RESUMO
BACKGROUND: The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known. METHODS: In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily antiretroviral regimens as initial therapy for HIV-1 infection: abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA level > or = 1000 copies per milliliter at or after 16 weeks and before 24 weeks, or > or = 200 copies per milliliter at or after 24 weeks). RESULTS: A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P<0.001), with 57 virologic failures (14%) in the abacavir-lamivudine group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the first adverse event was also shorter in the abacavir-lamivudine group (P<0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48. CONCLUSIONS: In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine. (ClinicalTrials.gov number, NCT00118898.)
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , HIV-1 , Lamivudina/uso terapêutico , Organofosfonatos/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Adolescente , Adulto , Análise de Variância , Fármacos Anti-HIV/efeitos adversos , Contagem de Linfócito CD4 , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Didesoxinucleosídeos , Método Duplo-Cego , Combinação de Medicamentos , Farmacorresistência Viral , Emtricitabina , Feminino , Fraturas Ósseas/induzido quimicamente , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/efeitos adversos , RNA Viral/sangue , Tenofovir , Equivalência Terapêutica , Fatores de Tempo , Falha de Tratamento , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Limited data compare once-daily options for initial therapy for HIV-1. OBJECTIVE: To compare time to virologic failure; first grade-3 or -4 sign, symptom, or laboratory abnormality (safety); and change or discontinuation of regimen (tolerability) for atazanavir plus ritonavir with efavirenz-containing initial therapy for HIV-1. DESIGN: A randomized equivalence trial accrued from September 2005 to November 2007, with median follow-up of 138 weeks. Regimens were assigned by using a central computer, stratified by screening HIV-1 RNA level less than 100 000 copies/mL or 100 000 copies/mL or greater; blinding was known only to the site pharmacist. (ClinicalTrials.gov registration number: NCT00118898) SETTING: 59 AIDS Clinical Trials Group sites in the United States and Puerto Rico. PATIENTS: Antiretroviral-naive patients. INTERVENTION: Open-label atazanavir plus ritonavir or efavirenz, each given with with placebo-controlled abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine. MEASUREMENTS: Primary outcomes were time to virologic failure, safety, and tolerability events. Secondary end points included proportion of patients with HIV-1 RNA level less than 50 copies/mL, emergence of drug resistance, changes in CD4 cell counts, calculated creatinine clearance, and lipid levels. RESULTS: 463 eligible patients were randomly assigned to receive atazanavir plus ritonavir and 465 were assigned to receive efavirenz, both with abacavir-lamivudine; 322 (70%) and 324 (70%), respectively, completed follow-up. The respective numbers of participants in each group who received tenofovir DF-emtricitabine were 465 and 464; 342 (74%) and 343 (74%) completed follow-up. Primary efficacy was similar in the group that received atazanavir plus ritonavir and and the group that received efavirenz and did not differ according to whether abacavir-lamivudine or tenofovir DF-emtricitabine was also given. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively, although CIs did not meet prespecified criteria for equivalence. The time to safety (P = 0.048) and tolerability (P < 0.001) events was longer in persons given atazanavir plus ritonavir than in those given efavirenz with abacavir-lamivudine but not with tenofovir DF-emtricitabine. LIMITATIONS: Neither HLA-B*5701 nor resistance testing was the standard of care when A5202 enrolled patients. The third drugs, atazanavir plus ritonavir and efavirenz, were open-label; the nucleoside reverse transcriptase inhibitors were prematurely unblinded in the high viral load stratum; and 32% of patients modified or discontinued treatment with their third drug. CONCLUSION: Atazanavir plus ritonavir and efavirenz have similar antiviral activity when used with abacavir-lamivudine or tenofovir DF-emtricitabine. PRIMARY FUNDING SOURCE: National Institutes of Health.
Assuntos
Benzoxazinas/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Oligopeptídeos/uso terapêutico , Piridinas/uso terapêutico , Ritonavir/uso terapêutico , Adolescente , Adulto , Alcinos , Sulfato de Atazanavir , Benzoxazinas/efeitos adversos , Contagem de Linfócito CD4 , Ciclopropanos , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/efeitos adversos , HIV-1/efeitos dos fármacos , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Piridinas/efeitos adversos , Ritonavir/efeitos adversos , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Long-term effects of abacavir (ABC)-lamivudine (3TC), compared with tenofovir (TDF)-emtricitabine (FTC) with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r), on bone mineral density (BMD) have not been analyzed. METHODS: A5224s was a substudy of A5202, in which HIV-infected treatment-naive participants were randomized and blinded to receive ABC-3TC or TDF-FTC with open-label EFV or ATV/r. Primary bone end points included Dual-emission X-ray absorbtiometry (DXA)-measured percent changes in spine and hip BMD at week 96. Primary analyses were intent-to-treat. Statistical tests used the factorial design and included linear regression, 2-sample t, log-rank, and Fisher's exact tests. RESULTS: Two hundred sixty-nine persons randomized to 4 arms of ABC-3TC or TDF-FTC with EFV or ATV/r. At baseline, 85% were male, and 47% were white non-Hispanic; the median HIV-1 RNA load was 4.6 log(10) copies/mL, the median age was 38 years, the median weight was 76 kg, and the median CD4 cell count was 233 cells/µL. At week 96, the mean percentage changes from baseline in spine and hip BMD for ABC-3TC versus TDF-FTC were -1.3% and -3.3% (P = .004) and -2.6% and -4.0% (P = .024), respectively; and for EFV versus ATV/r were -1.7% and -3.1% (P = .035) and -3.1% and -3.4% (P = .61), respectively. Bone fracture was observed in 5.6% of participants. The probability of bone fractures and time to first fracture were not different across components. CONCLUSIONS: Compared with ABC-3TC, TDF-FTC-treated participants had significantly greater decreases in spine and hip BMD, whereas ATV/r led to more significant losses in spine, but not hip, BMD than EFV. Clinical Trials Registration. NCT00118898.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Fraturas Ósseas/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Osteoporose/induzido quimicamente , Absorciometria de Fóton , Adenina/efeitos adversos , Adenina/análogos & derivados , Adulto , Alcinos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Sulfato de Atazanavir , Benzoxazinas/efeitos adversos , Contagem de Linfócito CD4 , Ciclopropanos , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Didesoxinucleosídeos/efeitos adversos , Combinação de Medicamentos , Quimioterapia Combinada , Emtricitabina , Feminino , Fraturas Ósseas/epidemiologia , Infecções por HIV/complicações , Humanos , Análise de Intenção de Tratamento , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Organofosfonatos/efeitos adversos , Piridinas/efeitos adversos , Fatores de Risco , Ritonavir/efeitos adversos , Tenofovir , Carga ViralRESUMO
BACKGROUND: AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human immunodeficiency virus (HIV)-infected treatment-naive patients, stratified by screening HIV RNA (< or ≥ 10(5) copies/mL). Due to higher virologic failure with ABC/3TC in the high HIV RNA stratum, blinded treatment was stopped in this group, but study follow-up continued for all patients. METHODS: Primary endpoints were times to virologic failure, regimen modification, and safety event. RESULTS: In the low HIV RNA stratum, time to virologic failure was similar for ABC/3TC vs TDF/FTC with ATV/r (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.76, 2.05) or EFV (HR 1.23, 95% CI 0.77, 1.96), with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV. Prior to stopping blinded treatment in the high stratum, higher virologic failure rates were seen with ABC/3TC with EFV (HR 2.46, 95% CI 1.20, 5.05) or ATV/r (HR 2.22, 95% CI 1.19, 4.14). CONCLUSIONS: In the low HIV RNA stratum, times to virologic failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r. In the high stratum, virologic failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Desoxicitidina/análogos & derivados , Didesoxinucleosídeos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Lamivudina/administração & dosagem , Organofosfonatos/administração & dosagem , Adenina/administração & dosagem , Adulto , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Desoxicitidina/administração & dosagem , Método Duplo-Cego , Emtricitabina , Feminino , HIV/genética , Infecções por HIV/virologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , RNA Viral/sangue , Tenofovir , Carga ViralRESUMO
BACKGROUND: Limited data exist regarding how medications for pediatric use can be developed to minimize medication errors. The integrase inhibitor raltegravir was developed for use in neonates (≥2 kg). Anticipating that neonatal administration would be performed primarily by mothers with varying degrees of health literacy, a health literate, patient-focused, iterative process was conducted to update/redesign the raltegravir granules for oral suspension pediatric kit and instructions for use (IFU) for neonatal use to be ready for regulatory submission. METHODS: Prototypes of an updated/redesigned raltegravir IFU were systematically assessed through multi-stage, iterative testing and evaluation involving untrained lay individuals with varying levels of health literacy, healthcare professionals and health literacy experts. RESULTS: This iterative process resulted in numerous refinements to the IFU and kit, including wording, layout, presentation, colored syringes and additional instructional steps. The revised raltegravir pediatric kit and IFU (to include neonatal dosing) were approved by the US Food and Drug Administration in 2017 and the European Union in 2018. No reported medication errors related to IFU utilization had been reported as of March 2021, reflecting >3 years of commercial use worldwide. CONCLUSIONS: This patient-focused process produced health literate instructions for preparing and administering an antiretroviral for neonatal use with complex dosing requirements. Testing demonstrated that lay users with a range of health literacy levels were able to accurately mix, measure and administer the product. This process demonstrates how a neonatal medication can be optimized for use through collaboration between the infectious disease expert community and a manufacturer.
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Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Letramento em Saúde/métodos , Assistência Centrada no Paciente/métodos , Raltegravir Potássico/administração & dosagem , Inibidores de Integrase de HIV/uso terapêutico , Pessoal de Saúde , Humanos , Recém-Nascido , Erros de Medicação/prevenção & controle , Raltegravir Potássico/uso terapêuticoRESUMO
BACKGROUND: A 2019 public workshop convened by the National Academies of Sciences, Engineering and Medicine (NASEM) Roundtable on Health Literacy identified a need to develop evidence-based guidance for best practices for health literacy and patient activation in clinical trials. PURPOSE: To identify studies of health literacy interventions within medical care or clinical trial settings that were associated with improved measures of health literacy or patient activation, to help inform best practices in the clinical trial process. DATA SOURCES: Literature searches were conducted in PubMed, the Cumulative Index to Nursing and Allied Health Literature, SCOPUS, Cochrane, and Web of Science from January 2009 to June 2021. STUDY SELECTION: Of 3592 records screened, 22 records investigating 27 unique health literacy interventions in randomized controlled studies were included for qualitative synthesis. DATA EXTRACTION: Data screening and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. DATA SYNTHESIS: Types of health literacy interventions were multimedia or technology-based (11 studies), simplification of written material (six studies) and in-person sessions (five studies). These interventions were applied at various stages in the healthcare and clinical trial process. All studies used unique outcome measures, including patient comprehension, quality of informed consent, and patient activation and engagement. CONCLUSIONS: The findings of our study suggest that best practice guidelines recommend health literacy interventions during the clinical trial process, presentation of information in multiple forms, involvement of patients in information optimization, and improved standardization in health literacy outcome measures.
Assuntos
Letramento em Saúde , Compreensão , Humanos , Consentimento Livre e Esclarecido , Assistência Centrada no PacienteRESUMO
BACKGROUND: We compare the effect of 4 different antiretroviral regimens on limb and visceral fat. METHODS: A5224s was a substudy of A5202, a trial of human immunodeficiency virus type 1 (HIV-1)-infected, treatment-naive subjects randomized to blinded abacavir-lamivudine (ABC-3TC) or tenofovir DF-emtricitabine (TDF-FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV-r). The primary endpoint was the presence of lipoatrophy (≥ 10% loss of limb fat) at week 96 by intent-to-treat (ITT) analysis. Secondary endpoints included changes in limb and visceral fat. Statistical tests included linear regression, binomial, two-sample t test, and Fisher's exact test. RESULTS: A5224s enrolled 269 subjects; 85% were male, and 47% were white non-Hispanic. The subjects had a median baseline HIV-1 RNA level of 4.6 log(10) copies/mL, a median age of 38 years, a median CD4+ cell count of 233 cells/µL, median limb fat of 7.4 kg, median visceral adipose tissue (VAT) of 84.1 cm(2), and VAT: total adipose tissue (TAT) ratio of 0.31. At week 96, estimated prevalence of lipoatrophy (upper 95% confidence interval [CI]) was 18% (25%) for ABC-3TC and 15% (22%) for TDF-FTC (P = .70); this was not significantly less than the hypothesized 15% for both (P ≥ .55 for both). The secondary as-treated (AT) analysis showed similar results. At week 96, the estimated mean percentage change from baseline in VAT was higher for the ATV-r group than for the EFV group (26.6% vs 12.4%; P = .090 in ITT analysis and 30.0% vs 14.5%; P = .10 in AT analysis); however, the percentage change in VAT:TAT was similar by ITT and AT analysis (P ≥ .60 for both). Results were similar for absolute changes in VAT and VAT:TAT. CONCLUSIONS: ABC-3TC- and TDF-FTC-based regimens increased limb and visceral fat at week 96, with a similar prevalence of lipoatrophy. Compared to the EFV group, subjects assigned to ATV-r had a trend towards higher mean percentage increase in VAT. CLINICAL TRIALS REGISTRATION: NCT00118898.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Síndrome de Lipodistrofia Associada ao HIV/induzido quimicamente , Adulto , Distribuição da Gordura Corporal , Feminino , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Limited health literacy negatively impacts understanding of medication-related information. We describe an innovative methodology designed to optimize user understanding of patient medication labeling through the systematic application of evidence-based health literacy principles, using the Patient Package Insert (PPI) for bezlotoxumab (ZINPLAVA™, Merck & Co., Inc., Kenilworth, NJ, USA) as an example. METHODS: We used a mixed-model, iterative approach consisting of three phases: (1) content development; (2) focus group testing; and (3) comprehension testing. Content development was based on evidence-based health literacy principles and conducted through a collaborative partnership between industry and academia professionals. The PPI was then tested in four focus groups, two in Atlanta and two in Chicago, with an emphasis on collecting feedback from respondents with limited health literacy, evaluated using the Newest Vital Sign (NVS) health literacy assessment tool. Subsequent comprehension testing included patients with C. diff, caregivers, and general population members, with a pre-defined target sample of 25% with limited health literacy identified through two health literacy assessment tools: the Single Item Literacy Screener and the NVS. RESULTS: Content development of the bezlotoxumab PPI occurred in May 2015. In June 2015, focus group respondents (n = 34) provided generally favorable feedback, with insights revolving around organization and usability; language and comprehension; and volume of information. Comprehension testing of the revised PPI resulted in average comprehension scores of 96% for the overall population (n = 59), 90% for individuals presenting with limited health literacy (n = 14), and 97% for those with adequate health literacy (n = 45). This PPI development approach was similarly effective for subsequent products across diverse therapeutic areas, with comprehension scores ≥ 86% for all participants (n = 1197). CONCLUSION: This methodology represents a significant advancement for the development of understandable patient medication labeling, especially for people with limited health literacy.
Assuntos
Letramento em Saúde , Rotulagem de Medicamentos , Humanos , IdiomaRESUMO
BACKGROUND: Health literacy is increasingly being recognized as a widespread public health challenge in Europe. This commentary explores the importance of health literacy amongst cancer patients (ie, cancer literacy) and examines how cancer literacy can be improved through the practical application of health literacy principles within the context of providing timely, patient-centered, value-based care in Europe. MAIN BODY: Despite implementation of evidence-based cancer prevention programs and increased cancer survival rates, low cancer literacy may impact the personal capacity to manage risks and adversely impact behavior and outcomes. Cancer literacy poses a unique set of challenges compared to other types of health literacy, as patient decisions regarding screening, treatment, and side effect management are often complex, and timely decision-making is more critical. Accordingly, European health policies increasingly recognize the importance of health literacy. The European Patients Forum, European Cancer Patient Coalition, and the Association of European Cancer Leagues supported a joint statement, "Europe Let's Do More for Health," which emphasizes the need to empower citizens and patients by addressing health literacy, self-management, and shared decision-making. Implementation of comprehensive programs and strategies will be important to improve health literacy. Cancer literacy can be improved through application of health literacy principles in the communication and cooperation with professionals, patients and caregivers for providing timely, patient-centered, value-based care. Recommendations are made for further action to improve cancer literacy in Europe through coordinated efforts among providers, organizations, patients, and research. A policy paper developed by the European Joint Action on Cancer Control provides practical recommendations that Member States can take to reduce social inequalities in cancer care and defines focus areas that are closely connected with the need to improve cancer literacy. CONCLUSION: Improved personal cancer literacy combined with health literate organizations and systems can potentially improve the quality of care and health outcomes among patients with cancer. National Cancer Control Plans and Europe's Beating Cancer Plan can strengthen cancer literacy.
RESUMO
Globally, antimicrobial resistance (AMR) is a serious problem causing 700,000 deaths annually. By 2050, AMR is expected to cause approximately 10 million deaths globally each year if allowed to increase at the present rate. Many individuals have limited knowledge regarding appropriate antibiotic use and AMR. Most antibiotic use occurs in the outpatient setting, with approximately 30% of antibiotics prescribed deemed unnecessary. Antimicrobial stewardship (AMS) is a means to reduce inappropriate antibiotic use and AMR. While existing AMS efforts generally focus on the inpatient setting, a significant gap is present in the outpatient setting. A common theme across various national action plans to reduce AMR is the need for education and awareness. The importance of communicating information in a manner easily comprehended by the patient in addition to productive clinician-patient dialogue cannot be overestimated. Enhancing the public's and patients' AMS health literacy is an underrecognized approach to help address AMR. We describe Four Core Elements of Enhancing AMS Health Literacy in the Outpatient Setting, utilizing the Centers for Disease Control and Prevention's framework: (1) leadership commitment, (2) intervention/action, (3) tracking/reporting, and (4) education/expertise. We call upon leaders in outpatient settings to embrace this approach to curb inappropriate antimicrobial use.
Assuntos
Antibacterianos/uso terapêutico , Gestão de Antimicrobianos , Infecções Bacterianas/tratamento farmacológico , Farmacorresistência Bacteriana , Letramento em Saúde , Promoção da Saúde/métodos , Pacientes Ambulatoriais/educação , Pacientes Ambulatoriais/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estados UnidosRESUMO
Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p < .001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquine-treated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants. Clinical Trials Registry Number: NCT00819390.
Assuntos
Cloroquina/administração & dosagem , Infecções por HIV/imunologia , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Adolescente , Adulto , Idoso , Linfócitos T CD8-Positivos/imunologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: Concern about costs and antiretroviral therapy (ART)-associated toxicities led to the consideration of CD4 driven strategies for the management of HIV. That approach was evaluated in the SMART trial that reported an unexpected increase of cardiovascular events after treatment interruption (TI). Our goal was to evaluate fasting metabolic changes associated with interruption of antiretroviral therapy and relate them to changes of immune activation markers and cardiovascular risk. METHODOLOGY: ACTG 5102 enrolled 47 HIV-1-infected subjects on stable ART, with <200 HIV RNA copies/mL and CD4 cell count >or=500 cells/microL. Subjects were randomly assigned to continue ART for 18 weeks with or without 3 cycles of interleukin-2 (IL-2) (cycle = 4.5 million IU sc BID x 5 days every 8 weeks). After 18 weeks ART was discontinued in all subjects until the CD4 cell count dropped below 350 cells/microL. Glucose and lipid parameters were evaluated every 8 weeks initially and at weeks 2, 4, 8 and every 8 weeks after TI. Immune activation was evaluated by flow-cytometry and soluble TNFR2 levels. PRINCIPAL FINDINGS: By week 8 of TI, levels of total cholesterol (TC) (median (Q1, Q3) (-0.73 (-1.19, -0.18) mmol/L, p<0.0001), LDL, HDL cholesterol (-0.36(-0.73,-0.03)mmol/L, p = 0.0007 and -0.05(-0.26,0.03), p = 0.0033, respectively) and triglycerides decreased (-0.40 (-0.84, 0.07) mmol/L, p = 0.005). However the TC/HDL ratio remained unchanged (-0.09 (-1.2, 0.5), p = 0.2). Glucose and insulin levels did not change (p = 0.6 and 0.8, respectively). After TI there was marked increase in immune activation (CD8+/HLA-DR+/CD38+ cells, 34% (13, 43), p<0.0001) and soluble TNFR2 (1089 ng/L (-189, 1655), p = 0.0008) coinciding with the rebound of HIV viremia. CONCLUSIONS: Our data suggests that interrupting antiretroviral therapy does not reduce cardiovascular disease (CVD) risk, as the improvements in lipid parameters are modest and overshadowed by the decreased HDL levels. Increased immune cell activation and systemic inflammatory responses associated with recrudescent HIV viremia may provide a more cogent explanation for the increased cardiovascular risk associated with treatment interruption and HIV infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT00015704.
Assuntos
Doenças Cardiovasculares/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/fisiologia , Terapia Antirretroviral de Alta Atividade , Colesterol/metabolismo , HDL-Colesterol/metabolismo , Doença Crônica , Glucose/metabolismo , Infecções por HIV/complicações , Humanos , Interleucina-2/uso terapêutico , Metabolismo dos Lipídeos , Fatores de RiscoRESUMO
BACKGROUND: Although an intermittent antiviral treatment (ART) strategy may limit long-term toxicity and cost, there is concern about the risk for virologic failure, selection of drug resistance mutations, and disease progression. By boosting CD4 T-cell counts, interleukin 2 (IL-2) could safely prolong the duration of treatment interruption (TI) in a CD4-driven strategy. METHODS: The AIDS Clinical Trials Group (ACTG) study A5102 evaluated 3 cycles of IL-2 before TI, on clinical and immunologic outcomes, using a CD4 T-cell count of <350 cells/mm as the threshold for restarting ART. Forty-seven HIV-infected subjects on potent ART with CD4 T-cell counts of > or =500 cells/mm or more and HIV RNA levels of less than 200 copies/mL were randomized to arm A (ART + three 5-day cycles of IL-2 at 4.5 million U, Sc, BID every 8 weeks, n = 23) or arm B (ART alone, n = 24) for 18 weeks (step 1). At the end of step 1, subjects with a CD4 T-cell count of > or =500 cells/mm or more stopped ART until a CD4 count of <350 cells/mm (step 2). CD4 T-cell count, time to return of viremia, and the emergence of drug resistance mutations after TI were compared between study arms. RESULTS: IL-2 recipients maintained higher CD4 counts during TI for 48 weeks with a waning of the CD4 effect by 72 weeks. A sustained CD4 T-cell count of more than 350 cells/mm and more durable TI were associated with a higher nadir CD4 T-cell count before ART and higher naive CD4 T-cell count at entry. After TI, a higher viral set point and drug resistance mutations at virologic rebound were associated with a shorter time to CD4 T-cell count of less than 350 cell/mm. There were no differences in the magnitude of virologic rebound (at week 8 of step 2, median log10 HIV RNA level was 4.23 for arm A and 4.21 for arm B) or the steady-state HIV-1 RNA level after week 8. CONCLUSIONS: IL-2 before TI did not prolong time to CD4 of less than 350 cells/mm. A TI strategy utilizing a CD4 T-cell threshold of less than 350 cells/mm for restarting ART appears generally safe with most subjects in both arms remaining off ART for more than 1 year. Implications of our results for TI strategies include the potential advantage of starting ART at higher CD4 T-cell levels while avoiding any drug resistance and evaluating immunomodulators or drugs to reduce T-cell activation and HIV-1 RNA rebound during the TI.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Contagem de Linfócito CD4 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Interleucina-2/administração & dosagem , Adulto , Fármacos Anti-HIV/uso terapêutico , Esquema de Medicação , Farmacorresistência Viral/genética , Feminino , Humanos , Interleucina-2/uso terapêutico , Masculino , Projetos Piloto , RNA Viral/sangue , Fatores de Tempo , ViremiaRESUMO
All genetic types of severe combined immunodeficiency (SCID) can be cured by stem cell transplantation from related donors. The survival rate approaches 80%, and most deaths result from opportunistic infections acquired before transplantation. It was hypothesized that the survival rate and kinetics of immune reconstitution would be improved for infants receiving transplants in the neonatal period (first 28 days of life), prior to the development of infections. A 19.2-year retrospective/prospective analysis compared immune function in 21 SCID infants receiving transplants in the neonatal period with that in 70 SCID infants receiving transplants later. Lymphocyte phenotypes, proliferative responses to mitogens, immunoglobulin levels, and T-cell antigen receptor excision circles (TRECs) were measured before transplantation and sequentially after transplantation. Of 21 SCID infants with transplantations in the neonatal period, 20 (95%) survive. Neonates were lymphopenic at birth (1118 +/- 128 lymphocytes per cubic millimeter). Infants receiving transplants early developed higher lymphocyte responses to phytohemagglutinin and higher numbers of CD3(+) and CD45RA(+) T cells in the first 3 years of life than those receiving transplants late (P <.05). TRECs peaked earlier and with higher values (P <.01) in the neonatal transplantations (181 days to 1 year) than in the late transplantations (1 to 3 years). SCID recipients of allogeneic, related hematopoietic stem cells in the neonatal period had higher levels of T-cell reconstitution and thymic output and a higher survival rate than those receiving transplants after 28 days of life. An improved outcome for this otherwise fatal syndrome could be achieved with newborn screening for lymphopenia so that transplantation could be performed under favorable thymopoietic conditions.
Assuntos
Transplante de Medula Óssea/mortalidade , Imunodeficiência Combinada Severa/terapia , Timo/fisiologia , Fatores Etários , Linfócitos B/imunologia , Transplante de Medula Óssea/imunologia , Doença Enxerto-Hospedeiro/imunologia , Humanos , Recém-Nascido , Ativação Linfocitária/efeitos dos fármacos , Contagem de Linfócitos , Fito-Hemaglutininas/farmacologia , Estudos Prospectivos , Estudos Retrospectivos , Imunodeficiência Combinada Severa/mortalidade , Taxa de Sobrevida , Linfócitos T/imunologia , Timo/imunologiaRESUMO
Purine nucleoside phosphorylase deficiency is a primary immunodeficiency syndrome characterized by the triad of recurrent infection, neurologic dysfunction, and autoimmunity. This patient presented atypically with few infections and normal T-cell function. Progressive lymphopenia, ataxia, and developmental delay led to diagnosis. Umbilical cord blood transplantation corrected the immunodeficiency.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Síndromes de Imunodeficiência/cirurgia , Purina-Núcleosídeo Fosforilase/deficiência , Deficiências do Desenvolvimento/enzimologia , Deficiências do Desenvolvimento/etiologia , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/enzimologia , Lactente , Linfopenia/enzimologia , Linfopenia/etiologia , MasculinoRESUMO
Chronic mucocutaneous candidiasis is a heterogeneous group of immunodeficiencies associated with persistent candidal infections. Patients with chronic mucocutaneous candidiasis are rarely associated with systemic infections caused by other fungi, but almost never by Candida. The authors report a case of a 16-year-old with chronic mucocutaneous candidiasis who developed a fungemia with Candida tropicalis.
Assuntos
Candida tropicalis , Candidíase Mucocutânea Crônica/complicações , Candidíase/microbiologia , Fungemia/microbiologia , Adolescente , Evolução Fatal , Feminino , Humanos , Hospedeiro ImunocomprometidoRESUMO
Six young patients with X-linked agammaglobulinemia and proven mutations in Btk were treated with cord blood or bone marrow transplants from HLA-matched siblings. Complete blood counts, serum chemistries, serum immunoglobulin concentrations, lymphocyte cell surface markers, and physical findings were evaluated at 3- to 5-day intervals for the first 2 weeks after transplant and then every 3 to 6 months. The first three patients were not given any preparative regimen or antirejection drugs and at 24 to 42 months posttransplant these patients have shown no benefit or harm related to the transplants. The second three patients were not given a preparative regimen but were treated with cyclosporine A (70 days) and mycophenolate mophetil (28 days) after transplant. Two of these patients have developed normal sized, nontender cervical lymph nodes 3 to 12 months after transplant but none of the three patients have shown an increase in serum IgM or an increase in the number of peripheral blood B cells. It is likely that successful engraftment will require more aggressive immunosupressive medications.