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Biomedical subjects

Kenneth McIntosh

Publications and source records attributed to Kenneth McIntosh.

At least 19 recordsLinked to original sources
PubMed2006

The Pediatric AIDS Severity Score (PASS): a multidimensional AIDS-severity adjustment for pediatric HIV infection.

BACKGROUND: A severity staging system predictive of mortality for perinatally HIV-infected children is needed for clinical and research purposes. METHODS: A pediatric AIDS severity score (PASS) was developed using baseline sociodemographic, clinical, immunologic, and functional measures obtained from 786 perinatally HIV-infected children enrolled into a prospective cohort study (PACTG 219) in the pre-highly active antiretroviral therapy (HAART) era (pre-1996). PASS was then validated among 392 perinatally HIV-infected children randomly sampled from the original source population (n = 1178). Survival estimates and hazard ratios (HRs) were obtained using the Kaplan-Meier method and proportional hazards models, respectively. The most predictive models were determined using Harrell's "C" statistic. RESULTS: Overall survival was 95% and 90% at 1 and 2 years of follow-up, respectively. The most comprehensive model for predicting mortality, termed the "Full" PASS, included CD4% <15 (HR = 3.9), CDC category C (HR = 2.6), BMI <10% (HR = 2.4), a low (<70) neuropsychological score (HR = 2.6), a general health rating <5 (HR = 2.4), and an elevated symptoms score (HR = 1.9). These determinants were highly predictive of mortality (C statistic = 0.841). CONCLUSIONS: PASS will be helpful in assessing the effectiveness of ART among children with HIV infection, particularly when randomized clinical trials are not possible due to ethical and feasibility concerns.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Simple Pediatric AIDS Severity Score (PASS): a pediatric severity score for resource-limited settings.

BACKGROUND: A multidimensional pediatric AIDS severity score (PASS) has been developed for severity adjustment and as a predictive model for mortality in a pediatric HIV-infected population. While the prognostic value of PASS is relevant in the US setting, there is a need to develop a simpler model of PASS for use in resource-limited settings where CD4% values and HIV RNA levels may not be available to assess prognosis and guide treatment decisions. METHODS: A Simple PASS model was developed including baseline weight percentile, WHO stage, symptoms, a general health rating, total lymphocyte count, packed-cell volume, and albumin measures from 1178 perinatally HIV-infected children enrolled into a prospective cohort study (PACTG 219). This prognostic model was then validated among 952 perinatally HIV-infected children enrolled in other PACTG research studies at the same sites. Survival estimates and Hazard Ratios (HR) were obtained using the Kaplan-Meier method and proportional hazards models, respectively. The predictive ability of the models was determined using Harrell's "C" statistic. RESULTS: Of the clinical measures and assays considered in this study, weight percentile, WHO stage, symptomatology, general health rating, total lymphocyte count, packed-cell volume, and albumin were found to be predictive of mortality. The simple PASS model including only the simple clinical measures and assays was found to be predictive of mortality (C statistic = 0.852). Its discriminative ability for mortality was comparable to a model consisting of the Simple PASS plus CD4% (C statistic = 0.871). CONCLUSION: The Simple PASS scoring system provides a reasonable alternative to CD4% values and HIV viral-load levels to assess prognosis and guide decisions about antiretroviral therapy initiation in resource-limited settings.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Effect of perinatal antiretroviral drug exposure on hematologic values in HIV-uninfected children: An analysis of the women and infants transmission study.

BACKGROUND: With the increasing use of antiretroviral (ARV) drugs to prevent mother-to-child transmission of human immunodeficiency virus (HIV), large numbers of infants are exposed, with possible consequent toxicity. METHODS: Hematologic values in 1820 uninfected HIV- and ARV-exposed children were compared with those in 351 ARV-unexposed children from the Women and Infants Transmission Study. Hemoglobin concentrations and platelet, neutrophil, lymphocyte, and CD4+ and CD8+ cell counts were analyzed at birth and ages 2, 6, 12, 18, and 24 months. Multivariate analysis was conducted age 0-2 and 6-24 months, with adjustment for multiple cofactors. RESULTS: Hemoglobin concentrations and neutrophil, lymphocyte, and CD4+ cell counts were significantly lower at age 0-2 months in infants exposed to ARV drugs than in those who were not. At 6-24 months, differences in hemoglobin concentrations and neutrophil counts were no longer significant, whereas differences in platelet, lymphocyte, and CD4+ cell counts persisted and CD8+ cell counts became significantly lower. In comparison with ARV monotherapy, combination therapy was associated with larger decreases in neutrophil, lymphocyte, and CD8+ cell counts at age 0-2 months but with only differences in CD8+ cell counts at age 6-24 months. Clinically significant abnormalities were rare and did not differ by exposure to ARV drugs. CONCLUSION: Infants exposed to ARV drugs have small but significant differences in several hematologic parameters for the first 24 months of life. These results indicate the need for long-term follow-up of uninfected infants with ARV exposure.

Adolescent↗
PubMed2006

Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study.

CONTEXT: Postnatal transmission of human immunodeficiency virus-1 (HIV) via breastfeeding reverses gains achieved by perinatal antiretroviral interventions. OBJECTIVE: To compare the efficacy and safety of 2 infant feeding strategies for the prevention of postnatal mother-to-child HIV transmission. DESIGN, SETTING, AND PATIENTS: A 2 x 2 factorial randomized clinical trial with peripartum (single-dose nevirapine vs placebo) and postpartum infant feeding (formula vs breastfeeding with infant zidovudine prophylaxis) interventions. In Botswana between March 27, 2001, and October 29, 2003, 1200 HIV-positive pregnant women were randomized from 4 district hospitals. Infants were evaluated at birth, monthly until age 7 months, at age 9 months, then every third month through age 18 months. INTERVENTION: All of the mothers received zidovudine 300 mg orally twice daily from 34 weeks' gestation and during labor. Mothers and infants were randomized to receive single-dose nevirapine or placebo. Infants were randomized to 6 months of breastfeeding plus prophylactic infant zidovudine (breastfed plus zidovudine), or formula feeding plus 1 month of infant zidovudine (formula fed). MAIN OUTCOME MEASURES: Primary efficacy (HIV infection by age 7 months and HIV-free survival by age 18 months) and safety (occurrence of infant adverse events by 7 months of age) end points were evaluated in 1179 infants. RESULTS: The 7-month HIV infection rates were 5.6% (32 infants in the formula-fed group) vs 9.0% (51 infants in the breastfed plus zidovudine group) (P = .04; 95% confidence interval for difference, -6.4% to -0.4%). Cumulative mortality or HIV infection rates at 18 months were 80 infants (13.9%, formula fed) vs 86 infants (15.1% breastfed plus zidovudine) (P = .60; 95% confidence interval for difference, -5.3% to 2.9%). Cumulative infant mortality at 7 months was significantly higher for the formula-fed group than for the breastfed plus zidovudine group (9.3% vs 4.9%; P = .003), but this difference diminished beyond month 7 such that the time-to-mortality distributions through age 18 months were not significantly different (P = .21). CONCLUSIONS: Breastfeeding with zidovudine prophylaxis was not as effective as formula feeding in preventing postnatal HIV transmission, but was associated with a lower mortality rate at 7 months. Both strategies had comparable HIV-free survival at 18 months. These results demonstrate the risk of formula feeding to infants in sub-Saharan Africa, and the need for studies of alternative strategies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00197587.

Anti-HIV Agents↗
PubMed2006

Absence of detectable viremia in a perinatally HIV-1-infected teenager after discontinuation of antiretroviral therapy.

A 15-year-old girl with perinatal HIV-1 infection has remained asymptomatic with undetectable plasma HIV-1 viremia for more than 5 years after discontinuing all antiretroviral therapy. Viral sequence analysis of proviral HIV-1 DNA revealed no evident fitness-attenuating deletions or mutations. This subject exhibited an unusually robust HIV-specific T-cell response, with an intact CD4+ T cell-proliferative response to HIV-1 antigens. In addition, the subject was found to be heterozygous for the 32-bp deletion in the CCR5 gene, which encodes the primary coreceptor for HIV-1 entry into cells. This mutation mediates profound resistance to HIV infection in homozygotes and has been associated with delayed disease progression in heterozygotes after both horizontal and vertical HIV-1 infection. Although adults with long-term nonprogressive HIV disease have been studied at length, there is no prior description in the literature of a perinatally HIV-infected child whose plasma HIV-1 viremia is controlled to undetectable levels in the absence of antiretroviral therapy.

Adolescent↗
PubMed2006

Growth of human immunodeficiency virus-uninfected children exposed to perinatal zidovudine for the prevention of mother-to-child human immunodeficiency virus transmission.

BACKGROUND: Perinatal human immunodeficiency virus (HIV) prevention programs have been implemented in several countries, and many children have been or will be exposed to antiretrovirals in utero and during their first weeks of life. Although reducing substantially the number of infected children, the potential adverse consequences of these treatments on the health of HIV-uninfected children need to be assessed. OBJECTIVE: To investigate the impact of in utero and postnatal zidovudine exposure on the growth of HIV-uninfected children born to HIV-infected women. METHODS: We used data prospectively collected in 1408 live born children participating in a clinical trial comparing zidovudine regimens of different durations to prevent perinatal transmission in Thailand (PHPT-1). We used a linear mixed model to analyze the anthropometric measurements (weight for age, height for age and weight for height Z-scores) until 18 months of age according to zidovudine treatment duration (mothers, <7.5 weeks versus more; infants, 3 days versus >4 weeks). RESULTS: Children exposed in utero for >7.5 weeks had a slightly lower birth weight (Z-score difference, 0.08; P = 0.003). However, zidovudine exposure had no effect on the evolution of Z-scores from 6 weeks to 18 months of age. CONCLUSIONS: Although a longer in utero zidovudine exposure may have had a negative impact on birth weight, the magnitude of this effect was small and faded over time. Neither the total nor the postnatal duration of exposure was associated with changes in infant Z-scores from 6 weeks to 18 months of age.

Anti-HIV Agents↗
PubMed2006

Quality of life for children and adolescents: impact of HIV infection and antiretroviral treatment.

BACKGROUND: HIV/AIDS mortality rates in the United States are declining; pediatric HIV has become a chronic disease, with quality of life (QoL) outcomes assuming greater importance. OBJECTIVES: To compare QoL among HIV-infected and uninfected children and to assess the impact of different antiretroviral regimens on QoL among HIV-infected children. METHODS: Perinatally exposed, HIV-infected (N = 1847) and uninfected (N = 712) children and adolescents were studied. Among infected children, 1283 were available for the antiretroviral regimen analysis. QoL domain scores were assessed for subjects 6 months to 4 years, 5 to 11 years, and 12 to 21 years of age, and the impact of infection status and alternative treatment regimens on QoL domains was evaluated. RESULTS: HIV infection was associated with significantly worse mean adjusted scores for functional status among children 6 months to 4 years of age and health perceptions, physical resilience, physical functioning, and social/role functioning among those 5 to 11 years of age. However, uninfected children 5 to 11 years of age reported significantly worse psychological functioning. HIV-infected children (5-11 years of age) and adolescents (12-21 years of age) receiving no antiretroviral treatment had worse health perceptions. Adolescents receiving no antiretroviral agents also had worse symptoms. When antiretroviral regimens were compared, adolescents receiving protease inhibitor plus nonnucleoside reverse transcriptase inhibitor-containing therapy had worse symptoms, compared with those receiving protease inhibitor-containing therapy; otherwise, no significant differences were found. CONCLUSIONS: Generally parents of HIV-infected children 6 months to 4 years and 5 to 11 years of age generally reported lower mean QoL scores than did parents of uninfected children, although worse psychological functioning was reported for uninfected children. HIV-infected adolescents not receiving antiretroviral treatment had worse health perceptions and symptoms. We found no consistent QoL differences among children receiving different antiretroviral regimens.

Activities of Daily Living↗
PubMed2006

A behavioral and cognitive profile of clinically stable HIV-infected children.

OBJECTIVE: The purpose of this research was to characterize behavioral and cognitive profiles of clinically and immunologically stable antiretroviral-experienced HIV-infected children. METHODS: Two hundred seventy-four previously treated HIV-infected children aged 2 to 17 years were assessed for behavioral, developmental, and cognitive functioning. Correlations between neuropsychological measures, age, and CD4 lymphocyte count were investigated. RESULTS: The most common behavioral problems, as measured by the Conners' Parent Rating Scale, were psychosomatic (28%), learning (25%), hyperactivity (20%), impulsive-hyperactive (19%), conduct (16%), and anxiety (8%) problems. Mean Wechsler Intelligence Scale for Children-III scores were less than established population norms; the mean verbal IQ was 85, the mean performance IQ was 90, and the mean full-scale score was 86. Hyperactivity was more frequent in children with a Wechsler Intelligence Scale for Children-III performance IQ of <90. Anxiety problems were more likely in children > or =9 years of age. Children with CD4 counts of <660 cells per mm3 were more likely to be identified as having a conduct disorder. No association was noted between behavioral problems and neuroimaging. CONCLUSIONS: Clinically and immunologically stable HIV-infected children had more frequent behavioral problems and lower developmental and cognitive scores than established childhood norms.

Adolescent↗
PubMed2005

HIV-1 viral escape in infancy followed by emergence of a variant-specific CTL response.

Mutational escape from the CTL response represents a major driving force for viral diversification in HIV-1-infected adults, but escape during infancy has not been described previously. We studied the immune response of perinatally infected children to an epitope (B57-TW10) that is targeted early during acute HIV-1 infection in adults expressing HLA-B57 and rapidly mutates under this selection pressure. Viral sequencing revealed the universal presence of escape mutations within TW10 among B57- and B5801-positive children. Mutations in TW10 and other B57-restricted epitopes arose early following perinatal infection of B57-positive children born to B57-negative mothers. Surprisingly, the majority of B57/5801-positive children exhibited a robust response to the TW10 escape variant while recognizing the wild-type epitope weakly or not at all. These data demonstrate that children, even during the first years of life, are able to mount functional immune responses of sufficient potency to drive immune escape. Moreover, our data suggest that the consequences of immune escape may differ during infancy because most children mount a strong variant-specific immune response following escape, which is rarely seen in adults. Taken together, these findings indicate that the developing immune system of children may exhibit greater plasticity in responding to a continually evolving chronic viral infection.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Immune reconstitution after receipt of highly active antiretroviral therapy in children with advanced or progressive HIV disease and complete or partial viral load response.

We assessed CD4 cell recovery in 175 children with advanced human immunodeficiency virus disease who had received a 4-drug antiretroviral regimen and were categorized as viral load (VL) responders (VLRs), partial VLRs, or non-VLRs. Median CD4 cell counts increased from baseline to week 48, and, among children with maximal follow-up, increases in CD4 cell counts were sustained to week 96 among VLRs and partial VLRs but not among non-VLRs. For VL rebounders still in the study, CD4 cell counts remained increased for 32 weeks after VL rebound. Sustained immunologic benefits can be achieved even with partial VL response in children with advanced disease.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Antiretroviral treatment in pediatric HIV infection in the United States: from clinical trials to clinical practice.

CONTEXT: Antiretroviral therapy (ART) for pediatric human immunodeficiency virus (HIV) infection has evolved from simple nucleoside reverse transcriptase inhibitor (NRTI) regimens to complex combination therapies based largely on evidence from clinical trials. However, the integration of novel ART into the clinical care of pediatric HIV infection has not been examined. OBJECTIVES: To describe changes in the treatment of pediatric HIV infection in the United States from 1987-2003, to assess concordance of initial regimens with US pediatric guidelines, and to identify predictors of the first regimen switch. DESIGN, SETTING, AND PARTICIPANTS: The study population included 766 perinatally HIV-infected children in the Pediatric AIDS Clinical Trials Group 219C cohort born before January 1, 2004, who had not participated in an ART clinical trial at 219C enrollment or during follow-up. MAIN OUTCOME MEASURES: Proportion of children receiving specific ART regimens, proportion of children initiating ART according to pediatric guidelines, and time to first regimen switch (risk of switching). RESULTS: Single and dual NRTI regimens were used most frequently through 1997. In 1998, 2 years after protease inhibitors were approved for adult HIV infection and at the time pediatric guidelines were issued, regimens of highly active antiretroviral therapy including a protease inhibitor became most frequently used. From 1998-2003, 22% of children initiated ART with a regimen not recommended by pediatric guidelines. In multivariate regression, the risk of switching decreased with age at ART initiation (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.94-0.99) and increased with year of initiation (HR, 1.28; 95% CI, 1.23-1.33). The risk of switching was higher in children who started with 1 NRTI (HR, 8.05; 95% CI, 5.80-11.18), 2 NRTIs (HR, 4.08; 95% CI, 3.08-5.40), or an unconventional regimen (HR, 6.23; 95% CI, 3.36-11.54) vs children who started with a protease inhibitor-containing regimen; and in children who initiated ART at CD4 T lymphocyte percentages less than 15 vs 15 or greater (HR, 2.90; 95% CI, 1.03-8.13). CONCLUSIONS: There was a short lag between the identification of novel ART and its adoption in the pediatric community. A variety of regimens were used, including some unorthodox therapies. Important predictors of first regimen switch were identified.

Adolescent↗
PubMed2005

Switch from ritonavir to indinavir in combination therapy for HIV-1-infected children.

BACKGROUND: Protease inhibitors are an effective component of combination antiretroviral treatment for children infected with human immunodeficiency virus 1 (HIV-1), but tolerance or toxicity issues sometimes require an alternative therapeutic strategy. METHODS: HIV-1-infected children aged 2-17 years received combination therapy with either stavudine plus ritonavir or with zidovudine, lamivudine, and ritonavir as part of a randomized clinical trial. Twenty-one months after the start of the trial, ritonavir in capsule formulation became unavailable. The treatment regimen for 25 children was switched from ritonavir capsules to indinavir capsules (500 mg/m(2) every 8 h). The other study drugs remained unchanged. A matched-pairs analysis was performed to compare the results for these 25 children with the results for 25 matched children whose treatment regimen continued to include ritonavir (in liquid formulation). RESULTS: There were no significant differences in the percentage of children with an HIV-1 RNA load of <or=200 copies/mL between the group receiving indinavir and the matched group receiving ritonavir (52% vs. 68%, at the start of indinavir treatment; 42% vs. 52%, at week 12; and 50% vs. 56%, at week 24). Similarly, there were no significant differences between the treatment groups with respect to median CD4 cell counts over time. Toxicities observed in the children treated with indinavir were most often flank pain or headache (16%), renal dysfunction (16%), hematuria (12%), and skin rash (12%) and were consistent with toxicities reported elsewhere. There was no evidence that the switch from ritonavir to indinavir therapy altered the pharmacokinetics of indinavir as a result of residual cytochrome P450 induction or inhibition caused by ritonavir. CONCLUSIONS: The switch from one protease inhibitor (ritonavir) to another (indinavir) as a component of combination antiretroviral treatment in this patient population was a practical therapeutic strategy.

Adolescent↗
PubMed2005

Predictors of immunologic long-term nonprogression in HIV-infected children: implications for initiating therapy.

BACKGROUND: Early markers that predict immunologic long-term nonprogression in infants with perinatally acquired HIV infection might assist in subsequent antiretroviral treatment decisions. OBJECTIVES: We sought to identify early markers of immunologic long-term HIV disease nonprogression. METHODS: We analyzed immunologic and virologic characteristics at 1 and 2 months of age in HIV-infected children who were enrolled in the Women and Infants Transmission Study and born before 1995, comparing immunologic long-term nonprogressors (ILTNPs; n = 10) with non-ILTNPs (n = 127). ILTNPs were children who survived to 8 years or older with CD4 percentages of 25% or greater and counts of 500 cells/mm 3 or more without receiving highly active antiretroviral therapy. Non-ILTNPs were defined as all other HIV-infected children. Receiver operating characteristic curve analysis was used to assess combined sensitivity and specificity for each of these characteristics and to determine potential threshold values to discriminate between ILTNPs and non-ILTNPs. RESULTS: Characteristics in the first 2 months of life associated with ILTNP status in univariate analysis included higher CD4 percentages, lower CD8 + percentages, lower CD8 + HLA-DR + percentages, and lower HIV-1 RNA PCR values. In receiver operating characteristic analysis CD8 + HLA-DR + percentage had the best combined sensitivity and specificity for discriminating between ILTNPs and non-ILTNPs. CD8 + HLA-DR + percentages of 5% or less predicted ILTNP status with 80% sensitivity and 80% specificity. In multivariate analysis CD8 + HLA-DR+ percentage of 5% or less remained a significant predictor of ILTNP status after adjusting for CD3 + CD4 + percentage and HIV-1 RNA PCR value (odds ratio, 15.4; 95% CI, 1.9-124.7). CONCLUSION: CD8 + HLA-DR + T-lymphocyte percentage of less than 5% at 1 to 2 months of age might be predictive for ILTNP status but should not be used at this time to make treatment-deferral decisions. Immune activation in HIV-infected infants might herald more disease progression. Further study of the use of this subpopulation in early infancy to predict ILTNP status is warranted.

CD8-Positive T-Lymphocytes↗
PubMed2005

History and recent advances in coronavirus discovery.

Human coronaviruses, first characterized in the 1960s, are responsible for a substantial proportion of upper respiratory tract infections in children. Since 2003, at least 5 new human coronaviruses have been identified, including the severe acute respiratory syndrome coronavirus, which caused significant morbidity and mortality. NL63, representing a group of newly identified group I coronaviruses that includes NL and the New Haven coronavirus, has been identified worldwide. These viruses are associated with both upper and lower respiratory tract disease and are likely common human pathogens. The global distribution of a newly identified group II coronavirus, HKU1, has not yet been established. Coronavirology has advanced significantly in the past few years. The SARS epidemic put the animal coronaviruses in the spotlight. The background and history relative to this important and expanding research area are reviewed here.

Adult↗
PubMed2005

Neuropsychological functioning and viral load in stable antiretroviral therapy-experienced HIV-infected children.

OBJECTIVE: Neuropsychological functioning and its correlation with viral load were investigated for previously treated HIV-infected children who underwent a change in treatment regimen. METHODS: Thirteen age-appropriate measures of cognitive, neurologic, and behavioral functioning were administered to 489 HIV-infected children who were aged 4 months to 17 years and had been treated previously for at least 16 weeks with antiretroviral therapy. These clinically and immunologically stable children were randomized onto 1 of 7 drug treatment combinations, 6 of which included a protease inhibitor (PI), and evaluated prospectively for 48 weeks with respect to changes in neuropsychological performance and viral load. RESULTS: Neuropsychological functioning was significantly poorer at baseline for the HIV-infected children as compared with established norms for their age. Children with higher viral load had poorer cognitive, both-hands fine-motor, and neurologic signs at baseline, but single-hand fine-motor and behavioral functioning were not correlated with viral load. After 48 weeks of treatment with PI-containing combination therapy, there was significant improvement in only the vocabulary score. Neuropsychological changes did not differ among the 6 PI-containing combination regimens. At week 48, even children with a viral load response below the level of detection (RNA < or =400 copies/mL) still showed poorer neuropsychological functioning compared with established norms. CONCLUSION: Poor neuropsychological functioning was seen for HIV-infected children and was worse for children with higher viral loads. Only 1 measure of neuropsychological functioning showed improvement after treatment with PI-containing combination therapy, and the extent of that improvement was relatively minor. Treatment strategies for children with HIV disease need to be reevaluated so that they consider restoration of neuropsychological functioning in addition to lowering the viral load.

Adolescent↗