ritonavir and Insulin-Resistance

Coronavirus disease 2019 (COVID-19) is a global pandemic that is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus-2. Data from several countries have shown higher morbidity and mortality among individuals with chronic metabolic diseases, such as diabetes mellitus. In this review, we explore the contributing factors for poorer prognosis in these individuals. As a significant proportion of patients with COVID-19 also have diabetes mellitus, this adds another layer of complexity to their management. We explore potential interactions between antidiabetic medications and renin-angiotensin-aldosterone system inhibitors with COVID-19. Suggested recommendations for the use of antidiabetic medications for COVID-19 patients with diabetes mellitus are provided. We also review pertinent clinical considerations in the management of diabetic ketoacidosis in COVID-19 patients. In addition, we aim to increase clinicians' awareness of the metabolic effects of promising drug therapies for COVID-19. Finally, we highlight the importance of timely vaccinations for patients with diabetes mellitus.

Topics: Antibodies, Monoclonal, Humanized; Antiviral Agents; Blood Glucose; Chloroquine; Comorbidity; COVID-19; COVID-19 Drug Treatment; COVID-19 Vaccines; Diabetes Complications; Diabetes Mellitus; Diabetic Ketoacidosis; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Glucagon-Like Peptide-1 Receptor; Glycemic Control; Humans; Hydroxychloroquine; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Interferon Type I; Lopinavir; Lung; Metformin; Obesity; Pancreas; Ritonavir; Severity of Illness Index; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones

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

Virological failure of antiretroviral treatment increases the morbidity and mortality associated with AIDS. With currently available drugs it is possible to achieve an HIV - PVL < 50 copies of aRNA/mL in a significant percentage of patients with virological failure, even in those who accumulate a considerable number of resistant mutations in the viral genome. Compliance continues to be the most significant cause of antiretroviral treatment failure. Atazanavir boosted with ritonavir has clear advantages over other protease inhibitors (PI), such as its administration once per day, low number of tablets and a good tolerance which helps in compliance, as well as a lower metabolic toxicity and a resistances profile different to other PIs. Boosted Atazanavir in rescue treatments would be strongly recommended in patients naive to a PI or when there are < 3 mutations in the basic genotype in positions: 10F/I/V, 16E, 33I/F/V, 46I/L, 60E, 84V, 85 V and 90M of the protease gene, particularly when the patient has problems of compliance to antiretroviral treatment or metabolic disorders, such as dyslipaemia, insulin resistance, fasting blood glucose changes, a cardiovascular risk at 10 years of > 10% or cardiovascular disease.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Clinical Trials as Topic; Drug Resistance, Viral; Drug Synergism; Dyslipidemias; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Insulin Resistance; Oligopeptides; Patient Compliance; Point Mutation; Pyridines; Ritonavir; Salvage Therapy; Treatment Outcome; Viral Load

Atazanavir (ATV) is a protease inhibitor (PI) in which its main qualities, compared to other PI are dosing convenience, good tolerability and excellent metabolic profile. These characteristics makes it more like a nonnucleoside than a PI, but with the increased genetic barrier common to PI. It is indicated in initial treatment, simplification treatment or a change due to toxicity and in first line rescue treatment. The administering of ATV boosted with ritonavir (300/100 mg/d) has been approved in Europe in all clinical situations. In naïve patients it has been combined with practically all the nucleoside analogue pairs and has shown to be as effective as lopinavir/ritonavir and even efavirenz. In the USA, this indication has been approved for almost 5 years and ATV has become the most prescribed PI, while the EMEA has approved it this year. ATV is an optimal drug to replace other antiretrovirals in simplification strategies or changes due to toxicity. In several studies it has been shown that, in patients with good virological control, it can LPV/r or another PI, the therapeutic efficacy being maintained, with excellent tolerance and an improved lipid profile, and decreasing the cardiovascular risk. This strategy is widely used in Spain. In this scenario some patients could benefit from non-boosted ATV treatment (400 mg/d). ATV is an effective and very attractive option in first line rescue treatments in which the virus shows little or no resistance to PI, as its simplicity and tolerability can improve problems with compliance, the main cause of therapeutic failure. In patients with moderate resistance to PI, ATV is as effective as LPV/r. The survival of patients with HIV infection is increasingly longer and factors such as tolerability, cardiovascular risk and the adaptability of the treatment to the lifestyle of the patient, become more important, therefore ATV must play an important role in the treatment of HIV-infection.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Clinical Trials as Topic; Cohort Studies; Comorbidity; Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hyperbilirubinemia; Insulin Resistance; Oligopeptides; Patient Acceptance of Health Care; Pyridines; Ritonavir; Salvage Therapy; Treatment Outcome; Viral Load

The phase 4, METABOLIK trial demonstrated that changes in metabolic parameters with darunavir with low-dose ritonavir (DRV/r) were comparable to those observed with atazanavir with low-dose ritonavir (ATV/r). A comprehensive assessment of the effects of these agents on insulin sensitivity will provide additional, relevant clinical information.. In this substudy of METABOLIK, HIV-1-infected, antiretroviral agent-naïve male subjects aged ≥18 years with a viral load of >1,000 copies/mL were randomized to receive DRV/r 800/100 mg once daily (qd) or ATV/r 300/100 mg qd, both with a fixed dose of tenofovir disoproxil fumarate/emtricitabine 300/200 mg qd. The effects of DRV/r versus ATV/r on insulin sensitivity over 48 weeks were compared using the euglycemic hyperinsulinemic clamp, the preferred method to assess insulin sensitivity; primary end point was the effect on insulin sensitivity during the first 12 weeks.. Twenty-seven subjects completed the study. In the DRV/r arm (n=14), median glucose disposal from baseline through weeks 12 and 48 was 9.3, 11.4, and 9.9 mg/kg*min, respectively; in the ATV/r arm (n=13), these values were 8.9, 8.6, and 9.1 mg/kg*min, respectively. Median insulin sensitivity in the DRV/r arm at baseline, week 12, and week 48 was 24.0, 25.0, and 21.5 mg/kg*min per μIU/mL×100, respectively; these values in the ATV/r arm were 20.7, 22.0, and 22.0 mg/kg*min per μIU/mL×100, respectively. Most subjects had ≥1 adverse event, including three serious adverse events (n=2 [DRV/r], n=1 [ATV/r]).. DRV/r and ATV/r displayed similar modest effects on insulin sensitivity using a euglycemic hyperinsulinemic clamp.

Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Darunavir; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Ritonavir; Viral Load; Young Adult

Few studies have assessed metabolic and body composition alterations in perinatally HIV-infected African children on antiretroviral therapy (ART). We compared metabolic profiles and regional fat of children on ritonavir-boosted lopinavir (lopinavir/ritonavir), lamivudine and stavudine to those switched to nevirapine, lamivudine and stavudine.. This study evaluated metabolic and body composition outcomes in 156 HIV-infected children completing a randomised trial that assessed the continued use of lopinavir/ritonavir-based ART or switch to nevirapine-based ART in Johannesburg, South Africa (2005-2010). Fasting total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides total and regional body fat (BF) were measured. A clinical assessment for lipodystrophy (LD) was conducted.. 156 children (mean age 5.1±0.8 years, mean duration of treatment 4.2±0.7 years, mean time since randomisation 3.4±0.7 years) were enrolled. 85 were randomised to the lopinavir/ritonavir group and 71 to the nevirapine group. The lopinavir/ritonavir group had lower mean HDL (1.3±0.4 vs 1.5±0.4 mmol/l, p<0.001) and higher mean TC (4.4±1.0 vs 4.1±0.8 mmol/l, p=0.097), LDL (2.6±0.9 vs 2.3±0.7 mmol/l, p=0.018) and triglycerides (1.1±0.4 vs 0.8±0.3 mmol/l, p<0.001). The lopinavir/ritonavir group had more total BF by mean skinfold sum (43±11.1 vs 39±10.1 mm, p=0.031) and BF% by bioelectrical impedance analysis (17.0±7.0 vs 14.1±8.0%, p=0.022). Thirteen (8.4%) met criteria for LD.. Unfavourable alterations in lipid profile and triglycerides, and differences in fat are detectable in young HIV-infected South African children receiving lopinavir/ritonavir-based regimens versus those switched to nevirapine-based regimens. Interventions to mitigate these alterations are warranted to reduce long-term cardiovascular disease risk.

Topics: Anti-HIV Agents; Body Composition; Child; Child, Preschool; Cross-Sectional Studies; Drug Therapy, Combination; Female; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Infant; Insulin Resistance; Lamivudine; Lipids; Lopinavir; Male; Nevirapine; Ritonavir; South Africa; Stavudine

We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4(+) cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, -0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Atazanavir Sulfate; Biomarkers; CD4 Lymphocyte Count; Darunavir; Disease Progression; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Glomerular Filtration Rate; HIV Protease Inhibitors; HIV-1; Humans; Insulin Resistance; Lipids; Male; Middle Aged; Oligopeptides; Pilot Projects; Pyridines; Ritonavir; RNA, Viral; Sulfonamides; Time Factors; Treatment Outcome; Viral Load; Young Adult

Some HIV protease inhibitors (PIs), including full-dose ritonavir (800 mg) and ritonavir-boosted lopinavir, acutely induce insulin resistance in the absence of HIV infection and changes in body composition. Boosting dose ritonavir (100-200 mg) is the most commonly prescribed PI, yet its effects on glucose metabolism have not been described in the absence of another PI.. In this randomized, double-blind, cross-over study, a single dose of ritonavir 200 mg or placebo was given to healthy HIV-seronegative volunteers before assessment of insulin sensitivity by euglycemic hyperinsulinemic clamp.. Boosting dose ritonavir had no effect on insulin-mediated glucose disposal (M/I, placebo: 8.59 ± 0.83 vs. ritonavir: 8.51 ± 0.64 mg/kg per minute per μU/mL insulin, P = 0.89).. A single boosting dose of ritonavir does not alter insulin sensitivity, suggesting lopinavir is likely responsible for the induction of insulin resistance demonstrated in prior short-term studies of lopinavir/ritonavir. There is a dose-dependent effect of ritonavir on insulin sensitivity.

Topics: Adult; Aged; Anti-HIV Agents; Cross-Over Studies; Double-Blind Method; Female; Glucose; Human Experimentation; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Placebos; Ritonavir

Antiretroviral therapy is associated with metabolic complications, including dyslipidaemia, body fat changes and insulin resistance. Healthy volunteer studies have demonstrated a decrease in glucose disposal associated with dosing with specific antiretrovirals.. HIV-type-1-positive male participants were randomized to receive tenofovir disoproxil fumarate and lamivudine, with either fosamprenavir (FPV)/ritonavir or lopinavir (LPV)/ritonavir twice daily. A hyperinsulinaemic euglycaemic clamp was performed at baseline and at 2 weeks after commencing treatment. The homeostasis model assessment index for insulin resistance (HOMA-IR) was also calculated at these time points. Changes in lipids and lipoprotein subfractions (by nuclear magnetic resonance spectroscopy) were assessed. A pharmacokinetic assessment was undertaken at week 2.. A total of 27 participants were enrolled. There was no significant change in whole-body insulin sensitivity or HOMA-IR from baseline or between groups. Total cholesterol increased significantly, by 6.6% with FPV and 10.9% with LPV. The changes in lipids and lipoprotein subfractions were similar between groups with increases in triglycerides, very low-density lipoprotein (VLDL) and chylomicrons, and low-density lipoprotein (LDL) particles. Although the total high-density lipoprotein (HDL) particles were not significantly altered, a decrease in small HDL particles was seen. Changes in VLDL and chylomicron particles in both groups and triglycerides and small HDL particles in the LPV group were statistically significant.. In HIV-type-1-positive men initiating antiretroviral therapy with FPV- or LPV-based regimens, there were no significant changes in whole-body insulin sensitivity after 2 weeks. A proatherogenic lipid profile characterized by increases in triglycerides, VLDL and chylomicron particles and LDL particles, and a decrease in small HDL particles, was observed in both groups.

Topics: Adenine; Adipose Tissue; Adult; Anti-HIV Agents; Blood Glucose; Carbamates; Confidence Intervals; Drug Administration Schedule; Drug Combinations; Dyslipidemias; Furans; HIV Infections; HIV-1; Humans; Insulin; Insulin Resistance; Lamivudine; Lipids; Lopinavir; Male; Organophosphates; Organophosphonates; Pyrimidinones; Ritonavir; Sulfonamides; Tenofovir

Dyslipidemia alone does not fully explain the increase in cardiovascular events among patients receiving protease inhibitor (PI)-based treatment for human immunodeficiency virus infection. Some PIs, such as indinavir, directly induce endothelial dysfunction, an effect that may mediate that portion of the increase in cardiovascular events that is not attributable to dyslipidemia.. Endothelium-dependent vasodilation, insulin-mediated vasodilation, and whole-body and leg glucose uptake during use of a 1-h euglycemic hyperinsulinemic clamp (insulin infusion, 40 mU/m(2)/min) were measured in healthy men before and after 4 weeks of treatment with placebo (12 men), with 400 mg atazanavir per day (9 men), or with 400 mg lopinavir and 100 mg ritonavir twice per day (9 men).. Median age (36 years) and mean body mass index SD (23.4+/-2.6; calculated as weight in kilograms divided by the square of height in meters) did not differ between groups. Endothelium-dependent vasodilation, expressed as the percentage change in the leg blood flow response to intrafemoral artery infusion of 15 microg/min of the endothelium-dependent vasodilator methacholine, did not change after 4 weeks of treatment in any group:mean percentage change +/- SD, 154+/-102 from baseline and 242+/-254 at week 4 with atazanavir (P=.36), 76+/-62 and 86+/-79, respectively, with lopinavir-ritonavir (P=.68), and 111+/-86 and 127+/-153, respectively,with placebo (P=.63; for between-group differences, P=.55). The response to the endothelium-independent vasodilator nitroprusside was not different at week 4 for any group, nor was insulin-mediated vasodilation or leg or whole-body insulin-mediated glucose uptake (all within-group P values were 1.1).. Unlike the dramatic impairment seen with indinavir, the newer PIs atazanavir and lopinavir-ritonavir do not induce endothelial dysfunction in healthy subjects. Thus, endothelial dysfunction does not appear to be a PI drug class effect. The cause of the non-lipid-mediated increase in cardiovascular events that are reported with PIs remains unclear.

Topics: Adult; Atazanavir Sulfate; Drug Therapy, Combination; Endothelium, Vascular; Glucose; Glucose Clamp Technique; HIV Protease Inhibitors; HIV Seronegativity; Humans; Insulin Resistance; Lopinavir; Male; Muscle, Skeletal; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Treatment Outcome; Vasodilation

Topics: Adult; Blood Glucose; Cardiovascular Diseases; CD4 Lymphocyte Count; Cholesterol; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Insulin Resistance; Lipids; Lopinavir; Male; Pyrimidinones; Risk Factors; Ritonavir

Thymidine-based nucleoside analogue reverse transcriptase inhibitors and some protease inhibitors of HIV are associated with lipoatrophy, relative central fat accumulation and insulin resistance. The latter associations have not been well evaluated prospectively in adults commencing antiretroviral therapy. We studied the effects of protease inhibitor-based antiretroviral regimens on body composition, insulin sensitivity and adipocytokine levels.. 48-week substudy of a randomized, open-label, three-arm trial.. Hospital and community HIV clinics.. 140 HIV-infected adults naive to antiretroviral therapy.. Tipranavir/ritonavir [500/200 mg twice a day (TPV/r200)] or [500/100 mg twice a day (TPV/r100)] or lopinavir/ritonavir [400/100 mg twice a day (LPV/r)], each with tenofovir + lamivudine.. Body composition [dual-energy x-ray absorptiometry for limb fat; L4, abdominal computed tomography for visceral adipose tissue (VAT)]; and fasting metabolic parameters. The primary analysis was change in limb fat mass in each TPV/r group vs. LPV/r.. Limb fat increased in all three groups: LPV/r (1.17 kg) versus TPV/r200 (0.83 kg; P = 0.16) and TPV/r100 (0.41 kg; P = 0.07). VAT decreased in all groups: LPV/r (-3 cm) vs. TPV/r200 (-9 cm; P = 0.04) and TPV/r100 (-6 cm; P = 0.40). No significant change in insulin sensitivity was observed, including by oral glucose tolerance testing. The increase in leptin levels was significantly correlated with the increase in limb fat mass (r = 0.67; P < 0.0001). Despite increased limb fat, adiponectin levels increased, but significantly more with TPV/r200 (+6010 ng/ml; P < 0.0001) or TPV/r100 (+4497 ng/ml; P = 0.002) when compared with LPV/r (+1360 ng/ml).. Unlike many other antiretroviral regimens, TPV/r or LPV/r with tenofovir-lamivudine increased subcutaneous fat without evidence for increasing visceral fat or insulin resistance over 48 weeks.

Topics: Adiponectin; Adult; Body Composition; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin Resistance; Lopinavir; Male; Pyridines; Pyrimidinones; Pyrones; Ritonavir; Sulfonamides

Treatment of human immunodeficiency virus (HIV) with protease inhibitors (PIs) is associated with insulin resistance, triglyceride-rich dyslipidemia, and fat redistribution. Atazanavir (ATV), a potent once-daily PI, has been recognized for its convenience to patients, and some studies describe improved lipid metabolism. However, its effects on insulin sensitivity have not been elucidated. We conducted this study to test the hypothesis that ATV improves insulin resistance and dyslipidemia.. We prospectively studied 9 HIV-infected men with dyslipidemia (median age, 53 years; baseline triglyceride level, >200 mg/dL) on stable PI-containing antiretroviral therapy who elected to change PI therapy to ritonavir-boosted ATV therapy, dose of 300/100 mg. We measured insulin resistance at baseline and after 12 weeks of therapy using a hyperinsulinemic euglycemic clamp (insulin dose, 200 mU/m minute). Fasting lipid profiles and body composition (whole-body dual energy x-ray absorptiometry) were also measured at baseline and after 12 weeks.. All 9 patients completed the study and maintained undetectable viral loads (<50 copies/mL) and stable CD4 counts. After 12 weeks, insulin sensitivity significantly improved (+28%; P = 0.008) in all patients. Triglyceride levels also improved.. Using the gold-standard euglycemic clamp, ritonavir-boosted ATV therapy improved PI-induced insulin resistance among dyslipidemic HIV-infected men on PI-based antiretroviral therapy. These findings were not attributable to a change in body weight and provide further evidence for ATV's unique metabolic profile among the PIs.

Topics: Adult; Aged; Atazanavir Sulfate; Body Composition; Dyslipidemias; HIV Infections; HIV Protease Inhibitors; Humans; Insulin Resistance; Male; Middle Aged; Oligopeptides; Prospective Studies; Pyridines; Ritonavir; Treatment Outcome; Triglycerides

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.. 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.. 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.. 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.

Topics: Adult; Aged; Blood Glucose; Carbamates; Double-Blind Method; Energy Metabolism; Furans; Glucose Clamp Technique; HIV Protease Inhibitors; Humans; Indinavir; Insulin; Insulin Resistance; Lactic Acid; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Sulfonamides

Previously, we found that 4 weeks of treatment with lopinavir-ritonavir did not decrease insulin sensitivity but did increase adiponectin levels. In the present study, a single dose of lopinavir-ritonavir decreases insulin sensitivity but does not alter adiponectin levels. Insulin resistance from protease inhibitors may decrease with prolonged use; an increase in adiponectin levels may mediate this effect.

Topics: Adiponectin; Adult; Aged; Anti-HIV Agents; Blood Glucose; Double-Blind Method; Humans; Insulin; Insulin Resistance; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

The HIV protease inhibitor (PI) atazanavir does not impair insulin sensitivity acutely but ritonavir and lopinavir induce insulin resistance at therapeutic concentrations.. To test the hypothesis that atazanavir combined with a lower dose of ritonavir would have significantly less effect on glucose metabolism than lopinavir/ritonavir in vitro and clinically.. Glucose uptake was measured following insulin stimulation in differentiated human adipocytes in the presence of ritonavir (2 micromol/l) combined with either atazanavir or lopinavir (3-30 micromol/l). These data were examined clinically using the hyperinsulinemic euglycemic clamp and oral glucose tolerance testing (OGTT) in 26 healthy HIV-negative men treated with atazanavir/ritonavir (300/100 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) for 10 days in a randomized cross-over study.. Atazanavir inhibited glucose uptake in vitro significantly less than lopinavir and ritonavir at all concentrations. Ritonavir (2 micromol/l) combined with either atazanavir or lopinavir (3-30 micromol/l) did not further inhibit glucose uptake. During euglycemic clamp, there was no significant change from baseline insulin sensitivity with atazanavir/ritonavir (P = 0.132), while insulin sensitivity significantly decreased with lopinavir/ritonavir from the baseline (-25%; P < 0.001) and from that seen with atazanavir/ritonavir (-18%; P = 0.023). During OGTT, the HOMA insulin resistance index significantly increased from baseline at 120 min with atazanavir/ritonavir and at 150 min with lopinavir/ritonavir. The area under the curve of glucose increased significantly with lopinavir/ritonavir but not with atazanavir/ritonavir.. Both glucose uptake in vitro and clinical insulin sensitivity in healthy volunteers demonstrate differential effects on glucose metabolism by the combination PI atazanavir/ritonavir and lopinavir/ritonavir.

Topics: Adipocytes; Adult; Atazanavir Sulfate; Cell Differentiation; Cross-Over Studies; Drug Combinations; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; HIV Protease Inhibitors; HIV Seronegativity; Humans; Insulin Resistance; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir

The molecular basis of lipodystrophy, a syndrome associated with HIV antiretroviral (ARV) therapy, remains unknown.. To examine whether ARV therapy might inhibit the expression of CD36, which is known to play an important role in fatty acid and glucose metabolism, and if this might contribute to the metabolic alterations associated with lipodystrophy.. The effects of ARV therapy on CD36 levels was examined in vivo in a prospective cohort of individuals treated with ARV therapy and in vitro in assays of human cell lines exposed to ARV drugs.. Monocyte CD36 levels were assessed by flow cytometry at baseline and after 7 days of therapy in five healthy volunteers and 10 treatment-naive HIV-1-infected individuals. ARV therapy included protease inhibitors (ritonavir, nelfinavir or lopinavir/ritonavir). In addition, human cell lines (THP-1 and C32) were assessed for CD36 levels pre and post-ritonavir treatment.. Three of four healthy controls (one withdrew because of adverse effects) and 6 of 10 HIV-1-infected individuals had a 50 to > 90% decrease in monocyte CD36 levels after 7 days of therapy. One of ten HIV-infected subjects had a 30% decrease, and the remaining individuals had no change or an increase in CD36 levels. CD36 levels decreased significantly in human cell lines treated with ritonavir but not in those treated with zidovudine.. ARV therapy resulted in a marked decrease in CD36 in approximately 70% of our participants. Sustained ARV therapy-induced CD36 deficiency may contribute to insulin resistance and other metabolic complications of lipodystrophy.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD36 Antigens; Cell Line; Cohort Studies; HIV Infections; HIV-1; Humans; In Vitro Techniques; Insulin Resistance; Lipodystrophy; Monocytes; Prospective Studies; Ritonavir; Zidovudine

Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used ART has no cardiometabolic toxicity. Protease inhibitors have been associated with cardiometabolic risk, integrase-strand-transfer-inhibitors (INSTI) with weight gain and the CCR5 inhibitor maraviroc with improved vascular function. We have previously reported that the INSTI dolutegravir and maraviroc improved, and ritonavir-boosted atazanavir(atazanavir/r) worsened, inflammation and senescence in human coronary artery endothelial cells (HCAEC)s from adult controls. Here, we analyzed the pathways involved in the drugs' effects on inflammation, senescence and also insulin resistance.. We analyzed the involvement of the anti-inflammatory SIRT-1 pathway in HCAECs. Then, we performed a transcriptomic analysis of the effect of dolutegravir, maraviroc and atazanavir/r and used siRNA-silencing to address ubiquitin-specific-peptidase-18 (USP18) involvement into ART effects.. Dolutegravir reduced inflammation by decreasing NFκB activation and IL-6/IL-8/sICAM-1/sVCAM-1 secretion, as did maraviroc with a milder effect. However, when SIRT-1 was inhibited by splitomicin, the drugs anti-inflammatory effects were maintained, indicating that they were SIRT-1-independant. From the transcriptomic analysis we selected USP18, previously shown to decrease inflammation and insulin-resistance. USP18-silencing enhanced basal inflammation and senescence. Maraviroc still inhibited NFκB activation, cytokine/adhesion molecules secretion and senescence but the effects of dolutegravir and atazanavir/r were lost, suggesting that they involved USP18. Otherwise, in HCAECs, dolutegravir improved and atazanavir/r worsened insulin resistance while maraviroc had no effect. In USP18-silenced cells, basal insulin resistance was increased, but dolutegravir and atazanavir/r kept their effect on insulin sensitivity, indicating that USP18 was dispensable.. USP18 reduced basal inflammation, senescence and insulin resistance in coronary endothelial cells. Dolutegravir and atazanavir/r, but not maraviroc, exerted opposite effects on inflammation and senescence that involved USP18. Otherwise, dolutegravir improved and atazanavir/r worsened insulin resistance independently of USP18. Thus, in endothelial cells, dolutegravir and atazanavir/r oppositely affected pathways leading to inflammation, senescence and insulin resistance.

Topics: Anti-HIV Agents; Atazanavir Sulfate; Cells, Cultured; Comorbidity; Coronary Vessels; Endothelial Cells; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Insulin Resistance; Male; Maraviroc; NF-kappa B; Oxazines; Piperazines; Pyridones; Ritonavir; Signal Transduction; Sirtuin 1; Ubiquitin Thiolesterase

In previous studies that investigated the impact of direct-acting antiviral (DAA) treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients have been compared to baseline values with either end of treatment or post-treatment values. The results are inconsistent. We evaluated patients throughout the treatment and after treatment.. 121 patients were included in the study. 93 patients were treated with sofosbuvir/ledipasvir±Ribavirin (RBV), and 28 patients were treated with ombitasvir/paritaprevir/ritonavir+dasabuvir±RBV. Total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG) and homeostatic model assessment-insulin resistance (HOMA-IR) levels were measured at the onset of treatment, after the1st month of treatment, at the end of treatment, and 6 and 12 months after the end of treatment.. 117 patients were genotype 1. Sustained virological response was 98.4%. HOMA-IR values during treatment were significantly higher than at the beginning of treatment (p=0.0001). At 12 months there was a decrease in HOMA-IR, but this was not statistically significant (p=0.2048). TC and LDL levels were significantly increased in the first month of treatment (TC; 159±30, 180±34 mg/dl; LDL; 84±28, 100±30 mg/dl, respectively) (p<0.0001) and this increase was present during and after treatment. There was no statistically significant increase in TG (p=0120). Both treatment regimens showed similar effects on HOMA-IR, TC, and LDL.. Patients with HCV treated with DAAs drugs showed increased IR, TC, and LDL cholesterol levels during treatment. After the end of treatment, IR goes back to normal, while the elevated TC and LDL levels persist indefinitely.

Topics: Aged; Anilides; Antiviral Agents; Benzimidazoles; Blood Glucose; Cholesterol; Cyclopropanes; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Insulin Resistance; Lactams, Macrocyclic; Lipid Metabolism; Lipoproteins, LDL; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Triglycerides; Valine

An observational, prospective, cohort study was performed to assess changes in insulin sensitivity and serum leptin level after a switch from a ritonavir-boosted PI (PI/r) to raltegravir or dolutegravir in HIV-infected adults on stable combination ART (cART).. Non-diabetic HIV-infected patients receiving suppressive cART including tenofovir disoproxil fumarate/emtricitabine plus one PI/r, who underwent a switch from the PI/r to raltegravir (group A) or dolutegravir (group B), were enrolled in the study. Serum levels of insulin, leptin and the homeostasis model assessment of insulin resistance (HOMA) index were evaluated during a 12 month follow-up.. Overall, 86 patients were enrolled: 45 patients were included in group A and 41 were included in group B. The mean age was 45.7 years and 74 (86%) patients were male. After 12 months of follow-up, a significant reduction in the mean concentration of leptin and insulin was reported both in group A [-0.61 ng/mL (P < 0.001) and -2.5 mIU/L (P = 0.008), respectively] and in group B [-0.54 ng/mL (P = 0.005) and -2.1 mIU/L (P = 0.017), respectively], without a significant difference between the groups. A significant and comparable reduction in the mean HOMA index was reported both in group A [-0.55 (P = 0.004)] and in group B [-0.49 (P < 0.001)], as well as a significant decrease in lipid levels.. In HIV-positive subjects on suppressive cART, the switch from a PI/r to raltegravir or dolutegravir led to a significant and comparable reduction in both HOMA index and serum leptin level, reflecting a similar and significant improvement in insulin sensitivity.

Topics: Adult; Antiretroviral Therapy, Highly Active; Biomarkers; Coinfection; Drug Substitution; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Oxazines; Piperazines; Prospective Studies; Pyridones; Raltegravir Potassium; Risk Factors; Ritonavir; Treatment Outcome; Viral Load

Direct-acting antiviral agents (DAAs) have been widely used for chronic hepatitis C (CHC) treatment recently. The characteristics of glucose abnormalities after DAAs therapy however, remain elusive. We aimed to elucidate the mutual impact between treatment response and parameters of glucose abnormalities after DAAs therapy in CHC patients. CHC patients who received DAAs therapy were recruited. The primary outcome measurements were their insulin resistance (IR) and beta-cell function assessed by the homeostasis model assessment (HOMA) method before treatment and at end-of-follow-up (EOF). Sixty-five CHC patients (19 males, mean age = 59.8 ± 10.3 years) were consecutively enrolled. They included 47 (72.3%) patients of genotype-1 infection. The treatment regimens among patients were sofosbuvir in 30 patients, paritaprevir-ritonavir/ombitasvir/dasabuvir in 23 patients, and asunaprevir/daclatasvir in 12 patients respectively. The overall sustained virological response rate was 98.5%. The mean IR at EOF was 2.6 ± 1.8, which was not significantly different from baseline level (2.7 ± 2.9, P = 0.75). There was a significant improvement of beta-cell function at EOF compared to baseline (107.7 ± 86.8 to 86.7 ± 44.5, P = 0.05). The amelioration of beta-cell function at EOF was significantly observed among 23 patients of high baseline IR (166.7 ± 111.3 of baseline vs 105.7 ± 48.2 of EOF, P = 0.04). Six (60%) of the 10 pre-diabetic patients at baseline achieved a normoglycemic state at EOF. Successful eradication of HCV by DAAs might improve glucose abnormalities in CHC patients, particularly among those who had high IR.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Glucose; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Insulin Resistance; Insulin-Secreting Cells; Isoquinolines; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Pyrrolidines; Ritonavir; Sofosbuvir; Sulfonamides; Uracil; Valine

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.. 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.. 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).. RAL was not associated with measurable change in glycaemic, metabolic or inflammatory effects.

Topics: Adiponectin; Adolescent; Adult; Anti-HIV Agents; C-Reactive Protein; CD36 Antigens; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Glucose Clamp Technique; Healthy Volunteers; Humans; Insulin Resistance; Leptin; Lopinavir; Male; Middle Aged; Raltegravir Potassium; Random Allocation; Ritonavir; Triglycerides

Hemeoxygenase-1 (HO-1) has recently been identified as a major driver of metaflammation and obesity-related insulin resistance (IR). Drug-induced IR increases cardiovascular risk within the HIV-1-infected population receiving antiretroviral therapy (ART). We therefore investigated a possible role of HO-1 in ART-induced IR.. Effects of HIV-1 protease inhibitor ritonavir and integrase inhibitor raltegravir (RAL) on expression levels of HO-1 and proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, IL-8, tumor necrosis factor-α (TNFα), chemokine (C-C motif) ligand 5 (CCL5), and monocyte chemotactic protein 1 (MCP-1), were studied in monocyte and hepatocyte cell lines. Plasma levels of HO-1 and inflammatory markers were measured in insulin-resistant and insulin-sensitive HIV-1-infected patients under ART and seronegative controls.. We show that, in contrast to RAL, ritonavir treatment significantly increases mRNA expression levels of HO-1, IL-8, TNFα, CCL5, and MCP-1 in vitro in a dose-dependent manner. HO-1 plasma levels were significantly higher in insulin-resistant compared to insulin-sensitive patients on ritonavir-boosted ART (lopinavir/ritonavir group: 3.90 ± 1.15 vs 2.56 ± 1.07 ng/mL, P < 0.005 and darunavir/ritonavir group: 3.16 ± 1.37 vs 2.28 ± 1.23 U/mL, P < 0.05) and were correlated with expression levels of TNFα in individuals on ritonavir-boosted ART (lopinavir/ritonavir group: r = 0.108, P < 0.05 and darunavir/ritonavir group: r = 0.221, P < 0.05) but not in HIV-1-infected individuals receiving RAL or in seronegative controls.. HIV-1-infected patients on stable ART are often faced with non-AIDS-related metabolic comorbidities, increasing their individual cardiovascular risk. Here, we provide insight into a novel mechanism of ritonavir-induced IR involving proinflammatory properties of HO-1. Our initial observations might also provide prognostic value in the future to identify patients at risk for the development type 2 diabetes mellitus.

Topics: Cell Line; Cytokines; Gene Expression Profiling; Heme Oxygenase-1; Hepatocytes; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Insulin Resistance; Monocytes; Ritonavir

Lopinavir/ritonavir (LPV/r) is associated with insulin resistance (IR). We aim to determine the prevalence of IR, dyslipidemia and their inter-relationships with adipokines in HIV-infected children treated with LPV/r-based highly active antiretroviral therapy (HAART).. Twenty-eight children were enrolled. Fasting glucose, insulin, lipid profiles, adipokines, and oral glucose tolerance tests were performed.. The prevalence of IR, pre-diabetes mellitus, and hypertriglyceridemia was 42.9(12/28), 10.7(3/28), and 75.0(21/28)% respectively. No case met the definition for diabetes mellitus (DM) and lipodystrophy. Children with IR had higher BMI z-score, triglyceride levels but unchanged leptin or adiponectin levels compared to those without IR. Longer duration of LPV/r-based HAART was associated with increased levels of triglyceride and total cholesterol.. We describe high prevalence of IR, pre-diabetes mellitus, and dyslipidemia among HIV-infected children receiving LPV/r-based HAART. Pre-diabetes mellitus or DM or IR screening might be important for early diagnosis and intervention in these children.

Topics: Adipokines; Adolescent; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Blood Glucose; Child; Child, Preschool; Dyslipidemias; Female; HIV Infections; Humans; Insulin Resistance; Lipids; Lopinavir; Male; Pregnancy; Ritonavir; Thailand

Ritonavir-boosted protease inhibitors (PIs) could adversely affect metabolism and adipose tissue to different extents, depending on the molecule. Using drugs with minimal adverse metabolic effects is an important consideration in at-risk HIV-infected patients. In vitro adipocyte models can be useful for comparing the effects of different PIs.. We compared the effects of darunavir, darunavir/ritonavir, atazanavir/ritonavir and lopinavir/ritonavir in murine and human adipocytes on differentiation, mitochondrial function, reactive oxygen species (ROS) production and insulin sensitivity.. In human and murine adipocytes, differentiation evaluated by lipid content and protein expression of adipogenic markers, mitochondrial function evaluated by aggregation of the cationic dye JC-1 and by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide lysis, and mitochondrial mass evaluated by MitoTracker fluorescence and the expression of mitochondrial proteins were unaffected by darunavir, mildly affected by darunavir/ritonavir and further altered by atazanavir/ritonavir and lopinavir/ritonavir. ROS production was unaltered by darunavir and darunavir/ritonavir but was increased by lopinavir/ritonavir and atazanavir/ritonavir. Regarding insulin sensitivity, darunavir and darunavir/ritonavir had no significant effect on insulin activation of protein kinase B (Akt/PKB) and MAP kinase and of glucose transport, whereas lopinavir/ritonavir and atazanavir/ritonavir partly impaired the effect of insulin. The effect of atazanavir/ritonavir was generally milder than that of lopinavir/ritonavir.. The various PIs differentially modified adipocyte functions. Darunavir alone did not affect adipocyte functions and only modestly altered differentiation and mitochondrial function when associated with ritonavir. Lopinavir/ritonavir adversely affected differentiation and lipid content, mitochondrial function, ROS production and insulin sensitivity, and the effect of atazanavir/ritonavir was intermediate. Thus, in vitro, darunavir/ritonavir presented a safer metabolic profile on adipocytes than atazanavir/ritonavir and lopinavir/ritonavir.

Topics: Adipocytes; Animals; Atazanavir Sulfate; Cell Differentiation; Cells, Cultured; Darunavir; HIV Protease Inhibitors; Humans; Insulin Resistance; Lipolysis; Lopinavir; Mice; Mitochondria; Oligopeptides; Pyridines; Reactive Oxygen Species; Ritonavir; Sulfonamides

HIV-associated neurocognitive disorders (HAND) remain prevalent even with widespread use of combination antiretroviral therapy (ART), suggesting a potential role for co-morbidities in neurologic decline. Indeed, it is well established that ART drugs, particularly HIV protease inhibitors, can induce hyperlipidemia, lipodystrophy, and insulin resistance; all of which are associated with neurologic impairment. This study was designed to determine how metabolic dysfunction might contribute to cognitive impairment and to reveal specific metabolic co-morbidities that could be targeted to preserve brain function. Adult male C57BL/6 mice were thus treated with clinically relevant doses of lopinavir/ritonavir for 4 weeks, and subjected to thorough metabolic, neurobehavioral, and biochemical analyses. Data show that lopinavir/ritonavir resulted in manifestations of lipodystrophy, insulin resistance, and hyperlipidemia. Evaluation of neurologic function revealed cognitive impairment and increased learned helplessness, but not motor impairment following treatment with lopinavir/ritonavir. Further analyses revealed a significant linear relationship between cognitive performance and specific markers of lipodystrophy and insulin resistance. Finally, analysis of brain injury indicated that lopinavir/ritonavir treatment resulted in cerebrovascular injury associated with decreased synaptic markers and increased inflammation, and that the cerebral cortex was more vulnerable than the cerebellum or hippocampus. Collectively, these data reveal an intimate link between metabolic co-morbidities and cognitive impairment, and suggest that remediation of selective aspects of metabolic syndrome could potentially reduce the prevalence or severity HIV-associated neurocognitive disorders.

Topics: Animals; Brain Injuries; Cerebral Cortex; Hippocampus; HIV Protease Inhibitors; Hyperlipidemias; Insulin Resistance; Lipodystrophy; Lopinavir; Male; Mice; Mice, Inbred C57BL; Ritonavir

Thirty-nine HIV-1-infected patients treated for 156 weeks with a new nucleoside analogue-sparing regimen [raltegravir, etravirine and maraviroc (REM) or raltegravir, etravirine and darunavir/ritonavir (RED)] showed a uniform increase in fasting glucose levels and a uniform decrease in insulin secretory capacity. Diabetes mellitus occurred in one RED-treated and four REM-treated patients. A worsening glucose tolerance was observed in highly treatment-experienced HIV-infected patients receiving effective antiretroviral therapy after virological failure.

Topics: Anti-HIV Agents; Blood Glucose; Cyclohexanes; Darunavir; Fasting; Glucose Tolerance Test; HIV Protease Inhibitors; HIV Seropositivity; HIV-1; Humans; Insulin; Insulin Resistance; Maraviroc; Nitriles; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Treatment Outcome; Triazoles; Viral Load

To examine the relationship of free testosterone (FT) and sex hormone-binding globulin (SHBG) with insulin resistance and diabetes mellitus (DM) in HIV disease.. Cross-sectional analysis from 322 HIV-uninfected and 534 HIV-infected men in the Multicenter AIDS Cohort Study.. : The main outcomes were DM and homeostasis model assessment-insulin resistance (HOMA-IR). DM was defined as fasting serum glucose ≥126 or self-reported DM and use of DM medications. HOMA-IR was calculated from fasting serum glucose and fasting insulin.. Compared with HIV-uninfected men in our sample, HIV-infected men were younger, with lower body mass index, and more often black. HIV-infected men had lower FT (P < 0.001) and higher SHBG (P < 0.0001). The adjusted odds ratio for DM was 1.98 (95% confidence interval: 1.04 to 3.78); mean adjusted log HOMA-IR was 0.21 units higher in HIV-infected men (P < 0.0001). Log SHBG, but not log FT, was associated with DM (odds ratio = 0.44, 95% confidence interval: 0.25 to 0.80) in both groups. Log FT and log SHBG were inversely related to insulin resistance (P < 0.05 for both) independent of HIV.. Compared with HIV-uninfected men, HIV-infected men had lower FT, higher SHBG, and more insulin resistance and DM. Lower FT and lower SHBG were associated with insulin resistance regardless of HIV serostatus. This suggests that sex hormones play a role in the pathogenesis of glucose abnormalities among HIV-infected men.

Topics: Adult; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus; Fasting; HIV Infections; HIV Protease Inhibitors; Humans; Insulin Resistance; Logistic Models; Lopinavir; Male; Middle Aged; Odds Ratio; Reverse Transcriptase Inhibitors; Ritonavir; Sex Hormone-Binding Globulin; Stavudine; Testosterone

Protease inhibitors (PIs), such as atazanavir sulfate and ritonavir, are used clinically to prevent the progression of HIV and are known to induce insulin resistance. To determine whether PI-mediated insulin resistance is induced by activation of pro-inflammatory cascades, L6 skeletal muscle cells were treated ±atazanavir sulfate, ritonavir, or atazanavir sulfate + ritonavir, and ±insulin. Treatment with atazanavir sulfate, ritonavir, or atazanavir sulfate + ritonavir for 24 or 48 h significantly increased basal glucose uptake (P<0.05) and atazanavir sulfate + ritonavir treatment increased basal glucose uptake significantly more than ritonavir or atazanavir sulfate treatment alone (P<0.05). Atazanavir sulfate + ritonavir treatment for 48 h completely prevented insulin stimulation of glucose uptake (P>0.05). When compared to untreated cells, basal palmitate uptake and oxidation was found to be significantly higher in cells treated with PIs alone or in combination (P<0.05). Prior PI treatment alone or in combination prevented (P>0.05) the insulin-mediated increase in palmitate uptake and the insulin-mediated decrease in palmitate oxidation observed in the control group. Atazanavir sulfate treatment alone or in combination with ritonavir significantly increased JNK1/2 phosphorylation when compared to the control or ritonavir group (P<0.05) and this was accompanied by a rise (P<0.05) in AKT(Ser473) phosphorylation in the basal state. Total JNK1/2 and p38 MAPK protein content and p38 MAPK phosphorylation state were not altered in any of the treatment groups (P>0.05). Our data indicate that, in muscle cells, PIs induce metabolic dysfunction that is not limited to insulin-sensitive metabolism and that is potentially mediated by a rise in JNK1/2 pro-inflammatory signaling.

Topics: Animals; Atazanavir Sulfate; Cell Line; Glucose; HIV Protease Inhibitors; Insulin Resistance; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Muscle Fibers, Skeletal; Oligopeptides; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases; Palmitates; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyridines; Rats; Ritonavir; Signal Transduction; Time Factors

HIV protease inhibitors acutely block glucose transporters (GLUTs) in vitro, and this may contribute to altered glucose homeostasis in vivo. However, several GLUT-independent mechanisms have been postulated. To determine the contribution of GLUT blockade to protease inhibitor-mediated glucose dysregulation, the effects of ritonavir were investigated in mice lacking the insulin-sensitive glucose transporter GLUT4 (G4KO). G4KO and control C57BL/6J mice were administered ritonavir or vehicle at the start of an intraperitoneal glucose tolerance test and during hyperinsulinemic-euglycemic clamps. G4KO mice exhibited elevated fasting blood glucose compared with C57BL/6J mice. Ritonavir impaired glucose tolerance in control mice but did not exacerbate glucose intolerance in G4KO mice. Similarly, ritonavir reduced peripheral insulin sensitivity in control mice but not in G4KO mice. Serum insulin levels were reduced in vivo in ritonavir-treated mice. Ritonavir reduced serum leptin levels in C57BL/6J mice but had no effect on serum adiponectin. No change in these adipokines was observed following ritonavir treatment of G4KO mice. These data confirm that a primary effect of ritonavir on peripheral glucose disposal is mediated through direct inhibition of GLUT4 activity in vivo. The ability of GLUT4 blockade to contribute to derangements in the other molecular pathways that influence insulin sensitivity remains to be determined.

Topics: Adipokines; Adipose Tissue; Animals; Blood Glucose; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Glucose Intolerance; Glucose Tolerance Test; Glucose Transporter Type 4; HIV Protease Inhibitors; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Ritonavir

Topics: Anti-HIV Agents; Atazanavir Sulfate; Drug Combinations; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Lopinavir; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir

Topics: Animals; Anti-HIV Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glucose Clamp Technique; Insulin Resistance; Male; Pyridines; Pyrones; Rats; Rats, Inbred WF; Ritonavir; Sulfonamides

Topics: Anti-HIV Agents; Cardiovascular Diseases; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Insulin Resistance; Ritonavir

The clinical use of HIV protease inhibitors (PIs) is associated with the development of peripheral insulin resistance. The incidence and degree of impaired glucose tolerance observed in treated patients vary considerably between drugs, however. To compare the ability of HIV PIs to alter peripheral glucose disposal acutely in a genetically identical model system at therapeutically relevant drug levels, healthy lean male rats previously naive to PI exposure were given ritonavir, amprenavir, lopinavir/ritonavir (4:1), or atazanavir by continuous intravenous infusion to achieve steady state drug levels of 10 or 25 muM rapidly. Under euglycemic hyperinsulinemic clamp conditions, a dose-dependent reduction in the peripheral glucose disposal rate (Rd) was observed with all the PIs except atazanavir. The rank order of sensitivity was ritonavir, lopinavir, and then amprenavir. Changes in skeletal muscle and heart 2-deoxyglucose (2-DOG) uptake correlated with reductions in Rd. All 3 of these PIs also produced significant reductions in 2-DOG uptake into primary rat adipocytes in vitro. Atazanavir had no effect on glucose uptake in vitro or in vivo. The in vivo potency of PIs to impair peripheral glucose disposal acutely correlates with the degree of insulin resistance observed in HIV-infected patients receiving these drugs. Preclinical testing of novel candidate PIs in a rodent model system may be useful in identifying the future risk of altering glucose homeostasis.

Topics: Adipocytes; Animals; Atazanavir Sulfate; Carbamates; Deoxyglucose; Dose-Response Relationship, Drug; Furans; Glucose; Glucose Clamp Technique; HIV Protease Inhibitors; Infusions, Intravenous; Insulin Resistance; Lopinavir; Male; Models, Animal; Muscle, Skeletal; Myocardium; Oligopeptides; Pyridines; Pyrimidinones; Rats; Ritonavir; Sulfonamides

Topics: Acanthosis Nigricans; Adult; Diabetes Mellitus; Didanosine; HIV Infections; HIV Protease Inhibitors; Humans; Insulin Resistance; Male; Ritonavir; Zidovudine

To describe a syndrome of peripheral lipodystrophy (fat wasting of the face, limbs and upper trunk), hyperlipidaemia and insulin resistance in patients receiving potent HIV protease inhibitor therapy.. Cross-sectional study.. Outpatient clinic of a university teaching hospital.. HIV-infected patients either receiving at least one protease inhibitor (n=116) or protease inhibitor-naive (n=32), and healthy men (n=47).. Lipodystrophy was assessed by physical examination and questionnaire and body composition by dual-energy X-ray absorptiometry. Fasting triglyceride, cholesterol, free fatty acid, glucose, insulin, C-peptide and fructosamine levels, other metabolic parameters, CD4 lymphocyte counts, and HIV RNA load were also assessed.. HIV protease inhibitor-naive patients had similar body composition to healthy men. HIV protease inhibitor therapy was associated with substantially lower total body fat (13.2 versus 18.7 kg in protease inhibitor-naive patients; P=0.005), and significantly higher total cholesterol and triglyceride levels. Lipodystrophy was observed clinically in 74 (64%) protease inhibitor recipients after a mean 13.9 months and 1(3%) protease inhibitor-naive patient (P=0.0001). Fat loss occurred in all regions except the abdomen after a median 10 months. Patients with lipodystrophy experienced a relative weight loss of 0.5 kg per month and had significantly higher triglyceride, cholesterol, insulin and C-peptide levels and were more insulin-resistant than protease inhibitor recipients without lipodystrophy. Patients receiving ritonavir and saquinavir in combination had significantly lower body fat, higher lipids and shorter time to lipodystrophy than patients receiving indinavir. Three (2%) patients developed new or worsening diabetes mellitus.. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance is a common complication of HIV protease inhibitors. Diabetes mellitus is relatively uncommon.

Topics: Adult; Anti-HIV Agents; Body Composition; Cross-Sectional Studies; Diabetes Mellitus; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Insulin Resistance; Lipodystrophy; Male; Nelfinavir; Risk Factors; Ritonavir; Saquinavir; Syndrome