Faculty Bibliography

BACKGROUND: We studied whether severely immunocompromised, human immunodeficiency virus (HIV)-infected children who were beginning highly active antiretroviral therapy (HAART) or changing HAART regimens could spontaneously respond to a recall antigen (tetanus toxoid [TT] vaccine) or respond to a recall antigen and neoantigen (hepatitis A virus [HAV] vaccine) after 3 vaccinations. METHODS: A total of 46 children who had CD4 cell percentages <15% and who demonstrated a >0.75-log reduction in plasma HIV RNA levels within 4 weeks of starting HAART were randomized to receive vaccinations with either TT or HAV vaccines during the first 6 months of HAART. Study subjects then received the alternate vaccine during the next 6 months of HAART. RESULTS: Despite the early decline in viremia and the later increase in the percentage of CD4 T cells, spontaneous recovery of cell-mediated immunity (CMI) was not seen for TT. Serologic responses to TT required 3 vaccinations and were comparable in both groups. Serologic responses to HAV were infrequent and of low titer, although the group that received HAV vaccine after receiving TT vaccine performed somewhat better. CMI to HAV was virtually absent. CONCLUSIONS: Severely immunocompromised children who are receiving HAART develop CMI and antibody to a recall antigen independent of the timing of vaccination, but they require a primary series of vaccinations. Antibodies to a neoantigen, HAV, developed when vaccination was delayed after initiation of HAART. CMI to a neoantigen was difficult to establish. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00004735/PACTG P1006

BACKGROUND: Perinatally infected long-term nonprogressors/slow progressors represent a select group of individuals. There is very limited information on this group of children beyond the first decade of life. A group of HIV-infected long-term nonprogressor/slow progressor children was studied. METHODS: We enrolled 20 HIV-infected adolescents who were receiving no or minimal therapy (defined as single or dual nucleoside therapy) before the age of 10 years and who had maintained CD4 counts above 25% for the first decade of life. We analyzed immunologic and virologic characteristics. Thymic receptor excision circles (TREC) were measured on stored frozen peripheral blood mononuclear cells. CD4 count, viral load and other pertinent information including race and age were obtained from individual medical records. RESULTS: Nine of the 20 patients recruited were noted to have developed falling CD4 counts at or around puberty, whereas the other 11 remained stable. There was no difference in TREC values or HIV RNA values before or after puberty between the 2 groups of patients. Those who remained stable, in terms of maintaining CD4 T cells as a group had falling viral loads with age. Those whose CD4 values declined after puberty had viral loads that did not decrease with age. CONCLUSION: A select group of patients who never received HAART during their first decade of life will continue to maintain good CD4 associated with declining HIV RNA values. Thymic output is not predictive of those that don't maintain CD4 T cells

BACKGROUND: CD8 cell responses to human immunodeficiency virus (HIV) have been correlated with virus control in adults, and this study outcome has been controversial. Attempts to establish the same correlation in small numbers of children have also been made, with similar controversy resulting. METHODS: A total of 110 perinatally infected children were studied. Nine of the children (mean age, 1.9 years vs. 11.8 years for the remaining 101 children) received treatment with antiretrovirals within the first 3 months of life. CD4 cell and HIV RNA levels were measured. Production of interferon- gamma after exposure to recombinant vaccinia vectors was measured by enzyme-linked immunospot (ELISPOT) assay. RESULTS: Responses to Pol and Gag antigens exceeded those to Nef and Env antigens, with responses significantly approximated by a quadratic function for which peak responses occurred at plasma HIV RNA levels of 103-104 HIV RNA copies/mL. Children who are treated early in life with highly active antiretroviral therapy have fewer total responses of ELISPOT-forming cells to HIV antigens than do children who are treated later in life

The effect of highly active antiretroviral therapy (HAART) in 85 children infected with human immunodeficiency virus type 1 (HIV-1) was compared retrospectively among Centers for Disease Control and Prevention (CDC) immunologic groups 1-3. The duration of HAART did not vary significantly among the immunologic groups (median, 39.07 months). The CD4 cell percentage increased in 39.1%, 58.3%, and 90% of patients in CDC groups 1-3, respectively (P <.001). HAART resulted in the suppression of HIV-1 below detectable levels in 34.8%, 25%, and 32% of patients in the 3 CDC groups, respectively, and in a frequent switch from syncytium-inducing to nonsyncytium-inducing virus. Thymic excision circles increased in a subset of patients with increases in CD4 cell percentage independently of HIV RNA level. The results support the option of delaying HAART in early asymptomatic HIV-1 disease in children and the use of other markers of disease progression, in addition to virus load

This cross-sectional study investigated the effect of early highly active antiretroviral therapy (HAART) on human immunodeficiency virus (HIV) type 1-specific CD8 T cell responses in children. HIV-1-specific CD8 T cell responses were quantified using an enzyme-linked immunospot assay to measure interferon-gamma-secreting cells. HIV-1-infected children were classified by time of HAART initiation prior to age 1 year or after age 2 years as early (n=24) or late (n=28) treated. The magnitude and breadth of the HIV-1-specific CD8 T cell response was significantly lower in children receiving early compared with late HAART treatment (P=.0007 and.0001, respectively). However, total CD8 T cell responses in the early HAART treatment group did not differ significantly from those of age-matched non-HAART-treated controls (n=30). Thus, the reduced magnitude and breadth of the HIV-1-specific CD8 T cell response in early HAART-treated children is due to their younger age

OBJECTIVE: To determine the long-term immunologic and virologic effects of highly active antiretroviral therapy (HAART) in children with AIDS. DESIGN: A prospective observational study. SETTING: Two pediatric HIV clinics. PARTICIPANTS: Twenty-five protease-inhibitor naive HIV-infected children (aged 2-18 years) with advanced disease (CD4 < or =6%). INTERVENTION: HAART (one protease inhibitor and one or more nucleoside analogs). Diphtheria and tetanus immunization in six patients after 18 months of therapy. MAIN OUTCOME MEASURES: Changes in percentage of CD4 cells and plasma HIV-1 RNA levels; post-treatment assays of lymphoproliferative responses to recall antigens; CD4 cell memory phenotype. RESULTS: Median duration of follow-up was 18.8 months (range, 7.5-28 months). At baseline the CD4 cell percentage was 2% (range, 0-6%), this increased significantly to 16% (range, 3-48%) above baseline at 12 months (P = 0.002). The mean maximum CD4 cell increase was 20.7% (range 4-48%) which corresponds to 657x10(6) cells/l (range, 30-2240x10(6) cells/l) above baseline. By contrast, the median viral load was not significantly lower at 12 months than at baseline (P = 0.34), and only 25% of the patients had sustained undetectable viral load. Of the reconstituted CD4 cells 70% were naive, and none of the subjects had lymphoproliferative responses to tetanus and diphtheria although 40% did develop responses to Candida, an environmental antigen. A single immunization with diphtheria and tetanus toxoid produced lymphoproliferative responses to tetanus in three out of six patients. CONCLUSIONS: HAART was associated with sustained increases in CD4 cell counts, despite a high incidence of 'virologic failure'. CD4 counts and the proportion of naive cells were higher than have been reported in adults, which may be a reflection of greater thymic activity in children. Memory cell clones for antigens encountered in the past which are not prevalent before therapy could not be expanded without additional antigenic exposure

OBJECTIVE: To determine whether the amount of p24 antigenemia in the first 6 months of life is a predictor of survival in children infected vertically with human immunodeficiency virus type 1. METHODS: A retrospective study of vertically infected infants and children who were followed prospectively from early infancy and who had quantitation of plasma p24 antigen concentration in the first 6 months of life. Infants were first stratified by duration of survival as infants who died before 2 years of age (short-term survivors) and infants who survived to 2 years of age (intermediate-term survivors). The median p24 antigen concentration and the proportion of infants in each group with high concentrations of antigen were compared. Analyses with and excluding all p24 determinations made after the use of antiretroviral agents were compared Kaplan-Meier product limit analysis was used to compare survival in infants with low and high antigenemia during the first 6 months of life. RESULTS: The median p24 antigen concentration in 15 short-term survivors was 228 pg/ml, compared with 14 pg/ml in 26 intermediate-term survivors (p < 0.05). The proportion of children with > 100 pg/ml of p24 was higher in short-term than in intermediate-term survivors (p = 0.01). Survival to 2 years of age in infants in whom all p24 antigen values during the first 6 months of life were 100 pg/ml or less was 91%, in comparison with 39% in infants with values greater than 100 pg/ml (p = 0.0017). CONCLUSIONS: Elevated p24 antigenemia in the first 6 months of life is associated with shorter survival and may be a useful predictor of outcome