The Romanian pediatric AIDS initiative.
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Anti-HIV Agents↗
Biomedical subjects
M W Kline
Publications and source records attributed to M W Kline.
Objective measures of allergic disease in children with human immunodeficiency virus infection.
BACKGROUND: Available information suggests that IgE levels are elevated in adults infected with human immunodeficiency virus (HIV), and that increased IgE levels correlate with allergic disease, with decreased CD4 counts, and with a poor prognosis. Data with respect to these factors in children are scant. OBJECTIVE: We investigated whether serum IgE levels are elevated in children with HIV and, if so, whether the serum IgE level correlates with the degree of immunodeficiency and/or objective indicators of allergic disease. METHODS: Serum IgE levels, CD4 counts, absolute eosinophil counts, and immediate hypersensitivity skin test (IHST) results were collected from 43 children with symptomatic HIV infection (mean age 7.2 years). Associations between serum IgE levels, CD4 counts, and eosinophil counts were investigated by multiple stepwise linear regression analysis. Data were stratified according to IHST positivity, and analysis of variance was used to compare mean values for age, CD4 counts, IgE levels, and eosinophil counts between the two groups. RESULTS: Serum IgE values were elevated more than 2 SDs above control age-matched mean values in 17 of 43 patients (40%). IHST results were positive in 12 of 43 patients (28%). CD4 counts were less than 200/mm3 in 17 of 43 patients (40%). Stepwise linear regression failed to demonstrate any correlation between serum IgE levels and either CD4 or eosinophil counts. With data divided into two groups according to IHST results (positive vs negative), analysis of variance failed to reveal significant differences between means for patient age, CD4 counts, IgE levels, or eosinophil counts. CONCLUSIONS: Our findings confirm that serum IgE levels are increased in children infected with HIV, just as in adults. However, an elevated serum IgE level did not correlate with allergic disease as measured by IHST results and eosinophil counts, nor with the degree of immune dysfunction as approximated by CD4 counts. The mechanism and significance of elevated serum IgE levels remain unclear in children with HIV, and warrant further investigation.
Acquired Immunodeficiency Syndrome↗
Role of placental cytokines and inflammation in vertical transmission of HIV infection.
In light of new evidence suggesting that maternal human immunodeficiency virus (HIV) infection produces at least a three-fold increase in the number of early spontaneous abortions, it is important to search for factors that may predispose to fetal wastage. Immunological factors are thought to play an important role in permitting the HLA-disparate fetus to continue to term, despite powerful maternal immune forces capable of rejection. In the context of a heightened incidence of spontaneous abortion in HIV infection, evidence is now accumulating that implicates an imbalance in immune factors in contributing to this fetal loss. Soluble immune factors, such as cytokines, have been suggested as contributing agents to recurrent spontaneous abortions. Inflammatory cytokines-interleukin 1beta, interleukin 6 and tumor necrosis factor alpha-have been measured in isolated placental trophoblastic cells in HIV-infected and non-infected pregnant women in an attempt to explore this hypothesis. These inflammatory cytokines and their messenger RNAs were significantly elevated before and after stimulation in HIV-infected women, supporting the belief that HIV-infected women present their fetuses a milieu of imbalanced immune factors capable of contributing to immunological rejection. In addition, these elevated inflammatory cytokine levels may contribute to HIV disease progression in fetuses by virtue of activation of HIV gene transcription factors similar to what has been demonstrated in in vitro systems. We therefore propose that HIV infection in pregnant women produces an altered state of certain soluble immune factors, which in concert with other immune factor abnormalities, such as loss of immune selection in the fetal thymus, predisposes the fetus to advanced HIV infection and possible spontaneous abortion.
Abortion, Spontaneous↗
Early spontaneous abortions and fetal thymic abnormalities in maternal-to-fetal HIV infection.
The thymus is thought to play a major role in the immunopathogenesis of human immunodeficiency virus (HIV) infection, particularly in maternal-to-fetal HIV transmission. Characteristic lesions of the HIV-infected thymus include a prominent CD4+ CD8+ T lymphocyte depletion at the corticomedullary junction, the region of the thymus where immune selection occurs. At least threefold excess early spontaneous abortions were noted in a cohort of 124 HIV-infected pregnant women. In these 13 abortuses a very high rate (54%) of HIV vertical transmission was documented, with the thymus gland particularly affected. It is possible that the thymic insult in HIV-infected fetuses contributes to immune rejection of the fetus, possibly by an imbalance of maternal and fetal T1- and T2-type cytokines, known to be important in HIV disease progression. We propose, therefore, that the early spontaneous abortions occurring in HIV-infected pregnant women are due, at least in part, to abnormal immune forces created by HIV infection of the thymus.
Abortion, Spontaneous↗
Otolaryngologic disease progression in children with human immunodeficiency virus infection.
OBJECTIVES: 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. DESIGN: Case series. SETTING: Academic, tertiary care children's hospital. PATIENTS: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSION: 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.
Disease Progression↗
Type 1 and type 2 cytokine profiles in children exposed to or infected with vertically transmitted human immunodeficiency virus.
In human immunodeficiency virus (HIV)-infected adults, cytokine production profiles switch from predominantly type 1 (interleukin-2 [IL-2] and gamma interferon [IFN-gamma]) to type 2 (IL-4 and IL-10) cytokines with disease progression. To test this hypothesis in vertically HIV-infected children, we measured cytokine transcription and production in rapid progressors (RPs), seroreverters (SRs), and those children exposed to HIV in utero (P0s). Production of type 1 and type 2 cytokines was measured in peripheral blood mononuclear cell cultures of 8 SR, 25 P0, and 11 RP children. Unstimulated cultures, irrespective of infection and stage of disease, produced similar levels of IL-2, IFN-gamma, IL-4, and IL-10. Upon stimulation with phytohemagglutinin (PHA) plus phorbol-12-myristate-13-acetate (PMA), RP children produced less IL-2 (P < 0.01) and IFN-gamma (P < 0.02) than SR children and also expressed significantly less IFN-gamma mRNA (P < 0.01) than SR children. RP children expressed significantly higher levels of IL-4 mRNA than P0 children (P < 0.03). There were no differences in the production of IL-10 by PHA-PMA-stimulated peripheral blood mononuclear cell cultures among the three groups of children. Our data with these pediatric patients suggest that a deficiency in mitogen-stimulated type 1 cytokine production and excess type 2 cytokine (IL-4) transcription correlate with disease progression. Additional studies with larger sample sizes are needed to test further the hypothesis of the type 1-to-type 2 cytokine switch in children infected with HIV.
Cells, Cultured↗
Issues in the design of clinical trials for safety in HIV-infected children.
The use of newly approved drugs for human immunodeficiency virus (HIV)-infected adults is limited in children until child-specific pharmacokinetic and safety data can be submitted to the Food and Drug Administration (FDA) to fulfill labeling requirements. Design of a clinical trial to assess drug safety in children requires a different set of issues from standard Phase II and III efficacy trials in adults. For example, Phase II trials in adults are done to collect preliminary efficacy information. In children, efficacy of the drug is assumed and only safety needs to be shown. As a result, control groups may not be required and it may not be necessary to show superiority of the new drug over a control. This paper describes these issues in some detail and gives examples of designs appropriate in different scenarios.
Adult↗
Oral manifestiations of pediatric human immunodeficeincy virus infection: a review of the literature.
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Child↗
Combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus infection: pharmacokinetic properties, safety, and immunologic and virologic effects.
OBJECTIVES: To obtain preliminary information on the pharmacokinetic properties, tolerance, safety, and antiviral activity of combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus (HIV) infection. METHODS: Eight children (median age, 6.6 years; range, 2.8 to 12 years) with advanced HIV disease (median CD4 + lymphocyte count at baseline, 42 cells/ microL; range, 8 to 553 cells/microL) were treated with stavudine (2 mg/kg per day in two divided doses) and didanosine (180 mg/m2 per day in two divided doses) for 24 weeks. Seven children had histories of prior zidovudine therapy. All children had received stavudine alone for 19 to 33 months before the addition of didanosine to the treatment regimen. Children were assessed clinically and with laboratory studies at baseline, weekly through week 4 of combination therapy, and every 4 weeks thereafter. RESULTS: Analysis of stavudine and didanosine plasma half-life values, clearances, and area under the plasma concentration-versus-time curves revealed no obvious clinical pharmacokinetic interaction between the drugs through study week 12. Combination therapy was well tolerated, and there were no drug-associated clinical or laboratory adverse events. Signs and symptoms of peripheral neuropathy were not observed. All three children with baseline CD4 + lymphocyte counts greater than 50 cells/muL had greater than 20% increases in their counts within the first 12 weeks of therapy; CD4 + lymphocyte count increases were not observed in the other children. Plasma HIV RNA concentrations showed median declines of 0.88 log10 (range, -3.41 log10 to 0.31 log10) and 0.30 log10 (range, -0.63 log10 to 0.89 log10) at study weeks 12 and 24, respectively. CONCLUSIONS: Combination therapy with stavudine and didanosine was well tolerated and safe in this small group of children with advanced HIV disease. Plasma HIV RNA concentration declines suggest a favorable effect of therapy on virus load. These findings should be confirmed, and the regimen's clinical efficacy should be examined, in controlled studies of HIV-infected children with less-advanced disease.
Antiviral Agents↗
Limited toxicity of prolonged therapy with high doses of amphotericin B lipid complex.
We describe six patients with invasive fungal infections who received large cumulative doses (22.3-73.6 g) of amphotericin B lipid complex (ABLC) over 21-121 weeks. The drug was well tolerated at these very large doses, and there was limited toxicity. Collectively, these patients received ABLC therapy for a mean of 53.8 weeks (range, 21-121 weeks). The mean serum creatinine level at the start of ABLC therapy was 1 mg/dL (range, 0.4-1.9 mg/dL), and at the end of therapy this level was 1.5 mg/dL (range, 1.0-2.0 mg/dL). Over the course of therapy, only two patients had serum creatinine levels of > or = 2 mg/dL, with transient peak serum creatinine levels of 3.5 and 2.8 mg/dL, respectively. Several patients required replacement therapy with oral or intravenous potassium. None of the patients had ABLC-associated toxic effects necessitating discontinuation of the treatment. ABLC may be given in substantially larger doses than conventional amphotericin B, and very high doses of ABLC that are administered over several months appear to be relatively less toxic than those of conventional amphotericin B.
Adolescent↗
Excess intrauterine fetal demise associated with maternal human immunodeficiency virus infection.
A prospective study of transplacental transmission of human immunodeficiency virus (HIV) showed an increased rate of spontaneous fetal demise in HIV-seropositive mothers: 14 losses in 124 pregnancies. HIV was detected in placental and fetal tissues in 7 of 14 by in situ hybridization. The proportion of fetal infection far exceeded the transmission rate of 13% in liveborn babies. No association was seen between fetal transmission and a maternal history of drug abuse or coinfections; mothers with AIDS more often had fetal loss associated with HIV transmission than did asymptomatic mothers. In affected fetuses, HIV was detected in many tissues and was associated with thymic pathology. This suggests that maternal HIV infection increases the risk for pregnancy loss associated with HIV transmission. The possibility that HIV may be fetotoxic, that thymic dysfunction may interfere with pregnancy progression, or that the intrauterine milieu in HIV-seropositive pregnancies may be unfavorable (or a combination of factors) should be considered.
Adolescent↗
Prolonged influenza A infection responsive to rimantadine therapy in a human immunodeficiency virus-infected child.
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Child↗
Sensitivity of immune complex-dissociated p24 antigen testing for early detection of human immunodeficiency virus in infants.
Several investigators have suggested that early diagnosis of human immunodeficiency virus (HIV) infection in infants could be accomplished with a modified, more-sensitive, acid-dissociated p24 antigen enzyme-linked immunosorbent assay (ELISA) technique (p24 antigen immune complex dissociation [ICD]). We compared detection of HIV infection by HIV culture, PCR, and p24 antigen ICD assays in 46 infants by using samples collected independently. The detection sensitivity of the p24 antigen ICD assay was 0% with cord blood samples (2 HIV-positive infants), 38% with plasma samples from infants under 3 months of age (8 HIV-positive infants), and 58% overall (12 HIV-positive infants). By contrast, the sensitivities of HIV culture and PCR were 50% for cord blood samples, 75% for plasma samples from infants under 3 months of age, and 83% overall. These results indicate that the p24 antigen ICD does not offer the sensitivity necessary for this assay to be used as an indicator of HIV infection in infants.
Antigen-Antibody Complex↗
Transport of recombinant human CD4-immunoglobulin G across the human placenta: pharmacokinetics and safety in six mother-infant pairs in AIDS clinical trial group protocol 146.
Recombinant CD4-immunoglobulin G (rCD4-IgG) is a 98-kDa human immunoglobulin-like protein that is produced by fusing the gp120 binding domain of CD4 to the Fc portion of the human IgG1 heavy chain. This hybrid molecule was given to human immunodeficiency virus (HIV)-infected pregnant women at the onset of labor by intravenous bolus at 1 mg/kg of body weight (group A; n = 3) and 1 week prior to and at the onset of labor by the same route and at the same dose (group B; n = 3). In addition to pharmacokinetic studies, safety in the mothers and infants was determined through routine chemistries, hematology, and urinalysis; immunologic and HIV infection statuses in the infants were assessed through lymphocyte cultures, p24 antigen level determination, culture of HIV from plasma, PCR, lymphocyte subset enumeration, quantitative immunoglobulin analysis, and lymphocyte proliferation. Thirty minutes after the rCD4-IgG injection, concentrations in maternal serum were 12 to 23 micrograms/ml. These concentrations declined slowly, with initial and terminal half-lives (mean +/- standard deviation) of 9.95 +/- 3.23 and 47.6 +/- 22.3 h, respectively. Infants were born 2.6 to 46.5 h after rCD4-IgG administration; concentrations of rCD4-IgG in cord blood ranged from 28 to 107 ng/ml. The half-life of rCD4-IgG in infants ranged from 5 to 29 h. These data demonstrate that the transfer of rCD4-IgG from the mother to the fetus is rapid and that newborns do not appear to have any difficulty eliminating rCD4-IgG. No safety concerns in mothers or infants were encountered. Although the study did not address the question of efficacy, none of the infants was HIV type 1 infected 36 months later. In summary, these findings document that bifunctional immune molecules can be transported across the placenta, and this general approach may be used in the future to block vertical transmission of HIV type 1.
Acquired Immunodeficiency Syndrome↗
Characteristics of children surviving to 5 years of age or older with vertically acquired HIV infection.
The objective of this study was to examine characteristics of long-term survivors (aged 5 years or older) of vertical human immunodeficiency virus (HIV) infection. A retrospective cohort study design was employed. Forty-eight (68%) of 71 children who were born before 1990 and evaluated in our center survived to at least 5 years of age; 41 (58%) children remain alive (median age, 7.3 years). Only one (11%) of nine children with initial acquired immunodeficiency syndrome (AIDS)-defining conditions in the first year of life survived to age 5, whereas 47 (76%) of 62 children who did not have AIDS by age 1 year were alive at 5 years of age (p = .0003). Seventeen (43%) of 40 children with AIDS-defining conditions before age 5, and all 31 children without such conditions, survived to age 5 years (p = .000001). All eight children with lymphoid interstitial pneumonitis/pulmonary lymphoid hyperplasia (LIP/PLH) as their sole AIDS-defining condition survived to age 5. All 24 children who had neither an AIDS-defining condition nor severe immunosuppression by 5 years of age, and 24 (51%) of 47 children who had either or both of these findings, survived to age 5 years (p = .00008). To date, only 16 (39%) of 41 surviving children older than 5 years of age have had an AIDS-defining condition. However, true nonprogression of HIV disease (no clinical signs or symptoms; no evidence of immunosuppression) was unusual, occurring in only two (5%) of the same 41 children. In our center, most children with vertical HIV infection survive to at least 5 years of age, but the prognosis is not as good for those who experience an AIDS-defining condition or severe immunosuppression in the first 5 years of life.
Acquired Immunodeficiency Syndrome↗
Early detection of HIV in infants: aspects of design and analysis for diagnostic test studies.
OBJECTIVE: To review investigations on the early detection of HIV infection in infants to determine adherence to traditional methods of study design and analysis for evaluating new laboratory tests. DATA SOURCES: A National Library of Medicine (MEDLINE) search was conducted to identify such investigations through 1993. Cited references in identified manuscripts were also considered. The search was restricted to investigations of human subjects and those published in the English language. STUDY SELECTION: Final inclusion criteria included (1) report of the age and human immunodeficiency virus (HIV) infection status of the subjects at the time of the diagnostic testing, and (2) presentation of data allowing confirmation of presented analyses and additional analyses. DATA EXTRACTION: Criteria for judging the investigations included (1) whether the criteria used to determine the positive and negative test results were defined; (2) whether the necessary sample size for the study was calculated; (3) whether the patients studied were representative of the patients to whom the test would be applied; (4) whether a gold standard evaluation was performed; (5) whether the outcomes included in the analyses were independent; (6) whether the test characteristics were properly analyzed; and, (7) whether confidence intervals were presented. DATA SYNTHESIS: An informative presentation of a diagnostic test should include as a minimum the seven criteria listed above. Only 21 of 36 (58%) of the studies incorporated at least three of the criteria. CONCLUSIONS: There is a wide variation in the manner in which investigations of diagnostic tests are conducted and the results reported. Increased awareness and use of standard study designs and analyses will allow the application of metanalyses. Such analyses will help guide the direction taken for finding and establishing early diagnostic procedures for HIV infection at birth or during infancy.
AIDS Serodiagnosis↗
A phase I/II evaluation of stavudine (d4T) in children with human immunodeficiency virus infection.
OBJECTIVES: To determine the pharmacokinetic properties, tolerance, safety, and preliminary activity of stavudine in human immunodeficiency virus (HIV)-infected children. DESIGN: Phase I/II, open and dose-ranging (0.125 to 4 mg/kg/day in two divided doses). PATIENTS: Thirty-seven HIV-infected children (median age, 5.5 years; range, 7 months to 15 years) with a median CD4+ lymphocyte count at baseline of 242 cells/microL (range 2 to 2290 cells/microL). Thirty children had symptomatic HIV disease at entry; seven had HIV-related immunosuppression alone. Twenty-nine subjects had a history of prior zidovudine (ZDV) therapy. RESULTS: As compared with adults receiving the same weight-adjusted doses, the children we studied had lower maximum observed stavudine plasma concentrations (CMAX) and area under the plasma concentration versus time curves (AUC), and more rapid stavudine elimination. The absolute oral bioavailability of the drug ranged from 61% to 78%. There was no plasma accumulation of the drug between day 1 and week 12. Week 12 cerebrospinal fluid stavudine concentrations in seven subjects, obtained approximately 2 to 3 hours after oral doses, ranged from 16% to 97% of concomitant plasma concentrations. Stavudine was well-tolerated and there were no dose-related clinical or laboratory adverse events. One subject with baseline neurologic abnormalities experienced a transient episode of apparent pain or discomfort in her fingers, possibly related to stavudine. All other adverse events were attributed to underlying disease. Stavudine activity, measured indirectly by CD4+ lymphocyte count and serum p24 antigen concentration changes, was observed in some subjects. Progression of HIV disease and survival correlated with prior ZDV therapy, HIV disease classification, baseline CD4+ lymphocyte count, and weight growth velocity. CONCLUSIONS: Stavudine appears to hold promise for the treatment of HIV infection in children. Its pharmacokinetic properties are consistent and predictable, and it appears to be remarkably well-tolerated and safe. Although our study was not designed to assess the drug's efficacy, preliminary clinical and laboratory evidence of activity was observed.
Administration, Oral↗
Association between anti-human immunodeficiency virus type 1 (HIV-1) antibody-dependent cellular cytotoxicity antibody titers at birth and vertical transmission of HIV-1.
Because vertical transmission of human immunodeficiency virus type 1 (HIV-1) from mother to infant occurs in only 15%-35% of possible opportunities, natural immune defenses of the mother, fetus, or neonate may be protective against infection. The relation between antibody-dependent cellular cytotoxicity (ADCC) antibodies and HIV-1 infection was explored in 78 neonates born to HIV-infected women. More than 90% of sera had measurable ADCC titers against HIV-1IIIB. Infant titers were closely correlated with maternal titers but were independent of total IgG and total antibody reactive to the same strain in whole virus ELISA. At birth, mean ADCC antibody levels of infants or their mothers were the same for infants who were infected and those who ultimately seroreverted and remained healthy. ADCC antibody titers against HIV-1SF2 were weakly correlated with anti-HIV-1IIIB titers and did not predict protection from HIV-1 infection. High levels of anti-HIV-1 ADCC antibody at birth are not protective against vertical transmission of HIV-1.
Antibody-Dependent Cell Cytotoxicity↗