Adiponectin and Leptin Levels in Chinese Patientswith HIV-Related Lipodystrophy:A 30-Month Prospective Study

Ling Luo, Lu Zhang, Meimei Tao, Zhifeng Qiu, Jing Xie, Yang Han, Ming Li, and Taisheng Li

Abstract

The relationship of adipocytokine with the development of HIV-related lipodystrophy was investigated in acase-control study. Adipocytokine, lipid, and glycemic parameters were measured at every visit. Logistic re-gression analysis was used to assess the HIV-LD risk factors and the Spearman correlation coefficients test wasused to assess the correlation between adiponectin with other metabolic variables. Most of the patients (96.3%)developed HIV-LD after month 12. Comparing the baseline adiponectin, the adiponectin concentration of theHIV-LD group rose by month 6 and began to decrease substantially by month 18; this reduction was maintaineduntil month 30 ( p< 0.05). Comparing the HIV-NLD group, the adiponectin concentration at months 18, 24, and30 were significantly lower in the HIV-LD group. The leptin concentration of both the HIV-LD and HIV-NLDgroups remained stable. Patients in the lower concentration of baseline adiponectin and greater adiponectinchange rate at month 18 presented with increased odds ratio for HIV-LD. The adiponectin level had a correlationwith serum triglycerides (r¼�0.616, p< 0.0001), serum insulin concentration (r¼�0.494, p¼ 0.001), and HDL-C(r¼ 0.673, p< 0.0001). The adiponectin concentration of HIV-LD began to decrease substantially by month 18.The lower baseline concentration of adiponectin and the greater change rate at month 18 were independent riskfactors of HIV-LD. The adiponectin level had a correlation with serum triglycerides, serum insulin concentration,and HDL-C, suggesting that adiponectin may link the metabolic abnormalities and HIV-LD.

Introduction

HIV-infected patients receiving antiretroviral thera-py often frequently develop a body fat redistribu-

tion syndrome, which is called HIV-related lipodystrophysyndrome (HIV-LD).1,2 HIV-LD was reported to be inde-pendently associated with adherence failure.3 Furthermore,metabolic abnormalities among HIV-LD, characterized bydyslipidemia and insulin resistance, predispose HIV-infectedpatients with fat redistribution to accelerated cardiovasculardisease.4,5

The dominant change of HIV-LD is reduction in subcuta-neous adipose tissue (SAT).6,7 Adipocytokine, fat-derivedcytokines, were reported to link the changes in adipose dis-tribution and the metabolic abnormalities in lipodystrophiesin non-HIV-infected patients.8 Therefore, we wish to investi-gate the relationship of adipocytokine and adipose distributionand the metabolic abnormalities of HIV-LD in this 30-monthprospective study.

Materials and Methods

Subjects

Fifty-two consecutive, ambulatory, HIV-infected patientswere recruited through the Infectious Diseases Clinic of thePeiking Union Medical College (PUMC) hospital in the study.Written informed consent was obtained in all cases. Patientswith any active opportunistic infection, neoplasm, or wastingsyndrome were excluded from the study. At baseline, allsubjects were antiretroviral therapy (ART) naive.

Follow-up

All patients were evaluated before the initiation of HAARTand every 6 months up to 30 months. All patients have beenfollowed up for efficiency, adherence to highly active anti-retroviral therapy (HAART), and side effects, especially thedevelopment of HIV-LD. The subjects returned to repeat thebaseline assessments, which included body weight, height,

Department of Infectious Diseases, Peking Union Medical College Hospital and AIDS Research Center, Chinese Academy of MedicalSciences and Peking Union Medical College, Beijing 100730, China.

AIDS RESEARCH AND HUMAN RETROVIRUSESVolume 25, Number 12, 2009ª Mary Ann Liebert, Inc.DOI: 10.1089=aid.2009.0072

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total cholesterol, triglycerides (TG), high-density lipoproteincholesterol (HDL-C), and low-density lipoprotein cholesterol(LDL-C), adipopectin, leptin, insulin, CD4 cell count, and viralload (VL). When HIV-LD was considered, dual-energy X-rayabsorptiometry (DEXA) was taken to quantify the body fatcomposition.

Lipodystrophy definition criteria

Clinical evaluation of lipodystrophy was obtained in everycase, and diagnosis was based on the concordance betweenthe opinion of two clinical examiners and that of the patient. Aquestionnaire on fat distribution with four possible answerswas used: no alterations, mild, moderate, and severe changes.Different body parts were examined: the face, the extremities,and the dorsocervical and abdominal regions. Body fatchanges included subcutaneous lipoatrophy (hollow cheeks,prominent superficial veins in the limbs, or flattening of thebuttocks) and central obesity (increased abdominal girth,breast enlargement, or dorsocervical fat pad). When concor-dance between the patient’s opinions and that of the clinicalexaminer with at least moderate changes within the sameanatomical location was reached, the diagnosis of lipody-strophy was considered.9–11

Individuals with HIV infection were divided into twogroups based on the results of the patient’s opinion and that ofthe clinical examiner. Those subjects who meet this diagnosiscriteria of HIV-LD were placed in the lipodystrophy group(HIV-LD) and other patients were placed in the non-lipodystrophy group (HIV-NLD).

When the diagnosis of lipodystrophy was considered, thepatient’s body fat distribution was examined by DEXA (GELunar Prodigy Advance, Madison, WI). The percentage oflimb fat was calculated as the total fat in the arms and legsexpressed as a percentage of total body fat.

Laboratory measurements

Blood was drawn from each subject after an overnight faston the morning of the study visit. Blood samples were im-mediately centrifuged at room temperature after collection.Total cholesterol, triglycerides, HDL-C, and LDL-C were de-termined by enzymatic methods using commercial kits (usingpreviously published methods). CD4þ lymphocyte cell countwas analyzed by three-color flow cytometry (Epics XL flowcytometry, Beckman Coulter, USA). Whole blood was incu-bated with monoclonal antibodies (MAb) against CD3 andCD4 (Immunotech, France). Absolute counts of CD3þCD4þ

T cells were then calculated using the results from the com-plete blood cell and lymphocyte differential counts. Humanimmunodeficiency virus 1 VL was measured on frozenEDTA-plasma samples by a branched DNA assay (version3.0, Bayer, USA). The limit of detection of the assay is from50 copies=ml to 50,000 copies=ml. The plasma levels of insulin,leptin, and adiponectin were measured by in-house enzyme-linked immunosorbent assays (ELISA), which were all de-veloped in the laboratory of the Department Endocrinology,Peking Union Medical College Hospital. The detection limit ofthe insulin assay was 0.8 pmol=liter, with no crossreactivity toproinsulin (<0.01%), and the assay had an interassay CV of<9.0%. Leptin sensitivity is 0.2 ng=ml with interassay CV<9.3%, respectively. The detection limit of the adiponectinassay was 0.5 ng=ml and the interassay CV was <10%.12–14

Statistical analysis

Statistical analysis was performed using SPSS 11.5. Con-tinuous variables are presented as means and SDs or medians.Data of viral load were logarithmically transformed to obtainnear normality before analysis. Because some data were notnormally distributed, as determined with the Kolmogorov-Smirnov test, Wilcoxon rank sum was used to compare vari-ables that were not normally distributed. A w2 test was used tocompare categorical variables. Risk factors for HIV-LD wereassessed using a stepwise logistic regression analysis. Asso-ciations among adiponectin, leptin, anthropometric variables,metabolic variables, CD4 count, and HIV RNA were deter-mined using the Spearman correlation coefficients test. Ap value of 0.05 was used to test for statistical significance, andall statistical tests were two tailed.

Results

At baseline, all the 52 ART-naive subjects were withoutalteration in fat distribution. The baseline characteristics inthe subjects are summarized in Table 1. During the follow-up period of 30 months, 27 subjects developed HIV-LD; theother subjects remained HIV-NLD. Comparing to those whoremained HIV-NLD, subjects who developed HIV-LD had alower level of CD4 cells and lower adiponectin concentrationat baseline ( p< 0.05). Age and viral burden were not sig-nificantly different between the HIV-LD and HIV-NLDgroups. The metabolic parameters BMI (body mass index),total cholesterol, HDL-C, LDL-C, triglycerides, leptin, andinsulin were not significantly different between the twogroups.

Of the 52 subjects, 35 patients (67.3%) commenced stavu-dine (d4T) with didanosine (ddI) as their nucleoside reversetranscriptase inhibitors (NRTI) backbone and 5 subjects (9.6%)started with d4T plus lamivudine (3TC). In all, 40 subjects(76.9%) commenced a d4T-containing regimen. Twelve pa-tients (23.1%) began with a zidovudine (ZDV)-containingregimen [nine subjects (17.3%) with 3TC and three subjects(5.8%) with DDI]. Only one patient used a protease inhibitor(PI)-containing regimen (indinavir), while the others usedeither nevirapine (NVP) (76.5%) or efavirenz (EFV) (21.5%) astheir nonnucleoside reverse transcriptase inhibitors (NNRTI)backbone. Of subjects (26=27) who developed HIV-LD 96.3%used a d4T-containing regimen and 56% of the subjects(14=25) who remain HIV-NLD used a d4T-containing regi-men. The percentage of patients using d4T was significantlydifferent between the two groups ( p¼ 0.001, Table 1).

During the follow-up period of 30 months, one patientdeveloped HIV-LD at month 12 and four patients developedHIV-LD at month 18. Most of the patients (96.3%) developedHIV-LD after month 12 and 81.5% of the patients devel-oped HIV-LD after month 18. When the diagnosis of lipody-strophy was considered, the patient’s body fat distributionwas examined by DEXA. The results of DEXA are shown inTable 2. Total fat and total fat percentage of subjects whodeveloped HIV-LD were significantly lower than that ofsubjects who remained HIV-NLD ( p< 0.05). Compared withthe HIV-NLD group, extremity fat and extremity fat per-centage were significantly lower and trunk fat percentage wassignificantly higher in the HIV-LD group. There was no dif-ference in the trunk fat in the two groups. The extremityfat:trunk fat ratio was lower in the HIV-LD group ( p< 0.05).

1266 LUO ET AL.

Comparing the baseline adiponectin concentration, theadiponectin concentration of the HIV-LD group rose bymonth 6. The adiponectin concentration of the HIV-LD groupdecreased substantially by month 18 and this reduction wasmaintained until month 30 ( p< 0.05). However, the adipo-nectin concentration of the HIV-NLD group remained stable(Fig. 1). As Fig. 1 shows, comparing the HIV-NLD group, theadiponectin concentration at months 18, 24, and 30 was sig-nificantly lower in the HIV-LD group.

The leptin concentration of both the HIV-LD and HIV-NLDgroup remained stable (Fig. 2). The leptin concentration of theHIV-LD group at month 12 was lower than the baseline leptinconcentration; however, it had not reached statistical signifi-cance.

Factors associated with HIV-LD are presented in Table 3.We found that there is a significant difference of adiponectinbetween the HIV-LD group and HIV-NLD group, with mostof the HIV-LD occurring after month 12; this step logistic re-gression analysis model also included adiponectin concen-

tration and changing rate at month 6, month 12, and month 18in addition to other metabolic parameters on baseline line.Change rate of adiponectin was expressed as (adiponectin –baseline adiponectin) baseline adiponectin. The resultinganalysis showed that baseline adiponectin concentration andchange rate of adiponectin at month 18 were both risk factorsassociated with the development of HIV-LD.

We also found that adiponectin had an inverse correlationwith serum triglycerides (r¼�0.616, p< 0.0001) and seruminsulin concentration (r¼�0.494, p¼ 0.001). We also found apositive correlation with HDL-C (r¼ 0.673, p< 0.0001). Nosignificant associations were noted between adiponectin andleptin, total cholesterol, LDL-C, CD4, and viral load (Table 4).

Discussion

The prevalence of HIV-related lipodystrophy in patients onHAART is approximately 40%15 and may reduce adherence toHAART, while the metabolic abnormalities, such as dyslipi-demia and insulin resistance, are reported to increase the riskof cardiovascular disease.16

d4T is regarded as one of the medications that can induceHIV-LD. In China, there are 650,000 people who are livingwith HIV infection, including about 75,000 AIDS patients. TheChinese government provides seven kinds of free anti-retroviral drugs; d4T, one of these drugs, is still in extensiveuse in China. In this study, the development of most of HIV-LD was mainly related to the use of d4T. The DEXA data inour study indicated that the dominant change of HIV-LD isreduction of extremity fat. Our data show that most of theHIV-LD occurred after month 12 (96.3% after month 12 and81.5% after month 18), which was consistent with the study ofKingsley et al. and Mahajan et al.17,18

Our results indicated that the adiponectin concentration ofthe HIV-LD group decreased substantially by month 18 and

Table 2. Body Fat Distribution Result by DEXA

Developed LD

p valueYes No

Total fat (kg) 9.02� 3.94 12.08� 4.50 0.021Total fat percentage (%) 19.16� 5.11 22.55� 5.72 0.045Extremity fat (kg) 2.73� 1.53 4.96� 2.27 <0.001Extremity fat

percentage (%)30.0� 7.8 41.4� 10.5 <0.001

Trunk fat (kg) 5.86� 2.53 6.56� 2.81 0.39Trunk fat percentage (%) 64.7� 8.0 53.8� 10.7 <0.001Extremity fat: trunk fat 0.49� 0.19 0.84� 0.38 <0.001

Table 1. Baseline Patients Characteristicsa

Developed LD

p valueYes No

n 27 25 —Male=female 13=14 12=13 0.991Age (years) 35.8� 7.4 34.2� 6.6 0.513CD4 cell (cells=ml) 70 (1–227) 119 (2–310) 0.032VL (log copies=ml) 4.72� 1.11 4.55� 0.91 0.558BMI (kg=m2) 21.5� 2.7 22.4� 2.5 0.90Cholesterol (mmol=liter) 3.70� 1.05 3.79� 1.03 0.758HDL-C (mmol=liter) 0.84� 0.27 0.94� 0.36 0.28LDL-C (mmol=liter) 1.90� 0.88 2.07� 0.60 0.412Triglycerides (mmol=liter) 1.42 (0.48–4.09) 1.12 (0.55–3.93) 0.172Adiponectin (mg=liter) 8.76 (3.38–14.44) 11.08 (3.92–17.73) 0.04b

Leptin (mg=liter) 1.77 (0–15.93) 2.06 (0–20.20) 0.469b

Insulin (mu=liter) 3.49 (0.26–56.73) 3.4 (1.68–25.44) 0.309D4T% 26=27 14=25 0.001AZT% 1=27 11=25 0.0013TC% 3=27 11=25 0.001DDI% 24=27 14=25 0.001NVP% 20=27 20=25 0.612EFV% 7=27 4=25 0.422

aData are measured as n� SD or median (interquartile range).bp value with sex adjusted.

ADIPONECTIN AND LEPTIN LEVELS IN HIV-LD PATIENTS 1267

this reduction was maintained until month 30. Adiponectin isa 30-kDa protein solely produced by adipocytes secreted bydifferentiated adipocytes.19,20 Recent studies have shown thatadiponectin expression is higher in subcutaneous fat thanvisceral fat in humans. Subcutaneous adipose tissue (SAT)accounts for approximately 85–90% of adipose tissue in leanindividuals and SAT may produce the majority of circulatingadiponectin. This adiponectin deficiency becomes prominentwith peripheral fat loss and thus loss of the adiponectinsupply. Therefore, subcutaneous fat loss may actually be re-sponsible for the decreased adiponectin level in the HIV-LD

group. A decreased level of adiponectin has been seen inanimal models of lipoatrophy.21 Our data also show that theadiponectin concentration of the HIV-LD group rose bymonth 6. The reason for the increase in the adiponectin levelafter a few weeks or months of therapy was probably acompensatory response from the adipose tissue through anegative feedback mechanism at least at the initial stages ofthe metabolic dysregulation.

Since plasma adiponectin was related to the total content ofsubcutaneous tissue in HIV-infected patients and the domi-nant change of HIV-LD is reduction in SAT, the correlation of

FIG. 1. Adiponectin in relation to HIV-LD. LD, HIV-related lipodystrophy patients; NLD, HIV non-LD patients. *Levels at18, 24, and 30 months versus baseline level in the HIV-LD group, p< 0.05; &HIV-LD versus the HIV-NLD group, p< 0.05.

1268 LUO ET AL.

the low level of adiponectin and the development of HIV-LDis that of a covariate, rather than a cause. Adiponectin has alsobeen reported to be inversely associated with rare forms ofcongenital and acquired lipodystrophies in non-HIV-infectedpatients. Addy et al. found that adipnectin levels were sig-nificantly lower in the HIV-infected patients exhibiting fatredistribution changes.22 However, this was a cross-sectionalstudy and cannot show the dynamic change of adiponectinduring the course of HAART.

The mechanism of the correlation of adiponectin andHIV-LD has not been well understood. HIV-LD have been

associated with high circulating levels of TNF-a.23 IncreasedTNF-a gene expression has also been found in subcutane-ous fat from patients with HIV lipodystrophy.24 TNF-a in-hibits adiponectin gene expression and secretion fromadipocytes in vitro.25 Therefore, this cytokine may play arole in the reduced adiponectin concentrations. In vitro,stavudine has been shown to reduce adiponectin secretionfrom adipocytes.26 The independent association of stavu-dine use with low adiponectin levels suggests that stavu-dine may not only reduce fat, but also alter adipocytefunction.

FIG. 2. Leptin in relation to HIV-LD. LD, HIV-related lipodystrophy syndrome patients; NLD, non-LD patients. &HIV-LDversus the HIV-NLD group, p< 0.05.

ADIPONECTIN AND LEPTIN LEVELS IN HIV-LD PATIENTS 1269

The previous study data on leptin are complex. Some cross-sectional studies suggest leptin level remain proportional tototal adiposity in HIV-LD. When patients with HIV lipody-strophy have total body fat mass similar to controls, leptinlevels are similar to those of both HIV-infected and healthycontrols.27,28 However, when lipodystrophy is accompaniedby lower total body fat mass, leptin levels are lower comparedto controls.26 Our observation of stable leptin concentration inpatients with HIV-LD is not consistent with these observa-tions in cross-sectional studies. In our study, patients withHIV-LD also have lower total body fat weight than the HIV-NLD group, although leptin levels are still similar to that ofthe HIV-NLD group. The reason why it is different from theprevious study is still not very clear and needs furtherresearch.

It has been reported that the development of lipodystrophysyndrome is clearly influenced by the type of ART and theduration of treatment and that d4T is strongly associated withthe loss of subcutaneous fat.29–31 Older age32 and low nadirCD4 cell count33 have both been identified as risk factors forlipodystrophy. The results of our study indicated that baselineadiponectin and the change in rate of adiponectin at month 18

were independently associated with the development of HIV-LD. The inverse correlations of the development of HIV-LDwith low baseline adiponectin and greater change rate ofadiponectin at month 18 suggest that individuals with lowerpretreatment adiponectin levels or with adiponectin de-creasing more significantly are more likely to experience HIV-LD.

Serum adiponectin levels demonstrated a strong negativerelationship with indices of insulin resistance such as fastinginsulin and triglycerides in the study of diabetes and rarelipodystrophy in non-HIV-infected patients. Our datashowed a similar inverse correlation between adiponectinlevel and serum triglycerides and insulin concentration inHIV-LD. We also found a positive relation between adipo-nectin and HDL-C concentration. Therefore our result sug-gests that reduced serum adiponectin levels may contribute tometabolic complications in patients with HIV-LD and mightlink the metabolic abnormalities and the changes in adiposedistribution in HIV-LD.

Our study has a number of limitations: the sample size wasrelatively small and only representative of those infected withHIV-1 in China, where d4T with ddI is one of the most com-monly used medication combinations as an NRTI backbone.The question of whether these associations have the samepredictive power in more diverse populations commencingother ART regimens remains unanswered. Given the explor-atory nature of our analysis, these findings need further val-idation in routine clinical care models.

Acknowledgments

We thank Yi Dai for evaluating the patients in the InfectiousDiseases Clinic of the Peiking Union Medical College hospital.This study was supported by the National Key TechnologiesR&D Programme for the 11th Five-year Plan (2008ZX10001-006), Ministry of Health Clinical HIV=AIDS Research Grant(2007–2009), and Beijing Science and Technology ProgramFund (D0906003040491).

Disclosure Statement

No competing financial interests exist.

Table 3. Stepwise Logistic Regression Showing Risk Factors of the Development of HIV-LD

Parameters Time p value OR (95% CI)

Adiponectin (mg=l) Baseline 0.025 0.746 (0.557–0.958)Change rate of ADP18

a At month 18 0.051 0.368 (0.135–1.004)Change rate of ADP6 At month 6 0.363 —Change rate of ADP12 At month 12 0.298 —Age (years) Baseline 0.878 —BMI (kg=m2) Baseline 0.134 —CD4 count (cells=ml) Baseline 0.084 —VL (log copies=ml) Baseline 0.675 —Leptin (mg=liter) Baseline 0.249 —LDL-C (mmol=liter) Baseline 0.140 —HDL-C (mmol=liter) Baseline 0.209 —Cholesterol (mmol=liter) Baseline 0.389 —Triglycerides (mmol=liter) Baseline 0.382 —Insulin (mu=liter) Baseline 0.854 —

aADP, adiponectin.

Table 4. Spearman Correlations of Adiponectin

with Other Factors at Month 18

Adiponectin

r-value p-value

Triglycerides (mmol=liter) �0.616 <0.001Insulin (mu=liter) �0.494 0.001HDL-C (mmol=liter) 0.673 <0.001Age (years) �0.249 0.099Sex 0.003 0.982BMI (kg=m2) �0.173 0.256CD4 (cells=ml) 0.070 0.650VL (log copies=ml) 0.177 0.245Cholesterol (mmol=liter) �0.097 0.524LDL-C (mmol=liter) 0.037 0.816Leptin (mg=liter) �0.088 0.564

1270 LUO ET AL.

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Address correspondence to:Ling Luo

Department of Infectious DiseasesPeking Union Medical College Hospital

Chinese Academy of Medical Sciencesand Peking Union Medical College

Beijing 100730, China

E-mail: luolingnk@yahoo.com.cn

1272 LUO ET AL.