Testing of an oral dosing technique for double-crested cormorants, Phalacocorax auritus, laughing gulls, Leucophaeus atricilla, homing pigeons, Columba livia, and western sandpipers, Calidris mauri, with artificially weather MC252 oil.

Scoping studies were designed to determine if double-crested cormorants (Phalacocorax auritus), laughing gulls (Leucophaues atricilla), homing pigeons (Columba livia) and western sandpipers (Calidris mauri) that were gavaged with a mixture of artificially weathered MC252 oil and food for either a single day or 4-5 consecutive days showed signs of oil toxicity. Where volume allowed, samples were collected for hematology, plasma protein electrophoresis, clinical chemistry and electrolytes, oxidative stress and organ weigh changes. Double-crested cormorants, laughing gulls and western sandpipers all excreted oil within 30min of dose, while pigeons regurgitated within less than one hour of dosing. There were species differences in the effectiveness of the dosing technique, with double-crested cormorants having the greatest number of responsive endpoints at the completion of the trial. Statistically significant changes in packed cell volume, white cell counts, alkaline phosphatase, alanine aminotransferase, creatine phosphokinase, gamma glutamyl transferase, uric acid, chloride, sodium, potassium, calcium, total glutathione, glutathione disulfide, reduced glutathione, spleen and liver weights were measured in double-crested cormorants. Homing pigeons had statistically significant changes in creatine phosphokinase, total glutathione, glutathione disulfide, reduced glutathione and Trolox equivalents. Laughing gulls exhibited statistically significant decreases in spleen and kidney weight, and no changes were observed in any measurement endpoints tested in western sandpipers.

Reprint of: Overview of avian toxicity studies for the Deepwater Horizon Natural Resource Damage Assessment.

The Oil Pollution Act of 1990 establishes liability for injuries to natural resources because of the release or threat of release of oil. Assessment of injury to natural resources resulting from an oil spill and development and implementation of a plan for the restoration, rehabilitation, replacement or acquisition of natural resources to compensate for those injuries is accomplished through the Natural Resource Damage Assessment (NRDA) process. The NRDA process began within a week of the Deepwater Horizon oil spill, which occurred on April 20, 2010. During the spill, more than 8500 dead and impaired birds representing at least 93 avian species were collected. In addition, there were more than 3500 birds observed to be visibly oiled. While information in the literature at the time helped to identify some of the effects of oil on birds, it was not sufficient to fully characterize the nature and extent of the injuries to the thousands of live oiled birds, or to quantify those injuries in terms of effects on bird viability. As a result, the US Fish and Wildlife Service proposed various assessment activities to inform NRDA injury determination and quantification analyses associated with the Deepwater Horizon oil spill, including avian toxicity studies. The goal of these studies was to evaluate the effects of oral exposure to 1-20ml of artificially weathered Mississippi Canyon 252 oil kg bw-1 day-1 from one to 28 days or one to five applications of oil to 20% of the bird's surface area. It was thought that these exposure levels would not result in immediate or short-term mortality but might result in physiological effects that ultimately could affect avian survival, reproduction and health. These studies included oral dosing studies, an external dosing study, metabolic and flight performance studies and field-based flight studies. Results of these studies indicated changes in hematologic endpoints including formation of Heinz bodies and changes in cell counts. There were also effects on multiple organ systems, cardiac function and oxidative status. External oiling affected flight patterns and time spent during flight tasks indicating that migration may be affected by short-term repeated exposure to oil. Feather damage also resulted in increased heat loss and energetic demands. The papers in this special issue indicate that the combined effects of oil toxicity and feather effects in avian species, even in the case of relatively light oiling, can significantly affect the overall health of birds.

Overview of avian toxicity studies for the Deepwater Horizon Natural Resource Damage Assessment.

The Oil Pollution Act of 1990 establishes liability for injuries to natural resources because of the release or threat of release of oil. Assessment of injury to natural resources resulting from an oil spill and development and implementation of a plan for the restoration, rehabilitation, replacement or acquisition of natural resources to compensate for those injuries is accomplished through the Natural Resource Damage Assessment (NRDA) process. The NRDA process began within a week of the Deepwater Horizon oil spill, which occurred on April 20, 2010. During the spill, more than 8500 dead and impaired birds representing at least 93 avian species were collected. In addition, there were more than 3500 birds observed to be visibly oiled. While information in the literature at the time helped to identify some of the effects of oil on birds, it was not sufficient to fully characterize the nature and extent of the injuries to the thousands of live oiled birds, or to quantify those injuries in terms of effects on bird viability. As a result, the US Fish and Wildlife Service proposed various assessment activities to inform NRDA injury determination and quantification analyses associated with the Deepwater Horizon oil spill, including avian toxicity studies. The goal of these studies was to evaluate the effects of oral exposure to 1-20ml of artificially weathered Mississippi Canyon 252 oil kg bw-1 day-1 from one to 28 days or one to five applications of oil to 20% of the bird's surface area. It was thought that these exposure levels would not result in immediate or short-term mortality but might result in physiological effects that ultimately could affect avian survival, reproduction and health. These studies included oral dosing studies, an external dosing study, metabolic and flight performance studies and field-based flight studies. Results of these studies indicated changes in hematologic endpoints including formation of Heinz bodies and changes in cell counts. There were also effects on multiple organ systems, cardiac function and oxidative status. External oiling affected flight patterns and time spent during flight tasks indicating that migration may be affected by short-term repeated exposure to oil. Feather damage also resulted in increased heat loss and energetic demands. The papers in this special issue indicate that the combined effects of oil toxicity and feather effects in avian species, even in the case of relatively light oiling, can significantly affect the overall health of birds.

Discordance between CD4 cell count and CD4 cell percentage: implications for when to start antiretroviral therapy in HIV-1 infected children.

OBJECTIVE: Antiretroviral therapy (ART) guidelines for HIV-1-infected children specify both absolute CD4 cell count and CD4 percentage thresholds at which consideration should be given to initiating ART. This leads to clinical dilemma when one marker is below the threshold, whereas the other is above. DESIGN: Data were obtained on a large group of children followed longitudinally in trials and cohort studies in Europe and the USA. Follow-up was censored 6 months after the start of any antiretroviral drug other than zidovudine monotherapy. METHODS: Discordance between CD4 cell count and percentage was defined in relation to ART initiation thresholds in World Health Organization (WHO) and European paediatric treatment guidelines. The relative prognostic value of CD4 cell count and percentage for progression to AIDS/death was investigated using time-updated Cox proportional hazards models, stratified by age. RESULTS: Among 3345 children, with a total of 21,815 pairs of CD4 measurements analysed, 980 developed AIDS and/or died after a median follow-up of 1.7 years. Over one-half of children had discordant values of CD4 cell markers at the first visit when one or both treatment thresholds were crossed and approximately one-third had the same pattern of discordance at a subsequent measurement. Models suggested that CD4 percentage had little or no prognostic value over and above that contained in CD4 cell count, irrespective of age. CONCLUSIONS: More emphasis should be placed on CD4 cell count than on CD4 percentage in deciding when to start ART in HIV-1-infected children.

Predictors of growth and body composition in HIV-infected children beginning or changing antiretroviral therapy.

OBJECTIVES: The aim of the study was to describe growth and body composition changes in HIV-positive children after they had initiated or changed antiretroviral therapy (ART) and to correlate these with viral, immune and treatment parameters. METHODS: Ninety-seven prepubertal HIV-positive children were observed over 48 weeks upon beginning or changing ART. Anthropometry and bioelectrical impedance analysis results were compared with results from the National Health and Nutrition Examination Survey 1999-2002 (NHANES) to generate z-scores and with results for HIV-exposed, uninfected children from the Women and Infants Transmission Study (WITS). Multivariate analysis was used to evaluate associations between growth and body composition and disease parameters. RESULTS: All baseline lean and fat mass measures were below those of controls from NHANES. Weight, height and fat free mass (FFM) index (FFM/height(2)) z-scores increased over time (P = 0.004, 0.037 and 0.027, respectively) and the waist:height ratio z-score decreased (P = 0.045), but body mass index and per cent body fat z-scores did not change. Measures did not increase more than in uninfected WITS controls. In multivariate analysis, baseline height, mid-thigh circumference and FFM z-scores related to CD4 percentage (P = 0.029, P = 0.008 and 0.020, respectively) and change in FFM and FFM index z-scores to CD4 percentage increase (P = 0.010 and 0.011, respectively). Compared with WITS controls, baseline differences in height and mid-thigh muscle circumference were also associated with CD4 percentage. Case-control differences in change in both subscapular skinfold (SSF) thickness and the SSF:triceps skinfold ratio were inversely associated with viral suppression. No measures related to ART class(es) at baseline or over time. CONCLUSIONS: In these HIV-positive children, beginning or changing ART was associated with improved growth and lean body mass (LBM), as indicated by FFM index. Height and LBM related to CD4 percentage at baseline and over time. Altered fat distribution and greater central adiposity were associated with detectable virus but not ART class(es) received.

Cognitive performance predicts treatment decisional abilities in mild to moderate dementia.

OBJECTIVE: To examine the contribution of neuropsychological test performance to treatment decision-making capacity in community volunteers with mild to moderate dementia. METHODS: The authors recruited volunteers (44 men, 44 women) with mild to moderate dementia from the community. Subjects completed a battery of 11 neuropsychological tests that assessed auditory and visual attention, logical memory, language, and executive function. To measure decision making capacity, the authors administered the Capacity to Consent to Treatment Interview, the Hopemont Capacity Assessment Interview, and the MacCarthur Competence Assessment Tool--Treatment. Each of these instruments individually scores four decisional abilities serving capacity: understanding, appreciation, reasoning, and expression of choice. The authors used principal components analysis to generate component scores for each ability across instruments, and to extract principal components for neuropsychological performance. RESULTS: Multiple linear regression analyses demonstrated that neuropsychological performance significantly predicted all four abilities. Specifically, it predicted 77.8% of the common variance for understanding, 39.4% for reasoning, 24.6% for appreciation, and 10.2% for expression of choice. Except for reasoning and appreciation, neuropsychological predictor (beta) profiles were unique for each ability. CONCLUSIONS: Neuropsychological performance substantially and differentially predicted capacity for treatment decisions in individuals with mild to moderate dementia. Relationships between elemental cognitive function and decisional capacity may differ in individuals whose decisional capacity is impaired by other disorders, such as mental illness.

Alternatives to HIV-1 RNA concentration and CD4 count to predict mortality in HIV-1-infected children in resource-poor settings.

Cheaper, simpler alternatives to CD4 lymphocyte count and HIV-1 RNA detection for assessing the prognosis of HIV-1 infection are needed for resource-poor settings. However, little is known about the predictive value of alternative assays, in particular in children. We assessed the prognostic value of total lymphocyte count, immune complex-dissociated p24 antigen, white blood cell count, packed-cell volume (haematocrit), and serum albumin for mortality in 376 HIV-1-infected, mainly African-American or Hispanic children enrolled during March, 1988 to January, 1991. In a Cox proportional hazards model, including all assay-alternatives to CD4 and RNA, total lymphocyte count (p<0.0001) and serum albumin (p=0.0107) independently predicted mortality. Further assessment of these markers is warranted in resource-poor settings.

Impact of protease inhibitor-containing combination antiretroviral therapies on height and weight growth in HIV-infected children.

OBJECTIVE: To examine beneficial or detrimental effects of protease inhibitor (PI)-containing antiretroviral regimens on height and weight growth in children with human immunodeficiency virus (HIV) infection. METHODS: A prospective cohort study was conducted of 906 HIV-infected children, from pediatric research clinics in the United States, who were between 3 months and 18 years of age and who had height and weight assessed in 1995 (before introduction of PIs in this population) and at least once more through 1999. Changes in age- and gender-adjusted height and weight growth associated with PI use were assessed. RESULTS: Compared with a healthy reference population, children were more affected in height (mean z score: -0.90 [18th percentile]) than in weight (mean z score: -0.42 [34th percentile]) at baseline (1995). Two thirds of children received at least 1 PI during 1996 to 1999. In the multivariate mixed effects regression models adjusted for baseline log(10) CD4 cell count, baseline age, gender, and race/ethnicity, the use of PIs was associated with per-year gains of 0.13 z scores in height and 0.05 z scores in weight relative to the expected growth with non-PI-containing regimens (eg, after 1 year of PI use, a representative 6-year-old boy in our study would be approximately 0.7 cm taller and 0.1 kg heavier than if he had not received PIs). No significant differential effects of PIs on height or weight growth according to specific agents or children's sociodemographic or clinical characteristics were found. CONCLUSIONS: Although the use of PI-containing regimens was not associated with growth retardation, it was associated with only small annual increments in height and weight growth in HIV-infected children.

UPBEAT: the impact of a psychogeriatric intervention in VA medical centers. Unified Psychogeriatric Biopsychosocial Evaluation and Treatment.

BACKGROUND: The Unified Psychogeriatric Biopsychosocial Evaluation and Treatment (UPBEAT) program provides individualized interdisciplinary mental health treatment and care coordination to elderly veterans whose comorbid depression, anxiety, or alcohol abuse may result in overuse of inpatient services and underuse of outpatient services. OBJECTIVES: To determine whether proactive screening of hospitalized patients can identify unrecognized comorbid psychiatric conditions and whether comprehensive assessment and psychogeriatric intervention can improve care while reducing inpatient use. DESIGN: Randomized trial. SUBJECTS: Veterans aged 60 and older hospitalized for nonpsychiatric medical or surgical treatment in 9 VA sites (UPBEAT, 814; usual care, 873). MEASURES: The Mental Health Inventory (MHI) anxiety and depression subscales, the Alcohol Use Disorder Identification Test (AUDIT) scores, RAND 36-Item Health Survey Short Form (SF-36), inpatient days and costs, ambulatory care clinic stops and costs, and mortality and readmission rates. RESULTS: Mental health and general health status scores improved equally from baseline to 12-month follow-up in both groups. UPBEAT increased outpatient costs by $1,171 (P <0.001) per patient, but lowered inpatient costs by $3,027 (P = 0.017), for an overall savings of $1,856 (P = 0.156). Inpatient savings were attributable to fewer bed days of care (3.30 days; P = 0.016) rather than fewer admissions. Patients with 1 or more pre-enrollment and postenrollment hospitalizations had the greatest overall savings ($6,015; P = 0.069). CONCLUSIONS: UPBEAT appears to accelerate the transition from inpatient to outpatient care for acute nonpsychiatric admissions. Care coordination and increased access to ambulatory psychiatric services produces similar improvement in mental health and general health status as usual care.

Recombinant CD4-IgG2 in human immunodeficiency virus type 1-infected children: phase 1/2 study. The Pediatric AIDS Clinical Trials Group Protocol 351 Study Team.

The use of recombinant CD4-IgG2 in pediatric human immunodeficiency virus type 1 (HIV-1) infection was evaluated by single and multidose intravenous infusions in 18 children in a phase 1/2 study. The study drug was well tolerated, and dose proportionality was observed in terms of area under time-concentration curve and peak serum concentration. Acute decreases of >0.7 log(10) copies/mL in serum HIV-1 RNA concentration were seen in 4 of the 6 children treated with 4 weekly 10 mg/kg doses. At 14 days after treatment, 3 children had sustained reductions in serum HIV-1 RNA; the other children had rebounded to baseline levels or above. By 28 days after therapy, the peak HIV-1 cellular infectious units was reduced in all 6 children, including the 2 who had experienced an earlier transient increase in values. Thus, recombinant CD4-IgG2 treatment of HIV-1-infected children appears to be well tolerated and capable of reducing HIV-1 burden.

Treatment-mediated changes in human immunodeficiency virus (HIV) type 1 RNA and CD4 cell counts as predictors of weight growth failure, cognitive decline, and survival in HIV-infected children.

This meta-analysis of 5 large studies of the Pediatric AIDS Clinical Trials Group was undertaken to evaluate the predictive value of antiretroviral treatment-mediated changes in 3 markers of human immunodeficiency virus (HIV) type 1 disease progression-HIV-1 RNA level, CD4 cell count, and CD4 percentage-for weight growth failure, cognitive decline, and survival in HIV-infected children. Proportional hazards models were used to assess the prognostic value of the markers at baseline and after 24 weeks of treatment, with data from 1089 children. Among children receiving nucleoside with or without nonnucleoside reverse-transcriptase inhibitors, higher immunologic and lower virologic markers at baseline and after 24 weeks were significant independent predictors of survival, whereas virologic markers were significant predictors of weight growth and cognitive failure in children >1 year old. The finding of differential age effects on pediatric-specific clinical outcomes emphasizes the need for continued investigation of treatment effects in children.

Timing of perinatal human immunodeficiency virus type 1 infection and rate of neurodevelopment. The Women and Infant Transmission Study Group.

BACKGROUND: Identifying HIV-1-infected children who are at greatest risk for disease-related morbidities is critical for optimal therapeutic as well as preventive care. Several factors have been implicated in HIV-1 disease onset and severity, including maternal and infant host characteristics, viral phenotype and timing of HIV-1 infection. Early HIV-1 culture positivity, i.e. intrauterine infection, has been associated with poor immunologic, virologic and clinical outcomes in children of HIV-infected women. However, a direct effect of timing of infection on neurodevelopmental outcome in infancy has not yet been identified. METHODS: Serial neurodevelopmental assessments were performed with 114 infants vertically infected with HIV-1 in a multicenter natural history, longitudinal study. Median mental and motor scores were compared at three time points. Longitudinal regression analyses were used to evaluate the neurodevelopmental functioning of children with early positive cultures and those with late positive cultures. RESULTS: Early infected infants scored significantly lower than late infected infants by 24 months of age and beyond on both mental (P = 0.05) and motor (P = 0.03) measures. Early HIV-1 infection was associated with a decline in estimated motor scores of 1 standard score point per month compared with 0.28 point in the late infected group (P < 0.02). Estimated mental scores of the early infected group declined 0.72 point/ month, whereas the average decline of the late infected group was 0.30 point/month (P < 0.13). CONCLUSION: Early HIV-1 infection increases a child's risk for poor neurodevelopmental functioning within the first 30 months of life.

Combination nucleoside analog reverse transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children: week 24 results of a randomized controlled trial--PACTG 377. Pediatric AIDS Clinical Trials Group 377 Study Team.

One hundred eighty-one antiretroviral-experienced, protease inhibitor-naive, clinically stable HIV-infected children between 4 months and 17 years of age were randomly assigned to receive one of four combination regimens to evaluate the change in plasma HIV RNA, safety, and tolerance when changing antiretroviral therapy to a protease inhibitor-containing combination regimen. All four regimens contained stavudine; in addition children received nevirapine plus ritonavir, lamivudine plus nelfinavir, nevirapine plus nelfinavir, or lamivudine plus nevirapine plus nelfinavir. Twelve additional children chose to receive stavudine plus lamivudine plus nelfinavir, with nelfinavir given bid, rather than tid as for the main regimens. Overall, 51% (89/176; 95% CI 43-58%) of the children on the randomized portion of the study had an HIV RNA response (< or =400 copies/ml) on at least two of the three HIV RNA determinations taken at Weeks 8, 12, and 16. At Week 24 the proportion of children with an HIV RNA response still on initial therapy was 47% (83/176; 95% CI 40-55%) and ranged from 41 to 61% for the four randomized treatment arms. Rash was frequently seen (27%) on the treatment arms containing nevirapine. At Week 24 64% (7/11, 95% CI 31-89%) of the children on the bid nelfinavir combination regimen were still on initial therapy with an HIV RNA response as compared with 46% (23/50; 95% CI 32-61%) on the corresponding tid nelfinavir combination regimen. A change in antiretroviral therapy to a protease inhibitor-containing regimen was associated with a virological response rate of approximately 50% for this patient population.

Early cognitive and motor development among infants born to women infected with human immunodeficiency virus. Women and Infants Transmission Study Group.

OBJECTIVE: To examine the frequency, timing, and factors associated with abnormal cognitive and motor development during the first 30 months of life in infants born to women infected with human immunodeficiency virus type 1 (HIV-1). METHODS: Serial neurodevelopmental assessment was performed with 595 infants born to women infected with HIV-1 in a multicenter, prospective, natural history cohort study. Survival analysis methods were used to evaluate 6 outcome events related to abnormal cognitive and motor growth (time to confirmed drop of 1 SD, time to first score <69, and time to confirmed drop of 2 SD) in Bayley Scales of Infant Development Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) scores among infected (n = 114) and uninfected (n = 481) infants. Proportional hazards modeling was used to evaluate the effects of HIV infection status, prematurity, prenatal exposure to illicit drugs, maternal educational attainment, and primary language. RESULTS: HIV-1 infection was significantly associated with increased risk for all outcome events related to abnormal mental and motor growth. Differences between infected and uninfected infants were apparent by 4 months of age. Prematurity was associated with increased risk for MDI <69 and PDI <69. Maternal education of <9 completed years was associated with increased risk for MDI <69. Neither prenatal exposure to illicit drugs nor primary language other than English was associated with abnormal development. CONCLUSION: A significant proportion of infants with HIV-1 infection show early and marked cognitive and motor delays or declines that may be important early indicators of HIV disease progression. These abnormalities are independent of other risk factors for developmental delay.

Interventions to prevent vertical transmission of HIV-1: effect on viral detection rate in early infant samples.

OBJECTIVE: To determine whether mode of delivery or the use of maternal or neonatal antiretroviral prophylaxis influence the age when HIV-1 can first be detected in infected infants, particularly the probability of detection at birth. METHODS: In a collaboration between four multicentre studies, data on 422 HIV-1 infected infants who were assessed by HIV-1 DNA PCR or cell culture before 14 days of age were analysed. Weibull mixture models were used to estimate the cumulative proportion of infants with detectable levels of HIV-1 according to use of maternal/neonatal antiretroviral therapy (mainly zidovudine monotherapy) and mode of delivery. RESULTS: HIV-1 was detected in 162 infants (38%) when they were first tested, at a median age of 2 days. At birth, it was estimated that 36% [95% confidence interval (CI), 31-41%] of infants have levels of virus that can be detected by DNA PCR or cell culture. This percentage was not associated with either mode of delivery (35% for vaginal delivery versus 40% for cesarean section delivery; P = 0.4) or the use of maternal or neonatal antiretroviral prophylaxis. Among infants with undetectable levels of HIV-1 at birth, the median time to viral detectability was estimated to be 14.8 days (95% CI, 12.9-16.8 days). This time was increased by 15% (95% CI, -11 to 48%; P = 0.3) among infants who were exposed to antiretroviral therapy postnatally compared with infants who were not exposed. No effect was observed for mode of delivery. CONCLUSIONS: The outcome of an early virological test for HIV-1 is thought to be related directly to the timing of transmission and cesarean section delivery primarily reduces the risk of intrapartum transmission. The absence of an association between mode of delivery and viral detectability at birth was therefore unexpected. There was no evidence that foetal or neonatal exposure to prophylactic zidovudine delays substantially the diagnosis of infection, although this cannot be inferred for combination antiretroviral therapy.

Quantification of human immunodeficiency virus type 1 p24 antigen and antibody rivals human immunodeficiency virus type 1 RNA and CD4+ enumeration for prognosis. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group.

BACKGROUND: The sensitivity, specificity and positive predictive value of baseline serum concentrations of HIV-1 immune complex-dissociated (ICD) p24 antigen for predicting disease progression and mortality were assessed and compared with results obtained for HIV-1 ICD p24 antigen with HIV-1 p24 antibody and for HIV-1 RNA with CD4+ lymphocyte percent. METHODS: Data from HIV-infected children enrolled in a North American clinical trial (National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial) were analyzed. Disease progression was defined as growth failure, CD4+ lymphocyte percent decline to <15% after study entry or development of an AIDS-defining opportunistic infection. RESULTS: Baseline samples were available for ICD p24 antigen testing (median concentration, 319 pg/ml; range, <50 to 15,640) in 240 children. The combination of detectable ICD p24 antigen and low p24 antibody was more sensitive but less specific than the combination of high HIV-1 RNA and low CD4+ lymphocyte percent in predicting disease progression and mortality. Using receiver operating characteristic curves, the specificity of ICD p24 antigen with p24 antibody for classifying children's disease progression or mortality was as great as, or greater than, HIV-1 RNA with CD4+ lymphocyte percent at points on the curve corresponding to higher sensitivity. CONCLUSIONS: The use of ICD p24 antigen with p24 antibody to identify children at high risk of disease progression or mortality could be a viable alternative to the more expensive and technically difficult HIV-1 RNA and CD4+ lymphocyte assays in resource-poor settings, including developing countries where the majority of children with HIV-1 infection reside.

HIV-1 genotypic zidovudine drug resistance and the risk of maternal--infant transmission in the women and infants transmission study. The Women and Infants Transmission Study Group.

OBJECTIVES: Although the treatment of pregnant women and their infants with zidovudine (ZDV) has been remarkably effective in preventing the perinatal transmission of human HIV-1, many potentially preventable infections still occur. To examine whether the risk of perinatal infection is increased among women who carry ZDV-resistant HIV-1, the role of genotypic ZDV resistance in perinatal transmission was evaluated. METHODS: The reverse transcriptase (RT) region of clinical isolates from culture supernatants of 142 HIV-1-infected women enrolled in the Women and Infants Transmission Study (WITS), who had been treated with ZDV during pregnancy was sequenced. Results from genotypic sequencing were linked to demographic, laboratory, and obstetrical databases, and the magnitude of association of having consensus drug-resistant HIV-1 RT mutations with transmission was estimated. RESULTS: Twenty-five per cent (34/142) of maternal isolates had at least one ZDV-associated resistance mutation. A lower CD4 cell percentage and count (P= 0.0001) and higher plasma HIV-1 RNA (P=0.006) were associated with having any ZDV resistance mutation at delivery. Having any RT resistance mutation [odds ratio (OR): 5.16; 95% confidence interval (CI): 1.40, 18.97; P=0 0.01], duration of ruptured membranes [OR: 1.13 (1.02, 1.26) per 4 h duration; P= 0.02], and total lymphocyte count [OR: 1.06 (1.01, 1.10) per 50 cells higher level; P=0.009] were independently associated with transmission in multivariate analysis. CONCLUSION: Maternal ZDV resistant virus was predictive of transmission, independent of viral load, in these mothers with moderately advanced HIV-1 disease, many of whom had been treated with ZDV before pregnancy.

Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team.

BACKGROUND: Maternal, obstetrical, and infant-related factors associated with the risk of perinatal transmission of human immunodeficiency virus type 1 (HIV-1) were identified before the widespread use of zidovudine therapy in pregnant women. The risk factors for transmission when women and infants receive zidovudine are not well characterized. METHODS: We examined the effects of maternal, obstetrical, and infant-related characteristics and maternal virologic and immunologic variables on the risk of perinatal transmission of HIV-1 among 480 women and their infants, all of whom received zidovudine. The women and infants were participating in a phase 3 trial of passive immunoprophylaxis for the prevention of perinatal transmission. RESULTS: In univariate analyses, the risk of perinatal transmission was associated with each of the following: decreased maternal CD4+ lymphocyte counts at base line; decreased maternal HIV p24 antibody levels at base line and delivery; increased maternal HIV-1 titer at base line and delivery; increased maternal HIV-1 RNA levels at base line and delivery; and the presence of chorioamnionitis at delivery. In multivariate analyses, the only independent risk factor was the maternal HIV-1 RNA level at base line (odds ratio for transmission, 2.4 per log increase in the number of copies; 95 percent confidence interval, 1.2 to 4.7; P=0.02) and at delivery (odds ratio, 3.4; 95 percent confidence interval, 1.7 to 6.8; P=0.001). There was no perinatal transmission of HIV-1 among the 84 women who had HIV-1 levels below the limit of detection (500 copies per milliliter) at base line or the 107 women who had undetectable levels at delivery. CONCLUSIONS: Among pregnant women and their infants, all treated with zidovudine, the maternal plasma HIV-1 RNA level was the best predictor of the risk of perinatal transmission of HIV-1. Antiretroviral therapy that reduces the HIV-1 RNA level to below 500 copies per milliliter appears to minimize the risk of perinatal transmission as well as improve the health of the women.

Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group.

BACKGROUND: The importance of plasma levels of human immunodeficiency virus type 1 (HIV-1) RNA in pregnant women in relation to the other factors known to influence the risk of transmission of infection to their infants is incompletely defined. We studied the relation of maternal plasma HIV-1 RNA levels to the risk of perinatal transmission and the timing of transmission. METHODS: We measured plasma HIV-1 RNA serially in 552 women with HIV-1 infection who had singleton pregnancies. The status of infection in their infants was assessed by culture of blood and further classified as early (if a culture of blood obtained within the first two days of life was positive) or late (if a culture of blood obtained in the first seven days of life was negative but subsequent cultures were positive). The rates of transmission at various levels of maternal plasma HIV-1 RNA were analyzed by tests for trend, with adjustment for covariates by stratification and logistic regression. RESULTS: Increasing geometric mean levels of plasma HIV-1 RNA were associated with increasing rates of transmission: the rate was 0 percent among women with less than 1000 copies per milliliter (0 of 57), 16.6 percent among women with 1000 to 10,000 copies per milliliter (32 of 193), 21.3 percent among women with 10,001 to 50,000 copies per milliliter (39 of 183), 30.9 percent among women with 50,001 to 100,000 copies per milliliter (17 of 55), and 40.6 percent among women with more than 100,000 copies per milliliter (26 of 64) (P<0.001). The treatment status of one woman was unknown. The highest rate of transmission was among women whose plasma HIV-1 RNA levels exceeded 100,000 copies per milliliter and who had not received zidovudine (19 of 30 women, 63.3 percent). Neither higher HIV-1 RNA levels early in pregnancy nor higher levels late in pregnancy were associated with the timing of infection in the infants. CONCLUSIONS: In pregnant women with HIV-1 infection the level of plasma HIV-1 RNA predicts the risk but not the timing of transmission of HIV-1 to their infants.

Serum HIV-1 p24 antibody, HIV-1 RNA copy number and CD4 lymphocyte percentage are independently associated with risk of mortality in HIV-1-infected children. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group.

OBJECTIVE: The role of HIV-1 antibody in modulating disease progression must be assessed in the context of other immune and viral load markers. We evaluated the association between HIV-1 p24 antibody, HIV-1 RNA, immune complex-dissociated (ICD) p24 antigen, CD4 cell percentage, and mortality in a cohort of 218 HIV-infected children enrolled in a trial of intravenous immunoglobulin prophylaxis of bacterial infections. METHODS: CD4 cell percentage was measured and sera collected and stored at baseline and every 3 months on study (1988-1991). Stored sera were assayed for HIV-1 p24 antibody, HIV-1 RNA, and ICD p24 antigen. Mortality was recorded during the trial and updated through 1996 (mean total follow-up, 6.3 years). RESULTS: Eighty-one (37%) children died; probability of mortality for children with baseline HIV-1 p24 antibody concentrations of undetectable (< 1), 1-4, 5-124, and > or = 125 reciprocal titer units (RTU) was 61, 50, 24, and 10%, respectively. A 3.5-fold increase in the relative risk (RR) of death [95% confidence interval (CI), 2.2-5.5] was observed among children with baseline HIV-1 p24 antibody concentration < 5 RTU compared with > or = 5 RTU. In multivariate analyses, p24 antibody, HIV-1 RNA, and CD4 cell percentage but not ICD p24 antigen were independently associated with mortality; the RR of death increased by 1.7 (95% CI, 1.3-2.1) for each log10 decrement in baseline HIV-1 p24 antibody. CONCLUSIONS: HIV-1 p24 antibody, HIV-1 RNA and CD4 cell percentage independently predict mortality amongst infected children. Whereas CD4 cell percentage provides an estimate of the general degree of immune suppression, HIV-1 p24 antibody could provide an easily obtained, inexpensive assessment of CD4 cell function and could augment prognostic information provided by CD4 cell count and viral load for clinical management of infected children.