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Background We aimed to measure the effect of raltegravir (RAL) on insulin sensitivity and surrogates of cardiovascular risk in healthy HIV-seronegative volunteers compared to that of lopinavir/r (LPV/r), a positive control.Methods An open-label, two phase crossover study in HIV-negative male subjects randomized 1:1 to receive either 2 weeks of LPV/r followed by a 2-week washout period and 2 weeks of RAL, or RAL initially followed by LPV/r. A hyperinsulinaemic euglycaemic clamp was performed prior to and following each 2-week dosing phase. Fasting samples for lipids, adiponectin, leptin, vascular inflammatory biomarkers and CD36 were also taken.Results A total of 16 subjects completed the study. At the baseline visit the mean insulin-stimulated glucose disposal per unit insulin (M/I) was 7.97 and 8.30 for LPV/r and RAL, respectively. The mean (sem) percentage change from baseline was -16.10% (3.84) after 2 weeks of LPV/r and -0.43% (4.83) after 2 weeks of RAL. Absolute M/I was 25% lower for LPV/r than for RAL (P=0.001). Triglycerides and total cholesterol rose significantly with LPV/r (+0.5 mmol/l, P=0.002 and +0.4 mmol/l, P<0.0001), but were unchanged with RAL. Proathrogenic lipid subfractions of low-density lipoprotein (LDL) cholesterol increased with LPV/r and were unaffected with RAL. LDL peak and mean particle diameter and LDL I significantly decreased with LPV/r (P<0.05), and trend of increased LDL III was detected. High-sensitivity C-reactive protein declined with RAL (-0.2 mg/l, P=0.043) but was elevated after LPV/r (+0.25 mg/l, P=0.03).Conclusions RAL was not associated with measurable change in glycaemic, metabolic or inflammatory effects.

Background Stavudine (d4T)-containing regimens are associated with a potential for lipoatrophy and dyslipidaemia. We assessed the safety and efficacy of reducing the dose of stavudine compared with switching to tenofovir or maintaining the standard dose of d4T.Methods Clinically stable HIV-infected patients receiving antiretroviral therapy containing stavudine 40 mg twice daily with a plasma HIV RNA <200 copies/ml for at least 6 months were randomized to maintain stavudine 40 mg twice daily (d4T40 arm), to reduce to 30 mg twice daily (d4T30 arm), or to switch from d4T to tenofovir (TDF arm).Results Fifty-eight (93% male) patients were included: 22 in the d4T40 arm, 19 in the d4T30 arm and 17 in TDF arm. At baseline, median time on d4T was 6 years (interquartile range [IQR] 2.6–7.1), median age 43 years (IQR 36–51) and median CD4+T-cell count was 587/mm3(IQR 329–892). At week 24, median limb fat changes (g) were as follows: d4T40=-182 (95% CI: -469—5); d4T30=527 (95% CI: -343–694); and TDF=402 (95% CI: 130–835; d4T40 versus TDF, P=0.0003). Significant differences between median values of laboratory parameters were detected: triglycerides (mg/dl): d4T40=19; d4T30=-23 and TDF=-79 (d4T40 versus TDF, P=0.03); and total cholesterol (mg/dl): d4t40=22, d4T30=-4, and TDF=-28 (d4T40 versus TDF, P=0.04). No significant difference was observed in mitochondrial function assessed in peripheral blood mononuclear cells.Conclusions Although both strategies were associated with a trend toward a decrease in plasma lipids and an increase in body fat, the only significant changes were observed among those who switched to tenofovir.

Objective A case definition of HIV lipodystrophy has recently been developed from a combination of clinical, metabolic and imaging/body composition variables using logistic regression methods. We aimed to evaluate whether artificial neural networks could improve the diagnostic accuracy.Methods The database of the case-control Lipodystrophy Case Definition Study was split into 504 subjects (265 with and 239 without lipodystrophy) used for training and 284 independent subjects (152 with and 132 without lipodystrophy) used for validation. Back-propagation neural networks with one or two middle layers were trained and validated. Results were compared against logistic regression models using the same information.Results Neural networks using clinical variables only (41 items) achieved consistently superior performance than logistic regression in terms of specificity, overall accuracy and area under the ROC curve. Their average sensitivity and specificity were 72.4 and 71.2%, as compared with 73.0 and 62.9% for logistic regression, respectively (area under the ROC curve, 0.784 vs 0.748). The discriminating performance of the neural networks was largely unaffected when built excluding 13 parameters that patients may not have readily available. The average sensitivity and specificity of the neural networks remained the same when metabolic variables were also considered (total 60 items) without a clear advantage against logistic regression (overall accuracy 71.8%). The performance of networks considering also body composition variables was similar to that of logistic regression (overall accuracy 78.5% for both).Conclusions Neural networks may offer a means to improve the discriminating performance for HIV lipodystrophy, when only clinical data are available and a rapid approximate diagnostic decision is needed. In this context, information on metabolic parameters is apparently not helpful in improving the diagnosis of HIV lipodystrophy, unless imaging and body composition studies are also obtained.

Background Hypertriglyceridaemia and insulin resistance are common in HIV-infected patients treated with protease inhibitors, particularly in those with lipodystrophy. Whether a therapeutic approach addressed to those metabolic abnormalities may have any impact on body fat is not clear.Methods Patients on stable antiretroviral therapy containing protease inhibitors, with abdominal obesity defined by increased waist-to-hip ratio, and plasma triglycerides >200 mg/dl, were randomized to receive blind medication consisting of metformin 850 mg, gemfibrozil 600 mg or placebo every 12 h for 1 year. Weight, height, waist and hip were measured, and fasting blood analyses, including at least CD4 cell count, plasma HIV-1 RNA, lactate, glucose, insulin, triglycerides, total, HDL and LDL cholesterol were performed at baseline and every 3 months. An oral glucose tolerance test, and assessments of total and regional fat by bioimpedance analysis and sonography, respectively, were also done at baseline, 6 and 12 months.Results One-hundred-and-eight patients were randomized to placebo (n=36), gemfibrozil (n=37) or metformin (n=35). There was absolute loss of total and regional fat in the three arms without significant changes in the waist-to-hip ratio. However, the loss of fat in patients on gemfibrozil was significantly lower than in patients on placebo. No patient discontinued study drugs due to adverse effects.Conclusion In this population of HIV-infected patients, there was a loss of fat along time. The finding of relative preservation of fat associated with gemfibrozil therapy deserves further investigation in the search of potential effective therapies for lipodystrophy in HIV-infected subjects.

The main objective of the present study was to ascertain if mitochondrial DNA (mtDNA) depletion as reported in HIV-infected patients with highly active antiretroviral therapy (HAART)-related lipodystrophy (LD) implies any degree of mitochondrial respiratory chain (MRC) dysfunction. For this purpose, we evaluated HIV patients on different HAART schedules with LD (group A; n=12) and on HAART but without LD (group B; n=12), and untreated HIV-infected patients as controls (group C; n=24). mtDNA content was determined on peripheral blood mononuclear cells (PBMCs) with a real-time PCR method. Complex II, III and IV activities of the MRC were simultaneously measured spectrophotometrically, as were spontaneous and stimulated oxygen consumption by PBMCs. Compared to controls (group C, 100%), patients with LD (group A) showed a decreased mtDNA content (54%, P<0.001), which was associated with a decline in complex III (62%, P<0.05) and IV activity (69%, P<0.05) (both complexes partially encoded by mtDNA), but not in complex II activity (exclusively encoded by nuclear DNA). Patients in group B showed a similar pattern of mitochondrial dysfunction but to a lesser extent and without statistical significance. Respiratory activities in both treated groups (A and B) did not differ in comparison with controls. We conclude that mtDNA depletion occurring during HAART is associated with deficiencies in MRC complexes partially encoded by mtDNA, which are detectable by PBMCs. Presented in ‘Late Breakers and Hot Topics’ session at 6th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, 17–21 November 2002.