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Article

Growth Velocity, Fat-Free Mass and Energy Intake Are Inversely Related to Viral Load in HIV-Infected Children¹

Stephen M. Arpadi^*2, Patricia A. Cuff^*, Donald P. Kotler, Jack Wang^**, Marukh Bamji, Michael Lange, Richard N. Pierson^,** and Dwight E. Matthews

^* Department of Pediatrics and HIV Center, Department of Medicine, and ^** Body Composition Unit, Columbia University College of Medicine and School of Public Health, St. Luke’s-Roosevelt Hospital Center, New York, NY; Department of Pediatrics, NY Medical College, Metropolitan Hospital Center; and Clinical Research Center, University of Vermont, Burlington, VT

²To whom correspondence should be addressed.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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 5th percentile for age, and 26 HIV-infected children with normal rates of growth (HIV+/GF-). Energy intake was measured by repeated 24-h dietary recall, resting energy expenditure (REE) by indirect calorimetry and total energy expenditure (TEE) by the doubly labeled water method. Fat-free mass (FFM) was determined by dual X-ray energy absorptiometry and plasma HIV RNA by the polymerase chain reaction method. The mean plasma HIV RNA content among the HIV+/GF+ group was nearly 1.5 log higher than that of the HIV+/GF- group (4.89 ± 1.08 vs. 3.43 ± 1.64 x10² copies/L, P = 0.009). The mean daily energy intake, and age-adjusted REE and TEE were lower in HIV+/GF+ children (P = 0.003, 0.06 and 0.16, respectively). HIV+/GF+ children had a mean daily energy deficit of 674 ± 732 kJ/d compared with HIV+/GF- children who had a mean energy surplus of 1448 ± 515 kJ/d (P = 0.030). There were no differences in REE after adjustment for differences in FFM and age using multiple regression analysis (P = 0.88). There was a significant inverse relationship between FFM and plasma HIV RNA [R² = 0.64, standard error of the estimate (SEE) = 3.23] and between viral load and 12-mo growth velocity (R² = 0.61, SE = 1.51). Viral load and energy intake were also inversely related (R² = 0.17, SEE = 573.2, P = 0.0125). In HIV-infected children, rate of growth, quantity of FFM and energy intake are closely related to the level of HIV replication. The energy intake of children with HIV-associated GF may not be adequate for supporting normal development of FFM and growth, despite possible decreases in total energy expenditure.

KEY WORDS: • HIV-associated growth failure • children • energy balance • viral load • fat-free mass

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Disturbances in growth, including growth failure(GF)³ and wasting, are common complications of childhood human immunodeficiency virus (HIV) infection and contribute to morbidity and mortality (Tovo et al. 1992 ). HIV-infected infants with poor growth have as much as a fivefold increase in the risk of early death (Berhane et al. 1997 ).

Studies of children with HIV infection reveal early compromise of both height and weight gain and alterations in body composition, especially in the lean or fat-free mass (FFM) (Arpadi et al. 1998 , McKinney and Roberson 1993 , Moye et al. 1996 , Saavedra et al. 1995 ). The etiology of growth failure and altered body composition in HIV infection is not well understood and may be multifactorial. Although endocrine disorders are encountered, including cases of growth hormone deficiency and hypothyroidism, no consistent endocrine abnormality has been identified (Hirschfeld et al. 1996 , Jospe and Powell 1990 , Laue et al. 1990 , Lepage et al. 1991 ). Gastrointestinal dysfunction, including infection and malabsorption, has also been reported but no clear relationship to growth failure has been documented (Italian Pediatric Intestinal/HIV Study Group 1993 , Yolken et al. 1990 ).

Among infants, HIV replication is associated with delays in growth (Pollack et al. 1997 ). The mechanism is unclear. HIV replication or possibly aspects of the host immune response appear to increase the basal metabolic demands in HIV-infected adults (Mulligan et al. 1997 ). In children, similar increases in energy expenditures, if uncompensated, would impair growth.

Previous studies performed in children with HIV have been limited to measurement of resting energy expenditure (REE) and have not included assessments of total energy expenditure (TEE) or of viral replication (Alfaro et al. 1995 , Henderson et al. 1998 ).

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

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Sixteen HIV-infected children with growth failure (HIV+/GF+) and 26 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 to 1997. Informed consent was obtained from the parent or guardian for each child before participation. Assent was also obtained when appropriate. The study was approved by the study site Institutional Review Board.

Growth failure was defined as a 12-mo height velocity 5th percentile for age using standard reference norms (Tanner and Davies 1985 ). HIV infection was diagnosed and disease stage classified using Centers for Disease Control criteria (Centers for Disease Control and Prevention 1994 ). Pubertal classification was performed according to Tanner (Marshall and Tanner 1970 and 1971 ).

Height-for-age, weight-for-age and weight-for-height percentiles were calculated using Epi-Info software (Dean et al. 1995 ). Information concerning prior illnesses or other HIV-related conditions, treatment and medications, and prior results of lymphocyte phenotype analyses were obtained from medical records. None of the subjects had clinically apparent renal or cardiac disease or had known or suspected active intercurrent illnesses at the time of evaluation.

Height was measured in triplicate to the nearest 0.1 cm using a Holtain wall-mounted stadiometer (Holtain Ltd., UK). Weight was determined to the nearest 0.1 kg using a balance scale. FFM was determined by dual X-ray energy absorptiometry (DPX, Lunar Radiation, Madison, WI) using pediatric software (version 8e).

Assessment of 24-h energy intake was obtained by a single investigator (P.A.C.) in a semistructured interview performed in person using food models on 1–3 occasions within 14 d of other study measurements. A standardized coding system was used to minimize error and increase reliability of interviewing and coding. Energy and macronutrient values of intake were calculated by a single investigator (P.A.C.) using the Minnesota Nutrition Data System (Nutrition Coordinating Center, Minneapolis, MN). 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 ).

REE 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. Attempts were made to minimize movements that might increase energy expenditures. Subjects rested quietly during a 15- to 30-min adaptation period after which measurements were performed for 20 min. 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, using a method adapted from Thomson et al. (1995) .

TEE was measured from the differential loss of stable isotopes of oxygen and hydrogen of water over a 10-d period after oral administration of a dose of [²H ¹⁸O] water. Each child was given an accurately defined oral dose of 0.15 g of H₂¹⁸O and 0.12 g of ²H₂O/kg body (Cambridge Isotope Labs, Andover, MA). Before the dose was given, a baseline urine specimen was collected. Additional urine specimens for measurement of isotope were collected 1, 2, 9 and 10 d after administration of doubly labeled water. Urine samples were analyzed for H₂¹⁸O and ²H₂O by isotope ratio mass spectrometry at the Biomedical Mass Spectrometry Facility at the University of Vermont. Total body water was determined from the initial dilution of the ¹⁸O- and ²H-isotopes in body water, and rate of CO₂ production was determined from the measured rates of ¹⁸O and ²H loss from body water using the methods previously documented by others (Prentice 1990 , Racette et al. 1994 , Scholler and Van Santen 1982 , Scholler et al. 1986 , Speakman et al. 1993 ) and more recently described by us for the specific procedures used here (Starling et al. 1998 ). The Weir formula was then used to determine oxygen consumed and TEE (kcal/d) from the measured rate of the CO₂ production, assuming a respiratory quotient of the food consumed of 0.85 (Black et al. 1986 ). The average daily energy cost of physical activity was estimated from the difference between TEE and REE (Goran et al. 1995 ). Energy intake minus TEE was used to estimate apparent daily energy balance.

Plasma HIV RNA was measured by the polymerase chain reaction (PCR) method (Amplicor HIV Monitor, Roche Molecular System, Roche Diagnostics, Indianapolis, IN) (Mulder et al. 1994 ). Plasma specimens were stored at -70°C and analyzed in duplicate. T-Lymphocyte subpopulations were measured using Coulter’s Q-pre method with monoclonal antibody staining reagents detecting CD4 (Coulter Immunology, Hialeah, FL) by two-color flow cytometry (Reddy and Greico 1991 ).

Data 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 (ANCOVA) 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, Cary, NC) software packages for personal computers. The level of significance for all statistical tests was < 0.05.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Selected demographic, anthropometric and clinical characteristics of study subjects are presented in Table 1 . Consistent with our classification criteria, the mean 12-mo growth rate (cm/y) and GV percentile, height-age percentile, and weight-age percentile were significantly lower in the HIV+/GF+ children compared with the HIV+/GF- group. No differences in the mean height, weight, and weight-for-height percentile were observed between the two groups. The mean age-adjusted FFM/height ratio was lower in the HIV+/GF+ group. The mean age-adjusted percentage of body fat did not differ significantly between the HIV+/GF+ children and HIV+/GF- children (19.8 ± 8.2 vs. 19.1 ± 8.4%). The HIV+/GF+ children were older, with more advanced disease and immunodeficiency than the children in the HIV+/GF- group. The mean CD4 number was significantly lower in the HIV+/GF+ group compared with the HIV+/GF- group, as was the CD4 percentage (8.3 ± 2.9 vs. 22.3 ± 2.2.0%, P = 0.008). The mean plasma HIV RNA content in HIV+/GF+ children exceeded that of HIV+/GF- children by nearly 1.5 log. Of 42 subjects, 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 expenditures.

The mean age-adjusted TEE tended to be lower in HIV+/GF+ children compared with HIV+/GF- children by 928 kJ/d (13%) (P = 0.110, Table 2 ). Significant differences were not observed in the mean age-adjusted TEE-REE, which reflects energy available for voluntary physical activity and thermic effects of food and growth, although children with GF had 599 kJ/d (21%) less energy available for these uses (P = 0.229) (Table 2) .

The results of analysis of overall daily energy balance indicated that the HIV+/GF+ children had a mean energy deficit of 674 kJ/d compared with HIV+/GF- children who had a mean energy surplus of 1448 kJ/d (P = 0.030) (Table 2) .

Additional multiple regression analyses evaluating the determinants of FFM and growth were performed. In separate analyses in which age was included, log plasma HIV RNA concentration was found to be a significant (negative) predictor of 12-mo GV and the quantity of FFM [GV (cm/y) = 12.75 - 0.58 · age (y) -0.77 · log viral load (VL; copies/dL), R² = 0.49, standard error of the estimate (SEE) = 1.69, P < 0.001 and FFM (kg) = 9.74 + 1.87 · age (y) - 1.17 · logVL, (copies/dL) R² = 0.63, SEE = 3.35, P < 0.0001]. Energy intake was also found to be significantly associated with 12-mo GV and FFM [GV (cm/y) = 7.16 - 0.59 · age (y) + 0.00031 · energy intake (kJ/d), R² = 0.43, SEE = 1.72, P < 0.0001 and FFM = 1.35 + 1.86 · age (y) + 0.0005 · dietary intake (kJ/d), R²=0.63, SEE = 3.21, P < 0.0001]. When multiple regression analysis of FFM on age, plasma HIV RNA concentration and energy intake was performed, a significant, inverse relationship between FFM and log plasma HIV RNA remained; however, energy intake was no longer a significant variable in the model (R² = 0.64, SEE = 3.23, P = 0.0001) (Table 3 ). Multiple regression analysis of GV performed with these same variables indicated that log HIV RNA and 12-mo GV also were inversely related (R² = 0.61, SEE = 1.51, P = 0.0001) (Table 4 ). Similar results were observed when energy balance was used instead of energy intake. Additional analyses using backward elimination revealed a significant inverse relationship between the level of VL and energy intake [energy intake (kJ/d) = (2016.2 - 1.9 · VL) · 4.184, R² = 0.17, SEE = 573.2, P = 0.0125]; age, sex, race and body mass index were included but not found to be significant.

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

It appears that inadequate energy intake may also contribute to the poor development of FFM and growth in children with HIV, although analysis with multiple regression indicates viral replication is the more important factor. The difference in dietary intake between children with GF and children with normal growth appears rather marginal at first. However, when energy balance is assessed, our data suggest that for some children with HIV, daily dietary intake may not be sufficient to meet metabolic demands and sustain normal growth. In general, because of limited reliability, results of energy intake assessed by 24-h dietary recall must be interpreted with caution. Henderson et al. (1998) also reported differences in daily food intake between HIV-infected children with growth retardation and those with normal rates of growth using 24-h weighed-food intake obtained during a 1-d hospital admission, possibly a more accurate method than the one used in our study (Barrett-Connor 1991 , Henderson et al. 1998 ). Our findings are also similar to studies of HIV-infected adults, indicating that decreased dietary intake is an important determinant of weight loss (Macallan et al. 1995 ). These findings suggest that HIV-associated growth failure may in part be a result of chronic low-grade undernutrition. Undernutrition, however, clearly is not the sole cause of growth and body composition abnormalities in children with HIV infection. Evidence to this effect comes from observations made before the use of potent antivirals, indicating that administration of additional energy does not reverse the deficits in height or lean body mass (Henderson et al. 1994 ).

In this study, we assessed whether hypermetabolism, e.g., elevated REE, might also contribute to poor growth in children infected with HIV. It was anticipated that replication of HIV and attendant cell turnover and host response would increase the basal metabolic energy expenditures. In contrast to studies performed in adults with HIV infection in which hypermetabolism is reported (Hommes et al. 1991 ), we did not detect hypermetabolism in either group of children we studied, a finding similar to other reports performed in children with HIV. In this study, children with HIV-associated growth failure tended to have reduced levels of energy expenditure compared with children with normal rates of growth. This is unexpected, especially in light of data that indicate that the level of viral replication influences REE (Mulligan et al. 1997 ). The absence of elevated REE in these children may be due in part to a lower amount of FFM, which is preferentially decreased in children infected with HIV, especially those with GF. Reductions in REE also occur as an adaptation to restricted dietary intake. This has been reported in otherwise healthy children with nutritionally based growth retardation in developing countries (Soares-Wynter and Walker 1996 ). Energy expenditure from physical activity also decreases in response to restricted dietary intake (Keys et al. 1950 ), although there is no indication that physical activity is compromised in the children we studied; in fact, the average activity-related energy expenditures in our subjects exceeded those reported in studies of healthy children. Although the differences in REE and TEE between children with GF and normal rates of growth were not significant, possibly because of the small sample size in this study, the magnitude of these differences (14% energy/d for TEE) is of potential clinical importance. A sample containing 45 subjects in each group is necessary for sufficient power to detect a difference of this magnitude (ß = 0.8, = 0.05).

The increased REE/kg FFM noted in the HIV+/GF+ children is reported in undernourished stunted children in developing countries and in a number of chronic diseases that affect childhood growth, including cystic fibrosis and asthma (Tomzesko et al. 1994 , Zeitlin et al. 1992 ). A similar trend was reported in HIV-infected children with growth retardation (Henderson et al. 1998 ). Although standardization of REE by using a REE/FFM or similar ratios has been used frequently in past investigations to compare individuals of different body size or body composition, spurious results may arise (Weinsier et al. 1992 ). The regression analysis we performed, which failed to detect differences between our two groups, provides a better estimate of differences in REE among the groups after accounting for differences in body composition and age (Poehlman and Toth 1995 ). Although we do not believe that the differences in the REE/FFM ratio between HIV-infected children with GF and those with normal rates of growth indicate true differences in underlying REE, it may reflect a greater organ:skeletal mass ratio in these children. In normal childhood growth, the proportion of organs that have higher resting energy requirements to skeletal muscle decreases (Holliday 1971 ). Additional assessments of the character of the FFM in children with HIV infection are required to clarify this.

At present, there is no height- or height velocity–defined diagnosis of abnormalities in linear growth included in the Centers for Disease Control Pediatric HIV classification system. AIDS Wasting, which involves weight loss or weight-gain decelerations, is the only specifically defined growth abnormality included for children. Our results indicate that poor linear growth is also 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 also be carefully assessed.

	ACKNOWLEDGMENTS

 
We gratefully acknowledge the contribution of Maitra Utpal, who performed viral load quantitation.

	FOOTNOTES

 
¹ Funded in part by Pediatric AIDS Foundation Grant 50641, National Institute of Health Grants DK 26687 and RR00109, and the Silverweed Foundation.

³ Abbreviations used: AIDS, acquired immunodeficiency syndrome; FFM, fat-free mass; GF, growth failure; GV, growth velocity; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; RDA, recommended daily allowance; REE, resting energy expenditure; SEE, standard error of the estimate; TEE, total energy expenditure; VL, viral replication.

Manuscript received January 18, 2000. Initial review completed February 26, 2000. Revision accepted June 14, 2000.

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