Growth velocity, fat-free mass and energy intake are inversely related to viral load in HIV-infected children.

The study objectives were to assess the relationships among human immunodeficiency virus (HIV) replication, energy balance, body composition and growth in children with HIV-associated growth failure (GF). Energy intake and expenditure, body composition and level of HIV RNA were measured in 16 HIV-infected children with growth failure (HIV+/GF+), defined as a 12-mo height velocity

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.

Psoriasis associated with human immunodeficiency virus in an infant.

Psoriasis is commonly reported in association with HIV in adults. A 3-month-old girl with HIV presented with a widespread eruption and was diagnosed with psoriasis. This is the first infant reported with psoriasis in association with HIV infection. The relationship between the two entities is discussed, as is the role of treatment with zidovudine.

Distinct risk factors for intrauterine and intrapartum human immunodeficiency virus transmission and consequences for disease progression in infected children. Perinatal AIDS Collaborative Transmission Study.

Predictors and prognosis of intrauterine and intrapartum human immunodeficiency virus (HIV) transmission were investigated among 432 children of HIV-infected women in the Perinatal AIDS Collaborative Transmission Study. Timing of transmission was inferred from polymerase chain reaction or viral culture within 2 days of birth. Proportions of infections due to intrauterine transmission were similar among women using (29%) or not using zidovudine (30%). Preterm delivery was strongly associated with intrapartum transmission (relative risk, 3.7; 95% confidence interval [CI], 2.2-6.1), particularly among infants delivered longer after membrane rupture, but was not associated with intrauterine transmission. Progression to AIDS or death increased 2.5-fold (95% CI, 1.1-5.8) among intrauterine infected children, adjusting for preterm delivery, and maternal CD4 cell count. Early transmission appears unlikely to explain instances of zidovudine failure. Preterm infants may be more vulnerable to HIV acquisition at delivery, especially if membrane rupture is prolonged. Intrauterine infection does not appear to increase risk of preterm delivery.

Effects of ZDV-based patient education on intentions toward ZDV use, HIV testing and reproduction among a US cohort of women.

This study examined the immediate effects of exposure to a patient education brochure concerning the risks and benefits of zidovudine (ZDV) therapy during pregnancy to reduce perinatal HIV transmission (protocol ACTG 076) on related knowledge, behavioural intentions and attitudes of women with and at-risk for HIV-infection. Self-reports were collected from 653 women of childbearing age from community family planning clinics and hospital-based HIV centres in 19 sites from nine US cities between May and November 1995. The intervention was a nine-page patient education brochure in Spanish, Creole and English versions, evently presenting the pros and cons of ZDV therapy to reduce perinatal HIV-transmission. Brochure exposure increased knowledge (p < 0.001) for all but one scale concerning ZDV resistance and increased the likelihood of women reporting intentions to take ZDV during pregnancy (p < 0.001) and to believe ZDV reduced transmission (p < 0.001). Brochure exposure had differential effects for some subpopulations. Intentions to have or terminate current or future pregnancies, knowledge about ZDV and attitudes toward ZDV varied mostly by ethnicity/race, language preference and HIV status. Pregnancy status, age, education and having an HIV-positive child had less impact on the brochure's effect, while income had no impact.

Mitochondrial oxidative metabolism during respiratory infection in riboflavin deficient mice.

Studies in children and mice have shown that respiratory infection alters riboflavin metabolism, resulting in increased urinary loss of this vitamin. This could be due to mobilization of riboflavin from the liver to blood because liver Flavin adenine dinucleotide (FAD) levels were lowered in the mice during infection. To understand the functional implications of lowered hepatic FAD levels during respiratory infection, flavoprotein functions such as oxidative phosphorylation and beta-oxidation of the liver mitochondria were examined during infection in mice. Weanling mice were fed either riboflavin-restricted or control diet for 18 days and then injected with a sublethal dose of Klebsiella pneumoniae. During infection, the state 3 respiratory rate with palmitoyl-L-carnitine and glutamate were significantly lowered (27-29%) in the riboflavin-restricted group, whereas in the control group 10% reduction was observed with palmitoyl-L-carnitine as substrate. A 22% reduction in the respiratory control ratio with palmitoyl-L-carnitine as substrate was observed during infection in the riboflavin-restricted group. The beta-oxidation of palmitoyl-L-carnitine was significantly lowered (29%) in the riboflavin-restricted infected group. The results of the study suggest that the effects of infection on vital physiologic functions were more pronounced in the riboflavin-restricted mice than in the control mice.

Association of human immunodeficiency virus (HIV) load early in life with disease progression among HIV-infected infants. New York City Perinatal HIV Transmission Collaborative Study Group.

The utility of RNA virus load to predict progression of human immunodeficiency virus (HIV)-1 disease was assessed in 89 HIV-1-infected children. Of 22 virus load values during week 1 of life, 17 were below the detection threshold. Geometric mean virus load increased to approximately 7 x 10(5) copies/mL by week 4, was sustained throughout the first 6 months of life, and then declined to 1.6 x 10(5) copies/mL during the third year. Samples from week 1 of life had little predictive value, but virus load during days 7-30 strongly predicted progression to CDC-3 classification or death (P = .024; risk ratio = 1.6), and virus load during months 2-3 predicted progression to CDC-C or death within the first 6 months of life (P = .002, risk ratio = 11). Virus load was highly associated with imminent vulnerability to CDC-C or death (P = .002) during the first 18 months of life. Except for values from the first week of life, virus load at any age through 18 months is strongly associated with risk of HIV disease progression.

Body composition in prepubertal children with human immunodeficiency virus type 1 infection.

OBJECTIVE: To characterize the body composition of human immunodeficiency virus (HIV)-infected children, especially those with growth failure (GF), using laboratory-based methods. DESIGN: A cross-sectional study of body composition measurements. SETTING: Urban, hospital-based body composition laboratory. PARTICIPANTS: Thirty-four prepubertal children with HIV infection, aged 4 to 11 years, recruited from a pediatric HIV clinic. Eighteen HIV-infected children with GF, 16 HIV-infected children with normal rates of growth, and 52 healthy children were studied. MAIN OUTCOME MEASUREMENTS: Anthropometrics, body cell mass (BCM) by total body potassium counting, body fat percent, fat mass, and fat-free mass (FFM) by dual-energy x-ray absorptiometry were determined. RESULTS: Both groups of boys with HIV infection had significantly lower FFM/height ratios compared with healthy boys. The mean BCM/height ratio was also lower in HIV-infected boys with GF compared with healthy boys. Measures of fat of the HIV-infected boys with GF did not differ from healthy controls, but a statistical trend suggesting decreased body fat percent and fat mass/height ratio was observed in HIV-infected boys without GF (P=.06 and .07, respectively). Mean height-for-age, weight-for-age, and weight-for-height percentiles were significantly decreased in HIV-infected boys regardless of growth status as compared with healthy boys. The mean FFM/ height and BCM/height ratios were decreased in HIV-infected girls with GF compared with healthy girls. Body fat percentage and fat mass/height ratio did not differ among the 3 groups of girls. The mean weight-for-height percentiles were not different among the 3 groups of girls. The HIV-infected girls with GF had significantly lower mean height-for-age and weight-for-age percentiles than HIV-infected girls without GF and healthy girls. The mean height-for-age percentiles of the HIV-infected girls with GF did not differ from the healthy girls. CONCLUSIONS: Boys and girls with HIV-associated GF had diminished FFM and BCM. The decrease in FFM and BCM was in striking contrast to the fat compartment, which was normal. Decreased FFM was also detected in boys with HIV infection and normal growth but not in girls with HIV infection and normal growth, suggesting that HIV infection may affect boys differently than girls. The preferential decrease in FFM and BCM over fat observed in these children is similar to findings reported in adults with acquired immunodeficiency syndrome wasting.

Incubation period of HIV-1 in perinatally infected children. New York City Perinatal HIV Transmission Collaborative Study Group.

OBJECTIVES: To estimate the distribution of the incubation period of HIV-1 among perinatally infected children and to test the hypothesis that this distribution has been changing over time. DESIGN: An analysis of 190 perinatally HIV-1-infected children born between 1986 and 1997 in eight medical centers in New York City to women enrolled in a prospective cohort study. METHODS: Non-parametric Kaplan-Meier method and parametric survival analysis. RESULTS: Using the Kaplan-Meier method it was estimated that among perinatally HIV-1-infected children, 48% [95% confidence interval (CI), 41-56] developed AIDS by 3 years of age after which the rate was less than 3% per year. Using a parametric survival analysis for extrapolation, it was predicted that 33% (95% CI, 23-43) would remain AIDS-free at 13 years of age. Median age at onset of AIDS was estimated to be 4.1 years (95% CI, 1.9-6.4) by parametric survival analysis. The year of birth was significantly associated with AIDS-free survival, suggesting an increase in the time to AIDS over the years. This association remained significant (P=0.03) after adjustment for those maternal characteristics that have also changed over time: timing of enrollment (prepartum versus postpartum), zidovudine, alcohol, and hard drug (heroin, cocaine or methadone) use during pregnancy. CONCLUSIONS: Although a substantial proportion of perinatally HIV-1-infected children develop AIDS very early in life, a significant and increasing percentage of them are expected to survive into adolescence without developing AIDS. Further research is needed to determine the factors associated with the lengthening survival to AIDS.

Vertical transmission of HIV in New York State: a basis for statewide testing of newborns.

Infants (n = 313) of HIV-infected mothers were enrolled (mean age 1.9 weeks, range 0-8 weeks) in a 3-year prospective study of vertical transmission. Fifty-six infants (17.9%) had laboratory and clinical evidence of HIV infection. Polymerase chain reaction (PCR) provided early and reliable identification of infected infants. Thirty-one of the 56 infected infants had specimens submitted when the infants were 4 weeks of age or less and 30 (97%) tested PCR positive. This percentage increased to 100% by 8 weeks of age when 51 of the 56 infected infants had specimens tested for that time period. Immune complex dissociation (ICD) antigen testing was a sensitive method for diagnosis of infection but only in infants older than 1 month. p24 antigen testing, although free of false positives, is less sensitive than either of the other methods. Among surrogate markers of HIV infection, elevation of soluble CD8 levels precedes an increase in immunoglobulin levels or a decline in CD4 T lymphocytes. Vertical transmission is significantly lower in Central and Western New York State than other regions. Transmission is significantly higher in low birthweight babies and in infants whose mothers have CD4 counts < 500. This study provided the basis for establishing a Pediatric HIV PCR Testing Service for the early diagnosis of HIV infection in neonates.

Effect of maternal CD4+ cell count, acquired immunodeficiency syndrome, and viral load on disease progression in infants with perinatally acquired human immunodeficiency virus type 1 infection. New York City Perinatal HIV Transmission Collaborative Study Group.

Among a cohort of 152 infants perinatally infected with human immunodeficiency virus type 1, and their mothers, we correlated infant outcome with material CD4+ lymphocyte count and the presence of maternal acquired immunodeficiency syndrome near delivery. In a subset of 50 mother-infant pairs, we also correlated infant outcome with maternal quantitative viral burden as measured by the nucleic acid sequence based amplification system. We found that low maternal CD4+ cell count and high viral burden were associated with decreased time to category C disease or death in infants infected with human immunodeficiency virus type 1. In a multivariate analysis, high maternal viral load and maternal acquired immunodeficiency syndrome were independently associated with shorter time to category C disease or death in infants with human immunodeficiency virus type 1 infection. High viral load in pregnant women, independent of the presence of advanced maternal disease, appears to increase the risk of rapidly progressive disease in their infected offspring.

Early detection of perinatal human immunodeficiency virus (HIV) type 1 infection using HIV RNA amplification and detection. New York City Perinatal HIV Transmission Collaborative Study.

Early diagnosis of perinatally transmitted human immunodeficiency virus type 1 (HIV) infection can guide early interventions. HIV coculture and DNA polymerase chain reaction (DNA-PCR) detect few HIV-infected infants at birth and 90%-100% by age 3 months. Because extracellular HIV RNA may appear soon after infection, a plasma HIV RNA assay was compared with DNA-PCR for early detection of perinatally infected infants. Blood-draw specimens (108) obtained at the same time from 49 HIV-infected infants and 10 specimens from 8 uninfected infants were tested. HIV RNA and DNA-PCR positivity rates were 56% and 33%, respectively, in 36 specimens from 36 infants <28 days of age (binomial test, P = .001). Among 81 specimens obtained after age 14 days, 79 (98%) were positive by HIV RNA testing. No HIV-infected infant specimens were DNA-PCR-positive and HIV RNA-negative. All specimens from 8 uninfected infants were HIV RNA-negative. These results suggest that plasma HIV RNA was detectable earlier and more reliably than HIV DNA in perinatal infection.

Timing of maternal-infant HIV transmission: associations between intrapartum factors and early polymerase chain reaction results. New York City Perinatal HIV Transmission Collaborative Study Group.

OBJECTIVE: To investigate the hypothesis that labour and delivery events, perinatal characteristics, and maternal factors are only associated with intrapartum HIV transmission, and not with intrauterine HIV transmission. METHODS: In the New York City Perinatal HIV Transmission Collaborative Study 276 infants of HIV-infected women were followed prospectively and had results of early polymerase chain reaction (PCR) tests available. Among infected children, intrauterine infection was presumed if HIV DNA was detected by PCR in samples collected from children aged < or = 3 days, and intrapartum infection was presumed if HIV DNA was not detected in these early samples. The proportion of infants with presumed intrauterine and intrapartum infections were compared by selected intrapartum, perinatal and maternal characteristics. RESULTS: Presumed intrapartum infection was found in 7% of infants delivered by Cesarean section and, among infants delivered vaginally, those with longer duration of membrane rupture (> 4 h) were significantly more likely to have presumed intrapartum HIV infection (22%) than those with shorter duration (9%; P = 0.02). There were no differences in presumed intrauterine HIV infection by mode of delivery or longer duration of membrane rupture. Infants born preterm and small for gestational age had significantly higher risks of presumed intrapartum infection, but only those who were small for gestational age had higher risks of intrauterine infection. CONCLUSION: Our results support the notion that selected intrapartum conditions, long duration of membrane rupture prior to delivery in particular, are independent risk factors for maternal-infant transmission, and suggest that preterm infants may be especially vulnerable to intrapartum HIV exposure.

The effect of maternal viral load on the risk of perinatal transmission of HIV-1. New York City Perinatal HIV Transmission Collaborative Study Group.

OBJECTIVE: To determine the effect of maternal viral load at delivery on the risk of perinatal transmission of HIV-1. DESIGN: A nested case-control study within a prospectively followed cohort of HIV-1-infected pregnant women and their infants. SETTING: The multicenter New York City Perinatal HIV Transmission Collaborative Study. PARTICIPANTS: Fifty-one women who gave birth to HIV-1 infected infants were frequency-matched within CD4+ cell count quintiles with 54 non-transmitting mothers. MAIN OUTCOME MEASURES: Maternal quantity of HIV-1 viral RNA was assayed in plasma obtained near delivery using the nucleic acid sequence-based amplification assay system. RESULTS: Viral RNA was detected in 73 (70%) out of 105 women and the median viral load was 16,000 RNA copies/ml in transmitters and 6,600 in non-transmitters (P < 0.01). When adjusted for maternal CD4+ count near delivery, women with measurable viral load were nearly sixfold more likely to transmit HIV-1 than women with viral load below detection [adjusted odds ratio (AOR), 5.8; 95% confidence interval (CI), 2.2 15.5]. The odds ratio for perinatal transmission of log10 viral load, adjusted for CD4 count was 2.7 (95% CI, 1.5-5.1). When stratified by the stage of HIV-1 disease, the only group with significant association between log10 viral load and transmission were AIDS-free women with CD4+ count > 500 x 10(6)/l (AOR, 9.1; 95% CI, 2.6-31.5). CONCLUSIONS: High maternal viral load increases the likelihood of perinatal transmission of HIV-1 in women without AIDS and advanced immunosuppression. HIV-1 infected pregnant women without advanced disease, shown by others to have the lowest risk of perinatal transmission, may benefit the most from efforts to identify and decrease viral load at delivery.

Prospective study of human immunodeficiency virus 1-related disease among 512 infants born to infected women in New York City. The New York City Perinatal HIV Transmission Collaborative Study Group.

OBJECTIVE: To determine the incidence of HIV-1-related clinical findings, mortality and predictors of death in a cohort of HIV-exposed infants followed from birth. METHODS: Data were collected approximately bimonthly during the first and second year of life and used in Kaplan-Meier and Cox proportional hazards survival analyses to predict time to the development of symptoms and death. RESULTS: One hundred sixteen infected and 396 uninfected infants were followed for a median of 26 months at 7 New York City hospitals from 1986 to 1995. Two or more nonspecific HIV-related symptoms, AIDS or death occurred in 83% of infected children by the first year. Fifty infected infants (43%) developed AIDS and 19 (38%) of these had Pneumocystis carinii pneumonia. Estimated median age at AIDS/death was 30 months and 64% of infected children remained alive and AIDS-free at 1 year. Estimated infant mortality among infected children was 160/1000 live births, and median survival after AIDS was 21 months; 55% of infected children survived > 12 months after diagnosis of AIDS. P. carinii pneumonia was the most common cause of death. Although birth CD4 values did not predict AIDS or death, CD4 counts as early as 6 months of age were highly correlated with both. Thirteen (68%) of 19 infants who remained AIDS-free up to 3 to 6 months of age with CD4 count < or = 1500 cells/microliters subsequently developed AIDS vs. 18 (30%) of 61 with CD4 count > 1500 (P = 0.0001). CONCLUSIONS: Most HIV-1-infected infants develop disease in the first year of life. AIDS or death can be predicted by a threshold CD4 count of 1500 cells/microliters at 3 to 6 months of age.

Flavin metabolism during respiratory infection in mice.

Previous control studies carried out in children showed that respiratory infection alters riboflavin metabolism and leads to excessive urinary losses of the vitamin. In order to understand the nature of biochemical changes in riboflavin metabolism during respiratory infection, a study was carried out using the mouse as the experimental model, and Klebsiella pneumoniae as the infective organism. Mice were fed on either a low (0.5 mg/kg)- or high (13.3 mg/kg)-riboflavin semi-synthetic diet. Infection resulted in a 5-6-fold higher excretion of riboflavin in the urine of mice fed on the low-riboflavin diet. Higher erythrocyte FAD levels and lower liver FAD levels were also observed during infection. Of the four enzymes involved in the synthesis and breakdown of the flavin coenzymes studied, the activity of hepatic flavokinase (ATP: riboflavin 5'-phosphotransferase; EC 2.7.1.26) was significantly lower, and that of FAD synthetase (ATP: FMN adenylyltransferase; EC 2.7.7.2) was higher during riboflavin restriction and infection. The activity of FMN (acid) phosphatase (EC 3.1.3.2) was unchanged, whereas FAD (nucleotide) pyrophosphatase (EC 3.6.1.9) activity was significantly higher both with the low-riboflavin diet and during infection. Thyroid hormone is known to modulate flavokinase activity and, hence, thyroid status was assessed. Plasma triiodothyronine (T3) levels were not affected, but thyroxine levels were lower in the mice fed on the low-riboflavin diet. However, plasma T3 was significantly lower during infection, suggesting a mechanistic role for the hormone in the reduction of flavokinase activity.