OBJECTIVE

To assess changes in metabolic parameters and body composition among 422 antiretroviral-naive patients randomized to 3 antiretroviral therapy (ART) strategies: protease inhibitor (PI; n = 141)-, nonnucleoside reverse transcriptase inhibitor (NNRTI; n = 141)-, or PI + NNRTI (n = 140)-based strategies with a median follow-up of 5 years.

METHODS

At baseline and 1-month (metabolic parameters only) and 4-month follow-up intervals, fat-free mass (FFM) and total body fat were calculated, anthropometric measurements were performed, and fasting metabolic parameters were obtained. Rates of change and mean change were compared.

RESULTS

The PI + NNRTI strategy resulted in greater increases in triglycerides and low-density lipoprotein cholesterol compared with the PI and the NNRTI strategies (P < 0.005), with no differences between the PI and NNRTI strategies. High-density lipoprotein cholesterol increased significantly more in the NNRTI strategy than in the PI strategy (P < 0.005). Insulin and insulin resistance increased similarly with all 3 strategies. Changes in total and regional body composition (loss of subcutaneous tissue area and gains in FFM, nonsubcutaneous tissue area, and visceral tissue area) were observed but did not differ by strategy.

CONCLUSIONS

Long-term follow-up of participants initiating 3 ART strategies demonstrated similar changes in total and regional fat, with no differences by ART strategy. The differential effects on lipid metabolism by strategy and the overall increases in insulin and insulin resistance with all 3 strategies necessitate close monitoring of patients on ART.

Phospholipid scramblase 1 (PLSCR1) is a member of PLSCR gene family that has been implicated in multiple cellular processes including movement of phospholipids, gene regulation, immuno-activation, and cell proliferation/apoptosis. In the present study, we identified PLSCR1 as a positive intracellular acute phase protein that is upregulated by LPS in liver, heart, and adipose tissue, but not skeletal muscle. LPS administration resulted in a marked increase in PLSCR1 mRNA and protein levels in the liver. This stimulation occurred rapidly (within 2 h), and was very sensitive to LPS (half-maximal response at 0.1 microg/mouse). Moreover, two other APR-inducers, zymosan and turpentine, also produced significant increases in PLSCR1 mRNA and protein levels, indicating that PLSCR1 was stimulated in a number of models of the APR. To determine signaling pathways by which LPS stimulated PLSCR1, we examined the effect of proinflammatory cytokines in vitro and in vivo. TNFalpha, IL-1beta, and IL-6 all stimulated PLSCR1 in cultured Hep B3 hepatocytes, whereas only TNFalpha stimulated PLSCR1 in cultured 3T3-L1 adipocytes, suggesting cell type-specific effects of cytokines. Furthermore, the LPS-stimulated increase in liver PLSCR1 mRNA was greatly attenuated by 80% in TNFalpha and IL-1beta receptor null mice as compared to wild-type controls. In contrast, PLSCR1 levels in adipose tissue were induced to a similar extent in TNFalpha and IL-1beta receptor null mice and controls. These results indicate that maximal stimulation of PLSCR1 by LPS in liver required TNFalpha and/or IL-1beta, whereas the stimulation of PLSCR1 in adipose tissue is not dependent on TNFalpha and/or IL-1beta. These data provide evidence that PLSCR1 is a positive intracellular acute phase protein with a tissue-specific mechanism for up-regulation.

BACKGROUND

HIV-associated adipose redistribution syndrome (HARS) is an HIV-associated disorder characterized by excess truncal fat, including visceral adipose tissue (VAT).

METHODS

From baseline to week 12 in this randomized, double-blind, placebo (PL)-controlled, multicenter trial investigating effects of recombinant human growth hormone (r-hGH; Serostim; EMD Serono Inc., Rockland, MA) in patients with HARS, 325 received induction (4 mg/d of r-hGH) or PL. At week 12, patients who initially received induction were rerandomized to 2 mg of r-hGH on alternate days (maintenance) or PL to week 36. Patients who initially received PL later received 4 mg/d of r-hGH. Change in VAT was the primary outcome. Key secondary outcomes included changes in non-high-density lipoprotein cholesterol (non-HDL-C) and limb fat.

RESULTS

At week 12, induction therapy resulted in decreased VAT (-32.6 vs. 0.5 cm2; P<0.001), limb fat (-0.4 vs. 0.2 kg; P<0.001), and non-HDL-C (-13.0 vs. -2.8 mg/dL; P=0.023) compared with PL. On r-hGH induction-maintenance (baseline to week 36), patients sustained losses in VAT and trunk fat but not losses of subcutaneous fat in the abdomen or limbs. Also, non-HDL-C remained significantly decreased on r-hGH but not on PL maintenance.

CONCLUSIONS

In patients with HARS, r-hGH induction-maintenance therapy produces greater relative losses of VAT and trunk fat than of subcutaneous fat and also has beneficial effects on the lipid profile.

OBJECTIVE

Complaints of dry skin in HIV-infected individuals were reported after the advent of HAART. The objective of the study was to evaluate the prevalence of dry skin and associated factors in HIV-infected and control subjects.

DESIGN

Cross-sectional.

METHODS

A total of 1026 HIV-infected subjects and 274 controls [from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based study of cardiovascular risk assessment] in the Study of Fat Redistribution and Metabolic Change in HIV infection (FRAM) had skin assessed by self-report and examination. Multivariable logistic regression identified factors associated with dry skin.

RESULTS

Self-reported dry skin was more prevalent in HIV-infected subjects than controls. In multivariable analysis, HIV infection was associated with self-reported dry skin. In HIV-infected men, current indinavir use, CD4 cell count less than 200 cells/microl and recent opportunistic infections were associated with dry skin. Indinavir use had an elevated risk in men with CD4 cell counts of 200 cells/microl or greater but not with CD4 cell counts less than 200 cells/microl. In HIV-infected women, a CD4 cell count less than 200 cells/microl was associated with dry skin; indinavir use did not reach statistical significance but, as in men, indinavir use had an elevated risk in those with higher CD4 cell counts than in those with CD4 cell counts less than cells/microl.

CONCLUSION

Dry skin is more common in HIV-infected individuals than controls. In HIV-infected individuals, low CD4 cell counts and indinavir use in those with higher CD4 cell counts are associated with dry skin.

BACKGROUND

Some HIV protease inhibitors (PIs) have been shown to induce insulin resistance in vitro but the degree to which specific PIs affect insulin sensitivity in humans is less well understood.

METHODS

In two separate double-blind, randomized, cross-over studies, we assessed the effects of a single dose of ritonavir (800 mg) and amprenavir (1200 mg) on insulin sensitivity (euglycemic hyperglycemic clamp) in healthy normal volunteers.

RESULTS

Ritonavir decreased insulin sensitivity (-15%; P = 0.008 versus placebo) and non-oxidative glucose disposal (-30%; P = 0.0004), whereas neither were affected by amprenavir administration.

CONCLUSION

Compared to previously performed studies of identical design using single doses of indinavir and lopinavir/ritonavir, a hierarchy of insulin resistance was observed with the greatest effect seen with indinavir followed by ritonavir and lopinavir/ritonavir, with little effect of amprenavir.

Inflammation can produce abnormalities that could increase the risk for atherosclerosis including alterations in lipid and lipoprotein metabolism. Apolipoprotein M is a recently described HDL-associated apoprotein expressed mainly in the liver and kidney with protective effects against atherosclerosis. In this study, we describe the regulation of apolipoprotein M during the acute phase response. Stimuli that produce systemic inflammation, LPS, zymosan, or turpentine, decrease apolipoprotein M mRNA levels in the liver and kidney. Treatment of Hep3B hepatoma cells with TNF or IL-1 also decreased apolipoprotein M mRNA levels. The decrease in apolipoprotein M mRNA leads to a decrease in apolipoprotein M secretion into the media in Hep3B cells and a decrease in mouse serum following LPS administration. Moreover, in humans with acute bacterial infections or chronic HIV infection, serum apolipoprotein M levels are decreased. Apolipoprotein M is a negative acute response protein that decreases during infection and inflammation. These results are consistent with the finding that infections and inflammatory disorders accompanied by systemic inflammation are associated with an increased risk of atherosclerosis.

People with HIV infection have metabolic abnormalities that resemble metabolic syndrome (hypertriglyceridemia, low high-density lipoprotein cholesterol, and insulin resistance), which is known to predict increased risk of cardiovascular disease (CVD). However, there is not one underlying cause for these abnormalities and they are not linked to each other. Rather, individual abnormalities can be affected by the host response to HIV itself, specific HIV drugs, classes of HIV drugs, HIV-associated lipoatrophy, or restoration to health. Furthermore, one component of metabolic syndrome, increased waist circumference, occurs less frequently in HIV infection. Thus, HIV infection supports the concept that metabolic syndrome does not represent a syndrome based on a common underlying pathophysiology. As might be predicted from these findings, the prevalence of CVD is higher in people with HIV infection. It remains to be determined whether CVD rates in HIV infection are higher than might be predicted from traditional risk factors, including smoking.

BACKGROUND

HIV infection and antiretroviral therapy are associated with dyslipidemia, but the association between regional adipose tissue depots and lipid levels is not defined.

METHODS

The association of magnetic resonance imaging-measured visceral adipose tissue (VAT) and regional subcutaneous adipose tissue (SAT) volume with fasting lipid parameters was analyzed by multivariable linear regression in 737 HIV-infected and 145 control men from the study of Fat Redistribution and Metabolic Change in HIV Infection.

RESULTS

HIV-infected men had higher median triglycerides (170 mg/dL vs. 107 mg/dL; P < 0.0001), lower high-density lipoprotein cholesterol (HDL-C; 38 mg/dL vs. 46 mg/dL; P < 0.0001), and lower low-density lipoprotein cholesterol (LDL-C; 105 mg/dL vs. 125 mg/dL; P < 0.0001) than controls. After adjustment, greater VAT was associated with higher triglycerides and lower HDL-C in HIV-infected and control men, whereas greater leg SAT was associated with lower triglycerides in HIV-infected men with a similar trend in controls. More upper trunk SAT was associated with higher LDL-C and lower HDL-C in controls, whereas more lower trunk SAT was associated with higher triglycerides in controls. After adjustment, HIV infection remained strongly associated (P < 0.0001) with higher triglycerides (+76%, 95% confidence interval [CI]: 53 to 103), lower LDL-C (-19%, 95% CI: -25 to -12), and lower HDL-C (-18%, 95% CI: -22 to -12).

CONCLUSIONS

HIV-infected men are more likely than controls to have higher triglycerides and lower HDL-C, which promote atherosclerosis, but also lower LDL-C. Less leg SAT and more VAT are important factors associated with high triglycerides and low HDL-C in HIV-infected men. The reduced leg SAT in HIV-infected men with lipoatrophy places them at increased risk for proatherogenic dyslipidemia.

OBJECTIVES

To assess long-term changes in subcutaneous tissue among antiretroviral-naive persons initiating 1 of 3 nucleoside reverse transcriptase inhibitor (NRTI)-containing regimens.

METHODS

We compared changes in 308 participants initiating stavudine plus lamivudine (d4T+3TC; N = 63), zidovudine plus lamivudine (ZDV+3TC; N = 192), and abacavir plus lamivudine (ABC+3TC; N = 53), along with protease inhibitors and/or non-NRTIs. Anthropometric measurements (skinfolds) were performed at baseline and 4-month intervals. Rates of change (mm/y) over 36 months, for the early period (months 4 through 12) and late period (months 16 through 36), were calculated.

RESULTS

The rates were negative (tissue loss) for the abdomen and thigh (d4T+3TC, ZDV+3TC) and triceps (ZDV+3TC) skinfolds. For ABC+3TC, most rates were positive (tissue gain). No differences among regimens were seen for the rates of change in the subscapular or suprascapular skinfolds. Rates in the early period were generally positive. The late period rates were negative for d4T+3TC and ZDV+3TC and significantly different from 0 for the abdomen and thigh (d4T+3TC, ZDV+3TC) and triceps (ZDV+3TC) skinfolds, whereas ABC+3TC had less loss in the late period. Most early versus late differences were significant for d4T+3TC and ZDV+3TC; only the triceps skinfold was significant for ABC+3TC.

CONCLUSIONS

In this prospective nonrandomized evaluation, subcutaneous tissue changes varied by regimen. Similar losses were demonstrated for d4T+3TC and ZDV+3TC, whereas ABC+3TC had gains. Temporal differences in rates for d4T+3TC and ZDV+3TC suggest initial recovery followed by long-term treatment effect.