saquinavir and Hyperlipidemias

To assess the correlation between antiretroviral treatment and dyslipidaemia in HIV-infected patients, and the role of bezafibrate as a lipid-lowering agent.. We retrospectively compared serum lipid levels of five groups of 40 patients, each of them treated with either saquinavir hard gel, indinavir, or ritonavir (associated with two nucleoside analogues), or dual nucleoside reverse transcriptase inhibitors (NRTI) with or without a non-nucleoside reverse transcriptase inhibitor (NNRTI), or not treated with antiretrovirals, randomly selected from nearly 1000 HIV-infected patients followed-up for >or= 12 months, while on the relevant therapy. Hypertriglyceridaemia was defined by triglyceride levels >or= 172 mg/dl, and hypercholesterolaemia by cholesterol levels >or= 200 mg/dl. All patients with triglyceridaemia > 300 mg/dl and cholesterolaemia > 220 mg/dl for at least 6 months, and unresponsive to a >or= 3-month diet, started bezafibrate (400 mg/day), and were prospectively followed-up at a

Topics: Bezafibrate; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Hypolipidemic Agents; Indinavir; Lipids; Retrospective Studies; Ritonavir; Saquinavir

Protease inhibitors (PIs) effectively inhibit replication of the human immunodeficiency virus (HIV), and reduce mortality and prolong survival in patients with HIV infection. Newer PIs saquinavir (soft gelatin capsule) and amprenavir, as well as other PIs, may be effective when administered twice/day. Adverse reactions may occur, as well as metabolic complications and interactions between PIs and other drugs, including other PIs. The strategy of combining PIs is based on specific pharmacologic interactions among the agents.

Topics: Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Lipodystrophy; Nelfinavir; Ritonavir; Saquinavir

To assess the 48-week efficacy, safety, pharmacokinetics, and resistance of double boosted protease inhibitors (PI), saquinavir (SQV), and lopinavir/ritonavir (LPV/r), in children who have failed nucleoside reverse transcription inhibitors /non-nucleoside reverse transcription inhibitors-based regimens.. Fifty children at 2 sites in Thailand were treated with standard dosing of SQV and LPV/r. CD4, HIV-RNA viral load (VL), plasma drug concentrations and safety laboratory evaluations were monitored. Virologic failure was defined as having 2 consecutive VL >400 copies/mL after week 12 of therapy. Intention to treat analysis was performed.. Baseline data were a median age of 9.3 years (interquartile range [IQR]: 7.1-11.2), Center for Disease Control and Prevention (CDC) classification N:A:B:C 4%:14%:68%:14%, VL 4.8 log10 (IQR: 4.5-5.1), CD4 7% (IQR: 3-9.5). At 48 weeks, 3 had died of bacterial infection but no cases had progressed CDC classification. Median CD4% rise was 9 (IQR: 5-16) and median HIV RNA reduction was -2.8 log10 (IQR: -3.2 to -1.4), both P < 0.001. Thirty-nine (78%) and 32 (64%) children had VL <400 and <50 with significant differences between the 2 sites. Five children (10%) had VL failure as a result of poor adherence to the drug regimen but no one had major PI mutations. Median serum cholesterol and triglyceride increased significantly (+35 mg/dL, +37 mg/dL, respectively, both P < 0.001). Mean minimum plasma concentrations (Cmin) of LPV and SQV were 4.6 and 1.24 mg/L, respectively.. Double boosted SQV/LPV/r resulted in significant CD4 rise and VL decline at 48 weeks. Hyperlipidemia was common. Cmin of both PIs exceeded therapeutic concentrations. Poor adherence caused failure in 10%. No major PI mutations were found.

Topics: Anti-HIV Agents; Blood Chemical Analysis; CD4 Lymphocyte Count; Child; Cholesterol; Drug Resistance, Viral; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; Saquinavir; Thailand; Treatment Refusal; Triglycerides; Viral Load

The aim of this study was to assess the long-term efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (NRTIs).. A total of 272 antiretroviral-naive patients with a CD4+ T-cell count of 200-350 cells/mm3 were treated with two NRTIs and saquinavir/ritonavir 1,600/100 mg per day for > 24 weeks. Patients were followed up every 12 weeks for CD4+ T-cell counts, HIV RNA levels, clinical and laboratory toxicities. Intention-to-treat analyses were used for the first 24 weeks of treatment and as-treated analysis after week 24.. The median baseline CD4+ T-cell count was 269 cells/mm3 and HIV RNA was 4.7 log10 copies/ml. At a median follow-up time of 56 (interquartile range [IQR] 25-113) weeks, 262/272 (96.3%) had HIV RNA < 400 copies/ml, with a median HIV RNA decline of -2.89 (IQR 3.31--2.37) log10 copies/ml (P < 0.001) and a median rise in CD4+ T-cell count of 192 (IQR 117-317) cells (P < 0.001). At weeks 24, 48, 72 and 96, 249/272 (91.5%), 157/164 (95.7%), 113/126 (89.7%) and 84/90 (93.3%) had HIV RNA < 400 copies/ml, respectively; at the same time points, 83.8%, 92.7%, 85.7% and 85.6% had HIV RNA < 50 copies/ml. Drug-related adverse events were reported in 6.30%. Significant rises in total cholesterol, triglyceride, low-density lipoprotein and high-density lipoprotein were seen.. First-line highly active antiretroviral therapy with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Drug Administration Schedule; Drug Combinations; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Thailand; Time Factors; Treatment Outcome; Viral Load

To compare information on body fat changes from questionnaire and clinical examination and to study lipoatrophy in HIV-1 patients on highly active antiretroviral therapy (HAART).. The study was cross-sectional within a randomized trial. One hundred and sixty-eight male HIV-1 patients were examined by questionnaire and clinical examination. Clinical lipoatrophy was studied and defined as fat wasting in the face, legs and/or arms. Fasting blood samples reflecting lipid and glucose metabolism were taken and the role of indinavir, ritonavir (RTV) and RTV/saquinavir (SQV) on lipoatrophy was investigated.. After a median of 17 months on HAART, concordance rates between information on changes in body fat from questionnaire and clinical examination were significant and varied from 70 to 96%. With a positive criteria of lipoatrophy in both assessments, 14% of patients had lipoatrophy. These patients had lower weight (P = 0.0007), weight loss from baseline (P = 0.003), lower circumferences at all measurements (P < 0.01), lower plasma triglycerides and low-density lipoprotein (LDL) (P < 0.05) and longer treatment with stavudine (P = 0.0009). Homeostasis model assessment (HOMA) estimates for insulin resistance and beta-cell function were comparable. Plasma cholesterol, triglycerides and very low-density lipoprotein (VLDL) were higher in patients receiving RTV or RTV/SQV (P < 0.03).. Questionnaire and clinical assessment provide concordant information on changes in body fat. Lipoatrophic patients on HAART with neither increase in abdominal circumference, nor hyperlipidaemia nor glucose intolerance may have side-effects to protease inhibitor treatment, to nucleoside reverse transcriptase inhibitor treatment (stavudine) or suffer from a drug-independent condition.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Composition; Cross-Sectional Studies; Drug Therapy, Combination; Glucose Intolerance; HIV Infections; HIV Protease Inhibitors; HIV Wasting Syndrome; Humans; Hyperlipidemias; Indinavir; Lipodystrophy; Male; Middle Aged; Ritonavir; Saquinavir; Stavudine; Surveys and Questionnaires

Topics: Adult; Anticholesteremic Agents; Drug Tolerance; Female; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Hyperlipidemias; Indinavir; Male; Nelfinavir; Pilot Projects; Pravastatin; Ritonavir; Saquinavir; Treatment Outcome

The relationship between plasma protease inhibitor (PI) trough concentrations and hyperlipidemic effects were evaluated retrospectively using data from 2 pilot clinical trials of a double-boosted PI regimen (saquinavir/lopinavir/ritonavir) in 25 HIV patients. The patients' median age was 39 years (range, 25-60). At baseline, PI-naive patients had a median viral load of 53 500 copies/mL and median CD4 of 296 cells/mm(3), while PI-experienced patients had 37 750 copies/mL and 214 cells/mm(3). Plasma PI trough concentrations of saquinavir, lopinavir, and ritonavir at week 12 were 520, 4482, and 153 ng/mL, respectively. At week 12, median fasting lipids increased significantly from baseline: total cholesterol increased from 165 to 189 mg/dL (P = .0005) and the triglyceride increased from 113 to 159 mg/dL (P = .001). There were no associations between PI trough concentrations at week 12 and the percent total cholesterol change at week 12. No associations were found between PI trough concentrations and lipid changes in HIV patients on a double-boosted PI regimen (saquinavir/lopinavir/ritonavir). Factors other than systemic exposure to PIs (such as host or genetic factors) may modulate the hyperlipidemic effect of PIs.

Topics: Adult; Clinical Trials as Topic; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lipids; Lopinavir; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrimidinones; Retrospective Studies; Ritonavir; Saquinavir

It is currently unknown whether gestational diabetes mellitus (GDM), a prevalent obstetrical complication, compounds the changes in drug disposition that occur naturally in pregnancy. Hyperlipidemia occurs in GDM. Using a rat model of GDM, we determined whether excess lipids compete with drugs for plasma protein binding. Because lipids activate nuclear receptors that regulate drug transporters and metabolic enzymes, we used proteome analysis to determine whether hyperlipidemia indirectly leads to the dysregulation of these proteins in the liver. GDM was induced on gestational day 6 (GD6) via streptozotocin injection. Controls received either vehicle alone or streptozotocin with subsequent insulin treatment. Liver and plasma were collected on GD20. Glyburide and saquinavir protein binding was determined by ultrafiltration, and an established solvent method was used for plasma delipidation. Proteomics analysis was performed by using isobaric tags for relative and absolute quantitation methodology with membrane-enriched hepatic protein samples. Relative to controls, GDM rat plasma contained more cholesterol and triglycerides. Plasma protein binding of glyburide and saquinavir was decreased in GDM. Delipidation normalized protein binding in GDM plasma. Proteins linked to lipid metabolism were strongly affected in the GDM proteomics data set, with prohyperlipidemic and antihyperlipidemic changes observed, and formed networks that implicated several nuclear receptors. Up-regulation of drug transporters and metabolic enzymes was observed (e.g., multidrug resistance 1/2, CYP2A1, CYP2B9, and CYP2D3). In this study, GDM-induced hyperlipidemia decreased protein binding and was associated with drug transporter and metabolic enzyme up-regulation in the liver. Both of these findings could change drug disposition in affected pregnancies, compounding changes associated with pregnancy itself.

Topics: Animals; Binding, Competitive; Biological Transport; Blood Proteins; Carrier Proteins; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Experimental; Diabetes, Gestational; Down-Regulation; Female; Gestational Age; Glyburide; Hyperlipidemias; Insulin; Lipid Metabolism; Lipids; Liver; Pregnancy; Protein Binding; Proteomics; Rats; Rats, Sprague-Dawley; Saquinavir; Streptozocin; Tandem Mass Spectrometry; Up-Regulation

Topics: Adipose Tissue; Adult; Aged; Cholesterol; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Male; Middle Aged; Nelfinavir; Retrospective Studies; Ritonavir; Saquinavir; Triglycerides

Topics: Acquired Immunodeficiency Syndrome; Adult; Cholesterol; Delavirdine; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Retinal Diseases; Retinal Vessels; Ritonavir; Saquinavir; Triglycerides; Viral Load; Zalcitabine

Topics: Adult; Anti-HIV Agents; Cholesterol; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Male; Nelfinavir; Ritonavir; Saquinavir; Triglycerides

Hyperlipidemia may complicate the use of HIV protease inhibitors (PIs) in AIDS therapy. To determine the cause of hyperlipidemia, the effect of PIs on lipid metabolism was examined with HepG2 liver cells and AKR/J mice. In HepG2 cells, the PIs ABT-378, nelfinavir, ritonavir, and saquinavir stimulated triglyceride synthesis; ritonavir increased cholesterol synthesis; and amprenavir and indinavir had no effect. Moreover, nelfinavir increased mRNA expression of diacylglycerol acyltransferase and fatty acid synthase. The retinoid X receptor agonist LG100268, but not the antagonist LG100754, further increased PI-stimulated triglyceride synthesis and mRNA expression of fatty acid synthase in vitro. In fed mice, nelfinavir or ritonavir did not affect serum glucose and cholesterol, whereas triglyceride and fatty acids increased 57% to 108%. In fasted mice, ritonavir increased serum glucose by 29%, cholesterol by 40%, and triglyceride by 99%, whereas nelfinavir had no effect, suggesting these PIs have different effects on metabolism. Consistent with the in vitro results, nelfinavir and ritonavir increased triglyceride 2- to 3-fold in fasted mice injected with Triton WR-1339, an inhibitor of triglyceride clearance. We propose that PI-associated hyperlipidemia is due to increased hepatic triglyceride synthesis and suggest that retinoids or meal restriction influences the effects of select PIs on lipid metabolism.

Topics: Acyltransferases; Animals; Blood Glucose; Carbon Radioisotopes; Cholesterol; Diacylglycerol O-Acyltransferase; Fasting; Fatty Acid Synthases; Fatty Acids; HIV Protease Inhibitors; Hyperlipidemias; Liver; Male; Mice; Mice, Inbred AKR; Nelfinavir; Nicotinic Acids; Postprandial Period; Receptors, Retinoic Acid; Retinoid X Receptors; Ritonavir; RNA, Messenger; Saquinavir; Tetrahydronaphthalenes; Transcription Factors; Triglycerides; Tumor Cells, Cultured

Topics: Adult; Anticholesteremic Agents; Atorvastatin; Drug Therapy, Combination; Female; Heptanoic Acids; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Male; Pyrroles; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir

Administration of protease inhibitors (PIs) to HIV-infected individuals has been associated with hyperlipidemia. In this study, we characterized the lipoprotein profile in subjects receiving ritonavir, indinavir, or nelfinavir, alone or in combination with saquinavir.. Plasma lipoprotein levels were quantified in 93 HIV-infected adults receiving PIs. Comparison was done with pretreatment values and with 28 nonPI-treated HIV-infected subjects. An elevation in plasma cholesterol levels was observed in all PI-treated groups but was more pronounced for ritonavir (2.0+/-0.3 mmol/L [mean+/-SEM], n=46, versus 0.1+/-0.2 mmol/L in nonPI treated group, P<0.001) than for indinavir (0.8+/-0.2 mmol/L, n=26, P=0.03) or nelfinavir (1.2+/-0.2 mmol/L, n=21, P=0.01). Administration of ritonavir, but not indinavir or nelfinavir, was associated with a marked elevation in plasma triglyceride levels (1.83+/-0.46 mmol/L, P=0.002). Plasma HDL-cholesterol levels remained unchanged. Combination of ritonavir or nelfinavir with saquinavir did not further elevate plasma lipid levels. A 48% increase in plasma levels of lipoprotein(a) was detected in PI-treated subjects with pretreatment Lp(a) values >20 mg/dL. Similar changes in plasma lipid levels were observed in 6 children receiving ritonavir.. Administration of PIs to HIV-infected individuals is associated with a marked, compound-specific dyslipidemia. The risk of pancreatitis and premature atherosclerosis due to PI-associated dyslipidemia remains to be established.

Topics: Adult; Anti-HIV Agents; Arteriosclerosis; Child; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Indinavir; Lipids; Lipoprotein(a); Lipoproteins; Logistic Models; Male; Nelfinavir; Risk Factors; Ritonavir; Saquinavir; Thyrotropin

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

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Therapy, Combination; HIV-1; Humans; Hyperlipidemias; Protease Inhibitors; Ritonavir; Saquinavir; Triglycerides

Topics: Anti-HIV Agents; Coronary Artery Disease; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Pancreatic Pseudocyst; Pancreatitis; Risk Factors; Ritonavir; Saquinavir