Thymidine reverse transcriptase inhibitors (tNRTI) are strong inhibitors of PPAR-gamma and clearly implicated as a cause of lipoatrophy. Thiazolidenediaones (TZD), potent PPAR-gamma agonists, would be expected to be beneficial in HIV lipoatrophy, but prior studies have been conflicting. None specifically excluded the use of tNRTIs. We report the first study in individuals treated with tNRTI-sparing regimens using a TZD for treatment of HIV lipoatrophy.
AbstractObjectives: Thiazoledinediones increase limb fat in HIV+ patients with lipoatrophy. However, their use in the general population has been associated with bone loss and fracture. We sought to determine the effects of rosiglitazone on bone metabolism in HIV-infected patients. Methods: HIV+ patients with lipoatrophy were randomized to rosiglitazone versus placebo for 48 weeks in a double-blind, placebo-controlled trial. Limb fat, bone mineral density (BMD), bone formation markers (procollagen type 1 amino-terminal propeptide [P1NP], osteocalcin [OC]) and bone resorption markers (C-terminal telopeptide of type I collagen [CTX]) were measured, along with receptor activator for nuclear factor kappa β ligand (RANKL), osteoprotegerin (OPG), and inflammatory cytokines. Results: Seventy-one subjects were randomized to rosiglitazone or placebo: 17% female and 51% white. Total BMD did not change significantly in either group. In the rosiglitazone group, P1NP showed statistically significant decreases at 24 and 48 weeks; however, changes compared to placebo were only significant at 24 weeks. OC decreased significantly in the rosiglitazone group at 24 weeks, but there were no between-group differences. CTX, RANKL, or OPG did not change for either group. Multivariable regression within the rosiglitazone arm showed P1NP changes were inversely associated with limb fat changes, protease inhibitors, and tenofovir use. Conclusion: Rosiglitazone use was associated with decreased bone formation, but it did not alter bone resorption or total BMD. The increase in limb fat that accompanies rosiglitazone use appears to be associated with decreased osteoblast activity. Further studies are needed to determine the effect of thiazoledinediones on bone health in HIV-infected persons.Keywords: bone mineral densitybone turnover markersHIVrosiglitazonethiazoledinediones
Background HIV-infected patients are at increased risk of cardiovascular disease (CVD). This study assessed long-term changes in carotid intima-media thickness (IMT) as a surrogate marker for CVD risk in HIV-infected children and young adults. Methods This was a longitudinal, observational study comparing carotid IMT in HIV-infected subjects who were 2–21 years old to matched controls over 144 weeks. Results A total of 34 HIV-infected subjects and 29 controls were included in the analyses. Among the HIV-infected group, median age was 10 years, 74% were black, and 65% were female. Overall, 91% were perinatally-infected with 82% on antiretroviral therapy and a median CD4 + T-cell count of 681 cells/mm 3 . At baseline, HIV-infected subjects had increased internal carotid artery (ICA) and common carotid artery (CCA) IMT (ICA, HIV-infected 0.90 mm versus controls 0.73 mm; P<0.01; CCA, HIV-infected 1.00 mm versus controls 0.90 mm; P=0.02). Relatively large changes in ICA and CCA IMT were seen from year to year in both groups. However, by week 144, there were no net changes in ICA or CCA IMT within the HIV-infected group. In the controls, CCA increased 0.1 mm and ICA increased 0.17 mm from baseline to week 144. ICA and CCA IMT were similar between groups by 144 weeks. Conclusions Despite variations from year to year in carotid IMT in HIV-infected children and healthy controls, likely due to arterial growth and/or luminal diameter change, little or no net change occurred in carotid IMT over the entire 144-week study period. This suggests that only small net changes occur over time in HIV-infected children despite an increased long-term risk of CVD.
Objectives: To assess the association of inflammatory and endothelial activation biomarkers with the presence of lipoatrophy in HIV-infected subjects and to examine the role of HIV, antiretroviral therapy (ART), and metabolic parameters in endothelial activation and inflammation. Design: Prospective, cross-sectional study including 4 groups: HIV+ on ART with HIV-1 RNA <1000 copies/mL with and without clinical lipoatrophy, HIV+ ART naive, and healthy controls. Methods: We measured plasma levels of inflammatory cytokines (tumor necrosis factor-α, soluble tumor necrosis factor receptors I and II, interleukin-6, C-reactive protein, and myeloperoxidase) and endothelial activation markers (soluble intercellular and vascular cell adhesion molecules and von Willebrand factor). Results: We enrolled 182 subjects. Limb fat and lipoatrophy status were not correlated with endothelial markers. Endothelial markers were higher in HIV+ ART naive when compared with healthy controls and with HIV+ on ART but were similar between HIV+ on ART and healthy controls. Neither endothelial nor inflammatory markers were correlated with HIV duration, CD4 count, lipids, glucose, or specific ART. Strong correlations were found between some inflammatory cytokines and endothelial markers. Conclusions: There is enhanced endothelial activation in ART naive, whereas HIV+ on ART has similar values to healthy controls. Lipoatrophy did not seem to affect endothelial activation. Results highlight a potential association between heightened inflammation and endothelial activation.
Carotid intima media thickness (CIMT) progresses faster in HIV-infected adults on antiretroviral therapy (ART) than the general population. It is unclear if the rate of progression is similarly faster in ART-naive, HIV-infected adults.This was a 48-week prospective cohort study to compare change in CIMT and inflammation markers in ART-naive, HIV-infected adults in no immediate need of ART (HIV-positive/ART-naive) and age/sex/body mass index (BMI)-matched controls (HIV-negative).A total of 85 HIV-positive/ART-naive and 45 HIV-negative participants were enrolled. In the HIV-positive/ART-naive group, median baseline CD4+ T-cell count and HIV-1 RNA were 535 cells/mm3 and 6,916 copies/ml. Baseline common carotid artery (CCA) and bulb CIMTs were similar between groups. Changes in CIMT to 48 weeks at both sites were not different within- or between-groups (median [IQR] change in HIV-positive/ART-naive versus HIV-negative CCA CIMT -0.0071 mm [-0.0267-0.0233] versus 0.0113 mm [-0.0117-0.0306]; P = 0.19 between-groups; and bulb CIMT 0.0017 mm [-0.0367-0.06167] versus 0.01 mm [-0.0383-0.0625]; P = 0.54). After adjustment for cardiovascular disease (CVD) risk factors, change in CCA CIMT was greater in HIV-negative participants (-0.0046 versus 0.0177 mm for HIV-positive/ART-naive versus HIV-negative; P = 0.01). In HIV-positive/ART-naive, interleukin (IL)-6, soluble tumour necrosis factor-α receptor (sTNFR)-II, vascular cell adhesion molecule-1 and intercellular adhesion molecule (ICAM)-1 were higher at both time points and D-dimer was higher at week 48 (P < 0.01 for all). IL-6, sTNFR-I and D-dimer increased over 48 weeks in HIV-positive/ART-naive participants (P < 0.01 for all). In HIV-positive/ART-naive participants, independent predictors of greater change in CCA CIMT were higher BMI (P = 0.05) and family history of CVD (P < 0.01) and of greater change in bulb CIMT were higher sTNFR-I (P = 0.03) and higher diastolic blood pressure (P < 0.01).In ART-naive HIV-infected adults at low risk of HIV disease progression and low cardiovascular risk, CIMT progression rate was similar to matched controls. In addition to traditional CVD risk factors, higher levels of sTNFR-I predicted greater bulb CIMT changes.
Objectives: Although physician- and patient-rated diagnoses of lipoatrophy are currently used as a basis for inclusion into clinical trials, few studies have compared physician- or patient-rated lipoatrophy severity with objective measures. We aim to assess the validity of physician- and patient-rated diagnoses of lipoatrophy by evaluating the correlation between clinical assessments of lipoatrophy and objective fat indices. Methods: This cross-sectional study evaluated the association between clinical lipoatrophy scores and DEXA-measured limb fat (n = 154) and subcutaneous fat mitochondrial DNA (mtDNA) levels (n = 80) in HIV+ individuals. Results: There was a signifi cant negative correlation between DEXA-measured limb fat and lipoatrophy scores generated by either the patients (r = –0.27, p = .008) or the physician (r = –0.48, p < .0001). Also, a signifi cant positive correlation was found between the patient-generated lipoatrophy score and the physician score (r = 0.68, p < .0001). However, there was no correlation between fat mtDNA levels and DEXA-measured limb fat (r = –0.09, p = .42) or between physician- or patient-generated lipoatrophy scores (r = –0.09, p = .43, and r = 0.04, p = .71, respectively). Conclusion: These results suggest that physician- and patient-rated lipoatrophy scores may be useful surrogates for more expensive measures of lipoatrophy, which could be reserved for research studies.
Human immunodeficiency virus (HIV)-infected patients are at increased risk of cardiovascular disease, which may be related to chronic inflammation and endothelial dysfunction despite virological control with antiretroviral therapy. The relationship between carotid intima-media thickness (IMT), a surrogate marker for cardiovascular disease, proinflammatory cytokines, and endothelial activation markers has not been fully explored in HIV-infected patients who are receiving antiretroviral therapy.We conducted a prospective, cross-sectional, observational study of treated HIV-infected patients and healthy control subjects to evaluate the relationship between carotid IMT, proinflammatory cytokines, endothelial activation biomarkers, and metabolic parameters in treated HIV-infected patients, compared with healthy control subjects.We enrolled 73 HIV-infected patients and 21 control subjects. Common carotid artery and internal carotid artery IMT measurements, as well as tumor necrosis factor-alpha, high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, and soluble vascular cell adhesion molecule-1 levels were higher in the HIV-infected group. High-sensitivity C-reactive protein was the only biomarker that was positively correlated with carotid IMT in both groups. In the HIV-infected group, soluble vascular cell adhesion molecule-1 was positively correlated with all inflammatory cytokine levels. In multiple regression analysis, soluble vascular cell adhesion molecule-1, myeloperoxidase, and tumor necrosis factor-alpha levels were all associated with internal carotid artery IMT in the HIV-infected group, whereas age was associated with both common carotid artery and internal carotid artery IMT.Enhanced endothelial activation, inflammation, and increased carotid IMT occur in HIV-infected patients despite antiretroviral therapy. Inflammatory markers are associated with endothelial activation, and both are associated with internal carotid artery IMT, supporting a potential role of inflammation in endothelial activation and cardiovascular disease in HIV infection.
Background The aim of this study was to assess the effect of antiretroviral therapy (ART) versus HIV on mitochondria in fat. Methods Subcutaneous fat was collected from 45 HIV-infected patients on ART with lipoatrophy, 11 HIV-infected ART-naive patients and nine healthy controls. Three mitochondrial transcripts: NADH dehydrogenase subunit 1 (ND1), cytochrome B (CYTB) and NADH dehydrogenase subunit 6 (ND6) genes were quantitated using TaqMan® probes and normalized to nuclear-encoded ribosomal L13. Results ND1/L13 and CYTB/L13 were lower in HIV-positive patients on ART with lipoatrophy versus ART-naive patients (3.4 versus 7.2 [ P=0.017] and 2.5 versus 4.6 [ P=0.006], respectively). No difference was found between ART-naive patients and controls ( P>0.70). ND6/ L13 was similar between all groups. Dual-energy X-ray absorptiometry-measured limb fat and mitochondrial DNA in fat were also lower in HIV-positive patients on ART with lipoatrophy versus HIV-infected, ART-naive patients (4,382 versus 7,662 g [ P=0.02] and 726 versus 1,372 copies/cell [ P=0.03], respectively), but no difference was found between ART-naive and controls. In a multiple regression analysis, limb fat correlated with all three mitochrondrial RNA, whereas mitochondrial DNA did not correlate with mitochondrial RNA or limb fat. Conclusions In contrast to ART-naive patients, HIV-positive patients on ART with lipoatrophy had significant depletion in mitochondrial DNA in fat and mitochondrial RNAs. This suggests that mitochondrial toxicity in lipoatrophy could be driven by ART and not by HIV itself. In addition, mitochondrial RNA abnormalities, and not mitochondrial DNA depletion, could be a key driving force behind lipoatrophy.
