- Click here for explanation of classification scheme.

• The objective of this study was to measure the energy intake and expenditure in HIV-infected pre-pubescent children, in order to assess the determinants of growth failure
• The relationships among HIV replication, energy balance, body composition and growth were also examined. 

No specific criteria were listed.

No specific criteria were listed.

Recruitment

HIV-infected children with growth failure (HIV+/GF+) and HIV-infected children with normal rates of growth HIV+/GF-) were enrolled from three hospital-based outpatient pediatric HIV/acquired immunodeficiency syndrome (AIDS) treatment programs from 1996-1997.

Design

• Case-control is implied, but no matching of between the two groups
• Cross-sectional, as measurements taken only one time.

Blinding Used

Implied for outcome measures.

Statistical Analysis

• Comparison of mean values of variables for the HIV+/GF+ and HIV+/GF- children were made using Student's T-tests
• Dietary intake and REE were standardized by body weight and amount of FFM to compare these variables among individuals of different body weight and with different amounts of FFM
• Regression model techniques were also used to analyze differences in energy intake and expenditures for the two study groups. Multiple regression models with either REE, FFM or growth velocity (GV) as the dependent variables and FFM, viral load, energy intake and group (HIV+/GF+ vs. HIV+/GF-) as independent variables were assessed in all subjects.
• Analysis of covariance was performed to adjust for the effect of age on CD4 number, dietary intake, FFM, REE and TEE
• All statistical calculations were performed using the STATA (Computing Resource Center, Santa Monica, CA) and SAS (SAS Institute) software packages for personal computers
• The level of significance for all statistical tests was under 0.05.

Timing of Measurements

• Children attending programs from 1996 to 1997
• Cross-sectional study: One-time measurement.

Dependent Variables

• REE: Resting energy expenditure was determined by assessing the resting metabolic rate after an overnight fast, using open-circuit indirect calorimetry with a ventilated canopy hood in a humidity and temperature-controlled environment.
• Movements were minimized
• Subjects rested quietly during a 15- to 30-minute adaptation period, after which measurements were performed for 20 minutes
• REE was expressed as a percentage of predicted value, using the WHO equations (FAO.WHO/UNU Expert Consultation 1985) and normalized for the quantity of FFM, the body compartment containing metabolically active tissue (see Thompson et al 1995 ref).
• TEE: Total energy expenditure was measured from the differential loss of stable isotopes of oxygen and hydrogen of water over a 10-day period after oral administration of a dose of [²H ¹⁸O] water
• Each child was given an accurately defined oral dose of approximately 0.15g of H₂¹⁸O and 0.12g of ²H₂O per kg body mass
• A baseline urine specimen was collected before the dose was given
• Additional urine specimens for measurement of isotope were collected one, two, nine and 10 days after administration of doubly-labeled water
• Urine samples were analyzed by isotope ratio mass spectrometry
• Total body water and rate of CO₂ production were calculated
• The Weir formula was used to determine oxygen consumption and TEE (kcal per day) from the measured rate of the CO₂ production, assuming a respiratory quotient of the food consumed of 0.85
• The average daily energy cost of physical activity was estimated from the difference between TEE and REE
• Energy intake minus TEE was used to estimate apparent daily energy balance. 
• Energy intake: Assessment of 24-hour energy intake using a semi-structured interview performed in person, using food models on one to three occasions within 14 days of other study measurements
• A standardized coding system used to minimize error and increase reliability
• Energy and macronutrient values of intake were calculated using the Minnesota Nutrition Data System
• The average daily energy intake for each child was compared to the published recommended daily allowance (RDA) according to age (Food and Nutrition Board 1989).
• FFM: Fat-free mass was determined by dual X-ray absorptiometry (DPX, Lunar Radiation, Madison, WI), using pediatric software (version 8e)
• GV: Growth velocity
• Growth failure was defined as a 12-month height velocity no higher than the fifth percentile for age, using standard reference norms (see Tanner and Davies, 1985, ref). 

Independent Variables

• Group: HIV+/GF+ (with growth failure) vs. HIV+/GF- (normal rate of growth)
• FFM (also included as independent in regression): Fat-free mass was determined by dual X-ray absorptiometry (DPX, Lunar Radiation, Madison, WI), using pediatric software (version 8e)
• Height: Measured in triplicate to the nearest 0.1cm, using a Holtain wall-mounted stadiometer
• Weight: Determined to the nearest 0.1kg, using a balance scale
• Viral load: Plasma HIV RNA was measured by the polymerase chain reaction method.

Control Variables

• HIV infection was diagnosed and disease stage classfied, using Centers for Disease Control criteria (1994)
• Pubertal classification was performed according to Tanner (see Marshall and Tanner, refs 1970, 1971)
• Information concerning prior illnesses or other HIV-related conditions, treatment and medications and prior results of lymphocyte phenotype analyses were obtained from medical records
• T-lymphocyte sub-populations were measured using Coulter's Q-pre method with monoclonal antibody-staining reagents, detecting CD4 by two-color flow cytometry.

Initial N

• 16 HIV-infected children with growth failure (five boys, 11 girls)
• 26 HIV-infected children with normal rates of growth (13 boys, 13 girls).

Attrition (final N)

None.

Age

• GF+: 8.3±2.4 years
• GF-: 6.5±1.8 years
• P=0.016.

Ethnicity

• GF+
• 6.25% white
• 31.25% black
• 62.5% Hispanic
• 0% other.
• GF-
• 11.54% white
• 42.3% black
• 42.3% Hispanic
• 3.85% other.

Anthropometrics

• Height (cm): GF+, 116.4±16.0; GF-, 117.1±12.1
• Weight (kg): GF+, 23.1±10.3; GF-, 23.5±9.0
• Weight-height (percentile): GF+, 66.1±31.0; GF-, 63.1±27.2
• Height-age (percentile): GF+, 6.6±8.5; GF-, 44.6±29.2; P<0.0001
• Weight-age (percentile): GF+, 16.0±24.2; GF-, 55.8±29.4; P<0.0001
• FFM/Height (g per cm²): GF+, 142.0±4.6; GF-, 165.0±5.5; P=0.0005
• Growth velocity (cm per year): GF+, 1.1±1.5; GF-, 6.6±1.1; P<0.0001
• Growth velocity (percentile): GF+, 1.1±1.2; GF-, 54.7±27.5; P<0.0001.

Disease and Medication Information

• CD4 count (x10⁶ cells per L): GF+, 218±99; GF-, 596±75; P=0.0065
• CD4 (percentage): GF+, 8.3±2.9; GF-, 22.3±2.2; P=0.008
• HIV RNA (log₁₀ copies per L): GF+, 4.89±1.08; GF-, 3.43±1.64; P=0.009
• CDC Class N: GF+, 0; GF-, 3.85%
• CDC Class A: GF+, 25%; GF-, 26.9%
• CDC Class B: GF+, 25%; GF-, 57.7%
• CDC Class C: GF+, 37.5%; GF-, 7.7%
• Unknown CDC class: GF+, 12.5%; GF-, 3.85%.

Using Antiretroviral Drugs

• Yes: GF+, 68.75%; GF-, 76.9%
• No: GF+, 31.25%; GF-, 23.1%.

Other Medication Information

• 31 were receiving one or more HIV reverse transcriptase inhibitors
• None were receiving anabolic agents (including megestrol acetate and corticosteroids), protease inhibitors or other medications known to affect appetite, energy intake or energy metabolism.

Location

Fospital-based outpatient pediatric HIV-AIDS treatment programs.

Table Two: Comparison of Age-Adjusted Energy Intake, Energy Expenditures and Energy Balance in Human Immunodeficiency Virus (HIV)-Infected Children with Growth Failure (GF) (HIV+/GF+) and Without GF (HIV+/GF-)

[Note: Values are means ±SE, N=16 HIV+/GF+ or 26 HIV+/GF-; all in kJ per day]

Variables	HIV+/GF+	HIV+/GF-	P-Value
Energy intake (EI)	5,640±653	8,305±490	0.003
Total Energy Expenditure (TEE)	6,038±431	6,966±314	0.110
Resting Energy Expenditure (REE)	3,895±222	4,452±172	0.063
TEE-REE	2,188±372	2,787±280	0.229
Energy balance (EI-TEE)	-674±732	1,448±515	0.30

  Other Findings

• Mean age-adjusted percentage of body fat
• HIV+/GF+: 19.8±8.2
• HIV+/GF-: 19.1±8.4%
• P>0.05.
• EI (percentage RDA for age)
• HIV+/GF+: 71.7±31.7%
• HIV+/GF-: 103.7±28.8%
• P=0.002.
• Daily energy intake per kg of body weight
• HIV+/GF+: 293.3±135.1
• HIV+/GF-: 367.4±110.5kJ/(kg*days)
• P=0.064.
• No differences in diet composition, including percentage of energy consumed as protein, fat or carbohydrates
• Mean age-adjusted REE in HIV+/GF+ group was 557kJ per day (12.5%) less than that of HIV+/GF- group (P=0.063: Table Two)
• Mean age-adjusted REE/FFM
• HIV+/GF+: 252.7±9.2
• HIV+/GF-: 223.8±7.1kJ/(kg*days)
• P=0.026.
• When assessed by multiple regression analysis (included differences in age), the relationship between REE and FFM did not differ between the two groups
• FFM (kg) was a main determinant of REE (kJ per day). Age and viral load did not contribute significantly to the regression model after accounting for differences in FFM.
• REE=(450.5+44.7*FFM)*4.184
• R2=0.61
• SEE=158
• P<0.0001.
• Energy balance measurements indicate the HIV+/GF+ children had a mean energy deficit, compared with mean energy surplus in the HIV+/GF- children
• Log plasma HIV RNA concentration was a significant negative predictor of 12-month GV and quantity of FFM
• GV (cm per year): 12.75-0.58 * age (years)-0.77*log viral load (copies per dL)
• R²: 0.49
• SEE=1.69
• P<0.001.
• FFM (kg): 9.74+1.87 * age (years)-1.17 * logVL (copies per dL)
• R²=0.63
• SEE=3.35
• P<0.0001.
• Energy intake was significantly associated with 12-month GV and FFM
• GV (cm per year): 7.16-0.59 * age (years)+0.00031 * energy intake (kJ per day)
• R²=0.43
• SEE=1.72
• P<0.001.
• FFM: 1.35 + 1.86 * age (years)+0.0005 * dietary intake (kJ per day)
• R²=0.63
• SEE=3.21
• P<0.0001.
• Multiple regression analysis of FFM on age, plasma HIV RNA concentration and energy intake demonstrated a significant, inverse relationship between FFM and log plasma HIV RNA. Energy intake was no longer a significant variable in the model (R²=0.64; SEE=3.23; P=0.0001).
• Log HIV RNA and 12-month GV were also inversely related (R²=0.61; SEE=1.51; P=0.0001)
• Additional analyses using backward elimination revealed a significant inverse relationship between the level of VL and energy intake
• Energy intake (kJ per day): (2,016.2-1.9*VL)*4.184
• R²=0.17
• SEE=573.2
• P=0.0125.
• Age, sex, race and body mass index were not found to be significant.
• Hypermetabolism was not detected in either group.

• The rate of growth of HIV-infected children was inversely related to the level of HIV replication
• Data suggest that for some children with HIV, daily dietary intake may not be sufficient to meet metabolic demands and sustain normal growth
• Children with HIV-associated growth failure tended to have reduced levels of energy expenditure, compared with children with normal rates of growth
• The differences in the REE/FFM ration between HIV-infected children with GF and those with normal rates of growth may not indicate true differences in underlying REE and may reflect a greater organ-skeletal mass ratio
• Poor linear growth was an indication of advanced disease
• Future investigations of the mechanism of disturbed growth in pediatric HIV infection will have to evaluate the role of viral replication and antiviral therapies on the dynamics of energy intake, anabolism and growth. The therapeutic use of anabolic agents for children with HIV-associated GF should be carefully assessed.

Limitations as indicated by authors:

• Assessment of the possible mechanistic pathways was not performed in this study
• Results of energy intake assessed by 24-hour dietary recall must be interpreted with caution
• Small sample size: Power analysis by authors indicated a sample of 45 in each group was needed to detect differences in REE and TEE.