Stephen Arpadi
With over 50% of adults on treatment reporting some degree of body shape or metabolic changes, and uncertainty over the mechanism and treatment, this is obviously an area of concern for paediatric care. Steven Arpadi is one of the first doctors to have presented research in this area we were very fortunate that he was also able to attend our meeting in London.
Symptoms of lipodystrophy reported in HIV-infected adults include fat depletion (lipoatrophy) - usually subcutaneous from the face, buttocks, arms and legs - and fat accumulation, usually visceral fat accumulation, but also buffalo hump, breast enlargement, bilateral symmetrical lipomatosis.
The metabolic alterations that have been reported in lipodystrophy include insulin resistance and hyperglycemia, hyperlipidemia and dyslipidemia which includes relative shifts in HDL and LDL and often an additional increase in the total cholesterol.
These lipid and insulin abnormalities which are occurring in the context of HIV are of concern as they are clearly established as risk factors for coronary heart disease.
There are a number of issues that have made the study of these abnormalities problematic. These fat and metabolic disorders are not seen exclusively in HIV diseases; acquired and congenital forms also exist. Also, the fat and metabolic abnormalities that are observed may not necessarily co-exist or be connected. Also while it seems to be the case that many physicians recognize lipodystrophy when they see it, at present there is no agreed objective case definition of 'lipodystrophy'. Evaluation of the sensitivity and specificity of patient self-reported body shape changes is also rather limited.
The estimated prevalence of these various, either individual or combined, body shape changes vary widely depending on the population of study and the criteria used. In a recently published review, Grunfeld suggested the prevalence of abnormalities may be as high as 83% in treated HIV-infected adults. [1] These body shape changes have been reported in men, women, various racial/ethnic groups, different geographic groups, and now we have data indicating the occurrence of fat abnormalities in children as well.
Lipodystrophy and children
Data is very sparse with regard to lipodystrophy in children. A survey performed by Babl and colleagues reported a prevalence of 1%, of physician assessed body fat distribution abnormalities across the US paediatric Aids clinical trial units. [2] There have also been case reports of lipodystrophy including hyperlipidemia to levels warranting intervention in children with PI use. [3, 4, 5]
We observed a nine year old whose parent reported concern about an increasing abdominal size about nine months after beginning a new therapy. This patient had also been a subject in a prior study of body composition performed initially to study growth failure and wasting in children, so a baseline Dual-X-ray energy absorptiometry (DEXA) scan was available for comparison.
During the 18 months between studies, (about nine or ten months after beginning his new regimen) the child had a normal growth velocity. Despite a weight gain of 3.5 kilos there was a loss in body fat of approximately 0.5kg. Given his increasing weight this represented about a 5% drop in terms of percent body fat. We saw loss of fat in his arms and in his legs - lipoatrophy - with increasing amounts of truncal fat. Intra-abdominal fat was assessed by means of a total body MRI and was found to be markedly increased. This boy also had elevated cholesterol and triglyceride levels.
After the age of five, indices of central fat in children are relatively stable and changes in the subscapular: triceps subcutaneous fat ratio doesn't change significantly again until after the onset of puberty. This makes this middle-age of childhood an ideal time to study these types alterations in regional fat distribution.
We recently performed a study to evaluate the relationship of regional fat re-ditribution and levels of triglyceride (TG) and cholesterol (CHL) in an longitudinal observational clinical cohort of 28 prepubescent vertically HIV-children. [6]
DEXA, random triglyceride and cholesterol levels, PCR RNA-viral load and lymphocyte subsets were analysed at baseline and follow-up. Between and within groups differences were assesd using OR and Fisher exact test for associations. Lipodystrophy was defined as requiring both a decrease in peripheral fat (arm and leg) and an increase in trunk fat, TG and CHL were compared to expected normal values from the US National Child Evaluation Programme.
The mean age was 7.5 years old (±2.3, range 4-12) with a normal weight for age but low height for age z-scores. Other mean baseline characteristics of the group ± SD included BMI (kg/m2) - 16.7 ± 3.2; Total body fat - 20.4 ± 8.3; CD4 count 457 ± 397; CD4% 19.8 ±12.4; Log HIV RNA 4.12 copies/ml ± 0.74.
Although only one of these children had been associated with a prior lipodystrophy concern, the study identified eight children (29%) as having fat reidistribution which met our criteria for lipodystophy. Three children had only fat loss and half the children had weight gain only.
Changes in weight and body composition baseline characteristics in children with and without lipodystrophy are shown in figures 1 and 2.
The only baseline factors for these two groups that were significantly determinant were baseline viral load, CD4 count (p<0.05) and CD4% (p<0.01). Age, sex, race, BMI, body fat and trunk extremity ratios were not found to be significant. PI-use (mainly saquinavir and ritonavir) and d4T-use were also found to correlate although no allowance was made for previous NRTI use and the lipodystrophy group were generally more heavily treated. Baseline triglyceride and cholesterol were not significant at follow up, but in the fat redistribution group, in the paired analysis, these did become apparent. Factors associated with >130mg TG were lipodystrophy (OR 11.4, 95%CI 1.0-13.5, p=0.058) and PI use (OR 3.0, 95%CI 1.7-5.3, p=0.02).
In summary, I think our data suggests that body fat changes are occurring in children with HIV; in many cases it is unnoticed or subclinical. In only one of the youngsters included here was there any prior concern about a change in body fat.
We also found an association between lipodystrophy and low CD4 count and CD4 percentage and high virus at baseline. It also seems to be associated with exposure to protease inhibitors and d4T. We found mild increases in triglycerides in children with lipodystrophy and these changes were associated with PI use. We did not find statistically significant changes in cholesterol.
The features of lipodystrophy and the factors associated with lipodystrophy and altered triglycerides in children appear to be similar to those reported in adults but are less severe. Nonetheless, in some of these children the levels of lipid alterations warrant clinical interventions.
It is also important that we concern ourselves with the possibilities that something related to HIV infection and/or its therapies may be putting our paediatric patients at greater risk for later coronary artery disease. At present the estimated increase in risk for coronary artery disease in adults with HIV infection is approximately 0.14% per year. We really need to weigh that against the benefits of decreased mortality that we see with therapy.
References:
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Fig 1. Baseline values in LD+ and
LD- children |
Fig 2. Changes in weight and body
composition |
Fig 3. Studies with early treatment |
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Click on slide for a larger view |
Click on slide for a larger view |
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Dr Stephen Arpadi
is an Associate Professor of Clinical Paediatrics and Public Health at Columbia
University. He is the Associate Medical Director of the Comprehensive HIV Care
Center at St. LukeÕs-Roosevelt Hospital Center in New York City and is the Director
of the Program for Children and Families, a multidisciplinary treatment program
for children and families affected by AIDS/HIV. He has conducted research in
growth, nutrition, and metabolism of paediatric HIV infection and has collaborated
on multiple studies of antiviral therapies for children with HIV/AIDS.
smarpadi@pol.net
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