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Prospective evaluation of the effects of antiretroviral therapy
on body composition in HIV-1-infected men starting therapy
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In the current issue of the journal AIDS (2003; 17(7):971-979), Australian researchers (Patrick W. G. Mallon; John Miller; David A. Cooper; Andrew Carr) reported on a prospective study of evaluation of the development of body changes in 40 men starting HAART. The authors conclude that the affect of body changes is due directly to ART and not to an immune "aetiology" (caused by the immune system). But I do not think they make the case for this very well. They did not study or do an analysis of some of the immune system aetiologies (causes) other researchers have suggested may be related to body changes. I think all agree, including researchers who suggest an immune aetiology, that ART plays a role in contributing to body changes. But the question is, is there an immune aetiology that contributes to body changes. And I don't think this is adequately addressed in this study to dismiss it as the authors do in their conclusions. Nonetheless, the study is interesting in montiring the course of the development of the body changes experienced by 40 men over 96 weeks of follow-up. Since this study was conducted in Australia it does not include African-Americans and I do not think it includes Hispanics.
Little prospective data are published on the natural history of HIV-associated lipodystrophy (HIVLD) in individuals beginning their first antiretroviral regimen. To investigate this a study was designed to explore changes in body
composition occurring with antiretroviral therapy. This study was a non-randomized, prospective, exploratory study of 40, HIV-infected men, naive to treatment, beginning antiretroviral therapy. Regular assessments of body composition, and metabolic and immunological parameters were performed.
We hypothesised that lipoatrophy occurs as a result of treatment with, and duration of, antiretroviral therapy, rather than being purely an immune phenomenon. To explore this hypothesis, we studied a cohort of antiretroviral-naive, HIV-infected men starting a variety of antiretroviral regimens, to determine changes in body composition resulting from therapy, and factors associated with these changes.
Baseline demographics were collected. The following assessments were performed at baseline, weeks 12, 24 and then every 24 weeks thereafter; CD4+ lymphocyte counts, plasma HIV RNA, fasting total cholesterol, estimated low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, glucose and insulin.
Total and regional body composition was quantified at screening, and at weeks 12, 24, 48 and every 48 weeks thereafter by dual-energy X-ray absorptiometry (DEXA) (Lunar DPXL; Madison, Wisconsin, USA) at a single reading site.
Estimates of central abdominal fat (CAF) and spinal bone mineral density (represented by 'T' score) were determined from a central window measurement.
A brief summary: Mean follow-up was 96 (SD 45) weeks of therapy. There were increases in limb fat, central abdominal fat and lean mass over the initial 24 weeks of therapy followed by a selective, progressive loss of limb fat from week 24. There was a median 13.6% [interquartile range (IQR), 0.9-26.3] loss of limb fat per year from week 24 onwards. Treatment with stavudine, higher baseline HIV RNA, higher baseline 'T' score and lower week 24 lean mass were associated with higher rate of limb fat loss from week 24. In multivariate analysis, treatment with stavudine was the strongest independent factor associated with rate of limb fat loss (P = 0.05). Hypercholesterolaemia developed early in treatment, whereas hypertriglyceridaemia, hyperinsulinaemia and decreased bone mineral density developed later. The largest changes in CD4 cell counts and HIV viral load, seen early into treatment, were associated with gain rather than loss of fat. The authors concluded this is the first prospective study demonstrating that treatment with antiretrovirals results in progressive, selective loss of limb fat. Loss of limb fat occurred after the period of most intense immune restoration, making an immune aetiology unlikely.
RESULTS
Forty patients were recruited between July 1997 and May 2000 with analysis performed in December 2001. At the time of analysis, all patients were alive, 90% of the cohort had completed 96 weeks of therapy and 50% had completed 144 weeks of therapy.
All median baseline metabolic parameters were within normal limits, as were body mass index (BMI) and bone mineral density. Almost half the cohort received a regimen containing a PI, with indinavir being the most common PI used. Five subjects received a regimen containing both PIs and non-nucleoside reverse transcriptase inhibitors (NNRTI). Roughly equal numbers were prescribed one of the three most common dual NRTI backbone regimens at that time: didanosine and stavudine, stavudine and lamivudine, and zidovudine and lamivudine. 10 patients were indinavir regimen, 8 on nelfinavir, 1 on saquinavir, 11 on efavirenz, 10 on nevirapine. 13 on ddI/d4T, 10 on AZT/3TC, 13 on d4T/3TC. Average viral load was about 100,000 copies/ml. Cd4s were on average 246. Average years since HIV diagnosis was 3. Median age was 39.5. 6 had an AIDS diagnosis.
Over the course of the study, 16 (40%) subjects changed therapy. Four (10%) subjects changed class from a PI to a NNRTI-containing regimen an average of 23 (range 12-36) months into the study. One subject changed from a PI to a
NNRTI-containing regimen due to virological failure 2 years into the study. All remaining changes were secondary to side effects. The most common drugs involved were stavudine with 11 changes after a mean of 7 [3-12] months of
treatment (six secondary to neuropathy, one secondary to symptomatic lactic acidaemia, one secondary to adherence problems and three for side effects not otherwise specified), didanosine (ddI) with five changes after a mean of 10
(3-24) months (three secondary to neuropathy, one secondary to nausea and one for other side effects), and indinavir with four changes after a mean of 8 (3-12) months (two secondary to renal calculi, one secondary to paronychia and one secondary to other side effects). No subject changed therapy as a result of changes in body composition.
Seventy percent of the cohort achieved viral load < 400 copies/ml by week 12, with no significant change seen between weeks 12 and 144. At the time of analysis, 82% of the cohort achieved an undetectable viral load (HIV RNA <
400 copies/ml). Median baseline CD4 cell count was 246 cells/l (range 0 to 836 cells/l). The largest rise in median CD4 lymphocyte count occurred by week 24 (median increase of 126 cells/l, P < 0.0001), with a further significant rise between weeks 24 and 144 (increase of 56 cells/l, P < 0.05).
BMI Change
There was a significant rise in BMI (22.5 to 24, P < 0.05) and lean mass (3% rise from baseline, P < 0.01) by week 12, which was sustained to week 48. At week 96 BMI had decreased to a level not significantly different from baseline.
Total body fat increased by median 20% to week 24 (P < 0.001) with no significant changes from week 24 onwards.
Central abdominal fat
In contrast to limb fat, after an initial increase to week 24, CAF was maintained after week 24, remaining significantly greater than baseline out to week 144. Baseline factors predicting larger mass of CAF at week 24 included
higher baseline total fat, limb fat, truncal fat and CAF, higher insulin concentrations and higher BMI. Factors associated with a greater percentage change in CAF between baseline and week 24 included lower baseline cholesterol and CD4 cell count and higher baseline HIV RNA. Subjects with more CAF at week 24 also had significantly higher week 24 truncal, limb and total fat, higher cholesterol, triglycerides, insulin, and lower HDL cholesterol and a higher BMI. A greater change in CD4 cell count from baseline correlated with changes in limb fat, truncal fat, CAF and total fat. Those taking a PI-containing regimen had significantly higher and those taking a NNRTI regimen had significantly lower CAF at week 24.
Bone mineral density
The 'T' score rose slightly to week 24 and then fell significantly to week 48 remaining significantly lower than baseline out to week 144. The percentage of the cohort with 'T' scores less than -1 (consistent with osteopenia) rose from 13% at baseline to 22% at week 144. There was little change in the number of the subjects with 'T' scores less than -2.5 consistent with osteoporosis (1 at baseline, 2 at week 144).
I did not see any information in the study of risk factors for bone loss in these individuals, such as smoking cigarettes, being sedentary, etc.
Metabolic parameters
Fasting total cholesterol and estimated LDL cholesterol rose significantly early into treatment with the largest rise occurring by week 12. Both remained significantly higher than baseline out to week 144. In contrast triglyceride concentrations did not rise significantly until week 96 and remained elevated out to week 144. Similarly, insulin concentrations rose late with significantly higher insulin concentrations occurring at week 144. Changes in fasting insulin were not significantly different between those prescribed PI-containing regimens [median, 1.2 mmol/l per year (IQR, -0.87 to 3.27)] and those prescribed PI-sparing regimens [0.65 mmol/l per year (IQR -0.7 to 2)].
The change in total and LDL cholesterol per year of treatment was 0.44 and 0.24 mmol/l, respectively. In a multivariate analysis of baseline variables, treatment with PIs (P = 0.006), lower baseline cholesterol (P = 0.02), and lower
baseline lean mass (P = 0.04) were independently associated with greater increases in total cholesterol. Similarly, use of PIs (P = 0.002) and lower baseline LDL (P = 0.04) were associated with the largest rises in LDL cholesterol.
The change in triglycerides concentrations was 0.14 mmol/l per year of treatment. No baseline factor determined change in triglyceride, although those with greater change in cholesterol per year also had significantly larger rises in triglycerides per year (P = 0.01).
HDL cholesterol rose by 0.1 mmol/l at week 24 (P < 0.01) but the rise was not sustained past week 96. Fasting glucose concentrations did not change (4.7 mmol/l at baseline versus 4.85 mmol/l at week 144).
Discussion
The complexity of the mechanisms underlying HIVLD is reflected in the results of this exploratory study. Most of the components of HIVLD, such as central fat accumulation, peripheral lipoatrophy and hyperlipidaemia were observed.
Contributions by drug classes and specific drugs, in addition to immunological and virological responses to therapy, were all shown to have some correlation with changes in body composition. From these results, a sequence of events
begins to emerge, providing an insight into possible primary and secondary events in the development of HIVLD. Of importance, these results reveal trends that run counter to some currently held theories about the possible mechanisms underlying HIVLD.
The gains in both central abdominal fat and limb fat seen during the first 24 weeks of treatment could be explained by general improvements in health and nutrition associated with treatment of HIV viraemia and reversal of the associated catabolic state. The simultaneous increase in lean mass also seen during this period support this viewpoint, suggesting that these changes result from general improvements in nutrition rather than a fat-specific process.
The gain in CAF during the initial 24 weeks of therapy may reflect the visceral fat accumulation reported in HIVLD. From week 24 onwards, there was an obvious selective, progressive loss of limb fat whereas both CAF and lean mass
were maintained. This likely represents the lipoatrophy that is characteristic of HIVLD. Maintained levels of CAF in the presence of limb fat loss could result in the central fat becoming more pronounced clinically to patients or physicians as limb fat declined.
Of interest is the correlation noted between CAF and limb fat. Although by 3 years both gain in central fat and loss of limb fat are present, the two processes do not appear to be occurring simultaneously and may be part of separate aetiologies - the increase in CAF probably in response to nutritional improvement (and therefore a secondary effect of drug treatment), whereas the loss of limb fat was probably a result of long-term antiretroviral drug use. However, excess fat accumulation resulting from changes in nutritional requirements alone would be expected to decrease over time as the body gains muscle mass. The fact that this fails to occur in this cohort may indicate that the persistent accumulation of abdominal fat seen after week 24 is a reflection of a pathological process. Whether this is related to immune restoration, continued drug exposure or other process is unclear from this study.
Loss of limb fat, however, developed in the absence of significant changes in HIVVL, and after the largest change in CD4 cell count had already occurred (Fig. 1a and 1b). This runs contrary to the hypothesis that HIVLD is part of a
cytokine-driven 'immune reconstitution' phenomenon . Indeed, during the period of most intense immune recovery, there was actually a gain, rather than a loss, of both limb fat and CAF.
Complex relationships between morphological and metabolic changes are apparent from this study. Those with higher baseline cholesterol values gained less limb fat and CAF to week 24. A first impression may be that these
subjects already have high baseline body fat deposits, thus explaining the higher cholesterol values and lower relative fat gains. However this was not the case, as no significant correlations existed between baseline cholesterol levels and mass of total or compartmental body fat (data not shown).
The importance of the cholesterol values is reflected in their strong association with subsequent loss of limb fat. Such an association has previously been reported. There are marked inter-individual variations in the function of adipose tissue, with evidence supporting a genetic basis for this variation. If higher cholesterol levels reflect poorly functioning adipose tissue, these individuals may be at higher risk of further adipose tissue dysfunction, resulting from the additional and continuing insults from antiretrovirals on adipose tissue (e.g. SREBP-1c) or mitochondrial function. This could explain the changes seen in this cohort.
Higher insulin concentrations associated with high CAF mass, seen in this study, is an association that has been well described in HIV-infected and uninfected populations. Other PI- induced mechanisms of insulin resistance, such as those involving dysfunction of the GLUT-4 glucose transporter, result in an acute insulin resistance. Although in vitro evidence exists to support such a mechanism, such an acute process should result in high insulin concentrations early in the course of treatment. This was not seen in this study, with hyperinsulinaemia occurring later into treatment.
Although the most detailed prospective study to date, the results from this study should be viewed in the context of study limitations. It could be argued that the fact that this was a non-randomized study, with no untreated controls, using various antiretroviral regimens, in a cohort of male only patients is a limitation. In addition, the use of total body DEXA to estimate CAF and bone mineral density is imperfect. Although significant associations were detected, these should be viewed in the context of the number of subjects involved in the study. It could be argued that the large number of comparisons studied and the multiple data points used leaves the results prone to false positives, although non-parametric analyses were employed in an attempt to limit this.
The number of treatment changes may or may not be viewed as a limitation. Treatment changes happen frequently in routine practice and as such, this study may provide a more accurate description of the development of HIVLD in clinical practice. In addition, development of HIVLD was not used as a reason for changing treatment. The impact of treatment changes on the overall analysis was minimal. For example, there were no significant differences in the rate of limb fat loss in those who stopped stavudine, nor in the accumulation of CAF in those who stopped indinavir (data not shown).
Objective changes in body composition correlating with HIV associated lipodystrophy only became readily apparent after 2 years of antiretroviral treatment in this cohort. This has consequences with respect to published studies alluding to the metabolically friendly profile of certain drugs or drug combinations, which have a relatively short follow-up period. Importantly, this study shows how the development of lipoatrophy is relatively independent of
changes in immune function, being more a product of continued exposure to antiretroviral drugs.
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