Description and Pathophysiology of the ART-Related Metabolic Alterations

Dyslipidemia

Increased levels of TG and cholesterol, together with decreased HDL and increased LDL cholesterol, have been described in HIV patients undergoing ART [31]. These alter­ations probably have multiple origins.

After the introduction of HAART, increased levels of lipids were constantly reported [31, 33]. Regarding the NRTIs, stavudine was associated with increased levels of TG [34]. However, the major con­tributor to dyslipidemia was the class of PIs. Studies performed in non-HIV-infected con­trol subjects revealed that RTV was able, after a few days, to alter lipid parameters with hyper-TG and increased cholesterol levels. Similarly, boosting concentrations of RTV in association with LPV increased TG levels. By contrast, atazanavir was associat­ed with a safe metabolic profile [35]. NNR- TIs are also able to modify lipid parameters: NVP increases total and HDL cholesterol levels but not TG [36]. EFV has a similar effect but increases cholesterol and TG. Var­ious phenotypes of dyslipidemia were reported in patients undergoing ART with PIs, but the major alterations are increased levels of TG, decreased levels of HDL, and increased content in small dense LDLs, a profile very similar to that seen in the clas­sic metabolic syndrome.

2 mmol/L and 60% had cholesterol levels above 5.5 mmol/L, whereas these values were 22% and 11%, respectively, in patients under NRTI treatment without PIs [37]. In the French cohort APROCO-TM, after 1 and

3 years of PI treatment, respectively, the prevalence of hyper-TG increased from 26 to 36% in men and from 20 to 25% in women. The prevalence of hypercholesterolemia was elevated between 55 and 60% in both groups [34]. At present, the use of PI with a more friendly metabolic effect such as atazanavir and the more generalized dietary and lipid-lowering drugs prescriptions allowed a reduction of the lipid values in this population [31].

The PI-induced alterations could result from a direct effect of the drugs, particular­ly at the liver level, resulting in modified lipid metabolism (Fig. 7). The synthesis and secretion of apoB, the major VLDL-linked apoprotein, are partly regulated by the bal­ance between the association to lipids and the degradation in the proteasome system involved in overall cellular protein degrada­tion. Thus, it has been shown, in in vitro models of hepatic cells, that RTV and SQV could inhibit the degradation of apoB by inhibiting the proteasome, which results in increased VLDL secretion [38]. When ani­mals were fed a high-fat diet, an increased synthesis of TG on VLDL was observed [39]. Moreover, RTV is able to increase VLDL secretion in mice through the activation of the lipogenic transcription factor SREBP-1 in the liver [40]. Regarding VLDL catabo­lism, Bonnet et al. presented interesting data [41] indicating that, in PI-treated patients, there was an accumulation of lipoparticles containing apoC-III and apo-E in association with apoB. These complex particles would represent persistent poten­tially atherogenic cholesterol-rich remnant particles derived from TG-rich lipoproteins.

In addition to a direct effect of some PIs on lipid metabolism, the altered repartition of body fat is probably also involved in lipid alterations. As explained above, for the metabolic syndrome, increased content in visceral fat as well as decreased peripheral adipose tissue are associated with an increased level of lipolysis and of FFA flux­es together with altered adipocytokine pro­duction: increased levels of TNF-α, IL-1, and IL-6 and decreased levels of adiponectin [42, 43]. Thus, even after the introduction of HAART, the severity of the inflammatory syndrome is markedly decreased as com­pared to the state of active infection. Patients with ART-related metabolic syn­drome still present a state of low-grade inflammation with increased cytokines and acute-phase proteins such as CRP, which could contribute to the dyslipidemia observed in these patients.

Fig. 7 Adverse effects of antiretroviral treatment on lipid and glucose metabolism. sdLDL, small dense LDL

Altered Glucose Tolerance, Diabetes and Insulin Resistance

The presence of altered glucose tolerance is observed in a minority of PI-treated patients, but its prevalence was high with the first generation PI and in particular with the wide use of indinavir. In the APRO- CO-TM French cohort, increased glycemia (either fasting hyperglycemia or glucose intolerance) increased from 17 to 27% in men after 1 and 3 years of treatment with PI, respectively, while diabetes increased from 4 to 9%. In women, alterations in glu­cose tolerance remained stable at 25% but the prevalence of diabetes increased from 2 to 11%.

Studies performed with non-HIV-infected control subjects revealed that IDV was able to induce insulin resistance and to modify glycemia after a few days [48]. After a single dose, IDV was able to decrease glucose uptake during a clamp test, indicating insulin resistance, which was rapid and reversible [49]. It is hypothesized that this effect could be due to inhibition of the insulin-sensitive glucose transporter GLUT4 that has been evidenced in in vitro studies. Similarly, LPV boosted by RTV induced an increased glycemia and insulinemia after 4 weeks in normal volunteers [35].

The prevalence of glucose alterations and insulin resistance has been consistently found to be higher in patients with lipodys­trophy than in patients without lipodystro­phy. A role for adipose tissue in insulin resistance resulting from altered cytokine production and increased lipolysis can be easily hypothesized, which would accentu­ate the metabolic disorders. As explained below, lipodystrophic adipose tissue pres­ents an altered profile of secreted cytokines with increased TNF-α and IL-6. These cytokines are responsible for insulin resist­ance at the adipocyte level resulting in increased lipolysis and FFA fluxes, which in turn induce insulin resistance at the level of the liver and muscles. In addition, lipodys- trophic adipose tissue has a decreased secretion of adiponectin, which could result in decreased lipid oxidation and glucose intake in the muscles, and in decreased lipid oxidation and increased glucose pro­duction in the liver as explained above. Therefore, the drug-induced alterations in glucose metabolism and in insulin sensitivi­ty are aggravated by the altered adipose tis­sue function due to lipodystrophy.