RESUMO
Objective: Secukinumab, a fully human monoclonal antibody that neutralizes interleukin-17A, improved the signs and symptoms of ankylosing spondylitis (AS) in three Phase 3 global studies (MEASURE 1, 2, and 3). Here, we describe the efficacy and safety results through Week 24 of a study of secukinumab in Japanese patients with active AS.Methods: In this multicenter, open-label, single arm, 52-week study, 30 AS patients self-administered secukinumab 150 mg subcutaneously at baseline, Weeks 1, 2, 3, and 4, and every 4 weeks thereafter. The primary efficacy endpoint was ASAS 20 response at Week 16. Overall safety and tolerability were assessed beyond Week 24 up to the data reporting cut-off date.Results: The ASAS 20 response rate was 70% (21/30) at Week 16, which was sustained to Week 24. Secukinumab was effective in various clinical outcomes including patient's global assessment of disease activity, spinal pain, nocturnal pain, physical function, spinal mobility, and CRP level. Comparable ASAS 20 and 40 responses were observed regardless of previous anti-TNF therapy. Secukinumab was well-tolerated with a safety profile consistent with previous reports.Conclusion: Secukinumab 150 mg provided sustained improvement in the signs and symptoms of Japanese AS patients through 24 weeks, with no new or unexpected safety signals.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Espondilite Anquilosante/tratamento farmacológico , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Injeções Subcutâneas , Japão , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Espondilite Anquilosante/diagnóstico , Fatores de Tempo , Resultado do TratamentoRESUMO
Idiopathic CD4 lymphopenia (ICL) is a rare syndrome defined by low CD4 T-cell counts (<300/µL) without evidence of HIV infection or other known cause of immunodeficiency. ICL confers an increased risk of opportunistic infections and has no established treatment. Interleukin-7 (IL-7) is fundamental for thymopoiesis, T-cell homeostasis, and survival of mature T cells, which provides a rationale for its potential use as an immunotherapeutic agent for ICL. We performed an open-label phase 1/2A dose-escalation trial of 3 subcutaneous doses of recombinant human IL-7 (rhIL-7) per week in patients with ICL who were at risk of disease progression. The primary objectives of the study were to assess safety and the immunomodulatory effects of rhIL-7 in ICL patients. Injection site reactions were the most frequently reported adverse events. One patient experienced a hypersensitivity reaction and developed non-neutralizing anti-IL-7 antibodies. Patients with autoimmune diseases that required systemic therapy at screening were excluded from the study; however, 1 participant developed systemic lupus erythematosus while on study and was excluded from further rhIL-7 dosing. Quantitatively, rhIL-7 led to an increase in the number of circulating CD4 and CD8 T cells and tissue-resident CD3 T cells in the gut mucosa and bone marrow. Functionally, these T cells were capable of producing cytokines after mitogenic stimulation. rhIL-7 was well tolerated at biologically active doses and may represent a promising therapeutic intervention in ICL. This trial was registered at www.clinicaltrials.gov as #NCT00839436.
Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Interleucina-7/administração & dosagem , T-Linfocitopenia Idiopática CD4-Positiva/tratamento farmacológico , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Imunofenotipagem , Interleucina-7/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Adulto JovemRESUMO
Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14(++)CD16(-) monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment.
Assuntos
Antígenos de Bactérias/imunologia , Síndrome Inflamatória da Reconstituição Imune/imunologia , Receptores de Lipopolissacarídeos/imunologia , Monócitos/imunologia , Receptores de IgG/imunologia , Tuberculose/imunologia , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Biomarcadores/sangue , Feminino , Proteínas Ligadas por GPI/imunologia , Humanos , Síndrome Inflamatória da Reconstituição Imune/genética , Masculino , Tuberculose/tratamento farmacológico , Tuberculose/genéticaRESUMO
IL-7 is essential for T-cell homeostasis. Elevated serum IL-7 levels in lymphopenic states, including HIV infection, are thought to be due to increased production by homeostatic feedback, decreased receptor-mediated clearance, or both. The goal of this study was to understand how immune reconstitution through antiretroviral therapy (ART) in HIV(+) patients affects IL-7 serum levels, expression of the IL-7 receptor (CD127), and T-cell cycling. Immunophenotypic analysis of T cells from 29 HIV(-) controls and 43 untreated HIV(+) patients (30 of whom were followed longitudinally for ≤ 24 months on ART) was performed. Restoration of both CD4(+) and CD8(+) T cells was driven by increases in CD127(+) naive and central memory T cells. CD4(+) T-cell subsets were not fully restored after 2 years of ART, whereas serum IL-7 levels normalized by 1 year of ART. Mathematical modeling indicated that changes in serum IL-7 levels could be accounted for by changes in the receptor concentration. These data suggest that T-cell restoration after ART in HIV infection is driven predominantly by CD127(+) cells and that decreases of serum IL-7 can be largely explained by improved CD127-mediated clearance.
Assuntos
Antirretrovirais/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Infecções por HIV/sangue , Interleucina-7/sangue , Receptores de Interleucina-7/biossíntese , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , Humanos , Imunofenotipagem , Interleucina-7/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Receptores de Interleucina-7/sangue , Receptores de Interleucina-7/imunologia , Subpopulações de Linfócitos T/imunologia , Carga Viral/efeitos dos fármacosRESUMO
Immune reconstitution inflammatory syndrome (IRIS) is a considerable problem in the treatment of HIV-infected patients. To identify immunologic correlates of IRIS, we characterized T-cell phenotypic markers and serum cytokine levels in HIV patients with a range of different AIDS-defining illnesses, before and at regular time points after initiation of antiretroviral therapy. Patients developing IRIS episodes displayed higher frequencies of effector memory, PD-1(+), HLA-DR(+), and Ki67(+) CD4(+) T cells than patients without IRIS. Moreover, PD-1(+) CD4(+) T cells in IRIS patients expressed increased levels of LAG-3, CTLA-4, and ICOS and had a Th1/Th17 skewed cytokine profile upon polyclonal stimulation. Elevated PD-1 and Ki67 expression was also seen in regulatory T cells of IRIS patients. Furthermore, IRIS patients displayed higher serum interferon-γ, compared with non-IRIS patients, near the time of their IRIS events and higher serum interleukin-7 levels, suggesting that the T-cell populations are also exposed to augmented homeostatic signals. In conclusion, our findings indicate that IRIS appears to be a predominantly CD4-mediated phenomenon with reconstituting effector and regulatory T cells showing evidence of increased activation from antigenic exposure. These studies are registered online at http://clinicaltrials.gov as NCT00557570 and NCT00286767.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Síndrome Inflamatória da Reconstituição Imune/etiologia , Síndrome Inflamatória da Reconstituição Imune/imunologia , Antígenos CD/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Estudos de Casos e Controles , Citocinas/sangue , HIV-1 , Humanos , Memória Imunológica , Ativação Linfocitária , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos , Subpopulações de Linfócitos T/imunologiaRESUMO
Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a clinical aggravation of TB symptoms observed among a fraction of HIV coinfected patients shortly after the start of antiretroviral therapy (ART). Of note, TB-IRIS is characterized by exacerbated inflammation and tissue damage that occurs in response to the elevated production of CD4+ T cell-derived IFN-γ. Nevertheless, the possible participation of CD8+ T cells in TB-IRIS development remains unclear. Methods: We performed a comprehensive assessment of the composition of CD8+ T cell memory subsets and their association with circulating inflammation-related molecules in TB-HIV coinfected patients initiating ART. Results: We found that TB-IRIS individuals display higher frequencies of Antigen-experienced CD8+ T cells during the onset of IRIS and that the levels of these cells positively correlate with baseline mycobacterial smear grade. TB-IRIS individuals exhibited higher frequencies of effector memory and lower percentages of naïve CD8+ T cells than their Non-IRIS counterparts. In both TB-IRIS and Non-IRIS patients, ART commencement was associated with fewer significant correlations among memory CD8+ T cells and cells from other immune compartments. Networks analysis revealed distinct patterns of correlation between each memory subset with inflammatory cytokines suggesting different dynamics of CD8+ T cell memory subsets reconstitution. TB-IRIS patients displayed lower levels of memory cells positive for CXCR3 (a chemokine receptor that plays a role in trafficking activated CD8+ T cells to the tissues) than Non-IRIS individuals before and after ART. Furthermore, we found that CXCR3+ naïve CD8+ T cells were inversely associated with the risk of TB-IRIS development. On the other hand, we noticed that the frequencies of CXCR3+ effector CD8+ T cells were positively associated with the probability of TB-IRIS development. Conclusion: Our data suggest that TB-IRIS individuals display a distinct profile of memory CD8+ T cell subsets reconstitution after ART initiation. Moreover, our data point to a differential association between the frequencies of CXCR3+ CD8+ T cells and the risk of TB-IRIS development. Collectively, our findings lend insights into the potential role of memory CD8+ T cells in TB-IRIS pathophysiology.
Assuntos
Infecções por HIV , Síndrome Inflamatória da Reconstituição Imune , Tuberculose , Linfócitos T CD8-Positivos , Humanos , Inflamação/complicações , Receptores CXCR3 , Subpopulações de Linfócitos TRESUMO
OBJECTIVE: To report the primary (1-year) results from PREVENT, the first phase III study evaluating secukinumab in patients with active nonradiographic axial spondyloarthritis (SpA). METHODS: A total of 555 patients were randomized (1:1:1) to receive subcutaneous secukinumab 150 mg with a loading dose (loading dose [LD] group), secukinumab 150 mg without a loading dose (non-loading dose [NL] group), or placebo weekly and then every 4 weeks starting at week 4. The NL group received placebo at weeks 1, 2, and 3 to maintain blinding. Switch to open-label secukinumab or standard of care was permitted after week 20. The study had 2 independent analysis plans, per European Union and non-US (plan A; week 16) and US (plan B; week 52) regulatory requirements. The primary end point was 40% improvement in disease activity according to the Assessment of SpondyloArthritis international Society (ASAS40) criteria at week 16 (in the LD group) and at week 52 (in the NL group) in tumor necrosis factor inhibitor (TNFi)-naive patients. Safety analyses included all patients who received ≥1 dose of study treatment. RESULTS: Overall, 481 patients completed 52 weeks of treatment, including 84.3% (156 of 185) in the LD group, 89.7% (165 of 184) in the NL group, and 86.0% (160 of 186) in the placebo group. The proportion of patients who switched to open-label or standard of care between weeks 20 and 48 was 50.8% in the LD group, 47.3% in the NL group, and 64.0% in the placebo group. Both primary and all secondary end points were met at week 16. The proportion of TNFi-naive patients who met ASAS40 was significantly higher for LD at week 16 (41.5%) and NL at week 52 (39.8%) versus placebo (29.2% at week 16 and 19.9% at week 52; both P < 0.05). No new safety findings were reported. CONCLUSION: Our findings indicate that secukinumab 150 mg provides significant and sustained improvement in signs and symptoms of nonradiographic axial SpA through 52 weeks. Safety was consistent with previous reports.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Espondiloartropatias/tratamento farmacológico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Most persons living with HIV (PLWH) experience a significant restoration of their immunity associated with successful inhibition of viral replication after antiretroviral therapy (ART) initiation. Nevertheless, with the robust quantitative and qualitative restoration of CD4+ T-lymphocytes, a fraction of patients co-infected with tuberculosis develop immune reconstitution inflammatory syndrome (TB-IRIS), a dysregulated inflammatory response that can be associated with significant tissue damage. Several studies underscored the role of adaptive immune cells in IRIS pathogenesis, but to what degree T lymphocyte activation contributes to TB-IRIS development remains largely elusive. Here, we sought to dissect the phenotypic landscape of T lymphocyte activation in PLWH coinfected with TB inititating ART, focusing on characterization of the profiles linked to development of TB-IRIS. We confirmed previous observations demonstrating that TB-IRIS individuals display pronounced CD4+ lymphopenia prior to ART initiation. Additionally, we found an ART-induced increase in T lymphocyte activation, proliferation and cytotoxicity among TB-IRIS patients. Importantly, we demonstrate that TB-IRIS subjects display higher frequencies of cytotoxic CD8+ T lymphocytes which is not affected by ART. Moreover, These patients exhibit higher levels of activated (HLA-DR+) and profilerative (Ki-67+) CD4+ T cells after ART commencenment than their Non-IRIS counterparts. Our network analysis reveal significant negative correlations between Total CD4+ T cells counts and the frequencies of Cytotoxic CD8+ T cells in our study population which could suggest the existance of compensatory mechanisms for Mtb-infected cells elimination in the face of severe CD4+ T cell lymphopenia. We also investigated the correlation between T lymphocyte activation profiles and the abundance of several inflammatory molecules in plasma. We applied unsupervised machine learning techniques to predict and diagnose TB-IRIS before and during ART. Our analyses suggest that CD4+ T cell activation markers are good TB-IRIS predictors, whereas the combination of CD4+ and CD8+ T cells markers are better at diagnosing TB-IRIS patients during IRIS events Overall, our findings contribute to a more refined understanding of immunological mechanisms in TB-IRIS pathogenesis that may assist in new diagnostic tools and more targeted patient management.
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome Inflamatória da Reconstituição Imune/imunologia , Ativação Linfocitária , Subpopulações de Linfócitos T/imunologia , Tuberculose/imunologia , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Biomarcadores , Relação CD4-CD8 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citotoxicidade Imunológica , Humanos , Síndrome Inflamatória da Reconstituição Imune/sangue , Síndrome Inflamatória da Reconstituição Imune/etiologia , Imunofenotipagem , Linfopenia/etiologia , Linfopenia/imunologia , Mycobacterium tuberculosis/imunologia , Estudos Observacionais como Assunto/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Estudos Retrospectivos , Tuberculose/complicaçõesRESUMO
BACKGROUND: To investigate the efficacy of secukinumab in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) grouped by disease activity as assessed by C-reactive protein (CRP) levels and/or magnetic resonance imaging (MRI) scores, human leukocyte antigen (HLA)-B27 status, and sex. METHODS: The phase III PREVENT study randomized (1:1:1) 555 patients to receive subcutaneous secukinumab 150 mg with (LD) or without (NL) loading dose or placebo weekly, followed by every 4 weeks starting at week 4. Here, we report the results of a post hoc analysis reporting the efficacy outcomes (pooled secukinumab) to 16 weeks by CRP, MRI, HLA-B27, and sex. RESULTS: Efficacy differences between the secukinumab and the placebo groups were highest in the CRP+, MRI+, HLA-B27+, and male subgroups, particularly for Ankylosing Spondylitis Disease Activity Score-CRP inactive disease and Assessment of SpondyloArthritis international Society (ASAS) partial remission outcomes. ASAS40 response rates in the CRP+/MRI+ subgroup was 52.3% (secukinumab) versus 21.8% (placebo; P < 0.0001) at week 16. ASAS40 response rates (secukinumab versus placebo) were 43.9% versus 32.6% in HLA-B27+, 32.7% versus 16.4% in HLA-B27- subgroups, 51.2% versus 30.8% in male, and 31.7% versus 25.3% in female patients, respectively. CONCLUSIONS: Secukinumab improved the signs and symptoms of nr-axSpA across patients grouped by CRP (+/-) and/or MRI (+/-) status, HLA-B27 (+/-) status, and sex. The highest treatment differences between secukinumab and placebo were observed in patients with both elevated CRP and evidence of sacroiliitis on MRI. Treatment difference was minimal between HLA-B27 (+) and (-) subgroups. Male patients had higher relative responses than female patients. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02696031 . Registered on 02 March 2016.
Assuntos
Espondilartrite , Espondilite Anquilosante , Anticorpos Monoclonais Humanizados , Feminino , Antígeno HLA-B27 , Humanos , Masculino , Espondilartrite/diagnóstico por imagem , Espondilartrite/tratamento farmacológico , Espondilite Anquilosante/diagnóstico por imagem , Espondilite Anquilosante/tratamento farmacológico , Resultado do TratamentoRESUMO
Biomarkers could be useful in evaluating immune reconstitution inflammatory syndrome (IRIS). A cohort of 45 HIV-1-infected, antiretroviral treatment (ART)-naive patients with baseline CD4 T cell counts Assuntos
Antirretrovirais/uso terapêutico
, Proteína C-Reativa/metabolismo
, Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo
, Infecções por HIV/sangue
, Infecções por HIV/tratamento farmacológico
, Síndrome Inflamatória da Reconstituição Imune/sangue
, Síndrome Inflamatória da Reconstituição Imune/epidemiologia
, Infecções Oportunistas Relacionadas com a AIDS/complicações
, Infecções Oportunistas Relacionadas com a AIDS/imunologia
, Adulto
, Autoanticorpos/sangue
, Autoanticorpos/imunologia
, Biomarcadores/sangue
, Contagem de Linfócito CD4
, Feminino
, HIV-1/isolamento & purificação
, Antígenos HLA-A/genética
, Humanos
, Síndrome Inflamatória da Reconstituição Imune/diagnóstico
, Síndrome Inflamatória da Reconstituição Imune/etiologia
, Contagem de Leucócitos
, Masculino
, Pessoa de Meia-Idade
, Estudos Retrospectivos
, Fatores de Risco
RESUMO
OBJECTIVE: Secukinumab 150 mg has demonstrated significant improvement in signs and symptoms of ankylosing spondylitis (AS), with response rates sustained for up to 5 years. Here, we report end-of-study 3-year efficacy and safety results of secukinumab 150 and 300 mg from the MEASURE 3 study. METHODS: A total of 226 patients was randomized to intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous (s.c.) secukinumab 300/150 mg every 4 weeks or a matched placebo. At week 16, placebo patients were re-randomized to s.c. secukinumab 300/150 mg. Analysis at week 156 included patients initially randomized to secukinumab and those who switched from placebo to secukinumab at week 16 (any secukinumab 300/150 mg). Outcome measures at week 156 included Assessment of Spondyloarthritis International Society (ASAS) 20/40, Bath Ankylosing Spondylitis Disease Activity Index, ASAS partial remission (PR), ASAS 5/6, and Ankylosing Spondylitis Disease Activity Score-C-reactive protein inactive disease. RESULTS: The retention rates from weeks 16 to 156 were 80.5% and 80.9% in secukinumab 300 and 150 mg, respectively. ASAS 20/40 response rates at week 156 were 75.0%/56.5% and 68.2%/47.7% for secukinumab 300 and 150 mg, respectively. At week 156, response rates on more stringent clinical end points (eg, ASAS 40, ASAS-PR) were higher with the 300-mg dose, particularly in tumor necrosis factor (TNF)-inadequate responder (IR) patients. No new safety findings were observed. CONCLUSION: Secukinumab (300 and 150 mg) provided sustained improvements through 3 years in the signs and symptoms of active AS. Improvements with secukinumab 300 mg were numerically higher compared with the 150-mg dose for some higher hurdle end points and in TNF-IR patients. The safety profile of secukinumab was consistent with previous reports.
RESUMO
Immune reconstitution inflammatory syndrome (IRIS) occurs in up to 40% of individuals co-infected with pulmonary tuberculosis (PTB) and HIV, primarily upon antiretroviral therapy (ART) initiation. Phenotypic changes in T-cells during TB-IRIS and their relationship with systemic inflammation are not fully understood. In this prospective cohort study, we followed 48 HIV-positive patients with PTB from South India before and after ART initiation, examining T-lymphocyte subsets and inflammatory biomarkers in peripheral blood. Quantification of naïve (CD27+CD45RO-) as well as effector memory CD4+ T cells (CD27-CD45RO+) at weeks 2-6 after ART initiation could distinguish TB-IRIS from non-IRIS individuals. Additional analyses revealed that ART reconstituted different quantities of CD4+ T lymphocyte subsets with preferential expansion of CXCR3+ CCR6- cells in TB-IRIS patients. Moreover, there was an expansion and functional restoration of central memory (CD27+CD45RO+) CXCR3+CCR6- CD4+ lymphocytes and corresponding cytokines, with reduction in CXCR3-CCR6+ cells after ART initiation only in those who developed TB-IRIS. Together, these observations trace a detailed picture of CD4+ T cell subsets tightly associated with IRIS, which may serve as targets for prophylactic and/or therapeutic interventions in the future.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Síndrome Inflamatória da Reconstituição Imune/imunologia , Receptores CCR6/imunologia , Receptores CXCR3/biossíntese , Receptores CXCR3/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Idoso , Antirretrovirais/administração & dosagem , Antirretrovirais/efeitos adversos , Antirretrovirais/imunologia , Linfócitos T CD4-Positivos/metabolismo , Estudos de Coortes , Coinfecção/imunologia , Coinfecção/parasitologia , Coinfecção/virologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/parasitologia , Humanos , Síndrome Inflamatória da Reconstituição Imune/induzido quimicamente , Memória Imunológica/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores CCR6/biossíntese , Receptores CCR6/genética , Receptores CXCR3/genética , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/virologiaRESUMO
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
RESUMO
PURPOSE: This study aimed to determine whether a blended Infant Massage-Parenting Enhancement Program (IMPEP) improved maternal psychosocial health outcomes (parenting stress, depressive symptoms, self-esteem, maternal attachment) and maternal-infant interaction among substance-addicted mothers (SAMs) actively engaged in outpatient rehabilitation. METHODS: Designed as a randomized, three-group controlled trial testing two levels of psychoeducational intervention (IMPEP vs. PEP) and a control group (standard care parenting resources), the study was conducted in two substance abuse centers in southeast Florida on a convenience sample of 138 recovering SAM-infant pairs. IMPEP or PEP classes were held weekly on Weeks 2-5, with data collected at baseline (Week 1), Week 6, and Week 12 via structured interviews, observation (Observation Checklist on Maternal-Infant Interaction), and self-administered questionnaires (Abidin Parenting Stress Index, Beck Depression Inventory, Rosenberg Self-Esteem Scale, Muller's Maternal Attachment Inventory), analyzed descriptively and inferentially using Kruskall-Wallis analysis of variance and post hoc Wilcoxon rank sum and Mann-Whitney U tests. RESULTS: Both IMPEP and PEP groups had significantly increased Parenting Stress Index scores (decreased parenting stress) and decreased Beck Depression Inventory scores (decreased depressive symptoms) compared to controls at Week 12, whereas there were no clinically meaningful differences among study groups in Rosenberg Self-Esteem Scale, Muller's Maternal Attachment Inventory, or Observation Checklist on Maternal-Infant Interaction scores. Only the IMPEP group showed significant improvements in both psychological and physical (waist-hip ratio) measures of parenting stress over time. CONCLUSIONS: The findings suggest that infant massage blended into a structured parenting program has value-added effects in decreasing parenting stress and maternal depressive symptoms, but not on SAM's self-esteem, attachment, or maternal-infant interaction.
Assuntos
Transtorno Depressivo/prevenção & controle , Comportamento Materno/psicologia , Relações Mãe-Filho/psicologia , Mães/educação , Mães/psicologia , Poder Familiar/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto , Feminino , Florida , Humanos , Lactente , Recém-Nascido , Masculino , Massagem , Avaliação de Programas e Projetos de Saúde , Autoimagem , Estresse Psicológico , Transtornos Relacionados ao Uso de Substâncias/reabilitação , Adulto JovemRESUMO
Interventions that build upon the natural components of early mother-infant interactions are critical to reversing the sequelae of maternal substance abuse and breaking the cycle of addiction. This paper proposes a theoretical model that blends infant massage (IM) into a planned parenting enhancement program (PEP) to promote improved health outcomes in recovering substance- abusing mothers (SAMs) and their babies. With 4.6 million women of child-bearing age regularly using cocaine in the United States and 750,000 drug-exposed births annually, maternal substance abuse highlights the multigenerational impact of drug use in high-risk populations and its risks to our children. The proposed IMPEP model provides a means to assist recovering SAMs in making cognitive-behavioral changes through new knowledge about parenting and parenting skills, with a special focus on infant stimulation via massage. The goal is to enable recovering SAMs to become confident and responsive mothers, empowering them to become effective parents. Pilot data suggest the Infant Massage Parenting Enhancement Program (IMPEP) is effective for both mother and infant, and merits a controlled systematic study.
Assuntos
Massagem/educação , Relações Mãe-Filho , Mães/educação , Poder Familiar , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Convalescença , Currículo , Estudos de Viabilidade , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Promoção da Saúde , Humanos , Lactente , Comportamento do Lactente , Cuidado do Lactente/métodos , Cuidado do Lactente/psicologia , Modelos de Enfermagem , Modelos Psicológicos , Mães/psicologia , Pesquisa em Avaliação de Enfermagem , Apego ao Objeto , Poder Familiar/psicologia , Enfermagem Pediátrica , Projetos Piloto , Avaliação de Programas e Projetos de Saúde , Psicologia da Criança , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: Immune restoration disease (IRD) can develop in HIV-infected patients following antiretroviral therapy (ART) initiation as unmasking or paradoxical worsening of opportunistic infections and, rarely, autoimmune phenomena. Although IRD usually occurs in the first months of ART during memory CD4 T-cell recovery, Graves' disease occurs as a distinctive late-onset IRD and its pathogenesis is unclear. DESIGN: Seven patients who developed Graves' disease following ART initiation from the primary HIV care clinic at the National Institutes of Health were retrospectively identified and each was matched with two HIV-infected controls based on age, sex, and baseline CD4 T-cell count. Laboratory evaluations on stored cryopreserved samples were performed. METHODS: Immunophenotyping of peripheral blood mononuclear cells (PBMCs), T-cell receptor excision circle (TREC) analysis in PBMCs, measurement of serum cytokines, and luciferase immunoprecipitation systems (LIPS) analysis for autoimmune antibodies were performed on stored samples for cases and controls at baseline and longitudinally following ART initiation. TSH/thyrotropin receptor (TSH-R) antibody testing was performed on serum from cases. Data were analyzed using nonparametric testing. RESULTS: In comparison with controls, the proportion of naive CD4 T cells increased significantly (Pâ=â0.0027) in the Graves' disease-IRD patients. TREC/10 PBMCs also increased significantly following ART in Graves' disease-IRD patients compared with controls (Pâ=â0.0071). Similarly, LIPS analysis demonstrated increases in nonthyroid-related autoantibody titers over time following ART in cases compared with controls. CONCLUSION: Our data suggest that Graves' disease-IRD, in contrast to early-onset IRD, is associated with naive and primary thymic emigrant CD4 T-cell recovery and inappropriate autoantibody production.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Doença de Graves/imunologia , Infecções por HIV/complicações , Síndrome Inflamatória da Reconstituição Imune/imunologia , Adulto , Antirretrovirais/uso terapêutico , Autoanticorpos/sangue , Estudos de Casos e Controles , Citocinas/sangue , Doença de Graves/patologia , Infecções por HIV/tratamento farmacológico , Humanos , Síndrome Inflamatória da Reconstituição Imune/patologia , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: The incidence, manifestations, outcome and clinical predictors of paradoxical TB-IRIS in patients with HIV and culture confirmed pulmonary tuberculosis (PTB) in India have not been studied prospectively. METHODS: HIV+ patients with culture confirmed PTB started on anti-tuberculosis therapy (ATT) were followed prospectively after anti-retroviral therapy (ART) initiation. Established criteria for IRIS diagnosis were used including decline in plasma HIV RNA at IRIS event. Pre-ART plasma levels of interleukin (IL)-6 and C-reactive protein (CRP) were measured. Univariate and multivariate logistic regression models were used to evaluate associations between baseline variables and IRIS. RESULTS: Of 57 patients enrolled, 48 had complete follow up data. Median ATT-ART interval was 28 days (interquartile range, IQR 14-47). IRIS events occurred in 26 patients (54.2%) at a median of 11 days (IQR: 7-16) after ART initiation. Corticosteroids were required for treatment of most IRIS events that resolved within a median of 13 days (IQR: 9-23). Two patients died due to CNS TB-IRIS. Lower CD4(+) T-cell counts, higher plasma HIV RNA levels, lower CD4/CD8 ratio, lower hemoglobin, shorter ATT to ART interval, extra-pulmonary or miliary TB and higher plasma IL-6 and CRP levels at baseline were associated with paradoxical TB-IRIS in the univariate analysis. Shorter ATT to ART interval, lower hemoglobin and higher IL-6 and CRP levels remained significant in the multivariate analysis. CONCLUSION: Paradoxical TB-IRIS frequently complicates HIV-TB therapy in India. IL-6 and CRP may assist in predicting IRIS events and serve as potential targets for immune interventions.
Assuntos
Infecções por HIV/complicações , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Síndrome Inflamatória da Reconstituição Imune/epidemiologia , Síndrome Inflamatória da Reconstituição Imune/etiologia , Interleucina-6 , Tuberculose Pulmonar/complicações , Proteína C-Reativa/análise , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Incidência , Índia/epidemiologia , Interleucina-6/sangue , Modelos Logísticos , Estudos Prospectivos , Estatísticas não Paramétricas , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/epidemiologiaRESUMO
OBJECTIVE: HIV infection is associated with coagulation abnormalities and significantly increased risk of venous thrombosis. It has been shown that higher plasma levels of coagulation and inflammatory biomarkers predicted mortality in HIV. We investigated the relationship between venous thrombosis and HIV-related characteristics, traditional risk factors of hypercoagulability, and pre-event levels of biomarkers. DESIGN: A retrospective case-control study of 23 HIV-infected individuals who experienced an incident venous thromboembolic event while enrolled in National Institutes of Health studies from 1995 to 2010 and 69 age-matched and sex-matched HIV-infected individuals without known venous thromboembolism (VTE). METHODS: Biomarkers of inflammation, endothelial dysfunction, coagulation, tissue fibrosis, and cytomegalovirus (CMV) reactivation were assessed by ELISA-based assays and PCR using plasma obtained prior to the event. RESULTS: VTE events were related to nadir CD4 cell count, lifetime history of multiple opportunistic infections, CMV disease, CMV viremia, immunological AIDS, active infection, and provocation (i.e., recent hospitalization, surgery, or trauma). VTE events were independently associated with increased plasma levels of P-selectin (P = 0.002), D-dimer (P = 0.01), and hyaluronic acid (P = 0.009) in a multivariate analysis. No significant differences in antiretroviral or interleukin-2 exposures, plasma HIV viremia, or other traditional risk factors were observed. CONCLUSION: Severe immunodeficiency, active infection, and provocation are associated with venous thromboembolic disease in HIV. Biomarkers of endothelial dysfunction, coagulation, and tissue fibrosis may help identify HIV-infected patients at elevated risk of VTE.