Specific patterns of CD4-associated immunosenescence in vertically HIV-infected subjects.

Vertical transmission of human immunodeficiency virus (HIV) represents an important world-wide health problem although the incidence in developed countries has been drastically reduced by the extensive use of highly active antiretroviral therapy. Vertically HIV-infected subjects have been exposed to the virus during the maturation of their immune systems and have suffered a persistent chronic activation throughout their lifetime; the consequences of this situation for their immune system are not fully understood. The objective of this study was to analyse immunosenescence-related parameters in different CD4 T-cell subsets. Fifty-seven vertically HIV-infected subjects and 32 age-matched healthy subjects were studied. Activation (HLA(-) DR(+) ), senescence (CD28(-) CD57(+) ) and proliferation (Ki67(+) ) were analysed on different CD4 T-cell subsets: naive (CD45RA(+) CD27(+) ), memory (CD45RO(+) CD27(+) ), effector memory (CD45RO(+) CD27(-) ) and effector memory RA (CD45RA(+) CD27(-) ). Compared with healthy subjects, vertically HIV-infected subjects showed increased naive and memory CD4 T-cell frequencies (p 0.035 and p 0.010, respectively) but similar frequencies of both effector subsets. Whereas naive CD4 T cells were not further altered, memory CD4 T cells presented increased levels of senescence and proliferation markers (p <0.001), effector memory CD4 T cells presented increased levels of activation, senescence and proliferation markers (p <0.001) and effector memory RA CD4 T cells presented increased levels of activation and senescence (p <0.001) compared with healthy subjects. Despite long periods of infection, vertically HIV-infected subjects show specific patterns of immunosenescence, revealing a preserved CD4 T-cell homeostasis for subset differentiation and distribution. Nevertheless, excepting the naive subpopulation, all subsets experienced some immunosenescence, pointing to uncertain consequences of the future aging process in these subjects.

High prevalence of X4/DM-tropic variants in children and adolescents infected with HIV-1 by vertical transmission.

BACKGROUND: We studied HIV coreceptor tropism in vertically HIV-infected children and adolescents with the objective of predicting the proportion of children and adolescents that could be treated with CCR5 (R5) antagonists. METHODS: One hundred eighteen multidrug-resistant pediatric patients (36 children and 82 adolescents) were enrolled in a cross-sectional study. Viral tropism was assessed using the new phenotypic HIV-1 tropism coreceptor assay information and Trofile. RESULTS: Of 118 antiretroviral-experienced HIV-infected children and adolescents, 49 (57.0%) had dual-tropic and 20 (23.3%) had X4-tropic viruses by tropism coreceptor assay information testing. Only 17 (19.7%) showed R5-tropic variants. HIV-1 coreceptor usage was not detectable in 32 of 118 (27%) patients. Among 24 children and 62 adolescents with tropism coreceptor assay information results, 17 (70.8%) children and 51 (82.2%) adolescents showed viruses with dual-tropic or X4-tropic variants. Additionally, Trofile (ES) was performed in 42 of 118 patients with HIV-1 RNA > 1000 copies/mL. No patient showed X4-tropic variants; dual-tropic viruses were observed in 12 (28.6%) patients. In 6 (14.3%) patients, HIV tropism could not be determined. X4-tropic variants were more common in children (P = 0.031). CD4 T cell percentage was significantly lower in children (P = 0.011) and adolescents (P = 0.027) with R5-tropic viruses than in those with X4-tropic viruses. CONCLUSIONS: The presence of X4-tropic variants in more than 80% of our cohort of antiretroviral-experienced children and adolescents with vertical HIV-1 infection indicates a very limited role for CCR5 antagonists as part of salvage regimens for highly treatment-experienced vertically HIV-1-infected patients with extensive antiretroviral drug resistance and limited treatment options.

[Recommendations issued by the Spanish Society of Pediatric Infectious Diseases for the follow-up of the child exposed to the human immunodeficiency virus and to antiretroviral drugs during pregnancy and the neonatal period]. / Recomendaciones de la Sociedad Española de Infectología Pediátrica para el seguimiento del niño expuesto al virus de la inmunodeficiencia humana y a fármacos antirretrovirales durante el embarazo y el periodo neonatal.

Human immunodeficiency virus vertical transmission in developed countries has dramatically decreased to less than 2% over the last 15 years due to the consecutive implementation of different prophylactic measures, including the use of antiretrovirals, elective cesarean section and refraining from breastfeeding. The follow-up of these otherwise healthy children is, by far, the most common situation related to HIV infection that general pediatricians currently face in routine clinical care in Spain. These recommendations issued by the Spanish Society of Pediatric Infectious Diseases attempt to summarize the main aspects of this follow-up, including birth management, type of feeding, neonatal antiretroviral prophylaxis, HIV infection diagnosis, common early comorbidities, short- and mid-term toxicities, vaccination and other prophylactic measures and long-term follow-up.

[In-utero antiretroviral exposure and mitochondrial toxicity in a cohort of uninfected infants born to HIV-1-infected women]. / Exposición a antirretrovirales y toxicidad mitocondrial en una cohorte de niños no infectados hijos de madres VIH positivas.

INTRODUCTION: In this study, we attempt to find out the percentage of uninfected infants born to HIV-infected women and exposed in-utero and perinatally to Antiretroviral Treatment (ART) that show high lactate levels, or any other mitochondrial damage markers (such as hypertransaminasaemia or hyperamylasaemia), during the first three months of age. We shall also establish whether certain drugs used in-utero are associated with higher lactate, transaminase or amylase levels. METHODS: We analysed the available data from 623 uninfected infants born in the Spanish FIPSE cohort that were born in the period 2000-2005. The normal values for lactate, transaminases and amylase were set according to AIDS Clinical Groups Trials toxicity tables for infants. RESULTS: The percentages of children with high lactate levels at 0.5; 1.5 and 3 months of age were 48%, 51.4% and 43% among those infants with available data. Respectively, the percentages of children with high AST values were 13.2; 10.4 and 17.2%. The values for high ALT were 3.3%; 3.4% and 5%. The percentages for hyperamylasaemia were 0%; 0.6% and 2.6%. We found no significant difference among the drugs used in utero for the four analysed biochemical markers along the first three months of age. CONCLUSIONS: We have found a high proportion of hyperlactataemia among infants exposed in-utero to ART, as shown in other cohorts of similar characteristics. No morbidity or mortality was communicated to the cohort analysis group. No ART drug among those used in-utero was statistically associated with a higher proportion of high lactate levels in these infants.

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.

Long-term efficacy and safety of fosamprenavir in human immunodeficiency virus-infected pediatric patients.

Fosamprenavir (FPV) efficacy in human immunodeficiency virus (HIV)-infected pediatric patients is still being evaluated in ongoing clinical trials. The long-term efficacy and safety of FPV boosted with ritonavir (FPV/r) was evaluated in 20 antiretroviral-naive and antiretroviral-experienced HIV-vertically infected pediatric patients. Analyses of CD4(+) T-cells, HIV-ribonucleic acid (RNA), and clinical status were performed during a median of 180 weeks. Initially, median HIV-RNA was 4.6 log(10) in naive and 4.4 log(10) in pretreated patients. Median CD4(+) T-cell was 17% and 31%, respectively. After FPV/r treatment, 18 of 20 patients achieved undetectable HIV-RNA and 4 of 20 experienced adverse events. To date, FPV/r treatment has shown sustained antiviral response and immunologic improvement in our 20 patients.

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.

Impact of highly active antiretroviral therapy (HAART) on AIDS and death in a cohort of vertically HIV type 1-infected children: 1980-2006.

We evaluated the population effectiveness of highly active antiretroviral therapy (HAART) on the risk of AIDS and death in a multicenter cohort of 346 HIV-1 vertically infected children born between 1980 and 2006 in the Comunidad Autónoma de Madrid (CAM), Spain. Risks of AIDS and death in patients with the same duration of HIV infection were compared in different calendar periods [CP1: 1980-1989, CP2: 1990-1993 (reference), CP3: 1994-1996, CP4: 1997-1998, CP5: 1999-2006] through cumulative incidence curves and Cox proportional hazards models, allowing for late entry, that included the calendar period as the time-dependent covariate and adjusting for gender and mother's transmission category. The median follow-up was 11.8 years [interquartile range (IQR), 6.3-15.9]. Median CD4+ T cell percentage increased up to 26.5 in CP5 (IQR, 19.5-36.7) while the viral load decreased (median log(10) copies/ml in CP5, 3.66; IQR, 3.07-4.22). Multivariate analysis showed significant reduction in the risk of death since 1997 onward [CP4: adjusted hazard ratios (AHR), 0.29; 95% confidence interval (CI), 0.12-0.69; CP5: AHR, 0.06; 95% CI, 0.03-0.15]. Reduction in progression to AIDS reached borderline significance in CP4 (AHR, 0.49; 95% CI, 0.23-1.05) and was more marked in the last period (CP5: AHR, 0.30; 95% CI, 0.16-0.59). The reductions in the incidence of AIDS and death observed since 1996 were largely attributable to HAART.

[Growth of uninfected infants exposed to antiretrovirals born to HIV-infected woman]. / Exposición a antirretrovirales y crecimiento en una cohorte de niños no infectados, hijos de madre con VIH positivo.

INTRODUCTION: Recent reports show that Antiretroviral Treatment (ART) during pregnancy does not affect somatic growth of children born to HIV-infected mothers, are reassuring. The aim of this study is to perform an anthropometric analysis of the uninfected children followed in the Spanish FIPSE cohort during their first 18 months of life, and to describe the possible risk factors during pregnancy that may influence low birth weight. METHODS: The FIPSE cohort includes 8 public hospitals in Madrid, and prospectively follows children born to HIV-infected women at these hospitals. We collected data on 601 uninfected children, following standardised protocols, during their first 2 years of life. A P value<0.05 was considered statistically significant. Data from the Pablo Orbegozo Foundation were used to compare the means of our population with the standard weight, longitude an occipitofrontal circumference (OFC) of the Spanish population during the first 18 months of life. RESULTS: The mean weight was 2766g (+/-590), and 2967g (+/-427) when premature neonates were excluded. The proportion of Intrauterine Growth Restriction among non- premature neonates was 19.8% (95% CI: 16.3-23.8). Children born to mothers that used illicit drugs weighed less: 2752g (+/-325) vs. 3002g (+/ 435), P<0.001, as did children born to mothers who smoked during pregnancy: 2842g (+/-363) vs. 3018g (+/-444), P>0.001. Maternal anaemia did not influence the low birth weight of the children when premature neonates were excluded. We found no statistically significant differences depending on the ART received during pregnancy. Children born to mothers who had CD4 > 500 cell /mm were heavier (2834g +/-503) than those whose mothers had CD4 of less than 200 cell/mm (2565g +/-702), P=0.008. These differences disappeared when premature neonates were excluded. Children born to mothers with undetectable viral load were heavier (2866g +/-532 vs. 2704g +/-588, P=0.005), but these differences also disappeared when the prematures were excluded from the analysis. Mean weight, length, and OFC of our population at birth (excluding premature neonates) were lower than the Spanish standards. (z for weight=-0.83; z for length =-1.02; z for OFC=-1.00), but these differences are not statistically significant and disappear at 18 months of age (z for weight=-0.08; z for height=-0.32; z for OFC=-0.31). The type of ART did not have any significant influence. DISCUSSION: There is a very significant difference between the weight of the children born to mothers addicted to illicit drugs and the rest of the children. Similarly, the weight of the children born to smoking mothers is significantly lower. There was no association between maternal anaemia and the type of ART. The children of our population have lower weights, length and OFC at birth, but this may due to the high number of scheduled caesarean births, practised at 38 weeks of pregnancy (54.5%). Our children catch-up with anthropometric measurements during the first and second year of life, and these are similar to Spanish standards at 18 months old.

[Birth defects in a cohort of uninfected children born to HIV-infected women]. / Malformaciones congénitas en una cohorte de niños no infectados, hijos de madres infectadas por el virus de la inmunodeficiencia humana.

INTRODUCTION: Mother-to-Child HIV transmission is now just 1% in western countries, due to prevention measures. Antiretroviral Treatment (ART) drugs do have adverse effects, anaemia and myelosupression caused by cidovudina being the most commonly observed effects. In the present study, we have analysed the proportion and characteristics of congenital malformations (CM) or birth defects (BD) in a cohort of uninfected children born to HIV-infected women. METHODS: A total of 623 uninfected children belonging to the FIPSE cohort were followed up according to standardised protocols. This cohort includes 8 public hospitals from Madrid and follows up HIV-infected pregnant women and their children. Children were classified according to prematurity, ethnic origin, birth weight, withdrawal syndrome, in-utero treatment. Birth defects were described and defined according to the EUROCAT, the European registry for BD. Mild errors of morphogenesis were excluded from the analysis. Categorical variables were compared with the X(2) or the Fisher test. RESULTS: A total of 78% (486) of the mothers were of Caucasian origin; 18.8% (117) used some illicit drug (heroine, cocaine or methadone) during gestation; 51 mothers (8.1%) received no ART, 10 (1.6%) received monotherapy and 469 (75.3%) received HAART. BD were seen in 52 children, with the most frequent being genitourinary and cardiological. Anaemia in the first trimester was an associated risk for BD (17.9% vs. 8.1%, P = 0,04). Similarly, mothers who used any illicit drug (plus methadone), had a slightly higher risk for BD in their offspring (13.8% vs. 7.6%, P = 0,04) There was no increased risk for BD significantly associated with any of the in-utero used antiretrovirals, although Nevirapine use in-utero showed a protective effect. Children born to mothers who received ART in the first trimester had the same rate of BD (7.4%) as those whose mothers started ART in the second trimester (8.8%), P = 0,67. CONCLUSIONS: The proportion of BD that we have observed seems higher than those shown in other European teratogenicity studies and also higher than those shown in cohorts with HIV and antiretroviral exposed infants. This may be due to the fact that our series show the results of an active surveillance system (that includes ultrasound), where BD classically appear in a higher proportion. Immunovirological characteristics of the mother did not influence the proportion of BD, but anaemia in the fist trimester and the use of illicit drugs (or methadone) did. No specific antiretroviral drug was associated with an increase in BD, although Nevirapine showed a possible protective effect in the statistical analysis. Mothers who started antiretrovirals in the first trimester do not have more BD in their offspring than mothers who started on antiretrovirals later on.

Pathology in children of HIV women.

OBJECTIVE: To assess the frequency of perinatal pathology in children exposed to antiretrovirals in perinatal period. DESIGN: Retrospective observational cohort study. METHODS: Retrospective observational cohort study. Data collected among uninfected children born to HIV-infected women followed up from 1994 to 2006 in a tertiary Hospital. 220 uninfected children were studied. Factors studied included maternal, obstetrical and pediatric variables. RESULTS: The most common disorder found among children exposed to antiretroviral drugs was anemia (84%); 6,4% of children had neutropenia and more than 24% had thrombocytosis, a finding never described before. Prematurity (24%) and low birth weight (23.6%) rates were high. Several congenital malformations were found: Poland syndrome, angiomas, hypospadias, Pierre-Robin sequence, trisomy 8, craniostosis and others. Long-term follow-up revealed neurological, cardiological and ophthalmological pathologies. CONCLUSION: Some pathologies are frequent among children exposed to antiretroviral agents during perinatal life. It is crucial to carry out long-term studies to assess the safety of this therapy.

Immunological recovery and metabolic disorders in severe immunodeficiency HIV type 1-infected children on highly active antiretroviral therapy.

Little is known about immunologic reconstitution in children on highly active antiretroviral treatment (HAART) during very long-term periods. A retrospective study was carried out to assess the effectiveness and development of metabolic disorders after very long-term periods on HAART in HIV-infected children with severe immunodeficiency. We included 55 children who were stratified into three groups according to %CD4(+) pre-HAART and rate of immunologic recovery: (1) S1-Rec: CD4(+) < or =5% at baseline and slow immunologic recovery; (2) S2-Rec: CD4(+) 5-15% at baseline and slow immunologic recovery; (3) R-Rec: CD4(+) < or =15% at baseline and rapid immunologic recovery (reference group). An adequate immune recovery after 8 years on HAART was achieved by only 25% of children. S1-Rec never achieved a mean of CD4(+) > or =25% after 8 years on HAART. All children had a significant increase in plasma cholesterol levels during the first 2 years. Afterward, cholesterol levels reached a plateau and remained stable until year 8 of follow-up. Higher rates of lipodystrophy were found in the R-Rec group [14 (100%)] than in the S1-Rec group [9/19 (47.4%)] or the S2-Rec group [13/20 (65%)] at the end of the study (p = 0.006). Overall, having a low nadir of CD4(+) hindered immune reconstitution; however, children with rapid immunologic recovery showed a higher prevalence of the lipodystrophy syndrome.

[Anaemia and neutropenia in a cohort of non-infected children of HIV-positive mothers]. / Anemia y neutropenia en una cohorte de niños no infectados hijos de madres positivas para el virus de la inmunodeficiencia humana.

INTRODUCTION: Mother-to-child HIV transmission is currently around 1% in western countries, due to prevention measures. Antiretroviral drugs do have adverse effects, anaemia and myelosupression caused by AZT being the most observed effects. In the present study, we analyse the prevalence of anaemia and neutropenia in an uninfected children cohort born to HIV-infected women. MATERIAL AND METHODS: We followed up 623 uninfected children belonging to the FIPSE cohort according to standardised protocols. This cohort groups 8 hospitals from Madrid and follows up HIV infected pregnant women and their children. Anaemia and neutropenia were defined according to the ACTG (AIDS Clinical Trails Group) toxicity tables. Children were classified according to prematurity, ethnic origin, birth weight, withdrawal syndrome, in-utero treatment and neonatal prophylaxis. Categorical variables were compared with the chi2 or the Fisher tests. RESULTS: Anaemia was observed in 188 (30.1%) children during follow-up and 161 (25.8%) had anaemia grade 2 or higher. Prematurity (p < 0.001), low birth weight (p = 0.005) and Highly Active Antiretroviral Treatment (HAART) with Protease Inhibitors (p = 0.016) were associated with higher percentages of anaemia in children. Nadir haemoglobin values were reached by 6 weeks of life and anaemia was transient and disappeared by six months of age. Neutropenia was present in 41.9% (261 children) and 22.7% of the children had moderate-severe neutropenia. Prematurity was again associated with neutropenia (p = 0.01) and low birth weigh was associated only with moderate-severe neutropenia (p = 0.023). African infants had a higher percentage of neutropenia than the rest of the children (50% vs. 44%), although the differences were not significant. The type of in-utero treatment did not appear to influence the neutropenia. Neutropenia was still present in 12.5% of infants at 18 months of age. The type of neonatal prophylaxis to prevent mother-to-child transmission (monotherapy, dual therapy or triple therapy) did not influence either cytopenia. CONCLUSION: In our series, the proportion of children with anaemia is high: 30.1% Prematurity, low birth weight and HAART with IP were associated with a higher proportion of anaemia, which was transient and had little clinical relevance. The proportion of children with neutropenia was higher (41.9%) and was associated with prematurity, low birth weight and African origin. The type of neonatal prophylaxis does not seem to influence the development of cytopenias. Persistence of neutropenia (without clinical significance) was observed in a small percentage of the children 12.5%, at 18 months of age.

Long-term response to highly active antiretroviral therapy with lopinavir/ritonavir in pre-treated vertically HIV-infected children.

BACKGROUND: Immune recovery after prolonged highly active antiretroviral therapy (HAART) with lopinavir/ritonavir has been reported in adults but not in children. Our study aimed at evaluating the long-term use of lopinavir/ritonavir among children in a clinical setting. METHODS: We carried out a retrospective study on 69 protease inhibitor (PI)-experienced vertically HIV-infected children on HAART containing lopinavir/ritonavir. We analysed the changes in percentage CD4+ cell count (%CD4+) and viral load (VL) and identified prognostic factors to achieve CD4+ >25% and undetectable VL (uVL) ( 100,000 copies/mL. We found that %CD4+ at baseline had a strong positive association with achieving CD4+ >25% at 6, 12, 18, 24, 36 and 48 months of follow-up. We also found that length of PI use had a negative association with reaching CD4+ >25% at 24 and 48 months and achieving uVL at 12 and 24 months. VL at baseline had a negative association with achieving uVL at 18 and 24 months. CONCLUSIONS: Our study demonstrates ongoing immune recovery among children on HAART with lopinavir/ritonavir after 4 years of follow-up. Lopinavir/ritonavir, when given as part of a salvage regimen, is safe and well tolerated in HIV-infected children.

Slow progression of human immunodeficiency virus and hepatitis C virus disease in a cohort of coinfected children.

We carried out a retrospective study to determine the evolution of 23 vertically HIV-1/HCV coinfected children and 30 vertically HIV-1 infected children (control group). Six out of 23 HIV-1/HCV coinfected children developed AIDS versus 20 out of 30 HIV-1 children (P < 0.05). HIV-1/HCV children had a good evolution in relation to CD4 and HIV-RNA viral load. They presented higher CD8 counts than HIV-1 children during long periods, and slower progression of HCV liver disease.

[Changes in vertical HIV transmission: comparison between 1994 and 2004]. / Cambios en la transmisión vertical del virus de la inmunodeficiencia humana: comparación de los años 1994 y 2004.

BACKGROUND AND OBJECTIVE: Vertical transmission (VT) is the main route of human immunodeficiency virus (HIV) infection in children. Since the publication of PACTG 076 study in 1994, several preventive methods against the vertical transmission of the HIV have been developed. In this study, we compare the clinical and epidemiological profile of HIV-infected pregnant women and the VT rate in the years 1994 and 2004. PATIENTS AND METHOD: We looked at maternal, obstetric and pediatric variables of HIV-infected women and their children, born in 1994 and 2004, who were followed in Hospital La Paz. RESULTS: We included 40 mother-infant couples in 1994 and 35 couples in 2004. The HIV vertical transmission rate was 35% in 1994 and 0% in 2004. We did not find changes in Hepatitis C virus (HCV) vertical transmission. In 1994, HIV-infected mothers had a more advanced HIV-disease and the major route of HIV-transmission was the intravenous drug use. Vaginal delivery was more frequent and rupture of membranes was longer than in 2004. The main route of maternal HIV infection in 2004 was sexual contact. In this same year, the use of combination antiretroviral therapy, even during pregnancy, was generalized, the elective cesarean section was the most frequent form of delivery, and every newborn received zidovudine. CONCLUSIONS: In the last decade, there have been important epidemiological changes in HIV-infected mothers in our society. The administration of antiretroviral therapy during pregnancy and to the newborn, as well as other obstetric strategies, can prevent HIV vertical transmission. Nevertheless, we did not find any change in the risk of HCV vertical transmission.

Salvage therapy with abacavir and other reverse transcriptase inhibitors for human immunodeficiency-associated encephalopathy.

BACKGROUND: HIV-associated encephalopathy (HIV-AE) is a severe neurologic condition that affects HIV-infected children. The potential benefit of antiretroviral (ARV) agents with good cerebrospinal fluid (CSF) penetration remains to be defined. Abacavir (ABC) achieves good CSF concentrations and studies of high-dose ABC showed benefit in adults with HIV dementia. The present study evaluated the safety and virologic, immunologic and neuropsychological responses of an ARV regimen including high-dose ABC in children with HIV-AE. METHODS: Children between 3 months and 18 years old and abacavir-naive with HIV-AE and virologic failure were eligible. RESULTS: : Seventeen children (16 ARV-experienced) were enrolled and 14 children completed 48 weeks of therapy. The overall tolerability was good; 2 children had a possible hypersensitivity reaction. At week 48, 53% and 59% of the children achieved HIV RNA levels below the limit of quantitation in plasma and CSF, respectively. The median (25%-75% range) change of HIV RNA from baseline to week 48 was -2.29 (-0.81 to -2.47) log10 copies/mL in plasma and -0.94 (0 to -1.13) log10 copies/mL in CSF. The mean increases in CD4 (+/-standard error of mean) cell count and CD4% were 427 (+/-169) cells/mm and 8% (+/-2), respectively. Concentrations of soluble tumor necrosis factor receptor II were reduced in plasma and CSF. Children less than 6 years of age demonstrated significant neuropsychological improvement at week 48. CONCLUSIONS: In the present study with a limited number of children, highly active ARV therapy including high-dose ABC showed a safety profile similar to standard dose ABC and provided clinical, immunologic and virologic response in children with HIV-AE at week 48. Children less than 6 years of age also demonstrated significant neuropsychological improvement.

Immunological changes after highly active antiretroviral therapy with lopinavir-ritonavir in heavily pretreated HIV-infected children.

We evaluated the effect of salvage antiretroviral therapy with lopinavir/ritonavir (LPV/r) on the immune system of heavily antiretroviral pretreated HIV-infected children. We carried out a longitudinal study in 20 antiretroviral experienced HIV-infected children to determine the changes in several immunological parameters (T cell subsets, thymic function) every 3 months during 18 months of follow-up on salvage therapy with LPV/r. Statistical analyses were performed with the Wilcoxon test, taking as a reference the basal value at the entry in the study. HIV-infected children showed an increase of CD4+ T cells, a decrease in CD8+ T cells, and an increase in T cell rearrangement excision circle (TRECs) levels. The percentage of HIV children with undetectable viral load (VL < or = 400 copies/ml) increased significantly (p = 0.007) and the percentage with SI viral phenotype decreased significantly (p = 0.002) at the end of the study. Thus, the viral phenotype changed to NSI/R5 after salvage therapy with LPV/r. Interestingly, we observed a significant decrease of memory (CD4+ CD45RO+) and a moderate decrease of activated (CD4+ HLA-DR+, CD4+ HLA-DR+CD38, CD4+, CD45RO+HLA-DR+) CD4+ T cells during the follow-up. On the other hand, memory (CD8+ CD45RO+ and CD8+ CD45RO+CD38+), activated (CD8+ HLA-DR+CD38+, CD8+ HLA-DR+, CD8+ CD38+), and effector (CD8+ CD57+, CD8+ CD28(-)CD57+) CD8+ T cells had a very significant decrease during follow-up. Our data indicate an immune system reconstitution in heavily pretreated HIV-infected children in response to salvage therapy with LPV/r as a consequence of a decrease in immune system activation and an increase in thymic function.

Impact of highly active antiretroviral therapy on CD4+ T cells and viral load of children with AIDS: a population-based study.

In this study, we sought to characterize the changes over time at the population level on CD4(+) T cells and plasma viral load (VL) levels of HIV-1-infected children with or without AIDS. We carried out a retrospective study in 114 HIV-infected children during the calendar period that a highly active antiretroviral therapy (HAART) protocol was used. The HAART protocol consisted of three drugs: nucleoside analogue HIV-1 reverse transcriptase inhibitors, and/or HIV protease inhibitors, and/or nonnucleoside analogue HIV-1 reverse transcriptase inhibitors. The mean of CD4(+) T cells percentage and log(10) VL per calendar year were stratified by AIDS diagnostic. As new HAART strategies become available, an increase of CD4(+) T cells and a decrease of VL were observed over time, in children with and without AIDS. In 2001, children with AIDS reached values of CD4(+) T cells and VL similar to children without AIDS. In conclusion, our study shows that the generalized use of HAART has permitted improvement in immunological and virological status of HIV-infected children without AIDS, and more importantly in children with AIDS.

Achromobacter xylosoxidans bacteremia: a 10-year analysis of 54 cases.

Fifty-four cases of Achromobacter xylosoxidans bacteremia diagnosed over a 10-year period in patients from 2 months to 87 years of age were reviewed. Fifty-two episodes were nosocomial. The most frequent underlying condition was neoplasm (solid or hematological). The source of infection was a contaminated intravenous catheter in 35 patients (60%) and pneumonia in 6 patients. Eight (15%) patients died. The only risk factors significantly associated with mortality were age over 65 years and neutropenia. The results of in vitro susceptibility studies of the isolates showed that antibiotic therapy with antipseudomonal penicillins or carbapenems would be a reasonable choice. An epidemiological study conducted in the hemodialysis unit showed Achromobacter xylosoxidans in tap water and on the hands of two healthcare workers but not in the hemodialysis systems. Patients were probably contaminated when healthcare workers manipulated the intravenous catheters without wearing gloves.