indinavir-sulfate and HIV-Associated-Lipodystrophy-Syndrome

Molecular mechanisms behind the defects in insulin production and secretion associated with antihuman immunodeficiency virus (anti-HIV) therapy and the development of HIV-associated lipodystrophy syndrome (HALS) are discussed in this article. Data suggesting insulin resistance on the beta cell and defects in first-phase insulin release of HALS patients are presented. Hepatic extraction of insulin, nonglucose insulin secretagogues and insulin-like growth factor release may exert influence on the demand of circulating insulin and on insulin secretion in HIV-infected patients. Finally, the paucity in understanding the incretin effects in HIV and HIV therapy in relation to insulin secretion is highlighted.

Topics: Carbamates; Furans; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Nelfinavir; Ritonavir; Sulfonamides

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.

Topics: Adipose Tissue; Atherosclerosis; Cardiovascular Diseases; Cholesterol, HDL; Comorbidity; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Hyperlipidemias; Hypertriglyceridemia; Indinavir; Metabolic Syndrome; Prevalence; Risk Factors; Ritonavir; Terminology as Topic

Topics: Acidosis, Lactic; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Didanosine; Hemophilia A; Hemorrhage; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Nevirapine; Oxazines; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

to assess the incidence and risk factors for insulin resistance (IR) in a cohort of naive HIV-infected patients 48 weeks after starting highly active antiretroviral therapy (HAART).. prospective, two centre, observational, cohort study.. One-hundred and thirty-seven patients who started HAART and maintained the same regimen for 48 weeks were included. IR was determined by the homeostasis model assessment (HOMA-IR) method. Individuals with a HOMA-IR value >3.8 were defined as insulin resistant. Independent associations with the development of IR at 48 weeks were evaluated.. Seventeen (12.4%) individuals showed a HOMA-IR value >3.8 at baseline and were excluded for incidence analyses. Fifteen patients developed IR at 48 weeks of HAART, giving an incidence of 13%. Independent predictors of the development or IR were indinavir exposure (beta-coefficient 5.45, 95% confidence interval [CI] 1.30-22.8; P=0.02), and hepatitis C virus (HCV) antibody positivity (beta-coefficient 5.22, 95% CI 1.34-20.33; P=0.01). The appearance of IR was associated with a higher BMI (beta-coefficient 1.72 for each 2 kg/m2 increase, 95% CI 1.54-1.94; P=0.02) and with the presence of lipodystrophy at 48 weeks (beta-coefficient 5.59, 95% CI 1.45-21.5; P=0.01).. HAART induces the development of IR in previously naive non-insulin-resistant HIV-infected individuals, with an incidence of 13% in the first year of therapy. Indinavir exposure, and HCV coinfection are associated with an increased risk of developing IR.

Topics: Adult; Antiretroviral Therapy, Highly Active; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Incidence; Indinavir; Insulin Resistance; Male; Risk Factors

To compare the incidence of clinical lipodystrophy in HIV-1-infected patients receiving zidovudine or stavudine, in combination with indinavir and lamivudine, in a randomized trial.. NOVAVIR was a randomized multicentre trial comparing stavudine/lamivudine/indinavir and zidovudine/lamivudine/indinavir in 170 patients pretreated with zidovudine, didanosine or zalcitabine (> 6 months), but naive for lamivudine, stavudine and protease inhibitors. The incidence of clinical lipodystrophy and metabolic abnormalities was assessed in a subgroup of 101 patients after 30 months of follow-up.. The incidence of lipoatrophy was increased in the stavudine arm versus the zidovudine arm, as followed: facial atrophy: 48 versus 22% of patients, P = 0.011, lower limb atrophy: 49 versus 22% of patients, P = 0.006, buttock atrophy: 47 versus 20% of patients, P = 0.009, venomegaly: 57 versus 24% of patients, P = 0.001. There was no significant difference in the incidence of clinical signs of central fat accumulation nor in fasting metabolic parameters at month 30 between the two arms. In multivariate analyses, the stavudine arm, previous therapy with didanosine, and a lower CD4 cell count at study entry were associated with an increased risk of lipoatrophy, whereas older patients and women had an increased risk of lipohypertrophy.. Patients receiving stavudine/lamivudine/indinavir had a greater rate of clinical lipodystrophy, mainly lipoatrophy, than those treated with zidovudine/lamivudine/indinavir.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Constitution; Body Mass Index; Female; Follow-Up Studies; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Lamivudine; Male; Middle Aged; Risk Factors; Stavudine; Zidovudine

The highly active antiretroviral therapy (HAART) can cause a metabolic syndrome consisting of lipodystropy/lipoatrophy, dyslipidemia, and type 2 diabetes mellitus with an increased cardiovascular risk. The pathogenetic bases of HAART-associated lipodystrophy are poorly known. A genetic screen was used to evaluate proteins that are modulated in HIV-1-infected patients with or without lipodystrophy syndrome, that are routinely treated with HAART regimens. The most significant modulation was represented by FAP48 expression. Stable over-expression of FAP48 was able to alter, in vitro, adipogenesis, acting both on calcineurin and glucocorticoid pathways. Finally, we demonstrated that FAP48 over-expression was able to influence the capacity of some HIV drugs, Saquinavir and Efavirenz, but not Stavudine, Amprenavir, and Indinavir to inhibit adipocyte formation. In conclusion, this molecule could be a potential target for novel therapeutic approaches to the HAART related lipodystrophy in HIV patients.

Topics: Adaptor Proteins, Signal Transducing; Adipocytes; Alkynes; Animals; Antiretroviral Therapy, Highly Active; Benzoxazines; Calcineurin; Carbamates; Cell Differentiation; Cell Line; Cyclopropanes; Furans; Gene Expression; Glucocorticoids; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Mice; Saquinavir; Signal Transduction; Stavudine; Sulfonamides; Transfection

The pathogenesis of metabolic disturbances in treated HIV infection is incompletely understood.. Relationships between fasted metabolic parameters, body composition, and drug plasma concentrations were investigated in 59 patients who switched from failed nucleoside analogue treatment to ritonavir-boosted indinavir and efavirenz therapy. Metabolic parameters, peripheral fat, visceral adipose tissue (VAT) and drug plasma concentrations were measured prospectively.. Ritonavir exposure was found to be negatively correlated with high-density lipoprotein cholesterol (HDL-c) changes, with a 2.4% decrease in HDL-c for each unit increase in ritonavir concentration ratio. Significant associations between indinavir or efavirenz concentrations and metabolic disturbances were not observed. Total cholesterol (TC) correlated positively with high body mass index (BMI) and negatively with baseline limb fat mass: each unit increase in BMI and each kilogram reduction in baseline limb fat corresponded with a TC increase of 2.4% and 4.1%, respectively. Baseline triglyceride levels were lower in those patients with relatively greater limb fat mass: each kilogram reduction of total limb fat mass was associated with a 15.7% increase in triglyceride concentration. Changes in VAT were positively correlated with TC: for every unit TC increase a 0.3% VAT increase was observed (over 48 weeks).. Reduced limb fat mass at the start of the study treatment, increases in VAT mass, and higher plasma concentrations of ritonavir on study treatment were each--to varying degrees--associated with various metabolic disturbances.

Topics: Adipose Tissue; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Body Composition; Body Fat Distribution; Body Mass Index; Cholesterol; Cholesterol, HDL; Cyclopropanes; Extremities; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Intra-Abdominal Fat; Male; Reverse Transcriptase Inhibitors; Ritonavir; Thailand; Triglycerides

To determine the importance of lamin A/C for fat cell differentiation in vitro and for the anti-adipogenic activity of HIV protease inhibitors such as indinavir.. Lipodystrophy-associated and processing-defective mutants of lamin A were stably expressed at high levels in 3T3-L1 pre-adipocytes. Additionally, 3T3-L1 pre-adipocytes with stable reduction of lamin A/C or emerin were derived. The cells were differentiated for 8 days into mature adipocytes in the presence or absence of indinavir or nelfinavir.. 3T3-L1 cells stably expressing high levels of lipodystrophy-associated or processing-defective mutants of lamin A differentiated with comparable efficiencies to control cells. Similarly, cells with dramatically reduced lamin A levels differentiated as efficiently as controls. Although indinavir stimulated the accumulation of unprocessed lamin A, cells with dramatically reduced lamin A/C levels and no detectable prelamin A remained responsive to an indinavir-induced inhibition of adipogenesis.. The ability of HIV protease inhibitor to stimulate the accumulation of unprocessed lamin A is neither necessary nor sufficient to explain their anti-adipogenic activity. Furthermore, lamin A/C plays a minimal role in the differentiation of 3T3-L1.

Topics: Adipocytes; Adipogenesis; Cell Differentiation; Cell Nucleus; Cells, Cultured; Genetic Vectors; HIV Protease Inhibitors; HIV-Associated Lipodystrophy Syndrome; Humans; Indinavir; Lamin Type A; Membrane Proteins; Mutation; Nuclear Proteins; Protein Precursors; RNA, Small Interfering; Thymopoietins