Regional body composition beyond the 4-month follow-up visit differed significantly by study assignment (Fig. 4). For the mid-arm skinfold fat area, there was a significant decrease in regional fat for patients assigned to the ddI + d4T arm (P < 0.01), while there was a slight increase for the ABC + 3TC arm, with both being significantly different from each other (P < 0.01). For the waist skinfold fat area, a significant decline in the rate of change from zero was seen for the ddI + d4T arm (P = 0.03), while the ABC + 3TC arm had a significant increase (P = 0.02), with these 2 rates being significantly different from each other (P < 0.01). The skinfold fat-free areas for the mid-arm and waist increased from baseline to the 4-month follow-up visit in both arms, with no apparent change in the rates beyond that time point.
As part of a subgroup analysis, we assessed the relationship between hepatitis C infection and body composition changes. Within each of the treatment arms, no differences were seen in the rates of change for any of the body composition or metabolic measurements for those with or without hepatitis C infection. Furthermore, comparisons by treatment assignment did not identify any significant differences.
Use of thymidine analogue NRTIs has been associated with the occurrence of HIV-associated lipoatrophy.5,16-19,41,42 In this prospective evaluation comparing a thymidine analogue-containing regimen consisting of ddI + d4T to a thymidine analogue-sparing regimen consisting of ABC + 3TC in antiretroviral-naive patients initiating highly active antiretroviral therapy (HAART), our data demonstrated an initial increase in all body composition parameters (ie, BCM, TBF, and subcutaneous fat) regardless of treatment assignment. This initial increase was followed by a progressive and preferential loss of subcutaneous fat and TBF among those randomly assigned to treatment with ddI + d4T when compared with ABC + 3TC. The lack of decline in the thymidine analogue-sparing regimen supports recent findings of improvement in lipoatrophy being associated with the switch to thymidine analogue-sparing regimens.28,29 While initially all lipid parameters increased in both treatment arms, long-term treatment with ddI + d4T was associated with a decline in HDL cholesterol compared with ABC + 3TC. Furthermore, while both arms showed a decreasing LDL cholesterol, triglycerides increased more so for the ddI + d4T arm than the ABC + 3TC arm. Finally, a significant early and sustained increase in insulin and IR was seen in the ddI + d4T arm compared with the ABC + 3TC arm, despite a similar proportion of PI use in each study arm. While prior studies have demonstrated a dose-dependent early increase in IR associated with the use of HIV PIs,43,44 our findings support a potential role of ddI + d4T or ddI + d4T-related lipoatrophy in the development of IR.
Prospective randomized comparisons evaluating body composition changes among antiretroviral-naive patients are limited.6,23,24,26 In our study, body composition changes were demonstrated by an initial increase in the BCM and TBF in both arms, followed by a decrease in body fat noted only in patients assigned to the ddI + d4T arm, with the fat-free mass remaining relatively stable, consistent with previous studies.6,17 The gains noted during the first few months after initiation of HAART in BCM and TBF were coupled with the decrease in viral load. Similarly, the magnitude of the metabolic changes (ie, increases in triglycerides, HDL cholesterol, and LDL cholesterol) was greatest in the 1st month after initiation of antiretroviral therapy, regardless of treatment assignment, again paralleling the decline in HIV RNA, suggesting a direct effect of ongoing viral replication on the lipid parameters.
In our study, we noted the development of lipoatrophy with a progressive loss of subcutaneous fat with increasing cumulative antiretroviral exposure as previously reported.17,21,42 Diminished mitochondrial function has been proposed as causing lipoatrophy as well as a wide range of adverse events in HIV-infected persons taking NRTIs. However, the relationship between nucleoside analogues and lipoatrophy is confounded by the fact that NRTIs are not the only relevant cause of mitochondrial toxicity.45 Several studies of peripheral blood mononuclear cells and adipose tissue have shown evidence of mitochondrial DNA depletion in untreated HIV-infected subjects.46,47 While the mechanism by which nucleoside analogues contribute to the syndrome of lipoatrophy has not been fully elucidated, differential effects with certain NRTI combinations have been reported.26,45 Significant reductions in mitochondrial DNA have been observed in individuals receiving the combination of ddI and d4T, but not with the use of zidovudine, 3TC, or ABC, potentially indicating an additive effect of mitochondrial toxicity associated with certain NRTIs.48 Other studies in which patients on thymidine-containing regimens were switched from these agents to an ABC-containing regimen, improvement was noted in the peripheral lipoatrophy, with continued fat loss seen in those continuing their original regimen.12,27-29 Moreover, ABC and 3TC have not been associated with significant mitochondrial toxicity based on both in vitro and clinical experience.26,49 Nonetheless, our study is the first randomized study to assess the comparative effect of these 2 types of NRTIs in antiretroviral-naive patients.
Prior investigators have reported central obesity and lipoatrophy both prior to the initiation of antiretroviral therapy50 and with the use of HAART.5,15 In this study, with the initiation of HAART therapy, there was an initial increase in abdominal fat for both treatment arms, followed by a progressive loss for the ddI + d4T arm, but continued increase in abdominal fat for the ABC + 3TC arm. As abdominal obesity has been associated with higher risk of cardiovascular events,51 the ongoing effects of continued ABC + 3TC and its long-term implications require further investigation.
Waist-to-hip ratio (WHR) has been used as a marker of central obesity, which usually is accompanied by an increase in the waist circumference. However, WHR can also appear to increase when the hip circumference decreases. As seen in Figure 3, for the ddI + d4T arm, while the rates of change for both the waist and hip circumferences decreased, the decline was more rapid for the hip circumference, resulting in the WHR actually increasing. An opposite effect was seen with the ABC + 3TC arm, with both circumferences increasing but more slowly for the waist circumference, resulting in a declining WHR. These findings suggest that changes in the WHR may be misleading with respect to central obesity.
In this study, we used BIA and anthropometric measurements to assess body composition. Measurement of body composition in the clinical setting is hampered by the lack of a single method that is accurate, readily available, and affordable. Dual-energy x-ray absorptiometry (DEXA) is currently the most accepted laboratory technique for measuring body composition, because it is noninvasive, requires minimum efforts from the subjects, and is reliable.55 However, anthropometry performed by well-trained observers using standardized measurement protocols and tools34 has been used as a reliable tool for measuring body composition in HIV-infected patients.56,57 Recently, He et al58 compared anthropometric measurements of subcutaneous fat and lean areas to measurements obtained by MRI, supporting the comparability of our demonstrated changes in body composition with similarly designed prospective studies using DEXA.6,17
In summary, this prospective evaluation provides evidence that prolonged use of a thymidine analogue-containing regimen consisting of ddI + d4T compared with a thymidine analogue-sparing regimen consisting of ABC + 3TC in antiretroviral-naive patients resulted in the development of lipoatrophy as demonstrated by progressive loss of subcutaneous and TBF. The significant increase in insulin and IR noted in the ddI + d4T arm compared with the ABC + 3TC arm necessitates close monitoring for the development of diabetes or switching therapy to a thymidine analogue-sparing regimen. Conversely, the development of abdominal obesity in association with ABC + 3TC is also of concern. The demonstrated differential effect on lipid metabolism by treatment assignment necessitates ongoing longitudinal assessment of the effects of the different treatment strategies. Furthermore, this study highlights the importance of metabolic complications and the need for new agents not associated with these effects.
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