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Clinical Science

Racial Differences in Changes of Metabolic Parameters and Body Composition in Antiretroviral Therapy-Naive Persons Initiating Antiretroviral Therapy

Gibert, Cynthia L MD, MSc*†‡ ; Shlay, Judith C MD, MSPH§‖ ; Sharma, Shweta MS; Bartsch, Glenn ScD; Peng, Grace MS; Grunfeld, Carl MD, PhD#** for the Terry Beirn Community Programs for Clinical Research on AIDS and the International Network for Strategic Initiatives in Global HIV Trials

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: January 1, 2009 - Volume 50 - Issue 1 - p 44-53
doi: 10.1097/QAI.0b013e31818ce808
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Abstract

INTRODUCTION

Changes in metabolic and body composition parameters associated with HIV infection have been recognized since early in the HIV epidemic.1-4 The etiology of these changes has been attributed to HIV infection and antiretroviral therapy (ART).5-12 Among HIV-negative adults, racial/ethnic differences in the prevalence of dyslipidemia, impaired glucose metabolism, and insulin resistance (IR) have been well described as have differences in body composition.13-19 For those with HIV infection, these differences are less well defined, particularly in relationship to receipt of ART.20-23 Given the recognized risk of premature cardiovascular disease among individuals with HIV infection,24-28 understanding racial differences in metabolic parameters and body composition is of interest.

The aim of our study was to assess, among ART-naive African Americans, Latinos, and whites initiating ART, long-term changes in metabolic parameters and body composition for each racial/ethnic group and differences in these changes between these groups after adjusting for ART. Of particular interest were those changes associated with glucose and lipid metabolism.

METHODS

The FIRST (Flexible Initial Retrovirus Suppressive Therapies) study29 and the metabolic study,30 a substudy of FIRST, were long-term randomized clinical trials conducted by the Community Programs for Clinical Research on AIDS (CPCRA). The FIRST study (CPCRA 058) enrolled ART-naive persons who were offered coenrollment in the metabolic study (CPCRA 061). The metabolic study assessed changes in metabolic parameters and body composition among ART-naive persons randomized to 3 highly active treatment strategies. The design, eligibility criteria, and results of this study are published elsewhere.29,30 The metabolic study began in August 1999 and closed to follow-up in September 2005. A consent form approved by the institutional review board of each site was signed by each participant.

At enrollment, a baseline history and targeted physical examination were completed including demographic characteristics, current medications, and prior AIDS-related diagnoses.31 The research coordinator asked subjects which racial/ethnic group best fit them and their reply was recorded. Data collection for metabolic parameters and body composition has previously been described.9,30 Data were collected at baseline, month 1 (metabolic parameters only), month 4, and every 4 months thereafter. The measures of interest for these analyses included the following: triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, glucose, insulin, IR, total body fat, fat-free mass, body mass index (BMI), subcutaneous tissue areas of the mid arm, mid thigh, and waist, and nonsubcutaneous tissue areas of the mid arm and mid thigh, and the visceral tissue area at the waist.

Visceral tissue area was calculated by subtracting the waist subcutaneous tissue area from the total area of the cross section of the abdomen, which was calculated using the waist circumference. Visceral tissue area represents the visceral contents of the abdomen and reflects visceral adipose tissue. The waist subcutaneous tissue area was calculated using the waist circumference and the abdominal skinfold measurements.30 The subcutaneous and the nonsubcutaneous tissue areas of the mid arm and mid thigh were calculated in a similar manner.30 Anthropometric measurements were discontinued in April 2004 based on recommendations from the Data Safety Monitoring Board.

The cohort was a subset of the 422 participants enrolled in the metabolic study, of whom 412 (97.6%) identified themselves as belonging to one of the racial/ethnic groups, African American, Latino, or white. Hereafter, race/ethnicity will be referred to as race. Twelve participants on treatment for diabetes or hyperlipdemia at baseline were excluded. Only those with a baseline measurement and at least 1 follow-up measurement for any of the metabolic parameters or measures of body composition were included. The final sample consisted of 398 participants.

Statistical Analysis

Follow-up time was censored after the first report of diabetes treatment or use of lipid lowering drugs. For selected metabolic parameters and body composition measurements, the average change from baseline at each follow-up visit was calculated by race and the overall mean change from baseline was computed by race for each measure of interest.

Using repeat measurement analyses32 with random intercepts, multivariate regression models were used to compute the adjusted differences in the mean changes from baseline of various measurements by racial group. These regressions were adjusted for updated cumulative time on the following antiretroviral drugs: indinavir, nelfinavir, ritonavir; efavirenz, nevirapine, abacavir, didanosine, lamivudine (3TC), stavudine (d4T), and zidovudine; and baseline variables: age, gender, hepatitis C status, CD4+ cell count, log10 HIV RNA level, prior AIDS status, and BMI (for metabolic parameters only) and the baseline measurement of the dependent variable.

Using repeat measurement analyses32 with random intercepts and random slopes, unadjusted multivariate linear regression lines were fitted by race to follow-up data (beginning at 1 month for metabolic parameters and at 4 months for anthropometric measurements). Slopes of the lines were used to estimate the rates of change per year of follow-up by race for body composition measurements (at 4 months and thereafter) and metabolic parameters (at 1 month and thereafter). For comparisons of the rates of change by race, the repeated measurement analyses were adjusted for the same variables as above (except the baseline measurement). For pairwise comparisons involving the 3 race groups (ie, 3 rates of change or 3 mean changes), the nominal significance of the t test is given and should be less than 0.017 to be significant at 5% level using a Bonferroni adjustment. All statistical analyses were performed using SAS (version 8.0, SAS Institute, Cary, NC).

RESULTS

Baseline Characteristics

Among the 398 participants in this analysis, 243 (61%) were African Americans, 43 (11%) were Latinos, and 112 (28%) were whites. The baseline characteristics for the 3 groups are shown in Table 1. Overall, mean age was 38 years and 22% were female. The majority of female participants were African American (87%) with only 9% being Latino and 4% white. Other baseline parameters were similar in the 3 groups with the exception that the log10 HIV RNA was significantly higher for whites.

TABLE 1
TABLE 1:
Baseline Characteristics

The ART prescribed at baseline in this treatment-naive cohort is shown in Table 1. Nelfinavir without ritonavir boosting was prescribed more frequently to Latinos (58%) than whites (45%) or African Americans (36%) (P = 0.01). A ritonavir-boosted protease inhibitor (PI) was prescribed more frequently to African Americans (P = 0.03). With respect to nonnucleoside reverse transcriptase inhibitors use, the majority of participants in each group were prescribed efavirenz with no difference in the use of efavirenz or nevirapine by race. Nucleoside reverse transcriptase inhibitor usage was evenly distributed across the 3 groups.

Baseline metabolic and anthropometric measurements for the 3 races are shown in Table 2. The average HDL cholesterol levels were significantly higher in African Americans. Mean levels of insulin and IR were significantly higher for Latinos, whereas the mean glucose level was higher in whites. In general, baseline anthropometric measurements were similar for the 3 races except for the mean subcutaneous area of the waist (greater in Latinos) and the mean nonsubcutaneous tissue area of the mid thigh (greater in African Americans).

TABLE 2
TABLE 2:
Means and SDs of Laboratory and Anthropometric Measurements at Baseline by Race

Follow-Up Results

Median follow-up was 62 months (interquartile range 56-66 months). During follow-up, 87% of required anthropometric and metabolic measurements were obtained. The overall lost-to-follow-up rate (defined as missing the last 2 required measurements) was 13.4% for metabolic measurements and 8.9% for anthropometric measurements.

The rates of drug treatment for dyslipidemia were 2.9, 2.8, and 2.8 per 100 person-years for African Americans, Latinos, and whites, respectively. During follow-up, 13 participants required initiation of drug therapy for diabetes, the rates for African Americans, Latinos, and whites being 0.6, 1.6, and 0.6 per 100 person-years (P = 0.32). Forty-one participants required treatment for hypertension during the study with no difference between races.

For triglycerides, the mean changes from baseline at each follow-up visit by race were positive (Fig. 1A). The overall mean change for each race was significantly different from zero with the means for Latinos and whites being significantly greater than that for African Americans (Table 3). For Latinos and whites, mean triglyceride levels generally increased during follow-up, with the rates of change being positive and significantly different from zero and greater than the rate for African Americans (Fig. 1A).

TABLE 3
TABLE 3:
Mean Change by Race and Adjusted* Race Differences
FIGURE 1
FIGURE 1:
The mean change from baseline of selected metabolic parameters, (A) triglycerides, (B) HDL cholesterol, (C) LDL cholesterol, (D) glucose, (E) insulin, and (F) IR (HOMA), for each follow-up visit by racial group. At each follow-up visit, the unadjusted mean change from baseline is plotted with 95% confidence interval. For each racial group, the unadjusted rates of change (per year) beginning at the 1-month follow-up visit are calculated. The P values compare each rate of change with 0. The P values for the comparisons of the adjusted rates of change between races are also shown. All specimens were taken after an 8-hour fast. HOMA, Homeostasis Model Assessment.

Figure 1B presents the mean change in HDL cholesterol during follow-up for the 3 racial groups. For all 3 groups, there was a significant increase in the mean change in HDL cholesterol. This increase occurred within the first 4 months and was sustained throughout follow-up with no differences by race.

For LDL cholesterol, the initial increase in mean change was followed by a gradual decline for all groups. These changes did not differ by race (Fig. 1C). The rates of change were negative, significantly different from zero, and did not vary by race. The overall mean change was borderline, significantly lower for African Americans when compared with Latinos or whites (Table 3).

The mean change in glucose at each visit is presented in Figure 1D. Overall, the mean change was positive for the 3 races and significantly different from zero for African Americans and Latinos (Table 3). Compared with whites, Latinos had a significantly greater increase in glucose levels. The rate of change in glucose was positive for the 3 groups and significant for Latinos and African Americans, with the rate for Latinos being significantly greater than that for African Americans or whites (Fig. 1D).

The overall mean change in insulin was positive for the 3 races and significantly different from zero for African Americans and whites with no significant differences between groups (Table 3). The rates of change in insulin were positive and significantly different from zero with no differences between groups (Fig. 1E).

The mean change in IR at each follow-up visit is presented in Figure 1F. The overall mean changes in IR for the 3 races were positive with those for African Americans and Latinos being significantly different from zero (Table 3). These changes did not vary by race. IR increased significantly during follow-up for the 3 races, with the rate of change for Latinos being significantly greater than that for African Americans or whites (Fig. 1F).

On average, there was a significant increase in total body fat (except Latinos), fat-free mass, and BMI for the 3 races (Table 3). There were no significant differences between the groups for these measures.

The mean change in the waist subcutaneous tissue area at each visit is presented in Figure 2A and Table 3. The overall mean change was positive and significantly different from zero for African Americans and whites and negative but not significant for Latinos. The mean change (loss) in waist subcutaneous tissue area for Latinos was significantly different from the gain seen in African Americans and whites. Over time, the mean change decreased, with the negative rates of change for Latinos and whites being significantly different from zero (Fig. 2A). The rate of change for Latinos was greater (more loss) than for African Americans or whites (borderline significance).

FIGURE 2
FIGURE 2:
The mean change from baseline of selected body composition measurements, (A) waist subcutaneous tissue area, (B) visceral tissue area, (C) mid-arm subcutaneous tissue area, (D) mid-arm nonsubcutaneous tissue area, (E) mid-thigh subcutaneous tissue area, and (F) mid-thigh nonsubcutaneous tissue area, for each follow-up visit by racial group. At each follow-up visit, the unadjusted mean change from baseline is plotted with 95% confidence interval. For each racial group, the unadjusted rates of change (per year) beginning at the 4-month follow-up visit are calculated. The P values compare each rate of change with 0. The P values for the comparisons of the adjusted rates of change between races are also shown.

The mean change in the visceral tissue area (ie, waist nonsubcutaneous tissue area) by race at each follow-up visit is shown in Figure 2B. The overall mean change for each race was positive and significantly different from zero with no differences between the groups (Table 3). Visceral tissue area increased significantly during follow-up for Latinos and whites with the rate of change for whites being greater than that for African Americans (borderline significance).

The mean changes for the mid-arm subcutaneous tissue area at most visits for Latinos were negative and significant (Fig. 2C). Whites had a similar trend except changes were smaller and generally not significant. There was an initial increase in the mid-arm subcutaneous tissue area for African Americans followed by a decline after the second year of follow-up. The overall mean change for Latinos was significantly less (more loss) than that for either African Americans or whites (Table 3). The mean change decreased significantly during follow-up for all races (Fig. 2C). The rates of decline did not vary by race.

For the mid-arm nonsubcutaneous tissue area, the overall mean changes were positive and significantly different from zero with no significant differences between groups (Table 3). The rates of change in the mid-arm nonsubcutaneous tissue area were positive and significant for each race (Fig. 2D). The rate of change for Latinos was significantly greater than for African Americans.

The overall mean change in the mid-thigh subcutaneous tissue area is presented in Table 3. The mean change was positive and significantly different from zero only for African Americans, with no differences in mean changes between races (Table 3). The rates of change over time were negative and significant for all races with no differences between groups (Fig. 2E).

The overall mean changes in the mid-thigh nonsubcutaneous tissue area were positive for all races and significantly different from zero for African Americans and whites with no differences between the races (Table 3). The rates of change were negative for the 3 races with the rate for African Americans being significantly different from zero (Fig. 2F). The rates of change did not differ between groups.

DISCUSSION

Exposure to ART has been associated with HIV-related lipodystrophy and altered glucose and lipid metabolism.5-13,33-40 Whether there are racial differences in the predisposition to these changes has been of interest.20-23,41,42 In this long-term prospective study with a median follow-up of 5 years of treatment-naive individuals initiating ART, there were 2 patterns of changes in the metabolic and anthropometric measures. The first involves measures related to glucose metabolism (ie, glucose, insulin, and IR) and changes in subcutaneous tissue areas. For these measures, Latinos had the most unfavorable changes. A different pattern was observed for lipid metabolism (ie, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), with the changes for African Americans being less than those for Latinos and whites, whereas those for Latinos and whites were similar.

The risk of developing diabetes in HIV-infected persons has been a major concern given the association of hyperglycemia, impaired glucose tolerance, and IR with ART.6,8,11,30,43 In our study, the rates of change in glucose, insulin, and IR were positive indicating significant increases in these measures during follow-up. Comparisons of these rates adjusted for baseline variables and duration of ART lead to the conclusion that the rates of change for glucose, insulin, and IR for the Latinos were generally significantly greater than for either African Americans or whites. These differences in the rates should be free to a first order of approximation of the effects of any imbalances in the prescription of specific ART among the races. The regression model controlled for both the usage of 10 specific drugs and the length of time each was prescribed. The model also controlled for baseline variables including age, CD4+ cell count, and HIV RNA levels. The adjusted differences in rates therefore reflect inherent or biological racial differences independent of the possible effects of imbalances of the adjusting variables. The absolute values of the unadjusted rates are not free of the possible effects of the adjusting covariates such as the use of specific ARTs and lengths of time they were prescribed.

Comparisons of the adjusted mean changes of these same prediabetic measures, glucose, insulin, and IR, yield less clear conclusions. During the latter half of the follow-up, Latinos had large increases in these parameters, suggesting that over time the pattern of change for Latinos in these measures may be different from those for the other 2 races. The greater increase in IR in Latinos is similar to observations among non-HIV-infected US populations for Hispanics compared with non-Hispanic whites17; a cross-sectional study of an HIV-infected cohort also found that the prevalence of IR in this cohort was similar to that of non-HIV subjects included in the National Health and Nutrition Examination III.43

Limited data are available on changes in metabolic parameters and body composition in HIV-infected Latinos, particularly after ART initiation.20,44 In our study, Latinos were the most likely to have worsening glucose metabolism and IR, and lipoatrophy. Over 22% of the general US adult population has been reported to have metabolic syndrome45 with HIV-infected persons having a similar percentage.46 Rates of metabolic syndrome and diabetes in the United States are reported to be highest among Hispanics.15,47 African Americans also have higher rates of diabetes and IR than whites.14,15 Accordingly, the risk of developing diabetes may be increased in HIV-infected Latinos and African Americans reflecting inherent racial differences independent of ART usage.

The other pattern of change is this study involves that of lipid metabolism. We observed an increase in total cholesterol, LDL cholesterol, and triglycerides for the 3 races. The increase for African Americans was less than that for Latinos and whites for each of these lipids, but especially for triglycerides. Over time, the mean change in triglycerides was positive and significant for all 3 races. There was no difference in the mean increase in HDL cholesterol among the 3 races. Other studies have shown that ART has a minimal effect on HDL cholesterol.11,48,49 Among the racial groups in our study, the baseline mean triglyceride levels were not elevated.50 When comparing the adjusted changes in triglyceride levels, the mean changes and the rates of change for African Americans were less than those for whites or Latinos.

Increases in triglyceride levels in HIV-infected subjects have been reported after the initiation of all 3 classes of ART,48,49 but particularly with ritonavir-containing PI regimens.49,51-55 In our study, the PIs most commonly prescribed were nelfinavir, indinavir, and ritonavir-boosted PIs, with the African Americans more frequently being initially prescribed a ritonavir-boosted PI regimen, with the changes in triglyceride levels being adjusted for ART exposure. Accordingly, African Americans receiving ART may be at less risk for hypertriglyceridemia similar to studies of lipid metabolism in non-HIV-infected men and women comparing African American with white subjects.56 In the FIRST study, of which this study is a substudy, there was less increase in CD4+ cell count from baseline after initiation of ART among the African Americans than whites or Latinos.29 In an earlier study of the baseline data of this cohort, there was a correlation between an increased HIV RNA level and higher triglyceride and lower LDL cholesterol levels.21 Therefore, the smaller increase in triglyceride and LDL cholesterol levels among African Americans in our study could reflect poorer adherence to ART than the whites and Latinos coupled with less inherent racial risk of hypertriglyceridemia.56

In our study, the observed changes in LDL cholesterol and triglycerides along with the rates of initiation of treatment for both hyperlipidemia and hypertension support a potential risk for cardiovascular disease in HIV-infected persons receiving ART. These findings are similar to other studies of changes in lipids in PI-treated patients40,48,49,51,53 suggesting that not only use of ART but also the associated improvements in immune status and overall health after ART initiation coupled with age-related changes contribute to these changes.

The racial groups in our study generally experienced an increase in nonsubcutaneous peripheral tissue areas and visceral tissue area. The adjusted differences between the rates of change in subcutaneous tissue areas were greater (more negative) for Latinos than those for either African Americans or whites although these differences were not generally significant. In addition, comparisons of the adjusted means yielded some significant differences between the race groups. These changes over time in body composition and the more unfavorable metabolic parameters observed among the Latinos compared with the African Americans and whites in our study may reflect not only the impact of HIV infection and ART but also different genetic predisposition.

There are several limitations to our study. First, the sample size for Latinos in this study was not large. The metabolic and body composition changes among Latinos were, however, pronounced enough to allow an adequate comparison with whites and African Americans. Second, at the time of the study, the nucleoside reverse transcriptase inhibitor combinations most commonly prescribed were d4T + 3TC and ZDV + 3TC. Both thymidine analogues are now known to contribute to the development of lipoatrophy.9,10 More Latinos were prescribed d4T + 3TC than whites or African Americans. Furthermore, the most commonly prescribed PIs were nelfinavir and indinavir, with or without ritonavir. All 3 PIs, but particularly ritonavir, affect glucose and lipid metabolism.53 More African Americans were prescribed ritonavir at study entry. A major strength of these analyses is that the statistical model adjusted for the length of exposure to individual ARTs and other baseline factors when making comparisons between the racial groups.

In conclusion, the effects of ART on changes in metabolic parameters and body composition among Latinos, African Americans, and whites were associated with unfavorable changes for all racial groups with Latinos having the most unfavorable changes. Latinos had the greatest increase in glucose levels and IR and were more likely to have peripheral lipoatrophy. For all races, triglycerides and HDL cholesterol increased, whereas LDL cholesterol declined after an initial increase. As persons with HIV infection live longer and the demographics of the HIV epidemic change in the United States, with increasing rates of infection in African American and Hispanics,57-59 more effort should be expended to lower risks of cardiovascular disease and diabetes. Efforts should focus on increasing understanding of the clinical implications of the recognized changes in metabolic parameters and body composition associated with ART, particularly, by race and ethnicity.

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Keywords:

antiretroviral therapy; body composition; dyslipidemia; HIV; insulin resistance; race/ethnicity

© 2009 Lippincott Williams & Wilkins, Inc.