Using anthropometry to examine regional body composition changes (as opposed to a dichotomous outcome based upon self-report and clinical examination), we made several noteworthy observations in our study of Ugandan HIV-infected persons after initiation of a zidovudine-containing regimen. First, we found that total lean and fat mass as well as regional circumferences and skinfolds in peripheral and central body sites increased over the 12-month period on ART, suggesting restoration to health. Second, the increase in the tricep skinfold was blunted, which could indicate a zidovudine effect on peripheral subcutaneous fat recovery. Finally, we observed temporal differences in fat and lean mass recovery. Increases in lean mass and circumferences occurred early (first 6 months); by contrast, there was little increase in any of the skinfolds (which are thought to be a reliable measure of subcutaneous fat) until after 6 months of ART.
Our observations of an increase in peripheral and central body fat measured using anthropometry are consistent with studies from the United States and Australia.6–8
However, we found mean annual increases over the 12-month period; other studies6,7
reported trunk and limb fat increases [measured by dual-energy x-ray absorptiometry (DXA)] that appeared to peak 16 to 32 weeks after a stavudine- or zidovudine-containing regimen was started. Subsequent decreases in limb fat (thought to be due to the thymidine analogs) to levels near or below baseline levels and stabilization in trunk fat were observed after 48 weeks of therapy. A similar pattern was seen when circumferences of peripheral sites (thigh, arm, hip) and waist were studied.7
A possible reason for the difference between our study and those studies is that our participants had lower baseline CD4+
T cell counts and BMI. Our participants were also mostly on a zidovudine-containing regimen, whereas in other studies, patients were mostly on a stavudine-containing regimen6
; stavudine has been shown to cause greater limb fat loss than zidovudine in some studies.9,10
Interestingly, a South African study14
of 42 HIV-infected patients with mean CD4+
T cell count of 93 cells/μl found increases (waist, hip circumference, and tricep skinfold) that appeared to peak later (41–59 weeks after starting a stavudine-containing regimen). These findings suggest that regardless of the type of thymidine analog used, before direct effects of the drugs on adipose tissue can be observed, a threshold amount of fat and thus longer restoration to health (and fat recovery) period is needed. Sex differences may also account for some of these differences due to the large proportion of women included in African studies.
Our findings that the increase in tricep skinfold was blunted over the 12-month period is also consistent with the South African study.14
In that study, only the tricep skinfold declined to below baseline values by 111 weeks of follow-up. These studies suggest that similar to studies from the United States, Europe, and Australia,5–10
the thymidine analogs (stavudine and zidovudine) are associated with lipoatrophy or fat loss, particularly in peripheral body sites. Unexpectedly, we did not find that the increase in the thigh skinfold was blunted over time, possibly because we followed patients for only a 12-month period. A U.S. study found that mean decreases in the thigh skinfold were not observed until after 12 months on a zidovudine-containing regimen, but mean decreases were observed in the tricep skinfold within the first 12 months on therapy.8
The timing of fat loss associated with thymidine analogs may differ in the upper and lower extremity.
Interestingly, we observed that the increase in lean mass and circumferences (especially the waist) occurred mostly in the first 6 months after initiating ART, whereas there was little change in any skinfold measure during the same period. Similar changes have been observed in studies of women with anorexia nervosa in the initial weight recovery period.22–24
In these studies, central fat accumulation occurred at a greater rate than in healthy age-matched controls, while peripheral fat remained lower than or about the same as in controls. Some have hypothesized that the chronic nutritional deprivation associated with anorexia may lead to altered growth hormone secretion or hypercortisolemia that may influence central fat distribution during recovery.25
In contrast to our study, a consistent increase in muscle mass was not observed in these studies, likely because our patients had lower lean mass (from muscle wasting or cachexia) resulting from advanced HIV infection. The findings in anorexic patients could suggest that some reports of lipodystrophy in Africa are partly explained by the natural course of fat recovery after restoration to health, as opposed to a direct drug effect. Further study is needed to understand the mechanisms underlying the differences in timing of recovery of lean mass and fat mass in the viscera and subcutaneous compartments in HIV-infected men and women (particularly in food insecure settings) and its long-term implications.
It is noteworthy that we observed a gender-by-time interaction, where women had significant increases in most skinfold and circumference measures and men showed small increases over time. A study of postrenal transplant patients also found that women gained fat mass faster than men.26
Furthermore, a small retrospective study comparing HIV-infected persons before the advent of HAART to HIV-infected persons after the advent of HAART found that most of the weight difference in men was accounted for by the change in lean mass, whereas in women, most of the weight difference was accounted for by a change in fat mass.27
Differences in sex steroid levels between men and women have been postulated as a reason. In our population, other unmeasured factors such as social and cultural factors as well as access to food might also be possible explanations for this finding. Sex differences in recovery of total and regional fat warrant study in a larger cohort of HIV-infected men and women.
The limitations of our study include the small sample size and the relatively short follow-up period, which did not allow us to fully differentiate the restoration to health phase from the potential longer term effects of zidovudine in our population. We also were not able to assess body composition changes in controls over a similar 12-month period. We did not study the potential metabolic consequences of these body fat changes, because baseline fasting glucose and lipid values from these participants and limited fasting data over the 12 month period were well within the normal range (data not shown). While anthropometry is prone to some measurement variability, it is the most cost-effective method for obtaining objective and continuous measures of fat in resource-limited settings where direct measures of fat such as MRI, CT, or DXA scanning are not feasible.
In conclusion, regional anthropometry in peripheral and central body sites increased over a 12-month period after zidovudine-containing ART initiation in a cohort of HIV-infected persons from southwestern Uganda. This suggests a restoration to health that may be more prolonged than previously reported in resource-rich countries. Gains in tricep skinfold, a reliable marker of subcutaneous fat, appeared blunted, which could suggest an inhibitory effect of zidovudine on peripheral subcutaneous fat recovery. Further studies over a longer period of time in a large cohort of HIV-infected men and women compared to controls are needed to fully understand the body composition changes and potential metabolic consequences after the initiation of ART. Comparative studies with HIV-infected persons from resource-rich countries may also elucidate how environmental and nutritional factors may have an impact on the rate of recovery of lean and fat mass after initiation of ART.