A randomized comparative trial of stavudine (d4T) versus zidovudine (ZDV, AZT) in children with human immunodeficiency virus infection. AIDS Clinical Trials Group 240 Team.

OBJECTIVES: To compare the safety and tolerance of stavudine (d4T) versus zidovudine (ZDV, AZT) in symptomatic human immunodeficiency virus-infected children 3 months to 6 years of age. METHODS: In an initially double-blind trial, 212 evaluable human immunodeficiency virus-infected children who had received no more than 6 weeks of previous antiretroviral therapy were randomized to receive either d4T (1 mg/kg orally every 12 hours, maximum 40 mg orally every 12 hours) or zidovudine (180 mg/m2 orally every 6 hours, maximum 200 mg orally every 6 hours). The study was unblinded after a median follow-up period of 6.3 months; median follow-up at study closure was 17.3 months. Tolerance, safety, disease progression, and immunologic responses were evaluated. RESULTS: The patient population was young (median age, 1.2 years; range, 0.3 to 6.4 years), with a median baseline CD4+ lymphocyte count of 965 cells/microL (range, 18 to 4238 cells/microL). Neutropenia < 400/microL occurred significantly more commonly among zidovudine recipients (1-year event rates of 20% both up to the time of unblinding and throughout the entire study) than among children receiving d4T (1-year event rates of 5% up to the time of unblinding and 6% throughout the entire study). In exploratory activity analyses using all data collected until study closure, children treated with d4T showed consistently greater positive changes from baseline in weight-for-age-and-gender z scores. As expected in this population of young children, median absolute CD4+ lymphocyte counts decreased in both treatment groups. Smaller changes from baseline were noted among d4T recipients. CONCLUSIONS: In children between the ages of 3 months and 6 years, d4T and zidovudine are largely comparable in terms of safety and tolerance. Neutropenia occurs significantly less commonly among children treated with d4T. There was evidence that weight gain and absolute CD4+ lymphocyte counts were better maintained in children receiving d4T.

Maternal plasma human immunodeficiency virus type 1 RNA level: a determinant and projected threshold for mother-to-child transmission.

To prevent mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission, it is important to identify its determinants. Because HIV-1 RNA levels can be reduced by antiviral therapy, we examined the role of maternal plasma HIV-1 RNA level in mother-to-child transmission. We used quantitative competitive PCR to measure HIV-RNA in 30 infected pregnant women and then followed their infants prospectively; 27% of the women transmitted HIV-1 to their infants and maternal plasma HIV-1 RNA level correlated strikingly with transmission. Eight of the 10 women with the highest HIV-1 RNA levels at delivery (190,400-1,664,100 copies per ml of plasma) transmitted, while none of the 20 women with lower levels (500-155,800 copies per ml) did (P = 0.0002). Statistical analysis of the distribution of HIV-1 RNA loads in these 30 women projected a threshold for mother-to-child transmission in a larger population; the probability of a woman with a viral RNA level of < or = 100,000 copies per ml not transmitting is predicted to be 97%. Examination of serial HIV-1 RNA levels during pregnancy showed that viral load was stable in women who did not initiate or change antiviral therapy. These data identify maternal plasma HIV-1-RNA level as a major determinant of mother-to-child transmission and suggest that quantitation of HIV-1 RNA may predict the risk of transmission.

Quantitation of human immunodeficiency virus type 1 during pregnancy: relationship of viral titer to mother-to-child transmission and stability of viral load.

To develop strategies to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1), it is important to define the factors determining it. We examined the relationship between maternal HIV-1 titer and the occurrence of mother-to-child transmission. In addition, we quantitated HIV-1 longitudinally in mothers during pregnancy, at delivery, and up to 1 year postpartum. To examine transmission, we prospectively studied 19 mother-child pairs; in 5 pairs, HIV-1 transmission occurred. We used endpoint dilution culture of peripheral blood mononuclear cells to determine maternal viral titer and found that although 4 of 6 (67%) women with viral titers of > or = 125 HIV-1 infectious units per 10(6) cells transmitted HIV-1 to their infants, only 1 of 13 (7.6%) women with lower viral titers transmitted (P = 0.01). Twelve of the 19 mothers had HIV-1 loads determined serially 3-8 times over periods ranging from 18 to 65 weeks. Viral titers varied greatly between the 12 women, but the viral load in each woman remained stable over time. In this cohort, HIV-1 viral load remained stable during pregnancy and the greater the maternal viral burden, the more likely that transmission occurred. These two related findings suggest that determination of HIV-1 titers early in pregnancy may predict which women are at high risk of transmitting to their infants and may be used to counsel HIV-1-infected women of childbearing age. These data identify maternal viral titer as a major determinant of mother-to-child HIV-1 transmission and thereby provide the scientific rationale for therapeutic strategies designed to interrupt transmission by lowering viral load.

Cardiac abnormalities in children with sickle cell anemia.

The cardiac status of 64 children (ages 0.2 to 18 yr) with sickle cell anemia documented by hemoglobin electrophoresis was evaluated by echocardiography. Left atrial, left ventricular and aortic root dimensions were significantly increased in over 60 percent of these children at all ages compared to values for 99 normal black (non-SCA) control subjects. Left ventricular wall thickness was increased in only 20 percent of older children with sickle cell anemia. Estimated LV mass/m2 and left ventricular cardiac index were increased compared to control subjects (p less than 0.001). Left heart abnormalities expressed as a single composite function, derived from multivariate regression analysis, correlated well with severity of anemia expressed as grams of hemoglobin (r = -0.52, p = less than 0.001) and with percentage of hemoglobin S (r = 0.51, p less than 0.001), but not to the same extent with age. Echocardiographically assessed left ventricular function at rest was comparable to that of control subjects. These data suggest that the major cardiac abnormalities in children are related to the volume overload effects of chronic anemia, and that in this age group, there is no evidence for a distinct "sickle cell cardiomyopathy" or cardiac dysfunction.

Cardiovascular effects of hypertransfusion therapy in children with sickle cell anemia.

Thirteen children, age 1.9 to 14.8 years with documented sickle cell disease, underwent echocardiographic assessment of cardiac status while on and off periodic hypertransfusion therapy (HTX). Two to three units of washed packed red blood cells were transfused every 2-4 weeks in children with splenic sequestration crises, cerebrovascular accidents (CVA), aseptic necrosis of the femoral head, and miscellaneous complications of sickle cell disease to maintain hemoglobin (Hgb) concentrations of greater than or equal to 10 g/dl and % sickle hemoglobin (S Hgb) of less than or equal to 20%. This therapy administered over an average duration of 24 months resulted in normalization of left heart chamber enlargement and statistically significant decrease in heart rate, left ventricular mass, and cardiac output. Echocardiographically derived left ventricular function parameters remained normal on and off transfusion therapy. Changes in left ventricular diastolic dimension and cardiac output correlated with changes in % S Hgb (r = 0.59, p less than 0.001; and r = 0.54, p less than 0.001, respectively), and with changes in Hgb concentration (r = -0.78, r = -0.76, p less than 0.001). Expression of left heart abnormalities as a single composite function (Ydv), using multivariate regression analysis, allowed a comparison of cardiac status of 99 normal black controls, nontransfused sickle cell anemia (SCA) patients, and 13 study patients on and off HTX, and permitted serial assessment of cardiac status on and off treatment over 5 years in a single patient.(ABSTRACT TRUNCATED AT 250 WORDS)

M-mode echocardiography in normal children and adolescents: some new perspectives.

Normal M-mode echocardiography values were determined using computer-assisted measurements of echocardiograms (ECHO) in 202 children and young adults 25 days to 23 years of age: 77 were female, and 125 were male and, reflecting the population served by our Center, 99 were black and 103 were white children. The values for left and right heart wall thicknesses and chamber sizes were graphically displayed as a function of body surface area, and with an illustration of the regression line and 2 standard deviation (SD) range of normal for each parameter. In addition, normal ECHO predicting equations for dimension and function parameters were derived using multiple linear regression analysis with age, height, weight, sex, race, and heart rate as independent variables. A comparison was made between the observed data and the data derived from the normal predicting equations for each of the parameters. Also, values obtained from these equations were compared to data generated from other published normal predicting equations. A description of the digitizer measurements, computer interfacing, and a sample ECHO report form utilizing the predicted normal ranges for each of the parameters is presented. We propose that quantitative M-mode echocardiographic reporting should be easily accessible to all pediatric cardiology laboratories.

Estimation of circumferential fiber shortening velocity by echocardiography.

The M-mode and two-dimensional echocardiograms of 40 young patients were analyzed to compare the mean circumferential fiber shortening velocity (Vcf) of the left ventricle calculated separately by two methods. The mean circumferential fiber shortening velocity was derived from the M-mode echocardiogram as minor axis shortening/ejection time and derived from the two-dimensional echocardiogram as actual circumference change/ejection time. With computer assistance, circumference was determined from the short-axis two-dimensional echocardiographic images during end-diastole and end-systole. Good correlations were obtained between the left ventricular diameter derived by M-mode echocardiography and the vertical axis during end-diastole (r = 0.79) and end-systole (r = 0.88) derived by two-dimensional echocardiography. Likewise, high correlations were noted between diameter and circumference in end-diastole (r = 0.89) and end-systole (r = 0.88). However, comparison of Vcf obtained by M-mode echocardiography with that obtained by two-dimensional echocardiography showed only fair correlation (r = 0.68). Moreover, the diameter/circumference ratio determined in end-diastole and end-systole differed significantly (p less than 0.001), possibly owing to the change in geometry of the ventricular sector image during systole. Although Vcf derived by M-mode echocardiography is a useful index of left ventricular performance, it does not truly reflect the circumference change during systole.

Cardiac abnormalities in children with hyperthyroidism.

The cardiac status of 18 hyperthyroid (HT) children (9 black and 9 white) was evaluated by echocardiography. Mitral regurgitation (MR) was diagnosed clinically in 33% (6 of the 9 blacks). None of the 9 white children had MR. Left ventricular end-diastolic diameter (LVEDD) and volume (LVEDV) did not differ from the predicted normal (PN) based on body surface area and heart rate, except in those with MR where increased LVEDD and LVEDV were noted (p less than 0.02). LV mass was +1.75 standard deviations (sigma) of the PN (p less than 0.01), due to increased wall thickness of LVEDV. Left ventricular output (LVO) was +0.35 sigma PN (p = ns); however, when compared to that of normal children, LVO of HT was higher (p less than 0.001) due to the increased heart rate. Enhanced left ventricular contractility was suggested by increased rate of dimensional change during ejection (peak dD/dt-syst), with a mean value of -11.39 cm/sec as compared to the normal of -9.54 cm/sec (p less than 0.01). A linear multivariate regression equation differentiated the cardiac status of HT from that of normal children. Following treatment to euthyroid state, MR disappeared in 2 and became less in 4 patients. LVO, LV mass, and peak dD/dt-syst also became less. Significant cardiac changes occur in children with hyperthyroidism, which may be reversible in part after euthyroidism is restored.

An evaluation of the left atrial/aortic root ratio in children with ventricular septal defect.

Echocardiograms were performed in 80 infants and children with isolated ventricular septal defect (VSD) who underwent cardiac catheterization. The pulmonary-to-systemic flow ratio (Qp/Qs) was correlated with the echocardiographic left atrial-to-aortic root diameter ratio (LA/Ao), and a relatively poor correlation (r = 0.62) was found. The end-systolic diameters of the left atrium and aorta at the level of the aortic root, obtained from lateral cineangiograms of 55 of the 80 patients, were compared with the corresponding echocardiographic dimensions. To assess the possible effect of transducer beam angulation upon the echocardiographic determinations, the angiographic measurements were made at 0 degrees position (perpendicular to the frontal plane) and at angles of 5 degrees, 10 degrees, 15 degrees and 20 degrees from zero, using the aortic root center as the point of intersection. The echocardiographic and angiographic aortic root measurements were comparable (r = 0.95), and the angiographically derived aortic diameter did not vary with different angle projections. However, the left atrial angiographic dimensions were significantly influenced by the angle of projection. We conclude that the echocardiographic LA/Ao ratio cannot reliably estimate the severity of the shunt flow in VSD.