Unraveling HIV-1 diagnosis in special pediatric cases.

BACKGROUND: Early HIV-1 diagnosis and initiation of antiretroviral treatment is essential to prevent AIDS, and reduce mortality in children. HIV-1 molecular diagnosis in children before 18 months of age require, two independent samples to confirm a result. However, some patients have discordant virologic results in different samples, raising uncertainty for a conclusive diagnosis. We defined these patients as "special pediatric cases". OBJECTIVES: The aim of our study was to characterize the "special pediatric cases" among HIV-1 infected children diagnosed in a five-year period at our laboratory and evaluate the impact on the time to HIV-1 diagnosis. STUDY DESIGN: A total of 44 perinatally HIV-1 infected infants with molecular diagnostic performed at the Pediatric Garrahan Hospital were analyzed from 2013 to 2017. RESULTS: We identified eight "special pediatric cases". In the first samples, all of them had negative results by different DNA-PCR assays. Three infants had undetectable plasma viral load (pVL), four had low detectable pVL value, and one infant had no available pVL. All samples with detectable pVL, including those with low pVL (ie: 65copies/mL), had high pVL values at the end of the diagnosis. Considering the age of the HIV-1 infected children at the end of the diagnosis, five "special pediatric cases" (62 %) had a "late" positive diagnosis [mean (range) = 146 (89-268) days old]. CONCLUSIONS: These "special pediatric cases" are not as unusual as previously thought and are important diagnostic challenges. Also, this study add evidence to include the viral load assay in the molecular diagnostic algorithm for perinatal HIV-1 infection.

Pre-treatment drug resistance and HIV-1 subtypes in infants from Argentina with and without exposure to antiretroviral drugs for prevention of mother-to-child transmission.

OBJECTIVES: To assess the prevalence and patterns of pre-treatment HIV drug resistance (PDR) and HIV-1 subtype in infants from Argentina with exposure to different antiretroviral drugs (ARVs) for the prevention of mother-to-child transmission (PMTCT). PATIENTS AND METHODS: HIV-1 genotyping was performed in 115 infants (median age = 2.3 months) born between 2007 and 2014 to screen for drug resistance mutations (DRMs) before starting first-line ART. HIV-1 subtype was characterized by phylogenetic and recombination analysis. RESULTS: Overall, DRMs were found in 34 of 115 infants (PDR level 30% to any ARV, 3.5% to PIs, 12% to NRTIs and 22% to NNRTIs). Of the 115 infants, 22 (19.1%) were ARV-unexposed. Another 93 were ARV-exposed: 28 (24.3%) to short-course zidovudine monotherapy ARV prophylaxis; 25 (21.7%) to nevirapine-based ARV prophylaxis; 12 (10.4%) to perinatal infant zidovudine prophylaxis + maternal combination ART with NNRTIs; and 28 (24.3%) to perinatal infant zidovudine prophylaxis+maternal combination ART with PIs. Transmitted drug resistance among ARV-unexposed infants was 32% (5% to PIs, 9% to NRTIs and 18% to NNRTIs). ART-exposed infants showed multi-class ARV resistance. Importantly, vertical transmission of a triple-class-resistant virus was confirmed in one case. Patterns of DRMs predicted high-level resistance to NNRTIs in a similar and high proportion (>50%) of infants with at least one DRM independently of ARV exposure. BF recombinants were found in 74%, subtype B in 20%, subtype C in 3% and novel AG and AB recombinants in 3%. CONCLUSIONS: PDR in HIV-1-infected children from Argentina is among the highest reported, jeopardizing successful lifelong suppressive ART as well as the efficacy of current PMTCT regimens.

Impact of the time to achieve viral control on the dynamics of circulating HIV-1 reservoir in vertically infected children with long-term sustained virological suppression: A longitudinal study.

OBJECTIVE: Determine the decay rate of HIV-1 DNA reservoir in vertically infected children during sustained viral suppression (VS) and how it is affected by the age at VS. METHODS: This study included 37 HIV-1 vertically infected children on suppressive antiretroviral therapy for at least 4 years. Children were grouped according to the age of antiretroviral therapy initiation (≤0.5 or >0.5 yrs) and to the age at VS (≤1.5, between >1.5 and 4, and >4 years). Decay of cell-associated HIV-1 DNA (CA-HIV-DNA) level and 2-long terminal repeats (2-LTR) circles frequency were analyzed over 4 years of viral suppression using piecewise linear mixed-effects model with two splines and logistic regression, respectively. RESULTS: CA-HIV-DNA in peripheral blood mononuclear cells had a significant decay during the first two years of VS [-0.26 (95% CI: -0.43, -0.09) log10 copies per one million cells (cpm)/year], and subsequently reached a plateau [-0.06 (95% CI: -0.15, 0.55) log10 cpm/year]. The initial decay was higher in children who achieved VS by 1.5 years of age compared to those who achieved VS between >1.5 and 4 years and those after 4 years of age: -0.51 (95% CI:-0.94, -0.07), -0.35 (95% CI:-0.83, 0.14), and -0.21 (95% CI:-0.39, -0.02) log10cpm PBMC/year, respectively. The 2-LTR circles frequency decayed significantly, from 82.9% at pre-VS to 37.5% and 28.1% at 2 and 4 years of VS, respectively (P = .0009). CONCLUSIONS: These data highlight that achieving VS during the first 18 months of life limit the establishment of HIV-1 reservoirs, reinforcing the clinical benefit of very early effective therapy in children.

Transmisión vertical del VIH-1/sida: la mirada de los profesionales y madres que consultan en el Hospital J.P. Garrahan / Vertical transmission of HIV-1 / AIDS: the perspective of professionals and mothers of children with newly HIV-1 infection

El estudio se propuso abordar la situación actual de la transmisión ver-tical del virus VIH-1 en nuestro país, a través de la perspectiva de pro-fesionales y madres de niños con nuevo diagnóstico de infección por el virus VIH-1, que concurrieron al Hospital de Pediatría SAMIC Prof. Dr. Juan Pedro Garrahan durante los años 2013/2014, en busca de atención. Se analizaron, las dificultades o facilidades que se les presentaron a las mamás en el transcurso del control de su embarazo y en el momento del parto dentro del Sistema de Salud Público, así como también en el recorrido que realizaron dentro del Hospital Garrahan, en el proceso de diagnóstico y atención de la infección VIH-1 del niño.Se trató de un estudio con características cualitativas, el cual utilizó en-cuestas y entrevistas a madres y profesionales, las que luego fueron analizadas individual y colectivamente.Se identificaron nudos críticos, centrados en las dinámicas del traba-jo institucional, e interinstitucional, y la situación de vulnerabilidad social de la población afectada; difi-cultad para aplicar los lineamientos del Programa de Prevención de Transmisión Vertical de VIH-1, dentro de un sistema de salud fragmentado y desarticula-do, el cual a su vez presenta como actores comuni-tarios, familias viviendo en situación de riesgo o ex-clusión social. Estos factores, combinados actuarían promoviendo y facilitando la transmisión vertical del VIH-1 en nuestro país a través de un déficit de aten-ción oportuna y suficiente

This Project proposes an approach to the current situation of mother-to-child HIV/AIDS infection in Argentina through the perspective of health-care professionals and mothers of newly diagnosed children. It is an analysis of difficulties patients may encounter in the Public Health System, from prenatal control to diagnosis and care at different centers, specifically in the pediatric hospital Garrahan.Factors associated with vertical HIV/AIDS infection will be assessed as well as reasons why, in spite of an extensive network of services aiming at prevention, the set goals are not achieved. We evaluated the position of different players involved in the Prevention of Mother-to-Child Infection Program and interrelationships between public health-care policies and subsequent attitudes and behaviors in the population in their search for and use of these services. HIV/AIDS epidemic strategies of care have prioritized high technology and pharmacology. Nevertheless, social aspects, such as stigma and discrimination, important in disease development, have been largely ignored. Additional to prevention, human rights of people with HIV/AIDS should be considered. Accessibility of care was defined as successful contact with health-care providers. If failure of care is considered to be only a problem of health-care provision, beliefs and behavior of the population are not taken into account. Therefore, a shift of the concept of health-care provision to successful/failed contact between mothers of HIV-infected children and the health-care system will enable the inclusion of community life and health attitudes and practices improving management and taking better advantage of the resources for the prevention of mother-to-child HIV/AIDS infection

Role of 3 lipoprotein lipase variants in triglycerides in children receiving highly active antiretroviral therapy.

BACKGROUND: Lipoprotein lipase is a key enzyme in lipid metabolism, especially for plasma triglycerides (TGs). Genetic variants have been associated with lipid levels in healthy individuals, cardiovascular disease, obesity and diabetes. Our aim was to evaluate the influence of 3 polymorphisms: Hind III, Pvu II and S447X in plasma TG levels in human immunodeficiency virus-1-infected children under highly active antiretroviral therapy (HAART). METHODS: Fifty-two children diagnosed with human immunodeficiency virus-1 between 2005 and 2009 were retrospectively selected with at least 1 plasma TG level assessment. TG levels were examined before and after 1 year of HAART. Hypertriglyceridemia was defined as TG > 150 mg/dL. Hind III (H+/H-), Pvu II (P+/P-) and S447X (S/X) were determined by polymerase chain reaction and restricted fragment length polymorphism. The Wilcoxon sum-rank test was used to compare median plasma TG among groups. Also, allelic frequencies were estimated for these variants in an Argentinean population. RESULTS: Allelic frequencies for human immunodeficiency virus-1-infected children were: H-, 0.21; P-, 0.53; and X, 0.05 with no significant differences to controls. After 1 year of HAART, median TG levels were significantly lower in P-/P- (98.5 mg/dL) when compared with P+/P+ (180 mg/dL) (P = 0.039). The presence of the P- allele was associated with an 11-fold lower risk of hypertriglyceridemia. Hind III and S447X were not associated with TG at the selected time points. CONCLUSIONS: Our findings suggest a protective effect of lipoprotein lipase polymorphisms against hypertriglyceridemia in children after 1 year of HAART. These results could endorse a prompt nutritional or pharmacological intervention in patients lacking the P- allele.

Implementación del estudio farmacogenético de hipersensibilidad al abacavir HLA-B*5701 en Argentina / Implementation of pharmacogenetic study HLA-B*5701 to predict abacavir hipersensitivity in Argentina

El abacavir (ABC) es un antirretroviral inhibidor de la transcriptasa reversa del virus HIV-1 que está fuertemente asociado al desarrollo de reacciones de hipersensibilidad en individuos portadores del alelo HLA-B*5701. Objetivos: determinar la prevalencia del alelo HLA-B*5701 en pacientes HIV-1 positivos y en una población control de Argentina. Materiales y métodos: desde enero de 2012 hasta octubre de 2013 se estudiaron 869 pacientes HIV-1 positivos y 63 individuos no infectados con HIV-1. La detección del alelo HLA-B*5701 se realizó mediante un ensayo in house basado en la técnica de PCR en tiempo real, diseñado en nuestro laboratorio y validado según guías internacionales. Resultados: el primero de enero se implementó el estudio farmacogenético para la detección de hipersensibilidad al ABC en los pacientes incluidos en el Programa VIH/sida de la Dirección de SIDA y ETS, y en los niños infectados con HIV-1 del Hospital Garrahan. Para ello se adoptó un protocolo de envío, recepción y procesado de las muestras, con un informe detallado de los resultados. El alelo HLA-B*5701 se detectó en 42 individuos infectados con HIV-1 y en 3 individuos no infectados. Conclusiones: la prevalencia del alejo HLA-B*5701 en la población de pacientes infectados con HIV-1 y la población control fue la misma (4,8%), lo cual sugiere que la presencia de este alelo no influye en la infección por HIV-1. Esta prevalencia fue similar a la reportada para otras poblaciones de origen caucásico...

Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children.

BACKGROUND: Variability in MDR1 and PXR has been associated with differences in drug plasma levels and response to antiretroviral therapy. We investigated whether polymorphisms in MDR1 (T-129C, C1236T and C3435T) and PXR (C63396T) affect lopinavir plasma concentration and the virological or immunological response to HAART in HIV-1-infected children. METHODS: Genotypes were identified in 100 blood donors and 38 HIV-1-infected children. All children received HAART with lopinavir boosted with ritonavir (LPV/r) at the time of LPV plasma level quantification, before (Ctrough) and between 1 and 2h after (Cpost-dose) the administration of the next dose of drug. CD4(+) T-cell counts and plasma viral load were analyzed before and after the initiation of LPV/r. RESULTS: MDR1 1236T, MDR1 3435T and PXR 63396T alleles showed a frequency of ~50% while the MDR1 -129C allele only reached 5%. Children heterozygotes 1236CT showed a significantly lower LPV Cpost-dose than homozygotes 1236TT (median Cpost-dose=3.04 µg/ml and 6.50 µg/ml, respectively; p=0.016). Children heterozygotes 1236CT also had a lower decrease of viral load after 36 weeks of LPV/r exposure compared with homozygotes 1236CC (median viral load changes=-0.50 log 10 copies/ml and -2.08 log 10 copies/ml, respectively; p=0.047). No effect on the immunological response was observed for polymorphisms of MDR1 or PXR. CONCLUSIONS: Our results suggest that the MDR1 C1236T SNP significantly reduces LPV plasma concentration affecting the virological response to HAART. Heterozygotes 1236CT might have an altered level of P-gp expression/activity in enterocytes and CD4(+) T lymphocytes that limits the absorption of LPV leading to an impaired virological suppression.

Hypercholesterolemia is associated with the apolipoprotein C-III (APOC3) genotype in children receiving HAART: an eight-year retrospective study.

Polymorphisms in apolipoprotein genes have shown to be predictors of plasma lipid levels in adult cohorts receiving highly active antiretroviral therapy (HAART). Our objective was to confirm the association between the APOC3 genotype and plasma lipid levels in an HIV-1-infected pediatric cohort exposed to HAART. A total of 130 HIV-1-infected children/adolescents that attended a reference center in Argentina were selected for an 8-year longitudinal study with retrospective data collection. Longitudinal measurements of plasma triglycerides, total cholesterol, HDL-C and LDL-C were analyzed under linear or generalized linear mixed models. The contribution of the APOC3 genotype at sites -482, -455 and 3238 to plasma lipid levels prediction was tested after adjusting for potential confounders. Four major APOC3 haplotypes were observed for sites -482/-455/3238, with estimated frequencies of 0.60 (C/T/C), 0.14 (T/C/C), 0.11 (C/C/C), and 0.11 (T/C/G). The APOC3 genotype showed a significant effect only for the prediction of total cholesterol levels (p<0.0001). However, the magnitude of the differences observed was dependent on the drug combination (p = 0.0007) and the drug exposure duration at the time of the plasma lipid measurement (p = 0.0002). A lower risk of hypercholesterolemia was predicted for double and triple heterozygous individuals, mainly at the first few months after the initiation of Ritonavir-boosted protease inhibitor-based regimens. We report for the first time a significant contribution of the genotype to total cholesterol levels in a pediatric cohort under HAART. The genetic determination of APOC3 might have an impact on a large portion of HIV-1-infected children at the time of choosing the treatment regimens or on the counter-measures against the adverse effects of drugs.

HIV and pregnancy: maternal and neonatal evolution.

Data regarding epidemiological aspects, antiretroviral drug safety, and outcomes of HIV-infected pregnant women and their newborns are limited in Argentina. We underwent a retrospective analysis of registries of HIV-infected pregnant women assisted at Helios Salud, Buenos Aires, Argentina (1997-2006). Variables associated with preterm delivery and neonatal complications were analyzed by univariate and logistic regression analyses. A total of 204 mother-child binomium were included. Maternal age (median): 29 years; 32.5% without prior diagnosis of HIV-infection. Baseline median CD4 T-cell count: 417 cell/ul; 98% received antiretroviral drugs during pregnancy [2 nucleoside analogs plus either nevirapine (55%) or a protease inhibitor (32%)]. Overall incidence of toxicity was 12.5%: rash (8%), anemia (3.5%) and hepatotoxicity (1%). Rash was associated with exposure to nevirapine. Eighty one percent and 50% reached HIV-viral loads <1000 and <50 copies/ml at the end of pregnancy, respectively. Twenty six percent had obstetric complications and 16% had preterm delivery. Of the newborns, 1.6% had congenital defects and 9% had neonatal complications. Overall neonatal mortality was 1% and perinatal transmission was 0.7%. Protease inhibitor use and obstetric complications were associated to preterm delivery while obstetric complications were associated with neonatal complications. In our population, hepatotoxicity was low despite frequent use of nevirapine. Protease inhibitor use was associated to preterm delivery. A favorable virological response and a low rate of perinatal transmission was observed, what supports the consensus that antiretroviral therapy benefits during pregnancy outweigh risks of maternal and neonatal adverse events.

HIV and pregnancy: Maternal and neonatal evolution / HIV y embarazo: Evolución materna y neonatal

Data regarding epidemiological aspects, antiretroviral drug safety, and outcomes of HIV-infected pregnant women and their newborns are limited in Argentina. We underwent a retrospective analysis of registries of HIV-infected pregnant women assisted at Helios Salud, Buenos Aires, Argentina (1997-2006). Variables associated with preterm delivery and neonatal complications were analyzed by univariate and logistic regression analyses. A total of 204 mother-child binomium were included. Maternal age (median): 29 years; 32.5% without prior diagnosis of HIV-infection. Baseline median CD4 T-cell count: 417 cell/μl; 98% received antiretroviral drugs during pregnancy [2 nucleoside analogs plus either nevirapine (55%) or a protease inhibitor (32%)]. Overall incidence of toxicity was 12.5%: rash (8%), anemia (3.5%) and hepatotoxicity (1%). Rash was associated with exposure to nevirapine. Eighty one percent and 50% reached HIV-viral loads <1000 and <50 copies/ml at the end of pregnancy, respectively. Twenty six percent had obstetric complications and 16% had preterm delivery. Of the newborns, 1.6% had congenital defects and 9% had neonatal complications. Overall neonatal mortality was 1% and perinatal transmission was 0.7%. Protease inhibitor use and obstetric complications were associated to preterm delivery while obstetric complications were associated with neonatal complications. In our population, hepatotoxicity was low despite frequent use of nevirapine. Protease inhibitor use was associated to preterm delivery. A favorable virological response and a low rate of perinatal transmission was observed, what supports the consensus that antiretroviral therapy benefits during pregnancy outweigh risks of maternal and neonatal adverse events.

La información sobre aspectos epidemiológicos, seguridad de drogas antirretrovirales y evolución de mujeres embarazadas HIV positivas y sus hijos es limitada en la Argentina. Realizamos un análisis retrospectivo de registros de embarazadas HIV positivas asistidas en Helios Salud, Buenos Aires, Argentina (1997-2006). Las variables asociadas con parto prematuro y complicaciones neonatales se estudiaron mediante análisis univariado y regresión logística. Estudiamos 204 binomios madre-hijo. Edad materna (mediana): 29 años, 32.5% sin diagnóstico previo de HIV. Recuento de linfocitos T CD4+ (mediana): 417 células/μl. El 98% recibió tratamiento antirretroviral durante el embarazo [dos análogos de nucleósidos más nevirapina (55%) o un inhibidor de proteasa (32%)]. La incidencia global de toxicidad fue 12.5%: erupción cutánea (8%), anemia (3.5%) y hepatotoxicidad (1%). La exposición a nevirapina se asoció con rash. El 81% y 50% alcanzaron cargas virales <1000 y <50 copias/ml preparto, respectivamente. Cesárea programada: 68%; complicaciones obstétricas: 26%; parto prematuro: 16%. De los neonatos, 1.6% presentaron defectos congénitos y el 9% complicaciones neonatales. La mortalidad neonatal fue 1% y la transmisión vertical: 0.7%. Las complicaciones obstétricas y el uso de inhibidores de proteasa se asociaron a parto prematuro; las complicaciones obstétricas se asociaron con complicaciones neonatales. La tasa de hepatotoxicidad fue baja a pesar de la utilización frecuente de nevirapina; el uso de inhibidores de proteasa se asoció a parto prematuro. Se observó una respuesta virológica favorable y una baja tasa de transmisión vertical, lo que apoya el consenso de que el beneficio de las drogas antirretrovirales durante el embarazo supera el riesgo de efectos adversos maternos y neonatales.

HIV type-1 genotypic resistance profiles in vertically infected patients from Argentina reveal an association between K103N+L100I and L74V mutations.

BACKGROUND: Patterns and pathways of HIV type-1 (HIV-1) antiretroviral (ARV) drug resistance-associated mutations in clinical isolates are conditioned by ARV history and factors such as viral subtype and fitness. Our aim was to analyse the frequency and association of ARV drug resistance mutations in a group of long-term vertically infected patients from Argentina. METHODS: Plasma samples from 71 patients (38 children and 33 adolescents) were collected for genotypic HIV-1 ARV resistance testing during the period between February 2006 and October 2008. Statistically significant pairwise associations between ARV resistance mutations in pol, as well as associations between mutations and drug exposure, were identified using Fisher's exact tests with Bonferroni and false discovery rate corrections. Phylogenetic analyses were performed for subtype assignment. RESULTS: In protease (PR), resistance-associated mutations M46I/L, I54M/L/V/A/S and V82A/F/T/S/M/I were associated with each other and with minor mutations at codons 10, 24 and 71. Mutations V82A/F/T/S/M/I were primarily selected by the administration of ritonavir (RTV) in an historical ARV regimen. In reverse transcriptase, thymidine analogue mutation (TAM)1 profile was more common than TAM2. The non-nucleoside K103N+L100I mutations were observed at high frequency (15.5%) and were significantly associated with the nucleoside mutation L74V in BF recombinants. CONCLUSIONS: Associations of mutations at PR sites reflect the frequent use of RTV at an early time in this group of patients and convergent resistance mechanisms driven by the high exposure to protease inhibitors, as well as local HIV-1 diversity. The results provide clinical evidence of a molecular interaction between K103N+L100I and L74V mutations at the reverse transcriptase gene in vivo, limiting the future use of second-generation non-nucleoside reverse transcriptase inhibitors such as etravirine.

MDR1 3435T and 1236T alleles delay disease progression to pediatric AIDS but have no effect on HIV-1 vertical transmission.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the MDR1 gene, coding for the drug transporter P-glycoprotein, may modulate the response to antiretroviral therapy and susceptibility to HIV-1 infection. We investigated whether the MDR1 SNPs C1236T (exon 12) and C3435T (exon 26) affect HIV-1 vertical transmission and progression to pediatric AIDS. METHODS: The MDR1 genotypes were identified by PCR-restriction fragment length polymorphism (RFLP) assays in 219 HIV-infected, 128 exposed uninfected children and 231 HIV-seronegative blood donors. Genotype and haplotype frequencies were estimated in the different groups. The median follow-up time of the infected cohort was 108 months and AIDS-free time was evaluated for the different MDR1 genotypes in 171 HIV-infected children. RESULTS: We found that both C1236T and C3435T polymorphisms were highly frequent in the studied groups (approximately 0.44) and showed strong linkage disequilibrium. There was no association between MDR1 genotypes and HIV-1 vertical transmission. However, a protective effect against progression to AIDS was associated with MDR1 3435CT, 1236CT and 1236TT genotypes (P = 0.005, P = 0.024 and P = 0.026, respectively). Moreover, haplotype pairs' analysis showed that the 3435CT/1236CT and 3435CT/1236TT exerted a significant protection against progression to pediatric AIDS (P = 0.0025 and P = 0.006, respectively). CONCLUSION: We conclude that in Argentinean children, MDR1 genotypes are associated with progression to AIDS, but they do not affect HIV-1 susceptibility by vertical transmission. These results support the notion that P-glycoprotein plays a role in HIV-1 infection independently from its role in drug transport.

[Highly active antiretroviral therapy in HIV sero-positive children. Disease progression by baseline clinical, immunological and virological status]. / Tratamiento antirretroviral de gran actividad en niños VIH positivos. Evolución de la enfermedad relacionada con parámetros clínicos, inmunológicos y virológicos al comienzo del tratamiento.

INTRODUCTION: Highly active antiretroviral therapy (HAART) has been administered to children infected with human immunodeficiency virus (HIV) since 1996. This kind of therapy is effective in achieving viral suppression and stopping disease progression but prolonged administration increases the risk of toxic effects, favours the onset of viral resistance and leads to decreased adherence. The aim of the present study was to determine prognostic factors among clinical, immunological and virological parameters at the beginning of HAART. POPULATION AND METHODS: We performed a prospective-retrospective observational analysis of a cohort or 564 HIV+ children assisted in Hospitals of Buenos Aires and Rosario, Argentina, treated with HAART since 1998 (media of treatment: 46.78 months. Range: 2-91 months). Patients were divided in groups according to age (younger or older than one year), and outcome (favourable or unfavourable). Stage, CD4 lymphocytes percentage, CD4 lymphocyte cell count and viral load at the beginning of treatment were analyzed with outcome by means of chi(2) tests, and logistic regression. RESULTS: No differences were observed on the percentage of CD4 T cells and viral load at baseline, between children under one year of age with good (n= 79) or bad outcomes (n= 4). Among older children (450 with good outcome, 31 with unfavourable), the following were identified as predictors of bad outcome: HAART initiation during stage C (p= 0.006), CD4 T-cell percentage below 15 percent (p< 0.001) and CD4 absolute value below 500 cells/mm(3) (p= 0.003). CONCLUSIONS: Children older than one year will have better outcome when HAART is initiated before stage C, with more than 15% CD4 or more than 500 cells/mm(3).

Tratamiento antirretroviral de gran actividad en niños VIH positivos: evolución de la enfermedad relacionada con parámetros clínicos, inmunológicos y virológicos al comienzo del tratamiento / Highly active antiretroviral therapy in HIV sero-positive children: disease progression by baseline clinical, immunological and virological status

Introducción. Desde 1996, los niños infectados por el virus de la inmunodeficiencia humana reciben tratamientos antirretrovirales denominados de gran actividad (TARGA). El inicio tardío puede restarle eficacia; la administración prolongada aumenta el riesgo de episodios adversos y desarrollo de resistencia, y dificulta la adherencia. Nuestro objetivo fue establecer si existe relación entre los parámetros clínicos, inmunológicos y virológicos al inicio del tratamiento TARGA, y la evolución de los pacientes. Población, material y métodos. Estudio retrospectivo-prospectivo observacional de una cohorte de niños VIH positivos tratados con TARGA a partir de 1998 (n= 564) en hospitales de Buenos Aires y Rosario (promedio de tratamiento: 46,78 meses. Intervalo: 2-91 meses). Se los agrupó según edad (menor o mayor de un año) y evolución (favorable o desfavorable). Se correlacionaron el estadio clínico, porcentaje de linfocitos CD4 y carga viral al comienzo del tratamiento con la evolución. Resultados. No hubo diferencias entre porcentaje y recuento de CD4 y carga viral al inicio entre los niños menores de un año con buena (n= 79) o mala evolución (n: 4). Entre los niños mayores (450 con buena evolución, 31 con evolución desfavorable), fueron predictores de mala evolución al iniciar TARGA, el compromiso clínico grave (estadio C) (p= 0,006), CD4 menor 15 por ciento (p< 0,001) y recuento de CD4 menor de 500 células/mm3 (p= 0,003). Conclusiones. Los niños mayores de un año tienen mejor pronóstico cuando empiezan tratamiento en estadios previos al C, con CD4 > 15 por ciento o más de 500 células CD4/mm3.(AU)

Tratamiento antirretroviral de gran actividad en niños VIH positivos: evolución de la enfermedad relacionada con parámetros clínicos, inmunológicos y virológicos al comienzo del tratamiento / Highly active antiretroviral therapy in HIV sero-positive children: disease progression by baseline clinical, immunological and virological status

Introducción. Desde 1996, los niños infectados por el virus de la inmunodeficiencia humana reciben tratamientos antirretrovirales denominados de gran actividad (TARGA). El inicio tardío puede restarle eficacia; la administración prolongada aumenta el riesgo de episodios adversos y desarrollo de resistencia, y dificulta la adherencia. Nuestro objetivo fue establecer si existe relación entre los parámetros clínicos, inmunológicos y virológicos al inicio del tratamiento TARGA, y la evolución de los pacientes. Población, material y métodos. Estudio retrospectivo-prospectivo observacional de una cohorte de niños VIH positivos tratados con TARGA a partir de 1998 (n= 564) en hospitales de Buenos Aires y Rosario (promedio de tratamiento: 46,78 meses. Intervalo: 2-91 meses). Se los agrupó según edad (menor o mayor de un año) y evolución (favorable o desfavorable). Se correlacionaron el estadio clínico, porcentaje de linfocitos CD4 y carga viral al comienzo del tratamiento con la evolución. Resultados. No hubo diferencias entre porcentaje y recuento de CD4 y carga viral al inicio entre los niños menores de un año con buena (n= 79) o mala evolución (n: 4). Entre los niños mayores (450 con buena evolución, 31 con evolución desfavorable), fueron predictores de mala evolución al iniciar TARGA, el compromiso clínico grave (estadio C) (p= 0,006), CD4 menor 15 por ciento (p< 0,001) y recuento de CD4 menor de 500 células/mm3 (p= 0,003). Conclusiones. Los niños mayores de un año tienen mejor pronóstico cuando empiezan tratamiento en estadios previos al C, con CD4 > 15 por ciento o más de 500 células CD4/mm3.

Pharmacokinetic study of the variability of indinavir drug levels when boosted with ritonavir in HIV-infected children.

The aim of this work is to: (1) assess therapeutic drug monitoring of indinavir (IDV) during clinical routine practice in HIV-infected children, whose antiretroviral treatment includes IDV boosted with ritonavir (RTV), and (2) describe a possible relationship between IDV pharmacokinetics and MDR1 genotypes. In 21 ambulatory pediatric patients receiving IDV plus RTV, IDV plasma levels and MDR1 genotypes on exon 26 (C3435T) were determined. Nine of the 21 patients initially receiving 250 mg/m(2) IDV yielded trough levels below 0.10 microg/ml (median: 0.21, range: 0.04-1.31 microg/ml). When the dosage was increased to 400 mg/m(2) IDV plus 100 mg/m(2) RTV b.i.d., all, except 1 patient, achieved levels above 0.10 microg/ml. Pharmacokinetic analysis showed higher volume of distribution median values related to the C/C genotype in comparison with C/T or T/T genotypes for exon 26 (4.57 vs. 1.20 and 1.50 l/kg, respectively; p = 0.002). Although a higher median value of clearance was observed with the C/C genotype, the difference was not statistically significant (1.43 vs. 0.27 and 0.42 l/h, respectively; p = 0.052). These results may be explained by a reduced absorption of the drug, related with lower plasma IDV levels in patients carrying the C/C genotype in exon 26.

Programa de Capacitación para Profesionales y Familias para Mejorar la Adherencia en Niños con Infección HIV / Training programme for professionals and families in order to improve compliance in children with HIV infection

Para que un programa de adherencia sea exitoso se requiere el trabajo conjunto del equipo de salud con los padres y los niños. El objetivo de este proyecto fue desarrollar un programa de capacitación dirigido a profesionales y familias para mejorar la adherencia al tratamiento en niños con infección HIV. Material y métodos: las actividades realizadas con los profesionales incluyeron talleres, cursos presenciales y a distancia; con las familias se realizaron talleres y reuniones con elaboración conjunta de materiales de capacitación. Los resultados esperados fueron la intensificación del trabajo interdisciplinario para profundizar los conocimientos y promover los cambios de actitudes y prácticas de los profesionales y las familias que participaban del programa. Resultados: se incorporaron 20 centros asistenciales de la Ciudad de Buenos Aires, Gran Buenos Aires y el resto del país. El 81% de los profesionales consideró que los talleres significaron un aporte importante para su aprendizaje y la atención de los pacientes. se trabajo con contenidos comunes en los módulos y se definieron factores protectores y de riesgo de las familias y los niños. Se analizaron percepciones y prácticas de las familias, lo que permitió pensar como impacta la prescripción del tratamiento en el proceso de autoatención de los pacientes, sus hipótesis y creencias y la presencia de las redes de sosten y acompañamiento. Conclusión: se pudo concretar la capacitación docente asistencial con efectos prácticos en el lugar de trabajo. es de remarcar la importancia de la recuperación de las prácticas que las familias realizan para poder sostener la adherencia al tratamiento(AU)

Programa de Capacitación para Profesionales y Familias para Mejorar la Adherencia en Niños con Infección HIV / Training programme for professionals and families in order to improve compliance in children with HIV infection

Para que un programa de adherencia sea exitoso se requiere el trabajo conjunto del equipo de salud con los padres y los niños. El objetivo de este proyecto fue desarrollar un programa de capacitación dirigido a profesionales y familias para mejorar la adherencia al tratamiento en niños con infección HIV. Material y métodos: las actividades realizadas con los profesionales incluyeron talleres, cursos presenciales y a distancia; con las familias se realizaron talleres y reuniones con elaboración conjunta de materiales de capacitación. Los resultados esperados fueron la intensificación del trabajo interdisciplinario para profundizar los conocimientos y promover los cambios de actitudes y prácticas de los profesionales y las familias que participaban del programa. Resultados: se incorporaron 20 centros asistenciales de la Ciudad de Buenos Aires, Gran Buenos Aires y el resto del país. El 81% de los profesionales consideró que los talleres significaron un aporte importante para su aprendizaje y la atención de los pacientes. se trabajo con contenidos comunes en los módulos y se definieron factores protectores y de riesgo de las familias y los niños. Se analizaron percepciones y prácticas de las familias, lo que permitió pensar como impacta la prescripción del tratamiento en el proceso de autoatención de los pacientes, sus hipótesis y creencias y la presencia de las redes de sosten y acompañamiento. Conclusión: se pudo concretar la capacitación docente asistencial con efectos prácticos en el lugar de trabajo. es de remarcar la importancia de la recuperación de las prácticas que las familias realizan para poder sostener la adherencia al tratamiento

High IL-7 plasma levels may induce and predict the emergence of HIV-1 virulent strains in pediatric infection.

BACKGROUND: HIV-1 infection results in severe immunodeficiency when T-cell loss cannot be compensated. IL-7 is one of the main cytokines involved in the maintenance of T-cell homeostasis. However, IL-7 can also enhance HIV-1 replication in vivo and lead to an accelerated progression of AIDS. OBJECTIVE: The aim of our study was to evaluate if the increase of IL-7 levels in response to CD4+ T cell depletion could favor the emergence of HIV-1 strains with more aggressive phenotypes in pediatric infection. STUDY DESIGN: Plasma IL-7 levels were measured in 42 HIV-1 vertically infected infants at different times of infection, and HIV-1 isolates were obtained from primary cell cultures to determine replication rate and syncytium-inducing (SI) capability on MT-2 cell line. RESULTS: IL-7 levels were significantly higher in infants harboring HIV-1 SI strains compared to those with non-syncytium-inducing (NSI) viruses (p<0.0001). Likewise, IL-7 levels were higher in infants with rapid replicating viral strains versus those with slow replicating viruses (p=0.0006). Despite the strong negative correlation between IL-7 levels and CD4+ T lymphocyte counts (r=-0.55, p=0.0001), covariance analysis demonstrated that the high levels of IL-7 were associated with more virulent phenotype features (SI and rapid replicating strains) independently of CD4+ T cell depletion. In 19 of the 42 infants, longitudinal follow-up studies showed that SI to NSI phenotype switch can occur after HAART administration, with a reduction in IL-7 levels and an increase in CD4+ T cell counts. CONCLUSIONS: IL-7 response to T-cell depletion may enhance T-cell production, but at the same time may foster HIV-1 disease progression favoring the emergence of more virulent HIV-1 strains characterized by SI capability and rapid replication rate.

Relevance of viral phenotype in the early AIDS outcome of pediatric HIV-1 primary infection.

In infants the clinical course of HIV-1 infection is bimodal, differing considerably from that of adults. The effect of HIV-1 phenotypic features and plasma viral load on the clinical course of infection has been well established in adults, whereas in children it remains controversial. The aim of this study was to prospectively evaluate the effect of HIV-1 replication phenotypes during the first year of primary infection in the development of premature immunosuppression and early pediatric AIDS. In 62 vertically infected children replication rates of HIV-1 isolates from primary cultures and syncytium-inducing capability in MT-2 cell line were evaluated, together with plasma viral load. It was observed that rapid replication rate and syncytium-inducing phenotype accelerate the early onset of pediatric AIDS (p = 0.02 and p = 0.04, respectively). Rapid replication kinetics was the only significantly independent variable for early clinical outcome (risk ratio, 2.48; p = 0.02). Both viral properties contributed to rapid CD4+ T-cell depletion (p = 0.05 for rapid replication rate, p = 0.01 for syncytium-inducing viral phenotype). Plasma viral burden higher than 5.5 log(10) copies/mL after 6 mo of age tended to be associated with disease progression. In conclusion, initial HIV-1 biologic features in pediatric primary infection by vertical transmission may influence the progression to early immunosuppression and development of AIDS.