Limb Fat Loss Research Articles

Contribution of genetic background and antiretroviral therapy to body fat changes in antiretroviral-naive HIV-infected adults.

To evaluate the association of host genetics with changes in limb or trunk fat in a group of antiretroviral therapy (ART)-naive HIV-infected patients prospectively followed up according to the initiation and the type of ART. Fifty single nucleotide polymorphisms (SNPs) in 26 genes, associated with obesity, insulin resistance, lipid metabolism or lipodystrophy in previously published genetic studies, were assessed in ART-naive HIV-infected Caucasian patients divided into three groups: 24 (27%) did not start ART, 29 (32.6%) received zidovudine or stavudine and 36 (40.4%) received neither zidovudine nor stavudine in their initial regimen. Patients underwent body fat measurements (using dual-energy X-ray absorptiometry) at baseline and Month 12. A multivariate model using backward stepwise elimination was used to assess the influence of SNPs and baseline levels of non-genetic covariates on changes in limb or trunk fat. The baseline characteristics were: 73% men, 17% coinfected with hepatitis C virus and/or hepatitis B virus, median age 37 years, median CD4+ T cell count 228/mm(3), median HIV-RNA 5.2 log copies/mL, median plasma glucose 85 mg/dL, median plasma insulin 9.1 IU/mL, median limb fat 5.6 kg and median trunk fat 7.0 kg. There were no baseline differences among the three groups except for the CD4+ T cell count. The decrease in limb fat was greater in the no-ART group relative to the other two groups (P < 0.05). The multivariate model showed associations of rs1801278 in IRS1 (P = 0.029, OR = 0.13), baseline viral load (P = 0.006; OR = 4.453) and baseline glucose levels (P = 0.008, OR = 0.926) with loss of limb fat, and rs2228671 in LDLR (P = 0.012, OR = 0.108), rs405509 in APOE (P = 0.048, OR = 0.205), baseline viral load (P = 0.005, OR = 0.186) and baseline CD4+ T cell count (P = 0.01, OR = 1.008) with gain of trunk fat. Specific polymorphisms in IRS1 (limb fat loss) and LDLR and APOE (trunk fat gain) were identified as independent markers of fat changes irrespective of the initiation of ART and the type of ART and deserve further validation.

HIV-Associated Lipodystrophy: Impact of Antiretroviral Therapy

In the late 1990s, reports of unusual changes in body fat distribution named 'lipodystrophy' (LD) began to appear in HIV patients mitigating the enormous enthusiasm about improvement of survival and quality of life provided by the combinations of antiretroviral (ARV) drug classes, the so-called highly active antiretroviral therapy (HAART), which had just become available at that time. The objective of this paper is to critically review the literature on LD and to discuss the impact of newer ARV agents, namely atazanavir, darunavir and raltegravir, as well as strategies of the late HAART era, including single-tablet regimens and nucleoside-sparing regimens. Studies in which LD was measured by dual-energy x-ray absorptiometry or by abdominal computed tomography or magnetic resonance imaging scan only, were included. We were unable to identify studies depicting a negative impact of drugs or ARV regimens on limb fat loss. On the contrary, a few studies identified a negative impact of atazanavir/ritonavir or darunavir/ritonavir on trunk fat increase. It should be noted that this anthropometric measure is a poor instrument since it cannot distinguish between subcutaneous and visceral fat. We conclude that presumably the body fat changes currently observed in HIV-infected patients is the net result of competing phenomena: on one side the natural history of lipohypertrophy as a result of HIV and HAART impact, and on the other side the physiological body fat changes observed in the aging population.

Systematic Review of Antiretroviral-Associated Lipodystrophy: Lipoatrophy, but Not Central Fat Gain, Is an Antiretroviral Adverse Drug Reaction

BackgroundLipoatrophy and/or central fat gain are observed frequently in patients on antiretroviral therapy (ART). Both are assumed to be antiretroviral adverse drug reactions.MethodsWe conducted a systematic review to determine whether fat loss or gain was more common in HIV-infected patients on ART than in uninfected controls; was associated with specific antiretrovirals; and would reverse after switching antiretrovirals.ResultsTwenty-seven studies met our inclusion criteria. One cohort study reported more lipoatrophy, less subcutaneous fat gain, but no difference in central fat gain in HIV-infected patients on ART than in controls. Randomised controlled trials (RCTs) showed more limb fat loss (or less fat gain) with the following regimens: stavudine (versus other nucleoside reverse transcriptase inhibitors (NRTIs)); efavirenz (versus protease inhibitors (PIs)); and NRTI-containing (versus NRTI-sparing). RCTs showed increased subcutaneous fat after switching to NRTI-sparing regimens or from stavudine/zidovudine to abacavir/tenofovir. There were no significant between-group differences in trunk and/or visceral fat gain in RCTs of various regimens, but results from efavirenz versus PI regimens were inconsistent. There was no significant between-group differences in central fat gain in RCTs switched to NRTI-sparing regimens, or from PI-containing regimens.ConclusionsThere is clear evidence of a causal relationship between NRTIs (especially thymidine analogues) and lipoatrophy, with concomitant PIs possibly having an ameliorating effect or efavirenz causing additive toxicity. By contrast, central fat gain appears to be a consequence of treating HIV infection, because it is not different from controls, is not linked to any antiretroviral class, and doesn't improve on switching.

Impact of switching from zidovudine/lamivudine to tenofovir/emtricitabine on lipoatrophy: the RECOMB study

Lipoatrophy is a long-term adverse effect of some antiretrovirals that affects quality of life, compromises adherence and may limit the clinical impact of HIV treatments. This paper explores the effect of tenofovir/emtricitabine (TDF/FTC) on the amount of limb fat in patients with virological suppression. A randomized, prospective clinical trial was performed to compare continuation on a zidovudine/lamivudine (ZDV/3TC)-based regimen with switching to a TDF/FTC-based regimen in terms of the effect on limb fat mass as assessed by DEXA over a 72-week period. Eighty patients were included (39 in the TDF/FTC arm and 41 in the ZDV/3TC arm) and 73 completed the study (37 and 36, respectively). In the switch arm, limb fat increased by a median of 540 g from baseline (P = 0.022), while in the ZDV/3TC arm it decreased by a median of 379 g (P = 0.112; p between groups = 0.007). Subjects with baseline limb fat ≤ 7200 g, previous time on ZDV > 5 years or a body mass index > 25 kg/m(2) experienced higher limb fat gains than other subjects, and these differences were statistically significant. Haemoglobin increased by a median of 1.0 g/dL in the TDF/FTC arm (P < 0.001) and remained unchanged in the ZDV/3TC arm (p between groups = 0.0002). There were no significant differences between groups in other secondary endpoints (body weight, total body and trunk fat content, total body bone mineral density, laboratory parameters, CD4 cell count and viral load). Switching from a ZDV/3TC-based to a TDF/FTC-based regimen led to a statistically significant improvement in limb fat, in contrast to the progressive loss of limb fat in subjects continuing ZDV/3TC.

A Randomized Comparative 96-Week Trial of Boosted Atazanavir versus Continued Boosted Protease Inhibitor in HIV-1 Patients with Abdominal Adiposity

Abdominal adiposity in HIV-1 patients initiating antiretroviral therapy may be part of a restoration-to-health phenomenon. Lipoatrophy is associated with long-term thymidine analogue therapy. Individual protease inhibitors (PIs) differ in their effects on lipids and insulin resistance. A randomized open-label multicentre 96-week trial compared changes in fat distribution in patients with suppressed HIV-1 RNA and abdominal adiposity, who either continued on their current twice-daily ritonavir-boosted PI (PI/r) or switched to once-daily boosted atazanavir (ATV/r). Treatment with two nucleoside reverse transcriptase inhibitors was unchanged. Body composition was assessed by dual-energy x-ray absorptiometry (DEXA) and abdominal computerized tomography (CT) scanning. In total, 201 patients were randomized; 131 switched to ATV/r. Viral suppression (<50 copies/ml) was similarly maintained (93% ATV/r versus 89% PI/r). Mean changes from baseline in trunk-to-limb fat ratio were similar; difference estimates 0.03 (95% CI -0.06, 0.12; P=0.48 at week 48) and 0.02 (95% CI -0.10, 0.14; P=0.73 at week 96). More patients in the PI/r arm had a decrease of ≥20% in limb fat from baseline at week 96. Significantly greater reductions in proatherogenic lipids occurred following switch to ATV/r. Both treatment regimens were generally well-tolerated; the incidence of grade 3-4 treatment-related clinical adverse events was 34% among ATV/r recipients versus 4% of PI/r-treated patients. Switching to ATV/r had no demonstrable benefit on abdominal adiposity. Maintenance of efficacy, less limb fat loss and marked reduction in proatherogenic lipids was observed with ATV/r compared with continuing a PI/r regimen.

Decline in adipogenesis contributes to peripheral subcutaneous fat loss in older humans

Aging is associated with redistribution of body fat characterized by a relative loss of subcutaneous limb fat and accumulation in trunk and visceral areas. The loss of subcutaneous peripheral fat is associated with metabolic abnormalities, particularly insulin resistance. The causes and mechanisms of loss of peripheral fat with aging are not completely clear.The aim of this study was to assess whether defects in adipogenesis contribute to fat loss in aging humans, as suggested from animal studies.Preadipocytes isolated from subcutaneous peripheral fat of healthy young and elderly subjects were compared in their ability to replicate and differentiate.The results show that both the rate of replication of subcutaneous peripheral preadipocytes and their ability to differentiate are impaired with aging. The reduction in adipogenesis is accompanied by a higher plasma level of the inflammatory marker, soluble tumor necrosis factor receptor 2, and greater release of tumor necrosis factor α from fat tissue. Thus, the gradual loss of peripheral fat in aging humans may in part result from a defect in adipogenesis, which may be linked to inflammation and/or to increased release of proinflammatory cytokines from fat tissue.(Supported by NIH grants DK049316 and 5‐MO1‐RR‐10710; and New York Empire Clinical Research Investigator Program (ECRIP) fellowships to GC and SS)

Peripheral and Central Fat Changes in Subjects Randomized to Abacavir-Lamivudine or Tenofovir-Emtricitabine With Atazanavir-Ritonavir or Efavirenz: ACTG Study A5224s

We compare the effect of 4 different antiretroviral regimens on limb and visceral fat. A5224s was a substudy of A5202, a trial of human immunodeficiency virus type 1 (HIV-1)-infected, treatment-naive subjects randomized to blinded abacavir-lamivudine (ABC-3TC) or tenofovir DF-emtricitabine (TDF-FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV-r). The primary endpoint was the presence of lipoatrophy (≥ 10% loss of limb fat) at week 96 by intent-to-treat (ITT) analysis. Secondary endpoints included changes in limb and visceral fat. Statistical tests included linear regression, binomial, two-sample t test, and Fisher's exact test. A5224s enrolled 269 subjects; 85% were male, and 47% were white non-Hispanic. The subjects had a median baseline HIV-1 RNA level of 4.6 log(10) copies/mL, a median age of 38 years, a median CD4+ cell count of 233 cells/μL, median limb fat of 7.4 kg, median visceral adipose tissue (VAT) of 84.1 cm(2), and VAT: total adipose tissue (TAT) ratio of 0.31. At week 96, estimated prevalence of lipoatrophy (upper 95% confidence interval [CI]) was 18% (25%) for ABC-3TC and 15% (22%) for TDF-FTC (P = .70); this was not significantly less than the hypothesized 15% for both (P ≥ .55 for both). The secondary as-treated (AT) analysis showed similar results. At week 96, the estimated mean percentage change from baseline in VAT was higher for the ATV-r group than for the EFV group (26.6% vs 12.4%; P = .090 in ITT analysis and 30.0% vs 14.5%; P = .10 in AT analysis); however, the percentage change in VAT:TAT was similar by ITT and AT analysis (P ≥ .60 for both). Results were similar for absolute changes in VAT and VAT:TAT. ABC-3TC- and TDF-FTC-based regimens increased limb and visceral fat at week 96, with a similar prevalence of lipoatrophy. Compared to the EFV group, subjects assigned to ATV-r had a trend towards higher mean percentage increase in VAT. NCT00118898.

How Much Fat Loss Is Needed for Lipoatrophy to Become Clinically Evident?

The objective of this study was to evaluate how much limb fat is needed to be lost for lipoatrophy to become clinically evident. Antiretroviral drug-naive patients from a randomized trial comparing stavudine or abacavir plus lamivudine and efavirenz, who had subjective assessment to detect clinically evident lipoatrophy (standardized questionnaire) and objective measurements of limb fat (dual X-ray absorptiometry) at baseline, 48 weeks, and 96 weeks were included. ROC curves were used to assess the sensitivity and specificity of several cut-off values of absolute and percent limb fat loss for diagnosing lipoatrophy. Of 54 patients included, 13 (24%) had subjective lipoatrophy at 96 weeks. After 96 weeks, median limb fat change was -2.3 kg (interquartile range: -5.2, +0.2) and 0.4 kg (interquartile range: -7.2, +3.4) in patients with and without lipoatrophy, respectively. Median percent limb fat change was -45.5% (interquartile range: -78.0, +3.7) and 5.5% (interquartile range: -62.8, +95.6), respectively. The cut-off values of absolute and percent limb fat loss showing the best sensitivity and specificity values were -1.5 kg (sensitivity, 77%; specificity, 76%) and -30% (sensitivity, 85%; specificity, 73%). At least 30% limb fat is needed to be lost in HIV-infected patients for lipoatrophy to become clinically evident.

Proinflammatory Cytokine Changes in Clinically Stable, Virologically Suppressed, HIV-Infected Patients Switching From Protease Inhibitors to Abacavir

To the Editor: Excess cardiovascular risk has been observed in HIV-infected patients,1 driven by traditional risk factors such as smoking, hypertension, diabetes, and aging, although therapy-induced hyperlipidemia and HIV-induced proinflammatory state and immune activation seem to play a role.2-4 A recent report from the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study, one of the largest cohorts evaluating cardiovascular risk in HIV-infected patients, assessed the associations between nucleoside analogues and myocardial infarction. Contrary to the hypothesis expecting a role for thymidine analogues because of their negative effects on plasma lipids, insulin sensitivity, and limb fat loss, DAD investigators unexpectedly found that the recent use of didanosine and abacavir increased the risk of myocardial infarction by 50% and 90%, respectively.5 These findings were even more surprising as abacavir has a neutral lipid profile, does not interfere with insulin sensitivity, is not associated with limb fat loss in naive patients, and even promotes a fat increase in patients with lipoatrophy switching to abacavir from thymidine analogues.6,7 Although the DAD investigators adjusted the effect of abacavir as much as possible, the possibility of bias cannot definitively be ruled out. However, if abacavir really plays a role in promoting cardiovascular disease, other mechanisms apart from lipid changes, insulin sensitivity, and body fat alterations would have to be involved. Several studies have shown that changes in inflammatory cytokines such as adiponectin and tumor necrosis factor (TNF)-alpha may be related to increased cardiovascular risk in the general population.8-10 More recently, this association has been suggested in HIV-infected patients, mainly those with uncontrolled viral replication before initiating or after discontinuing antiretroviral therapy.1-3 The Nevirapine, Efavirenz and Abacavir (NEFA) trial assessed the relative merits of abacavir, efavirenz, or nevirapine as substitutes for the protease inhibitor (PI) component in stable virologically suppressed patients treated with a first-generation, unboosted PI and willing to simplify their regimen.11 In an intensive metabolic substudy of NEFA,12 we found favorable lipid changes in patients switching to any of the 3 options, namely a decrease in total cholesterol in the abacavir group, an increase in HDL cholesterol, and a decrease in the ratio of total cholesterol (TC) and high-density lipoprotein (HDL) cholesterol (TC:HDL) in the nonnucleoside reverse transcriptase inhibitor (NNRTI) groups.12 In addition, adiponectin and soluble tumor necrosis factor alpha receptor type 2 (sTNFR2) were assessed in baseline and 96-week serum samples adequately stored at −80°C for further laboratory analysis, contemplated in the initial design before the substudy. Plasma adiponectin was determined by radioimmunoassay (Linco Research, St. Charles, MO) with a detection threshold of 1 ng/mL and plasma sTNFR2 by a solid-phase enzyme immunoassay with amplified reactivity (Biosource Europe, Fleurus, Belgium) and a detection threshold of 0.1 ng/mL. In samples from 54 of 90 patients included in the metabolic substudy who continued with the assigned drug up to the end of follow-up (18 abacavir, 19 nevirapine, and 17 efavirenz), an increase in adiponectin levels and a decrease in sTNFR2 were observed in the overall population 96 weeks after the PI switch.12 We now present an analysis of the changes observed in these adipokines according to the antiretroviral regimen received in the NEFA metabolic substudy.

Objective amount of limb fat in HIV‐infected subjects with subjective diagnosis of lipoatrophy

The relationship between the subjective diagnosis of lipoatrophy and the objective amount of limb fat loss in HIV-infected adults is unclear. Using Medline, we identified published articles reporting the amount of arm, leg or limb fat measured by dual X-ray absorptiometry in HIV-infected patients with moderate-severe lipoatrophy and in healthy non-HIV-infected adults. We calculated the relative content of fat in the limbs, arms and legs of lipoatrophic patients with regard to the weighted arithmetic means of those fat values in healthy controls. We found 799 patients from 10 articles, and 73 healthy controls from two articles. Limb fat ranged from 2.6 to 4.4 kg in patients, and from 7.1 to 7.2 kg in controls. Both patients and controls were almost exclusively men, of white race, and in their forties. Weighted arithmetic means of arm, leg and limb fat in HIV-infected patients with clinically evident lipoatrophy were 1.0, 2.1 and 3.1 kg, respectively (48, 41 and 43% relative to healthy non-HIV-infected males, respectively). The diagnosis of lipoatrophy was highly correlated with the amount of limb fat, irrespective of the investigators. HIV-infected men with clinically evident lipoatrophy had a limb fat loss of >50% compared with non-HIV-infected healthy males.

Genetic analysis implicates resistin in HIV lipodystrophy

To investigate the role of genetic variation in influencing the risk of metabolic complications associated with highly active antiretroviral therapy (HAART). Cluster analysis of metabolic traits of 189 patients enrolled in ACTG5005s, the metabolic substudy of ACTG384, a clinical trial of HAART, was performed to identify a subgroup of individuals with increased risk of developing a cluster of metabolic abnormalities after exposure to HAART. Almost 300 single nucleotide polymorphisms in 135 candidate genes were evaluated for their association with this subgroup. A subgroup of patients was identified that had a normal metabolic profile at baseline but developed significantly elevated lipids and insulin resistance on HAART. This high-risk subgroup of patients also experienced significant body composition changes, particularly limb fat loss. Candidate gene analysis revealed that a single nucleotide polymorphism in resistin, a gene previously implicated in obesity and insulin resistance, was associated with this high-risk group (P = 0.0003). Genetic variation in resistin is associated with metabolic complications caused by HAART.

Hemochromatosis Gene Polymorphisms, Mitochondrial Haplogroups, and Peripheral Lipoatrophy during Antiretroviral Therapy

Antiretroviral therapy (ART)-associated lipoatrophy involves mitochondrial dysfunction. Iron metabolism impacts mitochondrial function and oxidative stress. Mitochondrial haplogroups and hemochromatosis gene (HFE) polymorphisms have been associated with ART-induced neuropathy. We assessed relationships between these variants and lipoatrophy. The AIDS Clinical Trials Group 384 study randomized ART-naive individuals to receive didanosine-stavudine or zidovudine-lamivudine, combined with efavirenz and/or nelfinavir. Substudy A5005s evaluated fat distribution by dual-energy X-ray absorptiometry (DEXA). We characterized HFE polymorphisms 845G>A and 187C>G and European mitochondrial haplogroups in A5005s participants who consented to genetic analyses. Among 96 participants (58% were white, and 10% were female) with baseline and 48 or 64 week DEXA data, the median limb fat change was -8.8% (interquartile range, -28.7% to +15.6%). HFE 187C/G heterozygotes (n = 23) had less limb fat loss than 187C/C homozygotes (n = 71) (+6.1% vs. -12.5%; P = .02) and were less likely to develop lipoatrophy after adjustment for age, sex, race, and ART randomization (odds ratio, 0.31; 95% confidence interval, 0.10-0.95; P = .04). Among non-Hispanic white participants, median limb fat change was +26.1% among 5 participants with mitochondrial haplogroup J, compared with -9.7% among 49 participants with other mitochondrial haplogroups (P = .07). HFE 187C>G and, possibly, mitochondrial haplogroup J gave relative protection against lipoatrophy during ART in A5005s. These associations should be replicated in other studies.

Early changes in adipokine levels and baseline limb fat may predict HIV lipoatrophy over 2 years following initiation of antiretroviral therapy*

No biological marker has been identified that predicts the development of lipodystrophy (LD). We investigated whether metabolic and body composition parameters could predict the development of LD over 2 years in adults initiating antiretroviral therapy (ART). We used stored plasma collected at baseline and weeks 12, 24 and 48 from adults initiating combination ART. Adipocytokine, inflammatory cytokine, lipid and glycaemic parameters were measured and related to subsequent lipoatrophy (loss of limb fat mass of at least 2 kg from weeks 24 to 96 by dual-energy X-ray absorptiometry) and an increase in visceral adipose tissue (VAT; an increase of at least 18 cm(2) from baseline to week 48 by abdominal computed tomography). Risk factors associated with limb fat loss and VAT gain were analysed by logistic regression. Fifty-four HIV-infected, treatment-naïve adults were included in the study: 53 (98%) of them were men, and they had a median age of 39 years [interquartile range (IQR) 34-48 years] and a median body mass index of 22.6 kg/m(2) (IQR 20-24.8 kg/m(2)). In multivariate analysis, a higher baseline limb fat percentage, and a 1 mmol/L increase in plasma leptin levels during the first 6 months of ART, independently predicted a peripheral fat loss of > or = 2 kg [odds ratio (OR) 2.58, 95% confidence interval (CI) 1.04-6.41; OR 3.15, 95% CI 1.34-7.35, respectively). VAT changes showed a borderline association with high baseline tumour necrosis factor-alpha levels and hip circumference (OR 1.04, 95% CI 1.00-1.07; OR 1.44, 95% CI 1.07-1.95, respectively). In ART-naïve men, higher baseline limb fat and an early increase in leptin concentrations may predict the subsequent development of lipoatrophy. We did not find the same risk factors in the two different groups of patients with peripheral fat loss and central fat gain, suggesting a partially independent pathogenesis.

Long-Term Body Fat Outcomes in Antiretroviral-Naive Participants Randomized to Nelfinavir or Efavirenz or Both Plus Dual Nucleosides

Long-term regional body fat outcomes have not been well described in randomized antiretroviral drug trials. Dual x-ray absorptiometry (DXA) scans were performed every 16 weeks on a subset of 157 antiretroviral-naive participants who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine and lamivudine or stavudine and didanosine, in a multicenter trial. Participants with any available data after baseline up to week 144 contributed to this as-treated analysis. Limb fat increased similarly in all groups during the first 32 weeks. After week 32, limb fat changed by - 1.7% per year for zidovudine-lamivudine and by -19.0% per year for didanosine-stavudine (mixed model analysis of variance [MMANOVA], P < 0.0001). Adjusting for nucleoside backbone, there was an additional decrease in limb fat of -8.7% per year for the combined nelfinavir and nelfinavir + efavirenz group compared with the efavirenz group (MMANOVA, P = 0.03). Among participants receiving zidovudine-lamivudine, after week 32, limb fat changed by +2.7% per year with efavirenz and by -7.9% per year for the combined nelfinavir and nelfinavir + efavirenz group (MMANOVA, P = 0.03). Over 144 weeks, zidovudine-lamivudine was superior to didanosine-stavudine with regard to limb fat loss. The combination of zidovudine, lamivudine, and efavirenz showed no overall pattern suggesting limb fat loss over time and was significantly superior to the pooled zidovudine-lamivudine-nelfinavir (with and without efavirenz) arms.

Switching to a Protease Inhibitor-Containing, Nucleoside-Sparing Regimen (Lopinavir/Ritonavir Plus Efavirenz) Increases Limb Fat But Raises Serum Lipid Levels

Subcutaneous limb fat loss continues to be one the most troubling side effects of long-term antiretroviral regimens. Nucleoside analogues and protease inhibitors (PIs) have been linked to the development of this complication. We evaluated the effects of nucleoside-sparing and PI-sparing regimens on fat distribution, bone mineral density, and metabolic parameters in 62 subjects, who were not selected for lipoatrophy, with advanced HIV (nadir CD4 count <or=200 cells/mm or HIV RNA level >or=80,000 copies/mL) and an undetectable HIV viral load. Participants were randomized to switch their initial successful antiretroviral regimen to open-label lopinavir/ritonavir (LPV/r) at a dose of 533/133 mg twice a day and efavirenz (EFV) at a dose of 600 mg/d (the nucleoside-sparing arm) versus EFV and 2 nucleoside analogues (the PI-sparing arm). At week 48, the median change in limb fat in the nucleoside-sparing arm was 562 g (6%, interquartile range [IQR]: -218-1186 g) versus a loss of -242 g (-4%, IQR: -539-452 g) in the nucleoside-containing PI-sparing arm (P = 0.086). At the time of last observation (median = 102 weeks, IQR: 73-152 weeks), a median gain of 782 g (10%, IQR: -380-1168 g) of limb fat was noted in the nonnucleoside arm (n = 22) versus a loss of 850 g (-15%, IQR: -1270 to -526 g) in the nucleoside-containing arm (n = 25; P = 0.002). The switch to a nucleoside-sparing combination antiretroviral regimen (LPV/r + EFV) was associated with significant improvement in limb fat. These results provide additional evidence that nucleoside analogues are important in the progressive limb fat loss that characterizes antiretroviral treatment and that switching medications can significantly improve this complication. This option has to be carefully balanced with the potential to increase serum lipid levels and the trend to increase virologic failure.

The Safety and Efficacy of Tenofovir DF in Combination with Lamivudine and Efavirenz Through 6 Years in Antiretroviral-Naïve HIV-1—Infected Patients

Background: Study 903 is a phase 3 trial with a completed 144-week, double-blind phase comparing tenofovir DF (TDF) to stavudine (d4T) in combination with lamivudine (3TC) and efavirenz (EFV) and an ongoing additional 336-week open-label extension phase. Method: Patients in Brazil, Argentina, and the Dominican Republic who completed the 144-week double-blind phase on TDF were eligible to roll over to the extension phase (weeks 144-480). Results from an interim week 288 analysis are presented. Results: Eighty-six patients (62% male, 70% white) initially randomized to the TDF arm continued treatment with TDF. At the end of the 144-week, double-blind phase, 85 of the 86 had HIV-1 RNA <400 copies/mL, of whom 84% maintained virologic suppression through week 288. CD4 counts continued to improve with a mean increase of 135 cells/mm3 from entry into the open-label extension to week 288. No patient discontinued due to renal adverse events. Small changes in bone mineral density at the lumbar spine and hip were seen in the first 48 weeks but were nonprogressive through 288 weeks. Mean limb fat increased from 8.0 kg at week 96 to 8.8 kg at week 288. Conclusion: Through 288 weeks, once-daily TDF+3TC+EFV demonstrated sustained antiretroviral activity with continued immunologic recovery. TDF treatment was not associated with renal adverse events or limb fat loss in antiretroviral-naïve patients.

Less Lipoatrophy and Better Lipid Profile With Abacavir as Compared to Stavudine

To assess lipoatrophy, other toxicities, and efficacy associated with abacavir as compared with stavudine in HIV-infected antiretroviral-naive patients. This was a prospective, randomized, open trial, stratified by viral load and CD4 cell count, conducted January 2001 to July 2004. Two hundred thirty-seven adult patients with HIV infection initiating antiretroviral therapy were assigned to receive abacavir (n = 115) or stavudine (n = 122), both combined with lamivudine and efavirenz. The primary endpoint was the proportion of patients with lipoatrophy as assessed by physician and patient observation at 96 weeks. A lower proportion of patients assigned to abacavir developed clinical signs of lipoatrophy (4.8% vs. 38.3%; P < 0.001). These observations were confirmed by anthropometric data. Dual energy x-ray absorptiometry (DEXA) scans performed in 57 patients showed significantly greater total limb fat loss in the stavudine arm (-1579 vs. 913 g; P < 0.001). The lipid profile in abacavir patients presented more favorable changes in the levels of triglycerides (P = 0.03), high-density lipoprotein cholesterol (HDLc; P < 0.001), and apolipoprotein A1 (P < 0.001) as well as in the ratio between total cholesterol and HDLc (P = 0.005). Throughout the study, a higher proportion of patients in the stavudine group received lipid-lowering agents as compared to the abacavir group (17% vs. 4%; P = 0.002). Similar virologic and immunologic responses were observed. Assuming the limitations inherent to clinical assessment, this study shows a notably weaker association of abacavir with lipoatrophy than stavudine. DEXA scans and anthropometric measurements supported the clinical findings. In addition, the lipid changes that occurred were more favorable in patients receiving abacavir.

Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides

To determine if particular components of antiretroviral drug regimens are associated with greater insulin resistance, dyslipidemia, and peripheral lipoatrophy. Metabolic and body composition variables were measured prospectively over 64 weeks in 334 antiretroviral-naive, HIV-infected subjects who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine/lamivudine or didanosine/stavudine in a factorial design, multicenter trial. Subjects assigned to efavirenz (n = 110) were compared with those assigned to nelfinavir (n = 99); subjects assigned to zidovudine/lamivudine (n = 154) were compared with those assigned to didanosine/stavudine (n = 180). A subset of 157 subjects had serial dual-energy X-ray absorptiometry (DEXA) scans. Lipid measures increased in all groups. Greater increases in high density lipoprotein (HDL) cholesterol occurred with efavirenz than with nelfinavir. Greater increases in total cholesterol, non-HDL cholesterol and HDL cholesterol occurred with stavudine and didanosine than with zidovudine/lamivudine. There were no differences in insulin resistance in the comparisons. After initial increases in the first 16 weeks, median limb fat decreased. Greater changes in percentage changes in limb fat occurred with didanosine/stavudine (-16.8%) than with zidovudine/lamivudine (+4.0%; P < 0.001 for overall change from baseline) and with nelfinavir (-13.1%) compared with efavirenz (+1.8%; P = 0.003). Over 64 weeks, all regimens were associated with increases in lipids but insulin resistance did not differ between groups. Regimens containing didanosine/stavudine and regimens containing nelfinavir were associated with greater loss of limb fat.

Adipose tissue expression of IL-18 and HIV-associated lipodystrophy.

IL-18 is an inducer of apoptosis/tissue injury. IL-18 messenger RNA expression was examined in adipose tissue (AT) obtained from HIV patients with lipodystrophy, without lipodystrophy and healthy controls. IL-18 mRNA was expressed in AT at increased levels in lipodystrophy-positive compared with lipodystrophy-negative patients and healthy controls. Higher levels of IL-18 mRNA were found in femoral-gluteal AT compared with abdominal AT, and correlated with limb fat loss. These findings suggest that IL-18 is linked to HIV-associated lipodystrophy.

Progression of Lipodystrophy (LD) with Continued Thymidine Analogue Usage: Long-Term Follow-Up from a Randomized Clinical Trial (The PIILR Study)

Purpose: During the 24-week PIILR study of protease inhibitor (PI) withdrawal, improved lipids and reduction in intraabdominal visceral fat was seen, however, there was also a loss of subcutaneous limb fat in patients with HIV-lipodystrophy (LD). It was hypothesized that overall improvement in LD may require a longer period of time off PIs. Method: Follow-up of patients randomized to stop or continue PI-based therapy for 24 weeks, in a multicenter study, was continued for up to 120 weeks. Biochemistry and lipid parameters were assessed every 3 months. DEXA and CT scans were performed annually. Limb fat, visceral adipose tissue, and the lipodystrophy case definition score (LCDS) were used as indicators of LD severity. Results: Forty-five male patients with baseline and week 120 body composition data were assessed. There were no significant changes in the limb fat or visceral adipose tissue (VAT) components of LD, with the exception of the LCDS (change from baseline +5.79, p < .001). Control of viral replication was maintained and lipid and glycemic parameters were unchanged over the 120-week follow-up. Linear regression analysis showed on-study usage of stavudine was independently and significantly correlated with both decreased limb fat mass and a higher LCDS. Conclusion: Body composition or metabolic features of LD did not improve over 2 years of observation in patients remaining on predominantly PI-sparing therapy. LD was adversely influenced by continued stavudine use.