Disease Progression In HIV-infected Children Research Articles

Nutritional Deficiencies and Food Insecurity Among HIV-infected Children in Tanzania

Poor nutrition has been associated with impaired immunity and accelerated disease progression in HIV-infected children. The aim of this study was to quantify the levels of nutrient intake in HIV-infected children and compare these to standard recommendations. We surveyed HIV-infected Tanzanian children enrolled in a pediatric care program that provided routine nutritional counseling and vitamin supplementation. We obtained anthropometric measurements and determined 24-hour macronutrient and micronutrient intakes and food insecurity. Values were compared to recommended nutrient intakes based on age and gender. We interviewed 48 pairs of children and their caregiver(s). The age of the child ranged from 2-14 years; median age 6 and 60% female. The median weight-for-height z-score for children ≤ 5 years was 0.69 and BMI-for-age z-scores for children >5 was -0.84. Macronutrient evaluation showed that 29 (60%) children were deficient in dietary intake of energy; deficiency was more common in older children (p=0.004). Micronutrient evaluation shows that over half of study subjects were deficient in dietary intake of vitamin A, vitamin D, vitamin E, thiamine, riboflavin, niacin, folate, vitamin B12, and calcium. Food insecurity was reported by 20 (58%) caregivers. The diets of many HIV-infected children at a specialized treatment center in Tanzania do not meet recommended levels of macro-and micro-nutrients. Food insecurity was a contributory factor. Enhanced dietary counseling and provision of macro- and micro-nutrient supplements will be necessary to achieve optimal nutrition for most HIV-infected children in resource-poor regions.

Mannose-binding Lectin and the Risk of HIV Transmission and Disease Progression in Children

Mannose-binding lectin (MBL) can activate the complement system by binding to carbohydrates, such as those presented on the HIV virion surface. It is unclear whether genetically determined MBL deficiency is related to vertical HIV transmission and disease progression in HIV-infected children. A literature search of Medline, Embase and Cochrane Central Register identified all relevant studies on MBL and HIV infection in children. We extracted information on the characteristics of the study group, method of MBL analysis, outcome definitions, follow-up and the risk estimates. The validity of each study was assessed. Nine studies were retrieved. Most were of good validity, but risk adjustment for confounders was missing in 6 studies. Age, treatment and outcome definitions differed between the study groups. In most of the studies, MBL deficiency was associated with an increased frequency of vertical HIV transmission and an increased speed of disease progression. In the 2 most valid studies, carriers of variant genes had an increased odds ratio for transmission and an increased relative hazard for disease progression and central nervous system impairment, especially in children <2 years of age. MBL deficiency is associated with an increased risk of vertical HIV transmission. How this risk relates to other factors that influence transmission is unclear. The association between HIV disease progression and MBL deficiency is most pronounced in children <2 years of age, probably due to immaturity of their adaptive immunity.

Reliability of absolute lymphocyte count as a marker to assess the need to initiate antiretroviral therapy in HIV-infected children

CD4 counts are a standard laboratory measure of disease progression in HIV-infected children. However, CD4 counting is done by flow cytometry and may not always be possible in every centre treating HIV-infected children in resource-limited countries. Absolute Lymphocyte Count (ALC) can be derived easily by performing a routine white blood cell count. The World Health Organization (WHO) in 2006 had recommended ALC to identify HIV-infected children in need of ART in resource-limited settings, when CD4 cell count is not available. This study aims to assess the reliability of using ALC as a marker for starting antiretroviral therapy (ART) in HIV-infected children in a tertiary hospital setting. Retrospective analysis of 46 HIV-infected children who presented at a pediatric HIV clinic at a tertiary referral centre from 2002-2005. Using WHO 2006 guidelines for cutoff values of ALC and 2008 guidelines for CD4% as a comparative standard, a retrospective analysis was done on ART-naοve HIV-infected children who underwent baseline CD4% and ALC, and sensitivity and specificity of ALC was calculated. Fischer exact two-tailed analysis was used to correlate ALC and CD4 and need for starting ART. Sensitivity of ALC was 27.6% (72.4% were false negatives), specificity was 70.6%, with positive predictive value of 61.5%. On comparison across all clinical stages of disease, only 13/46 children (28.2%) would have been started on ART according to ALC cutoffs versus 29/46 children (63.04%) using CD4 criteria (P value=0.0015). In children with WHO clinical Stage 1 or 2 of disease, only 1/11 (9.1%) children were identified by ALC as requiring ART as opposed to 6/11 (54.5%) children by CD4% (P=0.0635). ALC is an unreliable marker to determine the need for starting ART in HIV-infected children.

Avaliação dos parâmetros hematológicos, virológicos e antropométricos como marcadores de progressão em crianças infectadas pelo HIV-1

OBJECTIVE: To analyze total lymphocyte count, total leukocyte count, hemoglobin levels, nutritional status, CD4+ T-lymphocyte count and viral load as markers of disease progression and/or death in HIV-infected children. METHODS: This retrospective cohort study assessed antiretroviral naive HIV-infected children who were asymptomatic or had mild and/or moderate symptoms. The events of interest were: progression to clinical category C (according to the classification of the Centers for Disease Control and Prevention - CDC, 1994) or death. Values of total leukocyte count, total lymphocyte count, hemoglobin, weight-for-age z score, CD4+ T-lymphocyte count and plasma viral load obtained at admission were considered in the risk analysis of events of interest. The population was stratified into age groups: 12 to 36 to < 60 months. RESULTS: One hundred and twenty patients, admitted between 1997 and 2003, met the inclusion criteria for the present study. The total median of follow-up duration was 7.4 months (25-75% interquartile range = 3.8-21.1). In the multivariate analysis, only CD4+ T-lymphocytes count, according to the categories of the World Health Organization, and weight-for-age z score ≤ -2 were predictors of risk for disease progression in children older than 12 months. In children younger than 12 months, none of the variables was associated with risk of progression. CONCLUSION: Nutritional status is an important aspect in the assessment of risk of disease progression in HIV-infected children older than 12 months.

CD95 (APO-1/Fas) expression on naive CD4(+) T cells increases with disease progression in HIV-infected children and adolescents: effect of highly active antiretroviral therapy (HAART).

We studied the expression of the CD95 receptor (APO-1/Fas) on peripheral blood T cell subpopulations in 37 HIV-1-infected children and adolescents stratified according to disease stage or antiretroviral treatment regimen and compared the results to values obtained in 12 healthy age-matched control subjects. CD95 expression on CD45RA(+) CD45RO(-)/CD62L(+) (resting/naive) and CD45RO(+) CD45RA(-) (primed/memory) CD4(+) and CD8(+) T cells was assessed quantitatively by four-color and three-color flow cytometry. CD4(+) T cells contained a population of predominantly CD95(-) resting/naive cells and a population of CD95(high) primed/memory cells, whereas CD8(+) T cells had a more uniform pattern of CD95 expression. The percentage of CD95(+) CD4(+) T cells increased with disease progression because of both an augmented median fluorescence intensity on resting/naïve cells and an increased percentage of CD95(high) cells. Patients with highly active antiretroviral combination therapy who maintained stable CD4 counts in the presence of elevated plasma viral load had nearly normal numbers of CD95(-) resting/naive CD4(+) T cells, whereas CD95 expression in the CD8(+) T cell subset was still elevated compared with control subjects. Low CD95 expression on resting/naive CD4(+) T cells may therefore indicate a low risk for disease progression in antiretrovirally treated and untreated patients.

Surrogate markers of disease progression in HIV-infected children in Rio de Janeiro, Brazil.

In order to test the predictive value of immune complex-dissociated p24 antigenaemia (ICD-p24Ag), beta 2 microglobulin (beta 2-M), and neopterin as markers of disease progression, 53 HIV-1 infected children (mean age 68 months) and nine HIV-negative controls (mean age 65 months) were studied prospectively for 9 months. Five were classified in category E (CDC-1994) and seroreverted during the study, 14 in category A, nine in category B, and 25 in category C (CDC-1994). Blood samples were taken at medium intervals of 61 days and tested for ICD-p24Ag, beta 2 microglobulin, and neopterin. The results were correlated with clinical outcome and CD4-lymphocyte counts. All three groups (A, B, C) of symptomatic children had similar positivity in an ICD-p24Ag test (48.1, 58.8, and 51.0 per cent, respectively), and all in group E had negative p24 antigenaemia. beta 2 microglobulin and neopterin tests showed no correlation with clinical stages of HIV-1 infection. There was no significant correlation between these three tests with age-matched CD4 lymphocyte counts (p > 0.05). In contrast, the CD4 lymphocyte count correlated well with disease stages. These data suggest that the markers evaluated in the present study do not correlate well with clinical findings or with CD4 lymphocyte counts. Of all the markers tested, CD4 count was the best to predict prognosis of HIV disease in this cohort.

Chemokine pattern in relation to disease state in human immunodeficiency virus-infected children.

Although beta chemokines can block human immunodeficiency virus (HIV) entry into target cells, their role in HIV disease progression is controversial. To determine the association of RANTES with HIV disease state, we examined constitutive mRNA expression by reverse-transcribed polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells (PBMCs) and induction of RANTES secretion by enzyme-linked immunosorbent assay (ELISA) in anti-CD3 monoclonal antibody (MAb)-stimulated cultures of PBMCs, and in CD4+ and CD8+ T cell subsets of 17 HIV-infected children. In comparison with uninfected subjects, PBMCs of HIV-infected children were deficient in both constitutive RANTES mRNA expression as well as in stimulus-induced RANTES production. Children in clinical category C were found to be more deficient than children in clinical category A. Expression of RANTES mRNA in PMBCs was inversely correlated with plasma virus load and correlated directly with CD4+ T cell counts. In T cell subsets, RANTES production was equivalent between CD4+ and CD8+ T cells in patients and controls but CD8+ T cells of children in clinical category A produced higher RANTES levels than those of children in clinical category C. The beta-chemokine RANTES may play an important role in slowing clinical disease progression in HIV-infected children.

Clonal Dominance Patterns of CD8 T Cells in Relation to Disease Progression in HIV-Infected Children

CD8 T cells are important mediators of cellular immune responses as evidenced by clonal expansions in the CD8 TCR V beta repertoire during primary HIV infection in adults. This study investigated the CD8 TCR V beta repertoire by complementarity-determining region 3 length analysis using multiplex PCR in purified peripheral blood CD8 T cells of 22 HIV-infected children (age range was 0.75-15 yr, mean was 8.2 +/- 4.1 yr). Evidence of clonal dominance in one or more V beta families was obtained in 15 of 22 children. The patterns of clonal dominance were designated as major, minor, single, and none to indicate the involvement of three or more, two, one, or no V beta families, respectively. A pattern of major or minor clonal dominance was observed in 12 children (group 1), whereas 10 children had single or no clonal dominance (group 2). In comparison with group 2, the children in group 1 had a higher percentage of CD4 cells (28.3 +/- 11.6 vs 8.6 +/- 4.8, p < 0.001); a higher stimulation index in lymphoproliferative responses to Candida (92.0 +/- 59.5 vs 12.3 +/- 14.4, p = 0.002), tetanus (76.3 +/- 51.2 vs 11.2 +/- 12.7, p = 0.002), and alloantigens (178.3 +/- 298.9 vs 32.9 +/- 35.2, p < 0.001); and a lower percentage of CD8+HLA-DR+CD38+ cells (37.4 +/- 13.1 vs 54.6 +/- 14.2, p < 0.01). The number of dominant CD8 T cell clones was significantly correlated with the percentage of CD4 T cells (r = 0.669, p < 0.001) but not with plasma HIV RNA. Compared with group 1, patients in group 2 had a 4.8 times greater probability of having < 15% CD4 cells. These findings indicate that CD8 clonal dominance in HIV-infected children reflects robustness of immune responses, regardless of time since infection and virus load.

CCR5 genotype and HIV-1 infection in perinatally-exposed infants.

The CCR5 chemokine receptor is required by non-syncytium HIV-1 strains to infect target cells. A 32 base pair deletion (delta32) in the CCR5 gene causes a structural CCR5 modification that does not permit HIV-1 entry into cells. The rate of the CCR5 delta32 was investigated in 137 children born from HIV-infected mothers. Overall, five (10.6%) of 47 HIV-infected infants showed the defect in heterozygosis vs. eight (8.9%) of 90 uninfected children. No CCR5 delta32 homozygotes were found. Interestingly, among infected children, five (21.7%) of 23 showing a slow disease progression were heterozygous for the CCR5 delta32, meanwhile none of the 24 infants with rapid disease course had the deletion (P = 0.022). In conclusion, the CCR5 delta32 defect does not protect against vertical HIV-1 transmission, but is associated with a delayed disease progression in HIV-infected children.

Plasma virus load evaluation in relation to disease progression in HIV-infected children.

The objective of this study was to investigate the relationship of plasma HIV RNA load with survival and disease progression in HIV-infected children and to determine its correlation with cellular HIV DNA. Virus load (VL, HIV RNA copies/ml) was determined retrospectively by nucleic acid sequence-based amplification (NASBA) assay in 144 stored plasma samples between birth and 48 months in 50 children of whom 40 are alive (age range, 2-13 years). On the basis of clinical and immunologic status children were classified as rapid progressors (RPs), or nonrapid progressors (NRPs). Proviral HIV DNA quantitated by QC-PCR (quantitative competitive polymerase chain reaction) in 24 children was compared with plasma HIV RNA. At age <3 months, plasma VL <750,000 copies/ml was associated with significantly higher survival to age >2 years (p < or =0.01) compared with a VL of > or =750,000 copies/ml. Increasing mortality was observed with increasing plasma HIV RNA levels at ages 3-24 months and baseline VL of infants who died before age 24 months was significantly higher (p = 0.004) than baseline VL of those who survived beyond 24 months. Although baseline VL in infants classified as RPs was higher than that of NRPs, the difference was not statistically significant. Among surviving children 2-13 years of age, the baseline VL obtained at <24 months of age was not predictive of disease severity. Although no significant correlation was noted between plasma HIV RNA and proviral DNA, the concurrence of positive and negative results was >80%. We conclude that high plasma HIV RNA in infancy is associated with increased mortality.

Immunological and virological markers of disease progression in HIV-infected children.

Polymerase chain reaction (PCR), virus culture and antigen detection assays are useful for early detection of vertically transmitted human immunodeficiency virus type 1 (HIV-1) infection in infants under 12 months of age. Sixty-four children born to HIV-1-seropositive mothers were evaluated. Thirteen children (20.3%) were repeatedly positive by PCR analysis. There was 100% concordance between the results obtained from PCR and culture assays. Measurement of p24 antigen in serum was, in contrast, a less sensitive marker of HIV infection: only 5/13 infants had positive p24 antigen results. We have investigated the relationship among the HIV-1 biological phenotype, replicative capacity of viral isolates, HIV RNA copy number in plasma, p24 antigenaemia, CD4 T lymphocyte counts and the clinical status in 13 HIV-infected infants. Six out of 13 HIV-1 isolates from these patients were classified as rapid/high and seven as slow/low. We have found a significantly positive correlation between the replication rate of HIV isolates and their capacity to induce syncytia in vitro. The HIV-1 isolates with rapid/high and syncytium-inducing phenotype, and isolates with slow/low and non-syncytium-inducing phenotype were obtained from infants who had HIV-1 RNA copy number ml(-1) plasma values of 27654-83520 and 1342-34321, respectively. Levels of HIV-1 RNA were measured in sequential plasma samples from three HIV-infected infants and their biological properties determined in vitro. Our findings indicate that infants who carried viruses with more cytophatic biological phenotype and who had higher viral RNA copy numbers in blood were more likely to have lower CD4+ T cell counts and more likely to develop full-blown AIDS.

Otolaryngologic disease progression in children with human immunodeficiency virus infection.

To evaluate the prevalence of otolaryngologic disease in children born to mothers infected with human immunodeficiency virus (HIV) and to assess the correlation between HIV disease severity and the incidence density of recurrent otitis media (OM) and sinusitis based on the revised 1994 Centers for Disease Control and Prevention (CDC) clinical-severity index. Case series. Academic, tertiary care children's hospital. One hundred forty-five children (73 boys, 72 girls) with vertically acquired HIV infection and 153 (77 boys, 76 girls) children who had maternal exposure to HIV but later were found not to be infected ("seroreverters"), followed up on a regular basis since birth. Prevalence of recurrent OM (3 episodes in 6 months or 4 episodes in 12 months), sinusitis, parotitis, and lymphadenopathy; incidence density of recurrent OM and sinusitis based on the 1994 CDC clinical-severity index. Sixty-four HIV-infected children (44%) and 13 seroreverters (8.5%) had recurrent OM (P < .001); 29 HIV-infected children (20%) and 1 seroreverter (0.6%) had sinusitis (P < .001). Eight HIV-infected patients developed tympanic membrane perforations and 25 HIV-infected children required otologic surgery. Three HIV-infected patients had parotitis. The incidence density of recurrent OM increased as HIV clinical (P = .001) and immunologic (P = .03) status worsened. In contrast, the incidence density of sinusitis did not significantly correlate with increased HIV disease severity. The prevalence of recurrent OM and sinusitis is significantly greater in HIV-infected children than in seroreverters. The incidence density of recurrent OM also significantly correlates with disease progression in HIV-infected children as measured by the 1994 CDC clinical-severity index.

Virus load as a marker of disease progression in HIV-infected children.

The relationship of virus load to clinical disease progression in HIV-infected children remains to be elucidated. In this study, HIV-1 proviral DNA load was determined in peripheral blood mononuclear cells (PBMCs) by the quantitative competitive DNA polymerase chain reaction assay (QC-PCR) in 47 HIV-infected children subdivided by age (group I, < or = 2 years; group II, > or = 5 years), who were further categorized to include 12 rapid progressors (RP, age < or = 2 years, Centers for Disease Control [CDC] defined clinical category C and/or immune category 3, or death before age 2 years) and slow progressors (SP, age > or = 5 years, excluding CDC categories C and/or immune category 3). Significantly higher mean proviral copies/10(3) PBMCs were detected in group I versus group II (75.4 +/- 104.3 and 13.0 +/- 17.8 respectively, p < 0.0001) and in RP (158.0 +/- 118.2) as compared to either SP (11.8 +/- 18.8, p < 0.0001) or other age-matched infected children (20.3 +/- 38.8, p < 0.0001). Thus HIV-infected children appear to have a higher cell-associated virus load early in life, especially in association with rapid disease progression.