The incidence of AIDS-defining illnesses at a current CD4 count ≥ 200 cells/µL in the post-combination antiretroviral therapy era.

BACKGROUND: Few studies consider the incidence of individual AIDS-defining illnesses (ADIs) at higher CD4 counts, relevant on a population level for monitoring and resource allocation. METHODS: Individuals from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) aged ≥14 years with ≥1 CD4 count of ≥200 µL between 1998 and 2010 were included. Incidence rates (per 1000 person-years of follow-up [PYFU]) were calculated for each ADI within different CD4 strata; Poisson regression, using generalized estimating equations and robust standard errors, was used to model rates of ADIs with current CD4 ≥500/µL. RESULTS: A total of 12 135 ADIs occurred at a CD4 count of ≥200 cells/µL among 207 539 persons with 1 154 803 PYFU. Incidence rates declined from 20.5 per 1000 PYFU (95% confidence interval [CI], 20.0-21.1 per 1000 PYFU) with current CD4 200-349 cells/µL to 4.1 per 1000 PYFU (95% CI, 3.6-4.6 per 1000 PYFU) with current CD4 ≥ 1000 cells/µL. Persons with a current CD4 of 500-749 cells/µL had a significantly higher rate of ADIs (adjusted incidence rate ratio [aIRR], 1.20; 95% CI, 1.10-1.32), whereas those with a current CD4 of ≥1000 cells/µL had a similar rate (aIRR, 0.92; 95% CI, .79-1.07), compared to a current CD4 of 750-999 cells/µL. Results were consistent in persons with high or low viral load. Findings were stronger for malignant ADIs (aIRR, 1.52; 95% CI, 1.25-1.86) than for nonmalignant ADIs (aIRR, 1.12; 95% CI, 1.01-1.25), comparing persons with a current CD4 of 500-749 cells/µL to 750-999 cells/µL. DISCUSSION: The incidence of ADIs was higher in individuals with a current CD4 count of 500-749 cells/µL compared to those with a CD4 count of 750-999 cells/µL, but did not decrease further at higher CD4 counts. Results were similar in patients virologically suppressed on combination antiretroviral therapy, suggesting that immune reconstitution is not complete until the CD4 increases to >750 cells/µL.

Past and future of HIV infection. A document based on expert opinion.

HIV infection is now almost 40 years old. In this time, along with the catastrophe and tragedy that it has entailed, it has also represented the capacity of modern society to take on a challenge of this magnitude and to transform an almost uniformly lethal disease into a chronic illness, compatible with a practically normal personal and relationship life. This anniversary seemed an ideal moment to pause and reflect on the future of HIV infection, the challenges that remain to be addressed and the prospects for the immediate future. This reflection has to go beyond merely technical approaches, by specialized professionals, to also address social and ethical aspects. For this reason, the Health Sciences Foundation convened a group of experts in different aspects of this disease to discuss a series of questions that seemed pertinent to all those present. Each question was presented by one of the participants and discussed by the group. The document we offer is the result of this reflection.

Brain activity in well-controlled perinatally HIV-infected young adults: a fMRI pilot study. / Actividad cerebral en jóvenes infectados por el virus de la inmunodeficiencia humana por transmisión vertical: estudio piloto de resonancia magnética funcional.

INTRODUCTION AND AIM: Perinatal transmission of human immunodeficiency virus (PHIV) is considered a chronic disease that has highlighted several cognitive deficits. From birth to early adulthood, cognition is known to play a fundamental role. However, although neurocognitive processes associated with PHIV have been extensively described by psychometric testing, data is scarce on neural activity from functional magnetic resonance imaging (fMRI) which provides in vivo physiological information. SUBJECTS AND METHODS: We studied described impaired cognitive processes using fMRI on a group of PHIV adolescents with good immunovirological indications and healthy matched controls. Psychological status and neurocognitive functions were also assessed. RESULTS: There were no significant differences between HIV+ and HIV- groups, either on neurocognitive testing nor in fMRI activity for phonological fluency tasks. Prolonged duration of cART was positively associated with greater brain activity in left inferior frontal gyrus (LIFG) which could indicate functional compensation. CONCLUSIONS: These results suggest that neural activity through fMRI in PHIV adolescents with good daily functioning and good immunovirological control may be similar to their peers.

TITLE: Actividad cerebral en jóvenes infectados por el virus de la inmunodeficiencia humana por transmisión vertical: estudio piloto de resonancia magnética funcional.Introducción y objetivos. La infección por el virus de la inmunodeficiencia humana de transmisión vertical (VIH-TV) constituye una enfermedad crónica que puede asociar múltiples alteraciones cognitivas que pueden influenciar el desarrollo de estos pacientes desde la infancia a la vida adulta. Sin embargo, aunque las alteraciones neurocognitivas vinculadas al VIH-TV están ampliamente descritas y valoradas mediante pruebas psicométricas, no existen apenas estudios de actividad neuronal medida a través de la resonancia magnética funcional (RMf). Sujetos y métodos. Analizar la utilidad de la RMf a través de la realización de tareas motoras y de fluidez verbal en un grupo de adolescentes y jóvenes con VIH-TV con buen control inmunovirológico y compararlo con un grupo control negativo de características similares. Se evaluaron también alteraciones psicológicas y funciones neurocognitivas. Resultados. No se encontraron diferencias significativas entre el grupo VIH+ y el grupo control para las tareas ejecutadas durante la RMf ni en la evaluación neurocognitiva. Un mayor tiempo de terapia combinada antirretroviral se asoció de forma directa con una mayor actividad en el giro frontal inferior izquierdo, lo cual podría indicar una posible compensación funcional. Conclusiones. Estos resultados sugieren que la actividad neuronal medida a través de la RMf en adolescentes con VIH-TV y buen control inmunovirológico es similar a la de sus pares.

Opportunistic infections and organ-specific diseases in HIV-1-infected children: a cohort study (1990-2006).

OBJECTIVES: Highly active antiretroviral therapy (HAART) has dramatically changed the natural history of HIV infection in children, but there are few studies in the literature about the incidence of clinical manifestations after HAART in this population, compared with adults. The aim of this study was to describe the influence of the widespread use of HAART on the development of opportunistic infections and organ-specific diseases in HIV-infected children. METHODS: An observational study of a cohort of 366 vertically HIV-infected children followed from 1990 to 2006 was carried out. According to the main antiretroviral protocol used, three calendar periods (CPs) were defined and compared: CP1 (1990-1996: no patients on HAART), CP2 (1997-1999: <60% on HAART) and CP3 (2000-2006: >60% on HAART). RESULTS: Children experienced a progressive increase in CD4 T cell count (P<0.05) and a decrease in HIV viral load from 1996 onwards (P<0.05). Similarly, rates of death, AIDS, opportunistic infections (bacteraemia, candidosis, cryptosporidiosis and bacterial pneumonia) and organ-specific diseases (wasting syndrome, thrombocytopenia, cardiomyopathy, lymphoid interstitial pneumonia and HIV-associated encephalopathy) were lower in CP2 and CP3 than in CP1. CONCLUSIONS: This study provides evidence of improved clinical outcomes in HIV-infected children over time and shows that mortality, AIDS, opportunistic infections and organ-specific diseases declined as HAART was progressively instituted in this population.

Significant differences between verbal and non-verbal intellectual scales on a perinatally HIV-infected cohort: from pediatrics to young adults.

Delayed neurodevelopment is a common outcome in perinatally HIV-infected children. Our aim was to assess the intellectual profile of our cohort, considering both the infection and socio-environmental related variables. A cross-sectional cohort study was undertaken at seven major hospitals in Spain belonging to the CoRISpeS cohort (n = 97). Patients were followed up according to a standard protocol. Intellectual measures, psychosocial profile and HIV infection-related data have been analysed. The average patient age was 15 years. The median CD4 cell percentage was 35% (1,59). Viral load was undetectable in 80% of the patients and 27% were on AIDS category; 38% of whom had encephalopathy. The average composite score of both crystallized intelligence (CI) and intelligence quotient (IQ) for the cohort was lower than that of the general population (p < 0.001). Results revealed a significant difference of 38% between crystallized and fluid intelligence. There was a clear association between IQ and age of diagnosis (p = 0.022); CI and CDC classification (p = 0.035), CD4 count (p = 0.011) and CD4 nadir (p = 0.001). Higher parental education was associated with better performance across all intelligence scales (p < 0.002). A regression model showed that CI was influenced by the academic level of caregivers (p = 0.002), age at start of cART (p = 0.050) and primary language (p = 0.058). Findings revealed significant differences in verbal and non-verbal intellectual scales resulting in a misleading IQ Composite score. Crystallized intelligence demonstrated the highest level of impairment despite adequate treatment and good immunovirological status, while fluid intelligence results were average. Caregiver level of education was the strongest factor across all intelligence measures.

Clinical practice update of antifungal prophylaxis in immunocompromised children.

Due to the rise in the number and types of immunosuppressed patients, invasive fungal infections (IFI) are an increasing and major cause of morbidity and mortality in immunocompromised adults and children. There is a broad group of pediatric patients at risk for IFI in whom primary and/or secondary antifungal prophylaxis (AFP) should be considered despite scant evidence. Pediatric groups at risk for IFI includes extremely premature infants in some settings, while in high-risk children with cancer receiving chemotherapy or undergoing haematopoietic stem cell transplantation (HCT), AFP against yeast and moulds is usually recommended. For solid organ transplanted, children, prophylaxis depends on the type of transplant and associated risk factors. In children with primary or acquired immunodeficiency such as HIV or long-term immunosuppressive treatment, AFP depends on the type of immunodeficiency and the degree of immunosuppression. Chronic granulomatous disease is associated with a particular high-risk of IFI and anti-mould prophylaxis is always indicated. In contrast, AFP is not generally recommended in children with long stay in intensive care units. The choice of AFP is limited by the approval of antifungal agents in different age groups and by their pharmacokinetics characteristics. This document aims to review current available information on AFP in children and to provide a comprehensive proposal for each type of patient.

Current aspects in sepsis approach. Turning things around.

The incidence and prevalence of sepsis depend on the definitions and records that we use and we may be underestimating their impact. Up to 60% of the cases come from the community and in 30-60% we obtain microbiological information. Sometimes its presentation is ambiguous and there may be a delay in its detection, especially in the fragile population. Procalcitonin is the most validated biomarker for bacterial sepsis and the one that best discriminates the non-infectious cause. Presepsin and pro-adrenomedullin are useful for early diagnosis, risk stratification and prognosis in septic patients. The combination of biomarkers is even more useful to clarify an infectious cause than any isolated biomarker. Resuscitation with artificial colloids has worse results than crystalloids, especially in patients with renal insufficiency. The combination of saline solution and balanced crystalloids is associated with a better prognosis. Albumin is only recommended in patients who require a large volume of fluids. The modern molecular methods on the direct sample or the identification by MALDI-TOF on positive blood culture have helped to shorten the response times in diagnosis, to optimize the antibiotic treatment and to facilitate stewardship programs. The hemodynamic response in neonates and children is different from that in adults. In neonatal sepsis, persistent pulmonary hypertension leads to an increase in right ventricular afterload and heart failure with hepatomegaly. Hypotension, poor cardiac output with elevated systemic vascular resistance (cold shock) is often a terminal sign in septic shock. Developing ultra-fast Point-of-Care tests (less than 30 minutes), implementing technologies based on omics, big data or massive sequencing or restoring "healthy" microbiomes in critical patients after treatment are the main focuses of research in sepsis. The main benefits of establishing a sepsis code are to decrease the time to achieve diagnosis and treatment, improve organization, unify criteria, promote teamwork to achieve common goals, increase participation, motivation and satisfaction among team members, and reduce costs.

Recommendations from SPNS/GEAM/SENBA/SENPE/AEDN/SEDCA/GESIDA on nutrition in the HIV-infected patient.

OBJECTIVE: to make recommendations on the approach to nutritional problems (malnutrition, cachexia, micronutrient deficiency, obesity, lipodystrophy) affecting HIV-infected patients. METHODS: these recommendations have been agreed upon by a group of expertes in the nutrition and care of HIV-infected patients, on behalf of the different groups involved in drafting them. Therefore, the latest advances in pathophysiology, epidemiology, and clinical care presented in studies published in medical journals or at scientific meetings were evaluated. RESULTS: there is no single method of evaluating nutrition, and diferent techniques--CT, MRI, and DXA--must be combined. The energy requirements of symptomatic patients increase by 20-30%. There is no evidence to support the increase in protein or fat intake. Micronutrient supplementation in only necessary in special circumstances (vitamin A in children and pregnant woman). Aerobic and resistance excercise is beneficial both for cardiovascular health and for improving lean mass and muscular strength. It is important to follow the rules of food safety at every stage in the chain. Therapeutic intervention in anorexia and cachexia must be tailored, by combining nutritional and pharmacological support (appetite stimulants, anabolic steroids, and, in some cases, testosterone). Artificial nutrition (oral supplementation, enteral or parenteral nutrition) is safe and efficacious, and improves nutritional status and response to therapy. In children, nutritional recommendations must be made early, and are a necessary component of therapy. CONCLUSION: appropriate nutritional evaluation and relevant therapeutic action are an essential part of the care of HIV-infected patients.

[Prevalence of resistance to antiretroviral drugs in Spain]. / Prevalencia de resistencia a fármacos antirretrovirales en España.

INTRODUCTION: The development of resistance to antiretroviral therapy (ART) reduces the effectiveness of these drugs in HIV-infected children. METHODS: We performed a cross-sectional study in 86 vertically HIV-infected children, divided into four groups according to prior treatment: group 1: nucleoside reverse transcriptase inhibitor (NRTI), group 2: NRTI and non-nucleoside reverse transcriptase inhibitor (NNRTI), group 3: NRTI and protease inhibitor (PI), group 4: NRTI, NNRTI and PI. RESULTS: In group 1 (11 children), the median treatment duration was 35 months (26 to 108). Nucleoside-associated mutations (NAMs) were found in 10 of these patients and the Q151M multiresistance mutation was found in two. The three children in group 2 were treated for 9, 32 and 42 months with NRTI and NNRTI. One child showed three NAMs and another showed Q151M. Two children had the K103N mutation. Group 3 (36 children) received treatment with NRTI and PI for 48.0 +/- 27.6 and 23.0 +/- 14.6 months, respectively. NAMs were observed in 94 % of the patients in this group, and one child showed the Q151M mutation. In group 4 (36 children) total treatment duration was 70.0 +/- 36.1 months (13.0 +/- 12.1 months with NNRTI, and 39.0 +/- 14.3 months with PI). NAMs were observed in all patients in this group, and Q151M was found in three children. K103N and Y181C were detected in 24 (67%) and 10 (28%) of the children respectively, while 32 (90%) showed primary mutations to PI. CONCLUSIONS: A high prevalence of resistance mutations to NRTI and early appearance of resistance to NNRTI were observed in treated children.

[Invasive fungal infections in children: similarities and differences with adults]. / Infección fúngica invasora en niños: diferencias y homologías con el adulto.

Invasive fungal infections (IFI) are a major cause of morbidity and mortality in immunocompromised adults and children. The purpose of this review was to update the epidemiological, clinical and therapeutic options in children, and to compare them with the adult population. Although there are important differences, the epidemiology, clinical features and risk factors for IFI have many similarities. Patient at risk include neutropenic hematology children, in whom Candida spp. y Aspergillus spp. predominate; primary immunodeficiencies, particularly chronic granulomatous disease with high susceptibility for Aspergillus spp.; and extremely premature infants, in whom C. albicans y C. parapsilosis are more prevalent. Premature babies are prone to dissemination, including the central nervous system. There are peculiarities in radiology and diagnostic biomarkers in children. In pulmonary aspergillosis, clasical signs in CT are usually absent. There is scant information on PCR and beta-D-glucan in children, and more limited on the performance of galactomannan enzyme immunoassay, that does not appear to be much different in neutropenic patients. There is a delay in the development of antifungals, limiting their use in children. Most azoles require therapeutic drug monitoring in children to optimize its safety and effectiveness. Pediatric treatment recommendations are mainly extrapolated from results of clinical trials performed in adults. There is no evidence for the benefit of preemptive therapy in children. It is necessary to foster specific pediatric studies with current and new antifungals to evaluate their pharmacokinetics, safety, and effectiveness at different ages in the pediatric population.

Sepsis in children with human immunodeficiency virus infection. The Madrid HIV Pediatric Infection Collaborative Study Group.

The aims of this retrospective study were to review the frequency and patterns of bacterial sepsis in children infected with human immunodeficiency virus. The charts of 233 human immunodeficiency virus-infected children cared for during a 10-year period in 4 tertiary hospitals in Madrid were reviewed. There were 43 episodes of sepsis in 31 (13%) children. Twenty of them had acquired immunodeficiency syndrome, 10 were class PA2 and 1 was class P1B. The most common organisms recovered were: nontyphoidal Salmonella, 10 cases (23%); Streptococcus pneumoniae, 9 cases (21%); Staphylococcus epidermidis, 6 cases (14%); Escherichia coli, 5 cases (12%); Enterococcus faecalis, 4 cases (9%); Campylobacter jejuni, 2 cases (5%). In 28 episodes of bacteremia there were other sites of associated infection: pneumonia, 6 cases; urinary tract infection (UTI), 5 cases; gastrointestinal disease, 4 cases; catheter-related bacteremia, 12 cases. Eight patients had more than 1 episode of bacteremia. The rate of complications was high: 6 children had septic shock; and 2 of them developed disseminated intravascular coagulation. There was 1 death directly related to sepsis.

[Prognostic markers of progression to AIDS in infants vertically infected by human immunodeficiency virus type-1]. / Marcadores predictivos de progresión a sida en niños infectados por transmisión vertical por el virus de la inmunodeficiencia humana tipo 1.

BACKGROUND: To study the prognostic AIDS progression value of the percentage of CD4+, CD8+, and plasma viral load (VL) (copies/ml) in HIV-1-vertically infected children. PATIENTS AND METHOD: We study a cohort of 115 HIV-1 infected children older than 12 months of age. The VL was quantified using standard molecular assay. CD4 and CD8 T lymphocytes were determined by flow cytometry. RESULTS: The children with a median of VL > 4.5 log10 (p < 0.001) and percentage of CD8+ < 25% (p = 0.05) during follow-up, progressed faster to AIDS than children with a median of VL < 4.5 log10 and CD8 > 25%. The relative risk (RR) of AIDS progression was 7-fold higher in children with median VL above 4.5 log10. When considering VL as a continuous variable, risk of progression to AIDS is 3.5-fold higher for each increase of one log10 of VL. The percentage of CD8+ T-cells had a RR of AIDS progression of 0.95/% CD8+ at entry to the study and of 0. 19/% CD8+ during follow-up, indicating protection against progression to AIDS. CONCLUSIONS: Our results indicate that each basal values at entry in the study and during the follow-up of the percentage of CD8+ and VL helps to determine the risk of AIDS progression in HIV-1-infected children. More interestingly, the use of the two predictive markers together had higher predictive value.

Short communication: evaluation of the effect of enfuvirtide in 11 HIV-1 vertically infected pediatric patients outside clinical trials.

The effect of enfuvirtide (ENF) in 11 HIV-1 heavily antiretroviral-experienced children and adolescents enrolled in the HIV-1 Paediatric Spanish cohort was further investigated. Patients who received ENF with novel drugs (etravirine, darunavir, and/or tipranavir) reached and maintained undetectable plasma HIV-1 RNA levels and showed immunological recovery within the first 3 months of therapy that was maintained during the follow-up. Viremia was not fully suppressed in patients who did not combine ENF with novel drugs but interestingly, immunological benefit was observed in half of these patients. Therefore, ENF showed a greater and more stable efficacy when administrated with novel drugs.

Report of a case of aggressive cytomegalovirus retinitis in an infant with AIDS.

A case of aggressive cytomegalovirus retinitis is reported in an infant with acquired immunodeficiency syndrome. Intravenous treatment with ganciclovir did not control the infection. The combination of ganciclovir and foscarnet was needed to obtain a complete response.

[Safety of liposomal amphotericin B in patients with high risk of nephrotoxicity]. / Seguridad de la anfotericina B liposomal en pacientes con elevado riesgo de nefrotoxicidad.

BACKGROUND: Amphotericin B is the medication of choice in systemic or invasive fungal infections, but its use often is limited by nephrotoxicity. Lipid formulations of amphotericin B have reduced this risk, but it is not known if these medications also prevent the deterioration of kidney function in patients with previous kidney failure or at risk of kidney failure, such as newborns and patients treated with cyclosporine A. METHOD: A retrospective analysis was made of epidemiological, clinical and analytic data collected from the clinical histories of patients with previous renal failure or at high risk of nephrotoxicity who were treated with liposomal amphotericin B at our hospital between January 1991 and January 1997. RESULTS: An analysis was made of 23 patients (15 men and 8 women, mean age 38 years) who met established criteria. All had severe immunosuppression. Twelve patients had been treated previously with conventional amphotericin B, but treatment was interrupted for kidney failure. The other 11 patients in the group received cyclosporine A (9 cases) or were at risk of nephrotoxicity because of their underlying disease or situation (2 cases). No deterioration of kidney function due to liposomal amphotericin B was observed in any patient. In 5 of the 12 patients who had deterioration of kidney function as a result of previous use of conventional amphotericin B and lived more than one week after changing treatment, it was observed that kidney function recovered and baseline creatinine levels were reached. CONCLUSIONS: Our findings suggest that liposomal amphotericin B can be used safely in immunocompromised patients with fungal infection who have failure or high risk of kidney failure.