Biterapia con atazanavir/ritonavir más raltegravir versus terapia triple en segunda línea: Ensayo ARTE / ATV/r+RAL (DT) after failure with NNRTI

Antecedentes: La terapia dual ha surgido como un nuevo concepto para el tratamiento del VIH. Este estudio tenía como objetivo comparar un régimen dual basado en ATV/r + RAL (TD) frente a estándar de tres drogas con ATV/r + TDF/FTC (TT) luego del fracaso de un primer esquema ba-sado en INNTR.ClinicalTrials.gov, Número: NCT01829802.Método: Estudio piloto abierto, multicéntrico y aleatoriza-do. Resultado primario: proporción de sujetos con ARN del VIH-1 menor a 50 copias/mL en semana 48 (S48). Resulta-dos secundarios: discontinuaciones asociadas a eventos adversos (EA), tiempo transcurrido hasta la supresión viral, desarrollo de mutaciones de resistencia a la integrasa y proteasa, cambio en recuento de CD4. Resultados: De los 57 participantes seleccionados, 34 fue-ron asignados aleatoriamente para recibir: TD (n: 18) o TT (n: 16). En semana 48, 67% (n: 12/18) en TD tuvo respues-ta virológica y 88% (n: 14/16) en rama según el análisis FDA, intención de tratamiento/expuestos (p = NS) y 73% (TD) y 93% (TT) según análisis por protocolo (p = NS). El cambio de CD4 entre basal - S48: +119 y +52 células/µL en DT y TT, respectivamente. Cuatro participantes en TD y uno en TT presentaron fracaso virológico en la semana 48. Un participante desarrolló una mutación de resistencia a integrasa (155H).Conclusión: ATV/r+RAL como terapia dual de segunda línea mostró una tendencia al fracaso virológico más frecuente, en comparación con TT, aunque el estudio piloto no tenía potencia para demostrar esta diferencia. Este estudio está registrado en ClinicalTrials.gov, Número: NCT01829802

Background: Dual therapy has emerged as a novel concept for HIV treatment. This study was aimed at comparing a nucleoside-sparing dual regimen consisting of ATV/r + RAL (DT) vs standard therapy of ATV/r + TDF/FTC (TT) among individuals failing first NNRTI-containing treatment.Methods: Randomized multicenter open-label pilot study. Primary outcome: proportion of subjects with plasma HIV-1 RNA below the limit of detection (<50 copies/mL) at 48 weeks (W48). Secondary outcomes: proportion of discontinuation due to adverse events (AEs), time until viral suppression, time until loss of virological response, development of integrase resistance mutations, and absolute change in CD4 counts. The primary outcome was analyzed using the FDA snapshot analysis.Results: Out of 57 participants screened, 34 were randomized to receive: DT (n: 18) or TT (n: 16). At W48, virological response was achieved in 67% (n: 12/18) of participants receiving DT and 88% (n: 14/16) receiving TT by FDA snapshot analysis (p = NS) and 73% and 93% by per-protocol analysis (p = NS). CD4 cell count median change from baseline to W48 was +119 and + 52 cell/µL in DT and TT, respectively. Four participants receiving DT and one TT presented virological failure at W48, with low pVL. One participant developed an integrase resistance mutation (155H) and suppressed later on TT.Conclusion: ATV/r+RAL as second-line therapy showed a trend to more frequent virological failure, compared to TT, although the study was unpowered to prove this difference. No major differences were seen in tolerance or toxicity.This study is registered with ClinicalTrials.gov, Number: NCT01829802

Phenotype, Polyfunctionality, and Antiviral Activity of in vitro Stimulated CD8+ T-Cells From HIV+ Subjects Who Initiated cART at Different Time-Points After Acute Infection.

Since anti-HIV treatment cannot cure the infection, many strategies have been proposed to eradicate the viral reservoir, which still remains as a major challenge. The success of some of these strategies will rely on the ability of HIV-specific CD8+ T-cells (CD8TC) to clear reactivated infected cells. Here, we aimed to investigate the phenotype and function of in vitro expanded CD8TC obtained from HIV+ subjects on combination antiretroviral therapy (cART), either initiated earlier (median = 3 months postinfection, ET: Early treatment) or later (median = 20 months postinfection, DT: Delayed treatment) after infection. Peripheral blood mononuclear cells from 12 DT and 13 ET subjects were obtained and stimulated with Nef and Gag peptide pools plus IL-2 for 14 days. ELISPOT was performed pre- and post-expansion. CD8TC memory/effector phenotype, PD-1 expression, polyfunctionality (CD107a/b, IFN-γ, IL-2, CCL4 (MIP-1ß), and/or TNF-α production) and antiviral activity were evaluated post-expansion. Magnitude of ELISPOT responses increased after expansion by 103 times, in both groups. Expanded cells were highly polyfunctional, regardless of time of cART initiation. The memory/effector phenotype distribution was sharply skewed toward an effector phenotype after expansion in both groups although ET subjects showed significantly higher proportions of stem-cell and central memory CD8TCs. PD-1 expression was clustered in HIV-specific effector memory CD8TCs, subset that also showed the highest proportion of cytokine-producing cells. Moreover, PD-1 expression directly correlated with CD8TC functionality. Expanded CD8TCs from DT and ET subjects were highly capable of mediating antiviral activity, measured by two different assays. Antiviral function directly correlated with the proportion of fully differentiated effector cells (viral inhibition assay) as well as with CD8TC polyfunctionality and PD-1 expression (VITAL assay). In sum, we show that, despite being dampened in subjects on cART, the HIV-specific CD8TC response could be selectively stimulated and expanded in vitro, presenting a high proportion of cells able to carry-out multiple effector functions. Timing of cART initiation had an impact on the memory/effector differentiation phenotype, most likely reflecting how different periods of antigen persistence affected immune function. Overall, these results have important implications for the design and evaluation of strategies aimed at modulating CD8TCs to achieve the HIV functional cure.

Asociación entre la calidad de vida relacionada con la salud y riesgo suicida en adolescentes: estudio transversal / Association of health-related quality of life and suicidal risk in adolescents: a cross-sectional study

INTRODUCCIÓN: El deterioro de la calidad de vida relacionada con la salud (CVRS) es un factor de riesgo de suicido en adultos; no obstante, poco se ha estudiado esta dimensión en adolescentes. OBJETIVO: Evaluar la asociación entre calidad de vida relacionada con la salud, medido con el EQ-5D-5L, y riesgo suicida en adolescentes y su capacidad de detección transversal de riesgo suicida. PACIENTES Y MÉTODO: 128 jóvenes (15-19 años) de la comuna de Puerto Aysén (Chile) respondieron transversalmente el EQ-5D-5L, la escala de suicidalidad de Okasha y dos preguntas de anclaje de riesgo in minente de suicidio. Se consideró como caso de riesgo suicida a un puntaje > 5 en la escala Okasha o la respuesta afirmativa a una de las preguntas de anclaje. Se calculó el valor índice con los perfiles de salud del EQ-5D-5L. Se estimaron Odds Ratios (OR's) con intervalos de confianza (IC95%), ajustando por confusores y se calcularon áreas bajo la curva ROC (AUC-ROC) para evaluar la capacidad de pesquisa del EQ-5D-5L. RESULTADOS: 21 (16,4%) adolescentes fueron considerados como casos de riesgo suicida. Controlando por confusores, las dimensiones del EQ-5D-5L que se asociaron con riesgo suicida fueron: dolor/malestar (OR: 2,5; IC95% 1,1-6,1) y ansiedad/depresión (OR: 2,2; IC95% 1,3-3,6). El AUR-ROC para ambas dimensiones fue del 0,85% (IC95% 0,75-0,91) y de 0,81% para el valor del índice del EQ-5D-5L (IC95% 0,72-0,89). CONCLUSIONES: La CVRS podría ser un factor de riesgo de suicidio en adolescentes; y el EQ-5D-5L que mide esta dimensión, podría ayudar a pesquisar futuros casos y casos ocultos de riesgo suicida.

INTRODUCTION: Health-related quality of life (HRQoL) deterioraton is a risk factor for suicide in adults, however, this aspect has been little studied in adolescents. OBJECTIVE: To evaluate the asso ciation between HRQoL (measured with EQ-5D-5L) and suicidal risk in adolescents and its capacity for cross-sectional detection of suicidal risk. PATIENTS AND METHOD: 128 adolescents (15-19 years old) from Puerto Aysen (Chile) responded to the EQ-5D-5L questionnaire, the Okasha Suicide Scale and two anchoring questions of imminent suicide risk. A suicide risk case was considered to have a > 5 score on the Okasha scale or the affirmative answer to one of the anchoring questions. The index value of EQ-5D-5L was calculated and Odds Ratios (ORs) were estimated with confidence intervals (95% CI), adjusted for confounders. Areas under the ROC curve (AUC-ROC) were calculated to assess the discriminatory performance of EQ-5D-5L. RESULTS: 21 (16.4%) adolescents were at suicidal risk. Controlling for confounders, the EQ-5D-5L dimensions associated with suicidal risk were pain/ discomfort (OR: 2.5; 95% CI 1.1-6.1) and anxiety/depression (OR: 2.2; 95% CI 1.3-3.6). The AUC- ROC for both dimensions was 85% (95% CI 0.75-0.91) and 81% for the EQ-5D-5L index value (95% CI 0.72-0.89). CONCLUSIONS: HRQoL could be a risk factor for suicide in adolescents and in this way, the EQ-5D-5L could help in searching for high risk and hidden cases of suicidal risk.

[RADAR: a program for the prevention of suicide in adolescents in the region of Aysen, Chile, preliminary results]. / El programa RADAR para la prevención del suicidio en adolescentes de la región de Aysén, Chile: resultados preliminares.

OBJECTIVE: We present the preliminary results of the implementation of RADAR: a community suicide prevention program in adolescents implemented in two high schools in a south region of Chile. METHOD: In a pilot study, during 2016, we implemented RADAR in two high schools of Puerto Aysen, in in the Region of Aysen of Chile. A total of 409 actors were trained (among students, school teachers, caregivers and health professionals) for the screening and referral of high suicide risk adolescents. RESULTS: Out of a total of 144 students who passed the RADAR screening systems, 29 cases were detected as suicide risk (20%) and 27 of them were opportunely referred to the Emergency Service of the Hospital of Puerto Aysen. In the second RADAR screening campaign, 3 months later, 90% of the cases no longer presented suicide risk. CONCLUSION: These results show the high proportion of ado lescents at risk of suicide who are not visible by the health system and the feasibility of implementing RADAR in the community as an effective suicide prevention intervention.

El programa RADAR para la prevención del suicidio en adolescentes de la región de Aysén, Chile: resultados preliminares / RADAR: a program for the prevention of suicide in adolescents in the region of Aysen, Chile, preliminary results

OBJETIVO: Dar a conocer los resultados preliminares del programa comunitario RADAR (Red para la Atención y Derivación de Adolescentes en Riesgo suicida). MÉTODO: Durante el 2016, RADAR fue implementado como prueba de concepto en dos colegios de Puerto Aysén de la Región de Aysén, Chile. Se capacitó un total de 409 participantes (entre alumnos, profesores de los colegios, apoderados y profesionales de la salud) para la pesquisa y derivación de adolescentes en riego de suicidio. RESULTADOS: De un total de 144 alumnos que pasaron los sistemas de pesquisa de RADAR, se detectaron 29 casos en riesgo suicida (20%) y 27 fueron derivados oportunamente al Servicio de Urgencia del Hos pital de Puerto Aysén. En la segunda campaña de pesquisa de RADAR, 3 meses después, el 90% de los casos ya no presentaba riesgo suicida. CONCLUSIÓN: Estos resultados muestran la alta proporción de adolescentes en riesgo suicida que no son visibilizados por el sistema de salud y la factibilidad de implementar RADAR en la comunidad como una intervención preventiva efectiva.

OBJECTIVE: We present the preliminary results of the implementation of RADAR: a community suicide prevention program in adolescents implemented in two high schools in a south region of Chile. METHOD: In a pilot study, during 2016, we implemented RADAR in two high schools of Puerto Aysen, in in the Region of Aysen of Chile. A total of 409 actors were trained (among students, school teachers, caregivers and health professionals) for the screening and referral of high suicide risk adolescents. RESULTS: Out of a total of 144 students who passed the RADAR screening systems, 29 cases were detected as suicide risk (20%) and 27 of them were opportunely referred to the Emergency Service of the Hospital of Puerto Aysen. In the second RADAR screening campaign, 3 months later, 90% of the cases no longer presented suicide risk. CONCLUSION: These results show the high proportion of ado lescents at risk of suicide who are not visible by the health system and the feasibility of implementing RADAR in the community as an effective suicide prevention intervention.

Biomarkers of Progression after HIV Acute/Early Infection: Nothing Compares to CD4⁺ T-cell Count?

Progression of HIV infection is variable among individuals, and definition disease progression biomarkers is still needed. Here, we aimed to categorize the predictive potential of several variables using feature selection methods and decision trees. A total of seventy-five treatment-naïve subjects were enrolled during acute/early HIV infection. CD4⁺ T-cell counts (CD4TC) and viral load (VL) levels were determined at enrollment and for one year. Immune activation, HIV-specific immune response, Human Leukocyte Antigen (HLA) and C-C chemokine receptor type 5 (CCR5) genotypes, and plasma levels of 39 cytokines were determined. Data were analyzed by machine learning and non-parametric methods. Variable hierarchization was performed by Weka correlation-based feature selection and J48 decision tree. Plasma interleukin (IL)-10, interferon gamma-induced protein (IP)-10, soluble IL-2 receptor alpha (sIL-2Rα) and tumor necrosis factor alpha (TNF-α) levels correlated directly with baseline VL, whereas IL-2, TNF-α, fibroblast growth factor (FGF)-2 and macrophage inflammatory protein (MIP)-1ß correlated directly with CD4⁺ T-cell activation (p < 0.05). However, none of these cytokines had good predictive values to distinguish "progressors" from "non-progressors". Similarly, immune activation, HIV-specific immune responses and HLA/CCR5 genotypes had low discrimination power. Baseline CD4TC was the most potent discerning variable with a cut-off of 438 cells/µL (accuracy = 0.93, κ-Cohen = 0.85). Limited discerning power of the other factors might be related to frequency, variability and/or sampling time. Future studies based on decision trees to identify biomarkers of post-treatment control are warrantied.

Macrophage HIV-1 infection in duodenal tissue of patients on long term HAART.

Mucosal surfaces play a major role in human immunodeficiency virus type 1 (HIV-1) transmission and pathogenesis. Since the role of intestinal macrophages as viral reservoirs during chronic HIV-1 infection has not been elucidated, we investigated the effects of successful therapy on intestinal HIV-1 persistence. Intestinal macrophage infection was demonstrated by the expression of p24 antigen by flow cytometry and by the presence of proviral DNA, assessed by PCR. Proviral DNA was detected in duodenal mucosa of HIV-infected patients under treatment with undetectable plasma viral load. These findings confirm that intestinal macrophages can act as viral reservoirs and permit HIV-1 production even after viral suppression following antiretroviral therapy.

Bienestar psicológico y estrategias de afrontamiento en adolescentes escolarizados de Tucumán (13 y 14 años) / Psychological well-being and coping strategies in scholar adolescents of Tucumán (13 and 14 years old)

Se comunican resultados obtenidos a partir de una investigación sobre bienestar psicológico y estrategias de afrontamiento con estudiantes adolescentes de 13 y 14 años de S. M. de Tucumán. Se administraron las Escalas de Bienestar Psicológico (BIEPS) y Afrontamiento (ACS), ambas adaptación Casullo. Se trata de un estudio descriptivo-comparativo realizado en una muestra de 247 varones y mujeres. Se analizó la distribución de la muestra según el criterio de alto y bajo bienestar, se correlacionaron estos datos con las 18 estrategias de afrontamiento. Se evaluó la “Situación Problemática” (ACS-1ª Parte) y la “Preocupación Principal” (ACS-2ª Parte) y se realizó un análisis comparativo según género. Se fundamenta la importancia atribuida al tema por la íntima vinculación del concepto “bienestar psicológico” con el de salud integral y como un componente indispensable del desarrollo humano. La investigación realizada aporta datos empíricos para el diseño de programas de prevención con adolescentes no consultantes.