratamento farmacológico , Infusões Parenterais , Modelos de Riscos Proporcionais , Estudos Prospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: The objective of this investigation was to establish the safety of high-dose (HD) acyclovir for the treatment of neonatal herpes simplex virus (HSV) disease. In addition, an estimate of therapeutic efficacy was sought, both with respect to mortality and to morbidity. Virologic efficacy of HD acyclovir was also assessed. PARTICIPANTS: Infants who were =28 days old and whose disease was considered to be caused by HSV were enrolled in this study. Patients with central nervous system (CNS; N = 28) or disseminated (N = 41) HSV infection were offered participation in the trial. A small number of patients with HSV disease limited to the skin, eyes, or mouth (SEM; N = 10) or whose disease was clinically consistent with HSV but who did not have virologic confirmation of infection (N = 9) also were enrolled on a compassionate basis. Only patients with virologically confirmed HSV disease were included in efficacy analyses. All enrolled patients were included in safety analyses. METHODS: The study was an open-label evaluation of intravenous acyclovir at dosages higher than the 30 mg/kg/d standard dosage approved by the US Food and Drug Administration. The first 16 patients enrolled received intermediate-dose (ID) acyclovir (45 mg/kg/d), and the next 72 patients received HD acyclovir (60 mg/kg/d). Acyclovir was administered in 3 divided daily doses for 21 days. Neonates were assessed prospectively throughout treatment and at scheduled follow-up visits for the first 4 years of life. Data were compared with those of a previous National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group trial in which patients received standard-dose (SD) acyclovir for 10 days and in which identical methods (with the exception of acyclovir dosage and duration of therapy) were used. RESULTS: Six (21%) of 29 HD acyclovir recipients whose HSV disease remained localized to the SEM or CNS experienced neutropenia. One of the 6 had an absolute neutrophil count <500/mm(3), and 5 patients had an absolute neutrophil count (ANC) between 500/mm(3) and 1000/mm(3). In all 6 cases, the ANC recovered during continuation of acyclovir at the same dosage or after completion of acyclovir therapy, and there were no apparent adverse sequelae of the transient neutropenia. No other drug-related adverse events were reported among ID or HD recipients, and no other laboratory aberrations could be correlated specifically with antiviral therapy. The survival rate for the patients with disseminated HSV disease treated with HD acyclovir was significantly higher than for those in the previous study treated with SD acyclovir, with an odds ratio (OR) of 3.3 (95% confidence interval [CI]: 1.4-7.9). For patients with CNS disease, however, survival rates were similar for the HD and SD groups. To assess the effect of HD acyclovir on survival for the entire population with neonatal HSV disease, the Cox proportional hazards regression analysis was performed with stratification for disease category (CNS versus disseminated). In performing this analysis, differences in mortality for each disease category were weighted to allow statistical comparison of the treatment dosage groups (HD, ID, and SD). This analysis indicated that the survival rate for patients treated with HD acyclovir was statistically significantly higher than for patients treated with SD acyclovir (OR: 3.3; 95% CI: 1.5-7.3). Recipients of HD acyclovir had a borderline significant decrease in morbidity compared with SD recipients, after stratification for the extent of disease (SEM vs CNS vs disseminated) and controlling for the potential confounding factors of HSV type (HSV-1 vs. HSV-2), prematurity, and disease severity (seizures). Patients treated with HD acyclovir were 6.6 times (adjusted OR; 95% CI: 0.8-113.6) as likely to be developmentally normal at 12 months of age as patients treated with SD therapy. CONCLUSION: These data support the use of a 21-day course of HD (60 mg/kg/d) intravenous acyclovir to treat neonatal CNS and disseminated HSV disease. Throughout the course of HD acyclovir therapy, serial ANC determination should be made at least twice weekly. Decreasing the acyclovir dosage or administering granulocyte colony-stimulating factor should be considered if the ANC remains below 500/mm(3) for a prolonged period.
Assuntos
Aciclovir/administração & dosagem , Herpes Simples/tratamento farmacológico , Aciclovir/uso terapêutico , Esquema de Medicação , Humanos , Recém-Nascido , Infusões Intravenosas , Injeções IntravenosasRESUMO
Virologic and immunologic responses were examined for 33 human immunodeficiency virus (HIV)-infected children who participated for > or = 96 weeks in a phase 1/2 protocol of 16 weeks of indinavir monotherapy, followed by the addition of zidovudine and lamivudine. At week 96, a median increase of 199 CD4+ T cells/microL and a median decrease of 0.74 log(10) HIV RNA copies/mL were observed. The relationship between control of viral replication and CD4) T cell count was examined. Patients were categorized into 3 response groups on the basis of duration and extent of control of viral replication. Of 21 children with a transient decrease in virus load of > or = 0.7 log(10) HIV RNA copies/mL from baseline, 7 experienced sustained increases in CD4+, CD4+ CD45RA+, and CD4+ CD45RO+ T cell counts. CD4+ CD45RA+ (naive) T cells were the major contributor to CD4+ T cell expansion. Continued long-term immunologic benefit may be experienced by a subset of children, despite only transient virologic suppression.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV , Indinavir/uso terapêutico , Lamivudina/uso terapêutico , Zidovudina/uso terapêutico , Adolescente , Antígenos CD4/análise , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Seguimentos , HIV/isolamento & purificação , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Antígenos Comuns de Leucócito/análise , Masculino , Proteína Tirosina Fosfatase não Receptora Tipo 1 , RNA Viral/análise , Carga ViralRESUMO
Protease genotype, as a variable in outcome to combination therapy for human immunodeficiency virus (HIV) type 1 infection, was evaluated among protease inhibitor-naive children and adolescents who had received extensive treatment with reverse-transcriptase inhibitors. After 24 weeks of combination therapy, 35% had viral and immune success (VSIS patients), 19% had viral and immune failure (VFIF patients), and 46% had viral failure but marked improvement in CD4 T cells (VFIS patients). Disease stage was the only pretherapy clinical variable associated with outcome (P=.02). Although reverse-transcriptase genotype was unrelated to outcome, pretherapy protease genotype was related significantly to therapy response (P=.005). Odds for immune or viral failure were 17.7 to 1 and 2.5 to 1, respectively, for protease genotype as a single variable. Protease genotype combined with disease stage and CD4 cell percentage predicted correct therapy response for 81% of patients (100% of VFIF, 78% of VSIS, and 75% of VFIS patiens). Naturally occurring amino acid polymorphisms in protease provide sensitive biomarkers for treatment response among inhibitor-naive patients with advanced HIV disease.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Protease de HIV/genética , HIV-1/enzimologia , Inibidores da Transcriptase Reversa/uso terapêutico , Adolescente , Substituição de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Quimioterapia Combinada , Feminino , Genótipo , Infecções por HIV/imunologia , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/genética , Humanos , Lactente , Masculino , Filogenia , Valor Preditivo dos Testes , Estudos Prospectivos , Análise de Sequência de DNA , Resultado do TratamentoRESUMO
OBJECTIVES: Abacavir (ABC) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. We compared the efficacy, safety, and tolerability of combination therapy with ABC, lamivudine (3TC), and zidovudine (ZDV) versus 3TC and ZDV in antiretroviral experienced HIV-1-infected children over 48 weeks. METHODS: Two hundred five HIV-1-infected children who had received previous antiretroviral therapy and had CD4(+) cell counts >/=100 cells/mm(3) were stratified by age and by previous treatment. Participants were randomly assigned to receive ABC (8 mg/kg twice daily [BID]) plus 3TC (4 mg/kg BID) and ZDV (180 mg/m(2) BID; ABC/3TC/ZDV group) or ABC placebo plus 3TC (4 mg/kg BID) and ZDV (180 mg/m(2); 3TC/ZDV group). Participants who met a protocol-defined switch criteria (plasma HIV-1 RNA >0.5 log(10) copies/mL above baseline at week 8 or >10 000 copies/mL after week 16) had the option to switch to open-label ABC plus any antiretroviral combination or continue randomized therapy or withdraw from the study. RESULTS: The Kaplan-Meier estimates (95% confidence interval) of the proportion of participants who maintained HIV-1 RNA levels =10 000 copies/mL for 48 weeks or more was significantly better in the ABC/3TC/ZDV group compared with the 3TC/ZDV group: 33% (23%-42%) versus 21% (13%-29%). At week 48, the proportions of participants with HIV-1 RNA =10 000 copies/mL were 36% versus 26% for the ABC/3TC/ZDV and 3TC/ZDV groups, respectively, by intent-to-treat analysis. For the subgroup of participants with baseline HIV-1 RNA >10 000 copies/mL, a significantly higher proportion of participants in the ABC/3TC/ZDV group had HIV-1 RNA =10 000 copies/mL compared with the 3TC/ZDV group (29% vs 12%) but no difference was observed in the subgroup of participants with baseline HIV-1 RNA =10 000 copies/mL (78% vs 72%). The median changes from baseline in CD4(+) cell counts were greater in the ABC/3TC/ZDV group than in the 3TC/ZDV group. Few participants (3%) experienced abacavir-related hypersensitivity reaction. CONCLUSIONS: ABC, in combination with 3TC and ZDV, provides additional antiretroviral activity over 48 weeks, compared with combination therapy with 3TC and ZDV in antiretroviral experienced HIV-1-infected children. ABC was safe and generally well-tolerated and should be considered an active component of combination antiretroviral therapy in this pediatric population.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/administração & dosagem , Lamivudina/administração & dosagem , Zidovudina/administração & dosagem , Adolescente , Fármacos Anti-HIV/efeitos adversos , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Intervalos de Confiança , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Crescimento/efeitos dos fármacos , HIV-1/genética , Humanos , Lactente , Masculino , RNA Viral/análise , RNA Viral/efeitos dos fármacosRESUMO
The T-cell receptor (TCR) CDR3 length heterogeneity is formed during recombination of individual Vbeta gene families. We hypothesized that CDR3 length diversity could be used to assess the fundamental differences within the TCR repertoire of CD45RA and CD45RO T-cell subpopulations. By using PCR-based spectratyping, nested primers for all 24 human Vbeta families were developed to amplify CDR3 lengths in immunomagnetically selected CD45RA and CD45RO subsets within both CD4(+) and CD8(+) T-cell populations. Umbilical cord blood mononuclear cells or peripheral blood mononuclear cells obtained from healthy newborns, infants, and children, as well as human immunodeficiency virus (HIV)-infected children, were analyzed. All T-cell subsets from newborn and healthy children demonstrated a Gaussian distribution of CDR3 lengths in separated T-cell subsets. In contrast, HIV-infected children had a high proportion of predominant CDR3 lengths within both CD45RA and CD45RO T-cell subpopulations, most commonly in CD8(+) CD45RO T cells. Sharp differences in clonal dominance and size distributions were observed when cells were separated into CD45RA or CD45RO subpopulations. These differences were not apparent in unfractionated CD4(+) or CD8(+) T cells from HIV-infected subjects. Sequence analysis of predominant CDR3 lengths revealed oligoclonal expansion within individual Vbeta families. Analysis of the CDR3 length diversity within CD45RA and CD45RO T cells provides a more accurate measure of disturbances in the TCR repertoire than analysis of unfractionated CD4 and CD8 T cells.
Assuntos
Regiões Determinantes de Complementaridade/genética , Infecções por HIV/genética , Infecções por HIV/imunologia , Antígenos Comuns de Leucócito/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Subpopulações de Linfócitos T/imunologia , Sequência de Aminoácidos , Sequência de Bases , Estudos de Casos e Controles , Criança , Primers do DNA/genética , Sangue Fetal/citologia , Sangue Fetal/imunologia , Variação Genética , Humanos , Lactente , Recém-Nascido , Dados de Sequência Molecular , Reação em Cadeia da PolimeraseRESUMO
The objective of this study was to identify phenotypic parameters that could distinguish among seemingly homogeneous non-syncytium-inducing (NSI) viruses and that might provide a surrogate marker for clinical progression in pediatric human immunodeficiency virus type 1 (HIV-1) infection. We undertook a pilot analysis of 15 independent HIV-1 isolates collected prospectively from two mothers and their four children who displayed a spectrum of disease stages ranging from CDC categories A1 to C3. Viruses were evaluated for their ability to replicate in primary cells (including monocyte-derived macrophages [MDM]) and cell lines, for their co-receptor preference and for genetic features of the V3 hypervariable domain of env. Virtually all isolates displayed NSI phenotypes that were restricted in their capacity to replicate in cell lines and displayed V3 loops with uniformly low net positive charges. NSI viruses from two symptomatic children and one mother were macrophage-tropic, whereas NSI isolates from two asymptomatic children were unable to replicate in MDM and were designated primary lymphotropic viruses. Only one isolate was syncytium-inducing (SI), replicated in a variety of cell lines and in MDM, used multiple co-receptors, and was dual tropic, rather than a mixture of T-cell tropic and M-tropic viruses, as assessed by genetic analysis. Phenotypic heterogeneity among NSI viruses is revealed in the ability of isolates to replicate in MDM. This characteristic is related to disease stage and provides a potentially new in vitro criterion to distinguish among NSI isolates that is unlinked to other surrogate markers.
Assuntos
Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , Macrófagos/virologia , Adulto , Sequência de Aminoácidos , Antígenos Virais/análise , Antígenos CD4/genética , Antígenos CD4/metabolismo , Linhagem Celular , Células Cultivadas , Pré-Escolar , Feminino , Células Gigantes/virologia , Proteína do Núcleo p24 do HIV/análise , Infecções por HIV/sangue , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Lactente , Leucócitos Mononucleares/virologia , Dados de Sequência Molecular , Fenótipo , Estudos Prospectivos , Estrutura Terciária de Proteína/genética , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Transfecção , Tropismo , Células U937 , Proteínas Virais/genética , Replicação ViralAssuntos
Proteína gp120 do Envelope de HIV/genética , HIV-1/classificação , Fragmentos de Peptídeos/genética , Sequência de Aminoácidos , Infecções por HIV/virologia , HIV-1/genética , HIV-1/fisiologia , Humanos , Macrófagos/virologia , Modelos Biológicos , Fenótipo , Valor Preditivo dos Testes , Receptores de HIV/metabolismoRESUMO
BACKGROUND: Dapsone is an alternative drug for Pneumocystis carinii pneumonia (PCP) prophylaxis in individuals intolerant to trimethoprim-sulfamethoxazole (T/S). There are, however, few data on the pharmacokinetics, toxicity or efficacy of dapsone in children. Design. Randomized, multicenter trial comparing daily (1 or 2 mg/kg) with weekly (4 mg/kg) dapsone regimens in 94 HIV-infected children intolerant to T/S. METHODS: Hematologic and hepatic toxicity was monitored, as well as the occurrence of skin rash, PCP or death. RESULTS: Initial pharmacokinetic data indicated that adequate serum dapsone concentrations were not achieved with the daily 1-mg/kg regimen; the daily dose was then increased to 2 mg/kg. Both short and long term hematologic toxicities were marginally greater in children receiving the daily 2 mg/kg compared with the weekly regimen. Allergic skin rashes were similar in children receiving the daily and weekly regimens (17% in both) and were not associated with prior history of rash with T/S. PCP occurred most frequently with the daily 1-mg/kg regimen (22.0 cases/100 patient years), least frequently with the daily 2-mg/kg regimen (0 case/100 patient years) and at intermediate frequency with the weekly regimen (9.5 cases/100 patient years). More deaths were observed in patients receiving the daily than the weekly regimen (8 vs. 2, respectively), although the deaths were not directly attributable to dapsone treatment. CONCLUSION: Although a weekly dapsone regimen of 4 mg/kg produced less hematologic toxicity than a daily regimen of 2 mg/kg, this advantage was offset by a trend toward higher breakthrough rates of PCP.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Anti-Infecciosos/administração & dosagem , Dapsona/administração & dosagem , Pneumonia por Pneumocystis/prevenção & controle , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/uso terapêutico , Criança , Pré-Escolar , Dapsona/efeitos adversos , Dapsona/uso terapêutico , Esquema de Medicação , Humanos , Lactente , Análise de RegressãoRESUMO
OBJECTIVE: To evaluate lymphocyte reconstitution after protease inhibitor therapy in children with human immunodeficiency virus (HIV) infection. STUDY DESIGN: Forty-four HIV-infected children receiving ritonavir monotherapy followed by the addition of zidovudine and didanosine were evaluated during a phase I/II clinical trial. The cohort had a median age of 6.8 years and advanced disease (57% Centers for Disease Control and Prevention stage C, 73% immune stage 3) and was naive to protease inhibitor therapy. RESULTS: After 4 weeks of therapy, there was a significant increase in CD4(+) and CD8(+) T cells. CD4(+) T cells continued to increase, whereas CD8(+) T cells returned to baseline by 24 weeks. Unexpectedly, there was a significant increase in B cells. Changes in CD4(+) T-cell subsets revealed an initial increase in CD4(+) CD45RO T cells followed by a sustained increase in CD4(+) CD45RA T cells. Children <6 years of age had the highest increase in all lymphocyte populations. Significant improvement in CD4(+) T-cell counts was observed even in those children whose viral burden returned to pre-therapy levels. CONCLUSIONS: Early increases in lymphocytes after ritonavir therapy are a result of recirculation, as shown by increases in B cells and CD4(+) CD45RO and CD8(+) T cells. Children exhibited a high potential to reconstitute CD4(+) CD45RA T cells even with advanced disease and incomplete viral suppression.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Inibidores da Protease de HIV/uso terapêutico , Ritonavir/uso terapêutico , Adolescente , Relação CD4-CD8 , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Criança , Pré-Escolar , Didanosina/uso terapêutico , Quimioterapia Combinada , Humanos , Imunofenotipagem , Lactente , Antígenos Comuns de Leucócito , Subpopulações de Linfócitos , Carga Viral , Zidovudina/uso terapêuticoRESUMO
Telomere shortening may reflect the total number of divisions experienced by a somatic cell and is associated with replicative senescence. We found that the average rate of telomere shortening in peripheral blood mononuclear cells (PBMCs) obtained longitudinally from nine different infants during the first 3 years of life (270 bp per year) is more than fourfold higher than in adults and does not correlate with telomerase activity. These results show that the rate of telomere loss changes during ontogeny, suggesting the existence of periods of accelerated cell division. Because human immunodeficiency virus (HIV) preferentially infects actively dividing cells, our observation suggesting accelerated cell division in children may provide an explanation for some of the distinctive pathogenic features of the HIV disease in infants, including higher viral loads and more rapid progression to acquired immunodeficiency syndrome (AIDS).
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Envelhecimento/genética , Telomerase/metabolismo , Telômero/genética , Adulto , Southern Blotting , Feminino , Infecções por HIV/transmissão , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Estudos Longitudinais , Gravidez , Complicações Infecciosas na Gravidez , Análise de Regressão , Fatores de Risco , Telômero/ultraestruturaAssuntos
Infecções por Bacillaceae/diagnóstico , Bacillus , Imunodeficiência Combinada Severa/diagnóstico , Dermatopatias Bacterianas/diagnóstico , Infecções por Bacillaceae/etiologia , Infecções por Bacillaceae/terapia , Terapia Combinada , Ligação Genética , Humanos , Lactente , Masculino , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Dermatopatias Bacterianas/etiologia , Dermatopatias Bacterianas/terapia , Cromossomo XRESUMO
BACKGROUND: Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose. METHODS: Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m2, 350 mg/m2, and 500 mg/m2 per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and >/=12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks. RESULTS: Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm3, and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy. CONCLUSIONS: Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine.